David K. Robinson, Ph. D.Vice President, BiologicsHead and Executive Director, Biologics and Vaccines CMC RegulatoryMerck & Co, Inc. Presenting on behalf of the International Federation of Pharmaceutical Manufacturers & Associations (IFPMA)WCBP CASS, Washington DC, USAJanuary 2014

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. 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. Access to Vaccines
• Vaccines have a tremendous positive impact
on human health globally
• Access to vaccines remains important
January, 20143

4. © IFPMA 20124
http://www.hhs.gov/nvpo/concepts/intro6.htm
The dramatic impact of vaccines
on human health

5. 5
http://www.hhs.gov/nvpo/concepts/intro6.htm
The dramatic impact of vaccines
on human health

6. 6
Mumps-United States, 1968-1996
http://www.hhs.gov/nvpo/concepts/intro6.htm
The dramatic impact of vaccines
on human health

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. © 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. 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. 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. 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. 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. 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. --
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. 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. • 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. 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. 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. 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. 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. 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. 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
Case Study I: Filing Requirements for New Drug
Product Facility
(>130 countries, approval of a post-marketing change)

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
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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
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. 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
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
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. 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
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. 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. 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. www.ifpma.org
January, 201447