Sanofi Pasteur: 95 Years of Vaccine Manufacturing in Canada

Home , Connaught Laboratories

Presented by Robert Van Exan, B.Sc., M.Sc., Ph.D. Director of Immunization Policy Public Affairs

R Van Exan - June 2008 1 Sanofi Pasteur’s heritage

2004 Sanofi Pasteur: new name after sanofi acquired Aventis

1999 Aventis Pasteur: new name after Rhone Poulenc and Hoechst merge into Aventis

1996 Pasteur Merieux Connaught: global name after Rhone Poulenc acquired Pasteur Merieux Serums & Vaccins on 1994

1990 Pasteur Merieux Sérums & Vaccins

1989 Institut Merieux acquires Connaught Laboratories

1985 Merieux Institute buys Pasteur Production. 1978 Connaught Laboratories Pasteur Vaccins is founded acquires Swiftwater Salk Institute Laboratories

1973 Val de Reuil Toronto Institut Pasteur 1914 Production is founded Connaught Laboratories is founded

Lyon Swiftwater 1897 1897 Pocono Biological Laboratories Institut Merieux is founded is founded

R Van Exan - June 2008 2 Overview of sanofi pasteur in Canada

Two Locations Connaught Campus: Sunnybrook Campus: 1,040 employees 60 research scientists

Connaught Campus (located at Steeles & Dufferin)

Sunnybrook Campus (Sunnybrook & Women’s College Health Sciences Centre)

R Van Exan - June 2008 3 Overview of sanofi pasteur in Canada

Research & Development: 250 employees Research, Development, Clinical, Medical and Regulatory

Industrial Operations: 600 employees – uniquely skilled and highly educated workforce 200 million doses/year to international markets

Commercial Operations: 150 employees – Sales, Marketing, Public Policy, and Legal 25 products – 14 million doses of vaccines/year in Canada

R Van Exan - June 2008 4 sanofi pasteur Canada Ltd.

History: Originated as Connaught Laboratories in 1914 at the Hygiene Department of U of T Opened manufacturing facility in 1917 on 150 acre farm at Steeles & Dufferin Dr. John Fitzgerald (Canadian Medical Hall of Fame) was the first director Historical Contributions – Biologicals of Medical significance

R Van Exan - June 2008 5 sanofi pasteur Canada Ltd.

Vaccines 9Pertussis vaccine Biologicals 9Polio vaccine 9Antitoxins 9Smallpox vaccine 9Insulin 9Acellular pertussis 9Epinephrine 9Combination vaccines 9Heparin 9Influenza vaccine 9Plasma Fractionation

9RPenicillin Van Exan - June 2008 6 1918-19: Influenza Pandemic

R Van Exan - June 2008 7 1918-19 – Connaught Supplies an Influenza Vaccine to the Nation

• During the pandemic there were frantic efforts to identify the cause of the disease and hopefully prepare a vaccine that might prevent it. Dr. Robert D. Defries • Scientists had first targeted a bacterium, B. influenza, as the cause of influenza in 1892 and then prepared a vaccine based on a variety of strains isolated from influenza cases. • Working day and night in a cramped lab, a small team under the direction of Dr. R.D. Defries, supplied Connaught’s influenza vaccine free of charge, to provincial health departments, hospitals, the military and other public health services across the country.

R Van Exan - June 2008 8 1918-19 – Connaught Supplies an Influenza Vaccine to the Nation

• Due to this unprecedented emergency, Connaught made no claims for the effectiveness of the vaccine, but kept careful records so that it could be evaluated.

Connaught’s efforts were greatly appreciated by provincial health departments, as well as by the newly established Department of National Health in Ottawa, its creation in 1919 directly attributed to the pandemic.

14 R Van Exan - June 2008 9 1943-46: Connaught & Modern Influenza Vaccine Development

• Modern understanding of influenza began in the early 1930’s when the virus was first isolated and cultivated in chicken eggs. • The virus is then inactivated with formaldehyde to make a vaccine. • There are three main types of influenza virus, but with many strains that change from year to year. • This variability means that the vaccine has to be modified every year in order to prevent influenza outbreaks

24 R Van Exan - June 2008 10 1957: Influenza Vaccine – Pandemic Preparations

The most serious influenza pandemic since 1918-19 was in 1957, sparking the emergency production of influenza vaccine at Connaught Laboratories on behalf of the federal and provincial governments in Canada

R Van Exan - June 2008 11 1976: “Swine Flu” Pandemic Preparations

• Fears of another influenza pandemic developed in 1976. • Fortunately this “Swine Flu” emergency did not materialize, although a large vaccine production and vaccination effort was launched in North America.

In Canada, Connaught Laboratories packaged bulk influenza vaccine supplied from a British manufacturer and conducted clinical trials that involved employee volunteers.

26 R Van Exan - June 2008 12 The History of Vaccine Development Man’s First Vaccine Chinese inoculator 9Efficacy?with his patient. 9Safety?Immunization against smallpox was 9Delivery?popularized in eleventh century China by the 9ResearchBuddhists who Cost? practiced immunization 9Developmentby blowing powdered Cost? smallpox scabs into 9Manufacturing?the patients nose.

R Van Exan - June 2008 L. Barreto, “Canada & the Smallpox Vaccine Story, 1916-2003,” Canadian Conference on Counter-Terrorism, & Public Health, Toronto, Oct 30, 2003 13 Vaccine Development From the 18th to 21st Century

Most of the vaccine development has occurred in the last The world has moved from a single vaccine in two decades. 50 1798 to more than 45 vaccines in 2008.

40 genetically engineered conjugated polysaccharide 30 protein / polysaccharide killed whole organisms live attenuated 20

number of vaccines 10

0 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2008 year

R Van Exan - June 2008 14 Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1917 Most of the vaccine development has occurred in the last The world has moved from a single vaccine in two decades. 50 1798 to more than 45 vaccines in 2008.

40 genetically engineered conjugated polysaccharide 30 protein / polysaccharide killed whole organisms live attenuated 20

number of vaccines 10

0 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2008 year

R Van Exan - June 2008 15 Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1966 Most of the vaccine development has occurred in the last The world has moved from a single vaccine in two decades. 50 1798 to more than 45 vaccines in 2008.

40 genetically engineered conjugated polysaccharide 30 protein / polysaccharide killed whole organisms live attenuated 20

number of vaccines 10

0 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2008 year

R Van Exan - June 2008 16 Vaccine Development From the 18th to 21st Century Smallpox Vaccine – 1966 Most of the vaccine development has occurred in the last The world has moved from a single vaccine in two decades. 50 1798 to more than 45 vaccines in 2008.

40 genetically engineered conjugated polysaccharide 30 protein / polysaccharide killed whole organisms live attenuated 20

number of vaccines 10

0 1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2008 year

R Van Exan - June 2008 17 sanofi pasteur Canada Ltd.

Major Contributions: Eradication of Smallpox

Dr D A Henderson

"I appreciate only too well how many of the concepts in the execution of the smallpox program saw the first light of day over a glass of beer with Bob [Wilson] and Paul [Fenje].

What I don’t recall is whether the ideas stemmed from Wilson or Fenje, so perhaps they are better attributed to Wilje (or should it be Fenson?).“ D.A. Henderson to P. Fenje, June 18, 1979 Dr Paul Fenje Dr R. J Wilson

R Van Exan - June 2008 18 sanofi pasteur Canada Ltd.

Major Contributions: Eradication of Smallpox

R Van Exan - June 2008 19 Vaccine Development From the 18th to 21st Century

Most of the vaccine The world has moved from a single vaccine in development has 1798 to more than 45 vaccines in 2008. occurred in the last two decades. 50

40 genetically engineered conjugated polysaccharide protein / polysaccharide 30 killed whole organisms live attenuated 20 number vaccines of 10

1800 1900 1910 1920 1930 194050 19 1960 1970 1980 1990 2000 2008 R Van Exan - June 2008 year 20 Vaccine Development From the 18th to 21st Century

Polio Vaccine Most of the vaccine development has The world has moved from a single vaccine in occurred in the last 1798 to more than 40 vaccines in 2000. two decades. 50

40 genetically engineered conjugated polysaccharide protein / polysaccharide 30 killed whole organisms live attenuated 20 number vaccines of 10

1800 1900 1910 1920 1930 194050 19 1960 1970 1980 1990 2000 2008 R Van Exan - June 2008 year 21 Vaccine Development From the 18th to 21st Century

Polio Vaccine

Most of the vaccine development has The world has moved from a single vaccine in occurred in the last 1798 to more than 40 vaccines in 2000. two decades. 50

40 genetically engineered conjugated polysaccharide protein / polysaccharide 30 killed whole organisms live attenuated 20 number vaccines of 10

1800 1900 1910 1920 1930 194050 19 1960 1970 1980 1990 2000 2008 R Van Exan - June 2008 year 22 Vaccine Development From the 18th to 21st Century Polio Vaccine

The world has moved from a single vaccine in 1798 to more than 40 vaccines in 2000. 50

40 genetically engineered conjugated polysaccharide protein / polysaccharide 30 killed whole organisms live attenuated 20 number vaccines of 10

1800 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 R Van Exan - June 2008 year 23 sanofi pasteur Canada Ltd.

Major Contributions: Eradication of Polio

R Van Exan - June 2008 24 sanofi pasteur Canada Ltd.

Major Contributions: Eradication of Polio

R Van Exan - June 2008 25 Vaccine manufacturing – Industrialization

R Van Exan - June 2008 26 General Vaccine Production

Intracellular product Extracellular Product Fermentation – Cell Culture Cell Disruption (Fermentor) (Homogeniser) 12 to24 months Primary Recovery (filtration, centrifugation) Upstream Process

Purification (Capture, Precipitation, Polishing) Downstream Conjugation Inactivation Process Bulk Antigen

Formulation / Sterile Filtration Formulation Filling Freeze Drying Filling & Pkg Labelling & Packaging

R Van Exan - June 2008 Regulatory Lot Release 27 Cell Substrate

Viral vaccines need a cell substrate Validated vaccine approved cell bank 2 to 3 years to validate 1 month to grow cells to production level

R Van Exan - June 2008 28 Upstream Process – Growth Phase

The Room The Ingredients •Sterile The Fermentor Everything put into •Hepa filtered air •Must be self the fermentor must contained be validated…•Pressure balance •Cleaned and •Validated•Steam cell bank sterilization sterilized in place •Validated master •Computer seed•Sterile distilled water supply monitored •Culture medium etc •Gowning procedures

Quality Regulations: Three levels of barrier to protect the product

R Van Exan - June 2008 29 Upstream Process Primary Recovery

Cell Disruption • Mechanical • Chemical

Clarification • Centrifugation: • Filtration: • Chromatography

Clarifying centrifuge

R Van Exan - June 2008 30 Downstream Process

Primary Objective: • removal of impurities • Maintain biological activity

Secondary Objective: • Clearance of adventitious agents

Inactivation • Chemical or physical • BPL, formaldehyde, heat

Filtration

R Van Exan - June 2008 31 Formulation

Dilution

Adjuvant (eg adsorption to AlOH or AlPO4) Stabilizers Preservatives Blending antigens Polio trivalent = type 1 + type 2 + type 3 Pneumococcal polysaccharide = 23 serotypes Meningococcal polysaccharide = 4 serotypes Pneumococcal conjugate = 7 serotypes Acellular Pertussis = 1 to 5 different antigens (PT, FHA, Pertactin, Fim2, Fim3) Combination Vaccines MMR = 3 vaccines (Measles, Mumps, Rubella) Pentacel = 5 vaccines

R Van Exan - June 2008 32 Filling & Packaging

Sterile filling Liquid vaccines Freeze dried vaccines

Physical Inspection

Labelling & Packaging

Storage 2-8oC Frozen

Shipping Cold Chain

R Van Exan - June 2008 33 Quality Control

Identity Quantity (specific activity) Purity (quantification of contaminants) Characterization (size, structure, sequencing) Activity (Immunology testing, in vitro based system) Potency in relevant animal model (correlates of protection) Microbial sterility, pyrogenicity, toxicity, general safety, etc.

R Van Exan - June 2008 34 Acellular Pertussis and Combination vaccines

In 1997 sanofi pasteur introduced Pentacel™ an Acellular Pertussis combination Vaccine which contains: 5 component acellular pertussis Diphtheria Tetanus IPV Hib

The research, development & manufacturing for Pentacel™ combination is completely Canadian

R Van Exan - June 2008 35 5-Component Pertussis

Purified Pertussis Vaccine Components Pertusis toxoid FHA Fim 2 Fim 3 Pertactin (69kDa)

Other Combination Vaccine Components IPV (Vero or MRC-5) Tetanus Toxoid Diphtheria (D or d) Hib (Tet toxoid) conjugate

R Van Exan - June 2008 36 Manufacturing today - Pentacel

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R Van Exan - June 2008 37 Increasing Regulatory Requirements

R Van Exan - June 2008 38 Compliance Revolution A Paradigm Shift

9Control of production systems Compliance Revolution & processes Harmonization – Global Standards 9Validation of production environment FDA Reorganization – Team Biologics 9Strengthened compliance Emphasis on process & validation penalties Electronic Record Validation Higher regulatory standards Complex testing Retrospective validation of legacy systems technologies Validation of Major Simple seed banks & Regulatory end product raw materials Paradigm Shift tests

1914 1950’s 1980’s 1990’s 2000 R Van Exan - June 2008 39 New concept in cGMP Now compliance requires: Demonstration of control and reproducibility of all systems and processes throughout the full manufacturing cycle. Dramatic increase in facilities investments, time, data and personnel

Q.A.

Batch Bulk QC FF QC Pack QC Release Dist

Submission to F/FD agencies 3 to 4 * But Flu : 6 to 7 months months 9* to 22 months

R Van Exan - June 2008 40 Impact of Increasing Regulatory Compliance on the Vaccine Industry Lot Release Testing of every lot by manufacturer and regulator – test discrepancies Lot Failures

Increased Regulatory Compliance increase production failures as regulations become more stringent reduced capacity increased production cost supply disruptions

Increased Regulatory Penalties FDA “team biologics” Large fines Plant closures

R Van Exan - June 2008 41 Impact of Increasing Regulatory Compliance on the Vaccine Industry

Process Improvements and Process Change Removal of materials of animal origin Removal of blood products Removal of Thimerosal Increased cost of production

Cold chain disruption Increased cold chain monitoring – increased loss of shipments Increased cost of shipping

R Van Exan - June 2008 42 Removal of Thimerosal from DTaP vaccines

Without Thimerosal only single dose vials possible Manufacturing process changed to ensure greater aseptic conditions for filling of single dose vial without preservative Manufacturing yields drop due to need to overfill every vial Reformulation requires re-licensing, a complex and lengthy procedure Net results: approximately 2 years of development work for an existing product and 25% reduced output

R Van Exan - June 2008 43 Timeline for Capacity Increase

2004 2005 2006 2007 2008 2009

Packaging

Decision Fermentor needed Lyo Filling

Facility

Decision timeline for capacity increase

R Van Exan - June 2008 44 Impact of the Compliance Revolution

Increased Vaccine Production Costs Manufacturing Costs Quality Control and Quality Assurance Costs Manufacturing facility costs

Reduced Capacity WIP Losses Longer production cycles

Reduced Profitability Plant closures Companies leaving the industry

R Van Exan - June 2008 45 Global Vaccine Supply

Toronto France Swiftwater

Top 5 Manufacturers 2006 GSK 22.6% Wyeth 13.8% Only 5 companies responsible sanofi pasteur 24.6% for 84% of vaccine sales MSD 16.5% globally Novartis 6.0%

R Van Exan - June 2008 46 Next…….

R Van Exan - June 2008 47