How to ensure the Stability of Products in Clinical Trials an Industry Perspective. Volker Schnaible

Transcription

1 How to ensure the Stability of Products in Clinical Trials an Industry Perspective Volker Schnaible

2 Outline Why do we need stable development products? How to ensure stability How to use stability data for setting of retest period How to set shelf life specification limits for clinical trial material Overall summary

3 Outline Why do we need stable development products? How to ensure stability How to use stability data for setting of retest period How to set shelf life specification limits for clinical trial material Overall summary

4 Why do we need stable development products? Seen at:

5 Stability is important for all stages of pharmacutical development! Clear cut preclinical results No useless harming of animals GLP-Tox Phase 1 Phase 2 Phase 3 Market Clear cut clinical trial results Patient s safety Clinical / market supply With regard to stability we re all in the same boat!

6 Outline Why do we need stable development products? How to ensure stability How to use stability data for setting of retest period How to set shelf life specification limits for clinical trial material Overall summary

7 Stability is our concern right from the start Design of a stable molecule: Hot spot analysis of amino acid sequence Develop suitable product manufacturing processes Develop a stable product Formulation development before initiation of GLP Tox studies (including extreme stress studies (e.g. ph, temperature, freeze/thaw, shaking) ) Use of standardized & qualified primary packaging material

8 Benefits of considering stability right from the start Get information about weak points of the molecule Have stability indicating methods in place Stable formulation for GLP-Tox and EIH identified Ability to perform GLP-Tox studies with material that is representative for clinical trial material

9 Stability has to be ensured along the supply chain Manufacturing of API Manufacturing of DP Storage and shipment Administration

10 Stability of API Manufacturing is performed under GMP Design adequate process for market supply (e.g. evaluate hold steps) Comprehensive release analytics Stability studies to monitor API stability Ensure representativeness e.g. by using mini tanks or addition of steel chips Storage of API at adequate temperature

11 Essential stability programme for API (example) Data at storage temperature ensure availability of API for DP manufacturing Data at elevated temperature (e.g. 4 C / 25 C) and data of freeze/thaw studies ensure suitability of API for manufacturing of DP

12 Manufacturing of drug product Manufacturing is performed under GMP Consider impact of manufacturing steps (e.g. pumping, contact with tubing) Use of standardized manufacturing equipment and processes Comprehensive release analytics Storage at adequate temperature

13 Essential stability programme for DP (example) Provide database for setting of retest period Provide database for setting of shelf life specification limits Samples stored at elevated temperatures Give deeper insight in stability indicating properties of methods Establish stability indicating profile Establish degradation pathways Assessment of temperature excursions

14 Stability/compatibility is ensured for administration Compatibility/stability studies with administration material e.g. syringes, infusion bags, infusion lines i.v.: perform simulated administration s.c.: evaluation of hold times Stability after reconstitution for lyophilisates Handling & storing instructions are provided in IB

15 Summary Stability is our concern right from the start Design of a stable molecule Develop suitable manufacturing processes Develop a stable DP Stability has to be ensured along the supply chain Manufacturing of API Manufacturing of DP Storage and shipment Administration

16 Outline Why do we need stable development products? How to ensure stability How to use stability data for setting of retest period How to set shelf life specification limits for clinical trial material Overall summary

17 How to use stability data for setting of retest period Drug substance is often stored at -20 C or lower In case the freeze/thaw stability has been shown, retest period can be assigned based on extrapolated data Procedure for DP (and DS if stored non-frozen) Identify product quality attributes that change over time High medical need requires timely initiation of clinical trials Retest period needs to be based on extrapolation rather than real time data Unfortunately, acceptance of extrapolated data differs between regulatory authorities

18 No change of ph over time ph 7 ph Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

19 No change of osmolality over time Osmolality 400 mosm/kg Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

20 No change of turbidity over time Turbidity 21 FTU Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

21 No change of protein content over time Protein_content_UV 14 mg/ml Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

22 No change of potency over time Potency 150 relative_potency_% Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

23 SE-HPLC indicates slight change of purity 6 months 5 C (black/red) 6 months 25 C (blue) 24 months 5 C AU HMW Monomer LMW LMW Minutes

24 Time course of purity by SE-HPLC (Monomer) Monomer 100 area% Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

25 IE-HPLC indicates change of purity 6 months 5 C (black/red) 6 months 25 C (blue) months 5 C Main Peak 1 Main Peak AU Minutes

26 Time course of purity by IE-HPLC (Main Peak 2) Main_Peak_ area% Batch1_5 C Batch2_5 C Batch1_25 C Batch2_25 C Time (months) short term degradation at 25 C exceeds long term degradation at 25 C degradation at 2-8 C and 25 C is linear

27 Degradation monitored by IE-HPLC is linear and comparable for different batches Delta_Main_Peak_ area% Ref_mat 95/99% TI -Ref_mat 95/99% TI Batch1_5 C Batch2_5 C Batch3_5 C Batch4_5 C Batch5_5 C Batch6_5 C Batch1_25 C Batch2_25 C Batch3_25 C Batch4_25 C Batch5_25 C Batch6_25 C Time (months)

28 Extrapolation by linear regression is justified linear regression based on 9 months data linear regression based on 24 months data = actual stability data

29 Summary Product quality attributes that change over time have to be identified Change of stability data over time is linear Setting of retest period based on extrapolated data is justified

30 Outline Why do we need stable development products? How to ensure stability How to use stability data for setting of retest period How to set shelf life specification limits for clinical trial material Overall summary

31 Shelf life specification limits for clinical trial material (1) Pharmacopeial limits are defined for Sterility parenteral products have to be sterile Bacterial endotoxins 5 EU / (kg(bodyweight) * hour) Subvisible particles 6000 ( 10µm) ; 600 ( 25µm) Extractable volume corresponds Identity positive identity Formulation studies give guidance on: Colour Clarity ph Osmolality

32 Shelf life specification limits for clinical trial material (2) Preclinical and clinical requirements give guidance on Potency Content Limits for purity parameters are difficult to set in early clinical stages. Consideration of information about Closely related products ( platform molecules) Tox-material Characterisation Manufacturing process Consult with preclinical and clinical experts Specification limits may be reassessed if more information gets available

33 Overall Conclusions Product stability cannot be reduced to stability testing Criticality of stability information is highly dependent on storage condition Setting of retest period based on extrapolated data is justified Extension of retest period can be handled according to internal change control systems and should not trigger IMPD update & approval

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