3rs in quality control of human vaccines: opportunities ... · sanofi policy: “as a key element...
TRANSCRIPT
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
| 3 3Rs Asian Congress 2016
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
3Rs Asian Congress 2016 | 4
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
| 6 3Rs Asian Congress 2016
3Rs Asian Congress 2016 | 7
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
3Rs Asian Congress 2016 | 8
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
3Rs Asian Congress 2016 | 9
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 Asian Congress 2016 | 10
3Rs successes and barriers
| 11 3Rs Asian Congress 2016
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
3Rs Asian Congress 2016 | 12
(*) 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
3Rs Asian Congress 2016 | 13
(*) Partial implementation depending on
product & market
Current Limitations to 3Rs implementation
3Rs Asian Congress 2016 | 14
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
3Rs Asian Congress 2016 | 15
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
| 16 3Rs Asian Congress 2016
Time for change
Based on the demonstration of the scientific relevance of new test
3Rs Asian Congress 2016 | 17
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
3Rs Asian Congress 2016 | 18
1:1 replacement
Integrated approach
Conclusion
3Rs Asian Congress 2016 | 19
● 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
3Rs Asian Congress 2016 | 20
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
3Rs Asian Congress 2016 | 23
Thank you
3Rs Asian Congress 2016 | 24