EBF Recommendation for Stability Testing of Anti-Drug Antibodies; Lessons Learned from Anti-Vaccine Antibody Stability Studies

Transcription

1 EBF Recommendation for Stability Testing of Anti-Drug Antibodies; Lessons Learned from Anti-Vaccine Antibody Stability Studies Presenter: Janka Ryding Presentation based on publication: Pihl S, Michaut L, Hendriks J, Loebbert R, Ryding J, Nemansky M, Vermet L, Companjen A. Bioanalysis, 2014 May;6(10):

2 Disclaimer European Bioanalysis Forum (EBF) is in no way affiliated with the BioPharmaceutical Emerging Best Practices Association (BEBPA) European Bioanalysis Forum is in no way affiliated with the organization or execution of the Neutralizing Antibody Assay Conference, January 26-27, 2015; Palm Springs, CA 2

3 Eurpean Bioanalytical Forum (EBF) The bioanalytical voice of the European Pharma industry Non-profit organization founded 2006 Consists of bioanalytical scientists working within the pharmaceutical industry R&D GOAL is to: a) implement a platform for discussions for pharma, academia, regulatory and CROs b) harmonization of industry practices 3

4 Introduction Testing for unwanted immunogenicity towards biological drugs is part of the analytical program for non-clinical and clinical studies The term ADA in this talk is used as a collective term of anti-drug antibodies (no distinction between binding or neutralizing antibodies) Validation procedures and acceptance criteria for stability testing of antibodies should be based on: a) international guidelines b) internationally recognized conference reports c) scientific publications d) scientific rationale 4

5 FDA and EMA Guidelines Dec 2009 FDA Draft Immunogenicity Guidance: No specific recommendations on antibody stability testing FDA recommends storing patient samples in a manner that preserves antibody reactivity at the time of testing. Freezing and thawing patient samples may also affect assay results and those results should be evaluated May 2001 FDA Guideline: Bioanalytical Method Validation No recommendations on antibody stability testing. Antibody stability is only mentioned in conjunction with monitoring assay reagent stability. However, drug analyte stability is mentioned extensively on page 6-7*. Feb 2014 FDA Draft Guideline: Bioanalytical Method validation* 5

6 FDA and EMA Guidelines July 2007 EMA Guideline on Immunogenicity Assessment of Biotechnology-derived Therapeutic Proteins No recommendations on antibody stability testing. EMA recommends that antibodies need to be characterized on a case-by-case basis but stability is not mentioned Feb 2012 EMA Guideline: Bioanalytical Method Validation No recommendations on antibody stability testing. Antibody stability is only mentioned in conjunction with monitoring assay reagent stability. CONCLUSION: no formal recommendation exists 6

7 Current Stability Testing Process in Companies Derived from best practices in regulated quantitative bioanalysis Commonly includes: a) Short-term stability (STS) testing: Freeze/thaw Bench-top In-process sample stability a) Long-term stability (LTS) testing: Storage of samples from the sample is taken to the analysis is performed 7

8 Definition of Short- and Long-term Stability as Per the US FDA Guidelines STS Bench-top stability is assessed by keeping stability samples at room temperature for 4 24 h Freeze/thaw stability is assessed for the number of anticipated freeze/thaw cycles during analysis. Samples are stored frozen for a minimum of 24 h and then thawed unassisted at room temperature. When thawed, the samples are refrozen for Stability of processed samples is the test of the final processed sample prior to detection LTS Confirms analyte stability in the test system matrix and container covering the length of time from sample collection to sample analysis 8

9 What Are the Best Practices? 9

10 Survey Results Continued

11 Survey Results Continued.. Survey Companies providing data on testing ADA/AVA longterm stability (n) ADA/AVA assessments in long-term stability studies (n) Detected instability 1 7 >48 (ADA); 1 (AVA) NO (ADA); 1 (AVA) NO Total 10 >55 (ADA); 2 (AVA) NO CONCLUSION: No instability was observed for the investigated ADAs and AVAs 11

12 Assumptions Testing of ADA stability using spiked control samples reflect the stability of surrogate controls stored under certain conditions over time ADA stability is the same whether it is specific to drug X or drug Y [Shankar et al, 2008] ADA stability can be approximated by the stability of serum or plasma immunoglobulin specific to any antigen 12

13 Assumptions AVA stability testing, could be directly extrapolated to stability testing of ADAs Supported by litterature: Michaut et al. demonstrates the stability of anti-vaccine IgG that was stored for up to 3.6 years at -80 C Hendriks et al. demonstrates the stability of anti-vaccine polyclonal antibodies for up to 4.6 years at -80 C, both for IgG-binding antibodies and for functional NAbs 8 freeze/thaw cycles: the antibody-binding capacity remains within acceptable ranges, although a trend in decrease of 13% in titer can be observed 13

14 Conclusion & EBF Reccomendation Survey result indicate that no long-term ADA instability has been observed for >55 different biological drugs Further supported by references to long-term stability studies conducted with AVAs, which successfully demonstrate stability in all investigated cases RECOMMENDATION 1: Not relevant to assess ADA LTS RECOMMENDATION 2: ADA STS should be assessed Bench-top stability Freeze/thaw 14

15 Acknowledgements EBF members who participated in the survey Topic team 37: Susanne Pihl (Lundbeck) Jenny Hendricks (Crucell) Laurent Vermet (Sanofi) Lydia Michaut (Novartis) Martin Nemansky (PRA) Ralf Loebbert (Abbvie) Arjen Companjen (Crucell) Janka Ryding (Ferring) Sponsor: Arjen Companjen 15