1. Slide 1 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Training Workshop for Evaluators from National Medicines Regulatory Authorities in East African Community Dar Es Salaam, Tanzania Date: 10 to 14 September 2007 Evaluation of Quality and Interchangeability of Medicinal Products

2. Slide 2 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Evaluation of Quality and Interchangeability of Medicinal Products Finished Pharmaceutical Products  Stability/Shelf-life specification  Matrixing and bracketing Presenter: Deus K. Mubangizi, pharmacist, MSc(Pharm.) deuskm@yahoo.co.ukdeuskm@yahoo.co.uk, dmubangizi@nda.or.ugdmubangizi@nda.or.ug Chief Inspector of Drugs, National Drug Authority WHO expert

3. Slide 3 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.1.Manufacturing and marketing authorization 3.2.Pharmaceutical development 3.3.Formulation 3.4.Sites of manufacture 3.5.Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7.Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

4. Slide 4 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.12. Container labelling 3.13.Product information for health professionals 3.14.Patient information and package leaflet 3.15.Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

5. Slide 5 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing The purpose of stability testing is to provide evidence on how the quality of a FPP varies with time under the influence of a variety of environmental conditions such as temperature, humidity and light and to establish a shelf-life for the FPP, to determine the storage conditions and the in-use stability. To know about length of the time and conditions where efficacy, safety and quality of the FPP are maintained

6. Slide 6 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing  Lots included in the study: 1 production batch and 2 of pilot scale manufactured according to the process described in the dossier  Pilot scale batch for solid dosage forms is 10% of production scale or 100 000 whichever is greater  Parameters susceptible to change over storage should be followed: Organoleptic properties Assay of each API: ±10% of the label claim possible at the end of shelf-life Assay of degradation products Assay of antioxidants and chemical preservatives, check also for their efficacy Dissolution testing (limits should remain unchanged to release) Microbial contamination, sterility, bacterial endotoxins  In-use stability data (if applicable)

7. Slide 7 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing  Study should be performed in the claimed commercial packaging (container-closure)  Storage conditions and frequency of testing according to ICH Q1A(R2)  Minimum stability data to be submitted at time of submission: 12 months long term ICH 25°C/60% RH, 12 months intermediate ICH 30°C/65% RH and 6 months accelerated ICH 40°C/75% RH with exception according to Supplement 2 to the Main Generic guide  Unless otherwise justified, 30°C / 65% RH is the recommended storage condition for Prequalification  Definition of "significant change" is the same as ICH Q1A (R2) see later slide

8. Slide 8 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP) 3.11. Stability testing  Case of products packed in semi-permeable containers foreseen (liquid dosage forms susceptible to loss of solvent or water loss in low relative humidity condition). The storage condition will be long term ICH 25°C / 40% RH and accelerated 40°C/25% RH  Extrapolation of data to accord a longer shelf-life possible according to ICH Q1E + Supplement 2 in condition of commitments  Supplement 2: tentative 2 year re-test period and /or shelf-life may be accorded to APIs and corresponding solid forms (tablets and capsules) listed in Supplement 2 based only on 6 months accelerated data and 6 months long term data  Long term stability should anyhow be followed to cover the whole shelf-life accorded

9. Slide 9 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 SPECIFICATIONS  Should include those attributes that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy  Should cover as appropriate, the physical, chemical, biological and microbiological attributes, preservative content and functionality tests (e.g. for a dose delivery system)  Analytical procedures should be fully validated and stability indicating  Shelf life acceptance criteria should be derived from consideration of all available stability information

10. Slide 10 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 SPECIFICATION cont’  Justifiable differences between the shelf life and release acceptance criteria based on evaluation of stability data and changes observed on storage  Any differences between release and shelf life acceptance criteria for antimicrobial preservative content to be supported by development data  A single, primary stability batch should be tested for antimicrobial preservative effectiveness (in addition to preservative content) whether there is a difference between the release and shelf life acceptance criteria for preservative content or not

11. Slide 11 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 TESTING FREQUENCY  Long-term conditions : every 3 months over the first year, every 6 months over the second year and annually thereafter  Accelerated storage conditions: minimum of 3 points including the initial and final time points (e.g. 0, 3, & 6 months) from a 6-month study  When testing at the intermediate storage condition is called for as a result of significant at the accelerated storage condition, a minimum of 4 time points, including the initial and final time points (e.g. 0, 6, 9 & 12 months) from a 12-month study is recommended.  Reduced designs i.e. matrixing or bracketing can be applied, if justified

12. Slide 12 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 STORAGE CONDITIONS  Thermal stability, and if applicable, sensitivity to moisture or potential for solvent loss  The storage conditions and lengths of studies chosen to cover storage, shipment and subsequent use  Stability testing of the finished product after constitution or dilution to labelling, storage condition and in-use period of the constituted or diluted product  Long term studies : minimum of 6 months duration (1 st option) and 12 months (2 nd option) at the time of submission and should be continued for a period of time sufficient to cover the proposed shelf life

13. Slide 13 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 STORAGE CONDITIONS cont’ General Case STUDYSTUDY CONDITIONMIN TIME PERIOD Long term*25±2 º C/60±5%RH or6 months (option 1) 30±2 º C/65±5%RH 12 months (option 2) Intermediate 30±2 º C/65±5%RH 6 months Accelerated 40±2 º C/75±5%RH 6 months * It is up to applicant to decide whether long term stability studies are conducted at either of the conditions. If 30±2 º C/65±5%RH is chosen, then no additional data under intermediate conditions will be generated

14. Slide 14 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 STORAGE CONDITIONS cont’ If “significant change” occurs under accelerated studies, additional testing at the intermediate storage condition required  A “significant change” can be defined as –A 5% change in assay from its initial value –Any degradation product exceeding its acceptance criterion –Failure to meet acceptance criteria for appearance, physical attributes, or functionality tests (e.g. colour, phase separation, resuspendability, caking, hardness, dose delivery per actuation) Some changes in physical attributes (e.g. softening of suppositories, melting of creams, partial loss of adhesion for transdermal products) may be expected under accelerated conditions

15. Slide 15 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 IN-USE STABILITY TESTING  The content of multi-dose containers, due to repeated opening and closing  A minimum of 2 batches, at least pilot scale batches, should be subjected to the test. At least one should be chosen towards the end of its shelf-life  Test design should simulate the use of the product in practice including fill volume, dilution/constitution before use  The determined in-use shelf life should be stated on the label

16. Slide 16 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 IMPERMEABLE CONTAINERS  Sensitivity to moisture or potential for solvent loss is not of concern as there is a permanent barrier to passage of moisture or solvent  Therefore stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity conditions

17. Slide 17 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 FFP IN SEMI-PERMEABLE CONTAINERS  Aqueous based products packaged in semi-permeable containers should be evaluated for potential water loss  Studies should be carried out at low relative humidity to demonstrate that container can withstand low relative humidity environments A 5% water loss is considered significant after an equivalent of 3months at 40±2 º C/ NMT 25%RH; however for small container i.e. 1ml or unit-dose products, this may be appropriate if justified

18. Slide 18 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 FFP INTENDED FOR REFRIDGERATOR STORAGE STUDY STUDY CONDITIONS MIN. TIME PERIOD Long term 5 ± 3 º C6 months (option 1) 12 months (option 2) Accelerated 25±2 º C/60±5%RH6 months Significant change after 3-6months under accelerated the proposed shelf life should be based on real-time data Discussion should be provided to address the effects of short term excursions e.g. during shipment supported by testing of a single batch for a period shorter than 3 months but with more frequent testing than usual

19. Slide 19 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 STABILITY COMMITMENT  When available long-term stability data does not cover the proposed shelf life, a commitment should be made to continue stability studies in order to firmly establish the shelf life –Such data should be submitted once available  Where the data submitted is from fewer than 3 production batches, a commitment should be made to continue the long-term studies with additional production batches, to a total of at least 3  If the submission does not include data on production batches, a commitment should be made to place the first 3 production batches on long-term studies through the proposed shelf life and through 6months of accelerated study conditions

20. Slide 20 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 EVALUATION  A systematic approach to presentation and evaluation of the data  Degree of variability of individual batches to be evaluated  Where the data show little degradation and variability that it is apparent from looking at the data that the requested shelf life can be granted, it is not necessary to go through formal statistical analysis  Evaluation should not be limited to assay, but consideration of degradation products, appropriate attributes, adequacy of the mass balance and different stability and degradation performance

21. Slide 21 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 Extrapolation of data Limited extrapolation of the real-time data from long-term studies beyond the observed range to extend the shelf life may be applied on condition that: - mechanisms of degradation are known - results of accelerated stability testing are available - there is goodness of fit of any mathematical model to be used - supporting stability data exists The assumption is that the same degradation relationship will continue to apply beyond the observed data

22. Slide 22 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 SHELF LIFE  The expiration period of a product should be calculated from the date of release of that batch  The date of release should, under normal circumstances, not exceed 30days from the date of production  If batches are released exceeding 30days from the production date, the date of production i.e. the date that the first step is performed involving combining the active with the other ingredients, should be taken as the start of the shelf life

23. STABILITY TESTING – BRACKETING & MATRIXING

24. Slide 24 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 INTRODUCTION  It is possible to reduce the scheduled test points where the stability of the samples tested represents the stability of all the products in the range being assessed  This allows the saving of resources whilst providing acceptable proof of stability

25. Slide 25 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 DEFINITIONS  BRACKETING The design of a stability schedule such that at any time point, only the samples on the extremes e.g. of container size and/or dosage strengths are tested. The design assumes that the stability of the intermediate condition samples is represented by the extremes  MATRIXING The statistical design of a stability schedule so that only a fraction of the total number of samples are tested at any specified sampling point. At a subsequent sampling point, different sets of samples of the total number would be tested. The design assumes that the stability of the samples tested represents the stability of all the samples

26. Slide 26 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 PRECONDITIONS  The concept of using a reduced testing plan is acceptable only for products which are closely related  Where either bracketing or matrixing are used, the stability testing protocol should be justified by making use of stability data for both the API and the finished product  To justify bracketing around batches, it should be shown that batch to batch variability is small  It should be implied that not all the batches have to be started simultaneously i.e. the batches could be staggered compared to each other and the start of analysis

27. Slide 27 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 APPLICATION  BRACKETING Can be used for the testing of a new drug product available in 3 different strengths, in 2 types of packaging material and for one of these types, three different pack sizes PACK TYPE DOSAGE STRENGTH 50MG 75MG 100MG A B C A B C A B C Blisterx x x (x) (x) (x) x x x HDPE/15x x x (x) (x) (x) x x x HDPE/100(x) (x) (x) (x) (x) (x) (X) (x) (x) HDPE/500 x x x (x) (x) (x) x x x

28. Slide 28 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 APPLICATION  MATRIXING –It provides a systematic test protocol which ensures that ALL product strengths, types of packaging materials, pack size etc, are tested to THE SAME EXTENT. –Unlike bracketing, none of the product strengths, pack sizes, or product variants are excluded from testing –The applicant should demonstrate that the design is valid and will ensure that the testing of all variables is approximately evenly distributed (use of statistical programs)

29. Slide 29 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 ACCEPTANCE  It will normally be acceptable to apply bracketing or matrixing in the following cases: Strength (small or no change in proportion of ingredients); strength (where these are applied simply changing/varying the amount of active and one or two major ingredients); container size (same contact materials); closure systems of demonstrated equivalence; different manufacturing sites (same company); batch size  In the following cases applying matrixing will normally be acceptable Strength (significant change in proportion of ingredients or change in one or two minor components; orientation of container; fill volumes of containers; containers (different contact materials); closure systems (non-equivalent performance); manufacturing process; manufacturing site (different company)

30. Slide 30 of 30D.K. Mubangizi, Dar Es Salaam Sept. 2007 THANK YOU