from manufacturing to the vaccinee – the complex journey of a … · 2018-04-02 · international...

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



6

Mumps-United States, 1968-1996



© IFPMA 2012 7


Rubella-United States, 1966-1996



© IFPMA 2012 8

HiB-United States, 1981-1995


Rubella-United States, 1966-1996



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

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%



Percentage disease reduction in the Americas from 1980 to 20091

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%



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

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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

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

OOH

OHCH3

O

O

O

O

OH

OH

CH2

OHC

NH

CH3

O

OO

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


Adsorption

Aseptic Filling




Capture Chromatography

Ultrafiltration

Sterile Filtration

Polishing Chromatography


January, 2014 19

Raw materials

Harvesting

Purification


Adsorption

Aseptic Filling




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)

• 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

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

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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

Indi

vidu

al N

atio

nal/R

egio

nal

Hea

lth A

utho

ritie

s

Case Study II: Stability Data and Approval Times for Change in Lyophilization Cycle (>20 countries, approval of a post-marketing change)

January, 2014 25

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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

Indi

vidu

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atio

nal/R

egio

nal

Hea

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utho

ritie

s

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)

27 January, 2014

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

1

2

3

Series1Series2Series3Series4Series5Series6

Takes Even Longer to Get A Change Approved in All Countries

Lag between filings

Approval in 20% of Countries



Approval in 80% of Countries Approval in 100% of Countries

Cha

nge

Num

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


Takes Even Longer to Get Multiple Changes Approved

Lag between filings






Cha

nge

Num

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



Lag between filings






Cha

nge

Num

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


Lag between filings






Cha

nge

Num

ber

1

2

3

0 1 2 3 4 5 6 7 8 Years

Some countries will only review one change at

a time


January, 2014

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0

1

2

3



Lag between filings






Cha

nge

Num

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


Overlapping Approvals Increase Supply Complexity

Lag between filings






Cha

nge

Num

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



Lag between filings






Cha

nge

Num

ber

1

2

3

0 1 2 3 4 5 6 7 8 Years


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



Lag between filings

Approval in 20% of Countries Approval in 40% of Countries




Cha

nge

Num

ber

1

2

3

0 1 2 3 4 5 6 7 8 Years


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 36

Each Vaccine is Tested via Dozens of Methods during Quality Control

January, 2014 37

Raw materials

Harvesting

Purification


Adsorption

Aseptic Filling




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 38

Raw materials

Harvesting

Purification


Adsorption

Aseptic Filling




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

39

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

40

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:

41

Small Molecules Biologics Live Virus Vaccines

January, 2014

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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

43

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

44 January, 2014

45

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

Vaccines help save lives

46

“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

47 January, 2014

Please visit IFPMA Website at: www.ifpma.org

January, 2014 48

http://www.ifpma.org/

from manufacturing to the vaccinee – the complex journey of a … · 2018-04-02 · international...

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