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

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

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

Access to Vaccines

• Vaccines have a tremendous positive impact

on human health globally

• Access to vaccines remains important

January, 2014 3

© IFPMA 2012 4

http://www.hhs.gov/nvpo/concepts/intro6.htm

The dramatic impact of vaccines

on human health

5



on human health

6

Mumps-United States, 1968-1996



on human health

© IFPMA 2012 7


Rubella-United States, 1966-1996



on human health

© IFPMA 2012 8

HiB-United States, 1981-1995


Rubella-United States, 1966-1996



on human health

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


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%


Neonatal

tetanus

Total


Percentage disease reduction in the Americas from 1980 to 20091


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%


Neonatal

tetanus

Total


Percentage disease reduction in Southeast Asia from 1980 to 20091

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).

http://www.cdc.gov/measles/outbreaks.html

http://www.cdc.gov/measles/outbreaks.html

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, 2014 13

- -

Human Papilloma Virus

Virus Like Particle

(Prophylactic Vaccine)

MW ~ 20,000,000 Da IgG Immunoglobin

(Therapeutic mAb)

MW ~ 150,000 Da

Vaccines are structurally complex

Simvastatin

(Cholesterol Lowering)

MW ~ 200 Da

14

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, 2014 15

• 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, 2014 16

P

O

OH

O

OH

OHCH

3

O

O

O

O

OH

OH

CH2

OHC

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

Each step has multiple unit operations

January, 2014 17

Raw

materials

Harvesting

Purification

Valence

Blending

Adjuvant

Adsorption

Aseptic

Filling Packaging

Aseptic

Filling

Fermen-

tation

or cell

culture

Quality: quality control, quality assurance

January, 2014 18

Raw

materials

Harvesting

Purification

Valence

Blending

Adjuvant

Adsorption

Aseptic

Filling Packaging

Aseptic

Filling

Fermen-

tation

or cell

culture


Capture Chromatography

Ultrafiltration

Sterile Filtration

Polishing Chromatography


January, 2014 19

Raw

materials

Harvesting

Purification

Valence

Blending

Adjuvant

Adsorption

Aseptic

Filling Packaging

Aseptic

Filling

Fermen-

tation

or cell

culture


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)


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, 2014 20

Processes for vaccines are

continuously improved (Variations)

21

• 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

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

Case Study I: Filing Requirements for New Drug

Product Facility (>130 countries, approval of a post-marketing change)

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

Ind

ivid

ual N

ational/R

egio

nal

Health A

uth

orities

Case Study II: Stability Data and Approval Times

for Change in Lyophilization Cycle (>20 countries, approval of a post-marketing change)

January, 2014 24

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

Ind

ivid

ual N

ational/R

egio

nal

Health A

uth

orities

Case Study II: Stability Data and Approval Times

for Change in Lyophilization Cycle (>20 countries, approval of a post-marketing change)

January, 2014

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

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 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

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

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 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

0 1 2 3 4 5 6 7 8

Years

Might file next change before

approvals have been received in all

countries

January, 2014

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


Changes Approved

Lag between filings





Approval in 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

0 1 2 3 4 5 6 7 8

Years

Might then file a third change

January, 2014

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 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

0 1 2 3 4 5 6 7 8

Years

Some countries

will only review

one change at

a time


Changes Approved

January, 2014

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


Changes Approved

Lag between filings





Approval in 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

0 1 2 3 4 5 6 7 8

Years

This can add 3

years or more

before approval in

all countries

January, 2014

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 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

0 1 2 3 4 5 6 7 8

Years

Two versions (pre-

and post-change

1) in inventory

January, 2014

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


Complexity

Lag between filings





Approval in 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

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

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


Complexity

Lag between filings





Approval in 100% of

Countries

Ch

an

ge N

um

ber

1

2

3

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

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, 2014 35

Each Vaccine is Tested via Dozens of

Methods during Quality Control

January, 2014 36

Raw

materials

Harvesting

Purification

Valence

Blending

Adjuvant

Adsorption

Aseptic

Filling Packaging

Aseptic

Filling

Fermen-

tation

or cell

culture


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

Each Vaccine is Tested via Dozens of

Methods during Quality Control

January, 2014 37

Raw

materials

Harvesting

Purification

Valence

Blending

Adjuvant

Adsorption

Aseptic

Filling Packaging

Aseptic

Filling

Fermen-

tation

or cell

culture


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

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

distributed January, 2014

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

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

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

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

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

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

44

January, 2014

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

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

www.ifpma.org

January, 2014 47

http://www.ifpma.org/

Technology

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