3Rs in Quality control of vaccines for human use: opportunities and barriers

Transcription

1 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, Rs Asian Congress

2 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

3 Animal use in vaccine quality control 3Rs Asian Congress

4 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

5 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

6 3Rs history and principles 3Rs Asian Congress

7 Why changing? Animal welfare 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 Science In vivo models act as a black box Relevance to human sometimes questionable Lack of robustness, many factors may affect outcome High variability Economics 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 3Rs Asian Congress

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! 3Rs Asian Congress

9 The concept of 3Rs in vaccine research and testing Replacement Reduction Refinement Methods which avoid or replace the use of animals Methods which minimise the number of animals per experiment 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) 3Rs Asian Congress

10 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 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

11 3Rs successes and barriers 3Rs Asian Congress

12 Where do we stand now (1/2) (*) Partial implementation depending on product & market Possible use of alternative methods Ph. Eur. Status at SP All vaccines Allow omission of abnormal toxicity test / general safety test Toxicity test for Diphtheria Toxoids Allow the use of VERO cell based method at DS Remove the test at DP Toxicity test for Pertussis toxoid Allow CHO cell-based assay to replace HIST : at DS At DP stage 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 Test for adventitious agents Removal of GP & embryonated eggs for cell bank testing Replace in vivo tests by broad molecular methods (HTS) On going General desc 01/ /2017 Partial* Partial* Partial* partial* Under devt Partial* On going Under devt 3Rs Asian Congress

13 Where do we stand now (2/2) (*) Partial implementation depending on product & market 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 Potency test for inactivated Polio Vaccine Allow in vitro test Potency test for inactivated Rabies Vaccine Allow in vitro test Potency test for inactivated Hepatitis A vaccine Allow in vitro test Potency test for inactivated Hepatitis B vaccine Allow in vitro test Partial* Partial* Partial* under devt 3Rs Asian Congress

14 Current Limitations to 3Rs implementation Regulatory hurdles Scientific 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 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 3Rs Asian Congress

15 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 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 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

16 Perspectives for the future 3Rs Asian Congress

17 Time for change Test Replacement Test Substitution Based on the demonstration of the scientific relevance of new test Potency tests Safety tests 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 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 3Rs Asian Congress

18 Time for change.. 1:1 replacement Integrated approach 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, Rs Asian Congress

19 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 3Rs Asian Congress

20 International collaborative efforts Human Rabies Vaccines (Potency test replacement) Harmonisation of 3Rs in Biologicals (deletion GST/ATT) HIST replacement international workshops & collaborative studies NIH ICVAM EDQM NC3Rs Vac2Vac project Vaccine batch to vaccine batch comparison by consistency testing 3Rs Asian Congress

21 VAC2VAC OVERVIEW The VAC2VAC project has received funding for 5 years from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement Nº Total project budget (March 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 3Rs asian congress

22 VAC2VAC PARTNERS 22

23 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

24 Thank you 3Rs Asian Congress