3rs in quality control of human vaccines: opportunities ... · sanofi policy: “as a key element...

3Rs in Quality control of vaccines for human use: opportunities and barriers Sylvie Uhlrich – Sanofi Pasteur Asian congress 2016 Alternatives and Animal Use in the Life Sciences, Karatsu, Saga, JAPAN – Nov 15-18, 2016

| 1 3Rs Asian Congress 2016

Presentation outline

● Animal use in vaccine quality control

● 3Rs history and principles

● 3Rs successes and barriers ● Overview of successes illustrated with few examples ● Regulatory & scientific barriers

● Perspectives for the future

● International collaboration ● Consistency approach

3Rs Asian Congress 2016 | 2

Animal use in vaccine quality control


Short history of animals in vaccine research and testing

● Vaccine quality control tests have their roots in the work of 19th century scientists (Pasteur, Koch, Behring, Ehrlich, …)

● Test design (multi-dilution assay, use of reference preparation, ED50) were introduced in the 30s-50s of previous century (Prigge)

● Current quality in vivo control tests for established vaccines have been developed in the 50s -70s of the previous century (Kendrick test, NIH, etc)

● Sharp increase in animal numbers for vaccine quality control since 50s


Current animal use for Vaccines

● Biologicals testing has the highest proportion of experiments causing

severe pain and distress to animals out of various types of experiments (basic research, toxicity testing, etc.)

● Use in Vaccine industry

● Vaccine development (Research, non clinical evaluation of safety & efficacy) ● Production ● Batch control testing (safety and potency testing)

● Vaccines batch control testing is responsible for ~90% of animal use at

vaccines manufacturers ● Batch control testing by manufacturers ● Batch control by National Control Laboratories

3Rs Asian Congress 2016

3Rs history and principles



Why changing?

●

• Animals are sentient beings • Large number of animals used for vaccine QC • Large % of animals used in vaccine QC exposed to severe

pain & distress • Societal concern using animals

Animal welfare

• In vivo models act as a black box • Relevance to human sometimes questionable • Lack of robustness, many factors may affect outcome • High variability

Science

• In vivo tests are time consuming and human resource demanding

• In vivo tests are expensive • Long cycle times • Variability can lead to rejection of safe and efficacious

vaccines, delays to market release & vaccine shortages

Economics


Regulatory context

● No global harmonized framework: Many worlds ● A vaccine may be registered in more than 100

countries for which there are different release requirements

● The same product lot may be used to supply multiple markets

Requirement to apply various in vivo methods for one product: ● Supply chain, testing and regulatory complexity ● More animals used per batch release e.g. 4 repeat testings at manufacturer & NCLs

Increased costs & timelines ● Long cycle time & high variability ● Risk of vaccine shortage

Example: Diphtheria potency

Lethal challenge on GP Multi-dilution assay (ED50) Ph. Eur; WHO; JP; ChPh One-dilution assay (limit) Ph. Eur; WHO Seroneutralisation (limit) US PHS

Immunogenicity assay ELISA or VERO cell assay on GP sera Ph. Eur ELISA or VERO cell assay on Mice sera CHPh

= 7 different methods!

The concept of 3Rs in vaccine research and testing

Replacement

• Methods which avoid or replace the use of animals

Reduction

• Methods which minimise the number of animals per experiment

Refinement

• Methods which minimise suffering and improve animal welfare


The principles of Humane Experimental Technique (1959)

William Russel Rex Burch

IABS conference at the zoological Gardens, London, 1985)

Legal basis in Europe

● EMA/CPMP/SWP/728/95 (adopted 1997): Replacement of animal studies by in vitro models

● Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the 66 Community code relating to medicinal products for human use (Consolidated version: 67 05/10/2009); 68

● Directive 2010/63/EU on the protection of animals used for scientific purposes on 3 June 2010. ● European Directive 2010/63/EU on the protection of animal used for

scientific purpose “Member States shall ensure that, wherever possible, a scientifically satisfactory method or testing strategy, not entailing the use of live animals, shall be used …”

● Sanofi policy: “As a key element of Corporate Social Responsibility, Sanofi commits to meet or exceed regulations and standards for the use of animals and to develop alternative approaches. Sanofi fully adheres to the 3Rs…”


3Rs successes and barriers


Where do we stand now (1/2)

Possible use of alternative methods Ph. Eur. Status at SP

All vaccines Allow omission of abnormal toxicity test / general safety test

Partial*

Toxicity test for Diphtheria Toxoids Allow the use of VERO cell based method at DS Remove the test at DP

Partial* Partial*

Toxicity test for Pertussis toxoid Allow CHO cell-based assay to replace HIST : at DS At DP stage

On going

partial* Under devt

Neurovirulence Test Oral Polio Vaccine Allow switch from non human primate to transgenic mice

IPV inactivation test Allow replacement of 1ry monkey kidney cells with L20B cell line

General desc°

Partial*

Test for adventitious agents • Removal of GP & embryonated eggs for cell bank testing • Replace in vivo tests by broad molecular methods (HTS)

01/2017 01/2017

On going Under devt


(*) Partial implementation depending on

product & market

Where do we stand now (2/2)

Possible use of alternative methods Ph. Eur. Status at SP

Potency tests D and T Toxoids • Allow using serology instead of lethal endpoints • Allow introducing single-dilution assay

Partial* Partial*

Potency test for inactivated Polio Vaccine Allow in vitro test

Partial*

Potency test for inactivated Rabies Vaccine Allow in vitro test

under devt

Potency test for inactivated Hepatitis A vaccine Allow in vitro test

Potency test for inactivated Hepatitis B vaccine Allow in vitro test


(*) Partial implementation depending on

product & market

Current Limitations to 3Rs implementation


Regulatory hurdles

• Lack of harmonization of regulatory requirements

• Prudence of Health Authorities to accept deviations from established guidelines

• Complexicity of regulatory changes do not generate strong incentive to develop and implement alternatives to animal testing

Scientific hurdles

• Inherent variability of in vivo assays

• In vivo assays not in line with ICH Q2(R1) validation requirements

• The attributes of the product will likely be assessed differently when changing from an in vivo to an in vitro method

• 1:1 comparaison challenging and not necessarily justified

Scientific hurdles

● The test methods used for routine QC are intended to monitor production consistency and to ensure comparability of quality attributes between commercial batches and clinical batches

● Information provided by in vivo and in vitro methods will be different

● An existing in vivo method may be substituted by more than 1 in vitro method in order to control key qualitative and quantitative attributes measured by the existing test


In Vivo assay Measure Complex

functional response

In Vitro assay Mimic specific elements of complex in vivo response

Agreement between methods should not always be expected

Perspectives for the future


Time for change

Based on the demonstration of the scientific relevance of new test


Test Replacement

Test Substitution

• Capability of new test to control key quality attributes and maintain link with batches found safe and efficacious through clinical studies or routine use

• In vitro test to detect differences relevant for production process

Potency tests

• In vitro method should be specific and at least as sensitive as in vivo assay

• Where possible, functional assay; if not possible, detection of parameter(s) reflecting mode of action of toxic component

Safety tests

Time for change…..

‘The consistency approach is a concept which includes the strict application of GMP rules and guidelines, process validation and in process and final product tests and is aimed at verifying if a manufacturing process produces final batches which are consistent with one that fulfils all the criteria of Quality, Safety and Efficacy as defined in the marketing authorization, ultimately resulting in replacement of routinely used in vivo tests.’

De Mattia et al, Biologicals 39:59-65, 2011


1:1 replacement

Integrated approach

Conclusion


● 3Rs acceptability based on ● Full GMP implementation ● Reliable, standardized and validated process; in process monitoring ● Consistent product demonstrated safe & efficacious ● Relevant science ● Tests Validated according to ICH Q2(R1)

● Regulatory acceptance

● Easier for new vaccines ● For existing vaccines, need to facilitate post approval changes

• An understanding, recognition and implementation of the change by all stakeholders in a timely manner

• Need for a global harmonization endorsed by an International organization • Involvement of all stakeholders (regulators, scientists, animal welfare

organizations, the public and decision makers) in communication of best practices

International collaborative efforts


HIST replacement 2010-2015 international

workshops & collaborative studies

● Human Rabies Vaccines (Potency test replacement) ● Harmonisation of 3Rs in Biologicals (deletion GST/ATT) Vac2Vac project

Vaccine batch to vaccine batch comparison by

consistency testing

ICVAM NC3Rs

EDQM NIH

VAC2VAC OVERVIEW

• The VAC2VAC project has received funding for 5 years from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement Nº115924.

Total project budget (March 2017- March 2022): • €7.85M EU funding in cash • €8.13M from EFPIA partners in kind

• 20 participants: 14 public partners, 6 EFPIA companies

• Objectives:

Provide proof of concept of consistency approach for batch release testing of established vaccines using sets (toolbox) of in vitro and analytical methods

• Expected results: Enhance replacement, reduction or refinement of animal use (3Rs) Development, optimization and evaluation of in vitro analytical methods to be used in the consistency approach for vaccine quality control Demonstrate proof of concept of consistency approach for several types of established veterinary and human model vaccines With regulators define procedural guidance for regulatory approval and routine use

21 3Rs asian congress 2016

VAC2VAC PARTNERS

22

Acknowledgements

Sanofi Pasteur France ● Emmanuelle Coppens, Manager Analytical Excellence, Quality Control ● Nolwenn Nougarede, R&D 3R coordinator, ● Frédéric Moysan, Animal Welfare Officer Sanofi Pasteur ● Patrice Riou, Director Virology & Immunology platform, Analytical R&D, Europe ● Laurent Mallet, AVP, Head of Analytical Research & Development, Europe

Sanofi Pasteur Canada ● Sue Nelson, Director, Analytical Expert 3Rs, Global Analytical Process & Technology


Thank you


3rs in quality control of human vaccines: opportunities ... · sanofi policy: “as a key element...

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