IFPMA: From Manufacturing to the Vaccinee – the Complex Journey of a Vaccine

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David K. Robinson, Ph. D. Vice President, Biologics Head and Executive Director, Biologics and Vaccines CMC Regulatory Merck & Co, Inc.

Presenting on behalf of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) WCBP CASS, Washington DC, USA January 2014

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IFPMA: From Manufacturing to the Vaccinee – the Complex Journey of a Vaccine

  1. 1. International Federation of Pharmaceutical Manufacturers & Associations From Manufacturing to the Vaccinee – the Complex Journey of a Vaccine David K. Robinson, Ph. D. Vice President, Biologics Head and Executive Director, Biologics and Vaccines CMC Regulatory Merck & Co, Inc. Presenting on behalf of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) WCBP CASS, Washington DC, USA January 2014 1 January, 2014
  2. 2. Introduction: Impact of Vaccines on Human Health I. The Complexity of Vaccines II. The Complexity of the Manufacturing Pathway III. The Complexity of the Regulatory Approval 2 January, 2014
  3. 3. Access to Vaccines • Vaccines have a tremendous positive impact on human health globally • Access to vaccines remains important January, 20143
  4. 4. © IFPMA 20124 http://www.hhs.gov/nvpo/concepts/intro6.htm The dramatic impact of vaccines on human health
  5. 5. 5 http://www.hhs.gov/nvpo/concepts/intro6.htm The dramatic impact of vaccines on human health
  6. 6. 6 Mumps-United States, 1968-1996 http://www.hhs.gov/nvpo/concepts/intro6.htm The dramatic impact of vaccines on human health
  7. 7. © IFPMA 20127 Mumps-United States, 1968-1996 Rubella-United States, 1966-1996 http://www.hhs.gov/nvpo/concepts/intro6.htm The dramatic impact of vaccines on human health
  8. 8. © IFPMA 20128 HiB-United States, 1981-1995 Mumps-United States, 1968-1996 Rubella-United States, 1966-1996 http://www.hhs.gov/nvpo/concepts/intro6.htm The dramatic impact of vaccines on human health
  9. 9. Vaccination efforts helped reduce the incidence of disease in Africaa 9 a Countries include: Algeria, Angola, Benin, Botswana, Burkina Faso, Burundi, Cameroon, Cape Verde, Central African Republic, Chad, Comoros, Republic of the Congo, Cote d’lvoire, Democratic Republic of the Congo, Equatorial Guinea, Eritrea, Ethiopia, Gabon, Gambia, Ghana, Guinea, Guinea-Bissau, Kenya, Lesotho, Liberia, Madagascar, Malawi, Mali, Mauritania, Mauritius, Mozambique, Namibia, Niger, Nigeria, Rwanda, Sao Tome and Principe, Senegal, Seychelles, Sierra Leone, South Africa, Swaziland, Togo, Uganda, United Republic of Tanzania, Zambia, and Zimbabwe. Percentage disease reduction in Africa from 1980 to 20091 83% 93% 73% 33% 96%100% Diphtheria Pertussis Neonatal tetanus Total tetanus Measles Polio References: 1. World Health Organization (WHO). WHO Vaccine-Preventable Diseases: Monitoring System. 2010 Global Summary. http://whqlibdoc.who.int/hq/2010/WHO_IVB_2010_eng.pdf. Accessed January 3, 2012. 2. World Health Organization (WHO). http://www.who.int/about/regions/afro/en/index.html. Accessed March 12, 2011. Percentage disease reduction in Africa from 1980 to 20091
  10. 10. Vaccination efforts helped reduce the incidence of disease in the Americasa 10 a Countries include: Antigua and Barbuda, Argentina, Bahamas, Barbados, Belize, Bolivia (Plurinational State of), Brazil, Canada, Chile, Colombia, Costa Rica, Cuba, Dominica, Dominican Republic, Ecuador, El Salvador, Grenada, Guatemala, Guyana, Haiti, Honduras, Jamaica, Mexico, Nicaragua, Panama, Paraguay, Peru, Saint Kitts and Nevis, Saint Lucia, Saint Vincent and the Grenadines, Suriname, Trinidad and Tobago, United States of America, Uruguay, and Venezuela (Bolivarian Republic of). References: 1. World Health Organization (WHO). WHO Vaccine-Preventable Diseases: Monitoring System. 2010 Global Summary. http://whqlibdoc.who.int/hq/2010/WHO_IVB_2010_eng.pdf. Accessed January 3, 2012. 2. World Health Organization (WHO). http://www.who.int/about/regions/amro/en/index.html. Accessed March 12, 2011. Percentage disease reduction in the Americas from 1980 to 20091 100%100% 92% 98%94%99% Diphtheria Pertussis Neonatal tetanus Total tetanus Measles Polio Percentage disease reduction in the Americas from 1980 to 20091
  11. 11. Vaccination efforts helped reduce the incidence of disease in Southeast Asiaa 11 a Countries include: Bangladesh, Bhutan, Democratic People’s Republic of Korea, India, Indonesia, Maldives, Myanmar, Nepal, Sri Lanka, Thailand, and Timor-Leste. References: 1. World Health Organization (WHO). WHO Vaccine-Preventable Diseases: Monitoring System. 2010 Global Summary. http://whqlibdoc.who.int/hq/2010/WHO_IVB_2010_eng.pdf. Accessed January 3, 2012. 2. World Health Organization (WHO). http://www.who.int/about/regions/searo/en/index.html. Accessed March 12, 2011. Percentage disease reduction in Southeast Asia from 1980 to 20091 96% 86% 97% 89% 99%99% Diphtheria Pertussis Neonatal tetanus Total tetanus Measles Polio Percentage disease reduction in Southeast Asia from 1980 to 20091
  12. 12. 1. Eurosurveillance. Vol. 12; 8, Feb. 22, 2007. http://www.eurosurveillance.org/ViewArticle.aspx?PublicationType=W&Volume=12&Issue=8&OrderNumber=1. Accessed April 5, 2011. 2. Eurosurveillance, Vol. 15; 23, June 10, 2010. http://www.eurosurveillance.org/ViewArticle.aspx?ArticleId=19586. Accessed April 5, 2011. 3. World Health Organization (WHO). Epidemiological Brief. Oct. 25, 2010. http://www.reliefweb.int/rw/rwb.nsf/db900SID/EGUA-8AUR9R?OpenDocument. Accessed April 5, 2011. 4. World Health Organization (WHO). Global Alert and Response (GAR). Nov. 13, 2010. http://www.who.int/csr/don/2010_11_13/en/index.html. Accessed April 5, 2011. 5. CDC. Outbreak Notice. March 18, 2011. http://wwwnc.cdc.gov/travel/content/outbreak-notice/polio- tajikistan-russia-central-asia.aspx. Accessed April 5, 2011. 6. CDC. March 15, 2011. http://www.cdc.gov/pertussis/outbreaks.html. Accessed April 5, 2011. 7. HealthMap. Global Health, Local Information. December 2010. http://healthmapblog.blogspot.com/2010_12_01_archive.html. Accessed April 19, 2011. 8. ISID. August 9, 2010.ttp://promedmail.org/pls/otn/f?p=2400:1001:333553816968016::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,84066. Accessed April 5, 2011. 9. World Health Organization (WHO). Global Alert and Response (GAR). March 8, 2011. http://www.who.int/csr/don/2011_03_08/en/index.html. Accessed April 5, 2011. 10. Global Poliio Eradication Initiative. January 15, 2014.. http://www.polioeradication.org/Dataandmonitoring/Poliothisweek.aspx.. Accessed January 22, 2014. 11. Centers for Disease Control. http://www.cdc.gov/measles/outbreaks.html. Accessed January 22, 2014 Access to Vaccines and Robust Vaccination Remains Important • Outbreaks of vaccine-preventable diseases still occur throughout the world (some selected examples) – Polio: Although India has gone three years without a case, nearly 500 cases were reported in Tajikistan throughout 2010, leaving 2 children paralyzed. Six new cases reported in just a single week this year (2014) in Pakistan. – Mumps: From January 2008 through June 2009, there were 16,352 notifications of cases in Macedonia. – Measles: From October , 2006, to January, 2007, there were 213 confirmed cases in Barcelona, Spain. From January 1 to August 24, 2013, 159 cases were reported in the United States (despite measles being declared officially eradicated in 2000).
  13. 13. Complexity of Vaccines – Vaccines are structurally complex – Vaccines of consistent quality are complex to manufacture – The need to provide protection against multiple serotypes of an infectious agent increases the complexity January, 201413
  14. 14. -- Human Papilloma Virus Virus Like Particle (Prophylactic Vaccine) MW ~ 20,000,000 DaIgG Immunoglobin (Therapeutic mAb) MW ~ 150,000 Da Vaccines are structurally complex Simvastatin (Cholesterol Lowering) MW ~ 200 Da 14
  15. 15. Vaccines can contain multiple components • 90% of cervical cancers worldwide are attributed to 7 HPV types • Second generation investigational HPV vaccine being developed for the prevention of cervical, vulvar, and vaginal cancers contains these 7 high risk HPV types, plus an additional 2 HPV types • Each of these 9 HPV types is prepared as a separate Drug Substance and combined in the vaccine. 1 de SanJose, et al., The Lancet. 2010. Impact of Adding 5 New HPV Types to Existing Quadrivalent Vaccine1 0 20 40 60 80 100 V503 GARDASIL Cumulative Attributed Prevalence (%) 70% ~90% HPV 16 HPV 18 HPV 45 HPV 31 HPV 33 HPV 52 HPV 58 Quadrivalent Investigational Nine-valent January, 201415
  16. 16. • Multicomponent polysaccharide vaccine indicated for active immunization for the prevention of pneumococcal disease caused by the serotypes contained in the vaccine • Contains 23 different bacterial polysaccharides • Each of these 23 polysaccharides is manufactured as a separate drug substance Vaccines can contain multiple components January, 201416 P O OH O OH OH CH3 O O O O OH OH CH2 OH C NH CH3 O O O OH CH2 OH Serotype 19A1 1) Katzenellenbogen, E., Jennings, H. J., Structural determination of the capsular polysaccharide of Streptococcus pneumoniae type 19A(57), Carbohydr. Res., 124, 235, 1983
  17. 17. Each step has multiple unit operations January, 201417 Raw materials Harvesting Purification Valence Blending Adjuvant Adsorption Aseptic Filling Packaging Aseptic Filling Fermen- tation or cell culture Quality: quality control, quality assurance
  18. 18. January, 201418 Raw materials Harvesting Purification Valence Blending Adjuvant Adsorption Aseptic Filling Packaging Aseptic Filling Fermen- tation or cell culture Quality: quality control, quality assurance Capture Chromatography Ultrafiltration Sterile Filtration Polishing Chromatography Each step has multiple unit operations
  19. 19. January, 201419 Raw materials Harvesting Purification Valence Blending Adjuvant Adsorption Aseptic Filling Packaging Aseptic Filling Fermen- tation or cell culture Quality: quality control, quality assurance Capture Chromatography Ultrafiltration Sterile Filtration Polishing Chromatography Each of the Drug Substance unit operations need to be individually optimized, demonstrated and executed for each of the individual polysaccharides, proteins and/or viruses in a multivalent vaccine (x4, x9, x23) Each step has multiple unit operations
  20. 20. Regulatory approval of vaccines can be complex • Manufacturing process changes may be required to increase access to necessary vaccines • These changes may require regulatory submissions • If licensed in multiple countries (10 to 130), multiple filings will be required January, 201420
  21. 21. Processes for vaccines are continuously improved (Variations) • Optimized Manufacturing Processes • Capacity Increases – Scale-up – New or Expanded Facility • Analytical – Improved methods – Changes in specifications as a result of agency questions during initial review – Changes in specification as a result of improved process capability • Unplanned Changes outside of Sponsor’s Control (e.g., Components, Raw Materials) • Market Preferences for Local Manufacturing • New Regulatory Requirements Many of the changes introduced to improve the vaccine process or increase vaccine access require regulatory notification and/or approval January, 2014
  22. 22. Case Studies* (3 in total) Manufacturer intends to increase capacity to enhance global access to a vaccine I. Add vaccine product facility to increase productivity II. Change lyophilization cycle to increase productivity III. Multiple improvements to increase capacity 22 * Regulatory requirements around the globe are very dynamic; therefore all sponsors should conduct their own regulatory assessments for any planned changes January, 2014
  23. 23. 23 Case Study I: Filing Requirements for New Drug Product Facility (>130 countries, approval of a post-marketing change)
  24. 24. Time to Approval (months) 0 5 10 15 20 25 30 1 2 3 4 5 6 7 8 9 1… 1… 1… 1… 1… 1… 1… 1… 1… 1… 2… Series1 IndividualNational/Regional HealthAuthorities Case Study II: Stability Data and Approval Times for Change in Lyophilization Cycle (>20 countries, approval of a post-marketing change) January, 201424
  25. 25. 25 Time to Approval (months) 0 5 10 15 20 25 30 1 2 3 4 5 6 7 8 9 1… 1… 1… 1… 1… 1… 1… 1… 1… 1… 2… Series1 Pre-approval not required No stability data required in submission Require 6 months stability data Require 3 months stability data Require US/EU approval or CPP (Certificate of Pharmaceutical Product) prior to submission or during review IndividualNational/Regional HealthAuthorities Case Study II: Stability Data and Approval Times for Change in Lyophilization Cycle (>20 countries, approval of a post-marketing change) January, 2014
  26. 26. Case study III Manufacturer intends to increase capacity to enhance global access to a vaccine I. Add additional vaccine product facility to increase productivity AND II. Change “lyo” cycle to increase productivity AND III. Change facility design to comply with new regulations (Annex II) 26 January, 2014
  27. 27. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Takes Even Longer to Get A Change Approved in All Countries Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 Can take an extra 2 years to get approval in last 20% of countries 0 1 2 3 4 5 6 7 8 Years January, 2014
  28. 28. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Takes Even Longer to Get Multiple Changes Approved Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Might file next change before approvals have been received in all countries January, 2014
  29. 29. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Takes Even Longer to Get Multiple Changes Approved Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Might then file a third change January, 2014
  30. 30. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Some countries will only review one change at a time Takes Even Longer to Get Multiple Changes Approved January, 2014
  31. 31. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Takes Even Longer to Get Multiple Changes Approved Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years This can add 3 years or more before approval in all countries January, 2014
  32. 32. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Overlapping Approvals Increase Supply Complexity Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Two versions (pre- and post-change 1) in inventory January, 2014
  33. 33. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Overlapping Approvals Increase Supply Complexity Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Two versions (pre- and post-change 1) in inventory Three versions in inventory January, 2014
  34. 34. 0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 1 2 3 Series1 Series2 Series3 Series4 Series5 Series6 Overlapping Approvals Increase Supply Complexity Lag between filings Approval in 20% of Countries Approval in 40% of Countries Approval in 60% of Countries Approval in 80% of Countries Approval in 100% of Countries ChangeNumber 123 0 1 2 3 4 5 6 7 8 Years Two versions (pre- and post-change 1) in inventory Three versions in inventory Four versions in inventory January, 2014
  35. 35. Testing of Vaccines can be Complex • Vaccines undergo multiple tests for release • Some countries require redundant lot-specific testing prior to release • Some countries have unique compendial testing requirements January, 201435
  36. 36. Each Vaccine is Tested via Dozens of Methods during Quality Control January, 201436 Raw materials Harvesting Purification Valence Blending Adjuvant Adsorption Aseptic Filling Packaging Aseptic Filling Fermen- tation or cell culture Quality: quality control, quality assurance Subset of release Tests for Hib Conjugate Vaccine • pH • Identity • Carrier protein content • Adjuvant content • Residual moisture • Sterility • Pyrogen content • Preservative content • General safety test (Innocuity) abnormal toxicity • Free carrier protein
  37. 37. Each Vaccine is Tested via Dozens of Methods during Quality Control January, 201437 Raw materials Harvesting Purification Valence Blending Adjuvant Adsorption Aseptic Filling Packaging Aseptic Filling Fermen- tation or cell culture Quality: quality control, quality assurance Subset of Release Tests for Hib Conjugate Vaccine • pH • Identity • Carrier protein content • Adjuvant content • Residual moisture • Sterility • Pyrogen content • Preservative content • General safety test (Innocuity) abnormal toxicity • Free carrier protein All non-compendial methods require transfer of methods, equipment and reagents to local & national testing labs
  38. 38. Redundant Testing Increases the Cost and Time to Get a Vaccine to Those in Need • Each lot of vaccine is tested by the Manufacturer prior to release • These same tests may be repeated by the official national control laboratory prior to export • Then, these same tests may be repeated again by the importing country • All vaccines have a limited shelf life • The time it takes for this redundant testing can leave little time left to distribute and administer the vaccine to those who most need it 38 Test X done by the manufacturer Test X repeated by the official national test lab prior to export Test X repeated again by the importing country Time left for distribution and administration of the vaccine Shelf-life (time from date of manufacture to expiry) of vaccine Test time varies, depending on each vaccine, each test and the capacity and capability of each testing laboratory Remaining time within which individual lot of vaccine can be distributedJanuary, 2014
  39. 39. 39 The Duplication of Reviews and Redundancy of Testing Add Complexity • Much of the regulatory review and testing is similar, but much is also individualized: – Many countries have specific national regulatory requirements that must be complied with. – The regulatory review time and complexity is further increased by the lack of recognition between Health Authorities; “all repeat the same review” which creates a continuous review process. – Multiple countries repeat release testing upon importation, even if that release testing has already been independently conducted by internationally recognized Health Authorities – Consequently further increases review time and release times, delaying the ability to provide access to patients. January, 2014
  40. 40. Challenges: Compendial Changes • Lack of harmonization across compendia adds complexity to regulatory compliance & surveillance, in addition to vaccine development and supply – WHO: 140 independent countries are using >30 pharmacopoeias (across national, regional, and international) • Lack of consistent communication & industry representation during the process of revising compendia forces manufacturers to be reactive v. pro- active – Potentially could impact compliance and disrupt the supply chain • Impact across range of drug products may not be well understood without input from industry – For example: adding a requirement that may be a minor change for a small molecule has a greater impact to a Live Virus Vaccine due to increasing complexity: 40 Small Molecules Biologics Live Virus Vaccines January, 2014
  41. 41. 41 Increased regulatory complexity • High rigor in regulatory standards and reviews help to ensure the quality of vaccines around the world – Reflecting the complexity of vaccine (composition, methods of manufacture, testing procedures), technical registration files are increasing in size and complexity – Resource constraints limit the ability to quickly review these increasingly complex submissions and to quickly conduct local testing January, 2014
  42. 42. 42 Increased regulatory complexity • High rigor in regulatory standards and reviews help to ensure the quality of vaccines around the world – Reflecting the complexity of vaccine (composition, methods of manufacture, testing procedures), technical registration files are increasing in size and complexity – Resource constraints limit the ability to quickly review these increasingly complex submissions and to quickly conduct local testing • However: – Redundant reviews may not greatly increase the assurance of product quality – Additional testing, beyond that conducted by the manufacturer and internationally recognized health authorities, adds little contribution in terms of additional assurance of the safety of the product January, 2014
  43. 43. To reduce regulatory complexity and enhance access to vaccines • Harmonize compendial requirements and provide for systems to update compendia • Harmonize data and information requirements to streamline submission preparation • Engage in mutual recognition of internationally recognized health authorities output to reduce: – Redundant reviews of submissions – Redundant testing of vaccine lots – Redundant facility inspections 43 January, 2014
  44. 44. 44 Conclusion • Vaccines are an important component in improving and maintaining public health around the globe • New, complex vaccines, high quality standards and the evolving regulatory environment combine to create a non sustainable situation, where the ability to enable access to patients can be hindered • To sustain worldwide access to vaccines, the regulatory environment needs to adapt. • Harmonization of regulatory requirements, partnerships in the review of applications, alignment on compendial methods, and a reduction in redundant testing would facilitate access January, 2014
  45. 45. Vaccines help save lives 45 “With the exception of safe water, no other modality, not even antibiotics, has had such a major effect on mortality reduction and population growth.” 1 Stanley A. Plotkin, MD Vaccine developer Emeritus Professor of Pediatrics University of Pennsylvania Emeritus Professor, Wistar Institute Reference: 1. Plotkin SL et al. In: Plotkin SA et al. Vaccines. 5th ed. Saunders; 2008:1–16. January, 2014
  46. 46. IFPMA-in-brief  Global, non-profit NGO with over 40 years of advocacy experience in the international arena  Based in Geneva, IFPMA has official relations with the UN, including the World Health Organization (WHO), World Intellectual Property Organization (WIPO), and the World Trade Organization (WTO)  IFPMA membership: • research-based pharmaceutical industry, including the biotechnology and vaccine sectors • national industry associations  Mission: The IFPMA advocates policies that encourage discovery of and access to life-saving and life-enhancing medicines to improve the health of people everywhere 46 January, 2014
  47. 47. www.ifpma.org January, 201447

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