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ISSUE REPORTSEPTEMBER 20232023The State of Obesity:BETTER POLICIES FOR A HEALTHIER AMERICASPECIAL FEATURE:20-Year Report Anniversary Retrospective2 TFAH tfah.org2TFAH BOARD OF DIRECTORSStephanie Mayfield Gibson,M.D.,FCAPChair of the TFAH Board of Directors Former Director,U.S.COVID-19 Response Initiative Resolve to Save LivesDavid Fleming,M.D.Vice Chair of the TFAH Board of DirectorsDistinguished Visiting FellowTrust for Americas HealthRobert T.Harris,M.D.,FACPTreasurer of the TFAH Board of DirectorsSenior Medical DirectorGeneral Dynamics Information Technology Theodore Spencer,M.J.Secretary of the TFAH Board of DirectorsCo-FounderTrust for Americas HealthCynthia M.Harris,Ph.D.,DABTDirector and ProfessorInstitute of Public Health,Florida A&M UniversityDavid Lakey,M.D.Chief Medical Officer and Vice Chancellor for Health Affairs The University of Texas SystemOctavio Martinez Jr.,M.D.,MPH,MBA,FAPAExecutive Director Hogg Foundation for Mental Health,The University of Texas at Austin John A.Rich,M.D.,MPHDirectorRUSH BMO Institute for Health Equity,Rush University Systems for HealthEduardo Sanchez,M.D.,MPHChief Medical Officer for Prevention and Chief of the Center for Health Metrics&Evaluation American Heart Association Umair A.Shah,M.D.,MPHSecretary of HealthWashington State Department of HealthVince Ventimiglia,J.D.Chairman of Board of Managers Leavitt PartnersTFAH LEADERSHIP STAFFJ.Nadine Gracia,M.D.,MSCEPresident and CEOTekisha Dwan Everette,Ph.D.,MPA,MPH,CPHExecutive Vice PresidentStacy MolanderChief Operating OfficerREPORT AUTHORSMolly Warren,S.M.Senior Health Policy Researcher and AnalystTrust for Americas HealthMadison WestAssociate Government Relations ManagerTrust for Americas HealthStacy Beck,J.D.ConsultantCONTRIBUTORSVinu Ilakkuvan,DrPHConsultantSarah Ketchen Lipson,Ph.D.,Ed.M.Associate ProfessorBoston University School of Public HealthPrincipal Investigator The Healthy Minds NetworkREVIEWERSChristina Economos,Ph.D.Dean,Professor,and New Balance Chair in Childhood NutritionFriedman School of Nutrition Science and Policy,and Medical School,Tufts UniversityCaron Whitaker,MADeputy Executive Director The League of American BicyclistsAcknowledgmentsTrust for Americas Health is a nonprofit,nonpartisan public health policy,research,and advocacy organization that promotes optimal health for every person and community and makes the prevention of illness and injury a national priority.The State of ObesityTABLE OF CONTENTSSEPTEMBER 2023Table of ContentsACKNOWLEDGMENTS.2TABLE OF CONTENTS.3LIST OF ACRONYMS AND ABBREVIATIONS.4INTRODUCTION.5SECTION 1:SPECIAL FEATURE:20 YEAR RETROSPECTIVE.10A.Obesity Trends Over Two Decades.10 Q&A with William Dietz,M.D.,Ph.D.:Solving the Obesity Crisis Requires Data,Investment,Political Will,and Provider Education.12B.Evolving Outlook on Obesity.15C.Policy Advances and Remaining Gaps.18 Major Policy Milestones to Improve Nutrition,Increase Physical Activity,and Prevent and Treat Obesity in the United States at Federal,State,and Local Levels,20042023.19SECTION 2:OBESITY-RELATED DATA AND TRENDS.22A.Trends in Adult Obesity.22 I.State Trends.23 II.Demographic Trends.24B.Trends in Youth Obesity .29 I.National Youth Obesity Rates.30 II.Young WIC Participants,Ages 2 to 4.30 III.Obesity Rates in Children and Teenagers,Ages 10 to 17.31 IV.High School Obesity Rates.31SECTION 3:OBESITY-RELATED POLICIES AND PROGRAMS.33A.Economics of What We Eat and Drink.33 I.Fiscal and Tax Policies that Promote Healthy Eating:Beverage Taxes,Healthy Food Financing Initiative,and the New Markets Tax Credit.33 II.Food and Beverage Marketing.34B.Nutrition Assistance,Standards,and Education.36 I.Federal Hunger and Nutrition Assistance:WIC,school/child nutrition programs,SNAP.36 II.Nutrition Incentive Programs.40 III.Childcare and Education Settings:Head Start,Early Care and Education State Requirements,K12 Local Wellness Programs,Farm to School/ECE,and Smart Snacks.40 IV.Dietary Guidelines,and Nutrition and Menu Labels.42C.Community Policies and Programs.44 I.Built Environment:Community Design and Land Use,Housing,Safe Routes to Schools,and Federal HUD and DOT Funding Programs.44 II.CDC State and Community Initiatives.46D.Healthcare Coverage and Programs.52 I.Medicare and Medicaid.52 II.Healthcare and Hospital Programs.54SECTION 4.RECOMMENDATIONS.57APPENDIX:OBESITY-RELATED INDICATORS AND POLICIES BY STATE.67REFERENCES.73View this report online at https:/www.tfah.org/report-details/state-of-obesity-202334TFAH tfah.orgLIST OF ACRONYMS AND ABBREVIATIONSAddressing Conditions to Improve Population Health program ACTionAffordable Care Act ACAAmerican Indian and Alaska Native AI/ANBehavioral Risk Factor Surveillance System BRFSSBody Mass Index BMICenters for Disease Control and Prevention CDCCenters for Medicare and Medicaid Services CMSChild and Adult Care Food Program CACFPChild Care and Development Block Grant CCDBGChildhood Obesity Research Demonstration project CORDChildrens Health Insurance Program Reauthorization Act CHIPRACommunity Development Financial Institutions Fund CDFI Community Eligibility Program CEPCommunity Health Needs Assessments CHNADiabetes Prevention Program DPPDivision of Nutrition,Physical Activity and Obesity DNPAOEarly Care and Education ECEElectronic Benefit Transfer EBTEvery Student Succeeds Act ESSAFederal Poverty Level FPLFiscal Year FYFood Insecurity Nutrition Incentive FINIFresh Fruit and Vegetable Program FFVPFront-of-package FOPGood Health and Wellness in Indian Country GHWICGus Schumacher Nutrition Incentive Program GusNIPHealthy Food Financing Initiative HFFIHealthy Incentives Pilot HIPHealthy,Hunger-Free Kids Act HHFKAHigh Obesity Program HOPNational Health and Nutrition Examination Survey NHANESNational School Lunch Program NSLPNew Markets Tax Credit NMTCOffice of Personnel Management OPMPreventive Health and Health Services Block Grant PHHSRacial and Ethnic Approaches to Community Health program REACHSafe Routes to School program SRTSSchool-Based Interventions to Promote Equity and Improve Health,Academic Achievement,and Well-Being of Students Healthy SchoolsSocial Determinants of Health SDOHSpecial Supplemental Nutrition Program for Women,Infants,and Children WICState Physical Activity and Nutrition program SPAN Summer Food Service Program SFSPSupplemental Nutrition Assistance Program SNAPThe George Washington University GWTrust for Americas Health TFAHU.S.Department of Agriculture USDAU.S.Department of Health and Human Services HHSU.S.Department of Housing and Urban Development HUDU.S.Department of Transportation DOTU.S.Food and Drug Administration FDAU.S.Preventive Services Task Force USPSTFUSDAs Food and Nutrition Services FNSYouth Risk Behavior Survey YRBSThe State of ObesityINTRODUCTION SEPTEMBER 2023INTRODUCTION Introduction This years State of Obesity report marks the 20th annual report from Trust for Americas Health(TFAH)on obesity in the United States.During that time,we have seen obesity rates rise across states,ages,sexes,racial/ethnic groups,and income.1,2,3,4,5,6 We have also seen ultra-processed food consumption and food advertising increase.7,8,9,10,11 Structural racism,discrimination,poverty,economic hardship,and food insecuritywhich have direct and indirect effects on the choices,habits,and health of Americansremain a major issue in the nation.12,13 And an ever-changing medical,technological,and political landscape continues to evolve.We have made important policy progress during the last two decades that has improved the lives of many Americans,yet large gaps and major underlying drivers of obesity persist.This year,our special feature is a retrospective on the last 20 years of data trends,the changing understanding and strategy around obesity,policy milestones,and the essential work remaining.051015202530354045All Adults Age 20 All Youth Age 2-19199920002017 202030.5A.9.9.7%Source:NHANESFIGURE 1:Adult and Youth Obesity Rates Over 20 Years:19992000 to 2017202056TFAH tfah.orgWHY DOES TFAH FOCUS ON OBESITY?Obesity is a serious and growing public health threat.The causes and drivers of obesity are complex and multifactorial,and include national trends like increased consumption of ultra-processed food,and social and economic conditions that influence the health and wellness options available to some Americans(e.g.,poverty and discrimination).16,17,18 Obesity is associated with a range of physical and mental conditions at the population level and is linked with higher healthcare costs and productivity losses.(1)Obesity increases the risk of a range of diseases for adultsincluding higher rates of complications and serious illness from COVID-19,type 2 diabetes,high blood pressure,heart disease,stroke,arthritis,depression,sleep apnea,liver disease,kidney disease,gallbladder disease,pregnancy complications,and many types of cancerand an overall risk of higher mortality.19,20,21,22,23 24,25,26,27,28,29,30,31,32(2)Children with obesity are also at greater risk for certain diseases,like type 2 diabetes,high blood pressure,and depression,and a child with obesity is more likely to have obesity as an adult.33,34,35,36,37 Children with obesity also have a higher risk of hospitalization and severe illness from COVID-19.38(3)Individuals with obesity have higher medical costs than lower-weight individuals.A 2021 study found that obesity accounted for$170 billion in higher medical costs annually in the United States.39 This includes billions in extra costs to the Medicare and Medicaid programs.40,41 Indirect,or nonmedical,costs from obesity also run into the billions due to missed time at school and work,lower productivity,premature mortality,and increased transportation costs.42,43 FACTS ABOUT OBESITY IN THE UNITED STATES National Adult Obesity Rate,20172020:41.9 percent Change in Adult Obesity Rate from 19992000 to 20172020:37 percent increaseNational Youth Obesity Rate,20172020:19.7 percentChange in Youth Obesity Rate from 19992000 to 20172020:42 percent increaseSource:NHANES Number of States with Adult Obesity Rates Above 35 Percent,2022:22Number of States with Adult Obesity Rates Above 35 Percent,2012:0Source:TFAH analysis of BRFSS dataNew 2022 state-level data from the Behavioral Risk Factor Surveillance System(BRFSS)confirm the long-term trend that adult obesity rates continue to climb,as they have been for decades(see Figure 2).This year,TFAHs analysis finds 29 states have had statistically significant increases between 2017 and 2022,with 22 states now having an adult obesity rate at 35 percent or higher.14,15 This report also includes a section that reviews the latest data available on adult and childhood obesity rates(see page 22),a section that examines key current and emerging policies(page 33),and,finally,a section that outlines recommended policy actions(page 57).0510152025303540452011 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022States with Adult Obesity Rates 3035 Percent35% Source:TFAH analysis of BRFSS dataFIGURE 2:Number of States with Adult Obesity Rates At 30 Percent or Higher,201120227 TFAH tfah.orgSUMMARY OF 2023 STATE OF OBESITY RECOMMENDATIONSTrust for Americas Health(TFAH)offers recommendations for federal,state,and local policymakers and other stakeholders each year.Our goalensuring that every community can support healthy lifestyles for allrequires a systems-level approach,including public policy changes across key sectors to ensure healthy choices are available and easy for everyone.A systems approach includes reducing longstanding structural and historic inequities;targeting obesity prevention programs to communities with the highest needs;and scaling and increasing evidence-based initiatives that create the healthy community environments to support optimal health and promote healthy behaviors and outcomes.A summary of TFAHs recommendations is below;the full recommendations are on page 57.1.Advance health equity by strategically dedicating federal resources to efforts that reduce obesity-related disparities and related conditions by:l Increasing funding for the Centers for Disease Control and Prevention(CDC)chronic disease and obesity prevention programs,including the State Physical Activity and Nutrition program,the Racial and Ethnic Approaches to Community Health program,and the Healthy Tribes program;l Expanding the Social Determinants of Health program at CDC to support multisector collaborations to address upstream drivers of chronic disease;l Instituting economic policies that reduce poverty at a population level;l Prioritizing health equity in planning and decision-making at federal agencies;andl Adapting federal grantmaking practices to ensure that the community-based organizations that are best able to conduct obesity prevention activities can navigate federal funding mechanisms.2.Decrease food and nutrition insecurity while improving nutritional quality of available foods by:l Guaranteeing healthy school meals for all and,in the interim,encouraging Community Eligibility Program participation;l Finalizing proposed rules to strengthen nutrition standards for school meals and snacks;l Maintaining eligibility,increasing the value of benefits,and ensuring there are no new participation barriers in the Supplemental Nutrition Assistance Program(SNAP);l Improving diet quality in SNAP through voluntary pilot programs and supporting programs that promote and incentivize healthy eating,like SNAP-Ed and the Gus Schumacher Nutrition Incentive Program;l Expanding access to the Special Supplemental Nutrition Program for Women,Infants,and Children for young children and postpartum women,codifying the fruit and vegetable benefit increase,and finalizing the proposed rule to improve the nutrition quality of the WIC benefit packages;l Creating a mandatory front-of-package label for processed foods to help consumers make informed choices;l Bolstering the Child and Adult Care Food Program by allowing a third meal service option,increasing reimbursements,simplifying administration,and continuing funding for nutrition and wellness education;l Expanding support for programs that promote maternal and child health,including breastfeeding support;l Improving the nutrition quality of the food that government agencies provide by uniformly implementing the Food Service Guidelines for Federal Facilities;8TFAH tfah.orgl Incentivizing healthy food options,like adding healthful corner stores,and supporting community gardens and farmers markets through community design;and l Increasing outreach to eligible families to apply for school meals and other nutrition assistance programs.3.Change the marketing and pricing strategies that lead to health disparities by:l Closing tax loopholes and eliminating business cost deductions for advertising of unhealthy food and beverages to children on television,online,and places frequented by children;l Discouraging unhealthy food and drink options by enacting sugar-sweetened beverage taxesand using the revenue to reduce health and socioeconomic disparities;l Incorporating local wellness policies that reduce unhealthy food and beverage marketing and advertising to children and adolescents,like by prohibiting coupons,sales,and advertising around schools.4.Make physical activity and the built environment safer and more accessible for all by:l Increasing federal education funding to support health and physical education,as well as programs that promote social-emotional learning and improve health outcomes for children;l Codifying and funding the update of the Physical Activity Guidelines for Americans every 10 years;l Boosting funding for active transportation projects like pedestrian and biking infrastructure and recreational trails in addition to adding flexibilities and increasing technical assistance to ensure all communities are able to access funding;l Making physical activity safer by making Safe Routes to Schools,Vision Zero,Complete Streets,and non-infrastructure projects eligible under the Highway Safety Improvement Program;l Identifying innovative methods for conducting physical education and prioritizing physical activity during schooltime;l Working locally to make community spaces more conducive and safer for physical activity,active transportation,and outdoor play;l Adopting and implementing Complete Streets principles;and l Encouraging outdoor play and activity for children via state and federal programs and additional park development for communities most in need.5.Work with the healthcare system to reduce disparities and close gaps in clinical-to-community settings by:l Increasing access to health insurance coverage by expanding Medicaid and making marketplace coverage even more affordable;l Clarifying to health insurers that obesity-related preventive healthcare services must be covered with no patient cost-sharing like all other grade A or B U.S.Preventive Services Task Force recommendations as required by current law,and ensuring continued free preventive coverage if legal challenges alter the current requirements;l Expanding the capacity of healthcare providers and payers to screen and refer individuals to social services and care coordination,to sufficiently reimburse and increase capacity for social services,and to better integrate social needs data into medical records;l Addressing root causes of health disparities by enacting the Health Equity and Accountability Act;l Requiring Medicare and Medicaid to cover obesity-related services,such as obesity and nutritional counseling and treatments,and providing additional funding to offer these services;l Prioritizing social and structural determinants of health in communities with high levels of obesity through community-directed goals and strategies,as well as evidence-based programs;andl Enabling Medicaid waivers to allow community-based organizations to be reimbursed for chronic disease prevention activities,to further incentivize cross-sector collaboration.9 TFAH tfah.orgWHAT IS OBESITY AND BMI?Public health and healthcare sectors define“obesity”as a disease where an individuals body fat and body-fat distribution exceed the level considered healthy.44,45 Body mass index(BMI)is a metric often used as a proxy for body fat because it is correlated with cardiometabolic risk,and it is simple and inexpensive to determineno invasive tests,specialized equipment,or prior diagnoses requiredand thus more universally available.BMI is a useful screening measure at the individual level to help clinicians decide which patients need additional assessment for chronic disease,and a useful population health measure to assess the distribution of BMI in populations so that resources can be targeted to certain geographic areas,groups,or others disproportionally affected by low or high weight for health.46Using BMI as a measure of obesity has several important considerations.First,the formula for calculating BMI as originally designed is not representative of all peoples.47 Secondly,BMI does not perfectly correlate with body fate.g.muscular individuals often have lower body fat than their BMI would suggestor risk for chronic disease;though it does correlate as well or better than other non-invasive,widely available measures.48 For individuals,a more holistic understanding of family/personal history,lifestyle factors,body fat,and body fat distribution are important to assessing cardiometabolic risk.On a population level,the risk that occurs at different BMIs vary by sex and race/ethnicity.For example,certain populations of Asian Americans have higher risks of cardiometabolic diseases at lower BMIs,and Black Americans have lower risks at higher BMIs.Some researchers have suggested adjusting BMI thresholds to estimate cardiometabolic risks more accurately in different populations.49The use of BMI by the public health and healthcare sectors has been a recent topic of discussionincluding a focus on its use as a diagnostic measure in the medical setting,as well as its historic,discriminatory origins and modern connection with weight-based stigma.50,51 In June 2023,the American Medical Association House of Delegates voted to adopt a new policy that outlines the limitations of BMI as an individual-level metric,supports additional education for physicians around BMI,and recommends BMI be used in conjunction with other measures in a clinical setting.52BMI is calculated by dividing a persons weight(in kilograms)by height(in meters)squared.The BMI formula for measurements in pounds and inches is:For adults,BMI is associated with the following weight classifications:Medical professionals measure childhood obesity differently,comparing a childs BMI with children of the same age and sex in a reference population that accounts for typical changes during growth and development.A childs BMI is expressed as a percentile relative to children from the reference population of the same age and sex based on growth charts developed by CDC using nationally representative height and weight data from American children from 1963 to 1965 and from 1988 to 1994.53 BMI=(Weight in pounds )x 703(Height in inches)x(Height in inches)BMI LEVELS FOR CHILDREN AGES 2-19BMI LevelWeight ClassificationBelow 5th percentileUnderweight5th to 85th percentileHealthy weight85th to 95th percentileOverweight95th percentile and greaterObesityBMI LEVELS FOR ADULTS AGES 20 AND OVERBMI LevelWeight ClassificationBelow 18.5Underweight18.5 to 25Healthy weight25 to 30Overweight30 and aboveObesity 40 and above Severe ObesityThe State of Obesity SECTION 1:SPECIAL FEATURE:20 YEAR RETROSPECTIVESECTION 1:SEPTEMBER 2023SPECIAL FEATURE:20 Year RetrospectiveTFAHs first obesity report was published in October 2004 with a new report released annually ever since.Much of the 2004 reports content had similar themes to this current report:it also documented obesity rates in the United States,implications for health risk and costs,framed the issue as primarily a public health and societal issue,and called for cross-sector action and policy changes at the national and state level to prevent and treat obesity in the United States.There have also been substantive changes in the understanding and outlook on obesity policy,an expanded understanding of social and structural drivers of obesity,and major changes in the medical,technological,and political landscape across the United States.This section reflects on the last 20 years of trends,the changing understanding and strategy within public health,and key progress and remaining gaps in nutrition,physical activity,and obesity policy.A.OBESITY TRENDS OVER TWO DECADESOver the last two decades,obesity rates have risen across the United States.According to National Health and Nutrition Examination Survey(NHANES)data,the U.S.obesity rate among adults ages 20 and older rose 37 percent and among youth ages 2 to 19 rose 42 percent between the 19992000 and 20172020 surveys.The change over time was slower for adults from 2003 to 2012,with a sharper increase in more recent survey years.For youth,obesity rates were steady from 2003 to 2014,but then followed by increases(see Figure 3).01020304050Percent of Youth Age 219 with ObesityPercent of Adults(Age 20 )with Obesity2017-2020201520162013201420112012200920102007200820052006200320042001200219992000Source:NHANESFIGURE 3:Percent of Adults and Youth with Obesity,199920201011 TFAH tfah.org0102030405060All Adults Age 20 MenWomenAsian Adults*Black AdultsLatino Adults*White AdultsAsian Men*Black MenLatino Men*White MenAsian Women*Black WomenLatina Women*White Women19992000*Note:19992000 data is not available.20172020Source:NHANESSource:NHANESThe increase in obesity rates cross all sex,racial/ethnic,and age groups where data are available.The amount of the increase varies by population,from the lower end(15 percent for Black boys and 16 percent for Black women)to the higher end(61 percent for white boys and 58 percent for white men)(see Figures 4 and 5 for adult and youth obesity rates in 19992000 and 20172020).FIGURE 4:Adult Obesity Rates by Select Characteristics in 19992000 and 20172020FIGURE 5:Youth Obesity Rates by Select Characteristics in 19992000 and 20172020 05101520253035All Youth Age 2-19BoysGirlsAsian Youth*Black YouthLatino Youth*White YouthAsian Boys*Black BoysLatino BoysWhite Boys*Asian Girls*Black GirlsLatina Girls*White Girls1999200020172020*Note:19992000 data is not available.12TFAH tfah.orgWilliam Dietz,M.D.,Ph.D.,is the director of the Sumner M.Redstone Global Center for Prevention and Wellness at the Milken Institute School of Public Health at The George Washington University(GW).Dietz is also the director of GWs STOP Obesity Alliance and co-chair of the Lancet Commission on Obesity.He is a past president of the American Society for Clinical Nutrition and the North American Association for the Study of Obesity.Before joining the GW faculty,Dietz was the director of Centers for Disease Control and Preventions Division of Nutrition,Physical Activity,and Obesity from 1997 to 2012.Prior to his appointment to CDC,Dietz was a professor of pediatrics at Tufts University School of Medicine.Dietz received his undergraduate degree from Wesleyan University and his M.D.from the University of Pennsylvania.TFAH:Youve worked in the area of nutrition,physical activity,and obesity prevention throughout your career.Over that time,whats been the most important progress within the policy arena and elsewhere?Whats been disappointing?Dr.Dietz:The most important outcome is that obesity is now widely recognized as a significant problem and that the problem is more than a cosmetic issue;its a health issue.One of the biggest things we did at CDC was to publish the state maps,so metrics have played a rolefrom how obesity is being measured to how the data are being displayed.Another important milestone was demonstrating the costs associated with obesity,which showed the need for policies and cost-effective interventions.An area of disappointmentIm not sure disappointment is the right wordbut only recently has there been an emphasis on the stigma and bias associated with obesity,which I think colors the whole approach.Despite the fact that obesity has been named a disease and that we have ample evidence of its adverse consequences,this notion that people are responsible for their obesity remains a challenge.It continues to affect almost every element of obesity treatment,from the individual to the population level.TFAH:As you reflect on the past 20 years,how has the way the field thinks about obesity evolved?Dr.Dietz:The most recent development,medication,is getting a lot of well-deserved attention because its results are approaching the impact of bariatric surgery.But,with 42 percent of the population having obesity,we have to recognize that we are not going to treat our way out of this disease.Im concerned that the legitimate emphasis on the effectiveness of medication will displace the need to continue to focus on preventative measures.TFAH:Are you concerned that the new attention to medications to treat obesity will lead to a deemphasis of the role of social determinants?Dr.Dietz:Yes,thats an important issue.Its not just the social determinants;the other relevant piece is cultural determinants.In many cases,cultural determinants are at least as powerful as social determinants.TFAH:We now have a better understanding that a combination of factors leads to obesity.How should we think about genetics vs.other contributing factors?Dr.Dietz:Theres no question that genetics affects the susceptibility to obesity,but genetics are widely misinterpreted as a cause of obesity.Susceptibility genes have been present in the population for millennia,but not until recently have we had an environment that reacts with those genes to produce obesity.TFAH:Despite extensive efforts to curb obesity rates,they have continued to rise year over year.Why do you think that is?Whats preventing substantial progress?Dr.Dietz:Resources and political will,and these are related.In addition,bias and stigma come into play,and are reflected in the reluctance to invest in obesity treatment due to the biased thinking that people are responsible for their obesity.Weve talked about social determinants,weve talked about cultural determinants,but the other major sector of determinants is commercial determinants.Commercial determinants are ubiquitous,beginning with the exposure of children to food ads on television and continuing through the intensive promotion of fast food and ultra-processed food.I believe that theres a relationship between Q&A with William Dietz,M.D.,Ph.D.:Solving the Obesity Crisis Requires Data,Investment,Political Will,and Provider Education13 TFAH tfah.orgultra-processed food,food access,and obesity in underserved neighborhoods,because of the reliance on corner stores,which in turn rely on sales of ultra-processed foods.TFAH:This years State of Obesity report includes an extensive list of policies to improve nutrition,increase physical activity,and prevent and treat obesity enacted over the last two decades.Which of the policies do you think has had the greatest impact?What would it take to scale those policies?Dr.Dietz:The White House Task Force on Childhood Obesity during the Obama Administration was a key.If you look carefully at the task force recommendations,many found their way into legislation.Thats directly attributable to former First Lady Michelle Obamas visibility and her willingness to talk openly about the importance of addressing nutrition and physical activity in kids.There were two or three major steps that were directly related to the task force or occurred around the same time.One was the revision of the Special Supplemental Nutrition Program for Women,Infants,and Children WIC package in 2010,implemented in 2011,which was subsequently associated with a decrease in prevalence of childhood obesity in WIC participants.The decreases in obesity were highly significant decreases and reflected a major policy step forward.What was interesting about these decreases is that they were greater in children of color than they were in the white population.A second policy was changes in school meal standards,which were also shown to have had an impact on the prevalence of obesity among low-income adolescents.These are two major policies and outcomes which had a major impact on obesity.What we dont know is if these effects were sustained throughout the pandemic,which threw a major wrench into all of these efforts,because schools,despite their best efforts,could not match the standards that were in place before COVID.I dont know the extent to which these standards have been reinstituted,but I think their suspension during COVID is partially responsible for the big increase in obesity rates in low-income children that we saw during the pandemic.TFAH:The two successful interventions youve described both target young people.Is that where the best chance to reverse the obesity trends exists?Is intervening in adulthood too late?Dr.Dietz:Well,it may be.The difference is an emphasis on prevention or an emphasis on treatmenttreatment necessitated by the consequences of obesity.Once someone has a BMI of 35 or above,preventative measures are not going to be particularly successful.That doesnt mean that we should move away from behavioral interventions that improve physical activity and nutrition in adultsbehavior change needs to be the cornerstone for any intervention.These nutrition and physical activity strategies need to be implemented at the population level and at the worksite level;theres substantial interest in preventive measures on the part of health plans and employers.Coming back to your question,about half of adult obesity begins in childhood,but the other half of obesity begins in adults,often young adults.This suggests we should focus preventative efforts on young adults.This is a huge opportunity,because those young adults are the folks who are having children.Theres an opportunity for a double effectsuccessful obesity prevention in those young adults may also prevent obesity in their children.We need to intervene at the family level.While we are talking about young families,we should also mention breastfeeding.Gestational weight gain is associated with increased obesity risk in children,and breastfeeding lowers that risk.All new mothers should be encouraged to breastfeed their babies,and policies should be in place to support breastfeeding.TFAH:What role should the federal government play in addressing the obesity crisis?How can the federal governments current commitments to preventing obesity be improved?Dr.Dietz:Again,political will is essential at the local,state,and federal level.But change is probably more likely at the state level than it is at the federal level.There are lots of opportunities for change at the state level.State employee health benefits and state Medicaid benefits are examples.Thats one place where we should focus our attention.We are starting to see and trying to fuel the development of political mobilization at the state level to focus on more effective treatment and prevention.A focus on treatment is particularly important because the costs of obesity and its comorbidities increase with the severity of the disease.TFAH:One of the pillars of GWs STOP Obesity Alliance is to ensure that healthcare providers have the tools and training to prevent and manage obesity.What are the main opportunities and barriers to enhancing provider education on treating obesity?Dr.Dietz:Our primary work at the STOP Obesity Alliance focuses on how to help primary care doctors intervene around obesity.If we are going to be successful in treating obesity,it has to be done within primary care settings but people in primary care are not well equipped on how to treat obesity.TFAH:What should primary care providers be taught?Do we know what the most effective inventions are?Dr.Dietz:One of the most challenging decisions for health plans,given the new and effective anti-obesity medications,is who to treat and how.For example,health plans cannot afford to start everyone in their plan with a BMI over 40 with significant comorbidity on one of the new anti-obesity medications.So,who should be treated and how?Solving this problem must begin with shared decision-making between patients and providers.However,obesity care is not something that has been routinely taught in medical schools or residency programs.An additional challenge is there are no quality measures for obesity treatment,so most health plans,unless they are really deliberate about it,they dont know what the prevalence of obesity is in their population,which means they cant track whos doing what,and they cant track costs.If your plan includes obesity treatment,the plan needs to measure the outcomes of care.Lack of metrics is one of the biggest gaps that stand between us and more sophisticated approaches to the treatment of obesity.TFAH:We know that weight-based discrimination and stigma are prevalent in our society,including in the healthcare system.How does this impact our ability to make progress,and what can we do to address it?Dr.Dietz:Within the field,we are recognizing that stigma is a major barrier both at the individual and population level.Providers need to recognize that obesity is a chronic disease that requires ongoing care and follow-up,and the care needs to be paid for.Youre probably familiar with the Obesity Action Coalition.For the first time since Ive been in the field,we have an effective patient advocacy group.Their lives are full of stories about the maltreatment theyve received from providers.Here at GW,we have patients who have talked to medical students about their lived negative experiences with healthcare providers.These presentations transform students perceptions of obesity and certainly sensitizes them to the kind of experiences people with obesity have had.Those experiences have an adverse effect on patient care and patient health.As many as 50 percent of providers still think that obesity is an individual behavior problem,not a disease.TFAH:As we close,talk about whats next for the sector.Is medication the future?Anything we havent covered?Dr.Dietz:Two thoughts.Effective medications are certainly a choice for severe obesity.But its important to define what we mean by the use of these medications.The lifetime of expense of the newest generation of drug therapy will break the bank.These drugs are associated with a rapid decline in weight and an eventual plateau.What would happen if once someone reaches that plateau,you put them on a weight maintenance drug that would be less costly and would be more effective?I think we are going to learn that pretty soon.Youre probably also aware of the older papers that showed that obesity spreads along social networks.An additional question is:can weight loss operate across social networks?And finally,can we invest in two-generation prevention by instituting preventive strategies in young adults and their children?14TFAH tfah.org15 TFAH tfah.orgB.EVOLVING OUTLOOK ON OBESITY Over the past 20 years,there has been an essential progression in the understanding and approach that the public health,medical,and policy fields take in their work in obesity prevention and treatmentincluding recognizing obesity as a chronic disease;emphasizing social determinants of health,equity,and a more comprehensive policy approach;and acknowledging the perniciousness of weight stigma,bias,and discrimination across our society.When this report series began in 2004,obesity was in the early stages of being recognized as a disease,with various governmental agencies and medical associations gradually moving toward a consensus:l In 1998,the National Institutes of Health stated that“obesity is a complex multifactorial chronic disease”in its report Clinical Guidelines on the Identification,Evaluation,and Treatment of Overweight and Obesity in Adults.54l In 2002,the Internal Revenue Service determined obesity treatment costs would qualify as deductible medical expenses,and the Social Security Administration found that obesity is a chronic disease that can be used in disability claims.55l In 2004,the Centers for Medicare and Medicaid Services(CMS)removed language from its Medicare coverage manual that stated,“obesity itself cannot be considered an illness,”opening treatment options for enrollees.Two years later,CMS began covering bariatric surgery under Medicare.56l In 2008,the Obesity Societya professional society focused on obesity science,treatment,and preventionsupported classifying obesity as a disease.57 l In 2013,the American Medical Association adopted a policy resolution recognizing obesity as a chronic disease requiring treatment and prevention interventions.58 More recently,a 2021 opinion poll by Morning Consult found that 65 percent of adults surveyed agreed that the federal government should recognize obesity as a disease,and 70 percent supported Medicare and similar programs recognizing obesity as a treatable medical condition.59 The recognition and acceptance of obesity as a disease helped elevate the seriousness of the issue,started to make treatment and health coverage options available for more individuals with obesity,and helped move away from individual blame and toward a better understanding of the complex,multifactorial causes and continuum of the disease.Another important shift in the obesity policy field has been the elevation of social determinants of health and health equity,and the need for a systems policy approach to tackle complex and interconnected societal issues.Cultural,social,environmental,and economic context has been a component of this work for decades.The first 2004 TFAH State of Obesity report called for moving past“an exclusive focus on individual action”and that“every segment of society has role to play,”and its policy recommendations centered around active living communities and access to affordable,healthy foods.60 Since then,an even wider view of context and conditions has been included in the series as an essential underlying element in obesity policy among advocates and many policymakers,in particular when it comes to addressing longstanding disparities in obesity.For example,TFAH 16TFAH tfah.orghas added stress,structural racism,discrimination,poverty,economic hardship,and food insecurity into our obesity policy work,in addition to long-standing work on improving available choices and behaviors directly related to diet,nutrition,and physical activity.More recently,TFAHs reports have featured some of these critical issues in order to highlight their importance:Food and Nutrition Insecurity Among Youth and Families(2022),COVID-19,Social Determinants of Health,and Obesity(2021),Food Insecurity and its Connection to Obesity(2020),and Racial and Ethnic Disparities in Obesity and Advancing Health Equity(2019).61The third major evolution in the obesity policy field has been a recognition of the pervasiveness of weight-based discrimination and stigma,and the need to better incorporate and elevate reducing discrimination and stigma into other streams of obesity prevention and treatment work.Research has demonstrated that weight-based discrimination is widespread in educational,workplace,and healthcare settings.62,63,64 It can include ridicule,bullying,and fewer social,educational,and employment opportunities,as well as a lower quality of healthcare.65 Furthermore,experiencing weight-based stigma actually increases the risk of unhealthy eating and the avoidance of exercise and healthcare.66 Even though it is one of the most common forms of discrimination in society today,most people experiencing weight-based discrimination lack legal protection.67 Recently,in the healthcare field,there have been discussions on advancing a more holistic approach to considering cardiometabolic health and obesity,and not a sole focus on weight or body mass index(BMI).68 BMI is a useful screening measure at the individual level to help clinicians decide which patients need additional assessment for chronic disease,and a useful population health measure to assess the distribution of BMI in populations so that resources can be targeted to certain geographic areas,groups,or others disproportionally affected by low or high weight for health.BMI does not,however,perfectly correlate with body fat;though it does correlate as well or better than other non-invasive,widely available measures.69 In June 2023,the American Medical Association House of Delegates voted to adopt a new policy that outlines the limitations of BMI as an individual-level metric,supports additional education for physicians around BMI,and recommends BMI be used in conjunction with other measures in a clinical setting.70(For more on BMI,see page 9,and more on Medical Education,Training,and Best Practices,see page 54.)Public health advocatesincluding TFAHalso need to consider their own role in contributing to weight-based stigma,as public health interventions that stigmatize obesity may have the opposite of their intended effect.71 This report was previously called Fas in Fat:How Obesity Threatens Our Future.The“F”stood for the“failure”of the nation to have a public health response that matched the level of a crisis that had reached epidemic proportions in the United States.Changing the name to State of Obesity was in recognition of the success of the first 10 years of the report in raising awareness,presenting policy ideas,and making progress on the end goal of ensuring that“healthy choices are easy,affordable and accessible choices for everyone.”72 While such a title raised attention,it also could be misinterpreted and inadvertently stigmatize individuals living with obesity.In addition to changing the title,the focus of the report has increasingly broadened to examine the many social determinants of health and underlying systemic inequities associated with obesity,and has adopted key lessons as knowledge in the field evolved,such as always using person-first language when referring to people with obesity and ensuring visuals reflect healthy actions and behaviors and are not stigmatizing body size or weight.This evolution and improvement across these three areas is a work in progress.Indeed,as TFAHalong with the public health,medical,and policy field at largecontinues our work on nutrition,physical activity,and obesity policy,we expect to continue to learn new lessons on what works and where we can do better.17 TFAH tfah.orgCULTURAL INSIGHTS ON NUTRITION,WEIGHT,AND FOOD SYSTEMSIn 2022,Vanderbilt Universitys Cultural Context of Health and Wellbeing Initiative released a report titled Reframing Childhood Obesity:Cultural Insights on Nutrition,Weight,and Food Systems.The report reviews interrelated historical and structural factors that frame food and weight beyond individual choice.It also highlights examples of how governments and public health programs in different countries define,support,and encourage healthy eating in their populations,particularly among children and youth.It offers three overall considerations on how to improve childhood obesity policy interventions:(1)food is more than nutrition,(2)health is more than weight,and(3)diet is more than individual choice.732022 WHITE HOUSE CONFERENCE ON HUNGER,NUTRITION,AND HEALTH AND THE FIRST YEAR OF ITS NATIONAL STRATEGY ON HUNGER,NUTRITION,AND HEALTHIn September 2022,the White House held the National Conference on Hunger,Nutrition,and Healththe first in 50 yearsbringing together elected officials,advocates,and leaders across sectors around the goal“of ending hunger and increasing healthy eating and physical activity by 2030 so fewer Americans experience diet-related diseases while reducing related health disparities.”At the conference,the White House released a five-pillar National Strategy to reach this goal:(1)Improve food access and affordability;(2)Integrate nutrition and health;(3)Empower all consumers to make and to have access to healthier choices;(4)Support physical activity for all;and(5)Enhance nutrition and food security research.74The White House also announced at the conference$8 billion in private-and public-sector commitments supporting the National Strategy.These commitments include philanthropic and in-kind contributions,healthcare innovation and education initiatives,and investment in new businesses.75 Since then,the White House has continued to build external support and partnerships across the country.It has also coordinated across the Biden-Harris Administration to implement new policies and rules that further the National Strategy,including three proposed rules:(1)make school meals healthier and accessible to more students,(2)improve nutrition standards and online purchasing for the WIC program,and(3)develop front-of-package labeling,new guidance on what food can be labeled“healthy,”and rules to reduce sodium content for food manufacturers.The Administration has also approved Medicaid demonstrations to test coverage of evidenced-based nutritional assistance and medically tailored meals.7618TFAH tfah.orgC.POLICY ADVANCES AND REMAINING GAPSOver the past 20 years,local,state,and federal governments have implemented important policy changes to help improve nutrition,increase physical activity,and prevent and treat obesity.The chart on page 19 illustrates the major policy milestones of the last 20 years and outcomes where research and evaluations are available.The policies have shown a range of positive results for individuals and communities,including higher fruit and vegetable consumption(e.g.,2004 Fresh Fruit and Vegetable Program expansion);less sugary beverage consumption(e.g.,various local sugary drink taxes);more active transportation and physical activity(e.g.,2005 Safe Routes to School programs);less food insecurity(e.g.,2020 COVID-19 flexibilities for U.S.Department of Agriculture(USDA)nutrition programs and various states universal school meal laws);and reduced obesity rates(e.g.,2009 WIC food package revisions for young children and 2010 changes to nutritional requirements for child nutrition programs).While these policy changes have been important and beneficial for certain populations,they also clearly have been insufficient in scale,funding,and impact to counter the underlying structural issues and larger,long-term trends that have been underway for many decades across the countryincluding longstanding societal challenges(e.g.,poverty,discrimination)that impact the choices,behaviors,and health of Americans;more food made away from home and increased consumption of ultra-processed foods;as well as continued growth in food advertising,which can shape preferences.77,78,79,80,81Americans have shifted to eating fewer minimally processed and unprocessed foods,and more ultra-processed foods,which are lower cost,readily accessible and convenient,and hyper-palatable.82,83,84,85,86,87(Ultra-processed foods are“ready-to-eat or ready-to-heat industrial formulations made mainly with ingredients refined or extracted from foods and contain additives but little to no whole food,”which tend to be high in fat,salt,and sugar and low in nutrients.)88 One study analyzing NHANES data found American adults ages 20 and older significantly increased their consumption of ultra-processed foods and significantly decreased minimally processed or unprocessed foods between the 20012002 to 20172018 surveys.89 A different study,also using NHANES data,specifically found that vegetable consumption for adults ages 20 and older remained constant between 19992000 and 20172018 surveys,while fruit consumption declined.90 A third study using NHANES data looked at the diets of youth ages 219 between 19992000 and 20172018 and had similar trends to adults:the amount of ultra-processed food that youth consumed increased and the amount of unprocessed food consumed declined.91At the same time,obesity prevention and treatment programs and research have been substantially underfunded for decades.In TFAHs inaugural report from 2004,the authors noted that“only 28 states have received funds to support a CDC-funded state-based nutrition and physical activity program aimed at reducing obesity and other chronic diseases.”92 The current,analogous program at CDC to fund state,local,territorial,and tribal programs to improve nutrition and increase physical activity is the State Physical Activity and Nutrition Program in the Division of Nutrition,Physical Activity and Obesity,which had funding for only 16 states for its 20182023 funding cycle and has funding for only 17 states for the 20242029 funding cycle.93,94 CDC has two other programs that fund specific areas and populations,but still leaves 11 states as well as all of the U.S.territories without federal obesity prevention program funding.95 In comparison,the Rudd Center for Food Policy and Obesity at the University of Connecticut estimates that food,beverage,and restaurant companies spend almost$14 billion per year on advertising,with more than 80 percent on fast food,sugary drinks,candy,and unhealthy snacks.A 2021 report from the Rudd Center found that fast food advertising topped$5 billion in 2019,an increase of$400 million since 2012.96 To make progress in preventing obesity across U.S.populations and geographies,the government needs to:l Significantly expand proven policy interventions and programsand their fundingto reach more people and communities;l Fill persistent gaps to improve food and nutrition access;l Have key sectors prioritize systemic changes in nutrition and healthy eating,including the food and beverage manufacturers,healthcare,and education systems;and l Make systemic changes to improve social and economic conditions and eliminate structural inequitiesso all communities in the United States have the resources to promote healthy eating and physical activity and support the health and well-being for all.Specific recommendations can be found in the Recommendation section beginning on page 57.19 TFAH tfah.orgMajor Policy Milestones to Improve Nutrition,Increase Physical Activity,and Prevent and Treat Obesity in the United States at Federal,State,and Local Levels,20042023YearPolicyDescriptionResults2004Recognizing obesity as a diseaseCMS removed language from its coverage manual that stated,“obesity is not an illness.”972004Child Nutrition and Special Supplemental Nutrition Program for Women,Infants,and Children(WIC)Reauthorization Act of 2004The law expanded several nutrition programs:the Fresh Fruit and Vegetable Program(FFVP),the Summer Food Service Program,and the Child and Adult Care Food Program(CACFP).It also required schools to draft and implement school wellness policies.98Research has shown that FFVP increases students consumption of fresh produce and is associated with a meaningful reduction in obesity for participating children.99,100,101An evaluation of CACFP found that participation in the program may reduce the prevalence of obesity.1022005Safe Routes to SchoolCongress funded Safe Routes to School programs in all 50 states.103Safe Routes to School projects increased walking and biking to school by 37 percent.1042006Updated Nutrition Facts labelsStarting January 1,2006,manufacturers were required to include transfat levels on Nutrition Facts labels.1052006Medicare coverage of bariatric surgeryCMS announced it would begin covering bariatric surgery for Medicare beneficiaries effective February 2006.106Bariatric surgery in the Medicare-eligible population is effective and leads to weight loss and decreased mortality.107,1082008Food,Conservation,and Energy Act of 2008(“the 2008 Farm Bill”)The bill increased monthly Supplemental Nutrition Assistance Program(SNAP)benefits;created the Healthy Incentives Pilot(HIP)program to encourage SNAP households to purchase fresh produce;and provided nationwide expansion of the FFVP.109HIP increased participants produce consumption by 11 percent.110Research has shown FFVP increases students consumption of fresh produce and is associated with a meaningful reduction in obesity for participating children.111,112,1132009WIC food package revisionsFederal rule overhauling WIC food packages,adding more fruits,vegetables,and whole grains,and incentives to promote breastfeeding.114After the WIC nutritional requirements were strengthened,obesity rates among children in the program declined.115,1162009Childrens Health Insurance Program Reauthorization Act of 2009CHIPRA authorized the Childhood Obesity Research Demonstration Project(CORD).117 In 2010,the Affordable Care Act provided funding,and in 2011 CDC awarded grants to four CORD projects,which combined obesity prevention in pediatric settings with public school interventions.118CORD 1.0 resulted in small but positive improvements in BMI and fruit and vegetable consumption among children at some sites.1192010National Diabetes Prevention ProgramCongress authorized CDC to establish and lead the National Diabetes Prevention Program(DPP).120Participants in National DPP can reduce their risk of developing diabetes by 58 percentor up to 71 percent for those over the age of 60.121,1222010Presidential Executive Order on Presidents Council on Fitness,Sports,and NutritionExpanded Councils mission to include education and promotion of good nutrition.1232010Affordable Care ActThe law(1)created the Prevention and Public Health Fund,which has helped support hospitals promoting breastfeeding,early child care projects,and other programs to reduce chronic disease;(2)expanded Medicaid coverage;(3)mandated coverage of obesity treatments and preventive recommended by the U.S.Preventive Services Task Force;(4)enhanced federal matches for states that provide Medicaid coverage for these treatments;(5)provided funding for CORD;(6)required nonprofit hospitals to address community health needs;and(7)required chain restaurants to post calorie counts.124,125,126Medicaid patients in states that expanded the program had greater improvement in weight management in community health centers between 20122017 than among patients in community health centers in non-expansion states.127The menu requirements have had a small but positive impact in purchased meal quality in U.S.chain restaurants.1282010Healthy,Hunger-Free Kids Act of 2010(HHFKA)HHFKA strengthened requirements for child nutrition programs,increased funding for school meals,strengthened school wellness policy requirements,and created the Community Eligibility Provision that allows schools to provide universal free school meals in high-poverty communities.129The new nutrition requirements reduced the prevalence of obesity among school lunch participants.130Universal school meal programs have been found to be positively associated with increased food security and improved nutrition.13120TFAH tfah.orgMajor Policy Milestones to Improve Nutrition,Increase Physical Activity,and Prevent and Treat Obesity in the United States at Federal,State,and Local Levels,20042023YearPolicyDescriptionResults2012Updated school meal nutrition standardsThe federal rule by USDA strengthening school meal nutrition standards went into effect:the National School Lunch Program had to comply starting in the 20122013 school year and the School Breakfast Program in the 20132014 school year.132The new nutrition requirements reduced the prevalence of obesity among school lunch participants.1332013Smart Snacks ruleThe rule establishing nutrition standards for all food sold in schools went into effect,with implementation required by July 1,2014.1342014High Obesity Program(HOP)CDC funded its first round of five-year HOP grants to 11 land grant universities to increase access to healthier food and safe places to be physically active in high-obesity counties.135HOP grants have helped more than 2 million people have increased access to healthy food and places to be physically active.1362014Agricultural Act of 2014(“2014 Farm Bill”)The law created the Healthy Food Financing Initiative(HFFI)to increase access to healthy food in under-resourced communities;created the Food Insecurity Nutrition Incentive(FINI)program to pilot innovative approaches to increase fruit and vegetable purchases among SNAP participants;required SNAP retailers to carry healthier food options;and allowed SNAP benefits to be used at more retailers.137,138While a preliminary evaluation of FINI found no statistically significant difference in fruit and vegetable intake from the program,a later report evaluating the program(which has since been renamed GusNIP)did find a significant increase in fruit and vegetable intake among program participants.1392014Office of Personnel Management(OPM)obesity coverageOPM released guidance encouraging federal health plans to cover obesity treatments and prohibiting them from excluding coverage based on the belief that obesity is a lifestyle condition or that obesity treatment is cosmetic.1402014Child Care and Development Block Grant(CCDBG)Act of 2014The CCDBG reauthorization law helped support the development of state nutrition and physical activity standards for childcare centers.1412015Berkeley,California,beverage taxBerkeleys one-cent-per-ounce tax on the distribution of sugar-sweetened drinks went into effect.142The tax led to a persistent long-term reduction in sugary beverage consumption.1432015Every Student Succeeds Act(ESSA)ESSA designated school health and physical education as part of a students“well-rounded education,”allowing significant federal funding of these subjects.1442016Nutrition label updatesRules updating Nutrition Facts labels went into effect,requiring the labels to be reformatted to make them easier to read,to more accurately reflect serving sizes,and to include additional information,such as added sugars;large companies were required to comply by July 2018 and small companies by July 2019.145A study found that those who accessed the new added sugar information on nutrition labels made healthier food choices.1462016Child and Adult Care Food Program(CACFP)nutrition standardsFederal rule aligning CACFP meal patterns with dietary guidelines as required by HHFKA went into effect,with compliance required by October 1,2017.147An evaluation of CACFP found that participation in the program may reduce the prevalence of obesity.1482016School wellness policy ruleSchools were required to meet HHFKAs expanded school wellness policy requirements.1492017Oakland,California beverage taxOaklands one-cent-per-ounce tax on the distribution of sugar-sweetened drinks went into effect.150The tax led to a substantial decline in sugary beverage purchases.1512017Philadelphia,Pennsylvania beverage taxPhiladelphias 1.5 cent-per-ounce tax on the distribution of sweetened drinks went into effect.152The tax led to a large reduction the sales of tax-eligible beverages.1532018Seattle,Washington beverage taxSeattles 1.75 cent-per-ounce tax on the distribution of sugar-sweetened beverages went into effect.154The law resulted in a net reduction in grams of sugar sold.15521 TFAH tfah.orgMajor Policy Milestones to Improve Nutrition,Increase Physical Activity,and Prevent and Treat Obesity in the United States at Federal,State,and Local Levels,20042023YearPolicyDescriptionResults2018San Francisco,California,beverage taxSan Franciscos one-cent-per-ounce tax on distribution of sugar-sweetened drinks,syrups,and powders went into effect.156After the tax,average sugar-sweetened beverage intake declined significantly.1572018Menu labelsLarge chain restaurants were required to start posting calorie counts.158The new rule led to a decrease in mean calories,saturated fat,and sugar in fast food meals.1592018Agriculture Improvement Act of 2018(“2018 Farm Bill”)The bill created the Gus Schumacher Nutrition Incentive Program(GusNIP),expanding the FINI pilot program.160,161An evaluation of GusNIP found a significant increase in fruit and vegetable intake among program participants.1622018Medicare Diabetes Prevention ProgramOn April 1,2018,CMS began covering Medicare DPP as a preventive service for Medicare beneficiaries.163A November 2022 evaluation of the Medicare DPP found that participants lost an average of 5.1 percent of their body weight.1642019SNAP Online Purchasing PilotUSDA piloted a program allowing SNAP participants to spend their benefits online.1652020Dietary guidelines by life stageUSDA and the U.S.Department of Health and Human Services(HHS)published Dietary Guidelines for Americans,20202025,which focuses on healthy eating for all life stages,including infancy,toddlerhood,childhood,adolescence,pregnancy,lactation,and older adulthood.1662020COVID-19 flexibilitiesThe Families First Coronavirus Response Act temporarily allowed USDA to waive many nutrition assistance program requirements,including allowing benefits to be issued remotely,school meals to be provided for free regardless of income,and school meals to be served outside of group settings and picked up by parents.The law also created the Pandemic-Electronic Benefit Transfer(EBT)program and increased SNAP benefits.167,168,169 2021The Infrastructure Investment and Jobs ActThe Infrastructure Act provided billions of new dollars for public transportation and active travel projects,set aside funding for bicycling and walking safety projects,as well as funding for states and localities to develop Complete Streets plans.1702021American Rescue PlanThe law temporarily tripled the cash-value benefit that allows WIC participants to purchase fruits and vegetables.171The benefit bump increased fruit and vegetable intake among children in the WIC program.1722021Thrifty Food Plan updateUSDA updated the Thrifty Food Plan to reflect current eating habits and food costs.1732022Universal school mealsCalifornia,Colorado,and Maine passed laws establishing free school meals for all.174,175,176Universal school meal programs around the world have been found to be positively associated with increased food security and improved nutrition.1772022OPM Coverage for Obesity MedicationOPM announced that federal health plans must cover Food and Drug Administration(FDA)-approved obesity medications starting in 2023.1782022Food Is Medicine policiesHHS encouraged states to pilot Medicaid initiatives addressing health-related social needs using Section 1115 funding,including nutrition supports such as nutrition counseling,produce prescriptions,and medically tailored meals.1792023Summer EBT ProgramCongress established a permanent Summer EBT program,which provides funds to families whose children participate in the School Lunch Program to buy groceries during the summer.1802023Universal school mealsMassachusetts,Michigan,Minnesota,New Mexico,and Vermont passed free-school-meals-for-all laws.181Universal school meal programs around the world have been found to be positively associated with increased food security and improved nutrition.182The State of Obesity SECTION 2:OBESITY-RELATED DATA AND TRENDSSECTION 2:SEPTEMBER 2023Obesity-Related Data and TrendsA.TRENDS IN ADULT OBESITYThe National Health and Nutrition Examination Survey(NHANES)conducts in-person physical examinations to determine participants height,weight,and other physical measures.The COVID-19 pandemic disrupted the 20192020 collection processes,so the latest data available is a combination of data from the 20172018 and 2019March 2020 surveys.The Behavioral Risk Factor Surveillance System(BRFSS)polls individuals about their health via telephone and was able to continue through the pandemic,including 2021 and 2022 data.Both NHANES and BRFSS show long-term trends of rising obesity rates among adults.183,184,185,186 The latest NHANES data shows the adult obesity rate passing 40 percent nationally.187 This subsection provides the most recent data available on adult obesity levels by state and by demographics.DATA SOURCES FOR ADULT OBESITY MEASURES1.The National Health and Nutrition Examination Survey(NHANES)is the source for the national obesity data in this report.As a survey,NHANES has two main advantages:(1)it examines a nationally representative sample of Americans ages 2 years and older;and(2)it combines interviews with physical examinations.The limitations of the survey include a time delay from collection to reporting and a small survey size(approximately 5,000 interviews)that is not designed to be used for state or local data.1882.The Behavioral Risk Factor Surveillance System(BRFSS)is the source for state-level adult obesity data in this report.As a survey,BRFSS has three major advantages:(1)it is the largest ongoing telephone health survey in the world(approximately 450,000 interviews per year);(2)each state survey is representative of the population of that state;and(3)the survey is conducted annually,so new obesity data are available each year.189 The main limitation of the survey includes its use of self-reported weight and height,which result in underestimates of obesity rates due to peoples tendency to over-report their height and under-report their weight.Also,the sample sizes in some states are too small to be useful for providing estimates about certain racial and ethnic groups.2223 TFAH tfah.orgI.State trends(BRFSS)State-level obesity rates vary considerably from a low of 24.3 percent in Washington,DC to a high of 41 percent in West Virginia,according to 2022 BRFSS data.Other key findings from the recently release data include:l In 2022,the adult obesity rate was at or above 35 percent in 22 states.Georgia,Virginia,and Wisconsin had adult obesity rates above 35 percent for the first time in 2022,joining 19 other states.l In comparison,no state had an adult obesity rate higher than 35 percent in 2012(see Figure 2 on page 6).l Between 2021 and 2022,no states had statistically significant increases or decreases in their obesity rate.This is a contrast to the prior year(2020 to 2021)when 17 states had significant increases in their adult obesity rate and one state(California)had a significant decline,and more in line with other years.For example,from 2019 to 2020,three states had statistically significant increases in their adult obesity rates.l In the prior five years(20172022),29 states had statistically significant increases in their obesity rate,underscoring the long-term trend of rising obesity rates across the country.For additional state-level data from BRFSS,see the charts on pages 26 28.Adult Obesity Rate by State,2022Percent Change in Adult Obesity Rate by State,20172022SOURCE:BRFSS 25%0055% CAWAORMTIDNVWYUTAZCONMNDSDNEKSOKTXMNIAMOARLAWIILINMIOHKYTNMSALMENYPAVANCSCGAWVFLVTNHMARICTNJDEMDAKHIDCSOURCE:BRFSSObesity rates increased 5%Obesity rates increased 5%Obesity rates increased 10%Obesity rates increased 15% CAWAORMTIDNVWYUTAZCONMNDSDNEKSOKTXMNIAMOARLAWIILINMIOHKYTNMSALMENYPAVANCSCGAWVFLVTNHMARICTNJDEMDAKHIDC24TFAH tfah.orgWHY ARE REPORTED NATIONAL OBESITY RATES HIGHER THAN STATE-BY-STATE RATES?How is it that fewer than half of states(22)have adult obesity rates exceeding 35 percent,yet the national obesity rate is 41.9 percent?Its because the two rates are from separate surveys with different methodologies and were conducted in different years.State obesity rates are from the BRFSS,which collects self-reported height and weight through landline and cellular telephone surveys.Research has demonstrated that people tend to overestimate their height and underestimate their weight.One study found that,due to this phenomenon,the BRFSS may underestimate obesity rates by 16 percent.190 NHANES,from which the national obesity rate is derived,calculates its obesity rate based on measurements obtained through in-person physical examinations.Accordingly,the higher rates found by NHANES are a more accurate reflection of obesity in the United States.191 NHANES does not have state-level data,which is why TFAH also uses BRFSS data.FIGURE 6:Percent of U.S.Adults With Obesity by Select Demographics,201720200 0P%WhiteWomenLatinaWomenBlackWomenAsianWomenWhiteMenLatinoMenBlackMenAsianMenWhiteAdultsLatinoAdultsBlackAdultsAsianAdultsWomenMenAllAdults41.9A.8A.8.1I.9E.6A.4.6.4E.2C.1.5W.9E.79.6%SOURCE:NHANESII.Demographic trends Obesity rates diverge along a number of demographic measures,including race/ethnicity,income,education,and geography.While obesity rates depend on many factorsfrom economic and community effects,to cultural and marketing influences,and individual-level behaviors all are inexorably linked with the social,economic,and environmental conditions that individuals experience.Broader equity issues,like structural racism and poverty,and community context shape daily life and available choices around healthy food,physical activity,education,jobs,financial security,etc.(together these are often called the“social determinants of health”),which systematically affect peoples weight and health.192 See Appendix beginning on page 67 for state-level indicators that track some of these structural factors,including community conditions(e.g.,poverty rate)and the built environment,active transportation,and food systems(e.g.,percentage of children who live in neighborhoods with sidewalks/walking paths),as well as state policies that improve conditions(e.g.,universal free school meals).25 TFAH tfah.orgl Race/ethnicity:Racial/ethnic disparities in obesity rates are significant(see Figure 6).l According to 20172020 NHANES data,Black Americans had the highest rate of obesity(49.9 percent)for adults ages 20 and higher,followed by Latino/a(45.6 percent),white(41.4 percent),and Asian(16.1 percent)adults.l More than half57.9 percentof Black women had obesity.That is the highest sex and race/ethnicity combination included in NHANESand an 18 percentage points difference compared with white women(39.6 percent).In contrast,Black men had an obesity rate of 40.4 percent,which is slightly lower than white men(43.1 percent).193l Asian adults overall had much lower rates of obesity than any other race/ethnicity reported in NHANES.Other studies have shown variation in obesity rates among different ethnicities and national origins within the population.For example,the 2020 National Health Interview Study found that Native Hawaiian and other Pacific Islander adults ages 18 and older had self-reported obesity rates of 45.8 percent,and Pacific Islander adults had obesity rates of 44.5 percent,while Asian adults had an obesity rate of 10.2 percent(and whites had a 32.3 percent obesity rate).194l There is also evidence suggesting that Asian people should have lower BMI cutoffs for overweight and obesity measures than other races and ethnicities,because they have higher health risks at lower BMIs.This includes a higher risk for type 2 diabetes and other metabolic diseases at lower BMIs.Since a high BMI is a factor in determining whether to test for diabetes,fewer Asian individuals are tested and diagnosed by healthcare providers.195 An estimated 40 percent of Asian people with diabetes have not been diagnosed,which is much higher than the overall population.196l It is also important to note that many national surveys,including NHANES,do not report data on health measures for American Indian and Alaska Native(AI/AN)people.The surveys that do exist do not gather or present findings by Tribal Nations.Available data show that the AI/AN population has high rates of obesity.The 2020 National Health Interview Survey,which is based on self-reported height and weight,finds 41.7 percent of AI/AN adults had obesity,which is slightly lower than Black adults in that survey(44.5 percent)and substantially higher than white adults(32.3 percent).197 This gap in the data highlights the need for more attention and resources to advance equitable data collection and reporting for populations of smaller sizes.l Income and education:Obesity rates were lower among adults living in higher-income households and adults with college degrees.l In 20172020,43.9 percent of adults living in households with incomes below 130 percent of the federal poverty level(FPL)had obesity,46.5 percent of adults in households at 130350 percent of FPL had obesity,and 39 percent of adults in households above 350 percent FPL had obesity.(In 2022,FPL was an annual income of$13,590 for an individual and$27,750 for a family of four.198)The trends varied by sex,with men in the below-130 percent FPL income category having slightly lower obesity rates(38.6 percent)than men in the middle-income(43.9 percent)and higher-income(42.4 percent)categories.For women,the data shows obesity rates in the lower-income category at 47.9 percent,middle-income category at 48.8 percent,and higher-income category at 35.1 percent.l In 20172020,40.1 percent of adults with less than a high school education had obesity compared with 46.4 percent of adults with a high school diploma and 34.1 percent of college graduates.199l Rural/urban:Rural areas and counties have higher rates of obesity and severe obesity.l According to 2016 BRFSS data,adult obesity rates were 19 percent higher in rural regions than they were in metro areas.More than one-third(34.2 percent)of adults in rural areas had self-reported obesity compared with 28.7 percent of metro adults.200 l Similarly,a CDC analysis of NHANES data found that adults(ages 20 and older)who lived in the most urban areas of the country(large“metropolitan statistical areas”)had the lowest obesity rates in 20132016.201 26TFAH tfah.orgAdult Obesity Rates and Related Health Indicators,2022ObesityOverweight&Obesity DiabetesPhysical InactivityHypertensionStatesPercent of Adults With ObesityRankPercent of Adults With Obesity or Were Overweight RankPercent of Adults with Diabetes RankPercent of Adults Who Were Physically InactiveRankPercent of Adults with HypertensionRankAlabama38.3672.0515.6328.4543.13Alaska32.13568.6 /-1.8258.6 /-14621.2 /-1.63630.341Arizona33.230-T66.73712.91422.825-T31.232-TArkansas37.4 /-1.812-T71 /-1.810-T16.3* /1.3230.4 /-1.7240.7 /-24California28.14662.84611.23020.93828.248Colorado25.05060.6498.15116.14926.350Connecticut30.64166.238-T10.63422.53131.531Delaware37.9871.86-T14.1822.628-T36.411D.C.24.3 /-2.15155.2 /-2.55418.3 /-1.347-T14.7 /-1.85128.5 /-2.147Florida31.63766.140-T12.81523.222n/a-Georgia37.01468.92412.31822.825-T37.410Hawaii25.94959.75011.7*24-T21.13729.943Idaho33.2 /-1.530-T68.5 /-1.526-T9.8 /-0.94020.8 /-1.33930.5 /-1.339Illinois33.428-T67.23411.922-T22.628-T30.440Indiana37.79-T71.010-T13.112-T27.3*734.8 /-1.217Iowa37.412-T71.2911.724-T25.31231.928Kansas35.71769.12311.42823.02434.618Kentucky37.79-T71.86-T15.0526.8940.35Louisiana40.1271.7814.8728.1640.26Maine33.13366.140-T11.131-T22.03334.1 /-1.321-TMaryland33.230-T67.6 /-1.328-T12.1 /-0.82020.2 /-14235.215-TMassachusetts27.24761.94710.435-T20.44030.838Michigan34.52367.332-T11.526-T23.12335.613Minnesota33.62668.526-T10.13819.94329.6 /-0.945Mississippi39.5472.13-T15.2431.7144.11Missouri36.41670.416-T11.922-T25.51135.2 /-1.315-TMontana30.54266.0428.347-T19.54530.9 /-1.437Nebraska35.32070.416-T10.83323.91832.527Nevada33.5 /-2.62767.4 /-2.530-T9.6 /-1.441-T26.1 /-2.41032.9 /-2.626New Hampshire30.2 /-1.74366.9 /-1.835-T10 /-0.93919.6 /-1.54431.1 /-1.634-TNew Jersey29.14565.84311.131-T22.628-T31.829New Mexico32.4 /-2.03469.3 /-1.921-T12.7 /-1.316-T23.8 /-1.81933.225New York30.14464.04511.526-T24.91431.134-TNorth Carolina34.12569.321-T12.21922.72735.414North Dakota35.4 /-1.81971 /-1.810-T9.6 /-141-T23.5 /-1.620-T31.2 /-1.532-TOhio38.1 /-1.2770.9 /-1.113-T13.1 /-0.712-T24.8 /-11536.012Oklahoma40.0372.3213.31129.2439.6 /-1.77Oregon30.9 /-1.53966.9 /-1.635-T10.4 /-1.135-T18.3 /-1.34731.1 /-1.534-TPennsylvania33.428-T67.628-T11.32921.834-T34.121-TRhode Island30.84067.4 /11.930-T12 /-1.12124.1 /-1.716-T33.4 /-1.723South Carolina35.02269.82013.41025.01337.99South Dakota36.8 /-3.31572.1 /-2.93-T9.5 /-1.84423.5 /-2.820-T34.2 /-2.720Tennessee38.9570.913-T14.9627.1838.18Texas35.51870.21813.8924.116-T33.324Utah31.13865.3448.347-T16.05026.949Vermont26.84860.9488.347-T19.24629.5 /-1.646Virginia35.22167.332-T12.716-T20.34134.519Washington31.73666.238-T9.641-T17.04830.242West Virginia41.0174.4117.7129.7343.7 /-1.52Wisconsin37.7 /-1.39-T70.6 /-1.31510.4 /-0/735-T21.8 /-1.134-T31.630Wyoming34.32469.9199.24522.33229.8 /-1.944SOURCE:TFAH analysis of Behavioral Risk Factor Surveillance System data For rankings,1=Highest Rate,and 51=Lowest Rate;T=Tie.Red and*indicate state rates that significantly increased between 2020 and 2021;Green and*indicate state rates that significantly decreased between 2020 and 2021;Bold indicates state rates that significantly increased between 2017 and 2022.Hypertension data is collected bi-annually;this data is from 2021.27 TFAH tfah.orgAdult Obesity Rates by Race/Ethnicity and Sex,20202022American Indian/Alaska Native*Asian*Black*Latino*White*StatesPercent of AI/AN Adults With ObesityRankPercent of Asian Adults With ObesityRankPercent of Black Adults With ObesityRankPercent of Latino Adults With ObesityRankPercent of White Adults With ObesityRankAlabama42.615n/a-49.3 /-2.3236.81736 /-1.39Alaska37.1 /-3.426-T24.8241.82233.439-T30.6 /-1.432Arizona47.0213.515-T40.92638.2 /-1.91227.9 /-0.941-TArkansas28.4 /-843n/a-46.6633.5 /-5.837-T36.6 /-1.27California37.02911.12842.51837.8 /-1.81325.8 /-1.346Colorado37.126-T10.03531.34131.04923.248Connecticut42.11813.21841.12436.02428.3 /-140Delaware40.12118.3646.3 /-3.4935.92533.5 /-1.519D.C.n/a-10.2 /-4.532-T38.3 /-2.33027 /-4.85012.9 /-1.350Floridan/a-n/a-n/a-n/a-n/a-Georgia32.93614.71342.81633.439-T32.6 /-1.122-THawaiin/a-17.3 /-1.3931.24231.4 /-3.14819.7 /-1.449Idaho45.28n/a-30.54536.718-T31.4 /-0.929Illinois32.03711.62641.02540.5631.8 /-1.427Indiana36.630-T8.237-T44.01339.21136.7 /-0.85-TIowa44.8911.82541.92137.11437.1 /-0.84Kansas42.9 /-6.91310.232-T39.62840.6535.2 /-0.711-TKentucky37.623n/a-44.71240.28-T38 /-1.22Louisiana43.71119.9446.5735.43036.18Maine36.132n/a-36.93434.63431.9 /-0.826Maryland24.84713.41741.6 /-1.52333.5 /-2.437-T30.2 /-0.835Massachusetts25.24610.63136.037-T33.042-T26.145Michigan30.1429.23642.11940.3734.3 /-0.916-TMinnesota45.94-T18.8536.037-T35.527-T32.2 /-0.624-TMississippi30.54123.3347.5 /-1.9444.7134.8 /-1.315Missouri33.63512.42342.61736.520-T35.5 /-0.910Montana41.819n/a-n/a-36.520-T29.3 /-0.938-TNebraska43.31212.620-T37.531-T36.915-T35.2 /-0.811-TNevada45.4715.8 /-6.31033.44034.8 /-3.332-T31.3 /-1.830-TNew Hampshire34.93410.92933.73936.718-T30.5 /-133New Jerseyn/a-11.22737.33333.439-T27.6 /-143New Mexico45.5 /-46n/a-37.531-T36.4 /-1.72225.7 /-1.447New York30.94012.620-T36.33533.042-T27.941-TNorth Carolina38.32215.51148.2332.94431.3 /-1.230-TNorth Dakota49.5 /-5.6127.6125.04935 /-73134.3 /-1.116-TOhio35.13312.81943.91436.32336.7 /-0.75-TOklahoma45.94-T13.71446.1 /-4.31039.71037.4 /-1.13Oregon37.2 /-8.624-T15.2 /-4.41231 /-7.44336.9 /-3.215-T29.3 /-0.938-TPennsylvania28.34410.73040.82733.935-T32.8 /-1.220-TRhode Island42.21712.02438.52933.935-T29.5 /-1.237South Carolina40.32017.5844.91132.74532.6 /-1.122-TSouth Dakota44.110n/a-28.94641.2235.2 /-1.811-TTennessee31.638-Tn/a-46.4834.832-T35 /-1.214Texas36.630T13.515-T43.51540.8432.224-TUtah46.738.237-T28.14835.527-T29.6 /-0.736Vermont31.638-Tn/a-28.64731.54727.5 /-144Virginia28.04512.620-T46.7532.54632.8 /-0.920-TWashington42.71410.232-T36.13635.82630.334West Virginia37.1 /-12.328n/a-42 /-6.12041.1 /-9.2340.3 /-11Wisconsin42.31617.7749.8135.527-T33.8 /-118Wyoming37.2 /-10.124-Tn/a-30.7 /-16.24440.2 /-58-T31.5 /-1.228SOURCE:TFAH analysis of Behavioral Risk Factor Surveillance System dataNOTE:For rankings,1=Highest Rate,and 51=Lowest Rate;T=Tie.*For race/ethnicity data,three years of data are needed for sufficient sample size;20202022 data were used here.Some data are not available due to an insufficient sample size.Because data from one year are not available for Florida,race/ethnicty data is not available for the state.28TFAH tfah.orgAdult Obesity Rates by Age,2022MaleFemaleAges 18-24Ages 25-44Ages 45-64Ages 65 StatesPercent of Men With ObesityRankPercent of Women With ObesityRankPercent With ObesityRankPercent With ObesityRankPercent With ObesityRankPercent With ObesityRankAlabama35.811-T40.6519.83640.21044.7436.2 /-3.12Alaska31.2 /-2.33733.3 /-2.73224.512-T32.7 /-3.235-T37.23528 /-2.840Arizona32.72733.82923.319-T34.42938.43130.429Arkansas35.3 /-2.613-T39.5 /-2.7927.6 /-6.8439.5 /-3.81343.3 /-2.98-T32.3 /-2.621-TCalifornia28.44627.7 /-245-T13.85131.54131.24825.5 /-2.647Colorado24.95025.25015.04724.65030.25023.948-TConnecticut30.44130.839-T19.638-T32.438-T34.34328.636Delaware35.3 /-3.113-T40.56-T28.0338.31743.11135 /-3.56D.C.21.55127.04823.3 /-9.119-T19.85133.5 /-44623.2 /-3.550Florida32.429-T30.839-T21.23031.94036.73729.232-TGeorgia34.12339.9825.9940.01141.120-T32.321-THawaii27.14824.6 /-2.15121.827-T30.14729.7 /-2.55118 /-2.751Idaho33.424-T33.03325.01133.93237.93330.927Illinois31.03835.72219.93531.24341.817-T31.624Indiana36.69-T38.71225.31041.0843.3 /-28-T32.420Iowa35.811-T39.11023.51739.21443.2 /-2.31035.1 /-2.35Kansas34.71836.81724.512-T39.91239.62431.525Kentucky38.7236.718-T24.11541.2742.01633.713Louisiana37.6542.5223.319-T42.9345.5337.31Maine32.6 /-1.92833.630-T23.41834.82838.6 /-2.32928.437Maryland31.5 /-1.83634.8 /-1.82622.224-T35.426-T38.5 /-23027.9 /-1.941Massachusetts28.04726.54914.05027.44932.34727.044Michigan33.424-T35.62319.73736.024-T39.52533.414Minnesota34.61932.63419.638-T34.33039.3 /-1.72632.023Mississippi37.07-T41.9326.3742.6446.9232.718Missouri35.2 /-2.215-T37.61322.12637.818-T42.91233.3 /-2.715-TMontana30.3 /-1.94230.839-T18.34132.4 /-2.938-T35.2 /-2.54128.1 /-2.138-TNebraska35.215-T35.42423.02335.426-T41.120-T34.68Nevada31.9 /-3.53335.3 /-3.82527.0536.422-T36 /-4.44028.7 /-4.235New Hampshire30.24330.3 /-2.443-T15.84630.34636.5 /-2.73827.4 /-242New Jersey30.73927.44714.54930.44534.04527.343New Mexico32.429-T32.4 /-2.73521.42937.818-T38.2 /-3.53223.9 /-2.848-TNew York29.94430.343-T20.13430.84434.54228.138-TNorth Carolina32.13236.12121.131-T34.23142.11530.131North Dakota37 /-2.57-T33.6 /-2.730-T23.1 /-5.52236.4 /-3.522-T42.2 /-3.21433.3 /-2.815-TOhio37.2639.01126.6639.11543.4735.3 /-1.94Oklahoma38.4341.6 /-2.2429.7244.1144.0634.211Oregon30.5 /-2.14031.4 /-2.23817.8 /-5.14432.53737.7 /-2.73425.946Pennsylvania32.429-T34.32716.04532.93339.02734.310Rhode Island29.84531.9 /-2.63624.512-T31.44234.14429.2 /-2.932-TSouth Carolina32.82637.21521.827-T38.51640.12330.6 /-1.928South Dakota36.69-T37 /-4.71619.34041.8641.5 /-5.81932.6 /-519Tennessee35.11742.7124.01642.5544.4533.812Texas34.42036.718-T20.93336.024-T42.71333.117Utah31.73430.54218.24232.83437.13630.2 /-2.430Vermont26 /-24927.745-T14.74828.04830.74926.5 /-2.645Virginia34.221-T36.32017.94337.12040.22234.87Washington31.63531.83721.131-T32.735-T36.13929.034West Virginia41.6140.5 /-2.36-T30.8143 /-3.7247.2 /-2.8135.8 /-2.63Wisconsin38.0437.31426.0840.5941.817-T34.4 /-29Wyoming34.2 /-2.621-T34.22822.2 /-7.624-T37 /-3.82138.8 /-32831.226SOURCE:TFAH analysis of Behavioral Risk Factor Surveillance System data NOTE:For rankings,1=Highest Rate,and 51=Lowest Rate;T=Tie.29 TFAH tfah.orgB.TRENDS IN YOUTH OBESITYAs with adults,obesity has been rising among children for decades.Between the inaugural 19761980 NHANES survey and the 20172020 survey,obesity rates for children ages 2 to 19 more than tripled,from 5.5 to 19.7 percent.202,203 This section includes the latest data available on childhood obesity.As with adults,this report relies on multiple surveys to better understand the full picture of childhood obesity.DATA SOURCES FOR CHILDHOOD OBESITY MEASURES1.The National Health and Nutrition Examination Survey(NHANES)is the primary source for national obesity data on adults and on children ages 2 to 19 in this report.NHANES is particularly valuable in that it combines interviews with physical examinations,including measured heights and weights,while also covering a wide age range of Americans.The downsides of the survey include a time delay from collection to reporting and no state or local data.The most recent NHANES data are from a combination of the 20172018 and 20192020 NHANES surveys since data collection was disrupted by the COVID-19 pandemic.2.The WIC Participant and Program Characteristics Report is a biennial census of low-income mothers and young children(under the age of 5)that the Special Supplemental Nutrition Program for Women,Infants,and Children(WIC)serves.204 Because obesity disproportionately affects individuals with low incomes,early childhood is a critical time for obesity prevention,and the data provide valuable information for evaluating the effectiveness of programs aimed at reducing obesity rates and health disparities.The most recent public WIC data are from 2020.3.The National Survey of Childrens Health surveys parents of children ages 0 to 17 about aspects of their childrens health,including height and weight for children ages 6 and older.An advantage of this survey is that it includes state-level data.A disadvantage is that height and weight data are parent-reported,not directly measured.The most recent data are from its 20192020 iteration.4.The Youth Risk Behavior Survey(YRBS)measures health behaviors,including eating habits and physical activity behaviors,as well as body-weight status(determined from self-reported height and weight),among students in grades 9 to 12.As in other surveys that use self-reported data to measure obesity,this survey likely underreports the true rates.205 YRBS officials conduct the survey in odd-numbered years;2019 is the most recent dataset available.The 2019 survey includes state-level samples for 44 states plus three U.S.territories,two tribal areas,and select large urban school districts,as well as a separate national sample.20630TFAH tfah.orgI.National Youth Obesity Rates(NHANES)The most recent national data,the 20172020 NHANES survey,found that 19.7 percent of youth ages 2 through 19 had obesity.The data show variation in obesity prevalence by demographic and socioeconomic groups:l Race/ethnicity:Black and Latino youth had higher rates of obesity than their Asian and white peers.Obesity prevalence for Asian youth was 9 percent,Black youth 24.8 percent,Latino/a youth 26.2 percent,and white youth 16.6 percent in 20172020.l Sex:Boys are slightly more likely to have obesity than girls.In 20172020,20.9 percent of boys had obesity,and 18.5 percent of girls had obesity.l Age:The prevalence of obesity increases with age.In 20172020,12.7 percent of children ages 2 to 5,20.7 percent of children ages 6 to 11,and 22.2 percent of children ages 12 to 19 had obesity.Between the 19761980 NHANES survey and the 20172020 survey,the percentage of children ages 2 to 19 with obesity overall tripled,with the obesity rates of teens ages 12 to 19 quadrupling.207l Household income:Children in households with lower incomes have higher rates of obesity.In 20172020,25.8 percent of children living in households with incomes below 130 percent of FPL had obesity,21.2 percent of children in households at 130350 percent of FPL had obesity,and 11.5 percent of children in households above 350 percent FPL had obesity.208II.Young WIC Participants,Ages 2 to 4(WIC Program Data)In 2020,14.6 percent of children ages 2 to 4 in the WIC program had obesity,and 15.3 percent were overweight.The percentage of children who were overweight or had obesity increased between 1992 and 2008,then decreased between 2010 and 2020 after a 2009 change in the WIC benefits to allow for healthier food options,including fruits,vegetables,seafood,and whole grains(see page 36 for more on WIC).American Indian and Latino/a children were the most likely to be overweight or have obesity compared with other races/ethnicities.209,210(See Figure 7 for current data by race/ethnicity and chart on page 32 for state-level data.)051015202530354015.3.6%Overall16.3%American Indian11.7.4%Asian13.7.1%Black16.3.5%Latino17.3.8%Pacific Islander15.9.3%WhiteOverweightObesityFIGURE 7:Percent of Children Ages 24 in WIC Program Who Are Overweight or Have Obesity,by Race/Ethnicity,2020Source:USDANote:For children,overweight is defined as BMI Percentiles 85 to 95 and obesity is 95.See page 9 for more on BMI calculations.31 TFAH tfah.orgSource:National Survey of Childrens Health10 % CAWAORMTIDNVWYUTAZCONMNDSDNEKSOKTXMNIAMOARLAWIILINMIOHKYTNMSALMENYPAVANCSCGAWVFLVTNHMARICTNJDEMDAKHIDCPercent of Children Ages 1017 with Obesity by State,20202021 III.Obesity Rates in Children and Teenagers,Ages 10 to 17(National Survey of Childrens Health)The National Survey of Childrens Health 20202021 survey reported that,nationwide,17.0 percent of children ages 10 to 17 had obesity and another 16.4 percent were overweight.The states with the highest rates of obesity for children ages 10 to 17 were West Virginia(26.0 percent),Kentucky(25.5 percent),and Louisiana(24.0 percent);the states with the lowest rates of obesity were Montana(10.2 percent),Colorado(10.8 percent),and Wyoming(11.5 percent).211 See chart on page 32 for more state data.IV.High School Obesity Rates(YRBS)According to 2021 YRBS data,16.3 percent of high school students(grades 9 to 12)nationwide had obesity and 16.0 percent were overweight.Obesity levels in 2021 were slightly higher than 2019(15.5 percent with obesity)and show an increase in the long-term;in 1999,obesity rates among high schoolers participating in the survey were at 10.6 percent.212,213Other takeaways:l The prevalence of obesity among high school students in different states varied considerably,from 10.2 percent in Utah to 26.9 percent in West Virginia.l There were also stark differences in obesity rates across demographic groups.Male students(18.7 percent)had higher obesity rates than female students(13.7 percent);bisexual(20.3)and questioning students(20.3 percent)had higher obesity rates than gay or lesbian(13.7)and heterosexual(15.0 percent)students;and AI/AN,Black,Latino,and Native Hawaiian/Pacific Islander students(all above 20 percent)had higher obesity rates than white(13.7 percent)and Asian(7.7 percent)students(see Figure 8).See page 32 for state-by-state data on obesity,overweight,and physical activity levels among high school students.0 0%Other Sexual Identity/QuestioningBisexualGay or lesbianHetero-sexualMulitple raceWhiteNative Hawaiian or Other Pacific IslanderLatinoBlackAsianAmerican Indian/Alaska NativeMaleFemaleOverall16.3.7.7).4%7.7!.2 .2.7(.5.5 .3 .3.7%FIGURE 8:Percent of High School Students with Obesity by Select Demographics,2021 Source:Youth Risk Behavior Survey32TFAH tfah.orgYouth Obesity Rates and Related Health IndicatorsYoung Children:Obesity,2020Children and Teenagers:Obesity and Physical Activity,20202021High School(HS)Students:Obesity,Overweight,Physical Activity,2021StatesPercent of Low-Income Children Ages 2-4 With ObesityPercent of Children Ages 10-17 With ObesityRankingPercent of Children Ages 617 Who Participated in 60 Minutes of Physical Activity Every Day Percent of HS Students With ObesityPercent of HS Students Who Were Overweight Percent of HS Students Who Were Physically Active 60 Minutes Every Day of the WeekAlabama15.622.14623.813.918.725.3Alaska20.114.21326.9n/an/an/aArizona13.314.414-T16.814.916.622.0Arkansas13.919.14024.119.416.325.6California17.014.414-T17.3n/an/an/aColorado8.810.8222.510.612.822.1Connecticut14.617.03021.915.116.621.7Delaware18.516.828-T22.717.015.421.6D.C.12.917.33316.320.416.916.9Florida13.516.22717.916.416.522.5Georgia13.116.828-T21.817.018.823.2Hawaii11.017.131-T17.414.914.023.1Idaho11.813.48-T22.911.912.218.4Illinois16.416.125-T23.115.614.824.1Indiana13.915.52025.017.614.819.2Iowa16.017.635-T24.815.816.029.2Kansas12.813.610-T24.417.018.427.1Kentucky15.425.55023.619.616.225.3Louisiana13.724.04917.518.717.824.0Maine14.314.61725.015.014.422.5Maryland16.920.34120.016.015.319.6Massachusetts16.813.81219.413.615.223.5Michigan13.817.131-T22.315.614.322.3Minnesota11.813.48-T24.8n/an/an/aMississippi14.423.14825.223.218.525.5Missouri12.718.938-T26.216.916.228.0Montana10.910.2127.811.814.025.9Nebraska16.013.610-T26.419.215.430.6Nevada11.918.23713.915.918.019.4New Hampshire16.015.21924.013.313.722.9New Jersey15.416.125-T17.313.815.722.1New Mexico12.720.94320.720.017.926.4New York13.815.62119.716.115.419.4North Carolina14.821.04419.119.013.719.1North Dakota15.612.6529.816.315.630.3Ohio13.015.82325.518.813.425.8Oklahoma13.217.53421.617.616.832.4Oregon14.714.51621.0n/an/an/aPennsylvania13.816.02425.017.314.521.1Rhode Island16.513.2618.515.517.221.2South Carolina13.121.64520.417.916.924.0South Dakota15.618.938-T24.316.615.328.2Tennessee14.922.54720.718.315.323.0Texas15.820.74215.622.117.225.7Utah8.812.0417.810.212.121.7Vermont14.515.72225.213.614.028.0Virginia15.617.635-T20.016.415.321.9Washington14.813.3722.6n/an/an/aWest Virginia16.426.05127.527.017.422.7Wisconsin15.214.91823.413.516.128.0Wyoming11.811.5329.7n/an/an/aSOURCE:WIC Participants and Program Characteristics Survey,USDASOURCE:National Survey of Childrens Health,HRSANOTE:For rankings,1=Highest Rate,and 51=Lowest Rate.T=Tie.NOTE:For rankings,1=Highest Rate,and 51=Lowest Rate,T=Tie.SOURCE:Youth Risk Behavior Survey,CDCThe State of ObesitySECTION 3:OBESITY-RELATED POLICIES AND PROGRAMSSEPTEMBER 2023SECTION 3Obesity-Related Policies and ProgramsA.ECONOMICS OF WHAT WE EAT AND DRINKFinancial levers can be valuable tools to influence behaviors that affect obesity.These include a range of policies,from financial incentives for investing in food system choice and improvements to taxes to discourage the consumption of unhealthy foods and beverages.I.Fiscal and Tax Policies that Promote Healthy Eating:Beverage Taxes,Healthy Food Financing Initiative,and the New Markets Tax Credit Beverage TaxesIn December 2022,the World Health Organization called on its member countries to tax sugar-sweetened drinks.214 A recent meta-analysis of 62 studies found that such taxes effectively discourage consumption.215 These taxes can also raise funds to support other public health priorities216,217 and to incentivize manufacturers to reduce the sugar content in their products.218,219,220 At least 85 countries currently impose some sort of beverage tax.221 In the United States,sugary beverages are a leading source of added sugar in the American diet,222 and researchers estimate a national tax could prevent half a million cases of childhood obesity over a decade.223 Eight U.S.cities have imposed beverage taxes,224 and multiple peer-reviewed studies have demonstrated these taxes have reduced purchases and consumption of sugary drinks.225,226,227,228,229 Despite their effectiveness,beverage taxes have faced political headwinds in recent years,in part due to lobbying by the beverage industry.230,231,232 In 2022,the West Virginia legislature voted to repeal its 71-year-old soda tax effective July 2024.233 This trend is also happening in other countries:in January 2023,the Israeli finance ministers first public act after taking office was to repeal a beverage tax imposed by the previous government.234Healthy Food Financing InitiativeAn estimated 40 million Americans lack easy access to fresh and nutritious food.235 Created by the 2014 Farm Bill,the Healthy Food Financing Initiative(HFFI)provides grant funding and technical assistance for programs that increase access to healthy food in under-resourced communities,helping to reduce food insecurity,revitalize low-income neighborhoods,and build a more equitable food system.236 The program is a public-private partnership funded by USDA and administered by the Reinvestment Fund,an independent community development financial institution.237 In 2022,the Biden Administration significantly expanded the grant program,boosting funding from$4 million to$22.6 million,as part of a broader effort to transform the U.S.food system.238HFFI funds efforts such as:l Northeast Grocers,a northeast Kansas City,Kansas,neighborhood coalition working to develop a cooperative,community-owned grocery store;239,2403334TFAH tfah.orgl Manuels Food Market,a family-run grocery store in Albuquerque,New Mexico,which used HFFI funding to renovate the store and build a commercial kitchen to prepare food;241,242 andl The Local Farm Cooperative in Selma,Alabama,a worker-owned and worker-operated co-op,which plans to open a mobile unit to sell fresh produce to underserved communities throughout Dallas County.243,244Despite the one-year increase,Congress appropriated just$3 million for HFFI for fiscal year(FY)2023.245 Congressional supporters of the program,meanwhile,have introduced legislation to reauthorize HFFI at$25 million for FY 2024,increasing the amount to$50 million by FY 2028,and hope their proposal will be included in the 2023 Farm Bill.246,247New Markets Tax CreditEstablished as part of the Community Renewal Tax Relief Act of 2000,the New Markets Tax Credit(NMTC)incentivizes taxpayers to invest in low-income communities that lack adequate access to capital.248 The credits are competitively awarded by the U.S.Treasurys Community Development Financial Institutions Fund(the CDFI Fund).NMTC-funded projects are expected to create jobs or otherwise improve the lives of residents by,for example,improving access to healthcare services,places to exercise,healthy food,and economic opportunity.Recent NMTC-funded projects include:l The recently completed construction of a new 50,000-square-foot warehouse and food distribution center in Grand Junction,Colorado,for the Food Bank of the Rockies,which will allow it to deliver 62 percent more meals annually;249l The renovation of Baltimores Lexington Market,the countrys longest continuously operating public market;250 andl A new 63,000-square-foot facility for the Food Bank of Western Massachusetts,which will allow the organization to extend its mission of combating food insecurity and is scheduled to open in Chicopee,Massachusetts,in September 2023.251In its most recent funding round,the CDFI Fund awarded$5
2024-07-23
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FORREST W.CRAWFORD,KYLE WEBSTER,GERALD LEWIS EPSTEIN,DEREK ROBERTS,JOSEPH FAIR,SELLA NEVOSecuring Co.
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SPECIAL REPORTCollaborating for a Robust Medical Device Reimbursement Pathway in IndiaSPECIAL REPORT.
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Healthcare 2024 The annual report on the most valuable and strongest Pharma,Medical Devices and Healthcare Services brands June 2024Brand Finance Healthcare 2 2024 All rights reserved.Brand Finance Plc.ContentsAbout Brand Finance 3Foreword 4David Haigh,Chairman&CEO,Brand FinanceRanking Analysis 7Pharma 25 9Medical Devices 25 15Healthcare Services 10 21Brand Guardianship Index 27Global Top Hospitals 31Methodology 40Our Services 46Our teams have experience across a wide range of disciplines from marketing and market research,to brand strategy and visual identity,to tax and accounting.Unique combination of expertiseBrand Finance,a chartered accountancy firm regulated by the Institute of Chartered Accountants in England and Wales,is the first brand valuation consultancy to join the International Valuation Standards Council.Our experts crafted standards(ISO 10668 and ISO 20671)and our methodology,certified by Austrian Standards,is officially approved by the Marketing Accountability Standards Board.Priding ourselves on technical credibilityWe put thousands of the worlds biggest brands to the test every year.Ranking brands across all sectors and countries,we publish over 100 reports annually.Quantifying the financial value of brandsBrand Finance was set up in 1996 with the aim of bridging the gap between marketing and finance.For more than 25 years,we have helped companies and organisations of all types to connect their brands to the bottom line.Bridging the gap between Marketing and FinanceAbout Brand FinanceThe worlds leading brand valuation consultancy.For business enquiries,please contact:Hugo HensleyValuation DFor media enquiries,please contact:Florina Cormack-LoydCommunications DFor all other enquiries: 44 207 389 ForewordBrand Finance Healthcare 4David Haigh Chairman&CEO,Brand FinanceBrand valuation helps companies understand the value of their brand and how it contributes to the overall value of the company.This important understanding can inform decision-making related to marketing and branding efforts,as well as provide a benchmark for future performance.It can also be used to help attract investors and secure financing,as a strong brand can be a valuable asset.Additionally,brand valuation can be useful in the event of a merger or acquisition,as it can help determine the value of the brand being acquired.Overall,brand valuation helps organisations understand the worth of their brand and how it fits into their overall business strategy.A strong brand can lead to improved business returns in several ways.First,a strong brand can help a company differentiate itself from its competitors and establish a unique identity in the market,which can lead to increased customer loyalty and retention.This,in turn,can lead to higher sales and revenue.A strong brand can also help a company command a higher price for its products or services,as consumers are willing to pay more for a brand they perceive as high-quality and trustworthy.In addition,a strong brand can help a company attract top talent,as employees may be more attracted to work for a well-known and reputable brand.Finally,a strong brand can provide a company with a competitive advantage and help it weather economic downturns or industry disruptions.This year,Brand Finance has invested more in researching and understanding customer perception of brands across the world than ever before,with original research taking place in dozens of jurisdictions globally.The report you are reading is based on this extensive original research,with the findings representing a catalyst for further conversations.If you want to help build a stronger brand,or if you want to better understand the value of your brand,please contact the Brand Finance team and I anytime.I look forward to the conversation and helping to build a more profitable future for your Gain InsightLeverage strategic insights to enhance your brands financial standing.Strategise effectively to position your brand as a market leader.Strategic GuidanceBenchmark your brand against industry standards for a competitive edge in the corporate landscape.Benchmark Your PerformanceEmpower your marketing team with comprehensive knowledge about your brands financial value.Empower Your Marketing TeamOptimise communication channels by understanding and articulating your brands financial significance.Enhance CommunicationDeepen your financial acumen and make well-informed decisions for corporate success.Deepen UnderstandingRequest your own Brand Value ReportBrand Finances Brand Value Report provides a complete breakdown of the assumptions,data sources,and calculations used to determine your brands value,as well as brand equity research.Each report includes expert recommendations for growing brand value,driving performance,and gaining insights into your position against 6,000 brandsOriginal market research on global,market and sector leading brands.Comprehensive coverage for market specific learnings that inform decision making.41 countriesBenchmark your brand against competitors and leverage industry level insights to empower your strategy.31 sectorsRobust market representation for a global perspective. 150,000 respondentsTake a longer view to track and learn from fast growing brands,market disrupters,and market leaders.Understand your brands standing in the market,what its known for relative to the competition,and what drives customer decision making so you can create a roadmap for success.8th consecutive yearStrategic InsightBrand Finances Global Brand Equity Monitor Research utilises a comprehensive framework to track and measure the core building blocks that underpin strong brands,while delivering nuanced insights that direct strategy for understanding,maintaining and building brand strength.Brands,and customer relationship with brands,are complex.As such they require attention,direction and measured support if theyre to fulfil their potential.Our brand equity reports deliver expert insight and recommendations to power your brand strategies and valuation.Get Full Access to our Global DataRanking AnalysisPharmaceutical Powerhouse:Johnson&Johnson is once again the worlds most valuable and strongest pharma brand Johnson&Johnson is the worlds most valuable pharma brand for the 6th consecutive year Pioneering innovation for Novo Nordisk and Lilly leads to impressive brand value growth,brand values up 64%and 53%,respectively The total brand value of the worlds top 25 most valuable pharma brands is up 6%to$97.5 billionBrand Finance Healthcare 9Pharma 25Once again,Johnson&Johnson has claimed the title of the worlds most valuable and strongest pharmaceutical brand.Johnson&Johnson has maintained its top-ranking position for brand value for the sixth consecutive year and this year has recorded a 5%increase in brand value to USD 13.4 billion.In addition to calculating brand value,Brand Finance also determines the relative strength of brands through a balanced scorecard of metrics evaluating marketing investment,stakeholder equity,and business performance.Compliant with ISO 20671,Brand Finances assessment of stakeholder equity incorporates original market research data from over 150,000 respondents in 41 countries and across 31 sectors.This year,Johnson&Johnson has also claimed the title of the worlds strongest pharmaceutical brand with a Brand Strength Index(BSI)score of 83.3 out of 100.In a strategic move that marked the largest restructuring in its nearly 140-year history,Johnson&Johnson completed the spinoff of its consumer business,under the new parent company Kenvue,which includes brands like Band-Aid,Tylenol,Neutrogena,and Clean&Clear.In the wake of COVID-19,weve witnessed a significant surge in the pharmaceutical industry,driven by the introduction of new pharmaceuticals such as vaccines to combat the global pandemic,and drugs addressing prevalent health concerns like the obesity epidemic.In this dynamic landscape,a pharmaceutical brands ability to build trust among the public,regulators,and investors has become a crucial determinant of success in the current financial climate.Hugo Hensley Valuation Director,Brand FinanceBrand Finance Healthcare 10Top 10 Most Valuable Pharma Brands 2024 Brand Finance Plc.2024Pharma 2541531098726 5% 4%-1% 6% 53% 64% 7%-60021121$13.4 bn$8.8 bn$6.1 bn$6.1 bn$5.9 bn$5.1 bn$4.4 bn$4.2 bn1 2%$5.7 bn 0%$5.5 bn Brand Finance Healthcare 11Top 10 Strongest Pharma Brands 2024 Brand Finance Plc.202441531098726 1.0 6.4-2.1-1.6-1.6-1.0-2.8 0.202111121183.379.877.277.075.174.172.572.22 -0.574.9 1.274.9 Pharma 25This signifies a deliberate shift in focus of the brand towards the pharmaceutical and MedTech sectors,enhancing operational efficiency and focusing on core expertise.Johnson&Johnsons restructuring mirrors a broader trend among industry leaders.Pfizer(brand value down 1%to USD 6.1 billion)and GSK(brand value up 6%to USD 3.8 billion)demerged its consumer health joint venture to create Haleon,known for products like Sensodyne toothpaste,while Novartis(brand value 10%to USD 3.3 billion)spun off its Generics and Biosimilars business,Sandoz.Sanofi(brand value up 7%to USD 4.4 billion)is also in the process of separating its consumer healthcare division.This movement underscores a shift towards streamlining operations and sharpening strategic focus to enhance competitiveness and drive sustainable growth within the pharmaceutical sector.Moreover,its worth noting that consumer health divisions often contribute significantly to a corporate brands public exposure and positive sentiment.This trend is exemplified by leaders such as Johnson&Johnson,Yunnan Baiyao,and Bayer,which currently hold the top three positions for BSI.Brand Finance Healthcare 12Brand Value Change 2023-2024(%)Brand Finance Plc.202464S%9%7%6%6%6%5%4%Pharma 25Pioneering innovation for Novo Nordisk and Lilly leads to impressive brand value growthNovo Nordisk(brand value USD 5.1 billion)and Lilly(brand value USD 5.9 billion)are the two fastest-growing pharma brands this year,up 64%and 53%,respectively.Novo Nordisk and Lilly exemplify success through adaptation.Their proactive strategies,particularly in the successful introduction of weight-loss drugs,have propelled them up the Brand Finance Pharma 25 ranking.Following skyrocketing demand,Novo Nordisks has become Europes most valuable company by market cap,overtaking LVMH.These brands have not only experienced substantial growth in their financial forecasts but also garnered significant public exposure.The success of Novo Nordisk and Lilly underscores a trend in the industry:brands that embrace innovation thrive.This is evident as Pfizer and AstraZeneca(brand value up 2%to USD 5.7 billion),despite their pivotal roles in developing COVID-19 vaccinations,showcase muted performances compared to their peak performances in 2022.Mixed performance among Chinese pharma brands Four Chinese brands feature in the ranking,recording mixed performances.Guangzhou Pharmaceutical has shown the strongest performance among Chinese brands,recording an 11%increase in brand value to USD 2.5 billion.This growth is attributed to rising demand for popular brands within its portfolio,alongside expanded sales channels.Sinopharm,the highest-ranked Chinese brand in 13th position,saw a 6cline in brand value to USD 3.6 billion.This decline was driven by weaker brand strength and long-term growth rates,despite strong revenue growth.Shanghai Pharmaceuticals Holding experienced a slight decline in brand value,down 1%,but has seen high demand for its Chinese medicine products.Yunnan Baiyao secures 25th spot in the ranking with a brand value of USD 822 million.2024 Rank2023 RankBrandCountry2024 Brand ValueBrand Value Change2023 Brand Value2024 Brand Rating2023 Brand Rating110Johnson&JohnsonUnited States$13,361 4.7%$12,759AAA-AAA-220RocheSwitzerland$8,783 3.7%$8,466AA AA 330PfizerUnited States$6,123-1.3%$6,201AA AA 440Merck&CoUnited States$6,107 5.9%$5,769AAAA 592LillyUnited States$5,916 53.1%$3,865AA AA651AstraZenecaUnited Kingdom$5,731 2.4%$5,595AA AA 761BayerGermany$5,485 0.3%$5,471AA AA 8142Novo NordiskDenmark$5,088 64.1%$3,101AAAA 981SanofiFrance$4,408 6.5%$4,139AA-AA1071Bristol Myers SquibbUnited States$4,158-5.6%$4,403AAAA11101AbbVieUnited States12132GSKUnited Kingdom13111SinopharmChina14121NovartisSwitzerland15150AmgenUnited States16160Guangzhou PharmaceuticalChina17170Gilead SciencesUnited States18180TakedaJapan19190Merck KGaAGermany20200SPHChina21210CSLAustralia22-3RegeneronUnited States23230TevaIsrael24221BiogenUnited States25250Yunnan BaiyaoChinaBrand Finance Healthcare 13Pharma-Brand Value Ranking(USDm)Top 25 most valuable Pharma brands 1-25Fresenius overtakes Medtronic as the most valuable medical devices brand Fresenius ends Medtronics 3-year reign as the most valuable medical devices brand,claiming the top spot following a 6%increase in brand value to$7.7 billion Unity Lab Services is the fastest growing medical devices brand,its brand value up 33% Philips is the strongest medical devices brand with a Brand Strength Index score of 78.3 out of 100Brand Finance Healthcare 15Medical Devices 25The medical devices sector experienced significant growth from 2020 to 2021 amid the pandemic,mirroring trends seen across other healthcare segments.However,with the world transitioning into a post-pandemic phase,the sector is gradually normalising.Post-COVID-19,there has been a surge in demand for wearable medical devices and remote patient monitoring systems.Additionally,the adoption of advanced technologies such as robotic surgery,AI,and machine learning has become commonplace.Fresenius overtakes Medtronic as the most valuable medical devices brandFresenius has overtaken Medtronic to secure the position as the worlds most valuable medical devices brand,following a 6%increase in brand value to USD 7.7 billion.Increased demand for plasma-derived therapies and autotransfusion treatments has contributed to Freseniuss expanding market presence.Additionally,Fresenius highlights that its surge in revenue is driven by rising admissions as individuals resume pre-COVID healthcare patterns.Conversely,Medtronic has experienced an 11crease in brand value to USD 7.2 billion,ending its three-year reign at the top of the ranking.This decline is attributed to unfavourable exchange rates and inflation,impacting the companys medical surgical portfolio.Ventilator sales saw a notable decline due to reduced COVID-19 rates compared to the previous year.However,modest growth in the cardiovascular and neuroscience portfolios partially offset these losses.Medtronic is also undergoing strategic changes,including mergers and acquisitions.The company aims to divest its patient monitoring and respiratory interventions businesses in the first half of fiscal year 2025,following the successful divestment of its renal care solutions business to Mozarc Medical.Brand Finance Healthcare 16Top 10 Most Valuable Medical Devices Brands 2024 Brand Finance Plc.2024Medical Devices 2541531098726 6%-11% 9% 5% 13%-2%- 14!0000313$7.7 bn$7.2 bn$5.5 bn$4.4 bn$4.4 bn$3.5 bn$2.9 bn$2.9 bn1 17%$4.3 bn -$4.0 bn Brand Finance Healthcare 17Brand Value Change 2023-2024(%)Brand Finance Plc.202433(%9%6%6%Medical Devices 25Unity Lab Services up 33%Unity Lab Services,a subsidiary of Thermo Fisher Scientific,emerges as the fastest-growing medical devices brand this year,experiencing a 33%surge in brand value to USD 2.0 billion.Despite a decline in COVID test sales,Thermo Fisher Scientific has demonstrated robust revenue growth.This achievement is attributed to the companys steadfast M&A strategy,which has been instrumental in driving its financial success.Thermo Fisher Scientific makes its debut in the ranking this year,claiming 7th position with a brand value of USD 4.0 billion,following sector reclassification.Philips is the strongest medical devices brandPhilips(brand value up 13%to USD4.4 billion)is the strongest medical devices brand with a Brand Strength Index score of 78.3 out of 100.In Brand Finances original market research,Philips has showcased notable growth across the Familiarity and Reputation metrics.Positive perceptions stemming from Philips licensing agreements for consumer electronics greatly contribute to its brand strength,complementing its medical devices division and enhancing its overall brand image.Philips licenses its brand for a range of consumer electronics products such as televisions,audio equipment,and smart home devices.Additionally,recent research scores highlight enhanced performance in the Environmental,Social&Governance metrics.Philips is actively involved in several initiatives to advance its ESG goals.These include commitments like sourcing over 75%of its total energy consumption from renewable sources by 2025.Additionally,Philips aims to impact 2 billion lives annually by 2025,aligning with its mission to enhance peoples health and well-being through meaningful innovation.Brand Finance Healthcare 18 5.0Top 10 Strongest Medical Devices Brands 2024 Brand Finance Plc.202441531098726 9.9 8.4 0.5 2.4-0.8-2.6-1.502212101178.372.470.668.267.966.865.664.01 -0.467.2 1.567.0 Medical Devices 252024 Rank2023 RankBrandCountry2024 Brand ValueBrand Value Change2023 Brand Value2024 Brand Rating2023 Brand Rating122FreseniusGermany$7,684 5.6%$7,277AA-211MedtronicUnited States$7,239-10.7%$8,103AA-AA-330AbbottUnited States$5,532 9.2%$5,068AA-AA-440Siemens HealthineersGermany$4,430 5.4%$4,202AA-AA-550PhilipsNetherlands$4,413 12.7%$3,915AA AA660StrykerUnited States$4,269 17.0%$3,650AA-AA-7-3Thermo Fisher ScientificUnited States$4,029-A -871BDUnited States$3,459-1.5%$3,512A AA-9-3DanaherUnited States$2,926-A1081Boston ScientificUnited States$2,880 13.9%$2,529AA-AA-11162Unity Lab ServiceUnited States12120Quest DiagnosticsUnited States13172AlconUnited States14101BaxterUnited States1591IlluminaUnited States16-3Intuitive SurgicalUnited States17141Smith&NephewUnited Kingdom18131TerumoJapan19151Zimmer BiometUnited States20181ResMedUnited States21111alignUnited States22201HologicUnited States23230EDWARDS LIFEUnited States24240CoopersUnited States25221ColoplastDenmarkBrand Finance Healthcare 19Medical Devices-Brand Value Ranking(USDm)Top 25 most valuable Medical Devices brands 1-25UnitedHealthcare tops the healthcare services sector for brand value and brand strength The collective value of the top 10 most valuable healthcare services brands has increased by 16%year-on-year,reaching$165.8 billion UnitedHealthcare tops the sector for both brand value and brand strength Cignas innovation leads to rapid brand value growth,up 33%Brand Finance Healthcare 21Healthcare Services 10The collective value of the top 10 most valuable healthcare services brands has increased by 23%year-on-year,reaching USD 165.8 billion.This growth is underpinned by several significant drivers.In the wake of the pandemic,there has been a notable societal shift towards prioritising healthcare-related issues.This heightened awareness has translated into increased healthcare spending,as individuals are now more willing to invest in their well-being.Additionally,advancements in technology have played a pivotal role in reshaping the healthcare landscape.These technological innovations have not only bolstered the efficiency of healthcare services but have also facilitated faster production processes while simultaneously driving down costs.Furthermore,demographic changes,such as the aging population,have led to a surge in demand for healthcare services.This demographic shift,combined with inflation-driven premium rate increases and the rising popularity of Medicare Advantage plans,underscores the sustained growth trajectory of the healthcare services sector.The most valuable healthcare services brands have experienced a 16%year-on-year increase in total value.This growth is indicative of a thriving sector,driven by several factors.The heightened significance of healthcare-related issues post-pandemic,coupled with continuous technological advancements,has bolstered sector efficiency and reduced production costs.Additionally,the ageing population has contributed to a surge in demand for healthcare services,further fuelling market expansion.Hugo Hensley Valuation Director,Brand FinanceBrand Finance Healthcare 22UnitedHealthcare tops sector for brand value and brand strengthUnitedHealthcare retains its position as the worlds most valuable healthcare services brand,boasting a 28%increase in brand value,now standing at USD 47.6 billion.For the first time in Medicares history,more than half of eligible people with Medicare are now enrolled in private Medicare Advantage plans and UnitedHealthcare is the largest provider of these.This expansion of the government segment has bolstered revenue streams for healthcare enterprises.Elevance Health(brand value up 28%to USD 25.5 billion)and Humana(brand value up 27%to USD 30.0 billion)are also both poised for a bigger resurgence as they also capitalise on the expansion through Medicare Advantage offerings.UnitedHealthcare also stands as the strongest healthcare services brand,with a BSI score of 79.0 out of 100.Notably,metrics including Familiarity,Consideration,and Recommendation have scored well,contributing to its robust BSI score.Top 10 Most Valuable Healthcare Services Brands 2024 Brand Finance Plc.2024Healthcare Services 1041531098726 28% 28% 27% 1% 21% 15% 30% 202100210$47.6 bn$25.5 bn$21.0 bn$20.4 bn$10.6 bn$8.1 bn$7.5 bn$6.0 bn2 33%$10.3 bn 29%$8.8 bn Brand Finance Healthcare 23Top 10 Strongest Healthcare Services Brands 2024 Brand Finance Plc.202441531098726 2.3 4.0 8.3 3.4 6.1 1.7 3.5 2.500212010279.074.974.474.267.762.460.758.53 1.566.9 -1.265.0 Healthcare Services 10Brand Finance Healthcare 24Brand Value Change 2023-2024(%)Brand Finance Plc.2024330)(! %1%Healthcare Services 10Cignas innovation leads to rapid brand value growthCigna emerges as the fastest-growing brand in the ranking,with its brand value soaring by 33%to USD 10.3 billion.The healthcare services industrys long-term growth trajectory is underpinned by the integration of software and platforms,a trend Cigna has adeptly embraced.Cignas innovative approach is exemplified by the establishment of MDLIVE,serving as a cornerstone for virtual care.MDLIVE offers a comprehensive range of virtual services,including primary,urgent,behavioural,and dermatological care.Total patient visits through MDLIVE experienced a substantial increase of approximately 20%,demonstrating the effectiveness of Cignas strategic initiatives in the digital healthcare space.2024 Rank2023 RankBrandCountry2024 Brand ValueBrand Value Change2023 Brand Value2024 Brand Rating2023 Brand Rating110UnitedHealthcareUnited States$47,632 28.4%$37,094AA AA 232AnthemUnited States$25,529 28.4%$19,883AA-AA-342HumanaUnited States$20,963 27.1%$16,497AA AA421OptumUnited States$20,376 1.2%$20,127AA-AA-550AetnaUnited States$10,574 21.4%$8,707AAAA660CignaUnited States$10,306 33.3%$7,731AAAA-782McKessonUnited States$8,822 28.7%$6,853A A871EvernorthUnited States$8,090 15.1%$7,029AA-A 990Cardinal HealthUnited States$7,523 30.5%$5,767A A 10122CencoraUnited States$5,991 19.9%$4,997AABrand Finance Healthcare 25Healthcare Services-Brand Value Ranking(USDm)Top 10 most valuable Healthcare Services brands 1-10Brand Finance Healthcare 26Ranking AnalysisAs part of its analysis,Brand Finance assesses specific brand attributes role in driving overall brand value.One such attribute growing rapidly in significance is sustainability.The Brand Finance Sustainability Perceptions Index determines the role of sustainability in driving consumer choice and which brands consumers believe to be most committed to sustainability,represented by Sustainability Perceptions Scores.The proportion of brand value attributable to sustainability perceptions,or Sustainability Perceptions Value,is then calculated for each brand.In addition to being the most valuable and strongest Healthcare Services brand,UnitedHealthcare has the highest Sustainability Perceptions Value,at USD 2.3 billion,in the whole healthcare sector.UnitedHealthcares position at the top of the Sustainability Perception Value table is not an assessment of its overall sustainability performance,Top 10 Pharma,Medical Devices and Healthcare Services Brands by Sustainability Perceptions Value Brand Finance Plc.202441531098726E:0.93 S:1.00 G:0.98E:0.94 S:0.96 G:0.97E:0.98 S:0.96 G:0.99E:0.92 S:0.96 G:0.95E:1.06 S:1.04 G:1.04E:0.98 S:1.00 G:1.00E:0.95 S:0.98 G:0.98E:0.90 S:0.95 G:0.94E:0.99 S:0.98 G:0.99E:0.99 S:0.98 G:0.95$2,293 m$1,213 m$985 m$981 m$951 m$486 m$431 m$425 m$658 m$495 m USDxx=Sustainability Perceptions Value x.x=Sustainability Perceptions Score/Sector Medianbut rather indicates how much brand value is tied to its sustainability perceptions.UnitedHealthcare also has the highest Gap Value of any brand across the overall healthcare sector.The Gap Value represents the difference between perceived sustainability and actual sustainability performance.A positive Gap Value indicates that a brands sustainability performance is better than its perceptions suggest.This implies that businesses could add significant value by making a concerted effort to communicate its sustainability achievements more effectively.In UnitedHealthcares case,this value exceeds USD 144 million.This suggests UnitedHealthcare could generate an additional USD 144 million in potential value for shareholders through enhanced communication of its impact and accomplishments in sustainability.Brand Guardianship IndexBrand Finance Healthcare 28Brand Guardianship IndexThe Brand Guardianship Index evaluates chief executives performance according to how well they manage and grow their companies brands.The results inform the ranking of an original survey of 500 equity analysts and journalists and 3,500 informed general public.Good CEOs enhance the reputation of their brands by nurturing relations with all stakeholders.This can be a tricky balance as the role of CEO is increasingly personality-focused,with some leaders scrutinised like celebrities.Having a vision for the businesss future is no longer enough.It is about forging an authentic public profile and reacting earnestly to reputational challenges and opportunities.The Brand Guardianship Index celebrates CEOs who balance the needs of UK brands,long-term brand building and personal reputation management.Annie Brown General Manager of UK Consulting,Brand FinanceBrand Finance Healthcare 29No1.Bruce Broussard,Humana,United StatesAs CEO since 2013,Broussard has led Humanas strategic shift towards an integrated healthcare model,expanding beyond health insurance into healthcare services.His tenure has seen Humana become one of the largest providers of privatised Medicare benefits,offering Medicare Advantage plans to millions of seniors.During his time at the company,which began in 2011,Broussard orchestrated several acquisitions to bolster Humanas presence in the healthcare sector.Now,after announcing his departure,Broussard will hand over the reins to Envision Healthcare CEO,Jim Rechtin,who will assume the role of CEO in the second half of 2024.No2.David Cordani,Cigna,United StatesDavid Cordani has led The Cigna Group as its Chief Executive Officer since 2009,assuming the role of President a year earlier in 2008.Over the years,under his stewardship,The Cigna Group has transformed into a Fortune 15 global health entity,nurturing over 180 million customer relationships,and employing a workforce of more than 70,000 worldwide.Brand Guardian IndexTop 10 Pharma,Medical Devices&Healthcare Services CEOs 2024 Brand Finance Plc.20244153109872668.667.067.066.764.760.759.859.4 61.3 60.8 Bruce BroussardBrian TylerDavid CordaniRob DavisAndrew WittyBelen GarijoPascal SoriotBernd MontagGail BoudreauxRobert FordBrand Finance Healthcare 30Brand Guardian Index His tenure reflects an understanding of customer engagement,brand cultivation,and the indispensable significance of data analytics and digital capabilities in fostering enterprise expansion.Under Cordanis leadership,Cigna has emerged as the fastest-growing healthcare services brand this year,with its brand value increasing by 33%.It also maintains its position as the 6th most valuable brand in the sector.No3.Andrew Witty,UnitedHealthcare,United StatesSir Andrew Witty assumed the role of CEO of UnitedHealthcare Group in February 2021,bringing with him a wealth of experience including from his role as CEO and director of the prominent pharmaceutical manufacturer GSK.Under his leadership,UnitedHealthcare has flourished into one of the nations largest providers of outpatient care,with nearly 10%of all US physicians either employed or affiliated with the organisation.Notably,during the COVID-19 pandemic,Witty temporarily stepped away from his current positions as president of UnitedHealth Group and CEO of Optum to co-lead the World Health Organization COVID-19 vaccine program.Global Top HospitalsMayo Clinic make it two years at the top as AIIMS and Singapore General Hospital break into top-4 in global hospital reputation study. Mayo Clinic is the worlds most reputable AMC for second year running Indias AIIMS and Singapore General Hospital both enter top 4 globally Mayo Clinic,Dana-Farber Cancer Institute and Groote Schuur Hospital lead three main brand attribute pillars:patient treatment,medical research,and education US-based AMCs continue to dominate the ranking,but regional leaders stand firmBrand Finance Healthcare 33Global Top HospitalsMayo Clinic is the worlds most reputable AMC for second year runningMayo Clinic Health System is the worlds strongest Academic Medical Centre(AMC)brand for the second consecutive year.Mayo Clinics Brand Strength Index(BSI)score has increase 1.2 points year-on-year to 86.9/100,placing it above Massachusetts General Hospital(83.5/100),which also maintains its second place standing for the second consecutive year.Mayo Clinic has continued to perform strongly across brand equity metrics within Brand Finances research,scoring highly for familiarity and awareness locally,regionally,and internationally.Reinforcing its strong reputation,Mayo Clinic also stands out as the AMC most actively embracing new technologies and advancements in Artificial Intelligence(AI),telemedicine,digital imaging,and robotics,when compared to other top regional leaders in the study-All India Institute of Medical Sciences,Singapore General Hospital,Charite,Hospital Italiano de Buenos Aires,King Faisal Specialist Hospital&Research Center,and Groote Schuur Hospital.A substantial 44%of healthcare professionals included in the research acknowledge Mayo Clinics leadership in integrating these cutting-edge elements into its healthcare services.In addition to technological prowess,Environmental,Social,and Governance(ESG)metrics were assessed,and Mayo Clinic emerges as the frontrunner in this domain as well.In the dynamic realm of healthcare,marked by the rising prominence of AI and telemedicine,AMCs are racing to seamlessly integrate these transformative trends.Our research at Brand Finance highlights the importance of staying at the vanguard of technological progress.Innovations in these high-profile categories not only bring global attention to an institution,but now rank among the attributes most important in driving a hospitals overall reputation.Hugo Hensley Valuation Director,Brand financeBrand Finance Healthcare 34Global Top HospitalsTop 10 Strongest AMC Hospitals 2024 Brand Finance Plc.202441531098726 1.7 3.1 0.2 2.0 3.5 0.5 8.0-1.600222122286.983.579.279.178.677.476.876.21 -1.678.2 1.278.0 Brand Finance Healthcare 35Global Top HospitalsIndias AIIMS and Singapore General Hospital both enter top 4 globally The All India Institute of Medical Sciences(AIIMS)has risen two positions in the rankings to claim the third spot(72.9/100),establishing itself as the top non-US based AMC.AIIMS offers comprehensive teaching,research,and patient-care facilities across 25 clinical departments.Particularly noteworthy is AIIMSs performance in metrics such as integration between teaching,research,and patient care,exemplifying its commitment to uniting these three pillars within a single institution.It was also amongst the leaders in attracting top medical research talent and attracting top medical student applications.While enjoying high familiarity and awareness at the local and regional levels,AIIMS international recognition is comparatively lower.Although there has been a yearly increase in these scores,an opportunity still exists for AIIMS to expand its global brand strength beyond its home region.AMCs in the Top 100241US Hospitals stand out in the top 100 Brand Finance Plc.2024Singapore General Hospital(SGH)with a BSI of 79.1/100 has entered the top four and is Asia Pacifics highest-ranked AMC.Serving as Singapores largest acute tertiary hospital,SGH boasts over 50 clinical specialties on its campus and takes pride in its role as an Academic Medical Centre,focusing on training healthcare professionals and conducting cutting-edge research.Year-on-year improvements in metrics such as having Specialist Healthcare Professionals recognized as world leaders in their fields and contributing new research and papers to the medical community,have contributed to enhancing SGHs overall reputation.Notably,collaborations,such as a partnership with Nanyang Technological University,to establish a Joint Research&Development Laboratory in 3D printing,aim to provide patients with customized medical devices and highlight continued investment in further medical innovation.Brand Finance Healthcare 36Mayo Clinic,Dana-Farber Cancer Institute and Groote Schuur Hospital lead three main research pillars:patient treatment,research,and educationThe research conducted by Brand Finance can be categorised into three main pillars:patient treatment,research,and education/training.These pillars represent essential elements within the healthcare ecosystem,each playing a key role in the advancement and success of medical institutions.Specialist hospitals,such as SickKids(74.6/100),continue to demonstrate commendable performance.SickKids secured the second position in patient treatment globally,second only to Mayo Clinic,and scored highly in metrics such as delivers world leading patient experience.The Canadian paediatric teaching hospital has established a strong reputation for patient care by crafting compelling narratives centred around patients Global Top HospitalsTop Hospitals in Three Main Assessment CategoriesResearchPatient TreatmentEducation Brand Finance Plc.2024and their families,primarily through its SickKids VS campaigns.The achievements of its SickKids VS The Unknown:Be A Light campaign were acknowledged with silver awards in two categories(Health&Wellness Education&Advocacy,and Integrated Campaign)at the 2022 Marketing Awards in Canada.In the realm of research,Dana-Farber Cancer Institute(76.2/100),another specialist hospital,takes the lead,earning notable recognition for its accomplishments in offers patients access to the latest clinical trials and attracts the top medical research talent.University Health Network(UHN)(75.4/100),the top-ranked Canadian hospital in the global ranking,also excels in research.Key to UHNs strategy is the regular dissemination of scientific findings and innovations.Being the largest health research organization in Canada and ranking first in the country for total research funding,UHNs affiliation with the University of Toronto is likely to further enhance its perception as a research leader.Brand Finance Healthcare 37Global Top HospitalsThis strong perception for research is translated through a high score in the contributes new research and papers to the medical community metric.In terms of attracting top medical research talent,Harvard Universitys brand appears to boost a brands reputation as the place to be for excellence in research.Three out of the top six brands recognized for attracting the top medical research talent are affiliated with Harvardnamely,Brigham&Womens,Mass General,and Dana-Farber Cancer Institute.Groote Schuur Hospital(67.9/100)emerges as the leader for education,while Monash Partners Academic Health Science Centre(Melbourne)(70.9/100)and the National University Health System(76.8/100)in Singapore also receive high accolades in this critical pillar.Groote Schuur Hospital,which is also Africas top-ranked AMC,scored 5th globally as known for scientific breakthroughs.Nearly 60 years after performing the first heart transplant,this highlights just how powerful positive headlines can be for building brand strength and the legacy that a scientific breakthrough can have.The hospitals reputation is further underscored by its close ties with the University of Cape Towns medical school and its ongoing commitment to innovation in the medical field.Brand Finance Healthcare 38Global Top HospitalsTop AMC Hospitals per Region Brand Finance Plc.2024US-based AMCs continue to dominate the ranking,but regional leaders stand firmThe US boasts 7 out of the top 10 AMCs,largely attributed to its more advanced healthcare market and the global awareness and familiarity of many of its leading hospitals.However,leaders within the six key regions researched outside North America continue to demonstrate robust performance,with five out of six of these regional leaders seeing their Brand Strength Index scores increase in 2024.Germanys Charite(75.2/100)was the only regional leader to see a year-on-year BSI drop,however,it still maintains its title as the highest ranked European AMC in the ranking.Global RankGlobal Rank#1Global Rank#14Global Rank#47Global Rank#4South AmericaAsia PacificMENAEuropeAfricaGlobal Rank#19Global Rank#20Global Rank#3South AsiaNorth AmericaKing Faisal Specialist Hospital&Research Center(KFSH&RC)has increased its BSI by 1.2 points for 2024,achieving a score of 73.9/100.This means it stays at 20th place in the global ranking for the second year and remains as the highest-ranked AMC in the Middle East.The hospital scored highly in local and regional awareness and familiarity,while also having a strong research reputation and reputation for adopting latest medical treatment or technology.This reflects KFSH&RCs continued efforts to advance medical technology,highlighted by its successful performance of the worlds first fully robotic liver transplant in 2023,helping position it as a global leader in minimally invasive transplant surgery.Brand Finance Healthcare 39Global Top HospitalsAMCs in Top 100 by Country Brand Finance Plc.2024In 2023,Saudi female astronaut Rayyanah Barnawi conducted a series of experiments aboard the International Space Station(ISS)on behalf of KFSH&RC.These experiments focused on studying immune cell reactions,monitoring responses to inflammation,and offering insights into the effects of the space environment on biology.This further solidified the hospitals reputation for medical innovation.AIIMS celebrates the title of the highest-ranked South Asian AMC,while fellow Indian hospital,Tata Memorial Centre,also saw a strong performance as the highest new entrant for 2024 at 13th position.Stand out metrics for the hospital were local and regional familiarity and awareness and delivering best in class patient outcomes.Across other regions,Argentinas Hospital Italiano de Buenos Aires stands out in Latin America,South Africas Groote Schuur Hospital takes the lead in Africa,and Singapore General Hospital(SGH)claims the top spot in the ranking for AMCs in the Asia Pacific region.North AmericaUSACanadaSpainFranceItalyNetherlandsSwitzerlandDenmarkSwedenEuropeUnited KingdomGermanyJapanAsia PacificSingaporeMENASaudi ArabiaQatarEgyptUAEIIsraelBahrainAfricaSouth AfricaBrazilSouth AmericaAustraliaSouth KoreaChinaArgentinaColombiaIndiaSouth AsiaSri LankaPakistanBangladeshMethodologyDefinitionsEnterprise ValueBranded Business ValueBrand ContributionMetaFacebookFacebookFacebook Enterprise ValueThe value of the entire enterprise,made up of multiple branded businesses.Where a company has a purely mono-branded architecture,the enterprise value is the same as branded business value.Brand Value Branded Business Value The value of a single branded business operating under the subject brand.A brand should be viewed in the context of the business in which it operates.Brand Finance always conducts a branded business valuation as part of any brand valuation.We evaluate the full brand value chain in order to understand the links between marketing investment,brand-tracking data,and stakeholder behaviour. Brand ContributionThe overall uplift in shareholder value that the business derives from owning the brand rather than operating a generic brand.The brand values contained in our league tables are those of the potentially transferable brand assets only,making brand contribution a wider concept.An assessment of overall brand contribution to a business provides additional insights to help optimise performance. Brand ValueThe value of the trade mark and associated marketing IP within the branded business.Brand Finance helped to craft the internationally recognised standard on Brand Valuation ISO 10668.It defines brand as a marketing-related intangible asset including,but not limited to,names,terms,signs,symbols,logos,and designs,intended to identify goods,services or entities,creating distinctive images and associations in the minds of stakeholders,thereby generating economic benefits.Brand ValueBrand Finance Healthcare 41What is Brand Value?Brand value refers to the present value of earnings specifically related to brand reputation.Organisations own and control these earnings by owning trademark rights.All brand valuation methodologies are essentially trying to identify this,although the approach and assumptions differ.As a result published brand values can be different.These differences are similar to the way equity analysts provide business valuations that are different to one another.The only way you find out the“real”value is by looking at what people really pay.As a result,Brand Finance always incorporates a review of what users of brands actually pay for the use of brands in the form of brand royalty agreements,which are found in more or less every sector in the world.This is sometimes known as the“Royalty Relief”methodology and is by far the most widely used approach for brand valuations since it is grounded in reality.It is the basis for a public rankings but we always augment it with a real understanding of peoples perceptions and their effects on demand from our database of market research on over 3000 brands in over 30 markets.Disclaimer Brand Finance has produced this study with an independent and unbiased analysis.The values derived and opinions produced in this study are based only on publicly available information and certain assumptions that Brand Finance used where such data was deficient or unclear.Brand Finance accepts no responsibility and will not be liable in the event that the publicly available information relied upon is subsequently found to be inaccurate.The opinions and financial analysis expressed in the report are not to be construed as providing investment or business advice.Brand Finance does not intend the report to be relied upon for any reason and excludes all liability to any body,government or organisation.Brand is defined as a bundle of trademarks and associated IP which can be used to take advantage of the perceptions of all stakeholders to provide a variety of economic benefits to the entity.Brand Valuation MethodologyBrand Finance Healthcare 421.Brand ImpactWe review what brands already pay in royalty agreements.This is augmented by an analysis of how brands impact profitability in the sector versus generic brands.This results in a range of possible royalties that could be charged in the sector for brands(for example a range of 0%to 2%of revenue).We adjust the rate higher or lower for brands by analysing Brand Strength.We analyse brand strength by looking at three core pillars:“Inputs”which are activities supporting the future strength of the brand;“Equity”which are real current perceptions sourced from our market research and other data partners;“Output”which are brand-related performance measures such as market share.Each brand is assigned a Brand Strength Index(BSI)score out of 100,which feeds into the brand value calculation.Based on the score,each brand is assigned a corresponding Brand Rating up to AAA in a format similar to a credit rating.2.Brand StrengthThe BSI score is applied to the royalty range to arrive at a royalty rate.For example,if the royalty range in a sector is 0-5%and a brand has a BSI score of 80 out of 100,then an appropriate royalty rate for the use of this brand in the given sector will be 4%.3.Brand Impact x Brand StrengthWe determine brand-specific revenues as a proportion of parent company revenues attributable to the brand in question and forecast those revenues by analysing historic revenues,equity analyst forecasts,and economic growth rates.We then apply the royalty rate to the forecast revenues to derive brand revenues and apply the relevant valuation assumptions to arrive at a discounted,post-tax present value which equals the brand value.4.Forecast Brand Value Calculation credibilityBrand Valuation MethodologyBrand Finance Healthcare 43Brand Strength MethodologyBrand Strength IndexMarketing InvestmentBusiness PerformanceStakeholder EquityWidely recognised factors deployed by marketers to create brand loyalty and market share.Perceptions of the brand among different stakeholder groups,with customers being the most important.Quantitative market and financial measures representing the success of the brand in achieving price and volume premium.Analytical rigour and transparency are at the heart of our approach to brand measurement at Brand Finance.Therefore,in order to adequately understand the strength of brands we conduct a structured,quantitative review of data that reflect the Brand Value Chain of brand-building activities,leading to brand awareness,perceptions and onwards to brand-influenced customer behaviour.To manage the Brand Value Chain process effectively we create and use the“Brand Strength Index”(BSI).This index is essentially a modified Balanced Scorecard split between the three core pillars of the Brand Value Chain:Brand Inputs,Brand Equity and Brand Performance.Brand Finance Healthcare 441.Attribute Selection and WeightingAlthough we follow a general structure incorporating the three pillars(Brand Inputs,Brand Equity and Brand Performance),the attributes included are different depending on the sector.A brand strength index for a luxury apparel brand will differ in structure from an index designed for a telecommunications brand.An index for luxury apparel brand may emphasize the exclusiveness,word of mouth recommendation,and price premium,whereas an index for a telecommunications company may emphasis customer service and ARPU as important metrics.These attributes are weighted according to their perceived importance in driving the following pillar:Brand Investment measures in driving Brand Equity;Brand Equity measures for Brand-Related Business Performance measures;and finally the relevance of Brand-Related Business Performance measures for driving business value.In order to convert raw data in to scores out of 10 that are comparable between attributes within the scorecard,we then have to benchmark each attribute.We do this by reviewing the distribution of the underlying data and creating a floor and ceiling based on that distribution.Each brand is assigned a Brand Strength Index(BSI)score out of 100,which feeds into the brand value calculation.Based on the score,each brand is assigned a corresponding rating up to AAA in a format similar to a credit rating.Analysing the three brand strength measures helps inform managers of a brands potential for future success.3.Benchmarking and Final ScoringBrands ability to influence purchase depends primarily on peoples perceptions.Therefore,the majority of the Brand Strength Index is derived from Brand Finances proprietary Global Brand Equity Research Monitor research,a quantitative study of a sample of over 100,000 people from the general public on their perceptions of over 4,000 brands in over 25 sectors and 37 countries.However,at Brand Finance we also believe that there are other measures that can be used to fill gaps that survey research may not capture.These include total investment levels for example in marketing,R&D,innovation expenditure,that can a better guide to future performance than surveys.They also include online measures such as ratings by review sites and social media engagement that can give a more granular understanding of marketing effectiveness.Finally they also include real behaviour for example net additions,customer churn and market share,to overcome the tendency for surveys to incorporate intended behaviour rather than real.Over a period of 3 to 4 months each year,we collect all this data across all the brands in our study in order to accurately measure their comparative strength.2.Data CollectionBrand Strength MethodologyBrand Finance Healthcare 45Our ServicesBrand Research What gets measured. Brand Audits Primary Research Syndicated Studies Brand Scorecards Research Analytics Soft PowerAre we building our brands strength effectively?How do I track and develop my brand equity?How strong are my competitors brands?Are there any holes in my existing brand tracker?What do different stakeholders think of my brand?Brand Evaluations are essential for understanding the strength of your brand against your competitors.Brand Strength is a key indicator of future brand value growth whether identifying the drivers of value or avoiding the areas of weakness,measuring your brand is the only way to manage it effectively.Questions we can help answer:Brand Finance Healthcare 47Consulting ServicesMake branding decisions using hard dataBrand Finance Healthcare 47In-depth external benchmarking comparisons against direct competitors across key KPIs through the Brand Strength Index framework.BenchmarkingDiagnose Brand Strengths&Weaknesses What is my brand known,and not known for?How do I leverage or optimize my brand position to grow brand value?Brand Associations&Market PositioningStatistical correlation analysis to understand what is important in driving Brand Consideration,Reputation,Brand Strength and Value.Drivers AnalysisBrand Insights Make your brands business case.Consulting ServicesBrand Finance Healthcare 48Brand Finance Healthcare 49 Brand Impact Analysis Tax&Transfer Pricing Litigation Support M&A Due Diligence Fair Value Exercises Investor ReportingBrand Valuations are used for a variety of purposes,including tax,finance,and marketing.Being the interpreter between the language of marketers and finance teams they provide structure for both to work together to maximise returns.How much is my brand worth?How much should I invest in marketing?How much damage does brand misuse cause?Am I tax compliant with the latest transfer pricing?How do I unlock value in a brand acquisition?Questions we can help answer:Brand Valuation Make your brands business case.Consulting ServicesOnce you understand the value of your brand,you can use it as tool to understand the business impacts of strategic branding decisions in terms of real financial returns.Which brand positioning do customers value most?What are our best brand extension opportunities in other categories and markets?Am I licensing my brand effectively?Have I fully optimised my brand portfolio?Am I carrying dead weight?Should I transfer my brand immediately?Is a masterbrand strategy the right choice for my business? Brand Positioning Brand Architecture Franchising&Licensing Brand Transition Marketing Mix Modelling Sponsorship StrategyQuestions we can help answer:Brand Strategy Make branding decisions with your eyes wide open.Consulting ServicesBrand Finance Healthcare 50Sustainability and ESG have never been more important considerations for marketers,finance professionals,and the brands they serve.Our sustainability services bring clarity,allowing you to make the right decisions to add value,protect yourself from risk,and do the right thing. Perceptions Evaluation and Tracking Sustainability ROI Analysis Competitor Insights and Positioning Recommendations Materiality Exercises Stakeholder Engagement and Workshops Sustainability Reporting and Disclosure Support How important is sustainability in driving the choices of customers,employees,and investors?Which sustainability issues are most relevant to my brand?How sustainable is my brand perceived to be versus competitors?What is the potential value of enhancing perceptions?Could value be at risk?If so,how much?How do I secure investment or budget allocation?How do I improve performance and perceptions?Questions we can help answer:Brand Sustainability Understand perceptions and align them with performance.Consulting ServicesBrand Finance Healthcare 51Sponsorships are often amongst the most extensive,influential,and expensive brand building activities a company can undertake.We use the same techniques applied in brand valuation,such as research,financial modelling,and strategic analysis.This approach helps marketing and finance managers to understand the effectiveness of sponsorships and maximise ROI.Advertising equivalency,and traditional research interpretation of sponsorships,fails to adequately address key questions around brand building and value creation.Brand Finance takes a broader view to understand sponsorships in the context of achieving brand and business objectives.Can I develop a sponsorship strategy to match commercial objectives?Is the partnership a good fit?What is the short-term impact on business performance?What impacts there on long-term brand building metrics?What is my financial return from the sponsorship investment?Should the partnership be renewed,and if so,at what price?How does my sports partnership compare to the market?Questions we can help answer:Sponsorship ServicesMaximise value from your sponsorships.Consulting Services Sponsorship Strategy Partnership Opportunity Analysis Return on Investment Analysis Partnership Tracking Sports Investment Due Diligence Sponsorship Prospectus building Activation Measurement&StrategyBrand Finance Healthcare 52Brand Dialogue Limited is a member of the Brand Finance Plc Group.With strategic planning and creative thinking,we develop communications plans to create dialogue with stakeholders that drives brand value.Our approach is integrated,employing tailored solutions for our clients across PR and marketing activations,to deliver strategic campaigns,helping us to establish and sustain strong client relationships.We also have a specific focus on geographic branding,including supporting nation brands and brands with a geographical indication(GI).Brand Dialogue Services Brand&Communications Strategy Campaign Planning Market Research&Insights Media AnalysisResearch,Strategy&Measurement Promotional Events Conference Management Native Advertising Retail MarketingMarketing&Events Crisis Communications Brand Positioning&Reputation Corporate Social Responsibility Geographic BrandingStrategic Communications Press Releases Bespoke Publications,Blogs&Newsletters Marketing Collateral Design Social Media ContentContent Creation Media Relations Press Trips&Events Strategic Partnerships&Influencer Outreach Social Media ManagementPublic Relations&CommunicationsFor further information on our services and valuation experience,please contact your local representative:Market ContactEmailAfricaJeremy Sampsonj.sampsonbrandfi Asia Pacifi cAlex Haigha.haighbrandfi AustraliaMark Crowem.crowebrandfi BrazilEduardo Chavese.chavesbrandfi CanadaLaurence Newelll.newellbrandfi China Scott Chens.chenbrandfi Denmark/Norway/SwedenCristobal Pohle Vazquezc.pohlebrandfi East Africa Walter Seremw.serembrandfi FranceBertrand Chovetb.chovetbrandfi Germany/Austria/SwitzerlandUlf-Brun Drechselu.drechselbrandfi IndiaAjimon Francisa.francisbrandfi IrelandAnnie Browna.brownbrandfi ItalyMassimo Pizzom.pizzobrandfi MexicoLaurence Newelll.newellbrandfi Middle EastAndrew Campbella.campbellbrandfi NigeriaTunde Odumerut.odumerubrandfi PhilippinesGary de Ocampog.deocampobrandfi PolandKonrad Jagodzinskik.jagodzinskibrandfi PortugalPilar Alonso Ulloap.alonsobrandfi RomaniaMihai Bogdanm.bogdanbrandfi South AmericaPilar Alonso Ulloap.alonsobrandfi SpainPilar Alonso Ulloap.alonsobrandfi Sri LankaDhanushika Shanmuganathand.shanmuganathanbrandfi SwedenMike Rocham.rochabrandfi TurkeyMuhterem Ilgnerm.ilgunerbrandfi United KingdomAnnie Browna.brownbrandfi USALaurence Newelll.newellbrandfi VietnamQuyen Luongq.luongbrandfi Brand Finance Network Brand Finance Healthcare 54Contact usT: 44(0)20 7389 9400E:W:
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Biomanufacturing Platform Biomanufacturing Policy Summit Report 2024 Policy pathways for biomanufacturing in Europe:strengths,weaknesses,opportunities and threats B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|2 Table of Contents Executive Summary.3 About the Biomanufacturing Platform.4 Keynote Speakers.5 Defragmenting&Accelerating Biomanufacturing-The Role of Policy.7 Out of the Box-A Global View on Biomanufacturing Policies.8 How does Policy deliver for Biomanufacturing-Looking Ahead.9 Biomanufacturing in Europe:Strengths,Weaknesses,Opportunities and Threats.10 _Strengths-what Europe is doing well or better positioned than other players.11 _Weaknesses-what Europe is doing badly or worse positioned than other players.11 _Opportunities-actions to reinforce strengths or tackle weaknesses.12 _Threats-potential weaknesses or consequences of internal or external trends.13 Biomanufacturing Champions&Success Stories.14 Summit Participant Organisations.16 B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|3 Executive Summary The Biomanufacturing Policy Summit is an annual meeting organised by EuropaBio that brings together biotech industry representatives and policymakers to discuss the most timely and relevant topics for biomanufacturing across sectors.The 2024 edition occurred in Brussels on 13th March and gathered 73 participants,including participants from the European Commission and the European Parliament.“Policy pathways for biomanufacturing in Europe”was the Summit theme and the umbrella topic for discussions on the best ways to defragment and accelerate biomanufacturing in the EU,plus biomanufacturing policies from other global regions.It is a critical timing for biomanufacturing,as different policy files and discussions are underway at EU level,with an impact on relevant products or processes including biopharmaceuticals,new genomic techniques,detergents,alternative proteins and cell-cultivation.This report summarizes the Summits main discussion points and takeaways and uses them as a foundation to build a Strengths,Weaknesses,Opportunities and Threats(SWOT)analysis for biomanufacturing in Europe.The analysis is further refined with data from recent reports and examples provided by EuropaBios members,in order to add evidence and practical examples to support the arguments.Following the 2023 report which presented 10 recommendations for biomanufacturing,the 2024 SWOT analysis aims to act as an open conclusion from the Summit,adding substance to the ongoing debate around biomanufacturing in Europe.The fast-moving global biomanufacturing landscape and its cross-sectoral nature poses complex challenges to Europe,as it needs to foster its strengths and tackle its weaknesses,without leaving behind any critical sector for European economy and citizens.Furthermore,its dynamic and diverse set of perspectives may reveal changes in the short or medium-term and different priorities across sectors and Member States(MS).Therefore,the report stresses the urgent need to address the question“What does the EU want to be?”and build an answer with pillars in innovation,skills,smart and agile legislation and financial instruments,and the Single Market.The EU needs a smart industrial policy for biotech and biomanufacturing rooted in science-based policymaking,which promotes and incentivises the scale-up of infrastructures and sustainable solutions and creates innovative and resilient supply-chains,whilst answering the EUs long-term ambitions.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|4 About the Biomanufacturing Platform EuropaBios Biomanufacturing Platform has the mission to represent biomanufacturing at the highest policy levels in Europe,build recognition and understanding in and around biomanufacturing and highlight its importance to Europes competitiveness,resilience,sustainability and innovation.EuropaBio champions biomanufacturing across its Healthcare,Industrial Biotechnology and National Associations Councils and as a cross-sectoral Platform brings these voices together to accelerate Europes growth.Main Platform Activities Biomanufacturing Policy Summit-The annual half day summit brings together stakeholders,such as industry representatives and policymakers,to discuss on the EUs ambitions for biomanufacturing and the tangible pathways to success across strategy,policy,regulation and legislation.2023-Report&Recommendations.Biomanufacturing Definition 101-One of the first challenges of the Platform was to shape a baseline definition for biomanufacturing,understandable to wider stakeholders and society.Read the full 101 Definition.Biomanufacturing in Our Lives-A set of story-telling videos that showcase different biomanufacturing products that we use or have a positive impact in our everyday lives.The first examples are Vitamin B2,Algal Omega-3,CAR T-cells,Detergents,Cheese.Biomanufacturing Global Series-A snapshot of biomanufacturing general statistics,main policy developments and data on targets and investments of key global players-USA,India,Japan and China-to contribute with evidence to the discussion and support the development of a strategic view for the EU.Biomanufacturing Library-A library of biomanufacturing policy,strategy and industry documents which is a living repository in constant growth and mutation.Visit the Library and if you or your organization has any relevant documents that might find common ground with it,please do not hesitate to get in touch.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|5 Keynote Speakers The Human Element:Skills development for Biomanufacturing Jan Beumer,Director People Experience,Pfizer Global Supply Pfizer is a global company with 36 manufacturing sites worldwide,providing medicines and vaccines to patients in over 180 countries and employing around 86,000 colleagues.The companys biomanufacturing site in Puurs is a key part of Pfizers global manufacturing network;as well as a volume increase of over 60%in the last 10 years,the site is subject to an investment of over 1.2 billion euros between 2023 and 2025,and currently employs around 4,500 highly educated people.The Puurs site is focused on innovation and automation,with a strong R&D ecosystem and a disciplined approach to execution.The company is addressing challenges in attracting and retaining STEM talent through a range of external partnerships with schools,universities,and educational centres,as well as internal initiatives such as training and development programmes.One such programme is the“Training is the new hiring”initiative,which aims to develop operators without technical backgrounds into higher job levels.Pfizer Puurs is committed to co-creating a pathway to find,attract,and retain STEM talent,and is working towards becoming the most attractive,diverse,and inclusive employer in the industry.Level up:New markets from Biomanufacturing Freya Burton,Chief Sustainability Officer,LanzaTech Carbon is the raw material of many final products that we use in our daily lives,but the key questions are:where does it come from,how is it processed and how is it disposed of?LanzaTech introduces a breakthrough biomanufacturing process that encompasses gasification,compression,clean up,fermentation,separation and storage,and transforms industrial off-gas,agricultural or municipal waste or CO2 from direct air capture into materials,fuels or proteins.LanzaTech has over 1300 patents granted worldwide with over 575 pending.The use of different microbes for the same feedstock in the same reactor results in different products and potentially expands the product portfolio.However,LanzaTech highlights that without financial or policy support,great technologies do not get a chance to deploy,and that there is the need to“adopt a technology neutral position and support all solutions”.It is time to rethink carbon,refining and harness biology to make everything we need.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|6 Precision Fermentation:Yes,to planet-friendly Food Solutions Sebastien Louvion,Chief Regulatory Office,Standing Ovation The need to supply food to a growing world population whilst proceeding with the agri-food transition to help fight climate change,led to the emergence and expansion of a new field:alternative proteins biomanufacturing,which leverages biotechnology in the agri-food sector.Startups and SMEs are key drivers of innovation and Standing Ovation is such an example with its animal-free caseins.The process of precision fermentation uses microorganisms as cell factories to produce proteins of interest.The final product,the proteins,are separated and purified from the starting microorganisms in the manufacturing process.They have the same nutritional and functional qualities as the animal proteins,and Standing Ovations caseins can be used in ice cream,yoghourt,cheese and other dairy applications.The benefits of the technology are two-fold:(1)offering an additional source of proteins to feed the world when the agri-food sector is already reaching maximum capacity whilst(2)also helping to decarbonise the industry and reduce the environmental footprint of protein production by 90%or more.The EU benefits from one of the best regulatory frameworks to ensure food safety,but it is also too slow and unpredictable with companies having to wait 2-3 years,sometimes more,before they can secure authorization to market a huge disadvantage for EU competitiveness.Standing Ovation calls for a streamlined science-based approach.The EU Belgian Presidency:Priorities for Life Sciences Thomas Van Cangh,Advisor,Cabinet of Belgian Prime Minister Belgium holds the Presidency of the Council of the EU in a critical moment for life sciences and Europe,with ongoing negotiations on key files such as the European Health Data Space and the EU Biotech and Biomanufacturing Initiative.In Belgium,the biotech sector conveyed two main priorities on biomanufacturing at EU level:access to capital and access to market.The first focuses on the need for a Capital Markets Union and pull of private capital,by attracting Venture Capital or de-fragmenting the stock market to ensure the necessary depth and liquidity required to support tech scale ups,a kind of“European NASDAQ”,building on existing structures.The second,addresses the need to optimise and improve the market access across sectors through simplification and smart regulation without compromising safety and quality standards.Lastly,it emphasizes the need to keep biotech and biomanufacturing in the upcoming political agenda,with the Councils Strategic Agenda and the Political Guidelines of the next European Commission.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|7 Defragmenting&Accelerating Biomanufacturing-The Role of Policy Panel:Jean Francois Bobier,BCG(Moderator)|Irene Sacristn-Snchez,DG SANTE-European Commission|Sabrina Conti,Merck|Anna Handschuh,Gourmey|Jeroen Hofenk,SwiftPharma The session brought together industry voices across different sectors and a European Commission biotechnology representative to address differences and commonalities on their challenges to defragment and accelerate biomanufacturing.Opening Statement Highlights It is important to have a regulatory environment that works in a coherent manner and builds trust.Additionally,it needs to be harmonised with countries outside the EU.The proposal for plants developed using NGTs currently being discussed in the EU is as an example of legislation impacts biomanufacturing,and shows how a solid regulatory framework based on flexible risk assessment and monitoring could ensure safety while promoting market uptake of new products.There is significant interdependence across the biotech ecosystem between SMEs,large companies and academia.The entire value-chain must be considered in the policymaking process.From a healthcare perspective,challenges were identified on(1)high reliance on non-EU suppliers of active pharmaceutical ingredients(APIs)and raw materials,(2)the EUs lack of competitiveness compared to other geographies and(3)the changing global geopolitical landscape.We must recognise food biotechnology and biomanufacturing as a critical part of the solution for Europes food security and sovereignty.Therefore,there is the need to resolve the regulatory challenges for novel foods in accessing the market,by aligning the single market as much as possible across MS and with the EU.Breakthrough biomanufacturing processes,namely in the health sector,hold the ability to enable flexible manufacturing which can be customised to answer to different needs.Nevertheless,new solutions face challenges such as regulatory uncertainty,sector mainstream actors inertia in innovation uptake and public understanding,due to knowledge deficit.Discussion Main Takeaways Awareness,Information&Understanding-There is the need to inform society on the applications of biotech impacting and improving everyday life,in order to raise awareness,build consumer trust,and promote market uptake of bio-based products.Better Regulation-New challenges linked to novel technologies do not necessarily mean the need for new legislation,they may need smarter legislative processes or be connected to mechanisms for streamlining implementation or enforcement of current legislation.Coalitions&Dialogue-A strong dialogue between industry and Institutions,is necessary to protect science,be competitive,and maintain and advance innovation for business and citizens in the EU.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|8 Out of the Box-A Global View on Biomanufacturing Policies Panel:Ion Arocena,AseBio(Moderator)|Virginie Le Coent,bioMrieux|Saskia Kliphuis,Corbion|Peter Steen Mortensen,Novonesis The session provided first-hand insights on global polices from companies with biomanufacturing facilities in other geographies,in order to derive challenges and opportunities to Europe across health and industrial biotech.Opening Statement Highlights The fragmentation of global legislation has an impact in the healthcare sector,namely through world pharmacopeias1.Its lack of harmonisation across countries(e.g.,EU,US,China)increases burden,reducing scale and speed which impact patient access.The importance of international collaboration was emphasized to modernise and harmonise regulation.An attractive ecosystem to retain and grow biomanufacturing in the EU is influenced by multiple factors,including policies and beyond.Decisions within fermentation manufacturing were guided by cost and availability of feedstock,energy prices,emissions frameworks and national tax regimes,in addition to the presence of existing manufacturing and proximity to customers.The EU must consider what is happening globally during its policymaking process.It must take into consideration the fact that businesses focus activities and further invest in geographies in which they are more commercially successful-the importance of the link between investment and return.There is a necessity to regulate suited to the science in question,rather than try to fit biotechnology into frameworks designed for chemicals.Discussion Main Takeaways Access&Availability of Feedstock-Europe would benefit from greater access to sustainable and cost-effective feedstock as it would enable the scaling-up of biomanufacturing and reduce final product costs,addressing a major market threshold for biomanufacturing.Shape the Regulatory Landscape-The EU has an opportunity to lead the global regulatory pathway,either through improvement of current frameworks or the creation of new and smarter platforms to support and de-risk biomanufacturing.Access to Market-The EU needs to improve its policy and regulatory processes in order to accelerate the access of new products to the market and therefore,be able to compete with other geographical regions.1 Pharmacopeias are the regulations that describe the methods for pharma quality control and cover,for instance,biopharmaceuticals,cell&gene therapies and small molecules.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|9 How does Policy deliver for Biomanufacturing-Looking Ahead Panel:Claire Skentelbery,EuropaBio(Moderator)|Sinead Keogh,Ibec|Wojciech Nowak,Novartis|Ana Maria Bravo,IFF|Christophe Lanneau,Genopole The session wrapped-up the afternoon of discussions,summarised the Summit main messages and set a long-term vision for biomanufacturing in Europe,from a corporate and national association perspective.“What does the EU want to be?”The answer to this question frames the main ask from the Summit,as it provides a strategic destination for biomanufacturing and therefore adds predictability and consistency to the pathway.Many factors are considered when building the answer.Regulation as an enabler,fit-for-purpose and future-proof in line with innovation and new biotechnologies,supported by tools such as regulatory sandboxes.Legislation should consider the biomanufacturing infrastructure in place and address the current accessibility of feedstock in Europe,EU as a whole,and its distribution across MS.Market uptake support of innovation and new biotechnologies,by consumers and patients,as they answer to the needs of citizens.An EU Single Market boost leveraged by legislative consistency across MS to derisk biomanufacturing of sustainable products.Skills are a competitive advantage to Europe,but scaling-up the investment on high-quality talent generation is need,namely through reskilling and upskilling.An industrial policy perspective for biotech and biomanufacturing,to ensure a high-level strategy for the EU that is built on European strengths and improves its competitiveness.Based on the remarks from the panel above,what can we say about what does the EU want to be?A region that encourages and rewards innovation for biomanufacturing through to competitive market access and citizen uptake.A region that has the resources,infrastructure and skills base to ensure that innovation and investment can flow for impact at scale.A region with a globally attractive market for biomanufacturing of advanced and sustainable products.A region that has a strong plan for how this will be achieved across sectors and MS.“The second Biomanufacturing Policy Summit demonstrates European progress when looking at the critical importance of biomanufacturing.There is a greater awareness and focus on what we need to achieve and the legislative environment that will enable Europe to succeed.”B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|10 Biomanufacturing in Europe:Strengths,Weaknesses,Opportunities and Threats This SWOT analysis is based on Summit discussions and recommendations by participants,reinforced with EuropaBio members inputs and external data.It reflects the EUs current position globally for biomanufacturing across sectors and compared to other regions.The analysis also highlights the factors behind each section and addresses how the EU could develop the optimum strategy to act on the SWOT as a whole.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|11 Strengths-what Europe is doing well or better positioned than other players High-quality R&D and Innovation-Europe is home of 42%of the worlds top 100 universities for life sciences,according to Times Higher Educations World University Rankings 2022.Additionally,it scores more strongly than US and China in high-quality publications covering health,agriculture and industrial biotech,according to CWTS Leiden Ranking 2022.This is translated into the business arena,with startups and SMEs building breakthrough innovations.Examples during the Summit included Standing Ovation and Gourmey in the food sector and SwiftPharma in the health sector.Skills Development-Europe benefits from a comparatively large pool of talent,with focus on collaboration and skills development through well-established and strong EU-wide research programmes.Talent generation relevant to biomanufacturing includes biotechnology,biomedical,biological engineering,plus broader engineering disciplines.The EU skills are a competitive advantage over other geographical regions,and have been able to deliver exceptional results,for instance in terms of R&D,as shown by the CWTS Leiden Ranking 2022.Current Infrastructure and Capacity-Europe has 21.7 million litres of capacity,approximately twice the US biomanufacturing capacity,according to a report from BCG and Synonym from February 2024.The fact is also supported by a report from the Good Food Institute in 2023,which states that 47%of global protein fermentation capacity is in Europe.Therefore,based on the data available,it is possible to state that Europe is currently well positioned in terms of infrastructure and capacity.Broad Strategic Drivers-The EU is anchored on a strong set of policies that steer and guide its overall direction.The existence of robust broad strategies such as the Green Deal,the General Pharmaceutical Legislation,the European Industrial Strategy and the Bioeconomy Strategy,are essential to lay the foundations for more specific strategies and to set high-level goals and targets.Weaknesses-what Europe is doing badly or worse positioned than other players Lack of Industrial Strategy for Biotechnology-The latest European strategy focusing exclusively on biotechnology dates from 2002 and the broader Bioeconomy Strategy updated in 2018,addresses biotech as a small part of the bigger picture.Regardless of the recently published communication“Building the future with nature:Boosting Biotechnology and Biomanufacturing in the EU”,which addresses this weakness,the EU lacks an industrial strategy for biotech and biomanufacturing compared to other global regions.Feedstock Access&Availability-Biomanufacturing relies heavily in bio-based feedstock2 within industrial biotechnology as the raw material to apply biotechnology at an industrial scale.Therefore,the ability to scale-up depends on the stable availability and price of feedstock.The EUs industry faces a major cost and access barrier,demonstrated by company decision making towards biomanufacturing investment outside the EU within fermentation.From a health sector perspective,Europe also depends significantly on externally produced ingredients such as Active Pharmaceutical Ingredients(APIs),and other raw materials within medicines manufacturing,which creates a direct risk to supply and innovation.2 Such as agricultural crops and residues,animal residues,forestry crops and residues.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|12 Funding Availability&Risk-For companies of all sizes to mature biotech and biomanufacturing innovation and outputs,they must attract or commit long-term investment,as highlighted for healthcare in the 2024 Charles Rivers Associates report.Additionally,their cutting-edge nature increases the risk of failure or encountering unexpected barriers.Startups and SMEs struggle to find adequate financial instruments in the EU to match the sector needs,such as scaling-up production,or policy incentives to create trust in the market and investors for long-term developments.Other global regions often have more mature investment markets,creating a competitive advantage for the maturation of innovation.Complex&Slow Market Access The complex regulatory and legislative frameworks at EU,Member State and even regional levels,create headwinds for companies within biomanufacturing,compared to other global regions.This is a particular challenge for startups and SMEs,which have limited resources and cannot afford a lengthy risk assessment process.Fragmented Single Market-The EUs market has its main strength on the Single Market and on its ability to leverage the 448 million inhabitants across 27 Member States.However,the complexity and lack of alignment between EU and Member State legislation for market delivery place challenges for biotech and biomanufacturing companies to harness the full potential of the EU Single Market and consequently,to create benefits for businesses and consumers.The fragmentation also weakens the ability to compete with other global regions or emerging competitors.Opportunities-actions to reinforce strengths or tackle weaknesses Boost Tech Transfer-Europe needs to foster its R&D and Innovation by creating effective channels to accelerate and improve technology transfer into biomanufacturing.The ability to scale innovation is critical to build impactful solutions in answering economic,societal and environmental challenges.Additionally,tech transfer and subsequent biomanufacturing will significantly benefit from full integration of data sharing,process digitalisation and the use of AI.Enhance Access to Capital-The ability to provide tailored financial instruments at the necessary scale would address the funding challenges and unleash the potential of Europes R&D.During the Summit,stakeholders suggested that the solutions could take form of the Capital Markets Union or a pull of private investment such as with incentives for Venture Capitals or the creation of a Nasdaq for biotech,as mentioned in the keynote speech from the Belgian Presidency of the Council of the EU.Lead the Global Regulatory Landscape-A global shift is taking place across sectors,towards the integration of biotech and biomanufacturing.This is in turn is changing the regulatory landscape.The EU should seize the moment and welcome it as an opportunity to shape the regulatory landscape globally through pioneering science-based and agile legislation that supports innovation and the new industrial paradigm of sustainable products powered by biotech.Infrastructure Transition&Construction-In addition to the current strong biomanufacturing capacity,Europe has an exceptional potential to use existing infrastructures and facilities from energy-intensive or other mainstream industries within biomanufacturing-an example showcased during the Summit was LanzaTech flagship plant in Belgium developed in partnership with the steel industry.Europes leading position in biomanufacturing capacity can be reinforced through the construction of new pilot B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|13 and commercial plants to answer to the growing demand across sectors,such as food,chemicals or health.Further Strengthen STEM Education-Europes leading position on skills development needs to be protected and reinforced through structured investment on the broad Science,Technology,Engineering and Mathematics(STEM)skills.The plan should address the reskilling and upskilling of the current workforce,as well as the engagement with younger generations to showcase the importance these skills to the future of the industry,as highlighted by Pfizer.This opportunity considers the growing demand for biomanufacturing skills and therefore,the need to strengthen Europes position,rather allowing it to become a weakness,due to shortages or increasing global competitiveness for workforce.Threats-potential weaknesses or consequences of internal or external trends Science-based vs Political-momentum-Biotechnology within the EU has often been subject to politically-driven decision making,unconnected to scientific evidence,proportionality,safety or industrial significance.The outcome is that major industrial transitions have been led by other global regions in the past,and risks occurring again in the future.This critically undermines the EUs targets for sustainable,resilient and competitive progress.A coordinated and structured alignment between the EU and MS has an essential role to play in order to ensure that emerging biotechnologies may grow competitively within the EU,building on the substantial public investment into the research behind their development.Supply-chain Security&Resilience-The current growing global protectionism marked by recent tariff disputes and geopolitical instability with Russias war on Ukraine,may pose challenges to the EUs health,manufacturing and food sectors,due to its reliance on external inputs.Biomanufacturing is part of the answer,using regionally produced bio-based inputs,instead of imported energy sources or intermediates,and manufacturing products that would usually be imported or available from a limited number of suppliers.Public Understanding and Uptake-Society and biotech have a long history in common dating back from the first biotech products:bread,wine,cheese and beer.Additionally,later,with the invention of vaccines and its unmeasurable benefits to human health.European citizens have long had a sensitive relationship with biotechnology despite widespread use,with flashpoints on key technology types or applications,reinforced through hesitance across stakeholders to be public champions.It is vital that public understanding is developed on the applications and development of biotechnology,with public champions across all stakeholders,including policy makers and industry.Competitive&Fast Moving Global Regions-A global race to mature biomanufacturing is ongoing,with key countries positioning themselves through investments and targets.The EUs competitiveness profile in terms of regulatory pathways for R&D,financial instruments,market access,scaling-up production and building or transitioning infrastructures is key.The overarching goal in the global race should be to ensure that biotech innovations originating in the EU have the opportunity to grow into biomanufacturing in the EU,at a competitive pace and across the different sectors.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|14 Biomanufacturing Champions&Success Stories “Rethinking carbon,biomanufacturing to save the planet”from LanzaTech LanzaTech is reshaping the way we think about raw materials.Gone are the days when we relied solely on the traditional linear approach of using carbon just once,often sourced from fossil fuels.Now,theres a greener choice.In partnership with steel maker,ArcelorMittal,LanzaTech technology has been deployed at the“Steelanol”facility in Belgium where the concept of waste gets a new meaning.There,carbon emissions from steel production are transformed into ethanol,through LanzaTechs biomanufacturing process of fermentation.By harnessing the power of biocatalysts,80 million liters of ethanol can be produced annually and used in various end products from fuels,apparel,cosmetics,and household goods,while reducing the emissions of the steel mill by 125,000 tonnes annually.This technology helps energy-intensive industries and consumer brands create value from waste.“Resilient biomanufacturing platform,for times of peace and crisis”from SwiftPharma The ability to produce at an industrial scale is key to deliver impactful solutions for economic,societal and environmental challenges.Nevertheless,in times of rapid and unpredictable change,it is critical to build agile solutions that are capable to be adapted and shifted towards the short-term needs with effective and reliable results.SwiftPharma created an innovative platform to produce a wide range of proteins using Nicotiana benthamiana plant.The bioplatform is modular,enabling the production of different proteins in parallel;linearly scalable,growing with the number of plants in place;and fast,producing a target protein in one month,scaling in three months,transferring to good manufacturing practice in another three months and commercial scale is ready to start.This approach to biomanufacturing is essential to answer to current and potential threats to human health.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|15 “A cutting-edge product and a market revolution,all with biomanufacturing”from Gourmey A transformation is underway in the agri-food sector,driven by the urgent need to meet booming global protein demand amidst rising concerns around food security,and human and planetary health.Cell cultivation is part of the answer to transitioning the current food systems,as it is able to biomanufacture high-quality animal proteins through a novel and sustainable process to supplement current methods.Gourmey has set the challenge high with its first product,by biomanufacturing a new option for foie gras lovers with cultivated proteins.Foie gras is one of the most exclusive and complex foods.With its flagship innovation,Gourmey showcases the potential of cell cultivation to create culinary-grade experiences.Gourmeys delicacy harnesses carefully selected cells from duck eggs combined with plant-based ingredients to please the most discerning chefs with distinct roasted top notes,buttery and caramel-like heart notes,and a long-lasting base of intense meatiness.By marrying innovation and heritage,shows how biomanufacturing can add a complementary and delicious protein source to future cuisines.“Training the present and preparing the future of biomanufacturing”from Pfizer People and skills are central to fuelling the industry of the future.Technological developments can only be designed,operated and improved by skilled professionals.For its manufacturing plant in Belgium,Pfizer Global Supply Puurs has been developing a comprehensive skills strategy to ensure that its workforce is well equipped for both todays and tomorrows challenges.The strategy focuses on in-house training in STEM skills,including to help reskill colleagues;it also seeks to help address gender imbalances in the STEM field.Finally,it focuses on future generations by developing partnerships with local schools and other establishments to educate children and young people on STEM skills and industry.Educate today to prepare for tomorrow.B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|16 Summit Participant Organisations Abolis AseBio-Spanish Bioindustry Association BASF BCG BIA UK BioIndustry Association BioDeutschland bioMrieux Cabinet of Belgian Prime Minister Circular Bio-Based Europe Joint Undertaking Corbion Council of European bioRegions CSL Behring DG AGRI-European Commission DG GROW-European Commission DG RTD-European Commission DG SANTE-European Commission dsm-firmenich EIT Health EuropaBio European Bioplastics European Biosolutions Coalition European Parliament Evonik Operations GmbH France Biotech Genopole Good Food Institute Europe Gourmey HERA-European Commission Ibec IFF Innovation Insights Sarl LanzaTech Merck Novartis Novonesis Pfizer Standing Ovation SwiftPharma B i o m a n u f a c t u r i n g P o l i c y S u m m i t R e p o r t 2 0 2 4|17 www.europabio.org
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Australias Clinical Trials SectorAdvancing innovative healthcare and powering economic growthJUNE 2024 2MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORDisclaimerThis report,the MTPConnect Australias Clinical Trials Sector final report,was prepared by L.E.K.Consulting Australia Pty Ltd(“L.E.K.”)for MTPConnect(the“User”).The report provides general information about the medical technology,pharmaceutical and biotechnology sector based on information provided by the User,sector participants,publicly available information and other third party sources.The report is to provide information and is for illustration purposes only.Accordingly,it must be considered in the context and purpose for which it has been prepared and not used for any other purpose.It cannot be relied upon by any recipient other than the User.In accepting this report you agree that L.E.K.Consulting Australia Pty Ltd.and their affiliates,members,directors,officers,employees and agents(“L.E.K.”)neither owe nor accept any duty or responsibility or liability to you or any third party,whether in contract,tort(including negligence),or breach of statutory duty or otherwise,howsoever arising,in connection with or arising from this report or the use you or any third party make of it.L.E.K.shall not be liable to you or any third party in respect of any loss,damage or expense of whatsoever nature that is caused by your or any third partys reliance or forany use you or any third party may choose to make of the report.3MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORForeword by Stuart Dignam,CEO of MTPConnect Clinical trials are an integral part of the research and development pipeline for new treatments and refinement and repurposing of existing treatments.They play a vital role in ensuring that all Australian patients continue to receive the best,safest and most effective treatments.MTPConnects clinical trials report,which was first published in 2017 and then updated in 2021 has been a valued resource for State and Federal governments,local and international sector participants and financial investors alike as it provides a holistic and comprehensive overview of the current state of the environment in Australia.It provides vital metrics around the economic and health impacts of clinical trials,a detailed analysis of clinical trial activity and outlines Australias position in the global market and priority focus areas to support sector growth.In this edition of the report,we build on our previous reports to highlight how the sector and the broad set of economic and activity metrics have evolved since 2019.As COVID-19 pandemic restrictions were eased,we saw a surge in clinical trial activity in Australia in 2021.But we have also seen those gains fall away,with trial numbers dropping back to pre-pandemic levels,letting slip the opportunity to entrench a greater share of global industry-sponsored trials in Australia.Although Australia has maintained its reputation as an attractive clinical trials destination from 2015-22,our conversations with sector stakeholders reinforce the need for urgent action across four key priorities:improving efficiency in trial start up,enhancing data transparency,increasing patient awareness and access to support recruitment,improving visibility and access to trials for patients and clinicians and expanding the workforce to support clinical trials growth.It is worth noting that these priorities have not changed much since our 2021 report,underscoring the need for urgent action.The National One Stop Shop initiative,which supports three of the four priorities,is a step in the right direction.It presents an opportunity for Australia to leverage its reputation for excellence in early phase trials to become more competitive in attracting late phase trials and deliver more life-saving innovations to Australian patients.Despite ongoing challenges across the sector,Australia is at an exciting juncture,with emerging innovation and trends that create significant new opportunities.Patient-centricity in trials is on the rise,enhancing patient engagement and outcomes.Digital health solutions are improving access to trials for our underserved regional and rural populations,while the emergence of precision medicine and innovative trial designs are revolutionising the clinical trial process and attracting greater investment into the clinical trials economy.Additionally,with regulatory change and uncertainty in the European Union and United States,Australia is well-positioned to leverage its faster trial environment to capture a greater share of the global market for medical device trials.As the world moves beyond the pandemic,it is imperative for Australia to ramp up investment in clinical trials to uphold its global competitiveness and continue delivering world-class healthcare to its people.Stuart Dignam 4MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORForeword by the Expert Advisory GroupMTPConnects clinical trials report plays a crucial role in the sector,and it has been doing so since its initial publication in 2017.By consistently tracking the sectors performance across key metrics related to economic impact and patient health benefits,as well as analysing clinical trials activity throughout Australia,this report fosters a shared understanding of the sectors broader impact on the economy.It also provides an opportunity for sector participants and stakeholders to reflect on progress achieved thus far and focus on addressing key priorities for continued growth.We take pride in contributing to its development,ensuring that it represents a diverse range of perspectives from across the sector.EAG member nameOrganisationPositionAna SvenssonNovo NordiskSenior Director,Clinical,Medical and Regulatory,Novo Nordisk OceaniaDavid LloydSouthern Star ResearchCEODavid WilksBristol Myers SquibbExecutive Director,Regional Head of RCO Pacific at Bristol Myers SquibbJanelle BowdenAccessCRManaging DirectorKylie SprostonBellberryCEOMelanie GentgallSanofiHead of Clinical Operations,Sanofi Translational Science HubSteve WebbAustralian Clinical Trials Alliance(ACTA)Board Director 5MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORExecutive summary 61.Introduction and context 112.Clinical trials activity and economic value 143.Australias position in the global clinical trial landscape 284.Future outlook and priorities for the sector 35Appendices 46Contents 6MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORExecutive summary This report,Australias Clinical Trials Sector:Advancing innovative healthcare and powering economic growth,is the result of extensive and comprehensive stakeholder engagement.It serves as an update to our previous 2021 and 2017 reviews,by providing a current snapshot of the size and scope of Australias clinical trials sector,highlighting areas of success and imperatives for improvement.The 2024 review examines how the value derived from clinical trials in Australia,and how the level of clinical trial activity has evolved over the past three years(2019-22).It also provides an update on the emerging opportunities and priorities that were foreshadowed in the 2021 report,considers how these have unfolded in recent years,and discusses in detail the future opportunities and areas for improvement facing the sector today.Australia has maintained its reputation as an attractive destination for clinical trials underpinned by the following factors:A strong reputation for the quality and global standing of its investigators and the networks that support them.Highly developed research infrastructure and systems that have enabled Australia to continue conducting clinical trials through disruptive global events such as the COVID-19 pandemic.High-quality data collection and overall compliance with Good Clinical Practice(GCP)guidelines,which ensures that data collected in Australian trials can support submissions to international regulators,including the United States Federal Drug Administration(FDA)and the European Unions European Medicine Agency(EMA).Specialised and dedicated early-phase infrastructure that enables the delivery of timely,high-quality trials,supported by streamlined processes and private ethics committees.The convenience and speed of the Therapeutic Good Administrations Clinical Trial Notification(CTN)scheme,which enables the faster start-up times that are particularly crucial for early phase trials.The financial support provided by the Australian governments extension of its research and development(R&D)tax incentives,improving Australias cost competitiveness.In 2022,the clinical trials sector in Australia employed c.7,700 Australians.Around 90,000 Australians participated in trials and there were 1,850 trials started.This activity saw c.$1.6 billion spent on clinical trials in 2022,up from c.$1.4 billion in 2019,which is largely attributable to increasing spend on trials,with the number of clinical trials declining slightly over the period.The exhibit below shows how these key metrics have trended over the past seven years.7MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORSource:ANZCTR;Clinicaltrials.gov;L.E.K.research and analysisMetricExpenditure$1.1 billion$1.4 billion$1.6 billion4.1201520192022CAGR%(2019-22)6,900 employees8,000 employees7,700 employees(1.5)Not reported95,00090,000(1.8)1,4601,8771,850(0.5)c.5%c.5%c.5%N/AEmploymentShare of global industry-sponsored trialsNumber of trials startedPatient participationAs our exhibit above highlights,the growth of the clinical trials sector since 2019 has been stagnant or declining across several metrics.While there was a robust rebound in 2021 following falls in key metrics in 2020 due to COVID-19,Australia has not maintained its post-COVID gains into 2022.Nonetheless,there are emerging opportunities that need to be capitalised on,and key priorities that need to be addressed urgently in order to ensure the sector continues to grow strongly.8MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORThere is growing awareness of a need for more patient centricity and diversity in clinical trials.Australia has a significant opportunity to capitalise on its diverse and multicultural population to attract more trials,recruit more participants,and ultimately serve and improve the health outcomes for more of Australias population,if it can effectively engage and support their participation and involvement in trials.Emerging opportunities in clinical trials 1Digital health solutions,such as teletrials offer promise in improving access to all Australians,particularly those in regional and remote areas.These communities have historically lacked the opportunity to participate in,and benefit from clinical trials due to their distance from research institutions.2Precision medicine offers a significant opportunity to improve patient outcomes.Clinical trials for the development of precision medicines are gaining momentum globally and locally with rapidly growing usage of biomarkers in trials,which is attracting significant government,non-industry,and industry investment.3Innovative trial designs,such as platform/umbrella/basket trials designs using strata or multi-factorial(multi-domain)designs,that can be used with or without adaptive methods,are growing and revolutionising trial processes with the support of government funding.These trials can enhance trial efficiency,providing patients with access to novel therapies sooner.4The tightening of medical device regulations in the European Union and United States is increasing the burden of proof and timelines for medical device trials.With Australian centres of excellence housing large,national medical device registries which can streamline patient recruitment and trial start-up times,Australia is well positioned as an increasingly attractive destination for medical device trials.5The five most significant emerging opportunities in the Australian clinical trials sector are focussed on patient engagement,digital health solutions,precision healthcare,innovative trial designs,and medical device trials:Key priorities for the sectors futureIn order for Australia to defend and build a strong competitive position in the global clinical trials market and continue to deliver benefits for patients,four key priority recommendations have been identified.Priority 1:Continue to improve the efficiency of the sectors clinical trial start-up processes,such as ethics and governance approvals.Australia has a strong global reputation in supporting early phase(Phase I and II)trials,but we have not had similar success in attracting the larger,more complex Phase III and IV trials.In order to grow Australias global share of Phase III and IV trials,it is critical to:Continue to streamline our ethics processes towards a true,single ethical review across all jurisdictions.Streamline site governance approval processes to improve consistency from site to site and study to study.Improve patient recruitment at each site(addressed in Priority 2 below)9MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORSince these later phase trials typically involve larger patient cohorts across multiple sites,they present an opportunity to further grow the economic benefits as well as patient health benefits from clinical trials.Priority 2:Enhance patient awareness and the ability to efficiently recruit patients at each clinical trial site,to improve site economics for these trials.Patient awareness and participation in clinical trials in Australia still lags countries such as the UK by a significant level.Australia has a diverse,multicultural population that could be further leveraged to attract more global clinical trials as companies are looking to demonstrate the efficacy of their novel medicines and devices in diverse populations.In order to do this,significant investment in patient awareness and engagement is required.Particularly,we need to engage with our culturally and linguistically diverse(CALD)populations and Aboriginal and Torres Strait Islander communities to improve awareness and understand and address their barriers to participation.Priority 3:Grow the size and capabilities of Australias clinical trials workforce.As highlighted by our metrics above,Australias clinical trials workforce has not grown since 2019.Stakeholders have continued to highlight the ongoing shortages of experienced Clinical Research Associates(CRAs)and Clinical Trials Coordinators(CTCs),which were also mentioned in the previous editions of this report and in the October 2021 MTPConnect REDI Initiative Skills Gap Analysis report.In order to grow the size and capabilities of the workforce,there needs to be greater awareness of career pathways and opportunities in the clinical trials sector among graduates,and better training and workforce development programs,such as those developed in recent years by the MTPConnect Researcher Exchange and Development within Industry(REDI)program and PRAXIS Australia.Investing in these areas will enable the growth of highly skilled jobs in the sector,and in turn,support further growth in clinical trial activity in Australia.Furthermore,Australia still lacks a reliable method of capturing clinical trials workforce metrics,an opportunity that that could greatly assist in addressing current workforce limitations.Priority 4:Enhance the sectors overall transparency,with better data collection,data tracking and data registries,particularly to track patient recruitment,participation and metrics related to medical device trials in addition to drug trials.Although the Australia New Zealand Clinical Trials Register(ANZCTR),Australias national registry for tracking clinical trial activity,collects,curates and maintains extensive clinical trials data,the current system relies on self-reporting.Consequently,there are gaps in the quantity and granularity of information supplied to ANZCTR by sponsors,and the currency of information.Particularly,we noted that there is a significant dearth of information recorded for medical device trials(where even the phase of trial is not commonly reported or recorded).This gap is not unique to Australia and is also seen in international databases such as ClinicalTrials.gov.Increasing the granularity of information would provide richer insights into Australias competitive position for trials by type,growth rates of certain types of trials and help inform workforce planning and policy development.10MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORAustralia has an opportunity to play a global leadership role in reviewing the clinical trials data that would be strategically useful to collect(e.g.,clinical trial start-up timelines,phase and therapeutic area information for medical device trials)and implement processes to collect this information efficiently.Progressing these recommendations will require commitment from the entire sector.All these stakeholders will need to increase their efforts around each of the four recommendations,to accelerate the pace of progress and position Australia as a more desirable destination than currently for global trial sponsors.Other competing countries and regions such as Singapore,UK,and South Korea are implementing measures to improve the attractiveness of their respective clinical trials sectors.Australia risks falling behind such countries if it does not take significant steps to address the priorities outlined above.11MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR1.Introduction and contextIntroduction to clinical trialsClinical trials are a critical link in the value chain for developing new therapies and technologies,to ultimately improve health outcomes across the world.Their primary purpose is to assess the safety and efficacy of new medical therapies,but also provide a pathway for patients who have failed other forms of treatment to access novel therapies that have yet to be brought to the broader market.Clinical trials can take many forms,with features and characteristics that can vary widely,depending on the unique circumstance of each study.The clinical trials defined in this report are segmented based on the four key parameters illustrated in Figure 1 below.Figure 1Four key parameters of clinical trialStudy typeObservationalInterventionalScopeDevicesStageNon-StagedSponsor Type/Funding SourceNon-industryIndustryIndustryGovernment BodyCharities/FoundationsDrugs and biologicsPhases I-IV(typically drugs)Pilot,pivotal and post-approval(typically medical devices)Treatment and proceduresBehavioural therapiesClinical practice improvementsPreventative careOther collaborative groupsSelf Funded/UnfundedUniversityHospitalTrials are sponsored and funded by a wide range of industry and non-industry stakeholders,including healthcare professionals and other industry sources,government sources,philanthropic donors,hospitals and universities,and patients.They span a wide range of interventions,methodological designs and scope of treatment strategies,from medical devices to drugs to behavioural therapy.Further background on the various sector participants and an overview of the clinical trial start-up process and its key parameters can be found in Appendix 3.Clinical trials involving therapeutic goods are typically categorised into phases that occur across the development lifecycle continuum.Most trials are classified into one of five phases(0-IV)that indicate the stage of development.Medical device trials sometimes fall within one of the four trial phases,but often go through stages instead.These stages might include a Pilot study,which include Early Feasibility studies,First In Human(FIH)studies or a Traditional Feasibility study(similar to combined Phase I and II trials);a Pivotal study(to confirm clinical efficacy and risks,similar to traditional Phase III trials);and Post-approval studies(to determine long term effectiveness and risks,similar to traditional Phase IV trials).12MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 2Clinical trial stages,drugs and medical devices1,2Source:ANZCTR Data field definitions;MTAA Clinical Trials Regulatory FrameworkMedical DeviceTrials PilotPost-approvalPivotalDrug TrialsPhase IVPhase IPhase IIIPhase IIPhase 0Exploratory,first-in-human(FIH)trials,behaviourthat assesses the of the drug in human subjects through microdoses,conducted prior to dose escalation and safety studiesEvaluates a new drugs effectiveness for specific indications in patients with the targeted disease and identify short-term side effects through controlled clinical studiesPost-marketing studies monitor drug safety,effectiveness,and optimal use after approval,assessing toxicity,risks,and benefitsConfirmatory investigations to evaluate performance and safety for a specified intended use to satisfy pre-market regulatory requirementsPre-market pilot studies encompass:Early feasibility studies First-in-human(FIH)studies Traditional feasibility studiesEstablish performance and safety to gain better understanding of device safety,long-term outcomes,health economicsGathers more data post-approval to evaluate drug effectiveness,safety,and potential adverse reactions,aiding in physician labeling Assess drug safety,metabolism,and dosage in humans,involving small groups to determine safe levels and potential side effectsContext for this reportIn 2017 and 2021,MTPConnect carried out holistic and comprehensive reviews of the state of the clinical trials market in Australia,with summary reports produced in both those years and with the 2021 report also containing data from the pre-pandemic period,up to the end of 2019.This 2024 report builds on the detail from those reviews and incorporates new data from 2020-2022,as an update to these previous reports.It examines how the value derived from clinical trials in Australia,and the volume and growth rates of Australian trials activity have evolved over the past three years(2019-22).It also provides a review and update of the emerging opportunities and priorities that were outlined in the 2021 report,considering these developments as Australia and the rest of the world recovers from the COVID pandemic.The report is structured as shown in Figure 3 below:1 ANZCTR,Data field definitions,accessed February 2024.2 MTAA,Clinical Trials Regulatory Framework,accessed February 2024.13MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 3How this report is structuredAn overview of the clinical trial process and context for this reportUpdate on the economic and health contribution of Australian clinical trials,and the volume and growth rates of clinical trials activity across several dimensionsUpdate on how Australias competitive positioning in the global clinical trial landscape has shifted since 2019 and the key drivers of this shiftOverview of emerging opportunities in clinical trials globally,and key priorities to drive improvements and growth in Australias clinical trials sectorChapter 2:Clinical trials activity and economic valueChapter 3:Australias position in the global clinical trial landscapeChapter 4:Future outlook and priorities for the sectorChapter 1:Introduction and contextMethodology in briefThis report has drawn on a wide range of information sources,both quantitative and qualitative,to update on recent developments in the sector.It includes information sourced from the MTPConnect industry survey,consultations with industry stakeholders,as well as clinical trials activity data from the ANZCTR and ClinicalTrials.gov.TopicSourceClinical trials activity and economic value ANZCTR ClinicalTrials.gov MTPConnect industry survey Desktop research and analysisAustralias position in the global clinical trial landscape ClinicalTrials.govFuture outlook and priorities for the sector Stakeholder consultations Desktop researchThe value derived from the clinical trial sector,including economic contribution,jobs and patient participation,are primarily drawn from a MTPConnect industry survey that was conducted in conjunction with Medicines Australia(MA),Medical Technology Association of Australia(MTAA)and AusBiotech.The survey respondents include medical technology,biotechnology and pharmaceutical(MTP)companies,contract research organisations(CROs)and clinical trial sites.In total,survey respondents contributed clinical trials data on approximately 400 clinical trials commenced in Australia,involving approximately 15,000 participants in 2022.Detailed information on the methodology used to calculate the appropriate economic and activity metrics shown in this report can be found in Appendix 4-7.14MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR2.Clinical trials activity and economic valueClinical trials activity in AustraliaOverview of clinical trials activity(2015-22)As Figure 4 shows,there were 1,850 clinical trials in Australia in 2022,according to data recorded by ANZCTR,which reflects an average(although inconsistent)annual growth rate of 3.4%since 2015.On average,drug trials grew by 3.4%per annum,device trials grew by 1.0%per annum,and Other trials grew by 4.1%per annum over this period,as shown in Figure 4 below.Clinical trial starts have returned to the pre-pandemic levels observed in 2019,after two years of volatility in 2020 and 2021.Figure 4Clinical trials by interventionClinical trials by intervenon(CY2015-22)544538610697 70170179968717415921217919717219918672883086194796882295896305001,0001,5002,000Number of clinical trials started142015102016202017212018112019920201620211420221,4601,5371,7031,8441,8771,7041,9721,850TotalOther*6.57.43.44.1(5.9)-6.53.43.21.0Drug&DeviceDeviceDrugCAGR%(CY2015-19)(CY2015-22)Note:*Other trials includes observaonal studies and intervenonal trials listed as Behaviour,Lifestyle,Prevenon research,as well as other treatments that do not involve a drug or medical deviceSource:ANZCTR Data(14 Nov 2023);L.E.K.analysisIndustry-sponsored trials,which aim to commercialise underlying intellectual property such as drugs and/or devices,accounted for almost a third of all clinical trials commenced throughout the period from 2015 to 2022,as shown in Figure 5 below.In the pandemic-affected years(2020 and 2021),the proportion was higher at 39%.Overall,industry-sponsored trials have been more resilient than non-industry sponsored trials through COVID-19,growing by 4.3%per annum from 2015-22.This compares to non-industry-sponsored trials,which have grown more slowly,at 3.0%per annum over the same period.A large proportion of industry-sponsored trials are funded by multinational companies,with only 9%of industry drug trial sponsors headquartered in Australia.3 This foreign investment makes a valuable contribution to patients and the broader economy in Australia,as highlighted earlier in this report.3 Trialtrove,total number of sponsors of Australian trials in 2022 with Australian headquarters,accessed February 2024 15MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 5Clinical trials by sponsor Source:ANZCTR Data(14 Nov 2023);L.E.K.analysisClinical trials by sponsor(CY2015-22)TotalIndustryNon industry6.56.56.53.44.33.09781,1201,1731,2361,2581,0391,2091,20448241753060861966576364605001,0001,5002,000Number of clinical trials started1,4601,5371,7031,8441,8771,7041,9721,850CAGR%(CY2015-19)(CY2015-22)20152016201720182019202020212022Non-industry sponsored trials or Investigator Initiated Trials(IITs)encompass a wide range,including both academic and collaborative group trials.While these trials do not typically deliver the foreign investment of many industry-sponsored ones,they still bring considerable benefits to the sector by supporting local research,improving clinical outcomes for patients,developing both the clinical trials workforce and infrastructure,and improving clinical practices through evidence-based guidelines.Figure 6Clinical trial activity by phaseSource:ANZCTR Data(14 Nov 2023);L.E.K.analysisClinical trials by phase(excluding trials with no reported phases)(CY2015-22)TotalPhase 45.4(0.9)3.0(6.0)1.20.05.8(6.0)15.39.5CAGR%(CY2015-19)(CY2015-22)1121301631751982212202111951842052582442543422742242042272592352372512248280807902004006008001,000Number of clinical trials started73475853613598668772756759871762Phase 1Phase 2Phase 320152016201720182019202020212022As described in Chapter 1 of this report,clinical trials can be classified into four phases(indicating the stage of development of a drug),while medical device trials can be classified into three stages or phases.Medical device trial phases are not captured by ANZCTR or ClinicalTrials.gov and are instead 16MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORclassified as Not applicable on these databases,an issue that is discussed in greater detail in Chapter 4 of this report.A large proportion of clinical trials do not need to go through all four phases and therefore might not have a phase nomenclature to report.As illustrated by Figure 6 above,Phase I trials have grown the fastest since 2015(9.5%per annum).Phase II trials have grown at 5.0%per annum.The number of Phase III trials have remained flat since 2015,and Phase IV trials have declined during this period by 6%per annum.Phase III and IV studies typically require larger patient numbers and multiple sites globally.Countries that can provide many sites with effective enrolment processes and efficient start-up timelines will be more attractive to sponsors looking to streamline trial operations and costs.Australias relatively small population and geographic spread,as well as the known need to streamline ethics and site governance processes,can hamper Australias ability to bid for these studies.As we increase our ability to engage and recruit our diverse population to clinical trials,improve our start-up processes,as well as improve the infrastructure to run trials outside metro centres,there is a real opportunity to increase the number of later phase trials we can attract to Australia.These trials are more likely to lead to regulatory approvals,as well as the direct economic benefits of the trial investment.Conduct of these trials in Australia also has the potential benefit of giving patients and clinicians early access and experience with these interventions,as well as information on their use in the Australian context for regulatory applications and health technology assessments which may help reduce uncertainty.Clinical trials activity by therapeutic areaThe level of clinical trials activity varies significantly by therapeutic area,reflecting areas of unmet need and R&D intensity,as well as Australias relative strengths versus other countries.Figure 7 below shows how clinical trials activity in ten leading therapeutic areas has grown since 2015.Figure 7Industry and non-industry clinical trials by conditionsSource:ANZCTR;ClinicalTrials.gov;L.E.K.analysisIndustry and non-industry clinical trials by condions,Australia(CY2015-22)PPT(CY2015-19)(CY2015-22)Percent of clinical trials started/Number of clinical trials(2.2)0.52.6(0.2)(0.5)1.0(3.8)0.90.61.11.2(0.3)2.7(1.0)(0.3)(0.1)(2.3)1.1(2.5)1.6Mental HealthOncologyNeurologicalCardiovascularRespiratoryMusculoskeletalInfeconOral and GastrointesnalMetabolic and EndocrineRenal and Urogenital020406080100201520162017201820192020202120229139571,0801,1641,1561,1251,2771,205 17MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOROncology is the most frequently studied therapeutic area in Australian clinical trials.According to the Australian Institute of Health and Welfare(AIHW),it also forms the largest burden of disease in Australia.4 However,the number of oncology clinical trials commenced annually has been consistent,at around 300 trial starts per year since 2018.The fastest growing of the five leading therapeutic areas in Australia is neurology,which has grown at 8%per annum since 2015.With an ageing global population,and an increased burden of dementia,strokes and other neurological diseases in people over the age of 65,there is a need to address care of these conditions,which could explain this increased activity.5 The adjacent therapeutic area of mental health has also displayed strong growth over the period.Both therapeutic areas have,and will continue to benefit from dedicated Medical Research Future Fund(MRFF)Missions,i.e.the Dementia,Ageing and Aged Care Mission,and the Million Minds Mental Health Research Mission,driving greater volumes of non-industry sponsored trials.6Clinical trial activity by stateThe relative intensity of clinical trial activity across states has remained constant since 2019.Of the clinical trials commenced in Australia in 2022,30%have sites in each of Victoria and NSW,in line with what was reported in 2021.Other locations-Western Australia,South Australia,the Northern Territory,Tasmania and Queensland have comparatively lesser activity,given their size and resources.Figure 8Number of clinical trial starts by state in 2022Number of clinical trial starts and share of Australian trials by state in 2022QLD400(22%)NSW566(31%)VIC548(30%)NT166(9%)SA319(22%)WA317(17%)TAS189(10%)ACT192(10%)Note:The sum of the percentages of each state are greater than 100cause each clinical trial could occur in multiple states,in which case it would be counted more than once in the figure aboveSource:ANZCTR Data(14 Nov 2023);L.E.K.analysisThis distribution is due to Victoria and NSW having the largest proportions of Australias population and the most developed clinical trials infrastructure.Both states host some of Australias largest teaching 4 AIHW,Australian Burden of Disease Study 20225 AIHW,Australian Burden of Disease Study 20226 Department of Health and Aged Care,All MRFF Initiatives,accessed February 2024.18MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORhospitals and cancer treatment centres,and of the 58 members of Association of Australian Medical Research Institutes(AAMRI),Victoria and NSW represent 18 and 19 members respectively.7 Despite the higher concentration of MRIs in Victoria and NSW,the presence of large MRIs in other states,such as the South Australian Health and Medical Research Institute(SAHMRI)in South Australia and the QIMR Berghofer Medical Research Institute in Queensland ensures that clinical trials activity is well distributed across states,with South Australia and Queensland holding 22%share of clinical trials activity each.Impact of COVID-19 on clinical trials activity COVID-19 significantly disrupted clinical trials in Australia and around the world.Many clinical trials were paused or postponed due to concerns regarding patient safety,or because of the diversion of healthcare infrastructure to treat COVID-19.The number of clinical trials commenced in Australia in 2020 fell by approximately 10%when compared to 2019.This decline was seen most in non-industry sponsored trials,which decreased from 1,258 in 2019 to 1,039 in 2020.By comparison,the number of industry-sponsored trials rose over the same period,from 619 trials in 2019 to 665 in 2020.Figure 9Clinical trials by sponsor and phaseClinical trials by sponsor(CY2015-22)Clinical trials by phase(CY2015-22)Source:ANZCTR Data(14 Nov 2023);L.E.K.analysis 1,2581,0391,2091,20461966576364605001,0001,5002,000Number of clinical trials started20192020202120221,8771,7041,9721,85019822122021124425434227423523725122419719918692477390290205001,0001,5002,000Thousands of clinical trials started7920194720205820215320221,8771,7041,9721,850172IndustryNon industryOtherDevicePhase 4Phase 3Phase 2Phase 1The total number of clinical trials bounced back strongly in 2021 as most of Australia came out of COVID-19 lockdowns and pandemic restrictions were eased,compared to many other parts of the world.This was largely driven by industry-sponsored clinical trial starts,with 763 trials commenced in 2021 compared to 665 in 2020.Non-industry sponsored trials increased by c.20tween 2020-21 from 1,039 trials in 2020 to 1,209 in 2021 but have yet to completely recover to pre-pandemic levels.This was likely driven by a combination of the following factors:Investigators and industry sponsors began trials in 2021 that were held back or paused in 2020,due to the impact of COVID-19.7 AAMRI website,List of members,accessed February 2024.19MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR Many other parts of the world with similar high quality healthcare systems like Australia continued to be impacted by COVID-19 in 2021(e.g.,through the Omicron strain).8,9 There was a rapid growth in infectious disease and/or respiratory trials related to the development of various COVID-19 vaccines and therapeutics.The urgency created by higher COVID-19 numbers also created more pressure on clinical trials,leading these to be carried out more quickly than usual.The volatility suffered by capital markets providing funding to MTP companies to conduct clinical trials has also likely affected the number of clinical trials observed in 2022,as shown in the following figure.Global venture capital investment in MTP companies began to decline from the latter half of 2021,a factor supported both by independent evidence and feedback from stakeholder conversations.10 Investors sought to preserve their cash in the face of macroeconomic uncertainties(such as the war in Ukraine and generally high global inflation rates).11 The collapse of the Silicon Valley Bank in 2023 was an additional shock to the system.12Figure 10Clinical trials by sponsorNote:*Investment into emerging therapeutic companies,that represent 95%of drug development companies Source:ANZCTR Data(14 Nov 2023);Biotechnology Innovation Organisation;L.E.K.analysisTotalIndustryNon industry6.56.56.53.44.33.0CAGR%(CY2015-19)(CY2015-22)48241753060861905101520253005001,0001,5002,000Number of clinical trials startedVenture capital investment*(CY2015-23)Billions(USD)97820151,12020161,17320171,23620181,25820196651,03920207631,20920216461,20420221,4601,5371,7031,8441,8771,7041,9721,850USRest of the worldClinical trials by sponsor(CY2015-22)All these factors have resulted in tighter R&D budgets for MTP companies and have dampened growth in clinical trial starts in Australia and globally.8 American Hospital Association,New Analysis Shows Continued Negative Impact of COVID-19 on Hospital&Health System Financial Health in 2021,March 2021.9 WHO,COVID-19 continues to disrupt essential health services in 90%of countries,April 2021.10 L.E.K./MTPConnect interviews with sector participants,2023.11 J.P.Morgan,Biopharma Licensing and Venture Report,2023.12 Harvard Business Review,Silicon Valley Banks Focus on Startups Was a Double-Edged Sword,March 2023.20MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOROverview of value derived from clinical trialsClinical trials make a significant,beneficial contribution to Australias health,wellbeing and economy.They deliver an array of direct and indirect health and economic benefits,including job creation,patient health benefits and sector skills development as highlighted in Figure 11 below.Figure 11Benefits across the broader sectorEconomic activityHealth sector benefitsPatient BenefitsMultiplier effectsTreatment expenditure and activityEmployment inmanufacturing&supply chaintherapy deliverypharmaceutical and biotech companiesHealthcare cost savingsIncreased investment in clinical trials that are attracted to the region due to improved accessInvestment in supply chainImproved standard of care and higher efficiencyImproved research culture&infrastructure in healthcareExpert staffHospital staffand researchers developnew skills and expertiseAdditional QALY upliftIncreased personal spendWider economy multiplier effectsIncreased workforce participation By healthy patientsResearch profileSector benefits contribute to an increased profile for Australian research,which ultimately leads to greater R&D spend and activityImproved treatment&patient outcomes,from Direct benefits of clinical trial participation(e.g.early access to novel treatments)Benefits from clinical evidence generated by clinical trialsSource:MTPConnects 2022 Sector Competitiveness Plan Report;Medicines Matter 2022 report;L.E.K.research and analysisThese benefits do not just apply to those patients who directly participate in clinical trials:their impacts resonate across the broader healthcare sector,through stronger research and health ecosystems and culture,improved standards of care and a more highly skilled workforce.Patients involved in clinical trials(even in placebo treatments)typically have better health outcomes,as do patients treated in hospitals conducting clinical trials,even if the latter are not involved in a clinical trial.The wider Australian economy also benefits,through increased workforce participation(from healthier patients),increased personal spending(by patients and sector employees)and increased tax revenues to support further government expenditure in the sector.All these benefits reinforce each other in turn.They are covered in more detail in Appendix 8,which focuses on the various components of value derived from clinical trials,a topic also addressed in the two previous reports.21MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORThis chapter analyses the economic and health benefits of clinical trials derived by Australia in 2022 and highlights how these have evolved as the sector has emerged from the impacts of the COVID-19 pandemic.Economic activity Clinical trials expenditure and fundingClinical trials contributed approximately$1.6 billion to the Australian economy through direct expenditure or investment in 2022,up by 13%from$1.4 billion in 2019.This represents a compound annual growth rate(CAGR)of 4.1%per annum between 2019-22.In comparison,the 2021 report showed that total clinical trials expenditure grew by 6.5%per annum between 2015-19.The slowing growth in expenditure between 2019-22 is largely attributed to the number of trials remaining flat over the period,due to the disruption caused by the COVID-19 pandemic.Overall,the total expenditure of$1.6 billion on clinical trials represents approximately 22%of total spending on health research in Australia in 2022,which is at the same level as in 2019.13Figure 12Value of clinical trials activity in Australia,by source of funding14,15,16,17Value of clinical trials activity in Australia,by source of funding(CY2015,2019,2022)93004008001,2001,600Millions of AUD101002015100160401,1002019150801201,25020221,1001,4001,6006.5%p.a.4.1%p.a.482619646Number of non-industry sponsored trials Number of industry sponsored trials97812581204OtherNHMRCMRFFIndustrySource:MRFF;AAMRI;NHMRC;PBS;ANZCTR;Clinicaltrials.gov;L.E.K.research and analysisThe expenditure on industry-sponsored trials increased by 4%per annum,from$1.1 billion in 2019 to$1.3 billion in 2022.This growth in economic value can be explained by two key factors:Growth in the number of industry-sponsored trials,which grew by 2.4%per annum from 619 trials in 2019 to 646 trials in 2022.This is discussed further in the following section of this report,Clinical trials activity in Australia.13 AIHW estimates of total spending on health research in Australia was$6.3 billion in 2019 and$7.3 billion in 2022.14 Industry refers to all trial expenditure sponsored by MTP companies.15 MRFF refers to all trial expenditure sponsored by the MRFF.16 NHMRC refers to all trial expenditure sponsored by the National Health and Medical Research Council(NHMRC).17 Other refers to all trial expenditure funded by non-government or other government sources,and university,hospital and MRI investment income.22MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR An increase in underlying operational costs for these trials,driven by the increase in the number of complex trials(including areas such as precision oncology),and rising costs of equipment,drugs and services as a result of inflation.Approximately 9%of industry-sponsored trial expenditure is related to medical device trials,with the remaining 91%related to drug trials.This mix reflects the relative proportion of total trial starts for medical device and drug trials in Australia in 2022.18 Expenditure by non-industry organisations(MRFF,NHMRC and Other in the figure above)such as universities,hospitals and MRIs on clinical trials was estimated at$350 million,an increase of 17%from$300 million from 2019.The MRFF funded$120 million of clinical trials expenditure in 2022.This included expenditure directly through its Clinical Trials Activity initiative,as well as expenditure through any MRFF Missions that included plans for clinical trials.The approach used by this report to calculate the total MRFF expenditure has been refined from the methodology used in the 2021 report,which only included the Clinical Trials Activity initiative.The revised approach provides a closer estimate of MRFF clinical trials expenditure.The$120 million estimate represents the probable minimum MRFF funding supporting clinical trials,as the MRFF also funds clinical research through other initiatives such as the Medical Research Commercialisation initiative,where clinical trial expenditure cannot be easily apportioned.The NHMRC funded$80 million of clinical trials expenditure in 2022 in the form of competitive grants.It should be noted that,like MRFF expenditure,this reports approach used to estimate the NHMRC contribution has been refined from that used in the 2021 report,based on insights from industry stakeholders.It now only includes expenditure through the Clinical Trials and Cohort Studies(CTCS)Grants scheme and excludes all other NHMRC grants.19 Expenditure by Others(such as universities,hospitals and MRIs)on clinical trials grew from$100 million in 2019 to$150 million in 2022(up 16%per annum).This income is derived from non-government sources(non-government grants from Trusts and Foundations,commercial income,philanthropy),other government sources(e.g.,state governments),and other sources(investment income,one-off income such as the sale of a large asset or one-off schemes).This growth continues an eight-year trend,where non-government sourced income has grown from 50%of total independent MRI revenue in 2014 to 64%in 2020.The largest drivers of the growth in Other expenditure are growing commercial incomes and other incomes,the latter benefitting most from one-off schemes started during the COVID-19 period.20,21 For context,non-industry sponsored trials in the United Kingdom account for a larger portion of the economic value generated by clinical research.In 2020,they contributed 33%($1.7 billion)of the total gross value added(GVA)by clinical research.22 In contrast,non-industry sponsored trials in Australia 18 See section Clinical trials activity in Australia for more detail.19 L.E.K./MTPConnect interviews with sector participants,2023.20 AAMRI,The AAMRI Report 2022.21 Commercial income reported by MRIs refers to income from licencing,royalties and other returns from commercialising their research intellectual property(IP)or collaboration with industry on research projects.22 United Kingdom,Department for Science,Innovation&Technology,Independent report:Commercial clinical trials in the UK:the Lord OShaughnessy review-final report,May 2023.23MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORduring the same period only accounted for 22%($300 million)of the total value of clinical trials.These findings underscore the necessity for greater government funding of clinical trials in Australia,particularly to support an increase in non-industry sponsored trial activity,in order to align with leading research nations internationally.It is worth noting that the overall expenditure on clinical trials includes the cost of investigational drugs and devices provided by sponsors in clinical trials.It does not include avoided healthcare costs,which are sometimes covered by trial sponsors.These include the cost of pathology testing,diagnostic imaging,in person clinical examinations and other incidental costs.Clinical trials employmentAs can be seen in Figure 13,approximately 7,700 people were directly employed by the clinical trials sector in 2022,a decrease of 3.8%relative to 2019 levels.Employees are comprised of two main categories:Clinical,research and management staff employed at MTP companies and service providers such as CROs,MRIs and academic trial centres.Clinical staff employed within hospitals,clinics and other trial sites.Figure 13Employment activity for clinical trials in AustraliaSource:ANZCTR;Clinicaltrials.gov;L.E.K.research and analysisNumber of clinicaltrials starts146018771850Employment activity for clinical trials in Australia(CY2015,2019,2022)4,7002,20002,0004,0006,0008,00010,000Number of FTEs20152,6005,40020192,6005,10020226,9008,0007,700Hospital staffResearch&management staffThe lack of growth in employment figures is supported by the overall number of clinical trial starts in Australia,which was 1,877 in 2019 and 1,850 in 2022.Sector participants have also cited a lack of growth in workforce over this period and noted several challenges,including:The research workforce,which has become increasingly casualised over this period as clinical trial sites in particular have faced increasing budgetary pressures.23 23 L.E.K./MTPConnect interviews with sector participants,2023.24MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR The lack of a clear pathway to recruit and develop new clinical research staff from universities and related professions.Individual companies are developing their own approaches to recruiting new staff(for example,from PhD programs).The 4cline in the clinical trials workforce between 2019-22 in the setting of a 1cline in clinical trials means research organisations are having to run more clinical trials with fewer staff.An over-burdened workforce increases risks of staff burnout,perpetuating even greater loss of staff from the sector,in addition to increased risk of reduced efficiency and quality of work.Developing a sustainable and skilled clinical trial workforce is a key priority for the sector,in order to ensure continued growth.This has been an ongoing issue across the sector,with this analysis showing that the size of clinical trial workforce has likely declined over the period.More needs to be done by industry and government sources to address this.This is discussed further in Chapter 4 of this report,Future Outlook and Priorities for the Sector.It should be noted that the total employment figure is likely to be higher because the employment estimate only considers full-time equivalent(FTE)employees who directly contribute to the trial process.It does not consider independent/sole contractors or clinical staff employed within hospitals,clinics and other trial sites,who may have indirect roles in clinical trials(for example,staff employed in pharmacy,pathology and imaging facilities).Patient and sector benefitsParticipant/patient benefits Patients are the main beneficiaries of clinical trials,and they derive benefit in a number of ways:Through early access to new medical/health interventions,that can result in better clinical outcomes such as higher survival or lower mortality rates.24 Through receiving closer clinical surveillance and better clinician adherence with evidence-based care,which ultimately leads to better health outcomes.This benefit extends not only to patients within trials,but also non-trial patients within trial-active hospitals.25,26 Trial participants can become more interested in their health and become more Activated empowered with the knowledge,skills and confidence to better manage their health,which often leads have better health outcomes.27 Evidence generated from the clinical trials supports improved clinical practice and the provision of new safe and effective treatments.Since publicly available data on the number of Australians who participate in clinical trials each year is limited,the 2021 edition of this report developed an estimate using MTPConnect industry survey results and an analysis of patient numbers by trial phase and therapy area.This report has further refined this 24 Bouzalmate-Hajjaj,Amira et al.,Benefits of Participation in Clinical Trials:An Umbrella Review.International Journal of Environmental Research and Public Health,November 2022.25 National Institutes of Health(NIH),Clinical Trials,Benefits,Risks and Safety Measures,accessed February 2024.26 Krzyzanowska,Kaplan,Sullivan,How may clinical research improve healthcare outcomes?,Annals of Oncology,November 2011.27 Greene,J.,Hibbard,J.H.,Why Does Patient Activation Matter?An Examination of the Relationships Between Patient Activation and Health-Related Outcomes.,Journal of General Internal Medicine,November 2011.25MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORmethodology to consider patient participation in industry-sponsored and non-industry sponsored trials separately.Details of the methodology can be found in Appendix 7.Figure 14Patient participation in clinical trials 2019,202220192022Source:ANZCTR;Clinicaltrials.gov;L.E.K.research and analysisEstimated number of patients to have participated in trials5000 Patients95,000Patients90,000PatientsBased on this updated methodology,an estimated 90,000 patients participated in clinical trials in Australia in 2022,representing a decline of approximately 5%from 95,000 patients in 2019.This difference is attributed to the following three factors:The change of methodology between calculating the 2019 and 2022 patient participation figures for non-industry sponsored trials.The overall volume of trials in 2022 has declined slightly compared to 2019,as mentioned earlier in this report.A continued shift in the phase mix of trials towards early phase trials(Phases I and II),as compared to later phase trials(Phases III and IV).These details are covered in Chapter 3 and 4 of this report.Early phase trials tend to have smaller patient cohorts compared to later phase trials,so the change in phase mix of trials drives a slight decline in overall patient participation.Approximately four out of every 1,000 Australians participate in clinical trials per year.While it is difficult to directly compare Australian patient participation with global benchmarks,there appears to be potential for even greater participation rates in Australia.When compared with clinical trial recruitment rates in the United Kingdom,where at least 19 out of every 1,000 British people participated in clinical trials in 2022,there is the potential to increase longer term participation by four to five times more than the current levels in Australia.28 A likely driver of this difference is the United Kingdoms higher rate of later-phase trials,which typically have greater participation rates than early-phase trials,as discussed above.In 2020,industry-sponsored trials in the United Kingdom had c.3x the number of Phase III trials 28 NIHR,NIHR Annual Report 2022/23,based on 1,289,937 trial participants in the U.K.between April 2021 and March 2022 across the NIHR CRN portfolio of trials,which represents only a subset of all trials.The U.K.population was approximately 67,500,000 in 2022.26MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORto Phase I trials.29 By comparison,ANZCTR data shows that industry-sponsored Phase I and III trials in Australia were roughly equal over the same period.Sector benefitsA strong and globally competitive clinical trials sector generates broader benefits for the healthcare ecosystem,including:Enhancing clinical capability and clinical practice development:clinical trials provide evidence of efficacy for new treatments and improvements to standards of care that deliver enduring benefits to Australias healthcare system,and also help identify unnecessary and ineffective interventions.The clinical staff involved in trials gain experience with innovative therapies that will become the future standards of care.This could lead to faster adoption and application of the latest R&D practices in clinical medicine,as well as the implementation of these into broader policy and practice in the sector.Attracting the best global clinical talent-Clinicians and researchers want to work at the cutting edge of their field.-This improves the sector in two ways:More skilled/knowledgeable clinicians/researchers help to improve Australias capabilities and reputation,attracting and enabling more complex and higher value clinical trials.More clinicians/researchers help to resolve the current lack of clinician/researcher capacity,which has been a longstanding issue,and growing more since COVID.Elevating translational research capability:the funding of trials contributes to infrastructure availability at clinical sites and supports further R&D in healthcare.In parallel,Investigator Initiated Trials(IITs)and high-quality academic research build further capability and capacity,elevate care standards in Australia and contribute to the international reputation of Australian medical experts,investigators and research staff.This further enhances Australias position as an attractive market for clinical trials and eventually,for the market entry of new and novel products.Supporting manufacturing of medical products:Australia is growing the medical product manufacturing industry,committing at least$1.5 billion to a Medical Manufacturing Fund,as one of the National Reconstruction Funds seven priority areas.30 Clinical trials are an important part of the commercialisation pathway for medical products.They also provide an avenue to test and validate Australias competitiveness in scaling up manufacturing capabilities in areas of research such as vaccine production,stem cell and gene therapies.Large-scale production can be anchored to the location where clinical trials take place.Providing products to local clinical trials can also be an important source of income for Australian medical manufacturers.The significance of these broader sector benefits was amplified throughout COVID-19.Australias clinical trials sector drove translational research and the development of several COVID-19 vaccine candidates,including homegrown and international candidates,rapidly skilled up thousands of healthcare practitioners in vaccine administration,provided trial participants with early access to protection against 29 Association of the British Pharmaceutical Industry,Clinical research in the UK:an opportunity for growth,2021.30 Department of Industry,Science,and Resources,October 2020.27MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORsevere COVID-19,and developed new manufacturing capabilities,such as the Moderna mRNA and CSL facilities in Victoria and the Sanofi Translational Science Hub in Queensland.The increase in economic activity and the flow-on benefits of conducting clinical trials contribute to the broader economy,multiplying the direct economic impact of these trials.These multiplier effects are difficult to determine accurately and as such,are excluded from the overall estimate of the economic impact of clinical trials in Australia.28MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR3.Australias position in the global clinical trial landscapeAustralias global position in clinical trialsOverall,Australia has maintained its share of industry-sponsored trials over the 2015-2022 period,sitting at a 5%market share across the 15 comparison countries studied in the 2021 and 2017 reports.This list has been maintained to allow for direct comparison between reports.As Figure 15 demonstrates,growth in global trials across these 15 countries has been flat since 2015,with between 9,000 and 10,000 trials commenced per year during 2015-2022.The research behind this report has also reviewed the material growth in countries outside the comparison set of 15,to identify up-and-coming markets.Poland and Brazil are two countries that have,in recent years,increased their activity in clinical trials.Poland has surpassed Denmark,the Netherlands,and Belgium in its share of global trials,with 2.5%of global trials in 2022.Brazil has demonstrated the greatest increase in share of trials across all countries in the top-20 countries globally,growing from 1.0%in 2019 to 1.4%in 2022.Figure 15Industry-sponsored drug and device trials across 15 common countries,2015-2022Note:*Includes Drug,Device,and Drug&Device intervention types only.Includes Industry sponsored trials only.Withdrawn trials are excluded.Trial counts are based on planned recruitment within each country the same trial may be counted in multiple countriesSource:ClinicalTrials.gov(as at 14/01/2024);L.E.K.analysisIndustry sponsored drug and device trials started,by 15 common countries*(CY2015-22)PPT(CY2015-19)(CY2015-22)Germany(1.6)(2.9)United Kingdom(1.0)(2.1)Canada(0.6)(1.4)Italy(0.1)(0.5)Korea,Republic of(0.1)(0.0)Belgium(0.7)(1.5)Netherlands(0.7)(0.9)Denmark0.0(0.6)Singapore(0.1)0.1 Malaysia0.0(0.0)Spain0.5 0.4 United States(0.5)0.4 China5.2 8.9 France(0.3)(0.5)Australia0.0 0.7 020406080100Percent of clinical trials started/Number of clinical trials4 154 165 175 184 195 205 215 229,0438,2419,0009,2189,3859,36711,1709,360On a per capita basis,Australia attracts approximately 19 industry-sponsored trials per one million people,and as such it leads the top 10 countries by industry-sponsored clinical trial share,as illustrated in Figure 16 below.Growth in the number of clinical trials in Australia across 2015 2022 sits second only to China,which has had explosive growth over this period,increasing its share of trials by 9%.Importantly,Chinas growth appears to stem from trials conducted by Chinese companies who are responsible for c.75%of all Chinese industry-sponsored trials.31 This serves as further evidence that Australia is a very attractive destination for industry-sponsored 31 Clinical Trials Arena,The great wall:why overseas sponsors are yet to fully tap into Chinas clinical trial resources,May 2022.29MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORclinical trials.However,as examined earlier in Chapter 2 under Participation/patient benefits,Australia still lags behind other countries such as the United Kingdom on overall(non-industry and industry-sponsored trial)patient participation rates,indicating fewer patients per trial than in other countries.Figure 16Industry-sponsored drug and device trials per capita,top 10 countries by shareNote:*Data represents only trials registered on ClinicalTrials.gov,which is a subset of all clinical trials and underestimates the number of trials per capitaSource:ClinicalTrials.gov(as at 14/01/2024)Industry-sponsored drug and device trials per capita,top-10 countries by share*Trials per million of population,2022Share of global trialsUnited States8.5 20.0%China0.8 8.0%Spain13.9 4.7%France9.1 4.4%Germany7.3 4.3%United Kingdom8.8 4.2nada13.4 3.7%Italy8.4 3.5%Australia18.5 3.4%Korea,Republic of17.1 3.1%As illustrated by Figure 17 below,Australia has continued its strong performance in global industry-sponsored early phase trials.In the 2020-22 period,its share of global,industry-sponsored Phase I and II trials increased by two percentage points over the previous period(2017-19).Australia has also held its share of multi-country,industry-sponsored Phase III trials at a steady 44%over 2020-22,similar to the 45%figure observed for 2017-19.However,its share of Phase IV trials has continued the downward trend seen in 2021,with 18%of multi-country,Phase IV trials having an Australian site in 2020-22,as compared to 21%in 2017-19.30MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 17Australias share of industry-sponsored drug and device trials,vs its share of multi-country trialsNote:*Includes Drug,Device,and Drug&Device intervention types only.Includes Industry sponsored trials only.Withdrawn trials are excluded;*Multi-country trials defined as trials with enrolment in more than three countries Source:ClinicalTrials.gov(as at 14/01/2024);L.E.K.analysis 6.0%8.7%8.2.81015Percent of all trials startedPhase 1Phase 2 2.2 2.245!D530456075Percent of all multi-country trials startedPhase IIIPhase IVOther-1.1-2.9-0.2CY2017-19CY2020-222017-192020-22246365CY2017-19395515CY2020-224901652CY2017-194731245CY2020-22Number of trials started in AustraliaNumber of multi-country trials started in Australia*Australias share of industry sponsored drug and device trials*,by phase(CY2017-19,CY2020-22)Australias share of multi-country*industry sponsored drug and device trials*,by phase(CY2017-19,CY2020-22)This decline in later-phase trials presents an opportunity for growth if Australia can implement appropriate mechanisms to incentivise industry investment in such trials.Stakeholder consultations have highlighted that multinational pharmaceutical and medical device companies are increasingly considering the ethical and economic implications of running late-stage trials in countries where they do not plan a commercial launch.This could particularly be the case for new modalities with no clear commercial pathways,such as cell and gene therapies and radiopharmaceuticals.Lowering the barrier to reimbursement for innovative therapies through improvements to the health technology assessment process may be a mechanism to help incentivise sponsors to initiate late-phase trials in Australia.This offers two key benefits;earlier(and ongoing)access to novel and typically expensive therapies for patients who might not otherwise have access to these medicines;and the possibility of attracting additional investment into late-stage trials,research and manufacturing infrastructure and new jobs.32 The ongoing Health Technology Assessment Policy and Methods Review provides an opportunity to ensure the reimbursement approval processes address this need.Figure 18 below shows supportive evidence that lower barriers to reimbursement incentivises companies to initiate late-phase trials in Australia.Analysis of unique,non-biosimilar molecules approved by the Therapeutic Good Administration(TGA)since 2019 shows that 84%of the molecules that successfully received Pharmaceutical Benefits Scheme(PBS)reimbursement approval had associated Phase III or IV trials in Australia.Conversely,only 64%of molecules that were not PBS reimbursed had associated Phase III or IV trials in Australia.This suggests either that therapies with a higher likelihood of PBS reimbursement are more likely to be trialled in Australia,or that evidence obtained in the Australian context is viewed more favourably by health technology assessment(HTA)review bodies.The causal relationship between these two outcomes is not clear,but the analysis suggests a link.32 L.E.K./MTPConnect interviews with sector participants,2023.31MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 18Number of unique TGA-approved moleculesNote:*The 168 molecules described in the chart exclude biosimilars;*There is a time-lag between TGA approval and PBS reimbursement,with 57%of TGA approved drugs in 2019 approved for reimbursement,compared to 11%in 2023,and 0%in 2024Source:Trialtrove;PBS;TGA;National Immunisation Program;L.E.K.research and analysisNumber of unique molecules with TGA approval*(CY2019-24)020406080100Per cent/number of unique molecules66%(111)34%(57)Non-PBSreimbursedPBS reimbursed*16816%(9)84%(48)Clinical trials associated with PBS reimbursed moleculesNo AustralianPhase III/IV trialsHas Australian Phase III/IV trials5733%(37)67%(74)Clinical trials associated with non-PBS reimbursed moleculesNo AustralianPhase III/IV trialsHas Australian Phase III/IV trials111Australias competitiveness by therapeutic areaAustralia has also maintained its competitiveness in the large oncology trials sector,with its share of global,multi-country oncology trials growing by 7%in 2020-22,as compared to 2017-19.Oncology trials represent the large majority of trial activity with 32%of all industry-sponsored trial starts globally over the period of 2020-22.33 Other key therapeutic areas where Australia has gained share over the last three-year period are respiratory(likely related to COVID-19),cardiovascular and nephrology.33 Trialtrove,calculated as the proportion of all industry trials within the oncology therapeutic area between the period of Jan 2020 Dec 2022.32MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORFigure 19Australias share of global industry-sponsored drug and device multi-country trials,by country and therapeutic areaNote:*Includes Drug,Device,and Drug&Device intervention types only.Includes Industry and Industry&Other sponsored trials only.Withdrawn trials are excluded.Multi-country trials are defined as having planned recruitment in more than three countries.Therapeutic areas were determined using a search of key words within the conditions field in the clinical trial database excludes trials where multiple therapeutic areas were foundSource:ClinicalTrials.gov(as at 14/01/2024);L.E.K.analysisAustralias share of global industry sponsored drug and device multi-country trials,by country and therapeutic area*(CY2017-19,CY2020-22)33067453245501315227CY2017-1939578464036332221216CY2020-22Number of multi-country trials started in Australia*43293826244535143230503144212837412838270255075100Gastro-intestinalOpthalmologyMusculo-skeletalEndocrin-ologyNephrologyCardiovascularInfectious diseaseRespiratoryNeurology/Mental HealthPercent of all global multi-country trials startedOncology 7.0 2.6 5.7-4.5 3.5-8.0 5.6 14.1 6.3-3.22017-192020-22Sources of competitive advantageAs Figure 19 shows,Australia has managed to maintain its overall share of global trials and it continues to strengthen its global share of early phase trials and oncology trials.These successes indicate that Australias traditional competitive advantages in hosting clinical trials still help Australia to differentiate itself in this market.Its key sources of competitive advantage are:A strong reputation for the quality and global standing of its investigators and the networks that support them.Robust research infrastructure and systems that enabled Australia to continue conducting clinical trials through disruptive global events such as the COVID-19 pandemic.High-quality data collection systems and overall compliance with Good Clinical Practice(GCP)guidelines,which ensures that data collected in Australian trials can support submissions to international regulators,including the United States Federal Drug Administration(FDA)and the European Unions European Medicine Agency(EMA).Specialised and dedicated early-phase infrastructure that enables the delivery of timely,high-quality trials,supported by streamlined processes and private ethics committees.The convenience and speed of the Therapeutic Good Administrations Clinical Trial Notification(CTN)scheme,which enables the faster start-up times that are particularly crucial for early phase trials.The tax relief provided by the Australian governments extension of its R&D tax incentives,improving Australias cost competitiveness.33MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORThe combination of these factors has not only continued to position Australia as an attractive clinical trials destination globally but has also served to grow the economic footprint of the sector.The case of BeiGenes rapid growth of its Australian operations(see below)is illustrative in this respect.Case study BeiGene BeiGene is a global biotechnology company specialising in the development of cancer treatment drugs.Founded in 2010 in Beijing,it has grown significantly throughout the world,with a particularly strong presence in both Beijing and the US.Between 2018 and 2023,it has rapidly grown outside of these two locations,with a 34%year on year growth rate across these five years.Since starting its first Australian clinical trial in 2013 for Lifirafenib,BeiGene has enrolled 2,200 patients in 40 trials in Australia.BeiGenes growth in Australia has also augmented the broader economy,adding over 180 jobs across six states in Australia,with approximately 75%of these employees working in clinical operations.Furthermore,BeiGenes product testing is deeply integrated into the healthcare system,with its treatments tested at over 300 sites and over 90 hospitals and clinics across Australia.Figure 20BeiGene timeline in AustraliaNotes:*Waldenstrms macroglobulinemia;*Mantle Cell LymphomaSource:Company website;L.E.K.research and analysisBegan clinical development of Pamiparib and Zanubrutinib in AustraliaAdrian Dunstan onboarded as the inaugural ANZ head to build the commercial team in AustraliaBeiGene opened its first Australian office in SydneyCommenced Australian operations and began clinical development of LifirafenibBRUKINSA(Zanubrutinib)received approval in Australia for the treatment of adult patients with WM*BRUKINSA(Zanubrutinib)listed on the Pharmaceutical Benefits Scheme(PBS)for Patients with MCL*FTE count 4FTE count 120FTE count 1802014Oct 2021Dec 20222013Mar 2022Oct 2021BeiGenes leadership attributes its increasing investment in Australia to the countrys strong clinical research ecosystem.In particular:34MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR1.A strong clinical trials networkAustralia hosts over 50 clinical trial networks providing Phase I to IV clinical trials.The industrys 7,700 strong workforce includes individuals with expertise spanning all aspects of life sciences.“BeiGenes leadership identified Australia as a country with strong commitment to clinical trials and the capabilities to successfully conduct complex and critical first-in-human studies”Dr Arthur Alston,BeiGene Head of Medical Affairs,APAC2.An efficient and globally recognised regulatory systemAustralia has a globally recognised regulatory system(accepted by the United States Food and Drug Administration,and similar bodies within Europe,the Middle East and Africa,among others)that leverages systems such as the Clinical Trials Notification(CTN)scheme to promote quicker regulatory approval.“On average in Australia,the first patient into a clinical trial after approvals is about three months,whereas in the US or the EU,its six to nine months its efficient”Adam Roach,BeiGene Head of APAC3.Attractive R&D grants and incentivesAustralia offers many grants and incentives to promote medical research and development.The NHMRC provides over$100 million in funding annually through various programs.Tax benefits are available under the R&D Tax Incentive scheme which BeiGene has been able to leverage to increase its investment in clinical trials.34 Other funds include the Medical Research Future Fund($750 million over 2022-32),the mRNA Clinical Trials Enabling Infrastructure Grant Opportunity and the Biomedical Translation Fund($500 million).34 Cancer Trials Australia,BeiGene works with Cancer Trials Australia for its Australian clinical trials,August 2019.35MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR4.Future outlook and priorities for the sectorThis final chapter identifies the themes and trends that will shape the future dynamics of clinical trials and determine the scope and nature of the opportunities for the Australian clinical trial sector.It outlines current impediments and areas for further development and highlights the key priorities for the future that will enable Australias clinical trials sector to continue to grow.Overall,these issues are consistent with and build on the opportunities and priorities identified in MTPConnects previous two reports.This reflects the growing need to address these challenges,in order to prevent the sector from stagnation or worse,decline.This chapter highlights some(but not all)of the last three years developments most notably,the National One Stop Shop(NOSS)reform and its potential for broad-based positive impacts on the sector.Emerging opportunities in clinical trialsOur 2021 report identified four emerging healthcare trends that could create new opportunities for Australias clinical trials stakeholders.These are still relevant today and our 2024 report has identified an additional fifth priority around medical device trials.The five priorities are:1.Patient awareness,engagement and centricity:Patient advocacy groups have played a significant role in increasing patient awareness and engagement in clinical trials,an important factor behind the successful growth of clinical trials.These groups are striving to heighten patient awareness,yet they continue to face challenges due to disparities in funding among advocacy organisations and suffer from the innate challenges of conveying information that requires technical proficiency to comprehend effectively.Consumer engagement and involvement is increasing,especially within academic trials.However,Australia still has significant headroom to grow patient participation in clinical trials.This can only be achieved by educating patients about clinical trials,the value they provide,and designing trials in such a way that engages patients and reduces barriers to participation.35 There is a need to further understand the experience of trial participants in the Australian context,to identify strategies for enhancing enrolment and retention in clinical trials,for example,cultural and language barriers,health and research literacy,and time and financial impacts.In particular,there is very limited engagement of Aboriginal and Torres Strait Islander and CALD communities in clinical trials,and no tracking of their participation in clinical trials.The awareness of the importance of engaging diverse populations is growing,highlighted by recommendations from the United States FDA which sets out guidance for sponsors to increase enrolment of underrepresented populations in clinical trials.36 There is also a growing understanding of how important patient centricity is to trial design.This includes trials that prioritise the needs of the patient from design to delivery,with the number of PubMed publications mentioning patient centricity in the context of clinical trials increasing by 78tween 2019 to 2022.Government support for patient centricity is also growing,with the Co-design of an Enhanced Consumer Engagement Process for HTA consultation that was delivered by the Australian Government Department of Health and Aged Care(DoHAC)in April 2024 proposing recommendations to enhance consumer engagement in relation to HTA processes undertaken by the TGA,Pharmaceutical 35 L.E.K./MTPConnect interviews with sector participants,2023.36United States FDA,Enhancing the Diversity of Clinical Trial Populations Eligibility Criteria,Enrolment Practices,and Trial Designs Guidance for Industry,November 2020.36MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORBenefits Advisory Committee(PBAC),and other HTA committees,and onwards to subsidised listing and post-market reviews.37 The emergence of decentralised clinical trials(DCT)is one of several solutions helping the shift towards patient centricity,by improving access for patients,especially those in rural and regional areas,and allowing trial designers to improve their understanding of patient perspectives from a broader demographic.As for patient centricity in trials,there has been a significant(300%)increase in clinical trials mentioning decentralisation between 2019 to 2022;however,the sample size for this remains small,with only 10 trials on Trialtrove reporting decentralisation in 2019,and wide variation in what decentralisation means.38OpportunityThere is a further need for flexible trial designs that involve and engage the diversity of patients,carers and communities(including Aboriginal and Torres Strait Islander peoples and other culturally and linguistically diverse communities).Improving access will allow Australia to better leverage its highly diverse population.39 Not only will this ensure that clinical trial study populations will more accurately reflect the patients likely to receive the therapy after approval,but will increase the attractiveness of Australia to trial sponsors seeking to meet diversity requirements.40 At the same time,there is more scope for advocacy group activity and other measures(including Government support of these groups)to continue raising patient awareness and engagement in trials.Allowing feedback from these broad and diverse patient groups to be integrated into trial design and management.Increasing patient awareness,engagement and understanding in clinical trials is also a key part of the NOSS mandate,and this could represent a key avenue for driving education and awareness campaigns to improve patient participation.Efforts to increase awareness will need to be matched with efforts to improve access,including improving the ability for patients to identify relevant trials,and working to support sites and sponsors in improving the dissemination of information on clinical trials.These measures will help Australias clinical trials sector achieve a broader patient reach and better clinical outcomes for all Australians and increase patient access,recruitment and retention in under-represented populations.Improving access to these populations will allow Australia to better leverage our population diversity and further increase Australias attractiveness in clinical trials,as awareness of the need for diversity in clinical trials participation globally continues to grow.4142 This will also help the Australian clinical trial sector attract more local and international clinical trials sponsors.37 Australian Government Department of Health and Aged Care:Co-design of an Enhanced Consumer Engagement Process for health technology assessment,202438 Symons,T,A mapping exercise to identify initiatives to support the implementation of decentralised clinical trials including teletrials in Australia,CT:IQ,December 202339 Australian Human Rights Commission,Face the facts:Cultural Diversity,accessed February 2024.40 L.E.K./MTPConnect interviews with sector participants,2023.41 L.E.K./MTPConnect interviews with sector participants,2023.42 Schwartz et al.,Why Diverse Clinical Trial Participation Matters,The New England Journal of Medicine,April 2023.37MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR2.Digital health solutions:The adoption of telehealth and other digital health solutions across the healthcare sector grew considerably during COVID-19.In clinical trial settings,digital health solutions have supported patient recruitment with online portals,e-consent,AI matching and patient engagement,and remote monitoring solutions.These solutions have been adopted and applied more recently and more often to healthy volunteer trials(for example,vaccine trials),which have less clinical complexity compared to patient-focused trials(for example,oncology trials).The creation and expansion of centralised,national patient registries is a digital health solution that has been highlighted by industry stakeholders as a useful tool for accelerating the trial patient recruitment process,especially for patients with rare and chronic diseases.Since the last iteration of this report,there has been some notable growth and development in this space.One example is the introduction of the$75 million Australian Teletrial Program,supported by government investment under the MRFF from 2021 onwards.The program aims to improve access to and participation in clinical trials for rural,regional,and remote Australians by using telehealth to connect clinical trial site clusters in these areas.43OpportunitySignificant potential exists for Australias clinical trials sector to increase and harmonise the adoption of digital health and AI in relevant clinical trials.Policies such as those relating to remote access to electronic medical records and patient data(in line with the Governments new digital health strategy)can be made simpler.There also needs to be appropriate digital literacy training provided to various parts of the community,to further minimise barriers to access.Remote monitoring and e-consent can reduce the need for travel that might otherwise make participation for those in rural and remote areas impossible.Increasing access increases the patient pool and reduces the financial and time burden on the patient.This will improve equitable access to clinical trials,as well as support improved patient recruitment and improved efficiencies in trial conduct.3.Precision healthcare:Precision medicine trials are expanding in number and scope,with over 63%of oncology trials in 2022 utilising biomarkers,up from 56%in 2015.44 The growth in these trials is further supported by innovative services such as PrOSPeCT,which has secured$185m of funding from government and industry for Comprehensive Genomic Profiling(CGP)-driven trials matching.PrOSPeCTPrOSPeCT(Precision Oncology Screening Platform Enabling Clinical Trials)is Australias largest cancer genomics initiative.It brings precision oncology trials to the Australian community by linking genomic technology to trials of new therapeutic products.Led by Omico and officially launched in July 202345,PrOSPeCT seeks to screen 20,000 late-stage cancer patients and place an additional 3,000 patients onto clinical trials within the next two years.43 Australian Teletrial Program website,accessed February 2024.44 Trialtrove,accessed February 2024.45 Omico website,accessed February 2024.38MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORThe$185 million program investment comprises$61.2 million from the Australian Governments Medical Products stream of the National Manufacturing Priority,$25 million from the NSW government,up to$20 million from Roche Australia,and a commercial collaboration between Omico,the National Computational Infrastructure at Australian National University,and the Children Cancer Institute.PrOSPeCTs key aims over the next two years are to:Undertake comprehensive genomic profiling of 20,000 cancer patients or people with unmet clinical needs.Empower$525 million in new direct investment in locally based clinical trials.Deliver 650 new jobs for research scientists involved in genomics,clinical trials and diagnosticsThe Governments commitment to precision healthcare in PrOSPeCT is mirrored in other organisations such as Zero Childhood Cancer project,which drew$67 million of joint funding from the MRFF and the Minderoo Foundation.46 The program provides in-depth genomic analysis to support cancer treatment for all Australian children.This creates opportunities to drive growth in the adjacent research area of paediatric trials,where stakeholders have been calling out for greater investment and there is evidence of sector evolution internationally,with the United States FDA now requiring companies to have a strategy for developing drugs for paediatric populations.47 The paediatric trial opportunity in Australia is small,but the benefit to patients and families,and the healthcare system could be large.48OpportunityThe Australian clinical trials sector can further develop the infrastructure,capabilities and skills required to support precision medicine trials.One approach involves expanding the reach of CGP services offered to patients,through innovative programs like PrOSPeCT and by establishing digital technologies to streamline how patients are matched onto trials.Improvements like these will continue to position Australia as an attractive destination for cancer trials and the next generation of biomarker enabled trials for conditions involving neurological disorders,rare diseases and the like.4.Innovative trial designs:There has been an increase in the number of platform/umbrella/basket trials designs using adaptive methods since 2020,as companies and academic sponsors look to develop new treatment combinations and pathways.49 These trial designs offer enhanced efficiency with the capacity to answer questions faster and at lower cost.Innovative trials are further encouraged through government funding such as the$23.7 million grant provided by the 2023 Innovative Trials and delivered through the MRFF.46 Zero Childhood Cancer website,accessed February 2024.47 United States FDA,Paediatric Research Equity Act.48 Lorentzos,M.S.et al.,Providing Australian children and adolescents with equitable access to new and emerging therapies through clinical trials:a call to action,The Medical Journal of Australia,January 2024.49 When comparing search results of terms basket study,umbrella study and adaptive clinical trial on clinicaltrials.gov(filtered for Australian results),2.3 times as many trials appeared in the 2020-22 period compared to 2017-19 period.39MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOROpportunityAdopting innovative trial designs will help the Australia clinical trials sector remain at the forefront of medical research in these complex and rapidly changing disease areas.To continue to be a country of choice for innovative trials,Australia needs to develop its ethics and governance capabilities to holistically encompass platform/umbrella/basket,N-of-1 and adaptive trials.5.Medical device trials:Global regulatory changes like medical device regulation(MDR)and in vitro diagnostic regulation(IVDR)in the European Union,50 and the FDAs proposed changes to in vitro diagnostic products(IVDs)in the United States,increases the burden of proof and timelines for medical device trials.51 The importance of clinical evidence of efficacy to drive medical device adoption by clinicians and patients is also growing,with the FDA releasing guidance for using real-world evidence(RWE)in medical device regulatory decision making in December 2023,and the TGA revising the clinical evidence guidelines for medical devices to improve the usage of RWE in medical device applications in February 2023.These changes present an opportunity for Australia to grow its share of device trials,which have been flat at approximately 10%of total trials over the last five years.OpportunityAustralia can leverage its sources of competitive advantage to grow the number of medical device trials conducted.This will require enhanced communication and promotion of Australias attractiveness as a clinical trials destination to medical device companies,to promote the same competitive advantages as those underpinning the far greater numbers of clinical trials held to test new and emerging drug therapies.Australia also houses numerous centres of excellence in medical device R&D,such as SAHMRI and Monash University,which house multiple national medical device registries.These registries can be leveraged to improve ease of medical device patient recruitment,especially in later-phase,post-market studies.50 European Commission,The European Union Medical Device Regulation,May 2021.51 United States FDA,Proposed rule regarding laboratory developed tests,September 2023.40MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORCase study Transcatheter Aortic Valve Implantation(TAVI),MedtronicMedtronic has been conducting first in human clinical trials in Australia for over a decade.Medtronic considers Australia an important destination for sites for global studies due to the quality ethics review process,short timeframes to commence studies,and the high-quality health workforce supporting trial activity.Both Medtronic and Edwards Lifesciences have conducted clinical studies in Australia for Transcatheter Aortic Valve Implantation(TAVI).Heart valve disease(HVD)affects more than half a million Australians,yet an estimated 250,000 Australians are unaware that they are living with the condition.If left untreated,HVD can damage the hearts valves,leading to heart failure,stroke,and arrhythmia(an irregular heartbeat),or death.Aortic Stenosis(AS)is the most prevalent type of acquired heart valve disease in Australia.Aortic stenosis occurs when the hearts aortic valve does not open properly,reducing the flow of blood as it exits the heart and is pumped to the rest of the body.Left untreated,aortic stenosis can result in heart failure and possibly death.Transcatheter Aortic Valve Implantation(TAVI)is a minimally invasive procedure to replace the aortic valve via a catheter inserted into the leg or chest.The alternative to TAVI is open-heart surgery to remove the damaged valve and replace it with an artificial valve.Today,over 700 Australian patients are able to benefit from TAVI thanks to some of Medtronics first in human TAVI clinical studies for those with severe AS at high,intermediate and low risk of surgery.This enabled them to avoid an open-heart surgery and received the minimally invasive TAVI valve replacement,whilst supporting evidence generation to enable broader access to the therapy in Australia.Australia had a number of leading clinicians and sites involved in TAVI first in human trials.From these first in human studies,Australian clinicians have become global proctors for this therapy,advisors to boards and committees to support product design and therapy development in clinical settings and leading experts and speakers and fellows sought after around the globe.Key priorities for the sectors futureThis report has reviewed the progress and achievements of the clinical trials sector in Australia over the past three years.As we have noted in the clinical trials activity metrics,this is a critical time for the sector as the global clinical trials landscape returns to post-pandemic trends.Australia has proven an attractive clinical trials destination,particularly for early phase trials,evidenced by its continued capture of share of the global market.As one of the only fully functioning countries for trials during the pandemic,it has demonstrated the well-known strength and capability of its healthcare and research systems.For global medical device and pharma companies holding clinical trials,Australia can be an attractive option:trials can commence quickly,patients can be easily recruited,and key opinion leaders,whose expertise is vital for enhancing the quality of clinical trials,are readily accessible.However,the global clinical trials sector is becoming increasingly competitive,and Australia must continue to take action to maintain and enhance sources of competitive advantage in the global market.41MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTORThere are four key priorities for promoting future growth in clinical trials activity in Australia,consistent with the priorities identified in the 2021 report.These priorities each relate to an existing problem/weakness in the Australian clinical trials landscape.1.Continue to improve the efficiency in clinical trial start-up processes,such as ethics and governance approvalsSector participants continue to praise Australias advantages in efficiency created by the Clinical Trials Notification(CTN)scheme,which offers quicker trial start-up timelines than other countries,particularly for early-phase(Phase I and II)trials,and the National Clinical Trials Governance Framework,introduced in 2023,which is being implemented progressively and helping to improve consistency in clinical trials delivery.52,53 However,ethics and governance approval processes across Australia remain highly individualised and vary between institutions and states.This complicates these processes and increases trial start-up times,which may deter trial sponsors from conducting trials in Australia.The impact is felt most often in later-phase trials(Phase III and IV),which tend to involve larger patient cohorts and multiple trial sites.Australias weakness in Phase III and IV trials,as demonstrated by the ongoing loss of global share of later-phase trials described in Chapter 3,represents an opportunity for growth.The solution involves two separate elements:The CTN scheme,which has been a significant source of competitive advantage for Australia,particularly in early phase trials,should be maintained for both device and drug trials.Cross-jurisdictional ethics and governance processes should continue to be streamlined.Australia has already harmonised drug and device registrations with other jurisdictions and should therefore be able to harmonise ethics and governance processes across Human Research Ethics Committees(HRECs)for large Phase 3 clinical trials in particular.Australias relatively smaller population with large geographical dispersion means that a unified national approach to attracting clinical trials is critical.The National One Stop Shop(NOSS),announced by the Federal Government in 2023(and outlined in the case study below),is aimed at addressing this issue and more broadly,improving the efficiency and interconnectedness of clinical trial start-up process in Australia.Case study the National One Stop Shop(NOSS)The National One Stop Shop aims to improve the efficiency and interconnectedness of the clinical trials start-up process in Australia through:Providing streamlined,cross-jurisdictional ethics and governance approvals that incorporates key application,notification,and approval systems.Aligning with the CTN and CTA schemes administered by the TGA.Creating an embedded and automated next-generation national clinical trials and research registry.52 L.E.K./MTPConnect interviews with sector participants,2023.53 Australian Commission On Safety And Quality In Health Care,The National Clinical Trials Governance Framework,2022 42MTPCONNECT.ORG.AUAUSTRALIAS CLINICAL TRIALS SECTOR Providing research management capability and sophisticated monitoring and reporting functionality for different users,including calculated data to support the accreditation of trial services.Creating a public website for Australians in the community to search for and access a clinical trial and enable sponsors to access accredited trial sites.These reforms have been developed through extensive stakeholder consultations involving more than 1,400 people throughout 2021-22.If implemented appropriately,the NOSS will build on the existing advantages to trial start-up times that Australia offers.These include the lack of a requirement for an active Investigational Drug(IND)or Identification of Medicinal Products(IDMP)in place,prior to initiating trials;and the speed of the TGA CTN scheme,which is a particular advantage for Phase I trials.The implementation of these reforms will be led by Emeritus Professor Ian Chubb,AC,FAA,FTSE,who will Chair the Inter-Governmental Policy Reform Group announced by The Hon Mark Butler MP,Minister for Health and Aged Care,at the Medtech23 conference organised by the Medical Technology Association of Australia(MTAA)in November 2023.The Inter-Governmental Policy Reform Group(IGPRG)will also have a key role in implementing and regulating the National Clinical Trials Governance Framework,which will ensure a nationally consistent approach to clinical trials at a site level.2.Enhance patient awareness and the ability to efficiently recruit patients at each clinical trial site,to improve site economics for these trials Patient recruitment is one of the greatest challenges in successfully operating and delivering clinical trials.Inefficient patient recruitment can result in longer trial durations and increasing trial costs.This issue is particularly relevant for sites in smaller Australian cities or regional areas,which are harder to recruit for and which become less attractive locations for the sponsors who conduct these trials.What results is a reduced access to clinical trials and healthcare for patients in these regions.There are five elements that contribute to a solution:Increase promotion and awareness campaigns to improve community awareness and diversity of clinical trials,especially in CALD and Aboriginal and Torres Strait Islander people,as well as improving infrastructure to support non-English speaking participants,and culturally/diversity sensitive trial practices.Increase patient centricity,through greater consumer involvement in clinical trial design and conduct,and the appropriate use of technology and decentralisation to improve trial design/access and improve patient recruitment per site.Patients may be recruited through primary care or directly through social media campaigns or teletrials.Embed clinical tr
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Biopharma DownstreamCritical Process ParametersWhite Paper2White Paper|Biopharma Downstream Critical Process ParametersContent1.Focus:PATDownstream _ 42.PAT for Biopharma _ 63.From Critical Quality Attributes to Critical Process Parameters of DSP Process _ 104.DSP Operation Units Overview:Skid Train _ 135.Operation Units Critical Process Parameters _ 175.1 Buffer Preparation 175.2 Purification Part I:Chromatography 235.3 Purification Part II:Concentration and Filtration 275.4 Viral Inactivation 305.5 Additional Unit Operations I:Centrifugation 335.6 Additional Unit Operations II:Refolding 346.Conclusions _ 357.References _ 36#1 CQA,CPP,KPI _ 5#2 PAT In-line/At-line/Off-line _ 8#3 Skid&Skid Train _ 13#4 Batch vs.Continuous/Single-Usevs.Reusable _ 16#5 On-Demand Buffer Dilution At Point of use _ 18#6 pH and Conductivity Dynamic Measurement _ 21#7 Single-Use Skid for LPLC Chromatography _ 26#8 Tangential Flow Filtration _ 28#9 Endogenous and Adventitious Viruses _ 31Info/examples boxes3White Paper|Biopharma Downstream Critical Process ParametersAbstractBiopharmaceutical downstream processing(DSP)plays a crucial role in the separation,purification,and formulation of therapeutic proteins and other active pharmaceutical ingredients(API).This white paper provides an overview of the key units in DSP skid train,including chromatography,ultrafiltration/di-afiltration,viral inactivation,and optional operations like centrifugation and refolding.Critical process parameters(CPPs)associated with each operation are discussed,along with the analytical process sensors used to monitor parameters.Both reusable and Single-Use technologies are presented,high-lighting their respective advantages and applications.By understanding the relationship between CPPs and desired product quality attributes,manufacturers can design efficient and robust DSP processes,ensuring product quality,safety,and efficacy in biopharmaceutical production.KeywordsBiopharmaceutical,Bioprocess monitoring,Critical Quality Attributes(CQA),Critical Process Param-eters(CPP),Centrifugation,Conductivity,Diafiltration,Downstream Processing(DSP),Drug product,Hamilton Process Analytics,In-line measurement,Ion Exchange Chromatography(IEX),microbial,Mi-crofiltration,mixing bag,mixing tank,monoclonal-antibody(mAb),pH,Process Analytical Technology,Process Analytics,Process Sensors,Protein Concentration,Protein Fraction,Protein A Chromatography,Purification,Redox(ORP),Refolding Reusable Technologies,Single-Use Technologies,Skid,Skid train,Tangential Flow Filtration(TFF),Ultrafiltration(UF),Viral Inactivation4White Paper|Biopharma Downstream Critical Process Parameters1.Focus:PATDownstreamThe FDAs 2004 guidance on“Pharmaceutical cGMP for the 21st century A risk-based approach”1,triggered the Process Analytical Technology(PAT)Initiative,which minimizes public health risks in pharmaceutical manufacturing through innovation in development,manufacturing,and quality as-surance.The regulatory framework of PAT 2 is designed to enhance and control the manufacturing process to achieve Quality-by-Design(QbD).To achieve QbD,you must identify the Critical Quality Attributes(CQAs)of a product,monitor the related Critical Process Parameters(CPPs),and the Key Performance Indicators(KPIs),and automatically control these parameters within the predefined limits.For additional details,refer to Keywords Box#1.As explained in this white paper,CQAs are challenging to measure directly during production.Along the upstream and downstream manufacturing processes,it is most common to monitor the CPPs and KPIs related to quality attributes.PAT recommends various tools including:Multivariate tools for process design,data acquisition,and analysis Process analyzers(e.g.,in-line sensors or automated at-line devices)Process control tools(e.g.,statistical process control software)Continuous improvement and knowledge management toolsAn appropriate combination of these tools may apply to a single-unit operation such as chromatography or filtration skid,or an entire manufacturing process portion like upstream or downstream.Process analyzers are a typical example of tools to measure process data.Their output is used for different scopes such as univariate mechanistic modeling,process characterization,or multivariate analysis such as the“golden-batch profile”and prediction models.This white paper focuses on the process analyzers used in the biopharma downstream process(DSP).It will focus mainly on the following unit operations:Buffer preparation/dilution Chromatography Filtration Virus inactivationIn addition to the focus ones,two other unit operations will be briefly addressed,as well:centrifugation and refolding.An overview of the critical quality attributes and of the most important critical process parameters will be provided,together with examples of the proper in-situ sensors and equipment used to monitor them.Figure 1 highlights an example of an in-situ process sensor purification step.5White Paper|Biopharma Downstream Critical Process ParametersKEYWORDSCQA,CPP,KPI The relationship between CQAs,CPP,and KPI is clear from their definitions according to the PAT literature:2,3,4Critical Quality Attribute(CQA)A physical,chemical,biological,or microbiological property or characteristic that should be within an appropriate limit,range,or distribution to ensure the desired product quality.Critical Process Parameter(CPP)A process parameter whose variability has an impact on a critical quality attribute and,therefore,should be monitored or controlled to ensure the process obtains the desired quality.Key Performance Indicator(KPI)A metric for the status of each production step.KPIs are related to CQAs and therefore influenced,as well,by the CPPs.As the CPPs remain within the pre-defined limits,the KPIs should indicate that each production step proceeds accordingly,which results in a product having a CQA within the appropriate limits.Figure 1:Graphical representation of Single-Use Skid for Protein Purification showing in-situ process sensors.The chart represents,among the others,the real-time monitoring of CPPs such as pH(yellow),Conductivity(red),and Abs-UV(violet)measured in the chromatography elution phase.(Image courtesy of Verdot IPS)#16White Paper|Biopharma Downstream Critical Process Parameters2.PAT for BiopharmaLiquidWasteCompressorAir FilterGas OutBioreactorHarvest TankWaterNutrientsCIPCleaningAirMedia Prep TankUpstreamDownstreamProtein AChromatographyTFF Filtration(or Diafiltration)TFF Filtration(or Diafiltration)VirusInactivationIonChromatographyBuffer PreparationFill&FinishCentrifugeLiquidWastePF(UV)PC(UV)PF(UV)PC(UV)Figure 2:Biopharmaceutical manufacturing process.This map shows the commonly monitored real-time Critical Process Parameters such as pH in green and Conductivity in red.This map is the updated version of the one previously published by Hamilton in the White Paper Biopharma PAT-Quality Attributes,CriticalProcess Parameters&KeyPerformance Indicators at the Bioreactor 5.7White Paper|Biopharma Downstream Critical Process ParametersDSPUSPUpstreamThe stage where biopharmaceuticals molecules are produced.At this stage,heterogeneity arises from the cells that are living subjects.According to minimal variations of the environment,they can produce higher or lower yield of product with a quality within the pre-defined limits while maintaining a bioactive molecular confirmation capable of delivering the expected healing effect on patients (eg.,Glycosylation patterns).DownstreamBiopharmaceuticals from upstream operations have to be purified and concentrated before turning them into medicines in a format that can be administered to patients(fill&finish).For example,proteins such as monoclonal antibodies(mAbs)must be separated from DNA and RNA fragments and any other contaminants to ensure that:The molecular structure is not altered,and it retains the healing effect.The product is not contaminated to be safe for clinical trials and patients.To use Process Analytical Technology(PAT)effectively in biopharmaceuticals,it is essential to reduce manual and off-line sampling and shift towards monitoring directly in the process.Since even the smallest changes in process parameters can significantly impact the final product,monitoring them in real-time can help reduce the chances of diminished yield and purity(refer to Keywords#2).Real-time monitoring is possible due to reusable or Single-Use sensors which can withstand the Clean-ing-in-place(CIP)and Sterilization-in-place(SIP)procedures only for reusable equipment required to minimize the risk of contamination.This is already common for the fundamental CPPs:e.g.,pH and Conductivity(see Figure 2).These will be described in detail in the following paragraphs.Manufacturing of biopharmaceutical products is a complex process 6,7,made of different steps.Existing scientific literature 5,8 to 12,already describes how the application of PAT to these com-plex processes enables significant improvement in upstream and in downstream.Real-time control of Critical Process Parameters to a tight set-point will ensure that the Critical Quality Attributes will be under control,too.For example,the control of buffers pH and Conductivity(CPPs)in each down-stream operation unit minimizes the risk of altering the glycosylation patterns of the mAbs(CQAs).The tight control of pH and Conductivity in DSP plays an important role to ensure a safe biopharmaceutical with the expected healing effect.8White Paper|Biopharma Downstream Critical Process ParametersKEYWORDSPAT In-line/At-line/Off-line The PAT guidance 1,2,and scientific literature 3,4,suggest that critical process parameters and quality attributes can be monitored using various methods.Real-time monitoring is typically achieved using in-line or on-line analytical methods,while at-line and off-line methods may be used when CPPs,KPIs,or CQAs cannot be accurately measured in a specific downstream operation unit.Off-lineOff-line measurement involves taking a sample manually out of the DSP skids under sterile conditions and analyzing it in the lab after physical pretreatments.Off-line sampling requires clear SOPs and skilled personnel to avoid accuracy problems.The major disadvantages of off-line measurement are the time-delay and lower measurement frequency,making it not a true PAT unless there are no other measurement possibilities.Automated controls are not possible in some cases.Off-line laboratory measurements are commonly used to monitor and validate the accuracy of in-line/on-line process analyzers.However,in the case of a chromatography or TFF skid,relying on static reference measurements may not provide reliable results.This is because in-line measurements are made in dynamic conditions within a pipe,which can affect the accuracy of reference measurements and account for observed differences between e.g.pH and Conductivity values.At-lineAt-line measurement involves removing a sample from the production process and analyzing it nearby,either manually or through automated sampling devices.It is commonly used for parameters that cannot be accurately measured in-situ or on-line.Maintaining sterile conditions is crucial for accurate results.At-line measurement offers advantages such as shortened time-delay compared to On-lineIn-line/In-situAt-lineOff-line#29White Paper|Biopharma Downstream Critical Process Parametersoff-line measurement and the possibility for automated control.However,a comparison between in-line dynamic measurement and static at-line measurement is affected by the same challenges explained for off-line methods.On-lineOn-line measurement involves diverting a sample from the manufacturing process with a bypass stream,which is automatically measured by process sensors.The sample may then be returned to the bioreactor.This method offers simple sterilization and easy access to the sample in stationary conditions.However,implementing this solution requires a modified skid or a specific skid design,which adds complexity to the setup.On-line monitoring is less common than in-line monitoring,but it allows for constant monitoring and control in real-time,making it one of the two methods that enable this capability.In-line/in-situIn in-line or in-situ measurement,the process sensor measures parameters directly in the skid.The measurements are sent in real-time to PLC/SCADA systems for automated control.Common process parameters for DSP in-situ measurement include pH,Conductivity and temperature.In-line and on-line sensors are the optimal choice for applying PAT principles.They accurately measure without manual intervention over the entire process run,which can last for weeks or months.However,reliable and accurate measurement requires proper operation and maintenance of the sensors.Calibration and cleaning should be implemented at specified intervals to prevent drift or signal loss.The sensors should also be compatible with repeated CIP and SIP cleanings and,for reusable equipment applications,the sensors must be able to withstand extended time at temperatures of 120 to 130 C without affecting their performance.10White Paper|Biopharma Downstream Critical Process Parameters3.From Critical Quality Attributes to Critical Process Parameters of DSP ProcessThere are numerous biopharmaceuticals produced using different culture types for various diseases.However,it is important to note that these biopharmaceuticals do not always cure diseases but rath-er treat or manage the symptoms.Table 1 shows a list of some biopharmaceuticals,their production culture types,and the diseases they target.Examples of BiopharmaceuticalsMarketing Autorisation Holder-EPAR 13Therapeutic AreaTypical Culture Type Insulin (Actrapid,Ryzodeg,Insulin lispro Sanofi,Humalog)Various holders:Novo Nordisk A/S,Sanofi Winthrop Industrie,Eli Lilly Nederland B.V.Diabetes(Type 1 and Type 2)Recombinant Escherichia coli(microbial)Saccharomyces cerevisiae(yeast)Adalimumab(Humira)AbbVie Deutschland GmbH Co.KGRheumatoid arthritis,psoriatic arthritis,ankylosing spondylitis,Crohns disease,ulcerative colitis,and psoriasisChinese Hamster Ovary(CHO)cell cultureEtanercept(Enbrel)Pfizer Europe MA EEIGRheumatoid arthritis,juvenile idiopathic arthritis,psoriatic arthritis,ankylosing spondylitis,and plaque psoriasisChinese Hamster Ovary(CHO)cell cultureTrastuzumab(Herceptin)Roche Registration GmbHHER2-positive breast cancer and metastatic gastric cancerChinese Hamster Ovary(CHO)cell cultureRituximab(MabThera)Roche Registration GmbHNon-Hodgkins lymphoma,chronic lymphocytic leukemia,rheumatoid arthritis,granulomatosis with polyangiitis,and microscopic polyangiitisChinese Hamster Ovary(CHO)cell cultureBevacizumab(Avastin)Roche Registration GmbHVarious types of cancer,including metastatic colorectal cancer,non-small cell lung cancer,glioblastoma,renal cell carcinoma,and ovarian cancerChinese Hamster Ovary(CHO)cell cultureSubsitute with Pegfilgrastim(Neulasta)Amgen Europe B.V.Neutropenia,cancerEscherichia coli(microbial)Infliximab(Remicade)Janssen Biologics B.V.Rheumatoid arthritis,Crohns disease,ulcerative colitis,ankylosing spondylitis,psoriatic arthritis,and plaque psoriasisMouse-murine hybridoma cell cultureTable 1:Biopharmaceutical examples according to typical culture type.Examples are taken from the Top 10 best-selling biologicals blockbusters-updated 2022 14.*Some of these biopharmaceuticals have biosimilar versions produced by different companies.A biosimilar is a biologic product that is very similar to an approved biologic product(the reference product)and has no clinically meaningful differences in safety,purity,or potency.Biosimilars are typically more affordable than the reference products,increasing patient access to these life-saving medicines.11White Paper|Biopharma Downstream Critical Process ParametersThe biopharmaceuticals listed in Table 1 must exhibit the desired biological activity and potency in their intended therapeutic application;in other words,they should show the therapeutic effect expected for the targeted disease.This is possible if their Critical Quality Attributes are within the expected ranges as a result of the corresponding Critical process parameter control.The CQAs and CPPs can vary de-pending on the specific biopharmaceutical and the production culture type.Table 2 and Table 3 show a list of the most common CQAs and CPPs to monitor and control for biopharmaceutical production processes,specifically for the downstream steps.CQAs Cluster Most common DSP CQAsCQA DescriptionPurity and impurity levelsProtein purityEnsuring that the desired biopharmaceutical is present at a high level of purity.Host cell proteins(HCPs)removalResidual proteins from the host cells(e.g.,E.coli,yeast,CHO cells)used in the production process should be minimized.DNA and RNA contentResidual host cell DNA and RNA should be reduced to acceptable levels.Protein structure and stabilityPrimary structureThe amino acid sequence must stay accurate and consistent.Secondary and tertiary structureProper folding of the biopharmaceutical is crucial for its functionality and stability.This is of specific importance in biopharmaceuticals produced with bacteria:those require a dedicated refolding step.Post-translational modifications(PTMs)Ensuring consistent glycosylation,phosphorylation,refolding,or other PTMs that may affect the biopharmaceuticals efficacy,stability,or immunogenicity.AggregationMinimizing the formation of aggregates or higher-order structures that could impact efficacy,stability,or immunogenicity.Product-related variantsMonitoring and controlling product-related variants such as isoforms,fragments,different charge profiles and other modified forms of the biopharmaceutical that could affect its efficacy,safety,or stability.Sterility and viral clearanceSterility and endotoxin levelsEnsuring the absence of microbial contamination and maintaining endotoxin levels within acceptable limits.Viral clearanceFor biopharmaceuticals produced in mammalian cell cultures(e.g.,CHO cells),ensuring that the downstream process effectively removes or inactivates potential viral contaminants.Table 2:Critical Quality Attributes ensuring the expected therapeutic effect for the diseases targeted in Table 1.This Table is obtained consolidating data from different sources 8,12,15-16,24It is important to note that the specific CQAs for a given biopharmaceutical will depend on the molecule,its intended use,and the regulatory requirements of the target market.Therefore,the CQAs should be carefully assessed and defined during the development and optimization of the downstream process.Since CQAs are indispensable,PAT principles will push to have them monitored and wherever possible controlled in real-time.Attempts are done trough molecular spectroscopy technologies:in-line and on-line sensors are typically based on molecular spectroscopy technologies such as Near-Infrared(NIR)and Raman.These sensors are secondary measurement technologies,which means they require calibra-tion using off-line reference methods and statistical multivariate data analysis(MVDA).The measure-ment accuracy of these methods is highly dependent on the specific bioprocess environment and the quality of the off-line measurements used for calibration.To date,few published studies demonstrate the use of global MVDA calibrations to predict critical qual-ity attributes for downstream with acceptable accuracy 30,they are more common in upstream appli-cations at the bioreactor 17.Especially DSP,the response time(up to some minutes)is often regarded 12White Paper|Biopharma Downstream Critical Process Parametersto be too slow since the desired reaction time is in seconds or less.As a result,these sensors are considered labor intensive and cost-prohibitive,and they do not deliver the expected performances to be successfully implemented introduction environments.In downstream,such solutions are the future,but not yet the present when compared to downstream.In this context,it is worth noting the ongoing efforts in the biopharmaceutical industry to advance real-time monitoring,as exemplified by the re-search projects coordinated within the BioPhorum Operations Group.In one such project 18,multiple biopharma companies are collaborating on a proof-of-concept study for real-time monitoring of aggre-gate content during chromatographic purification of monoclonal antibodies,specifically in the cation exchange bind and elute polishing step,utilizing real-time multi-angle light-scattering(RT-MALS)tech-nology.However,this initiative is currently in the feasibility testing phase.The complexity of these measurements explains why at-line and/or off-line methods remain the most prevalent options for CQAs monitoring 19-20,despite not being ideal for PAT compliance.This equip-ment may use various technologies such as High-Performance Liquid Chromatography(HPLC),Capil-lary Electrophoresis(CE),Mass Spectrometry(MS),or Enzyme-Linked Immunosorbent Assay(ELISA).These analyzers can be automated or semi-automated and often necessitate separate devices for sterile sampling.Moreover,measurement cycles typically require a relatively long time(minutes).How-ever,given the limitations of in-line and on-line sensors,at-line and off-line methods remain the only available options for measuring the CQAs in downstream processes.CQA Cluster Impacted by the CPP in the specific unitSterility and viral clearanceProtein structure and stabilityPurity and impurity levelsDSP Train Operation unitVirus Inactivation(Viral clearance)FiltrationChromatographyRefoldingCentrifugationCPPspHConductivity(Salt concentration)Protein concentration/Protein Fraction(UV)TemperatureFlow rate/pressureRedox environment(ORP)Dissolved Oxygen(for oxygen-sensitive proteins with risk of degradation)Turbidity Table 3:List of CPPs and how they can influence each DSP operation unit,the CQAs 15-16,21These are general examples of CPPs cluster types that can be correlated with the CQAs mentioned earlier.The specific CPPs and their impact on the CQAs will depend on the biopharmaceutical,the production culture type,and the downstream process steps used.A thorough understanding of the relationships between CPPs and CQAs is essential for the successful development,optimization,and control of the biopharmaceutical manufacturing process.In Chapter 4 a detailed analysis of DSP interconnected unit operations with corresponding CPPs and examples will be provided.13White Paper|Biopharma Downstream Critical Process Parameters4.DSP Operation Units Overview:Skid Train A downstream process,identified with all the steps between the initial production bioprocess and the final fill finish,typically consists of several interconnected operation units(=process steps),including cell harvesting,chromatography,ultrafiltration,diafiltration,and viral inactivation.To efficiently manage and perform these operations,the units are often carried out on separate,modular systems known as skids.KEYWORDSSkid&Skid Train SkidA skid is a self-contained,pre-assembled unit that houses all the necessary equipment,instrumentation,and controls required to perform a specific unit operation 21.Skids are designed to be easily integrated into a larger process,allowing for flexibility in configuring and reconfiguring the process layout as needed.This modular approach provides several advantages such as reduced installation time,ease of maintenance,improved process control,and the ability to scale up or scale down production as required.Skid-trainA skid train,in the context of biopharmaceutical processes,refers to a series of interconnected skids,each dedicated to a specific downstream unit operation 22.This arrangement enables a continuous,streamlined flow of material through the different purification and concentration steps,ultimately leading to the production of the final biopharmaceutical product.The skid train configuration allows for seamless integration and automation of the process,enhancing productivity,reducing the risk of contamination,and ensuring consistent product quality.#3Example of Tangiential-Flow-Filtration Skid.Image Courtesy of Donaldson(Solaris).14White Paper|Biopharma Downstream Critical Process ParametersFill&finishViral inactivation 1xThe entire sequence of a skid is referred to as“skid train”22.Although each specific production process presents a different number and/or combination of the single operations units,Figure 3 exemplifies a common downstream skid train in case of purification and concentration of monoclonal antibody.Filtration(UF/TFF/Diafiltration)1xTarget:selectively capture and purify monoclonal antibodies(mAbs)from complex mixtures by exploiting the high-affinity interaction between Protein A ligands and the Fc region of immunoglobulin G(IgG)antibodiesTarget:separate,concentrate,or purify target biomolecules based on their size and molecular weight,while simultaneously removing unwanted impurities or contaminants from the process streamTarget:separate and purify biomolecules such as proteins,based on their differences in charge.This separation is achieved through the reversible interaction between the charged molecules in a sample and the oppositely charged stationary phase(resin)within the chromatography column.Buffer preparationPurification/Polishing Ion Chromatography(IEX)2xFiltration(TFF/Diafiltration)1xCapture Protein A Chromatography 1xTarget:provide well-controlled,consistent,and high-quality buffer solutions that maintain the optimal conditions required for each unit operation in the purification process,ensuring the stability,functionality,and overall quality of the target biomoleculeTarget:eliminate or significantly reduce the presence of potential viral contaminants in the final product,ensuring the safety and quality of biopharmaceuticalsNote:2x or 1x=Number of skids for an average DSP.The sequence of the process steps can vary depending on the previous USP and the target proteins characteristics.Figure 3:mAb Downstream Skid Train Example 22-25In the biopharmaceutical industry,the operation units in a downstream processing(DSP)skid train have traditionally been based on batch processes,where each step is carried out sequentially and inde-pendently,with the material being collected and stored before moving on to the next stage.However,there has been a growing trend towards continuous processing 12,16,24,as it offers numerous ad-vantages such as improved process efficiency,reduced processing time,decreased facility footprint,and the potential for real-time monitoring and control.Continuous processing integrates the various Upstream Bioreactor Product15White Paper|Biopharma Downstream Critical Process Parametersunit operations in the DSP skid train to allow for a seamless flow of material,resulting in a more stream-lined and cost-effective production process.This shift towards continuous processing aligns with the industrys focus on enhancing productivity,product quality,and process robustness,while meeting the increasing market demands for biopharmaceutical products 23.Regardless of whether a downstream processing(DSP)skid train employs batch or continuous pro-cessing,the unit operations can be based on either reusable(multi-use)or Single-Use technologies.Reusable equipment is made of materials such as stainless steel(see Figure 4),which require thorough cleaning and sterilization between batches or runs.On the other hand,Single-Use technologies involve the use of disposable,pre-sterilized components such as plastic bags or pre-packed chromatography columns,which eliminate the need for cleaning and sterilization.Single-Use technologies have gained significant traction in recent years due to their advantages in reducing cross-contamination risks,min-imizing downtime,and providing greater flexibility in process design and scale-up.In the context of continuous processing,Single-Use technologies can be particularly beneficial as they facilitate faster changeover between runs,enable more efficient integration of unit operations,and support the growing demand for smaller,more flexible manufacturing facilities.Consequently,the adoption of Single-Use technologies aligns well with the shift towards continuous processing,contrib-uting to the overall improvement in process efficiency,product quality,and cost-effectiveness in bio-pharmaceutical manufacturing 16.Further details on pros and cons of different options are detailed in Keyword Box#4.Figure 4:Example of Stainless Steel Skid with Hamilton Conducell 4USF Arc conductivity sensor in flow-cell.For the complete description look at Hamilton Application Note“Arc sensors in oncologic and biosimilar applications”46.16White Paper|Biopharma Downstream Critical Process ParametersKEYWORDSBatch vs.Continuous/Single-Usevs.Reusable Batch vs.Continuous ProcessingThe main difference between batch and continuous biopharma processes lies in how the production process is carried out.In a batch process,production occurs in discrete batches,with each batch being processed separately and independently.The entire production cycle,including cell growth,harvesting,and downstream processing,is performed sequentially,with each step being completed before the next batch is started.This process is repeated for each new batch of product.In contrast,in a continuous biopharma process,production occurs in a continuous,uninterrupted manner.The cells are grown and harvested continuously,and the product is purified and formulated in real-time.The process can be maintained for long periods,sometimes weeks or even months,without stopping.Continuous bioprocessing can offer advantages such as higher productivity,reduced labor requirements,and lower operating costs,but it requires a more complex and sophisticated process control system 12,23.Both batch and continuous processes have advantages and disadvantages,and the choice of which to use depends on factors such as the specific product,the scale of production,and the available resources.Batch processes are still widely used in the biopharmaceutical industry,while continuous bioprocessing is becoming increasingly popular as a more efficient and cost-effective alternative.1Single-Use vs.ReusableSingle-Use and reusable refer to the type of equipment used in biopharmaceutical manufacturing processes.Single-Use equipment is designed for one-time use and is typically made of plastic materials.Single-Use systems are commonly used in upstream processes such as cell culture,where the risk of contamination is high,and the ability to switch between different processes or products quickly is desired.Single-Use systems offer several advantages such as reduced cleaning and sterilization requirements,faster turnaround times,and lower capital and operating costs 16,26.In contrast,multi-use equipment is designed for repeated use and is typically made of stainless steel.Multi-use systems are commonly used in downstream processes such as purification,where the process requires high-pressure and high-temperature conditions,and the equipment must be durable and long-lasting.Multi-use systems offer several advantages,such as better quality control,higher throughput capacity,and reduced waste generation.The choice of whether to use Single-Use or multi-use systems depends on factors such as the specific process requirements,the product being manufactured,and the available resources 27.Recently,Single-Use systems have gained popularity in biopharmaceutical manufacturing due to their flexibility,scalability,and cost-effectiveness.#417White Paper|Biopharma Downstream Critical Process Parameters5.Operation Units Critical Process ParametersA downstream process,identified with all the steps between the initial production bioprocess and the final fill finish,typically consists of several interconnected unit operations,including cell harvesting,chro-matography,ultrafiltration,diafiltration,and virus inactivation.To efficiently manage and perform these operations,the single-unit operations are often carried out on separate,modular systems known as skids.The skid train necessitates the in-line monitoring of Critical Process Parameters to ensure that the criti-cal quality attributes remain within specified limits,ultimately resulting in the expected therapeutic effect for the targeted disease.Detailed information regarding each operation unit and its associated CPPs will be detailed in the present Chapter 5.They focus primarily on monoclonal antibodies,although the topics presented apply to other biopharmaceuticals such as peptides and nucleic acids.5.1 Buffer PreparationBuffer solutions are critical components of biopharmaceutical processes,as they:1.Maintain optimal pH and ionic strength:Buffers help to maintain the appropriate pH and ionic strength required for each purification step,ensuring the desired biomolecule interactions,protein stability,and separation efficiency.2.Facilitate process-specific requirements:Buffers may contain additives or specific components such as salts,chaotropic agents,or detergents to aid in the purification process,like promoting protein solubility or enhancing the selectivity of chromatographic separations.3.Enable buffer exchange and desalting:Buffers are used in diafiltration or other desalting steps to replace the existing buffer or remove unwanted low-molecular-weight contaminants.Buffer preparation is a critical support function in bioprocessing facilities that develop monoclonal antibodies,gene therapies,and vaccines 28.These buffers are used in various purification stages,including chromatography,viral inactivation,filtration,and final formulation steps like tangential flow filtration and bulk filling.Each buffer has distinct chemical attributes that leverage pH and conductivity parameters to optimize process performance and provide a stable environment for target proteins.The selection and accurate preparation of an appropriate buffer are essential to maintain the activity of the target protein 29.Employing reusable or Single-Use technology or a combination of both,buffers are usually prepared and stocked before use.The two most important CPPs are pH and Conductivity and they are com-monly measured in-line 31-32,as described in Figure 5.Real-time monitoring through in-line pH and conductivity sensors can significantly streamline buffer prepa-ration and release processes,reducing the need for offline sampling.Notably,conductivity plays a crucial role.In addition to the information presented in Figure 5,here are some additional important applications:Determining Solution Concentration:Conductivity measurements can be used to establish the concentration of solutions,effectively detecting contaminants and assessing water purity.Buffer Homogeneity and Chromatography:Conductivity monitoring is essential for verifying the uniformity of buffer preparation.18White Paper|Biopharma Downstream Critical Process Parameters Cleaning Verification:By monitoring conductivity,we can ensure that cleaning agents are entirely removed after a system flush post-cleaning.Limiting Buffer Variability:Conductivity measurement aids in reducing batch-to-batch variability in buffer feedstock preparation.In-line Buffer Dilution Control:Conductivity,along with pH feedback control,can be used to effectively manage in-line buffer dilution.SkidPLCFigure 5:Buffer Preparation Critical Process ParameterspH maintains the optimal conditions required for each unit operation in the purification process.Precise control of pH is critical to ensure desired biomolecule interactions,protein stability,and separation efficiency.Deviations in pH can lead to reduced process performance,destroy the Protein A resin or even product loss due to aggregation,precipitation,or denaturation of the target biomolecule.Conductivity measures the ionic strength of the buffer solution,which can affect the performance of various purification steps,particularly in chromatography.Monitoring conductivity ensures the appropriate ionic strength is maintained,which is crucial for the selectivity and efficiency of the chromatographic separations.Deviations in conductivity can result in reduced separation performance,lower product purity,and decreased yield.TRENDSOn-Demand Buffer Dilution At Point of use Cytiva Allegro Connect Buffer Management System 31#5The biopharmaceutical industry is undergoing significant changes,including process intensification,higher product yields,and the need for multi-product facilities.This has led to a greater demand for process buffers,which must be prepared in a way that is cost-effective,efficient,and safe.Additionally,the industry is trending towards continuous bioprocessing,which requires different buffer demands.These changes have led to an increased volume and diversity of buffers required,highlighting the need for improved solutions and technological advancements in buffer preparation.The BioPhorum Technology Roadmap for the Biopharmaceutical Manufacturing Industry has recognized buffer preparation as an area that requires attention and innovation to meet the evolving needs of the industry.For more information19White Paper|Biopharma Downstream Critical Process ParametersTraditional buffer preparation is challenging due to its labor-intensive nature,large quantity of chemical reagents required,and significant footprint within a manufacturing plant.Buffer preparation dictates plant capacity and drives biopharma plant schedules,leading to time-consuming bottlenecks.Forward-thinking production teams are seeking effective ways to manage the buffer process to avoid being slowed down by these challenges.To address these challenges,utilizing in-line dilution of buffer concentrates,along with Single-Use fluid handling and mixing solutions,can be effective.This involves preparing multi-component buffer solutions in fixed vessels or Single-Use mixers at high concentrations and then diluting them for use in the process.CPPs:Conductivity and pH measurement stabilization before filling the biocontainer with triplicate in-line dilutions of 0.2 M Tris-HCl 1 M NaCl pH 8.1 by 20 x and 0.1 M Tris-HCl 0.5 M NaCl pH 8.0 by 10 xPain Points Caused by Traditional Buffer Preparation Large quantities of buffer are necessary Requiring significant floor space for manufacturing and storage The process of buffer preparation is inherently labor-intensive Benefits On-Demand In-line Dilution 75%reduction in floor space required for buffer storage A decrease in buffer production cost per liter(up to 12%)Integrated point-of-use delivery can make buffer management more time-efficient An example of skid capable of delivering the benefits listed is the Cytiva Allegro Connect Buffer Management System 31.The main CPP are pH and Conductivity,monitored respectively with Hamilton SU OneFerm Arc 120 and Conducell 4USF Arc 120.20White Paper|Biopharma Downstream Critical Process ParametersIn microbial production processes,it is still common to rely on reusable equipment,which typically in-cludes reusable process sensors for in-line measurements.These process sensors must be compliant with the same Sterilization-in-Place(SIP)and Cleaning-in-Place(CIP)treatments as the associated equipment to ensure proper sterilization and cleanliness.Meanwhile,in cell culture DSP processes,Single-Use equipment and corresponding Single-Use sensors are often preferred.One example of this is the Single-Use preparation skid Millipore Mobius Power Mix 32,which demonstrates the adoption of disposable technologies in modern biopharmaceutical manufacturing.Another recent trend involves the production of buffers at the point of use,aiming to reduce the facility footprint and ensure greater flexibility when switching between different processes.A diagram illus-trating this approach can be seen in Figure 6.In such applications,the response time and accuracy minimal drift of pH and conductivity measurements become even more critical,as the buffers are produced just in time.This emphasizes the importance of reliable and precise process monitoring to maintain optimal conditions and ensure efficient,high-quality biopharmaceutical production.AcidBaseSaltWFIBuffer 1Buffer 2Buffer 3Buffer 4Figure 6:In-line buffer dilutionA concrete example of skid capable to perform such operation is the Allegro Connect Buffer Man-agement System from Cytiva Corporation 31.21White Paper|Biopharma Downstream Critical Process ParametersTIPSpH and Conductivity Dynamic Measurement#6In addition to essential requirements such as GMP compliance,biocompatibility,and robustness against cleaning and sterilization processes,the important specifications for any process sensor include measurement range and accuracy tolerance.Response time is another significant specification;however,it largely depends on the entire measuring loop,which encompasses the cables and transmitter/integration system selected to convey the signal to the skid PLC.In dynamic conditions such as in-line buffer dilution,chromatography,and filtration,the specific requirements for these specifications depend on the particular biopharmaceutical downstream process being carried out.In the table below,the typical requirements for dynamic measurement of pH and conductivity are described.CPPMeasuring range(depending on application)Most common accuracy toleranceResponse time (t90 between two certified calibration standards)pH3.5 to 8.5 0.155-10 s(depending on application)Conductivity1.3 S/cm to 200 mS/cm 5%Typical requirements for pH and conductivity in downstream applications.The tolerances assume a constant process temperature(e.g.,ambient temperature 1C/F)and a constant flow rate.Specific applications may necessitate tighter tolerances in lower ranges.Source:Cytiva Allegro-Application Note Production of In-Specification Buffer on Demand for Batch Processes 31.Process sensors in flow-cell assuming both pH and conductivity are needed.Examples of Hamilton process sensors include OneFerm (Single-Use pH)and Conducell 4USF(reusable 4-pole conductivity).Flow DirectionPosition 1Position 222White Paper|Biopharma Downstream Critical Process ParametersTo keep the highest accuracy in flow cell applications,there are tips general for all parameters and others which are specific.Tips for Both pH and Conductivity Adhere to the maintenance recommendations provided in the sensor manuals by the manufacturer.Use certified buffers/standards for a 2-point calibration with reusable(RU)sensors.Regularly check sensor performance and perform an in-line calibration when necessary,especially for pre-calibrated Single-Use sensors.For sensor calibration or in-line product calibration(in-line process calibration),choose standards according to the application-specific measuring range:-For pH working range 3.5 to 8,use buffers pH 3.06 and 9.21 respectively-For conductivity,working range up to 100 mS/cm,use the corresponding standard e.g.,Hamilton Conductivity Standard 100 mS/cm Calibration should be performed under the same conditions as routine application such as temperature.If both pH and conductivity are required,their positions in the flow-cell do not influence each others measurements.The order of pH and conductivity placement does not affect accuracy,considering the specified accuracy and buffer flow direction.Tips for Conductivity Calibration must be performed in-line and in the same flow-cell as routine use to maintain the same cell constant and achieve the expected accuracy.Flow-rate/pressure does not significantly influence accuracy,considering the specified tolerances.Temperature has a direct impact on conductivity.Increasing temperature increases the mobility of ions within a solution and results in higher conductivity measurements.Temperature compensation can be performed using empirically derived temperature coefficients,which may be different for various solutions.Hamilton provides a graph and a temperature lookup table from 5 to 50C for every conductivity standard to determine the raw conductivity value of the liquid standard.pH sensors diaphragm in opposite direction vs.buffer flowTips for pH When using a Single-Use(SU)or reusable(RU)electrochemical sensor,position the sensor so that the diaphragm faces the opposite direction of the flow.The importance of conductivity:with proper sensor maintenance and calibration,the expected accuracy is possible up to 1 mS/cm.Changes in flow rate/pressure can influence accuracy(e.g.,going up to 4 bar or more).Choose certified standards:for example,Hamilton DuraCal pH Buffers and Conductivity StandardsWhy is the cell constant crucial for conductivity measurement accuracy?The cell constant is a crucial parameter for conductivity sensors,as it is used to relate the measured resistance of a solution to its actual conductivity.The cell constant(K)is defined as the ratio of the distance between the electrodes to the effective cross-sectional area of the electrodes within the conductivity sensor.It has units of cm-1 and is typically represented as K=L/A,where L is the distance between the electrodes and A is the effective electrode area.The cell constant is important for sensor accuracy because it helps to normalize the measured resistance for variations in electrode geometry and arrangement.A conductivity sensor is calibrated by using reference solutions with known conductivity values.This calibration process allows the sensor to accurately measure the conductivity of unknown samples by accounting for the unique cell constant of the sensor.If the cell constant is incorrect or changes over time(due to fouling or damage to the electrodes),the sensors accuracy will be compromised 33.Therefore,it is essential to maintain the sensor properly and calibrate it regularly to ensure that the cell constant remains accurate for reliable conductivity measurements.A=Area of Electrode Surface(cm2),L=Distance Between Electrodes(cm),V=Voltage,K=L/A=Cell Constant(cm-1)AALV23White Paper|Biopharma Downstream Critical Process Parameters5.2 Purification Part I:ChromatographyAfter the bioreactor,biopharmaceutical products such as monoclonal antibodies are collected in the harvest tank together with cellular debris,host-cell protein(HCP),and residue of DNA and RNA the next step is usually purification.Thus,purifying the desired biological active protein or biomolecule from debris or residual impurities.Chromatography is a widely used technique for the separation and purification of biomolecules such as mAbs,proteins,peptides,and nucleic acids,based on their chem-ical and physical properties 34.This is achieved through the selective interaction between the target biomolecule and a stationary phase(resin)within the chromatography column,while other impurities are washed away or the other way around.SkidPLCBuffers/HarvestTank ContentPF(UV)Flow CellFlow CellFlow CellFlow/PressurePurifiedProteinFractionsChromatographyColumnChormatography ProcessPF(UV)EquilibrateLoadWashEluteRegeneratePF(UV)ElutionStrengthRe-pack254 nm UV:DNA signal280 nm UV:Protein signalTime or volUVCycleYield%Conductivity monitoring is mandatory to maintain the appropriate ionic strength for efficient and selective biomolecule separation,contributing to the overall performance,product purity,and yield in the purification process.Difference between conductivity before/after column=Red flagFlow and pressure are controlled in order to optimize the process stream through the chromatography column,ensuring efficient separation,minimizing peak broadening,and preventing damage to the stationary phase or packed bed.If the pressure is too low,the flow rate will be insufficient,resulting in poor separation and longer processing times.Conversely,if the pressure is too high,it can lead to excessive flow rates,overloaded column,and potential damage to the column packing material.pH monitoring ensures optimal conditions for the selective interaction and separation of target biomolecules,thereby maintaining the efficiency,product quality,and overall performance of the purification process.Difference between pH before/after column=Red flagMeasuring protein fraction using UV serves to accurately monitor and identify the target biomolecule elution peaks to enable precise precise collection and separation of the desired product from impurities and contaminants.The desired biomolecule is separated based on the absorbance at a certain wavelength(usually 280 nm)to determine the presence and concentration of proteins in the collected fractions.UV detection is crucial here,as it allows operators to identify and pool the appropriate fractions containing the target protein(s).Figure 7:Chromatography Critical Process Parameters24White Paper|Biopharma Downstream Critical Process ParametersThere are various types of chromatography techniques used in DSP 22,35,including ion exchange chromatography,affinity chromatography(e.g.,Protein A chromatography),size exclusion chroma-tography,and hydrophobic interaction chromatography.Each of the aforementioned chromatography techniques caters to specific separation requirements and target biomolecule properties.The first two are the ones most common to find in mAb DSP trains:Protein A chromatography is particularly effective at separating mAbs from other proteins,including host cell proteins(HCPs),as well as some impurities like residual DNA/RNA,viruses,and other contaminants.Ion exchange chromatography(IEX),serves several purposes,including:Further purification of target molecules:IEX can be used as an additional step to remove residual impurities such as host cell proteins(HCPs),DNA/RNA,and other charged contaminants,after primary capture steps like Protein A chromatography.Separation of product variants:IEX can help separate and isolate different charge variants of the target molecule,which might arise due to post-translational modifications or other structural changes.This is particularly important in the production of monoclonal antibodies,where charge heterogeneity may impact product efficacy and safety.Buffer exchange and desalting:IEX can be employed for buffer exchange or desalting,which may be required before or after specific purification steps or for the final formulation of the product.In summary,the specific goal of chromatography is to separate and purify biomolecules based on their charge properties,enabling the removal of impurities,isolation of product variants,and buffer exchange,thereby contributing to the overall quality and safety of biopharmaceutical products.The most important CPPs for both types of Chromatography are the same:pH,Conductivity,Protein Fraction(commonly performed by UV measurement),and pressure/flow.They are all critical and they are all measured in-line per default,as described in the graphic of Figure 7.A deep-dive is furtherly presented in Focus Box#6 with tips on pH and Conductivity measurement in flow-cell.Considering the critical role of Conductivity and pH in-line monitoring in chromatography operation units,it is essential to highlight their distinct uses and significance beyond the information summarized in the figure.Conductivity,extensively monitored in process-scale liquid chromatography skids before and after columns,and invariably measured in Ion Exchange(IEX)skids,serves multiple purposes:Buffer Homogeneity and Chromatography:The monitoring of conductivity is crucial for verifying the salt concentration used in chromatography to elute specific proteins.Column Packing Efficiency:Conductivity can measure the bolus of salt,which aids in determining the efficiency of column packing.Regarding pH,it is a key property within the buffered mobile phase due to its critical impact on protein purification:Phase Interactions:Interactions between the mobile and stationary phases can influence chromato-graphic performance,thus affecting the separation profile between the product and impurities.Protein Elution:Proteins can be eluted using either a continuous or stepwise salt or pH gradient.A pH gradient separation requires a change of 1-2 pH units to separate proteins of different charges.25White Paper|Biopharma Downstream Critical Process Parameters Buffer Preparation:Product recovery,purity,and throughput can be negatively impacted by pH and conductivity variability in buffer preparation.pH Control:Incorrect pH control could result in the product failing to bind to a chromatography column or improper formulation of bulk drug substances.Reproducible Purification:Reliable and reproducible purification is achievable under optimal conditions of pH monitoring.Through these examples,we can see the critical role that real-time,in-line monitoring of pH and conductivity plays in maintaining the efficiency,reliability,and quality of bioprocessing operations.In regard to the technology used,Chromatography skids are increasingly moving towards Single-Use,at least for the“flow-kit/tube-kit”part.This is a pre-assembled,disposable set of components designed to facilitate fluid handling and connections in a Single-Use chromatography system.The flow-kit typ-ically includes tubing,connectors,valves,and sensors,which are pre-sterilized by gamma irradiation and ready to be connected to the Single-Use chromatography column and other components of the system(x-ray irradiation is an alternative currently under evaluation).These kits help to streamline the setup process,reduce the risk of cross-contamination,and minimize downtime between runs,making them an integral part of Single-Use chromatography skids in biopharmaceutical manufacturing.As mentioned,all flow kit components are commonly gamma sterilized in the range of 25-50 kGy de-pending on the product,its material composition,and the desired sterility assurance level(SAL).This includes the Single-Use process sensors,which must be compliant with a pre-defined shelf life after gamma irradiation.For example,Single-Use pH sensors built-in the flow-kits:Must be pre-calibrated as they cannot be dismounted for a 2-point calibration like reusable sensors(they are product-calibrated in the process)Must have at least 18 months of shelf-life after gamma irradiation Must guarantee an accuracy suitable for DSP application after gamma irradiation and dry storage:0.15 pH with provided calibration values.0.1 pH after product calibration at the measurement temperature An example of a Single-Use chromatography skid integrating flow-kit and such kind of compliant pro-cess sensor 37 is described in Box#7.26White Paper|Biopharma Downstream Critical Process ParametersEXAMPLESingle-Use Skid for LPLC Chromatography Verdot FlexiProChromatography LPLC is a low-pressure liquid chromatography process that operates under pressures less than 6bar.This technique allows for the transfer of molecules between a solid stationary phase(known as chromatography media or gel)and a liquid mobile phase,which conditions the stationary phase to desorb the molecules being purified.The stationary phase is located within a chromatography column,which is evenly distributed with the mobile phase from top to bottom by two distributors.The VERDOT Ips FlexiPro is a benchtop system adaptable to a wide range of chromatography processes.Inline dilution or gradient of aqueous buffers can be performed with the FlexiPro system.Only the most precise and reliable disposable sensors such as the Hamilton OneFerm or the Conducell 4USF are used in order to monitor the pH and Conductivity of the process and control the flow rate and dilution.Other critical process parame-ters such as Protein titer(UV),flow,and temperature are monitored as well.VERDOT Ips FlexiPro with Low Flow Kit including flow-cells and pH/Conductivity SensorsLPLC is typically used in the following cases Fine separation of“high”value molecules(2$/g in order of magnitude)Separating molecules of similar size,where filtration cant work Fragile molecules or cells Purification and concentration,in Bind&Elute mode:valuable molecules can be very diluted in the load solution and end up contained in the bed volume after adsorption.They can be eluted in 2-5 column volumes.The change of solvent in Bind&Elute mode can help further purify.Example in Reverse Phase Chromatography:load raw product in water,elute the target molecules in EtOH that can be easily evaporated.Adaptable to any kind of molecules:proteins,oligonucleotides,sugars,lipids,and cells(virus)#7For more information27White Paper|Biopharma Downstream Critical Process ParametersA separate discussion is required for Temperature:It is another important critical process parameter(CPP)in downstream processing,particularly in chromatography,as it can affect the efficiency,selec-tivity,and stability of biomolecules during the purification process.Temperature is seldomly measured directly in the process stream using sensors because controlling temperature often involves more comprehensive strategies the do not rely on in-line control:therefore,it is not present in Figure 7.For example,when low temperatures are required to maintain the stability of sensitive biomolecules,the entire chromatography assembly including the columns and associated equipment is typically placed in refrigerated rooms(2C to 8C,-35.6F to 46.4F)or cold cabinets(8C to 15C,-46.4F to 59F).This approach helps to ensure precise temperature control throughout the entire process,preserving the integrity and functionality of the target biomolecule and enhancing the overall performance of the chromatography step in downstream processing.Examples of biopharmaceuticals requiring low-tem-peratures are enzymes,viral vectors(for vaccines and gene therapy),and nucleic acids(plasmid DNA or mRNA).In their production,the skids,including process sensors,should comply with the low tem-peratures mentioned.5.3 Purification Part II:Concentration and FiltrationFiltration units normally follow the chromatography steps.Although skid trains may be different for different applications,several filtration unis are always present.They serve several purposes:1.Concentration:Ultrafiltration(UF)is used to concentrate the target biomolecule such as a protein or monoclonal antibody(mAb),by selectively retaining it on one side of a semipermeable mem-brane while allowing smaller molecules and solvents to pass through.2.Purification:Filtration can remove impurities such as host cell proteins,nucleic acids,viruses,and other contaminants that differ in size from the target biomolecule,contributing to the overall purity of the final product.3.Buffer exchange and desalting:Diafiltration(DF)is employed to exchange the buffer or remove salts and low-molecular-weight contaminants by diluting and concentrating the retentate through the controlled addition and removal of solvent across the semipermeable membrane.Filtration is possible either as dead-end filtration or more commonly in DSP as Tangential Flow Filtration(TFF)38.Explanation of both with examples 39,are presented in Box#8.TFF is a cross-flow filtra-tion method that uses a semi-permeable membrane(e.g.,made of polysulfone),to separate the target molecule from smaller molecules such as salts,contaminants,and by-products.28White Paper|Biopharma Downstream Critical Process ParametersTRENDSTangential Flow Filtration Donaldson(Solaris)Kronos&TytanBy changing the filter types,it is possible to execute the following with TFF:Particulate filtration Microfiltration Ultrafiltration Nanofiltration Reverse osmosis In regard to the CPP monitored within such skids:Hamilton pH and conductivity Arc sensors have been digitally integrated into the Solaris Process Control System(PCS)to provided to user/operator with multiple benefits over traditional analog sensor outputs such as:More robust communication protocol that is not susceptible to electrical noise Sensor health and diagnostic information available within the controlling software Calibration time is significantly reduced and simplified through parallel calibrations&batch calibrations only possible with digital“smart”sensors Sensor warnings/errors generated in real-time can help eliminate lost batches due to probes fouling during mid-runFor downstream operation,timing plays an important role.Clogged filter impact directly the duration of the filtration process and can negatively affect the folding properties of the targeted molecule;therefore,the capacity to provide in the end the expected healing effect.This is the reason why in biopharma DSP the method of choice is the tangential flow filtration(TFF),also named as cross-flow filtration.In contrast to a dead-end impact filter,where the product flows perpendicular to the filter and is susceptible to clogging,TFF operates with the product stream moving parallel to the filter.This facilitates the maintenance of solids in solution and limits the accumulation of a filter cake,which can contaminate the membrane.TFF enables a continuous and gradual concentration process,which permits samples to be concentrated up to 2.5 times faster as opposed to when using dead-end filtration.#8Examples of reusable benchtop and pilot/industrial scale TFF systems:Kronos skid and Tytan respectivelyFor more information29White Paper|Biopharma Downstream Critical Process ParametersThe pore sizes of the membranes used in UF and DF are typically determined by their Molecular Weight Cut-off(MWCO)value,which represents the approximate molecular weight of the smallest solute that is effectively retained by the membrane.The choice of MWCO depends on the target molecule and the purpose of the filtration step 40.For monoclonal antibodies(mAbs)and other large biomolecules,the MWCO values typically range from 10 kDa to 100 kDa.To concentrate and purify a target protein like an mAb,it is essential to choose a membrane with an MWCO that is smaller than the molecular weight of the target molecule but larger than most contaminants.Membranes with an MWCO of 30 kDa to 50 kDa are commonly used for an mAbs with a molecular weight of approximately 150 kDa.For buffer exchange or desalting purposes,a membrane with a larger MWCO(e.g.,100 kDa)can be used.The primary goal is to allow smaller molecules such as salts and buffer components to pass through the membrane while retaining the target protein.The efficient functioning of membranes and maintaining proper buffer conditions are crucial for pu-rifying and concentrating the product within the expected time while preserving product stability.In TFF skids,the monitored CPPs are associated with these aspects and include pH,conductivity,and pressure/flow 38.With monoclonal antibody purification,production-scale TFF systems can achieve flow rates of up to 600 L/hour to necessitate a rapid and.precise in-line measurement of all these pa-rameters under dynamic conditions(typically in flow cells).Figure 8 offers a comprehensive description of these CPPs and their functions.PC(UV)ConcentrationTankRententateFlowPressureTFF FiltrationModule(UR or DF)PC(UV)FeedPermeateBuffer fromBuffer PreparationSkidFlowPressurePumpPumpConcentrated solution retained on the feed side of the membraneIn-line pH measurement is essential to maintain the desired buffer conditions during TFF.The pH can influence the target molecules behavior,stability,and solubility,as well as affect membrane performance and fouling propensity.Protein concentration directly impacts product recovery,concentration,and quality.UV absorbance may be utilized as an in-line method to measure the endpoint of product concentration during TFF particularly for proteins and monoclonal antibodies,which exhibit strong absorbance at specific wavelengths(e.g.,280 nm)due to the presence of aromatic amino acids such as tryptophan,tyrosine,and phenylalanine.The filtrate that passes through the membrane,typically contains smaller molecules and solutesIn-line conductivity measurement is important,particularly during diafiltration,for monitoring the efficiency of buffer exchange and salt removal.It helps to determine the completion of the diafiltration process and confirms that the desired buffer conditions have been achieved.Flow rates Monitoring the feed flow rate(crossflow rate)and permeate flow rate ensures proper fluid dynamics,thus minimizing concentration polarization and fouling,and optimizing product recovery and concentration.Pressure In-line pressure measurements at various points in the TFF skid(e.g.,feed,retentate,and permeate lines)allow the monitoring of transmembrane pressure(TMP),which is crucial for controlling the filtration performance and preventing membrane fouling or damageFigure 8:Filtration Critical Process Parameters30White Paper|Biopharma Downstream Critical Process ParametersTwo other process parameters that can be monitored with TFF are protein concentration and tem-perature.Protein concentration:UV absorbance can be measured using in-line UV sensors or spectro-photometers installed directly in the TFF skids permeate or retentate line.The UV absorbance is proportional to the protein concentration in the solution,allowing for real-time monitoring of the concentration process.However;a calibration curve must be established using a series of protein standards with known concentrations and compliant with each specific application to accurately determine the protein concentration in the process stream based on the measured UV absorbance.Temperature:In-line temperature measurement ensures that the process is conducted within the optimal temperature range,which can affect the target molecules stability and solubility,and membrane performance.It is not always measured directly in the process stream using sensors,as controlling temperature typically involves broader strategies that do not depend on in-line con-trol,hence its absence in Figure 8.Like the explanation provided in the chromatography Chapter,filtration skids can also benefit from Single-Use technology.For Single-Use process sensors(such as pH,conductivity,flow,pressure,and protein concentration),and buffer liquid handling they employ flow-kits akin to those described earlier in the same Chapter.5.4 Viral InactivationViral inactivation is required to ensure the safety and quality of the final product,particularly for thera-peutic proteins and monoclonal antibodies derived from mammalian cell culture systems.This step is designed to eliminate or inactivate any potential endogenous and adventitious viral contaminants that might be present in the product stream.Common methods of viral inactivation include low pH treat-ment,solvent/detergent treatment,and exposure to heat or ultraviolet(UV)light.The choice of viral inactivation method depends on the nature of the target product,its stability,and the potential viral contaminants.To ensure the efficacy of viral inactivation,it is crucial to validate the process using model viruses and establish robust process controls.Implementing viral inactivation as the final DSP step helps to mitigate the risk of viral contamination and plays a vital role in meeting regulatory requirements while ensuring patient safety.31White Paper|Biopharma Downstream Critical Process ParametersKEYWORDSEndogenous and Adventitious Viruses Endogenous virusesThese are viruses that are integrated into the host cells genome and can be passed down from one generation of cells to another.In the case of biopharmaceutical production using mammalian cell lines,endogenous viruses may be present within the host cells and can potentially contaminate the product.Examples of endogenous viruses include retroviruses in the case of Chinese hamster ovary(CHO)cells and other mammalian cell lines.Adventitious virusesThese are viruses that are not part of the host cells genome but can be introduced into the bioprocess from external sources.Adventitious viruses can potentially contaminate the production process through raw materials(such as media,sera,or supplements),personnel,equipment,or the manufacturing environment.Examples of adventitious viruses include vesivirus,reovirus,and mouse minute virus(MMV).This white paper addresses the most common methods employed for viral inactivation,thus,low pH treatment 42.It is efficient,particularly for the inactivation of endogenous and adventitious viruses(see Box#7),in the production of monoclonal antibodies and other therapeutic proteins.An exemplary process is described in Figure 9.In a campaign,several cycles may be performed,as an entire product batch usually is not cleared all at once.In the context of viral inactivation in biopharmaceutical processes,endogenous and adventitious viruses refer to two different sources of potential viral contamination 41.Viral inactivation and removal steps in biopharmaceutical downstream processing are designed to address the risk of both endogenous and adventitious viral contaminants.Multiple orthogonal methods such as low pH treatment are employed to inactivate or remove a broad spectrum of viruses to ensure the safety and quality of the final product.Rigorous process validation and adherence to current good manufacturing practices(cGMP)are also essential in minimizing the risk of viral contamination.For these applications,in-line pH process sensors,either Single-Use or reusable,must be ready for compliance with the same GMP requirements of the skids they are built in,the system offers a solution that guarantees the expected low pH treatment is applied.#932White Paper|Biopharma Downstream Critical Process ParametersBuffer from BufferPreparation SkidVirus InactivationBuffer with Product(e.g.mAb)fromFiltration skidBuffer with Product(e.g.mAb)after Virus inactivation843.5Cycle 1Cycle 2TimepH12341234Virus Inactivation Mixer Skid(steel mixing tank or Single-Use mixing bag)pH is the most critical process parameter as it directly affects the effectiveness of the process.If the pH is too high,the virus may not be fully inactivated,which could lead to a risk of contamination or infection.On the other hand,if the pH is too low,it could potentially cause damage to the biopharmaceutical product,resulting in reduced yield or decreased product quality.Example of optimal profile steps according to pH measurement 43:1.Mixing and adjustment of pH:The protein solution is mixed with an acidic buffer,typically citrate or acetate,to lower the pH to a value in the range of 3.0 to 4.0.The exact target pH depends on the specific product and process requirements.The low pH conditions disrupt the viral envelope,leading to the inactivation of enveloped viruses.2.Incubation:The low-pH solution is incubated and held at a controlled temperature,usually between 20C and 30C for a specified period,generally between 30 minutes to a few hours.The incubation time and temperature are optimized based on the target proteins stability and the desired level of viral inactivation.3.Neutralization:After the incubation period,the pH of the solution is adjusted back to the proteins physiological pH range by adding a neutralizing buffer.This step restores the proteins native structure and activity,which may have been temporarily affected by the low pH conditions.At the end the mixing,the tank/bag is emptied and ready for the next run.4.pH sensor is exposed in an empty mixing tank/bag waiting for the new viral inactivation cycle.Figure 9:Viral inactivation process example with pH as the most Critical Process ParameterTo ensure the effectiveness of low pH treatment,it is important to closely monitor and control the pH throughout the process.This typically involves the use of pH sensors and automated control systems to adjust the pH as needed to maintain it within the desired range.Similar to other skids,viral inactivation can be performed using either Single-Use or reusable equipment.In the case of reusable equipment,a stainless steel mixer and reusable sensors are utilized.However,in Single-Use applications,mixing bags with pre-installed pH sensors are used.In such a case,the sensors must not only comply with Single-Use equipment cGMP requirements such as biocompatibility and gamma sterilization but they also need to be pre-calibrated.This is because they are built into the bag and cannot be calibrated like reusable sensors.The Hamilton OneFerm Single-Use pH sensor shown in Figure 10 is an example of such a sensor.33White Paper|Biopharma Downstream Critical Process ParametersOneFerm pH VP 70 NTCSensor(25C):58.11 mV/pH(98,23%)Zero-Point(25C):2 mV 243235 123456789 12345 2020-09-29OneFerm pH VP 70CH-7402 BonaduzINSIDE MIXING BAGOUTSIDE MIXING BAGFigure 10:Example of Single-Use pH Sensor for Downstream ApplicationsIn addition to pH,other critical process parameters for low pH viral inactivation may include the duration of the treatment,the concentration of the virus,and the temperature of the environment.By closely monitoring and controlling these parameters,biopharmaceutical manufacturers can ensure that their products are safe,effective,and meet the highest standards of quality.5.5 Additional Unit Operations I:Centrifugation Centrifugation is particularly useful in processes involving the separation of cells,cell debris,and other particulate matter from the product of interest 44.Here are some scenarios in which a centrifugation step is necessary:Cell harvest:Following the upstream cell culture or fermentation process,centrifugation is often employed as the first step to separate cells or cell debris from the culture broth.This is especially common for microbial or mammalian cell culture processes,where the product of interest is secreted into the culture medium.Clarification:After cell harvest,further clarification may be needed to remove finer particulates and other insoluble impurities before proceeding with the purification process.Centrifugation can be used as a primary or secondary clarification step,often in combination with other techniques such as microfiltration or depth filtration.Viral particles removal:In the production of viral vectors for gene therapy or vaccines,centrifugation can be used to separate viral particles from host cell debris,contaminants,and other impurities.Density gradient ultracentrifugation is a common technique used for this purpose because it provides a high degree of separation based on particle size and density.Precipitation:In some processes,a precipitation step is used to separate the target protein or other biomolecules from the solution.Centrifugation is typically employed to separate the precipitate from the supernatant,which can then be redissolved and subjected to further purification.34White Paper|Biopharma Downstream Critical Process ParametersThe critical process parameters(CPPs)are mainly related to the physical properties of the operation itself.These parameters ensure that the separation process is efficient without damaging the product.Centrifugal force,feed rate,and temperature are examples of CPPs that play a major role in this context.In this white paper,the attention is focused on two critical process parameters:turbidity and dissolved oxygen.When required,both turbidity and dissolved oxygen parameters need in-line monitoring via process sensors.Turbidity:It i s a measure of the cloudiness or haziness of a fluid caused by the presence of sus-pended particles.It provides valuable information about the efficiency of the separation process.A significant reduction in turbidity after centrifugation indicates that the process is effectively removing the suspended particles.Dissolved oxygen:It has an impact on the stability of oxygen-sensitive proteins:these products require processing under low-oxygen or anaerobic conditions,or the addition of antioxidants to maintain stability.The maximum concentration of dissolved oxygen allowed in downstream pro-cesses depends on the specific oxygen-sensitive product being manufactured and the sensitivity of that product to oxidative degradation.There is no universal value that can be applied to all bio-pharmaceutical products.The permissible levels of dissolved oxygen,especially in the cen-trifuge head-space must be determined on a case-by-case basis,taking into account the stabil-ity and activity of the product,as well as the desired shelf life and storage conditions.Typically,dissolved oxygen levels in solution are around 8-10 ppm(parts per million)at room temperature,although this can vary depending on temperature,pressure,and the presence of other dissolved gases.5.6 Additional Unit Operations II:RefoldingInclusion bodies are insoluble aggregates of misfolded and inactive proteins that form during high ex-pression levels and folding stress in bacterial systems like Escherichia coli.Refolding is a crucial step in downstream processing to recover the biologically active protein from inclusion bodies.Although bacterial systems may result in misfolded proteins,they are more cost-effective and faster than other expression platforms.Refolding enables the use of these systems while still achieving the desired product quality.The process happens in a mixing tank(reusable)or mixing bag(Single-Use)similar to those previously described for the viral inactivation.The critical process parameters involved are pH,denaturant con-centration(conductivity),protein concentration,and temperature.Those are all monitored with reusable or Single-Use sensors according to the skid of choice.Along with these critical process parameters,there is an additional parameter that can be monitored in-line:the redox conditions 45.For proteins containing disulfide bonds,the redox environment during refolding is crucial to ensure proper protein folding and functionality.The concentrations of reducing and oxidizing agents must be optimized to facilitate the correct formation of disulfide bonds and minimize the formation of incorrect disulfide link-ages.To summarize,refolding is an essential step in some biopharmaceutical downstream processes,par-ticularly when the target protein is expressed as inclusion bodies in bacterial systems.By monitoring and optimizing critical process parameters such as denaturant concentration,pH,protein concen-tration,temperature,and redox conditions,it is possible to recover the biologically active protein and ensure the desired product quality.35White Paper|Biopharma Downstream Critical Process Parameters6.ConclusionsBiopharmaceutical downstream processing(DSP)is a crucial and highly complex part of biomanufac-turing,responsible for the recovery,purification,and formulation of therapeutic proteins and other biomolecules.Similar to upstream processing,downstream processing has Critical Quality Attributes(CQAs)that must be stringently controlled to guarantee the biopharmaceutical products quality,safety,and efficacy.Since CQAs cannot yet be directly controlled in-line,Critical Process Parameters(CPPs)are regulated instead.Many unit operations make up the DSP train,and each operation features its own set of CPPs.Monitoring and controlling these CPPs is therefore essential for ensuring product quality.In this white paper,we have presented an overview of the key process units in DSP operations,in-cluding chromatography,ultrafiltration/diafiltration,viral inactivation,and optional operations such as centrifugation and refolding.We have examined the significant CPPs associated with each operation and the process sensors used for their monitoring.A summary overview can be found in Table 4.In-line or at-line/off-line?At-line;off-line monitoringIn-line monitoring(PAT Method of choice)DSP Train Unit OperationVirus Inactivation(Viral clearance)FiltrationChromatographyRefolding(optional for Bacteria production)CentrifugationCPPspHConductivity(Salt concentration)Protein concentration/Protein Fraction(UV)Temperature#Flow rate/pressure#Redox environment(ORP)#Dissolved Oxygen(for oxygen-sensitive proteins with risk of degradation)#Turbidity#CQA ClusterPurity and impurity levels Host cell proteins(HCPs)removal DNA and RNA contentPurity and impurity levels I,II,III structure Post-translational modifications(PTMs)Purity and impurity levels Sterility and endotoxin levels Viral clearanceTable 4:List of CPPs and CQA clusters vs.PAT in-line/at-line/off-line The availability of monitoring methods according to the scientific literature is represented with the indication of the corresponding measurement accuracy and robustness:Accuracy,robustness,and repeatability good enough to be commonly implemented for process controls Accuracy,robustness,and repeatability not commonly accepted for process control No standard option available36White Paper|Biopharma Downstream Critical Process ParametersThe appropriate combination of unit operations and optimization of their CPPs relies on the specific biopharmaceutical process and the product being manufactured.A comprehensive understanding of the relationship between CPPs and the desired product quality attributes is critical for designing an efficient and robust DSP process.To support the implementation and control of DSP processes,both reusable and Single-Use technolo-gies are available.These technologies offer various benefits and can be chosen based on factors such as process requirements,production scale,and budget constraints.In any scenario,the correct moni-toring and controlling of CPPs via suitable process sensors are crucial for achieving the desired product quality and ensuring the success of biopharmaceutical manufacturing.7.References1 U.S.Department of Health and Human Services(2004):Guidance for Industry.PAT A Framework for Innovative Pharmaceutical Development,Manufacturing,and Quality Assurance.Rockville.2 U.S.Department of Health and Human Services(2009):Guidance for Industry ICH Q8(R2)Pharmaceutical Development.Rockville.3 M.Mitchell,Determining Criticality-Process Parameters and Quality 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Biomanufacturing,423-458,Northeast Biomanufacturing Center and Collaborative(NBC2),201423 P.Gronemeyer,R.Ditz and J.Strube,Trends in Upstream and Downstream Process Development for Antibody Manufacturing,Bioengineering 2014,1,188-212;doi:10.3390/bioengineering104018824 G.Thakur,V.Hebbi,S.Parida,A.S.Rathore,Automation of Dead End Filtration:An Enabler for Continuous Processing of Biotherapeutics,Front.Bioeng.Biotechnol.,03 July 2020,Sec.Bioprocess Engineering,Volume 8-2020|https:/doi.org/10.3389/fbioe.2020.0075825 M.Kornecki,F.Mestmcker,S.Zobel-Roos,L.Heikaus de Figueiredo,Hartmut Schlter,J.Strube,Host Cell Proteins in Biologics Manufacturing:The Good,the Bad,and the Ugly,MDPI,Antibodies(Basel)2017 Sep 16;6(3):13.doi:10.3390/antib6030013.26 A.Matte.Recent Advances and Future Directions in Downstream Processing of Therapeutic Antibodies,International Journal of Molecular Science,2022,23,8663.https:/doi.org/10.3390/ijms2315866327 M.Bayer and others,DECHEMA expert group“Single-Use-Technology in Biopharmaceutical Manufacturing”.Technical State-of-the-Art and Risk Analysis on Single-Use Equipment in Continuous Processing Steps,Dechema Biotechnologie,ISBN:978-3-89746-226-7,March 202028 A.Johnston,K.A.Matthews,Bottlenecks in buffer preparation solving downstream issues for upstream gains,European Pharmaceutical Review,23 December 202229 S.Haigney,The Importance of Buffers in Downstream Processing,BioPharm International Vol.29,No.4,Pages:2629,April 2016.30 A.Milewska,G.Baekelandt,S.Boutaieb,V.Mozin,A.Falconbridge,In-line monitoring of protein concentration with MIR spectroscopy during UFDF,Engineering in Life Science,2022;https:/doi.org/10.1002/elsc.20220005031 Cytiva,Application Note Production of In-Specification Buffer on Demand for Batch Processes Allegro Connect Buffer Management System,Cytiva,USD 3411,202032 Millipore,Application note Mobius Power MIX 1000-Mixing Characterization for Buffer and Media Preparation,Lit.No.AN4349EN00 Ver.1.5,2017 01949,02/201733 ASTM D1125-14,Standard Test Methods for Electrical Conductivity and Resistivity of Water,www.astm.org,ASTM International,West Conshohocken,PA,2014.34 F.Thomas,Considering Purification and Separation in the Downstream Train,BioPharm International,March 2022 Issue,Volume 35,Issue 3,Pages:212335 C.Stamatis,S.Goldrick,D.Gruber,R.Turner,N.J.Titchener-Hooker,S.S.Farid,High throughput process development workflow with advanced decision-support for antibody purification,Elsevier,Journal of Chromatography A,1596,104116,201936 L.Hagel,G.Jagschies,G.Sofer,Chapter“Equipment”from“Handbook of Process Chromatography-Development,Manufacturing,Validation and Economics”,p.229 320,Elsevier Ltd.,ISBN 978-0-12-374023-6,200837 Verdot ips2,FlexiPro Single-Use LPLC System for Process scale-up and manufacturing,Bulletin DP-MKT-299-07 FlexiPro,January 202238 Pall Corporation,Introduction to Tangential Flow Filtration,2/22,DIGITAL,PM1.07.03,2022.39 Solaris Biotech,Why Use Tangential Flow Filtration(TFF)?https:/ Donaldson Brand)40 A.Arunkumar,N.Singh,J.Zhang,Single pass tangential flow filtration hybrid configurations for enhancing concentration of macromolecule solutions,United States Patent Application Publication,US 2021/0253633 A1,Aug 19,2021.41 S.Warreth,Detection and Clearance of Viruses in the Biopharmaceutical Industry,BioProcess International,https:/ 17,201942 CMC Biotech Working Group,“Chapter-4.6.2 Step 6:Low pH Viral Inactivation”of Text“Product Development and Realisation Case Study A-Mab,p127-133,October 2009 43 Pall Biotech,Cadence Virus Inactivation System-Single-Use Virus Inactivation System for Batch and Continuous Processing,Pall Corporation,USD 3246a1,202044 A.Pessoa Jr.And others,Biopharmaceuticals from microorganisms:from production to purification,Brazilian journal of microbiology 47S(2016),p.5163,Elsevier Editora Ltda,http:/dx.doi.org/10.1016/j.bjm.2016.10.00745 L.F.Vallejo,U.Rinas,Strategies for the recovery of active proteins through refolding of bacterial inclusion body proteins,Microbial Cell Factories,BioMed Central,September 2004,doi:10.1186/1475-2859-3-1146 Manuel Monitel,Hamilton Process Analytics,Arc Sensors in Reactors for Oncologic and Biosimilar Application, 2023 Hamilton Company.All rights reserved.All trademarks are owned and/or registered by Hamilton Company in the U.S.and/or other countries.111008137/01 06/2023To find a representative in your area,please visit: Europe,Asia&AfricaVia Crusch 8CH-7402 Bonaduz,SwitzerlandTel: 41-58-610-10-10contact.pa.chhamilton.chHamilton Americas&Pacific Rim4970 Energy WayReno,Nevada 89502 USATel: 1-775-858-3000Fax: 1-775-856-Unlock the secrets of bioprocessing excellence Access our extensive collection of white papers to discover expert insights and best practicesMission StatementWith our pioneering sensor technology,we solve biopharma challenges.
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Developing an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsThe Economics of Synthetic mRNA Capping StrategiesLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialAll Things mRNA Strategies for Effective mRNA Vaccine and Therapeutic DevelopmentJUNE 2024This custom ebook is sponsored by TriLink BioTechnologies,part of Maravai LifeSciences,and presented in partnership with BioPharm International.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT2 Exploring mRNAs PotentialChris Spivey,Editorial Director of Pharmaceutical Technology,hosts a wide-ranging discussion on the COVID-19 pandemic response,future government communications,and healthcare funding for mRNA with experts Dr.Kate Broderick,Chief Innovation Officer at Maravai LifeSciences,and Dr.Tom Madden,President&CEO at Acuitas Therapeutics.Highlights include supply chain modalities,ensuring a fully trained manufacturing workforce,combining delivery with gene-editing innovations,and epigenetic approaches to modulate gene expression moving toward the clinic.We conclude with the huge potential for RNA expression of monoclonal antibodies and protein replacement applications.Cover:Adapted from xyz / and Dr_Microbe/;Above:Matthieu/The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT3 PharmTech:Thank you very much for making the time today to speak about an increasingly important topic,which is mRNA coming out from obscurity from a few years ago.Were very lucky to have two genuine experts in the field,and Ill let them introduce themselves.Kate:Thanks so much,Chris.Its a pleasure to be here today and to join Tom in this exciting discussion.My name is Kate Broderick.I am Chief Innovation Officer at Maravai LifeSciences.We are a San Diego-based technology provider for developers in the field of nucleic acids.We are mostly associated with the CleanCap technology,which was,of course,a component of the Pfizer-BioNTech vaccine.Prior to joining Maravai,Ive spent my entire career as a nucleic acid drug developer.So its really exciting to be here today and to talk about this incredible technology and the power that it holds.Tom:Good day to you both.Great to meet you,Kate.I am looking forward to your comments and your thoughts.Like yourself,I am from the UK originally.I came out to do a postdoc at the University of British Columbia,imagining Id be there for a couple of years,and never quite made it back.My background is in academia.Ive worked in research at the University of British Columbia and held a position there for a number of years.The work we were doing had direct relevance to clinical applications,and so I moved into biotechnology.Ive spent almost all my working life in development of delivery systems for a variety of new types ABOUT THE SPEAKERSDr.Kate Broderick,Chief Innovation Officer at Maravai LifeSciences,has extensive experience and expertise in leading and liaising with multi-disciplinary groups from discovery and R&D to engineering and clinical teams.She brings strong and broad scientific expertise to TriLink BioTechnologies,which covers multiple areas,including gene delivery,medical devices,gene therapies for the treatment of various infectious diseases,cancer immunotherapies,and vaccine development.Additionally,she has extensive experience with non-viral delivery systems for a wide range of vaccine targets and cancer immunotherapies.Dr.Thomas D.Madden,President&CEO of Acuitas Therapeutics,is a world-renowned expert in the area of nanotechnology.Dr.Madden co-founded Acuitas Therapeutics in February 2009 and has guided the company into its position as a global leader through the development and application of lipid nanoparticle(LNP)technology.Acuitas Therapeutics partners with leading pharmaceutical and biotechnology companies and prestigious academic institutions around the world,providing its proprietary LNP delivery technology to enable new drugs based on nucleic acid therapeutics.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT4 of therapeutics.I think mRNA is now the most exciting opportunity to truly make significant advances in human health.Im President and CEO of Acuitas Therapeutics,which partnered with BioNTech and Pfizer to provide our delivery technology to them for the COVID-19 vaccine.Our team was incredibly proud of the accomplishments from that collaboration and for their opportunity to contribute to a solution to the COVID-19 pandemic.And so,again,Im delighted to be here and looking forward to the conversation.PharmTech:Its been very interesting to see a platform go from arguably a four-letter word on the investment side of things to a household name.Is the question mark in the science community totally removed from mRNA as a working therapeutic platform?Kate:I do think it is worth reminding ourselves that the general public didnt know anything about mRNA as a molecule until 2020,and now its used routinely in your daily lexicon.I do think thats quite an astounding thing that occurred during the last few years.From the perspective of a scientific background,has the platform been proven out?I would say absolutely.I think none of us could have hoped to have seen the efficacy that we saw during COVID with the vaccines.It was startling;it was like a poster child for everything you want in an infectious disease vaccine.But I will hasten to mention,that is not carried through to the general public.Whilst everybody embraced it during a global pandemic,I think there are really worrying signs now that the public is starting to drift away from the power of the science,and that is a real concern for me.Tom:Do I think its a proven platform?Absolutely.One of the things we need to remember is mRNA is a natural molecule.Each of our cells is translating tens of thousands of copies of mRNA every minute.So,its not as if weve come up with a new entity that were then introducing to people.This is something that their bodies are recognizing,and theyre used to dealing with.I do agree that theres a continuing need to educate the public,to educate regulatory officials and governments,who have the power over decision-making relating to new vaccines or therapeutics,to ensure that the science message continues to be heard.Because I totally agree with Kate,I think the biggest challenge is in misinformation that is just rife out there in the world.PharmTech:Do either of you have a way of reliably addressing public misconception or the politicization of this field?Tom:The way I think of mRNA vaccines is that theyre a much more elegant way in which we can train our immune system to“I think mRNA is now the most exciting opportunity to truly make significant advances in human health.”The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT5 be able to combat a potential infectious agent.In the past,weve simply taken the attenuated virus,the whole attenuated virus or killed virus,injected that into our bodies,and then relied on the protective effect from that.Viruses contain all sorts of proteins and DNA or RNA.I consider mRNA vaccines as a simpler,more elegant,and arguably safer alternative to conventional vaccines.Conventional vaccines have demonstrated decades of safety,so I think concerns over the new technology are truly overblown.PharmTech:I couldnt agree more.Look at the birth control issue,however.Settled science is still discussed in the public forum because there arent enough strong voices able to overwhelm that.Kate:I think Toms explanation is just spot on there.As you reflect on Operation Warp Speed,what was achieved was absolutely phenomenal and incredible work.But when you listen to General Gus Perna,outlining retroactively what they did right and what they did wrong,the number one thing they wish theyd done better was the communication part of it.Of course,we all had so many things going on during the pandemic.But reflecting back,perhaps that was a miss for us,as the scientific community,to go out there and really talk through exactly what Tom said.This is a natural molecule;this isnt something thats completely foreign to the body.But I do think that we,as the scientific community,need to own that.Maybe now is a good time to say that organizations like the Alliance for mRNA Medicine(AMM),which is an advocacy group that has a lot of purposes both in the scientific community but also for the general public,are what we need.We need to make the public comfortable with RNA-based medicines,because this truly could change the face of healthcare.But if nobody or if only a small portion of the population is willing to take it,then the impact is really for nothing.So I do think this is something that,perhaps at a government level,we should be taking extremely seriously.PharmTech:You talk about mRNA as a natural molecule,but we did tweak it and used N1-methyl pseudouridine,for example,as a modification,which is a natural modification.That is where some of the contending voices come in.They point to something like that as if its a problem or a potential problem.On the science side,is there a way to explain,to lets say an astrophysicist or someone who doesnt know biology,why you have such a good comfort level with this platform?Tom:Again,as you say,even the modified nucleotides are modified nucleotides that are found in nature.I think you could also point to examples of vaccines generated with SPONSORED CONTENTOn-demand webinar:Capping and manufacturing strategies to increase mRNA potency and reduce costsThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT6 modified and unmodified mRNA constructs,and,in fact,the safety profile is probably even more favorable for the modified nucleotide construct.I think there is certainly a strong scientific basis for it.I think when were talking about disinformation,though,sadly the science is often trumped by fear.I echo Kates comments that having a number of different companies trying to get out the message as to the safety and effectiveness of these types of therapeutics is far better achieved by an umbrella organization,a coalition like AMM,which can hopefully speak with a single voice.But also,I think we want to continue to educate scientists and regulators around the world.Again,I think one of the directions that AMM is intending to take is to be an expert group or to bring together expert groups that can advise on specific topics relating to these new types of therapeutics.PharmTech:Looking back at the pandemic on communication from the regulators,and from the big companies,they improved their ability to communicate and were even talking to competitors.Switching gears,from a manufacturing perspective,what sort of major obstacles or opportunities would you prioritize?Tom:One of the areas where were using mRNA is in the development of personalized cancer vaccines.Its an early clinical stage of development.Theres some encouraging clinical data,but theres a great deal more work thats needed.So the challenge that provides is the exact opposite of the challenge we had with the COVID-19 vaccine.Its not about how we can make kilogram or ton quantities of vaccine,but how can we make very small quantities of vaccine suitable for individual patients?Thats one of the areas where were working and others are working to automate and miniaturize the manufacturing process so that we can,and Id invite Kate to speak about this on the mRNA side because you need to generate individual mRNA constructs that are patient-specific and then formulate those into an LNP so that they can be administered to that patient in a very short period of time.Obviously,if youre a cancer patient,you dont want to be wasting any longer than absolutely necessary to receive the vaccine.Thats certainly one area of focus and challenge that I know a lot of people are engaged in.The other area is being able to disseminate the manufacturer of vaccines in a wide number of countries.One of the problems we had during the pandemic is that manufacturing sites were based in a small number of locations.I think we want to ensure that countries have more access and control over vaccine supplies in the future.Theres obviously a number of initiatives looking as far as possible to automate the manufacturing process so that it can be available for more local distribution.Kate:Tom is so right.I truly hope that in 5 to 10 years chemotherapy becomes something of a redundant treatment and that were looking at much more bespoke tailored approaches to cancer.But to emphasize Toms point,there was a beautiful study that came out of a large group in the UK called the TRACERx The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT7 Study,where they monitored peoples cancers over time and fairly frequently.Within the matter of a month,some of these tumors had completely changed their neoantigen profile.So,to Toms point,the need to have really unprecedented speed to make this,the promise of personalized vaccines prominent,is absolutely key now.Many people,of course,scaled up during the pandemic,which is a major stride forward for the field.I think now,keeping those manufacturing plants warm,thats going to be a challenge.Fingers crossed that we dont have another global pandemic.I think an issue that was really pertinent during the pandemic was supply chain.Theres a lot of work that needs to be done on the supply chain side,and certainly the US governments very keen on looking at modalities to do that.There are still a lot of elements that need to be tackled.Another interesting one that might not occur is that,during the pandemic,a major struggle for the manufacturers was having a trained workforce.This means ensuring in some ways that perhaps we partner with academic institutions so that were training the next round of manufacturers with a potential need for future pandemic preparedness.We need to think a little bit outside of the box about the experience we went through and what we can do to ensure that we have preparedness moving forward.PharmTech:Pain points present opportunities for doing a better job next time.Can you marry an mRNA platform to another technique like gene editing or something like that?Tom:Absolutely.Were working with a number of partners on a variety of gene-editing approaches.There are two potential delivery options for gene editing;one is viral and one is non-viral.I think people are recognizing the advantages of a non-viral approach because you can redose patients and its not a one-and-done therapeutic.We are supporting a number of partners developing a range of gene-editing modalities.What surprises me is how that field is growing,and how the technology around gene editing is improving to avoid cutting,using base editing,prime editing,and so on.There are important ethical discussions around how and where gene-editing therapeutics should be applied.Those are going on,and again,possibly an area AMM should consider engaging if youre not doing so already,because the delivery aspect is also critical there.But I think its an area that has enormous potential.Were also working with partners,looking at a variety of epigenetic approaches to modulate gene expression.This whole field is extremely vibrant at the moment.Theres a lot of nascent science that is moving towards the clinical.I think its going to be a very exciting time over the next several years,particularly as we get more clinical data coming out,hopefully confirming the earlier studies,and demonstrating the utility of gene editing in particular applications.Kate:I think Tom eloquently covered the editing profile,but I think were looking at the massive strides forward that,for The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT8 instance,Vertex is making towards the potential first approved product.If I could play devils advocate to that,if the public are having concerns about mRNA-based vaccines,you could extrapolate that they may have equally large,if not more concerns about things that could potentially edit their genome,coming back to that need for education.But on top of the CRISPR editing applications,think about the potential for RNA-based expression of monoclonal antibodies.That is an enormous market that could allow us to utilize the power of monoclonals in places where,for instance,due to the environment,that would be impossible.So lets think through what the potential as a messenger this molecule could do.For protein replacements,another obvious application,the sky to some degree is the limit.But we do need to think about how we message thispardon the punto those who would actually benefit from it.PharmTech:Beyond the vaccines,there are a lot of interesting uses.However,you would then need to get ahead of the public education part,because what is the point if people arent going to,as you said earlier,accept this as a modality?Where would you head next if it was all left to you?Tom:We generally work in sort of lockstep with our partners.So we are looking at where their clinical interest lies and trying to ensure that we support that.I agree with Kate.I think recombinant monoclonal antibodies have been incredibly important clinically and commercially,and they can be challenging and expensive to manufacture.I think the idea of using a messenger RNA so simply encoded and having the patients generate the monoclonal antibody and glycosylate the monoclonal antibody themselves is very attractive.There are examples of these therapeutics in clinical development at the moment.I think we need to get ahead of the public in terms of educating them about potential benefits of this.Theres an even bigger challenge when youre talking about gene editing or epigenetic modulation.I dont think its too soon to give serious thought to how we can ensure that theres a recognition of the clinical need.What are the patient populations that truly need these novel therapies that have no other options available to them?What are the safety studies that have been conducted and are being conducted to demonstrate that these therapies arent going to change the gene line?So that science is going on,but I dont think theres any sort of conversation or there are very limited conversations happening with policymakers or regulators.They are occurring,but they havent risen to the level of the general public at this point.SPONSORED CONTENT Keep up with advances in nucleic acids with the “Zone in with Zon”blogThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT9 PharmTech:Are there any misperceptions or myths about mRNA that we could debunk in a quick way?Some of the adjuvants that were included in the vaccine evinced cardiac issues.I think that was debunked,but there were a couple of others.Kate:Well,Chris,yours is a perfect example.It was debunked,but Elon Musk was Tweeting or X-ing or whatever you call it now,just recently,about the young gentleman,the basketball playerit wasnt direct that it was caused by the COVID vaccine,but was it caused by the COVID?Thats a real problem.And I think Chris,Tom,and I could speak for the rest of the day about the,quite frankly,ridiculous notions that were tied to RNA-based vaccines.But whenever theres a grain of something,its just being amplified.And it certainly isnt helping when we have people like Mr.Musk putting that out on social media.Tom:I think one of the things that is lost in the conversation is,even if there was some cross-reactivity between the spike protein and other components in the body,generally where we are seeing any safety signals from the vaccine;those are far more prevalent.Those same safety signals are far more prevalent in individuals infected by the virus.Thats lost in the conversation.The vaccine cant,in any way,elicit to any extent any of the side effects that you see with the virus.I think thats just an unrealistic expectation.PharmTech:Would you like to emphasize anything in particular or conjecture about something that you think would be of interest?Kate:The future for mRNA-based or RNA-based therapeutics is so incredibly bright.I am at wonder at the potential of this platform and at the applications that we can have a meaningful benefit on.I am so positive from a scientific perspective that that will be a reality in a fairly short manner of time.But Ill say again,and sorry for being a broken record,that I have major concerns about how we can do better at communicating the science in a meaningful way to the people who need to be convinced.Tom:I completely agree with Kate.I think the versatility of the mRNA technology really lends itself to trying to address diseases that have historically eluded a vaccine approach,like malaria,HIV,and tuberculosis,because we can express multiple different antigens or multiple variants of different antigens.As Kate mentioned earlier,we can rapidly adjust the constructs that we use and the antigens that we express to meet individual geographical requirements.Theres a huge potential there to truly advance human health.But,as weve said before,I think the biggest challenge is misinformation and misperception as to what these vaccines are and what they can do.People have to be willing to stand up and speak the truth and try,as I say,to be an advocate for this truly remarkable technology.PharmTech:That is a great emphasisthank youto finish on,because the FDA grasped onto the reconfigurability of the platform in a big way already.Its a genuine delight to talk to you both.mRNA.pDNA.GMP.CDMO.You abbreviate it,we can do it.Learn more at your probability of mRNA success.Partner with a global leader in mRNA development and manufacturing to help bring your next life-changing mRNA-based medicine from concept to patients.TriLink BioTechnologies delivers both depth of experience in the number of GMP batches successfully delivered and breadth of expertise across diverse applications to support you on your journey.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT11 C ancer messenger RNA(mRNA)vaccines have made headlines multiple times in 2023.In February,an mRNA vaccine for cancer received breakthrough therapy designation after demonstrating efficacy in a Phase II trial(1).In May,the National Institutes of Health announced that in a small clinical trial,a personalized mRNA vaccine prevented pancreatic cancer from recurring for about half of trial participants(2).These developments were catalyzed in part by the success of the mRNA vaccine for COVID-19.Unlike traditional vaccines,the manufacturing process for mRNA vaccines is cell-free and can be performed with synthetic enzymes.This allows for unprecedented speed and scale of mRNA vaccine development and Despite its success,clinical and logistical roadblocks to mRNA cancer vaccine development remain.Juan Grtner/AUTHORSAndreas Dreps,PhD SVP,Drug Development Services at ICON Martin Lachs,PhD VP,Project Management Oncology at ICONLogistical Considerations in mRNA Vaccine DevelopmentThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT12 manufacturing,which proved to be pivotal during the COVID-19 pandemic.In turn,the deployment of mRNA COVID-19 vaccines helped forge the robust supply chain for mRNA vaccine manufacturing that had not previously existed.Despite this success,clinical and logistical roadblocks to mRNA cancer vaccine development remain.This article reviews the therapeutic prospects of mRNA vaccines and considerations for clinical development that could help address present issues with patient recruitment,regulatory compliance,manufacturing,and funding.Developing therapeutic cancer mRNA vaccinesThe mRNA cancer vaccines currently in clinical development have been long awaited.For decades,researchers have tried and failed to develop an effective therapeutic cancer vaccine(3).However,advancements in clinical development have made it clear that success is no longer a question of“if”but“when”and,critically,“how.”Challenges of cancer vaccine developmentTo begin to answer the“how,”its helpful to understand why developing a vaccine for cancer has proven considerably more challenging than developing a vaccine against infectious pathogens.Conventional vaccines can directly provoke a targeted immune response in essentially the same way that an infection does:by exposing the immune system to a dead or weakened pathogen,or its parts.Exposing the immune system to a less-threatening form of a harmful pathogen is sufficient for the adaptive immune system to learn how to target the pathogen and repeat the targeted response if the pathogen is encountered in the future.Regardless,the“less threatening”form of a cancer cell is a healthy cell.So,in the case of cancer vaccine development,the options for provoking a targeted immune response are much more constrained.A cancer vaccine must trigger an immune response against cancer without provoking autoimmune-mediated damage to healthy cells and tissues,meaning that the antigen,or the molecule specifically targeted by the immune system,must be cancer specific.Traditional vaccination methods are not able to achieve this level of antigen specificity.A personalized approachOf the vaccination methods,an mRNA-based vaccine has been widely considered the most promising for cancer because it can be sufficiently precise.Unlike conventional vaccines that provoke the immune response directly,an mRNA vaccine only carries instructions that provoke the immune system indirectly(3).The mRNA instructions are“read”by healthy cells,which temporarily produce a foreign protein encoded by the mRNA.The production of foreign proteins by healthy cells then triggers a targeted immune response.This method can also be used to instruct cells to produce proteins that arent from pathogensincluding proteins expressed only by cancer cells.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT13 However,until recently,identifying appropriate cancer antigen candidates has been a major roadblock for cancer vaccine development.Many antigens commonly overexpressed in cancer are also expressed by healthy cells.Other cancer-specific antigens are the result of unique tumor mutations that vary between individuals(4).Presently,the most promising cancer mRNA vaccine candidates are personalized to take advantage of the unique proteins that arise from tumor mutations(neoantigens).Modernas personalized mRNA vaccine(mRNA-4157),which received breakthrough therapy designation for the treatment of melanoma,primes the immune response against 34 of these proteins at once(1).Combination therapiesHowever,even precisely targeted vaccines may not be effective on their own.Cancers that have survived long enough to endanger a patients health have generally developed ways to resist or evade a targeted immune response,often by co-opting mechanisms that help prevent autoimmune damage,such as an immune checkpoint(5).Consequently,mRNA cancer vaccines that are currently in development are administered in combination with another therapy that can help counteract immune evasion or suppression by cancer.For example,Modernas mRNA vaccine(mRNA-4157)is administered in combination with an immune checkpoint inhibitor(ICI),which helps immune cells that target cancer,called T cells,endure the tumor microenvironment.In a Phase IIb trial,this combination proved more successful than treatment with the ICI alone.After one year,157 patients treated with the combination therapy had a 44%reduced risk of cancer recurrence or death(1).Promising Phase I results,demonstrating strong T-cell responses,were also reported in June 2022 by BioNTech for a similarly personalized method of mRNA vaccination(BNT111)for patients with advanced melanoma.The vaccine,which targets the antigens NY-ESO-1,MAGE-A3,tyrosinase and TPTE,was administered in combination with an immune checkpoint inhibitor and chemotherapy(6).BNT111 received FDA Fast Track designation in November 2021.Another approach,which has demonstrated early clinical promise,is an mRNA vaccine that enhances the proliferation of T cells genetically engineered to target cancer Presently,the most promising cancer mRNA vaccine candidates are personalized to take advantage of the unique proteins that arise from tumor mutations(neoantigens).The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT14(chimeric antigen receptor CAR T cells).A September 2022 Phase I/IIa trial of a CLDN6-directed CAR T-cell therapy,in combination with an mRNA vaccine for the CLDN6 antigen,displayed one of the first examples of CAR T-cell efficacy in solid tumors,with 43%of patients treated with the combination therapy exhibiting tumor shrinkage(6).Logistical considerations for clinical developmentWhile evidence of efficacious mRNA vaccines for cancer accumulates,logistical challenges in cancer vaccine clinical development remain.Many of the considerations for personalized mRNA cancer vaccines are shared by other cell and gene therapies(CGTs),such as CAR T-cell therapy,where challenges with complexity and cost have limited scalability and inflated the costs of approved therapeutics.In turn,many of the learnings gained from developing CGTs are relevant to mRNA vaccine development,including in-patient recruitment,manufacturing,regulatory compliance,and funding.Patient recruitmentThe eligible population for mRNA-based cancer vaccines may include patients with solid tumors early in their disease course and is likely to be much larger than approved CGTs that primarily target rare diseases and blood cancer patients with failed prior treatments.A larger population of potential patients introduces new challenges and considerations for patient recruitment.Sponsors must understand where patients are and how eligible subpopulations can be identified and targeted.Identifying eligible subpopulations is especially difficult for cancer vaccines that target specific tumor antigens,where subpopulations of patients expressing these antigens need to be identified.Depending on the prevalence of the antigen in the population,this can dramatically limit patient eligibility.This issue may be somewhat ameliorated by personalized vaccines,or vaccines targeting multiple antigens,where the eligible population is larger(4).For example,more than 90%of melanoma patients express at least one of the antigens targeted by the BNT111 vaccine mentioned previously.Regardless of antigen-expression constraints,many cancer patients may be ineligible because of the stage of their cancer,or the treatments they have already undergone.In addition,eligible patients will be distributed across broad geographic locations,and many may not live within the travel distance of sites with appropriate resources and expertise to conduct a trial.New analytics capabilities that can sift out SPONSORED CONTENTWebinar|Overcoming Critical Barriers when Developing mRNA-based Cell TherapiesThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT15 potential study participants from electronic patient records and other digital sources are a considerable step forward,as are the technologies and strategies behind the shift from traditional site-based trial models to decentralized or hybrid clinical trials.Once eligible patients are identified,they must evaluate and choose a potentially transformative,yet essentially hypothetical,approach with the possibility of unknown risk where there may be several other therapeutic options.Therefore,successful patient recruitment requires early engagement,data presentation,and partnering with physicians and patient advocates.Manufacturing and supply chainAs with other personalized CGT products,the manufacturing platform and supply chain for cancer mRNA vaccines must be designed for the speedy production and delivery of unique products.However,learnings from supply chains and the manufacturing of other CGTs may need to adjust to larger scales to target a broader range of patients,such as those with solid tumors.At this larger scale,manufacturing approaches for personalized mRNA cancer vaccines must be able to consistently and quickly produce products of the right quality,independent of the vaccine“sequence,”and have the right technology and internal systems in place to establish a regulatory-compliant chain of custody.Speed is imperative because,for personalized treatments,manufacturing and delivery is a race against an individuals disease progression.Additionally,there is no room for manufacturing or supply chain error,and the manufacturing process must ensure there is no cross contamination of products.Achieving speed and scale in manufacturing without introducing error requires streamlining production,including generating cell banks that can produce plasmid vaccines and other drug substances when possible.Vaccine developers,such as BioNTech,have successfully implemented strategies to streamline manufacturing,reducing the manufacturing and delivery time of their mRNA cancer vaccines from three to four months to three to six weeks(7).Achieving speed and scale in manufacturing without introducing error requires streamlining production,including generating cell banks that can produce plasmid vaccines and other drug substances when possible.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT16 Additional considerations must be made during delivery as well.Cancer mRNA vaccines will require specialized storage to ensure stability and may also need to adhere to country-specific guidelines on import and export of CGTs.Given that many cancer vaccines will be personalized,the supply chain process must also implement product tracing to ensure products are segregated.Streamlined product release can benefit from the adoption of paperless approaches.Finally,growing considerations may need to be made for the coordination of manufacturing and the delivery of multiple different therapies at once,as the combination of CGTs for cancer become more commonplace(such as the combination mRNA vaccines and CAR T-cell therapies).Regulatory complianceConducting clinical trials for cancer vaccines involves complying with a range of local regulatory requirements.Regulatory review will include many facets of production and distribution,including the receipt of the initial plasmid,the dispatch of material to the clinic,supply chains for the equipment and materials used in the production processes,batch manufacturing record review,and analytical testing.The regulatory challenges for CGTs are eased,to some extent,by the existence of only partial or constantly evolving guidelines.This enables companies to work more closely with regulators in plotting approval pathways collaboratively.However,it requires early and proactive engagement.Ensuring that platforms are safe and will achieve clinical thresholds requires close relationships between drug developers,manufacturers,and regulatory authorities.Interdisciplinary collaboration during the initial planning and development stages can help ensure manufacturing platforms have a well-defined and validated manufacturing process that remains the same regardless of the specific mRNA sequence.FundingCGT manufacturing,for clinical trials and beyond,is often a high cost in terms of capital investment,the resources needed for manual processes,and the time taken to produce single therapies.Funding for these trials can be a limiting factor in mRNA cancer vaccine clinical development,particularly in the current global economic environment.Economic pressure is most impactful for emerging biopharma/biotechnology companies but impacts large pharmaceuticals as well.As the potential of mRNA vaccines for cancer becomes increasingly clear,mRNA vaccine clinical development has seen an influx of funding from government sources and investors.For example,the UK SPONSORED CONTENT Manufacturing services to accelerate your path from discovery to commercializationThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT17 government announced a collaboration with BioNTech aimed at boosting research into cancer vaccines(8).However,in the long run,making mRNA vaccines for cancer accessible to broader populations will require bringing down the cost of manufacturing single therapies.ConclusionWhile it is premature to say which evolving efforts in mRNA cancer vaccines will be most fruitful,all will benefit from accounting for key logistical considerations,including patient recruitment,manufacturing,regulatory compliance,and funding.Preliminary successes of mRNA vaccines suggest they will soon be an invaluable tool in the immunology toolbox.References1.Moderna and Merck Announce mRNA-4157/V940,an Investigational Personalized mRNA Cancer Vaccine,in Combination With KEYTRUDA(R)(pembrolizumab),was Granted Breakthrough Therapy Designation by the FDA for Adjuvant Treatment of Patients With High-Risk Melanoma Following Complete Resection.Moderna.Accessed April 6,2023.2.Rojas LA,Sethna Z,Soares KC,et al.Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.Nature.2023;618(7963):144-150.doi:10.1038/s41586-023-06063-y3.Barbier AJ,Jiang AY,Zhang P,Wooster R,Anderson DG.The clinical progress of mRNA vaccines and immunotherapies.Nat Biotechnol.2022;40(6):840-854.doi:10.1038/s41587-022-01294-24.Ingels J,De Cock L,Mayer RL,et al.Small-scale manufacturing of neoantigen-encoding messenger RNA for early-phase clinical trials.Cytotherapy.2022;24(2):213-222.doi:10.1016/j.jcyt.2021.08.0055.Ribas A.Adaptive immune resistance:how cancer protects from immune attack.Cancer Discov.2015;5(9):915-919.doi:10.1158/2159-8290.CD-15-05636.Mackensen A.BNT211-01:A Phase I Trial to Evaluate Safety and Efficacy of CLDN6 CAR T Cells and CLDN6-Encoding mRNA Vaccine-Mediated In Vivo Expansion in Patients with CLDN6-Positive Advanced Solid Tumours.2022.7.Vuksanaj K.Next-Generation Cancer Vaccines Get Personal.GEN-Genetic Engineering and Biotechnology News.Published August 9,2022.Accessed June 22,2023.8.New Partnership to Boost Research into Vaccines for Cancer.GOV.UK.Accessed July 24,2023.Republished from Dreps,A.and Lachs,M.Logistical Considerations in mRNA Vaccine Development.BioPharm International Emerging Therapies eBook.September 2023.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT18 Abstract&Executive SummarymRNA vaccines and therapeutics are expanding rapidly,in part fueled by the success of COVID-19 vaccines.Manufacturing mRNA requires significant expertise,equipment,and experience.An essential part of any mRNA compound is the 5 cap structure.The 5 cap is critical to the stability,expression,and immunogenicity of an mRNA.In-vitro transcribed mRNA is not capped by default,so capping must be built into the manufacturing process.Currently,there are three major options for capping mRNAs in vitro:Enzymatic capping,Anti-Reverse Cap Analog(ARCA)and CleanCap capping technology.To assess the complete cost of manufacturing an mRNA therapeutic,it is important to consider the difference in price,time,complexity,and availability for each of these methods.To better understand the complete manufacturing costs,customer experiences,and customer needs with regards to mRNA capping manufacturing,TriLink BioTechnologies commissioned a third-party study.This study,conducted by a third-party consulting firm,analyzed the manufacturing costs of the three methods of mRNA capping.The analysis included conversations with 30 subject matter experts,outside of TriLink,who are The Economics of Synthetic mRNA Capping Strategies netsay/The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT19 developing mRNA therapeutics from many different companies across the US and the EU.In this technical note,we present the qualitative findings of this analysis and qualitative quotations from customer experiences to estimate the relative cost of each of these capping methods.Introduction&Review of Currently Available TechnologiesManufacturing mRNA for vaccine and therapeutic applications requires significant expertise,equipment,and experience.Capping of synthetic mRNA must be built into the manufacturing process.The inherent nature and manufacturing requirements of the three available technologies for capping synthesized mRNAs can have a varied impact on the overall economics of the mRNA manufacturing requirements.Enzymatic capping is the historical option.The process and methods for enzymatic capping require two bioreactor reactions,the first to synthesize mRNA and the second to cap the mRNA.Thus,the capping is done post-transcriptionally.The often-used Vaccinia virus capping enzyme produces a Cap0 structure,which is not the natural Cap structure in eukaryotes.Therefore,enzymatic capping is often paired with a 2O-Methyltransferase reaction to produce the natural Cap1 structure.A major drawback to this technology is low yield,typically reaching expected recovery yield values in the range of 50-70cording to the third-party study.The lower recovery yield is due to the requirement for multiple bioreactors and subsequent purification steps.Yet,this is a popular option due to the readily available commercial reagents and enzymes required for this process.FIGURE 1:Overview of the manufacturing process for an mRNA with the enzymatic capping method.SPONSORED CONTENT Access technical resources to learn about CleanCap technologyThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT20 ARCA was one of the first co-transcriptional capping methods developed for manufacturing mRNAs.Although it is a co-transcriptional method,it produces a Cap0 structure similar to enzymatic strategies,and thus also requires two bioreactor reactions.In this case,the second reaction is a 2O-Methyltransferase reaction to replace the Cap0 with the naturally occurring Cap1 structure.The recovery yield with ARCA may be higher than enzymatic capping but varies depending on downstream purification steps.The third-party study indicates expected recovery yields with ARCA are between 50-80%.Like enzymatic capping,the reagents for ARCA are available from multiple commercial sources.“Im impressed by the crude transcription yield,which is 2-3 times higher with CleanCap than ARCA.Especially when you scale it up,thats something significant.With this high yield,you can save 20-30%of the budget.”EU Biopharma ExpertThe final mRNA capping strategy available is the CleanCap capping technology.The CleanCap technology was developed by TriLink BioTechnologies and was the first mRNA capping solution to produce a Cap1 structure during a single co-transcriptional reaction,thus requiring only one bioreactor and purification step.This simplified manufacturing process contributes to an expected recovery yield ranging from 80-95%from the crude yield,which is notably higher than the other two FIGURE 2:Overview of the manufacturing process for an mRNA with the ARCA capping method.SPONSORED CONTENT Accelerate therapeutic and vaccine development with an effective mRNA capping strategyThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT21 capping strategies,according to the third-party study.The patented CleanCap co-transcriptional technology is only available through TriLink BioTechnologies.There are many steps to producing a successful mRNA vaccine and/or therapy,but manufacturing a safe,effective product is a vital component to a programs success.The cost of manufacturing an in vitro transcribed mRNA can be substantial depending on client needs,but always requires specific personnel and equipment.With the rapid growth of mRNA-based therapeutics in drug development pipelines,the competition and need within this space is growing.It is becoming critical for a programs success to employ streamlined manufacturing processes.Here,we outline the major costs to consider for mRNA capping manufacturing,how they vary across the capping technologies,and,based on the third-party study,highlight some subject matter expert opinions on the process.Major Economic Considerations for mRNA Capping ManufacturingRecovery rate of in vitro synthesisIn vitro synthesis of mRNA can be a challenging biochemical reaction because of mRNAs inherent instability.The complexity of the reaction,combined with the need for pure product during pharmaceutical development,necessitates stringent purification and QC testing.Depending on the technology,equipment,downstream purification processes and user expertise,the expected overall yield ranges from 50%with enzymatic to 95%(the higher end of the range being associated with the use of CleanCap capping technology,as seen in the third-party study).FIGURE 3:Overview of the manufacturing process for an mRNA with the CleanCap capping method.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT22“With fewer steps and less processing time with CleanCap,there is the benefit of an almost full recovery rate.One purification step is all we need.”US Biopharma ExpertThe recovery rate directly influences the overall cost of product manufacturing:a higher recovery yield per reaction means less input is needed to produce the same amount of product,or,vice versa,a low recovery yield requires more input reagents for the same amount of final product.FIGURE 4 shows the direct reagent costs for the GMP manufacturing of 1 gram of mRNA product with each of the three outlined mRNA capping methods.This figure demonstrates how enzymatic capping and ARCA require additional reagent costs for the same amount of product due to their reduced yields per reaction.Overall,based on the findings of the third-party study,it is estimated both enzymatic capping and ARCA technologies lead to higher total reagent cost per quantity of produced mRNA:an estimate of$248 for enzymatic,$221 for ARCA and$215 for CleanCap technology.This data demonstrates how influential the recovery rate is on the total reaction reagent costs.FIGURE 4:Estimated recovery rate and reagent cost comparison for the three mRNA capping methods to produce 1 gram of GMP mRNA product.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT23 Throughout the manufacturing process,every bioreactor reaction has required subsequent purification and QC steps,each with their own costs.The third-party study estimates enzymatic reactions cost more,not simply due to their required reagents,but also due to repeating costs from necessary purification and QC follow-up steps.FIGURE 5 shows estimated purification costs across the three capping methods for both non-GMP and GMP manufacturing of 1 gram batch of mRNA product.Quite simply,the results from the study indicate that the second necessary bioreactor reaction for enzymatic and ARCA capping typically lead to doubled purification costs compared to capping with CleanCap technology.TimeTime is a significant cost for pharmaceutical development.Time saved during pharmaceutical development,including for mRNA vaccines and therapeutics,can directly lead to cost savings in two major ways.Reduced process time can increase the velocity of development and scale up,speeding up time to market for a program.The faster a pharmaceutical product reaches commercialization,the larger potential impact it can have on enhancing or saving patient lives.There is an opportunity cost in choosing complex and multi-step manufacturing methods,and a simpler manufacturing process can accelerate time to market and reduce costs associated with equipment and process errors.FIGURE 5:Estimated purification cost comparison for the three mRNA capping methods to produce 1 gram of either non-GMP or GMP mRNA product.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT24 One of the most straightforward ways to compare time savings for mRNA capping technologies is by examining the number of days it takes to produce one batch of mRNA product.Again,the number of bioreactor reactions needed with a manufacturing project greatly influences the time it takes to complete a round of synthesis.More bioreactor steps require more time.For GMP production of a single batch of mRNA,the estimated time for enzymatic capping was eleven days,for ARCA it was ten days and for CleanCap it was six days(FIGURE 6).These additional manufacturing days can be further compounded if there is a deviation or rework required in the manufacturing process,which is more likely to occur with multiple steps and multiple bioreactor reactions.In this side-by-side comparison in GMP mRNA production,CleanCap capping technology produced usable product nearly a week sooner than either of the other two technologies.FIGURE 6:Comparison of estimated calculated Manufacturing Time with each mRNA capping technology for a single batch of mRNA in non-GMP and GMP conditions.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT25“Learning from the COVID-19 vaccines,both enzymatic and co-transcription can be scaled up just fine.With CleanCap,we are eliminating the 10-25%risk of some process failure that needs process optimization during scale-up in enzymatic.”EU Biopharma ExpertA more holistic evaluation of time savings for mRNA capping strategies is to consider the time required for process development scale up during clinical development.Process optimization is required as reaction volumes change,and technical issues can arise with yield or quality as a biochemical reaction is scaled up.From a risk assessment standpoint,adding process steps expands the complexity of a process Failure Mode and Effect Analysis failure,which also slows the development process.Here again,the simplicity of a one-pot reaction provides a cost saving benefit to using CleanCap capping technology.On average,process development time utilizing CleanCap co-transcriptional technology is estimated to be about one-half of that required for enzymatic or ARCA capping(FIGURE 7).Two months of time savings in process development could have significant impact for earlier to market profit savings.The additional investment in skilled Full Time Employees(FTE)to run multi-step processes must also be factored in overall manufacturing cost calculations.Improved simplicity and time savings for the entire manufacturing process reduces the necessary labor and associated costs of FTEs to support the process.The simplicity of the manufacturing process when using CleanCap dramatically reduces the necessary labor costs as compared to the enzymatic and ARCA approaches(FIGURE 8).It is estimated for either non-GMP or GMP production,the use of CleanCap capping FIGURE 7:Comparison of estimated calculated Process Development Time for each mRNA capping technology.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT26 procedures typically leads to 70-75%lower overall labor costs than enzymatic or ARCA preparation,and requires an estimated 40wer FTEs and half the number of hours to complete the process(FIGURE 8).“Compared to CleanCap,the FTEs required for the purification double in enzymatic capping.It takes more time for them to prepare and set up the column and TFF.”US SMID Biopharma ExpertOverall,our research through the third-party study indicates an expected reduction in manufacturing time by using the CleanCap reagent technology for in vitro mRNA synthesis and capping.This has the potential to lead to higher profitability and a reduced time to market for new therapeutic programs.Cost-effectivenessCost-effectiveness describes the total cost of a particular mRNA capping process from start to finish in the manufacturing process.All manufacturing facets influence the cost and economics of mRNA capping methods and,thus,impact the overall cost-effectiveness of each strategy.FIGURE 8:Estimated labor cost comparison for the three mRNA capping methods to produce 1 gram of either non-GMP or GMP mRNA product.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT27 As FIGURE 9 shows,the expected higher yields,simplified reaction setup,reduced purification needs,and anticipated reduced labor costs all contribute to the CleanCap co-transcriptional technology being the most cost-effective mRNA capping strategy.The overall cost of the CleanCap technology is estimated to be 30%less than enzymatic capping and 20%less than ARCA.For 1 gram of GMP grade mRNA batch,this equates to approximately$135,000 saved with CleanCap capping reagent compared to enzymatic capping and$110,000 compared to ARCA capping.These estimates do not quantify the additional benefits associated with speed to market opportunity costs,which further establish CleanCap capping technology as an ideal in vitro mRNA capping method.“The benefit of high yield is going to be more apparent when we scale up.With this high yield,we can save 20-30%of overall manufacturing cost.”EU SMID Biopharma ExpertThe long-term success of a program will require manufacturing and production scale up as a pharmaceutical product enters and succeeds through the clinical phase.It is not uncommon to require a nearly 10-fold increase in pharmaceutical product output requirements during scale up.All the costs discussed thus far contribute to,and are magnified,as this large-scale up process takes place.CleanCap co-transcriptional technology offers considerable cost savings during these final stages of development.As FIGURE 10 shows,the costs are non-linear in the range of 1 gram to 40 gram mRNA scale up.At the greatest amount of production as predicted for Phase III studies,ARCA and enzymatic capping are estimated to be 30%and 40%more expensive than CleanCap capping technology,respectively.FIGURE 9:Comparison of Estimated Total Manufacturing Costs with each mRNA capping technology for 1 gram of GMP grade mRNA.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT28 FIGURE 10:Comparison of Estimated Total Manufacturing Cost with each mRNA capping technology as production scales from 1 gram to 40 grams of GMP grade mRNA.“With the existence of data from different approaches,biological efficiency,reduced immunogenicity.We are confident that CleanCap will have a higher probability of technical regulatory success.It goes into internal NPV model.”EU Large Biopharma ExpertConclusionAfter conducting a comprehensive qualitative and quantitative assessment,we present here an analysis of the comparative estimated manufacturing costs of the mRNA capping strategies.In assessing complexity and performance,the simplicity of the CleanCap technology has consistently demonstrated a high capping efficiency,batch-to-batch consistency,a high yield,low immunogenicity,and ability for simplified scale up.In terms of process development time,comparisons showed the CleanCap capping solution saves an estimated week of manufacturing time on a batch-by-batch basis and reduces process development time by an estimated 50%,compared to ARCA and enzymatic capping.Finally,reviewing cost-effectiveness,the use of the CleanCap capping solution demonstrated overall comprehensive manufacturing costs that are estimated to be 20-40%lower than other methods,dependent on scale.The economic data are clear:for in vitro mRNA capping,CleanCap offers the greatest benefit for its estimated cost.Data and customer insights conducted by a third-party consulting firm.Over 30%higher in protein expression and up to 50%reduction in process development time than legacy mRNA capping methodsAchieve an optimal mRNA Cap-1 structure with the most robust CleanCap M6 cap analog by TriLink.For more information visit numbers dont lieThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT30 Messenger RNA(mRNA)therapies are a relatively new technology,but the mRNA-based COVID-19 vaccines created developmental opportunities for therapies used to treat numerous diseases,including cancers and genetic diseases.Before the pandemic,mRNA was used primarily in diagnostics and in vitro diagnostic tests,and the analytical methods used to characterize mRNA were qualitative or semi-quantitative.Now that mRNA is being used as drug substances and drug products,there is a need for quantitative analytical methods with high sensitivity and specificity to characterize the structure,purity,and efficacy of mRNA.Control of raw materials in addition to the Developing an Analytical Framework for mRNACharacterizing mRNA-based therapeutics is similar to characterizing traditional biologics,but mRNA has some unique requirements that need attention.Adapted from artwork by TriLink BioTechnologies and Dan Race/ AUTHORKhaled YamoutPrincipal Consultant Yamout ConsultingThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT31 appropriate analytical tests that measure quality is crucial for manufacturing mRNA.TriLink developed several methods specifically for the quality attributes of mRNA.An ion-pair reversed-phase high-performance liquid chromatography(IP-RP-HPLC)method could be used for multiple aspects of mRNA characterization,including integrity and purity.Liquid chromatographymass spectrometry(LC-MS)methods can be used to measure capping efficiency and characterizing the poly(A)tail.An HPLC method can detect residual nucleoside triphosphates(NTPs),modified NTPs,and capping agents.As regulatory requirements continue to be established for mRNA therapies,these quantitative test methods will also need to continue to evolve.Analytical MethodsQuality requirements for mRNA as a drug substance biological molecule,tests include identity,content,characterization,integrity,purity,functionality/potency,safety,and other general methods.For mRNA in particular,it is important to analyze:Identity:measured in various ways,including sanger or next-generation sequencing(NGS),real-time reverse transcription-polymerase chain reaction(RT-PCR),or fingerprinting.Functionality:involves in vitro translation/Western blot cell-based assays to show that the correct protein that binds to the specific molecule or antigen for the therapy was made or cell-based assay.Content:can be measured by various methods,including RT-PCR,ultraviolet(UV)spectroscopy,and IP-RP-HPLC.IP-RP-HPLC can also be used to measure integrity and purity.To develop an IP-RP-HPLC method for this purpose,samples of five different types of mRNA drug substances were evaluated.This method differentiated among mRNA of different sequence lengths as well as separating different types of poly(A)tails and differentiating between a tail and no tail.Capillary-gel electrophoresis(CGE),which is an alternative method,cannot differentiate in this manner.The IP-RP-HPLC method could also be used to determine the stability of mRNA under conditions such as heat,acid,and base,which can be important when assessing shelf-life using stability tests.The method was found to be specific(differentiating tail vs.tail-less),linear(from concentrations of 0.001 mg/mL to 0.3 mg/mL),accurate(for 80,100,and 120%nominal concentration),and precise(less than 2%relative standard deviation).These results showed that the IP-RP-HPLC method can be used as a quantitative method for mRNA drug substance content and purity.SPONSORED CONTENT Chemically Modified mRNA as a Biologic:Developing an Analytical Framework for SuccessDr_Microbe/ The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT32 Capping efficiency:TriLink also developed LC-MS methods to measure the relative percentage capping efficiency.To measure capping efficiency,a DNAzyme is used to cleave the capping agent and LC-MS is used to quantify the capped and uncapped species.These quantities are used to calculate a percentage of relative capping efficiency.Poly(A)tail characterization:TriLink also developed LC-MS methods for poly(A)tail characterization.The poly(A)tail method is a multipart procedure.It involves:Enzymatic digestion of the main mRNA body,with the use of RNases that leave the poly(A)segment intact Enzymatic treatment to remove 3 phosphates Work-up of the reaction mixture LC-MS analysis of the undigested poly(A)segment to estimate the average length and distribution of lengthsIt is a qualitative to semi-quantitative method that provides a means to characterize mRNA material,compare the quality of the samples,and determine batch-to-batch reproducibility.The method can be used for characterization and product quality release.Residual impurities:Another critical quality attribute(CQA)to measure is the number of residual impurities.Residual impurities to be measured include DNA(using PCR),double-stranded RNA(using Immunoblot),proteins(using nano orange or bicinchoninic acid assay),solvents,and NTPs.To measure NTPs,residuals can be separated from mRNA using a spin column,and the resulting supernatant is evaluated with anion-exchange(AX)-HPLC.TriLink found that the quantitative method had a low limit of quantification;it could measure down to 0.04 mM for NTPs and 0.16 mM for CleanCap.The method was also precise,with less than a 5%relative standard deviation.The method can be used both in the quality control lab for product release and as an in-process test to monitor the consumption of NTP and the capping agent during in vitro transcription(IVT)for process control.Others:safety(endotoxin and bioburden),appearance,pH:The United States Pharmacopeia(USP)has published proposed guidelines for assessing the quality attributes of mRNA drug substances.These guidelines also include methods for additional analysis areas of mRNA vaccine quality:endotoxin,bioburden,sterility,appearance,and pH.Controlling and Measuring QualityThere are limited regulatory precedents for mRNA-based drug products,but traditional biologics have a history of more than 40 years of successful regulatory filings using defined quality requirements.Because there are similarities between the processes used to make mRNA and those used to make biological molecules,these existing quality requirements can be considered when developing an analytical framework for chemically modified mRNA.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT33 The manufacturing process for an mRNA drug substance has parallels to that of the manufacturing process of a protein.Both begin by making a cell bank,followed by cell amplification,expression,and purification steps.Both mRNA drug substance and traditional biologic processes require controls on the quality of the starting material,including cell banking;consistency of the manufacturing processes;identification of critical process parameters;clearance of impurities;environmental controls to meet safety requirements;and thorough characterization of structure,purity,and efficacy.For current mRNA-based vaccines,the mRNA drug substance is formulated as a drug product in a lipid nanoparticle to make a sterile,injectable drug product.Quality control and analytical testing requirements are well-defined for injectable drug products.There have been previously approved lipid nanoparticle drug products that serve as examples for regulatory requirements and quality control.Although much of the regulatory filing requirements for mRNA therapies can be compared with those for traditional biologics,others are not yet well defined.As such,control of quality and consistency must be maintained to ensure efficacy,purity,and safety.Raw Material ControlConsistent quality begins with the control of raw materials.The availability of high-quality raw materials to manufacture mRNA is currently a challenge because this therapy area is growing so fast.Developers and manufacturers want to be sure that their raw material source is producing high-quality drug products that are scalable to support the drug products lifecycle.The structure of an mRNA drug substance contains the mRNA coding region and elements for translating the gene of interest,including untranslated regions,a 5 cap,and the poly(A)tail.Both the capping agent and the poly(A)tail are crucial for binding to the ribosome to do the translation and obtain the protein of interest for a specific therapy.Raw materials for mRNA therapiesincluding NTPs,modified NTPs,and capping agentsmust be produced in a current good manufacturing practice(cGMP)environment to be used in GMP drug production.A GMP process is designed to have reproducible control over all impurities by controlling both the incoming materials and the process.This control is measured using release criteria and documentation of all data.The specifications for GMP-grade materials must be representative of SPONSORED CONTENT Analytical capabilities to empower the success of your mRNA programThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT34 the process.For example,for a synthetic process using ethanol as a solvent,the material should have a specification for residual ethanol that is measured to ensure that the solvent has been removed to specified levels.Synthetic GMP materials are inherently free from residual biological material,which is an advantage compared to non-synthetic materials,such as those made using an enzymatic process.TriLinks NTPs,modified NTPs,and CleanCap capping agents are all chemically synthesized.The synthetic CleanCap reagent allows for a single-pot IVT reaction that shortens the manufacturing time of the mRNA as compared to an enzymatic capping method.The resultant IVT reaction is robust and produces high-yield mRNA with approximately three times the yield as compared to traditional co-transcriptional enzymatic capping methods.It also produces a 5 Cap 1 structure,which is desirable because it is the most biologically active and least immunogenic structure.CleanCap is available in GMP-grades.In September 2022,TriLink launched a GMP grade of a modified NTP(N1-Methyl-Pseudouridine-5-Triphosphate).This modified NTP is used in both FDA-approved COVID-19 vaccines and is an important raw material for many mRNA therapeutics in development.The modified NTP is made with a synthetic process that controls both mono-and diphosphates.As a GMP product,it is tested for several specifications.For example,the ion-content test confirms that the material does not have excess ions,such as sodium.ConclusionmRNA therapies represent a breadth of new opportunities for treating diseases that remain difficult to treat.However,as a relatively new technology,it presents unique challenges to analytical approaches and techniques for molecule characterization,having previously been primarily used as a diagnostics tool rather than an agent of therapy.With the growing popularity of using mRNA in drug substances and drug products today,however,the need for quantitative analytical methods that can tackle the challenges of these complex molecules with accurate sensitivity and specificity is urgent now more than ever.The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT35 F or messenger RNA(mRNA)therapeutics and vaccines formulated as lipid nanoparticles(LNPs),the excipients receiving the most attention are the encapsulating lipids.While these compounds are crucial to the stability and delivery of mRNA-LNPs,the non-lipid excipients also play crucial roles in the function of final drug products.They impact the morphology and stability of these delivery systems,which in turn affects in vivo performance and the overall usefulness of mRNA drugs developed using nanoparticle technology.A number of non-lipid excipients neededNon-lipid excipients used to formulate mRNA-LNP products include solvents,salts,and sugars/Excipients Impact Stability in mRNA-LNP FormulationsLipids arent the only important ingredients influencing stability and in vivo performance.scienceDISPLAY/AUTHORCynthia A.Challener,PhDContributing Technical WriterMJH Life SciencesThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT36 cryoprotectants,according to David Jung,senior manager RD&I,nucleic acids at Evonik.Overall,these excipients serve the function of controlling the pH during the initial mixing and formation of the particle and ensuring stability upon storage of the material,he notes.More specifically,rapid mixing is the predominant technique for lipid nanoparticlemRNA formulations:an ethanol phase(lipid components)and an aqueous phase(mRNA molecules,usually in acetate or citrate buffers)are mixed under specific conditions(pH and flow rate),explains Luca Bruno,segment marketing manager,MilliporeSigma,the Life Science business of Merck KGaA,Darmstadt,Germany.Rapid mixing,he adds,allows scalability and reproducibility of mRNA-LNP formulation.Organic solvents and residual components are then removed by ultrafiltration.The mRNA-LNP drug substance is then formulated using a more physiological buffer,typically tris(hydroxymethyl)aminomethane-or phosphate-based together with salts such as sodium chloride or potassium chloride to adjust the ionic strength,Bruno observes.Storage conditions(as aqueous solutions,frozen,or lyophilized)must also be carefully considered in the context of mRNA-LNP clinical translation,according to Bruno,because they can affect the long-term stability of mRNA-LNP formulations.“Sugar stabilizers(sucrose in particular,trehalose or mannitol as alternative options)are commonly used for this application,”he says.Choosing the right non-lipid excipients importantIn addition to assuring long-term stability and in vivo performance,non-lipid excipients for mRNA-LNPs also play an important role in controlling manufacturing processes,Jung comments.“The selection of these excipients must therefore be done carefully.Typically,they are initially chosen based on their chemical and physical properties(i.e.,pKa and lyophilization characteristics,freezing point/state)because these attributes will determine compatibility with the drug substance.Because these choices may also impact the morphology of mRNA-LNPs,which can affect overall efficacy and stability,modifications may be required as determined by experimental testing,”he says.The susceptibility of mRNA to degradation requires that formulation buffers be free of any ribonuclease contamination.Testing of excipients for the absence of nuclease activity is therefore the preferred approach,Bruno stresses.Other product-quality attributes should also be determined,including endotoxin content and bioburden,SPONSORED CONTENT Technical Note|Optimized IVT process for better mRNA productionThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT37 as they play an important role in controlling the risk of contamination by these materials.Beyond the product-quality attributes,Bruno emphasizes the need to consider supplier related aspects for any excipients used in mRNA-LNPs,including non-lipid excipients.“Supply robustness and availability of supporting documentation are both essential if mRNA-LNP developers are to navigate regulatory challenges and ensure smooth manufacturing scale up and progression through clinical development to commercialization,”he adds.Focus on improving stabilitySince the approval of the COVID-19 mRNA vaccines and demonstration of their effectiveness,interest in mRNA-LNP therapeutics and vaccines has risen dramatically from all perspectives.In particular,the rise of the mRNA technology due to the COVID-19 pandemic and the manufacturing scale needed to produce vaccines shifted the attention to mRNA manufacturing needs,according to Bruno.“The development of non-lipid excipients has primarily focused on the quality attributes based on the specificity of the technology,”Bruno notes.For instance,the need for endonuclease-free materials required establishment of additional product-release testing methods and services to support drug manufacturers.There has also been a significant amount of effort placed on assessing non-lipid excipients that may improve the long-term stability of mRNA-LNP formulations,observes Jung.He points specifically to the use of different cryoprotectants to improve refrigerated storage stability.Lyophilization is also being explored as a means for eliminating cold-chain requirements,with several clinical-stage studies underway to assess the impact of lyophilization on the stability and in vivo efficacy of traditional mRNA-LNPs.Separate efforts are also underway to create novel delivery mechanisms for RNAs that are not dependent upon LNPs,Jung adds.Lipid advancesA key focus in the mRNA field is on lipid excipients and that will continue to be true for some time,contends Aditi Mehta,head of mRNA process and delivery,MilliporeSigma,the Life Science business of Merck KGaA,Darmstadt,Germany.“Despite the success of the COVID-19 vaccines,we still have not reached the full potential of mRNA therapeutics,and there are several hurdles.Insufficient targeting of organs beyond the liver or vaccinations,an acute immune response against LNP administration,stability issues,and the need of extreme low temperature for storage are key bottlenecks in the development of LNP medicines,”she says.These issues,Mehta observes,can be addressed through improvements in lipid and LNP design(e.g.,optimization of linker chemistry,addition of degradable The Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT38 bonds,more optimal synthetic routes,better LNP components,etc.).“Strategies such as design of novel ionizable lipids based on large libraries produced with combinatorial synthesis have been aiding the understanding of structure-function properties and enabling the design of unique lipids with improved properties(targeting,stability,tolerability),”she states.Data continues to be published on new lipid libraries that demonstrate delivery to different tissues/cells(1),Jung agrees.Targeting of mRNA-LNPs to specific tissues or cells can be achieved through either passive or active means.A majority of studies investigating ways to target LNPs have focused on passive targeting through modification of the LNP size,surface,and composition.Substitution or addition of an extra moiety(polymeric or lipidic)has also been shown to be beneficial for achieving passive targeting toward specific organs,according to Mehta.“Active targeting approaches leverage conjugation of lipid components with small molecules,antibodies,proteins,or aptamers,”Mehta comments.She points specifically to flexible platforms and highlights the ASSET platform developed in the lab of Prof.Dan Peer at Tel Aviv University(2).“This type of approach enables customized targeting towards any cell receptor and,therefore,any tissue or organ,”she says.Mehta does caution,however,that while there has been a tremendous push(and success)in this area over the past few years,there is still a long way to go and many challenges to overcome.Going beyond lipidsWhile lipids have predominated the mRNA delivery space,they are not the only materials that can provide effective delivery of these sensitive and highly charged drug substances.Hybrid lipidpolymer delivery systems,for instance,have been developed to harness and combine the advantages of both lipid and polymer nanoparticles,according to Mehta.“Polymers possess an inherent high degree of chemical variety that is not feasible with lipids,increasing tremendously the possibilities of chemical functions,such as promoting endosomal escape,controlled released of RNA,targeting,and finally stability,”she explains.Lipids,meanwhile,show great potential for enhancing bioavailability,improving pharmacokinetic profiles,and increasing biocompatibility.Strategies investigated to formulate hybrid systems include lipopolyplexes,hybrid LNPs,and others.As an example,Mehta notes that incorporation of biodegradable polymers SPONSORED CONTENT Premade mRNAs for process development experimentsThe Economics of Synthetic mRNA Capping StrategiesDeveloping an Analytical Framework for mRNAExcipients Impact Stability in mRNA-LNP FormulationsLogistical Considerations in mRNA Vaccine DevelopmentExploring mRNAs PotentialJUNE 2024|BIOPHARM INTERNATIONAL SPONSORED CONTENT39 such as poly(beta amino esters)in LNP formulations leads to improved and specific lung delivery,highlighting the potential of hybrid lipid-polymer nanoparticles(3).Evonik has a research agreement with Stanford University to develop and commercialize the charge-altering releasable transporter(CARTs)technology initially developed by the Waymouth lab.These polymeric materials can effectively encapsulate mRNA and then rapidly degrade through controlled self-immolative reaction to release the mRNA,according to Jung.“The first generation of CARTs showed mRNA delivery efficacy in a range of cell types in both in vitro and in vivo models,”Jung notes.He adds that subsequent generations of CARTs incorporating lipid side chains on the CART backbone structure(4)showed an improved delivery efficiency.Further generations of CARTs that are still under development,says Jung,have shown specific targeting capabilities in preliminary testing(5,6).References1.Kularatne,R.N.;Crist,R.M.;Stern,S.T.The Future of Tissue-Targeted Lipid Nanoparticle-Mediated Nucleic Acid Delivery.Pharmaceuticals 2022,15,897.https:/doi.org/10.3390/ph15070897 2.Kedmi,R.;Veiga,N;Ramishetti,S.Goldsmith,M.;Rosenblum,R.et al.A Modular Platform for Targeted RNAi Therapeutics.Nature Nanotechnology 2018 13,pp.214219.https:/doi.org/10.1038/s41565-017-0043-5.https:/ Cao;Zongxing He;Qimingxing Chen;Xiaoyan He;Lili Su,et al.Helper-Polymer Based Five-Element Nanoparticles(FNPs)for Lung-Specific mRNA Delivery with Long-Term Stability after Lyophilization.Nano Lett.2022,22,16,65806589.https:/doi.org/10.1021/acs.nanolett.2c01784.https:/pubs.acs.org/doi/10.1021/acs.nanolett.2c017844.McKinlay,C.J.;Vargas,J.R.;Blake,T.R.;and Waymouth,R.M.Charge-altering Releasable Transporters(CARTs)for the Delivery and Release of mRNA in Living Animals,PNAS,2017,Jan.9,114(4)E448-E456,https:/doi.org/10.1073/pnas.16141931145.McKinlay,C.J.;Benner,N.L.;Haabeth,O.A;and Wender,P.A.Enhanced mRNA Delivery into Lymphocytes Enabled by Lipid-varied Libraries of Charge-altering Releasable Transporters,PNAS.2018,June 11,115(26)E5859-E5866,https:/doi.org/10.1073/pnas.18053581156.Haabeth,O.A.W.;Lohmeyer,J.J.K.;Sallets,A.;Blake,T.R.;Sagiv-Barfi,I.et al.An mRNA SARS-CoV-2 Vaccine Employing Charge-Altering Releasable Transporters with a TLR-9 Agonist Induces Neutralizing Antibodies and T Cell Memory.ACS Central Science 2021 7(7),1191-1204 DOI:10.1021/acscentsci.1c00361.Republished from Challener,C.Excipients Impact Stability in mRNA-LNP Formulations.Pharmaceutical Technology 2023 47(3).
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