1. CPH training | January 2012 1 |1 | Stability testing of Active pharmaceutical ingredients Hua YIN

2. CPH training | January 2012 2 |2 | References This presentation make reference to: API Stability Lynda Paleshnuik. Assessment workshop. Copenhagen January 2010.

3. CPH training | January 2012 3 |3 | References  Generics Guideline  Stability Testing of APIs and FPPs -- WHO Stability Guide in TRS953 (2009) Annex 2:  ICH Q1(A, B, C, D and E)  Variation Guidance Appendix 4 (Stability Requirements for Variations) (TRS 943) Guideline on stability testing for applications for variations to a marketing authorization (EMA 2011)  FDC guideline-- TRS 929 Annex 5 (appendix 3, Table A.1)  Good storage practices: TRS 908  FDA, EMA—stability for existing API and FPP For PQP, when there are contradictions, the Generic quality guideline prevails

4. CPH training | January 2012 4 |4 | Stability –purpose  "Provide evidence of how the quality of an API or FPP varies with time under the influence of a variety of environmental factors such as temperature, humidity and light"  "Study of product-related factors that influence its quality, for example, interaction of API with excipients, packaging materials. In fixed-dose combination FPPs (FDCs) the interaction between two or more APIs also has to be considered.

5. CPH training | January 2012 5 |5 | API Stability –purpose  Understanding of the molecule  Validation of analytical methods  Selecting packaging  To establish a re-test period for the API. In exceptional cases, e.g. for unstable APIs, a shelf-life is given.  To establish storage conditions.  To establish/justify specification limits--derived from a consideration of available stability data

6. CPH training | January 2012 6 |6 | Overview  Stress Testing  Stability indicating method  Accelerate and long term  Evaluation  Stability Commitments  Examples  Common Deficiencies

7. CPH training | January 2012 7 |7 | API Stress Studies Stability testing under conditions exceeding those used for accelerated testing. Used to:  establish the inherent stability characteristics of the molecule  establish the degradation pathways  identify the likely degradation products  validate the stability indication power of the analytical methods

8. CPH training | January 2012 8 |8 | API Stress Studies The information can be used in:  Formulation development  Manufacturing process development  Ensure proper selection of stability-indicating analytical techniques  Preparing reference material of identified degradation products  Degradation pathways elucidation  Selection of proper packaging

9. CPH training | January 2012 9 |9 | 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.  If “protect from light” is stated in one of the officially recognized pharmacopoeia for the API, it is sufficient to state “protect from light” on labeling, in lieu of photostability studies, when the container closure system is shown to be light protective.  When no data are available, stress testing should be performed.

10. CPH training | January 2012 10 | API Stress Studies How to design stress studies?  No detailed stress testing strategy in Guidelines, i.e. experimental conditions and duration may need to be varied depending on the nature of the drug substance  Generic guideline refers to FDC guideline appendix 3, table A.1 (TRS 929 Annex 5) -- as examples

11. CPH training | January 2012 11 | API stability Stress testing – Typical Stress conditions

12. CPH training | January 2012 12 | API Stress Studies  1 API batch (pilot scale, representative of the production batch)  Should include:  Effect of temperatures  Humidity  Acid and base hydrolysis  Photolysis (generally as per Q1B)  Oxidation

13. CPH training | January 2012 13 | API Stress Studies  How much stressing is enough ?  10-30% loss of API assay (FDC guideline, as well as Generic guideline)  between 5% to 20% degradation (some literature)  approximately 10 % degradation is optimal for method validation (as assay limits are normally 90-110%)  balance between "purposeful degradation" and irrelevant artifacts (e.g., secondary degradation products).  degradation products not formed during accelerated or long-term stability studies--need not always to be examined

14. CPH training | January 2012 14 | Stress studies: Approach for Assessment: DO -Check if data is provided, either generated by supplier/applicant or from literature references -Check for compendial statement, “protect from light”. -Check that conditions are adequate -Check the extent of degradation -≈10% = adequate degradation -little or no degradants : verify if conditions are "harsh" enough. If yes, the API is considered stable. -Conclude on the degradation pathways, stability nature of the API

15. CPH training | January 2012 15 | Stress studies: Approach for Assessment : DON’T - spend excessive time with degradants generated in stress studies if they are not formed in practice. The impurities/degradants that must be closely investigated are those appearing when stored at long-term and accelerated conditions at greater than (or approaching) the identification threshold (the limit of individual unknowns, 0.1%).

16. CPH training | January 2012 16 | Stability indicating method  Without analytical methods it is not possible to know what has happened during stability  Assay  Impurities/Degradation Products  Chiral Purity  Dissolution  Preservative Content

17. CPH training | January 2012 17 | Stability indicating method  This is a chicken and egg problem – need analytical methods to analyze stability data – need stability information to validate methods  Start with preliminary method based on what is known of drug substance – can determine content of drug substance, can separate the known or expected degradants  Use preliminary method to analyze stress stability studies – evaluate ability of method to separate degradants i.e the specificity -- confirm peak purity, mass balance  Use this information to modify/improve method  stability studies and analytical method development work together

18. CPH training | January 2012 18 | API Stability: Stability protocol  Number of batch(es) and batch size(s)  Container closure system (s)  Conditions of storage  Tests and acceptance criteria (reference to test methods)  Testing frequency

19. CPH training | January 2012 19 | API Stability: Selection of Batches Primary Batches: API batches used in stability studies to establish retest period. Prequalification: 3 batches of at least pilot scale (as per Q1A). *Pilot batches must be of the same synthesis route, and with method of manufacture and procedure which simulates the final process for production batches.

20. CPH training | January 2012 20 | API Stability: 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

21. CPH training | January 2012 21 | API Stability: Tests and acceptance criteria Specifications: test attributes susceptible to change:  Appearance (description)  Degradation (related substances)  Assay  Enantiomer  Plus others susceptible to change, e.g. LOD Methods:  If same as in API specs, cross-reference  If different, provide methodology and validation data for impurity and assay methods  Methods should be stability-indicating

22. CPH training | January 2012 22 | API Stability: Tests and acceptance criteria Other parameters to be monitored  The API is low solubility and micronized, and the FPP is low dose (common for RH products). PSD is critical. PSD stability should be monitored for potential increase in particle size (due to discreet particles or particle agglomerates).  For a low solubility API, if there is evidence that polymorph stability may be an issue, polymorphic form should be monitored during stability studies.

23. CPH training | January 2012 23 | API Stability: Storage Conditions Climatic Zones  Zone I: 21°C/45% RH  Zone II: 25°C/60% RH (subtropical)  Zone III: 30°C/35% RH(hot/ dry)  Zone IVA: 30°C/65% RH (hot/ humid)  Zone IVB: 30°C/75% RH (hot/ very humid) Long term stability studies should cover all climatic zones if possible

24. CPH training | January 2012 24 | API Stability: Storage Conditions  The required long-term storage conditions for APIs in the Prequalification Programme:  30ºC±2ºC/65%±5%RH or 30ºC±2ºC/75%±5%RH.  Alternative conditions should be justified, e.g. storage at 30ºC is inappropriate for the API. (e.g. Tenofovir disoproxil fumarate )  If no stability studies at 30ºC, commitment to commence studies at 30ºC on the next 3 production scale batches, and to revise the storage condition/retest period, if applicable

25. CPH training | January 2012 25 | API Stability: Storage Conditions Storage condition Months 369121824364860 25ºC/60% 30ºC/75% or 30ºC/65% xxxxxxxxx 40ºC/75% xx For storage in a refrigerator 5ºC±3ºC xxxxxxxxx 25ºC/60% or 30ºC/65% or 30ºC/75% xx For storage in a freezer -20 ºC±5ºC xxxxxxxxx One batch at 5ºC, 20ºC, or 30ºC to address the effect of short-term excursions

26. CPH training | January 2012 26 | API Stability: 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, e.g 0, 3, 6. Intermediate: Four points including t 0 and t final, e.g 0, 6, 9, 12.

27. CPH training | January 2012 27 | Minimum data requirements at time of submission Storage temperature (ºC) Relative humidity (%) Minimum time period (months) Accelerated40±275±56 Intermediate *** Long-term30±265±5 or 75±56 *Where long-term conditions are 30ºC±2ºC/65%±5%RH or 30ºC±2ºC/75%±5%RH, there is no intermediate condition.

28. CPH training | January 2012 28 | What are expected in the stability reports?  General information: name, manufacturing sites, date of manufacturing of the API; batch number, batch size, container/clourse  Stability data in tables or graphs or both  Evaluation – Justify parameters tested (OoS, OoT discussion) – Statistical analysis, if necessary  Conclusions – Proposed retest date for drug substance – Proposed shelf-Life, if applicable – Proposed storage condition

29. CPH training | January 2012 29 | API Stability: Evaluation  Collect information  The innovator (e.g. EPAR)  Literature  Prequalified products  APIMFs  Confirm the number of batches, batch size, packaging, storage conditions, test frequencies, specification.  Review the stability results.  For an API, “significant change” is failure to meet the specification for any parameter

30. CPH training | January 2012 30 | API Stability: Evaluation  Begin with any significant change at the accelerated condition, and  the intermediate condition, if appropriate  then, review the trends and variability of the long-term data  Establish re-test and storage condition  Refer ICH Q1E appendix A decision Tree for any extrapolation

31. CPH training | January 2012 31 | API Stability: Evaluation Extrapolation of data: Extend the retest period or shelf life beyond the period covered by long- term data A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data as soon as these data become available.

32. CPH training | January 2012 32 | API Stability: Evaluation  No significant change at accelerated condition (6 months )  Little/no change and little/no variability for accelerated and long term data  statistical analysis is unnecessary X= Period covered by long-term data Y= proposed retest period or shelf life intended for storage at 25ºC or 30ºC intended for storage at refrigerator 2-8 ºC Y= 2X but NMT X + 12 months Y= 1.5X but NMT X + 6 months

33. CPH training | January 2012 33 | API Stability: Evaluation  No significant change at accelerated condition (6 months )  Change and/or variability observed for accelerated and/or long term data  Extrapolation may be proposed by providing Statistical analysis and/or relevant supporting data * * Satisfactory long term data from development batches (with a closely related formulation, packaged in similar container closure system, smaller scale than the primary batches)

34. CPH training | January 2012 34 | API Stability: Evaluation  Significant change at accelerated condition, but  No Significant change at intermediate condition  Extrapolation may be proposed by providing Statistical analysis and/or relevant supporting data

35. CPH training | January 2012 35 | API Stability: Evaluation  Significant change at accelerated condition, And  Significant change at intermediate condition  No extrapolation is allowed  In addition, a shorter retest period or shelf life than the period covered by long term data could be called for.

36. CPH training | January 2012 36 | API Stability: Evaluation For products intended for storage in a refrigerator (no intermediate)  Significant change at accelerated condition  No extrapolation is allowed  In addition, a shorter retest period or shelf life than the period covered by long term data could be called for.  If significant change occurs within the first 3 months' accelerated testing, a discussion should be provided to address the effect of short –term excursions

37. CPH training | January 2012 37 | API Stability: Evaluation Definition: re-test period The period of time during which the API is expected to remain within its specification, provided that the API has been stored under the defined conditions. After this period 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. Example: rifampicin

38. CPH training | January 2012 38 | API Stability: Stability Commitments  Primary stability study commitment When available long-term stability data on primary batches do not cover the proposed re-test period.  Commitment stability studies The long-term stability studies on at least three production batches. To determine that the API remains and can be expected to remain within the re-test period in all future batches.

39. CPH training | January 2012 39 | API Stability: Stability Commitments 1) A stability commitment is required when long term data does not cover the proposed re-test period. “The Applicant should undertake in writing to continue long-term testing of for a period of time sufficient to cover the whole provisional retest period and to report any significant changes or out-of- specification results immediately to WHO for the following batches : ”

40. CPH training | January 2012 40 | API Stability: Commitments 2) A stability commitment is required when data was not provided on three production scale batches. “Since stability data on three production scale batches were not provided with the application, the remaining number of consecutive production scale batches should be put on long-term stability testing. Any significant changes or out-of-specification results should be reported immediately to WHO. The approved stability protocol should be used for commitment batches.”

41. CPH training | January 2012 41 | API Stability: Commitments  Stability protocol should follow the same as primary batches but may change in batch numbers, batch size. Any differences in the stability protocols used for the primary batches and those proposed for the commitment batches should be scientifically justified.  In general, we do not request submission of the commitment results. But to report immediately for any OOS, OOT. The reports should be available for inspection. Therefore, a signed and dated commitment is requested and should be recorded.  When submitting post approval variations, e.g. extension shelf life, change in batch size, the data of commitment batches may be requested.

42. CPH training | January 2012 42 | API Stability Statements/Labelling  All containers should be clearly labeled with at least:  name of the material  batch number  expiry date or retest date  specified storage conditions  Name and address of the manufacturer (main generic G)  Recommended labeling statements provided in Appendix 3 of the New Guide.

43. CPH training | January 2012 43 |  b :"protect from moisture" should be added if applicable

44. CPH training | January 2012 44 | Example #1 API Re-test and Shelf-life Problem: The applicant has proposed a 12 month re-test period and a 48 month expiration period. They have provided data to support the re-test period, but not the shelf-life. Now what? Approach: Except in exceptional situations, the shelf-life is not required and is considered an extra assurance. Since a re-test period is defined, the applicant must re-test the API immediately prior to its use once the re-test period has been exceeded. The re-test period, which is supported by data, is approved.

45. CPH training | January 2012 45 | Example #2 No Accelerated Data Problem: Data is provided over the retest period at long-term conditions. No data is provided at accelerated conditions. The applicant argues that accelerated data is not necessary because long-term data covers the proposed retest period. Approach: Accelerated data is not only to support extrapolation, it is also to cover excursions outside the long-term storage conditions. Accelerated data is always required to support a retest or shelf-life period.

46. CPH training | January 2012 46 | Example #3 Extrapolation  6 months at 40ºC/75% data: no significant change observed  18 months data at 30 ºC75%, show little change and little variability.  What 's the maximum allowed retest period and storage condition?  X=18, the longest period allowed is up to 2X ( 36 months), but Not more than X + 12= 30 months

47. CPH training | January 2012 47 | Common Deficiencies These deficiencies are commonly encountered and lead to questions and delays in approval of a re-test period: 1.Failure to state the size of the lots used in the trial. 2.Failure to describe clearly the packaging used in the trial and to confirm whether it is identical to the proposed packaging. 3.Failure to accumulate stability data on the required number of lots. 4.Failure to define accurately the temperature and humidity conditions applied during the trial. ±2◦C, ±5%RH

48. CPH training | January 2012 48 | Common Deficiencies 5.Failure to fully describe test methods. 6.Failure to provide validation of analytical methods. 7.Expression of results as passes test or similar when a quantitative figure would be available. 8.Failure to include quantitative or semiquantitative determinations of the content of degradation products, or to provide only total content rather than values for individual impurities. 9.Use of an HPLC assay procedure to detect impurities without validation for the purpose.

49. CPH training | January 2012 49 | Common Deficiencies 10.Failure to comment or conduct additional tests when there is a lack of mass balance between the formation of degradation products and the loss of the active substance. For example, are the assay procedures sufficiently specific? Is the API volatile? Is it adsorbed on to the container wall? 11.Failure to conduct additional tests to investigate the significance of obvious alterations in the characteristics of the product. For example a distinct change in the colour of the product may necessitate additional investigation for degradation products. 12.Failure to discuss any OoS or OoT results

50. CPH training | January 2012 50 | Common Deficiencies 13.Failure to include information on the physical characteristics of the product during storage, such as particle size etc when considered critical attributes. 14.Failure to provide results from intermediate time stations to facilitate assessment of any trends in the parameters measured, when significant change is noted at accelerated conditions. 15.Attempting to extrapolate data obtained in the trial beyond reasonable limits.

51. CPH training | January 2012 51 | Thank you for your attention!