Waiving Target Animal Batch Safety Testing for vaccines 5th VICH Outreach Forum meeting, 24-25 February 2015, Washington DC Presented by Dr Kornelia Grein Head of Veterinary Medicines Department; EU Coordinator at VICH

Issues Batch safety testing for vaccines Why abondoning batch safety testing in laboratory animals and target animals: Developments in Europe during the last 20 years 3Rs International harmonization and waiving batch safety testing VICH guidelines Outlook for non-VICH countries, in particular Outreach Forum countries Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Batch safety testing for vaccines (1/4) In the past : “Classic” approach for safety testing applied, i.e. tests in laboratory animals (abnormal toxicity testing) and in target animals for each batch. High use of test animals. In EU: in early 90ies benefit of laboratory animals toxicity testing for batch safety was questioned and analysis made comparing results from tested batches against hypothesis if no such data were generated. Would we have missed unsafe batches? Result: testing did not provide additional safety. Laboratory animal toxicity batch safety testing was abandoned in 1996. Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Batch safety testing for vaccines (2/4) Target animal batch safety testing (TABST) continued. In EU analysis investigating value of TABST in safety assurance was made in late 90ies/early 2000s with results from large number of TABSTs. In 2005 waiving of TABST was introduced, subject to TABST of 10 consecutive batches with no findings showing consistency of production in light of experience gained. Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Batch safety testing for vaccines (3/4) In 2012, considering the VICH guidelines 42 - Test for reversion to virulence and GL44 - Developmental safety tests, the European Pharmacopoeia monographs for vaccines were revised, and the requirement for routine target animal batch safety tests was deleted. Only in specific cases, on ad-hoc basis, further testing. Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Batch safety testing for vaccines (4/4) Reasons that allowed deletion of routine batch safety testing: Experience with testing/analysis made: poor sensitivity despite using numerous animals in testing each year, very limited number of batches failing test, observation of field safety issues with batches compliant with TABST. New guarantees: General improvements in the manufacturing process of veterinary vaccines, introduction of new requirements of in-process testing, controls of starting materials, etc. GMP, pharmacovigilance 3Rs goal: Replacing, Refining and Reducing the use of animals in tests Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

30 October 2017 International harmonization and waiving of batch safety testing - VICH guidelines (1/3) Different requirements in different regions lead to duplication of tests (costs, unnecessary animal testing). Regional approach for waiving batch safety testing only of limited effect if not embraced at international level. In US and Japan: BST mainly abnormal toxicity testing, also some TABST. VICH supports 3Rs principles. Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

International harmonization and waiving of batch safety testing - VICH guidelines (2/3) Proposal EU to VICH for GL on criteria to waive batch safety testing (similar as 2005 EU approach). First step: GL50 on criteria for waiving TABST for inactivated vaccines. GL adopted in February 2013. At present: drafting of similar GL on waiving TABST for live vaccines, at step 2. Future intentions: develop guideline addressing abnormal toxicity testing. Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Outlook for non-VICH countries, in particular Outreach Forum countries So far intended impact in reduction of unnecessary animal tests not visible, despite waiving/deletion of TABST. Reason: wide variability in batch safety testing requirements globally, sometimes both abnormal toxicity test and TABST required for imported vaccines from EU. What can be done to improve situation? What is situation in Outreach countries regarding vaccine manufacturing and batch safety testing requirements? Is there interest to have more information / discussion on the matter? Waiving TABST for veterinary vaccines, 5th VOF meeting; K. Grein

Thank you for your attention Any questions Implementation of VICH guidelines