1. FPP Stability Lynda Paleshnuik Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2 |2 | Overview Selection of Batches Container Closure System Specifications: Stability-indicating quality parameters Testing Frequency Storage Conditions

3. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 3 |3 | Overview FPP Stability Commitment Evaluation/Extrapolation of data Statements/Labelling In-use Stability

4. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 4 |4 | Overview Variations Ongoing Studies Assessment Tips Common stability deficiencies

5. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 5 |5 | FPP Stability Selection of Batches Main Guide: NLT 3 (1 production and 2 at least pilot- scale) New Guide = Q1A: NLT 3 (2 at least pilot, 1 can be smaller*); New Guide only: NLT 2 pilot for conventional FPP with stable API. *if it is representative of production batches with regard to critical manufacturing steps

6. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 6 |6 | FPP Stability Selection of Batches Main Guide: COA’s should be provided, plus composition, batch size, batch # and manufacturing date. Main Guide = New Guide: - Each strength and container type/size should be studied unless bracketing/matrixing is applied. (Q1D) - FPP batches should use different lots of API where possible; - Batches should be as proposed re: –Formulation –Container/closure system –Manufacturing process simulates production process

7. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 7 |7 | Example problem Problem: Tablets have undergone significant formulation changes. Applicant provides many stability studies, using batches of both the previous and current formulations. The assessor doesn’t check which studies use the current formulation, decides some studies are redundant, arbitrarily chooses which studies to review. (Proposed formulation compared to BE: reduction of starch, binder change from PVP to gelatin) Result: Some studies reviewed were irrelevant or could be used as “supporting data only”. Some relevant studies were not reviewed.

8. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 8 |8 | FPP Stability Container/Closure Main Guide = New Guide = Q1A Should be the container proposed for marketing including any secondary packaging. If the same container is proposed in different sizes (container or fill size), bracketing may be applied. (Q1D)

9. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 9 |9 | FPP Stability Stability-indicating quality parameters Monitor parameters susceptible to change: Physical (description, moisture, quality parameters (DT, dissolution)); Moisture is particularly important for solid orals in blisters and strips. Chemical (assay, degradants, preservatives); Efficacy of additives, AMPE; Container/closure interactions, when applicable;

10. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 10 | FPP Stability Stability-indicating quality parameters The New Guide is in agreement with Q1A, plus includes Appendix 2, “Examples of Testing Parameters” for various FPP’s. More details on parameters and reporting of results are in Main Guide and Supplement 3. All three guides include the requirement: A single primary batch should be tested for AMPE at the proposed shelf-life.

11. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 11 | FPP Stability Testing Frequency Long term (Not in Main Guide) Q1A, New Guide: Year 1: every 3 months Year 2: every 6 months Subsequent years: annually Accelerated (Main Guide, Q1A, New Guide): Minimum three points including t 0 and t final, eg 0, 3, 6. Intermediate (Main Guide, Q1A, New Guide): Four points including t 0 and t final, eg 0, 6, 9, 12. Matrixing or bracketing may be applied if justified.

12. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 12 | FPP Stability Storage Conditions The New Guide mentions storage with: “due regard to the climatic conditions in which the product is intended to be marketed”, and discusses storage facility equipment tolerances.

13. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 13 | FPP Stability Submission Requirements At time of submission: FPP’s containing one stable API: (see S2) 6 months at 40◦C/75% 6 months at 30◦C/65%* Other FPP’s: 6 months at 40◦C/75% 12 months at 30◦C/65%* *It is preferred that long term studies be conducted at 30◦C/75% (Supp3). See “Evaluation”.

14. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 14 | FPP Stability Submission Requirements At time of submission: FPP’s for 2 nd line TB products 3 months accelerated and 3 months at long term on not less than 2 pilot scale batches (Data required at time of submission only. Requirements for prequalification remain the same.)

15. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 15 | FPP Stability Storage Conditions General Requirements (New Guide) Long-term: 25◦C/60%, 30◦C/65% or 30◦C/75% (25◦C/60% and 30◦C/65% are indicated in the Main Guide) Intermediate: 30◦C/65% = Main Guide Accelerated: 40◦C/75% = Main Guide Main Guide (2005): “Unless otherwise justified, 30°C ± 2°C/65% RH ± 5% RH is the real-time condition for the prequalification project.” (API and FPP)

16. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 16 | FPP Stability Storage Conditions Storage conditions for aqueous-based products in semi- permeable containers are the same in the Main Guide and New Guide/Q1A except for long-term study conditions: New Guide/Q1A: 25◦C/40% or 30◦C/35% Main Guide: 25◦C/40% or 30◦C/65%

17. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 17 | FPP Stability Storage Conditions For products to be stored in a refrigerator, freezer or below -20◦C, see Q1A and the New Guide (not in Main Guide). The New Guide includes tables as per Q1A, with the addition of the Zone IV storage (30◦C/75% for general case, 30◦C/65% and 30◦C/75% for accelerated conditions for refrigerated storage, 30◦C for freezer), and reduced minimum times for stable drugs.

18. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 18 | FPP Stability Storage Conditions Q1A leaves long-term conditions up to the applicant; the New Guide states it should be as per the zone “in which the FPP is intended to be marketed”. Under “FPP’s in impermeable containers”, the New Guide gives guidance as to how materials are classified as permeable or impermeable. (Not in Main or Q1A) (eg glass ampoules)

19. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 19 | FPP Stability Storage Conditions FPP in semi-permeable containers: The New Guide includes a complicated discussion of when water loss is a significant change (similar to Q1A). The New Guide also includes the Q1A section, “Example of an approach for determining water loss”. (The New Guide includes the calculations, which are absent in Q1A.)

20. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 20 | Example Problem During the assessment period: “Additional data accumulated during the assessment period of the registration application should be submitted… if requested.” [Main Guideline, Q1, New Guide]

21. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 21 | Example Problem HAxxx FDC: Proposed expiry 24 mo in bottles/blisters. First assessed Nov/07; 3 batches stated to be on stability; no summary of data in report, and according to batch manufacturing dates, the batches could only be 7 mo old. Updated data requested. Response reviewed July/08, at most 12 mo would be available. Report does not indicate the length of data provided. Applicant states only data in bottles is being provided, but assessor’s summary mentions both bottles and blisters. A provisional 24 mo expiry is accepted. Three comments went out, updated stability data was not requested. Response reviewed Sept/08; four comments went out, no request for updated stability.

22. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 22 | Example Problem Response reviewed Nov/08; the company is now mentioning potency drops (both API’s) of 5.5% and 6% (LT 2% observed in the only assessment report summary), for 6mo accelerated/12 mo LT studies, packaging unknown. No updated data was requested in previous 2 letters therefore none provided, and can’t verify in reports if data in both packages has been assessed. Batches would only be 18 mo old now. LT conditions are 30◦C/75% (according to first report), therefore there is no intermediate condition, and significant change should result in no extrapolation beyond long term data. The request for all updated data now goes out.

23. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 23 | Example Problem Updated stability data in all packaging formats should always be requested if there are other significant comments going out, unless the data provided covers the proposed shelf-life.

24. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 24 | Intermediate Conditions Data should be submitted at intermediate conditions when ‘significant change’ is observed at accelerated conditions. Note that there is no intermediate condition when long term conditions are 30◦C/65% or 30◦C/75%. See “Evaluation”.

25. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 25 | “Significant Change” For an FPP, significant change is any of: - failure of any parameter to meet the limits (exceptions next slide); - GT 5% change in assay from initial; - failure to pass S2 or L2 dissolution testing, ie n=12 (solid orals - exception next slide);. For FPP’s in semi-permeable containers, a 5% loss of water from initial (3 mo at 40◦C/25%) is significant change.

26. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 26 | “Significant Change” Exceptions: (Q1A/Q1E/New Guide): Some physical changes may be expected under accelerated conditions: - softening of suppositories (those intended to melt at 37◦C), melting of creams (but not phase separation), adhesion loss of transdermals. Also, for gel caps or gelatin-coated tablets, S2/L2 dissolution failure is not a significant change if there is an established link to cross- linking.

27. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 27 | FPP Stability Photostability Studies Main Guide: Data should be conducted on at least one primary batch of the FPP; see Q1B. (New Guide and Q1A state one batch, “if appropriate”.) Note: for PQP, if PhInt, USP or BP, states in the monograph for the FPP, "Protect from light", photostability data is not required.

28. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 28 | FPP Stability Other Stress Studies Compatibility studies: Main Guide 3.2.1: API-excipient and API-API. For FDC’s: TRS 929 appendix 3 Table A.1 (2005) and Supplement 2 (2006): 1) possible conditions for stress testing (API-API and API- excipient) 2) a format for reporting the results. NB: Q1A and the New Guide do not mention compatibility studies.

29. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 29 | FPP Stability Commitment Long-term data is required to confirm the proposed shelf- life. Main Guide, 3.11.1 and New Guide: When available long-term stability data on primary batches do not cover the proposed shelf-life period granted at the time of approval, a commitment should be made to continue the stability studies post approval in order to firmly establish the shelf-life period. The post-approval stability protocol for commitment batches should also be provided and should be the same as that for the primary batches, unless otherwise scientifically justified.

30. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 30 | FPP Stability Commitment New Guide/Q1A: Various scenarios are outlined as to when a commitment is required. A commitment is required in all three Guides unless long- term data on batches* was provided covering the proposed shelf- life. *For the commitment, note that the Main Guide refers to primary batches, whereas the New Guide and Q1A refer to production batches. Main Guide - primary batches: 3 batches, at least one production, the other two at least pilot (See 3.11.3). New Guide - 2 production (stable) or 3 production (not stable). Q1A – 3 production batches.

31. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 31 | FPP Stability Evaluation Purpose: to establish shelf-life and storage conditions. Main Guide: in agreement with Q1A. The New Guide includes statements from Supplement 2 for accepting a 24 month expiration. Examples follow.

32. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 32 | FPP Stability Evaluation Case 1: FPP is hard capsule or tablet containing a single stable (as per S2) API: A two year shelf-life can be assigned based on results of 6 months accelerated and 6 months long-term data, when all conditions in S2 are met. Storage conditions are based on long term study conditions.

33. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 33 | FPP Stability Evaluation Case 2: FPP-FDC is hard capsule or tablet containing multiple stable (as per S2) APIs: A two year shelf-life can be assigned based on results of 6 months accelerated and 6 months long-term data, when all conditions in S2 are met, including API-API compatibility studies.

34. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 34 | FPP Stability Evaluation Case 3: Data is provided for 12 months at 25◦C/60% and 6 months at 40◦C/75%. No significant change is noted. A shelf-life of 24 months (12 months + 12 months) can be assigned. Storage statement “Do not store above 25◦C” is required.

35. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 35 | FPP Stability Evaluation Case 4: Data is provided for 18 months at 30◦C/65% and 6 months at 40◦C/75%. Significant change is noted at 40◦C/75%. There is no intermediate storage condition.* A shelf-life of 18 months can be assigned. The shelf-life is based on real time data due to significant change observed at accelerated conditions. Storage statement “Do not store above 30◦C”. *See Q1A and New Guide under, “storage in a refrigerator” for guidance on approach when significant change is observed at accelerated conditions, when there is no intermediate storage condition.

36. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 36 | FPP Stability Evaluation Case 5: The applicant provides long term studies at 30◦C/65% that cover the proposed shelf-life, but no accelerated data. They state that accelerated data is unnecessary because long term data covers the shelf-life. Accelerated data is to cover “the effect of short term excursions outside the label storage condition, eg during shipping or handling”. Accelerated data should be submitted or the shelf-life cannot be granted.

37. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 37 | FPP Stability Evaluation Examples Related example: Product is to be stored in refrigerator. Refrigeration by the patient is recommended but not required if used within 30 days and stored below 25°C. The applicant only provided 30 days stability studies at 25◦C. Solution: 25°C is the accelerated condition for this product, and 6 months data is required regardless of the in-use intentions.

38. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 38 | FPP Stability –Example: Calculation of Shelf-life FPP with 24 month expiry includes premix with proposed 12 month expiry. Comment out (revised somewhat): “ It should be remembered that use of a PREMIX approaching its 12 months expiry period will result in a finished product with less than 12 month expiry period. In addition, shipment and distribution will further reduce the use period and may lead to financial losses if finished product is not used during the assigned shelf-life period. ”

39. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 39 | FPP Stability –Example: Calculation of Shelf-life “ You are requested to confirm your understanding of the definition of the starting point for the expiration period of a product, as the date of the production step of first mixing of the API with excipient(s). In order to qualify a 12 month expiration for the premix, the stability data required to establish a 24 month expiration of the FPP is a study on the FPP (3 batches), manufactured with premix at the maximum age (ie 12 months old), stored at ICH conditions for the period of time desired for the shelf-life product after release. For example, 24 month data on the FPP (produced with 12 month old premix) would be required to support an intended 24 month shelf-life for the product (from time of release). ” Company responded by reducing hold time of premix to 6 mo.

40. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 40 | FPP Stability Extrapolation of Data If data (6 mo acc/x mo LT) is within specifications with no significant change at accelerated conditions, the allowed shelf-life is double the long-term period x, but NMT x + 12 months. [In Main Guide but not in Q1A or New Guide. This is a generally accepted practice.] In PQP, a shelf-life greater than 24 months must be supported by real-time data on production batches.

41. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 41 | FPP Stability Statements/Labelling Storage conditions depend on the stability results and the conditions of long-term testing.

42. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 42 | FPP Stability Statements/Labelling Main Guide: (Not in Q1A or New Guide) 1)If no significant change was observed at 40◦C/75% and 30◦C/65%, the SmPC and PIL should state, “This FPP does not require any special storage conditions.” 2) If long-term storage was at 30◦C/65% and significant change was observed at 40◦C/75%, the SmPC/PIL should state, “Do not store above 30◦C” or “Store below 30◦C”. 3)If long-term storage was at 25◦C/60%, the SmPC/PIL should state, “Do not store above 25◦C” or “Store below 25◦C”. In New Guide and Main Guide, additional statements are required where protection from low temperatures is necessary or storage in refrigerator/freezer is required.

43. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 43 | FPP Stability Statements/Labelling New Guide: 1)The statement “This FPP does not require any special storage conditions” is not an option. 2)Statements, “Store below…” are no longer an option. Statements are, “Do not store above…” long-term storage conditions, or store in refrigerator/freezer when relevant. 3) Additional labelling statements are described where stability testing shows limiting factors, eg hygroscopic FPP’s, FPP’s cannot tolerate certain factors. See Appendix 3 to the New Guide.

44. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 44 | FPP Stability In-use studies In-use studies are for FPP intended to be diluted/reconstituted. (multi-use FPP) The New Guide has a separate section on In-Use Studies (2.2.10), and specifies using two different batches (at least pilot), one near the end of its shelf-life. Main Guide also specifies two batches, but not their size. (# of batches not specified in Q1A) NB: there is no in-use requirement (eg labelling “use within 30 days”) for dispersible tablets; a single dose is intended to be dispersed just prior to use.

45. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 45 | Stability - Variations The variation guideline (Annex 6 of TRS 943, 2007) Appendix 1 (minor changes) and Appendix 2 (major changes) should be considered along with: Appendix 4: “Stability-requirements for variations and changes to prequalifed FPPs”

46. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 46 | Stability – Variations Minor Changes API variations requiring new/additional stability data: #15: Change in re-test or storage conditions; requires data on 2 batches (at least pilot size), covering the requested period or storage condition.

47. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 47 | Stability-Variations Minor Changes FPP variations requiring new/additional stability data: #16: Change in excipient; requires 3 months accelerated and long-term data on 2 batches (at least pilot size).* #26: Change in primary packaging; requires 3 months stability data on 2 batches (at least pilot size).* #29: Change in batch size; #30: minor change in manufacture; require 3 months stability data on 1 batch (at least pilot size).* *Data must be available and must be provided if OOS.

48. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 48 | Stability-Variations Minor Changes #31: change in colour/flavour; requires 3 months stability data on 2 batches (at least pilot size). Photostability testing may be required.* #32: change in tablet coat weight/capsule shell weight; #33: change in headspace/surface-volume ratio of container; requires 3 months stability data on 2 batches (at least pilot size).* *Data must be available and must be provided if OOS.

49. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 49 | Stability-Variations Minor Changes #38: change in pack size; requires written commitment that studies will be conducted in accordance with WHO guidelines where stability parameters may be affected. #39: change in shelf-life or storage conditions; results of real-time studies on two production batches. Where appropriate, microbial testing should be included.

50. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 50 | Stability – Variations Minor Changes Appendix 4: Results of studies above should be compared to the results of studies on unchanged API/FPP.

51. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 51 | Example Situation There is a change, such as removal of scoreline. Check the variation guideline if unsure whether stability data would be required – find a similar scenario. Note that there are very few situations where stability data is requested outright. (HC guideline for change in score requires 1 st production batch to be added to stability protocol.)

52. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 52 | Stability – Variations Major Changes Examples: Change in manufacturing process of API Change in composition of FPP Change in immediate packaging of FPP See Appendix 4 of Variation Guide for discussion of requirements.

53. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 53 | FPP Stability Ongoing studies In New Guide only (not Main or Q1A): 2.2.12: “at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none is produced during that year).” The protocol should be provided.

54. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 54 | Assessment Tips 1) If a lot of data is submitted, check packaging, batches, conditions studied. Check that batches tested are relevant, ie are production or pilot as required, and if there have been formulation changes, confirm that they are the correct formulation (for eg by searching the reports for the batch #’s). If unclear, pose comment for clarification. 2) Stability-indicating parameters only – others such as identity, residual solvents, content uniformity are not relevant and do not need to be summarized.

55. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 55 | Assessment Tips Recognizing problem areas that warrant a closer look/more questions. Eg. Data is provided in such a way that a) trends cannot be determined, eg range of dissolution values but no average, or b) limits cannot be assessed, eg average dissolution but no range of individual values. Eg. Data shows a lack of mass balance, or variability in results without trends - may indicate problems with analytical methods.

56. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 56 | Assessment Tips When summarizing/discussing stability data, always: a) Reiterate the retest/shelf-life declared by the applicant and what has been considered acceptable by assessment of the data, b) State what shelf-life is actually declared in the labelling such as SmPC, and on the API/FPP specifications, c) Clearly state the actual length of data in the various packaging formats and storage conditions which was provided/assessed. d) Include the limits with reporting of results.

57. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 57 | Common Deficiencies These deficiencies are commonly encountered and lead to questions and delays in approval of a shelf life: 1. Failure to specify the formulations used in the trial, and to state which batches are identical to the proposed formulation. 2. Failure to state the size or scale of the batches used in the trial. 3. Failure to describe clearly the packaging used in the trial and to confirm whether it is identical to the proposed pack.

58. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 58 | Common Deficiencies 4. Failure to accumulate stability data on the required number of batches of the product. 5. Failure to define accurately the temperature and humidity conditions applied during the trial. 6. Failure to fully describe test methods and sample sizes. 7. Failure to provide validation of analytical methods.

59. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 59 | Common Deficiencies 8. Expression of results as passes test or similar when a quantitative figure would be available. 9. 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. 10. Use of an HPLC assay procedure to detect impurities without validation for the purpose. HPLC assay procedures as used for determination of the API are often unsuitable for separation and detection of impurities as they use too short a run time. Such a procedure would be acceptable if validated for impurity detection. Note, however, that long run times do not in themselves ensure good separation.

60. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 60 | Common Deficiencies 11. 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? 12. 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. 13. Failure to include information on the physical characteristics of the product during storage, such as dissolution characteristics, homogeneity, particle size etc.

61. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 61 | Common Deficiencies 14. Failure to include stability studies under conditions of high humidity for products that are to be registered in moisture- permeable containers, and especially for those which are potentially labile to moisture (for example, many antibiotics). 15. Failure to provide results from intermediate time stations to facilitate assessment of any trends in the parameters measured. 16. Failure to provide results for individual dosage units where these are available (for example, dissolution profiles). 17. Attempting to extrapolate data obtained in the trial beyond reasonable limits.

62. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 62 | Questions?