IABS conference 3Rs Alternatives and Consistency Testing in Vaccine Lot Release Testing

Transcription

1 IABS conference 3Rs Alternatives and Consistency Testing in Vaccine Lot Release Testing Coenraad Hendriksen (Intravacc) & Faculty of Veterinary Medicine, Utrecht University

2 Food for thought (vaccine q.c., laboratory animals, 3Rs and consistency approach) q Short history of animal use in vaccine research & testing in 3 slides q In vivo veritas? Or do we have to be critical? q 3Rs-alternatives and what has been achieved? q Time for a change!? The paradigm of consistency.

3 Animals in vaccine research & testing: A short history in 3 slides. Pasteur

4 Animals in vaccine research & testing: A short history in 3 slides. The case of Diphtheria Development: D antiserum/toxoid Isolation of causal organism Production of exotoxine Demonstration of protective antiserum Year Scientist Animal model 1884 Loeffler Pigeon, chicken, rabbit, guinea pig 1884 Roux & Yersin 1890 Behring & Kitasato Various species, GUINEA PIG Dog, mouse, rat, GUINEA PIG Large scale production antiserum Diphtheria toxoid Roux & Martin Ramon Dog, Sheep, Goat, Cow, HORSE Various animal species

5 Animals in vaccine research & testing: A short history in 3 slides. Model development and test design u Model development: Many animal models for lot release testing developed in the 50s 70s of the previous century (Kendrick test, NIH, etc). u Test design: introduction of multi-dilution assay, use reference preparation,and ED50 in the 30 50s of previous century (Prigge) u Sharp increase in animal numbers for vaccine quality control > 50s u Extensive animal use at RIVM > /year in the 70s

6 If vaccines have been highly efficient in fighting infectious diseases and laboratory animal usage has been instrumental to that : Why so moving away from animal use in vaccine quality control? What characterises a model to be ideal in Research & Testing? Relevant Reproducible Mechanistically understood Ethically/legally acceptable Cost effective In vivo veritas?

7 Why moving away from animal use in vaccine quality control? u In vivo veritas? : Relevance/reproducibility often disputed. Can t we do better now? u Practical objections : Economics u Moral/legal objections : Animals have an intrinsic value and are sentient beings..the use of live animals continues to be necessary.. However, this Directive represents an important step towards achieving the final goal of full replacement.as soon as it is scientifically possible to do so. (Recital 10, Directive 2010/63/EU)

8 THE CONCEPT OF 3RS IN VACCINE RESEARCH AND TESTING Conference organized by IABS. held at the Zoological Gardens, London, UK (April 24 26, 1985) Early 3Rs champions Jorn Lyng (DK) Peter Knight (UK) Hans Kreeftenberg (NL)

9 Thoughts and reflections Boek van mij Preface It is also important to note that because technology keeps evolving at such rapid rate, what seems impractical if not impossible today, may become possible next month or next year. This in turn means we must constantly reassess which animal tests are candicates for replacement. Jonn C.Petricciani (1987)

10 Recommendations ECVAM workshop (1994) Recommendations Status in 2015* All vaccines Omission of abnormal toxicity test Toxicity test for Diphtheria Toxoids Allow the use of the tissue culture method Safety test for Inactivated vet.vaccines Combine with potency testing Neurovirulence Test Oral Polio Vaccine Review endpoints in NHP test Potency tests D and T Toxoids Exclude lethal endpoints by using serology Introduce single-dilution assay * In Ph.Eur.

11 Recommendations ECVAM workshop (1994) Recommendation Status in 2015 Potency Rabies Vaccine Correlation of data from in vitro and in vivo methods should be investigated Potency test for Erysipelas Vaccine Give guidance on validation procedures for use of serological model Potency test for Leptospirosis Vaccine Show data on progress of in vitro test systems Potency test for inactivated Polio Vaccine Evaluate results on in vitro tests All vaccines with severe endpoints Implement guidelines for humane use and care (e.g. Humane endpoints)

12 30 years of experience with 3Rs alternatives: conclusions.the principle of 3Rs methods is well accepted now in vaccine lot release testing. But several problems with respect to validation and acceptance remain

13 Time for a change!? Moving to the 2nd generation 3Rs alternatives 1 st Generation 3R models: 1 : 1 replacement 2 nd Generation 3R models: part of integrated approach: analytical tools, in vitro don t make use of improvements in (in process) technolologies. in line with existing paradigm of lot release testing methods, bio-molecular techniques make use of progress in (in process) technologies part of novel paradigm of lot release testing

14 Food for thought? What is the difference with vaccine q.c. in the 80s? q Better characterisation of the product at product optimisation and production (consistency of starting material). q Improved optimisation and standardisation of production process (consistency of production process and product). q Tight in-process control and product monitoring with new and improved testing tools (consistency of tests performed). q Use of quality systems to guarantee consistency (GMP, QA, pharmacovigil.) (consistency in oversight).

15 CONSISTENCY TESTING: A NOVEL PARADIGM IN VACCINE LOT RELEASE TESTING? Consistency testing aims to characterize the first few lots (clinical, historical) of a (new) seed lot by using in vivo data (also from clinical studies) and non-animal data (in vitro, immuno-chemical; physico-chemical). Subsequent lots shall be tested for consistency in production (finger print) by using a set of non-animal tests

16 CONSISTENCY APPROACH IN LOT RELEASE TESTING: WHAT MAKES IT ATTRACTIVE? Quality is linked to well characterised clinical/historical and homologous lot (scientific benefit) Quality control is quicker (a few days instead of 2 months) (economic benefit) NO further animal use is required for lot release testing (animal welfare benefit)

17 Time for a change: how difficult can it be?

18 Time for a change: Hopeful Initiatives In General Notices of Ph.Eur, consistency of production with a view to reducing animal testing has recently been incorporated (Supplement 8.2, in force since July 2014). IMI2 call on consistency testing Final proposal to be submitted end of September

19 Take home Food for Thought Imagine that the European Parliament intends to introduce wants to ban the use of laboratory animals for vaccine lot release testing and also wants to stop the import of vaccines from outside Europe that have been tested on animals. Would you advise to continue using vaccines while testing the vaccines with non-animal methods? Would you advise to postpone the ban for 15 years? Or would you indicate that a ban is impossible at any time and the consequence of a ban would be to stop vaccination programmes?

20 Thanks for your attention