1. API Stability Testing WHO PQ Requirements Presented by Rutendo Kuwana Accra, Ghana December 2009

2. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 2 |2 | Overview Scope of presentation – Generic/Multisource preparations API - Stress Testing Selection of Batches Container Closure System Specifications: Stability indicating quality parameters Testing Frequency Storage Conditions

3. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 3 |3 | Overview Evaluation/Extrapolation of data Statements/Labelling Ongoing Stability Studies

4. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 4 |4 | Stability Assessment References Main Generics Guideline Supplement 2 to Main Generics Guideline TRS 863 Annex 5, current stability guideline TRS 937 (amendment of above) TRS 908 (modification of storage conditions) TRS 929 Annex 5 and Appendix 3 TRS 948 ICH Q1A, B, C, D and E TRS 943 Variation Guide Appendix 4 (Stability Requirements for Variations) EMR Regional Guideline based on QAS/06.179 QAS/06.179/Rev.3 Manual for Drug Regulatory Authorities (Annex 11) Etc…

5. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 5 |5 | Stability Assessment References Practical Approach: Main Generics Guideline (2005) and Supplement 2 (2006) [Referred to as “Main Guide” and S2 in this talk] ICH Q1A (2003) New WHO Stability Guide in TRS953 (2009): Annex 2: “Stability Testing of API’s and FPP’s”

6. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 6 |6 | Stability - purpose To establish a re-test period* for the API or a shelf-life for the FPP. To establish storage conditions. *In exceptional cases, eg for unstable API’s, a shelf-life is given.

7. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 7 |7 | API Stress Studies Stress testing is an important part of developmental studies. Used to: - establish degradation pathways and intrinsic stability, - validate stability-indicating power of methods In considering drug stability, attention must be paid to processes which may lead to instability of the product.

8. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 8 |8 | API Stress Studies When available, it is acceptable to provide relevant data published in the scientific literature to support the identified degradation pathways and products. When no data are available, stress testing should be performed.

9. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 9 |9 | API Stress Testing New Guide: should include the effect of: - temperature, in 10◦ increments above accelerated (ie 50◦C, 60◦C …) - humidity (75% or greater) - oxidation and photolysis, where appropriate - susceptibility of the API to hydrolysis across a justified range of pH values when in solution or suspension (as per Q1A).

10. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 10 | API stability Stress testing Requirement: 1 API batch. Photostability testing: generally as per Q1B, however for PQP, literature data can support/replace experimental data: If the PhInt, USP or EP states in the monograph for the API or FPP, "Protect from light", there is no need to request photostability data or testing.

11. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 11 | API stability Stress testing Main Generic guideline 2.7.1 suggested conditions

12. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 12 | Examples of physical stability stress testing conditions for drug substances - Industry Perspective (Source Handbook of stability testing and pharmaceutical development regulations, methodologies, and best practices)

13. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 13 | Stress studies: Approach The impurities/degradants that must be closely investigated are those appearing at greater than (or approaching) the identification threshold, (the limit on individual unknowns) when stored at long-term and accelerated conditions. A mass balance assessment may be necessary and should be based on the decrease in assay value and the increase in the amount of degradation products. Process related impurities to be monitored at release only with no need to monitor during long-term stability. However, if any of these impurities are shown to increase during storage, or if new impurities are developed, they should be considered as “degradants” or “degradation products”, and analytical methods must be developed to monitor them.

14. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 14 | Selection of Batches Definition of Primary Batches : Batches used in stability studies to establish retest (API) or shelf-life (FPP). [ICH Q1A and New Guide] 3 pilot batches* : For stable API, 2 pilot batches. *For API - Pilot batches must be of the same synthesis route, and method of manufacture and procedure that simulate the final process for production batches.

15. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 15 | Container Closure System Should be the same or simulate the container proposed for storage/distribution unless justification provided (ie container used in studies is less than or equally protective compared to proposed container) a functionally similar container may be used to mimic the cardboard or plastic drum that is usually used to store raw material. simulated small telescope drums are typically used for these types of studies. Ensure that thickness of the telescoped drum does not provide more or less protection than the warehouse drum

16. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 16 | API Stability Testing PART TWO

17. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 17 | API Stability: Specifications S pecifications: test attributes susceptible to change. Testing should cover physical, chemical, biological and microbiological attributes. Appendix 2 of the New Guide states appearance, assay, degradation plus others susceptible to change. For impurities, a specification for individual and total impurities must be set. Numerical data for individual (known and unknown) and total impurities to be reported instead of conforms or complies. NB: The upper and lower acceptance criteria limits for innovator products are based on the potency and/or impurity levels of the clinical lots and safety and efficacy considerations. There is no justification, normally, for generic source to request for less stringent specifications.

18. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 18 | Test Methods Only validated methods to be used and evidence of validation to be submitted or referenced to dossier Stability indicating methods must be developed to monitor the purity of the API as well as identification and quantitation of impurities Reference standards – information on sources and/or preparation and characterisation of in house primary and secondary working standards should be available Care required for methods used where no reference standard exists e.g. for related substances

19. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 19 | Other parameters to be monitored Commonly where the API is low solubility and micronized, and the FPP is low dose - PSD is critical Due to the potential for settling of material on storage, stability results for PSD should be provided to address this issue.

20. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 20 | Polymorphism If there is evidence that polymorph stability may be an issue, polymorphic stability should be demonstrated as part of routine stability studies. For solid dosage forms, the solubility, efficacy, and stability of a drug may depend on the particular crystalline state of the drug. The polymorphic content may be characterized by techniques such as x-ray powder diffraction, Raman and infrared spectroscopy.

21. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 21 | Testing Frequency Long term: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually Accelerated: Minimum three points including t 0 and t final, eg 0, 3, 6. Intermediate: Four points including t 0 and t final, eg 0, 6, 9, 12.

22. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 22 | Storage Conditions Requirements at time of submission: Stable API: (Supplement 2) 6 months at 40◦C/75% 6 months at 30◦C/65% Other API: 6 months at 40◦C/75% 12 months at 30◦C/65% PQP is moving towards long term at 30◦C/75% being the preferred

23. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 23 | API Stability Appendix 1 to TRS953 Long term stability testing conditions are determined by the climatic condition under which the API or FPP is intended to be stored. Zone I: temperate21◦C/45%RH Zone II: subtropical/mediterranean25◦C/60%RH Zone III: hot/dry30◦C/35%RH Zone VIa: hot/humid 30◦C/65%RH Zone VIb: hot/very humid30◦C/75%RH

24. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 24 | Storage Conditions II When long term data is conducted at 25◦C/60% and significant change is observed at accelerated conditions, data should be provided at intermediate conditions (eg 30◦C/65%). Tolerances - The chamber temperature must be controlled within ±2 ◦ C, and the humidity controlled within ±5% relative humidity.

25. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 25 | Storage Conditions III Where a valid CEP is provided: no data is required if the proposed retest is as per retest on CEP; if longer than the CEP retest is proposed, requirements as above.

26. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 26 | Stability Evaluation Establish the retest period and storage conditions based on stability data. “The approved retest date should be displayed on the container label and CoA.” (Main Guide). If little variability, statistical analysis is not necessary.

27. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 27 | Evaluation Extrapolation of data: Common scenario: Data (6 months Accelerated and "x" months LT) is within specifications with no significant change under accelerated conditions. The allowed re- test (API) or shelf life (FPP) is double the long-term period "x", but NMT "x" + 12 months. Stable API: 24 months re-test is allowed based on 6 months accelerated + 6 months long term data.

28. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 28 | Evaluation In prequalification, extensions beyond 24 months are not accepted without real-time long term data on production batches. e.g. for a stable API, a re-test (API) or Shelf Life (FPP) of 24 months may have been accepted based on 6months accelerated + 6months long-term, but to accept a longer re-test period, real-time data is required.

29. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 29 | API Stability Evaluation Definition: re-test period The period of time during which the API is expected to remain within its specification and, therefore, can be used in the manufacture of a given FPP, provided that the API has been stored under the defined conditions. After this period, a batch of API destined for use in the manufacture of an FPP should be re- tested for compliance with the specification and then used immediately. A batch of API can be re-tested multiple times and a different portion of the batch used after each re-test, as long as it continues to comply with the specification. For most substances known to be labile, it is more appropriate to establish a shelf life than a re-test period. The same may be true for certain antibiotics.

30. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 30 | Stability Statements/Labeling Recommended labeling statements provided in Appendix 3 of the New Guide. Note that “store below” is no longer an option. Storage is stated as, “Do not store above…” Storage statement and re-test (API) or shelf life (FPP) should be based on evaluation, based on: -Extent of data provided (x LT + 6 mo Acc); -Change(s) observed; -Actual LT storage conditions; -Batches (all production?), etc.

31. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 31 | Ongoing Stability Studies Purpose: to monitor the API and determine that it remains within specifications under the storage conditions, within the re-test period in all future batches The programme should be described in a written protocol and the results presented in a formal report. The programme should include at least one production batch per year, tested at least annually. An ongoing study should be conducted after any significant change to the synthetic route, process or container which may impact stability.

32. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 32 | Ongoing Stability Studies OOS results or atypical trends should be investigated and reported immediately to the relevant finished product manufacturer. The possible impact on batches on the market should be considered. A summary of data should be written and maintained, and should be subjected to periodic review.

33. Workshop on Planning, conduct and regulatory assessment of stability studies Accra, Ghana December 2009 33 | Stability Commitment Provide the post-approval stability protocol and stability-testing commitment, when applicable (Ref to ICH Q1A/B/E) A stability commitment is required when long term data does not cover the proposed re-test period If fewer than three submission batches are submitted then additional batches to be tested with the same stability protocol used for submission batches.