Alaa Khedr Ph.D . Professor Faculty of Pharmacy King Abdulaziz University

1. AlaaKhedr Ph.D. Professor Faculty of Pharmacy King Abdulaziz University E-mail: akhedr@kau.edu.sa كلية الصيدلة R aculty of Pharmacy F بسم الله الرحمن الرحيم اللهم صلي وسلم على سيدنا محمد STABILITY STUDY and EXPIRATION DATE

2. Abbreviations API Active Pharmaceutical Ingredient FDC Fixed-Dose Combination FPP Finished Pharmaceutical Product GMPGood Manufacturing Practices ICHInternational Conference on Harmonization MA Marketing Authorization DRA Drug Regulatory Authority MCA: Medicine Control Agency FDA: Food and Drug Administration NDA: New Drug Applications ANDA: Abbreviated New Drug Applications EU: European Union EMEA: European Medicinal Evaluation Agency CPMP: Committee for Proprietary Medicinal Products NTA: Notices To Applicant CDER / CFR: Code of Federal Register

3. Applicable guidelines • Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) November 2003, ICH • Guidance for Industry Q1E Evaluation of Stability Data U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) June 2004, ICH

4. Objectives 1- The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended  (1) storage conditions, (2) re-test periods and (3)shelf livesto be established. Temp. Humidity Light Drug 95.5% Drug 100% + Time (month) Degradation Prod. 4.5% 2- Safety and efficacy.

5. IQ/OQ/PQ, Data Logger Log sheets Written/Approved Compendia & Company Spcs Approved Docs ICH Stress testing Development Validation Represent. Chromatograms Purchase USP / Europ. RS Purchase Potential Impurities Storage cabinet Verified Batch size 3 batches Sampling protocol Design Before starting program execution we should have; Specification of Product All SOP’s Equipment & tools Stability Protocol Stability Indicating Analytical Method Reference Standards Drug product

6. Design Before starting program execution we should have; 1 Stability Protocol Written/Approved Who doing what? How to do the task Clear interpretation of procedures Stepwise manner Stability protocol is a signed/dated and approved document that describe the exact and clear procedure to start the stability testing of drug. The procedure should be described in a sequential stepwise manner, who doing what, how to do the task.

7. Design Before starting program execution we should have; Specification of Product All SOP’s 2 Info. Source 1 = Compendia (USP/BP) Info. Source 2 = FDA / ICH guidelines (Limits / general Official Procedure) Info. Source 3 = Supplier of raw material Info. Source 4 = Company approved specs of API and PFP

8. Design Before starting program execution we should have; 3 Equipment & tools IQ/OQ/PQ, Data Logger Log sheets Documentations are available = IQ/OQ/PQ Data Logger (calibrated) = Temp., Humidity Documents = Log sheets of operation, time, date How to operate the machine = SOP for machine

9. 3 Equipment & tools + Data loggers !!!! UV HPLC Dissolution Stability Cabinets Karl Fisher Balances Calibrated Glassware

10. 3 Equipment & tools + Data loggers !!!! Stability Cabinets A special cabinet for each condition Should be qualified / calibrated Monitor Temp. / humidity vs time. Time Three General conditions required. Deep freeze   Data loggers

11. Data Loggers (Types) sensor probe / thermocouple

12. Why we use Data Loggers ?How many sensor probe?How to position sensors? • To monitor Both, temperature and Relative Humidity along 24 hours. • To ensure consistency of the adjusted Temp. and RH. • Should be calibrated by supplier • Any deviation for NLT 6 hours, we should stop study and repeat using new samples. • Ex: Electricity shutdown, or instrument failer, no enough water inside instrument.

13. 3 Equipment & tools Photostability Cabinets At least one primary batch Should be tested Why we defined some products to be photosensitive, to which degree ? (use UV-A, 200 watts hours/m2) Illumination   : 1.2 million Lux hours Humidity range   : 40% to 95% ± 2% RH Temperature range    : 100c to 500C, ± 0.50C -- Use calibrated machine (candles/inch = ?) 3. Exposure time limit = ? (according to the limit of potential degradation products formed, and quinine HCl standard)

14. Design Before starting program execution we should have; 4 Stability Indicating Analytical Method ICH Stress testing Development Validation Represent. Chromatograms

15. Stability indicating Analytical Method The method is able to discriminate between principle drug and the degradation products and/or impurities Method: Compendial methods are claimed to be stability indicating Rules: ICH stress Guideline Plus: Photodegradation products & reconstitution testing Monitoring: Peaks of Potential impurities & Degradation products (previously define the cause)

16. Example of STRESS TESTING OF BETAHISTINE HCl heated NaOH HCl UV light Betaserc tablets H2O2

17. Analytical Method Performance How to present the analytical HPLC method PERFORMANCE PARAMETERS

18. What are the Stability-indicating quality parameters Stability studies should include testing of those attributes of the FPP that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. For instance, in case of tablets: ♦ appearance ♦ hardness ♦friability ♦moisture content ♦dissolution time ♦degradants ♦ assay ♦microbial purity

19. Batch size 3 batches Sampling protocol Design Before starting program execution we should have; 5 Drug Product

20. Selection of batches: 5 Drug product How many batches should be tested ? Batch size = ? Product unit Which Batches should be tested ? When should we repeat stability testing?

21. Selection of batches: 5 Drug product How many batches should be tested ? three, using 3 different batches of starting drug substance Batch size = ? Product unit Two pilot scale batches, third smaller if justified) Which Batches should be tested ? Stability studies should be performed on each individual strength and container size. When we should repeat stability testing? [1] In case of failed stability ..! [3] Application For ANDA (Pharm. Bioeq) !! [2] Modification? using raw material from different manufacturer, excepients  type/ratio change manufacturing procedure  modified. change of  package, closure.

22. Container / closure systems: The stability testing should be conducted on the dosage form stored in the proposed containers / closure system for marketing.

23. Design Before starting program execution we should have; 6 Reference Standards Purchase USP / Europ. Reference Standard) Purchase Potential Impurities Stored in Special Storage cabinet + log book (amount used, when, for what?) Verified (Melting point, IR, HPLC-RT as per USP/BP)

24. Major Variables Temperature Relative Humidity Light (Photostability) Stability after Reconstitution (dilution)

25. Typical storage condition and study duration [a] General Case (PERMEABLE) [b] Drug Products packaged in IMPERMEABLE containers [c] Drug Products packaged in SEMIPERMEABLE containers [d] Drug Products intended for storage in refrigerator [e] Drug Products intended for storage in freezer [f] Drug Products intended for storage below -20 ºC

26. Typical storage condition and study duration [a] General Case (PERMEABLE containers to moisture) • It is up to the applicant to decide the tem/RH for long term. • If 302C / 65 % RH  5% RH is the long term, then NO INTERMEDIATE cond.

27. Typical storage condition and study duration [b] Drug product packaged inIMPERMEABLE containers (to moisture or solvent loss) • Sensitivity to moisture or potential for solvent loss is not a concern for drug products packaged in impermeable containers that provide a permanent barrier to passage of moisture or solvent. • Thus, stability studies for products stored in impermeable containers can be conducted under any controlled or ambient humidity condition.

28. Typical storage condition and study duration [c] Drug products stored in SEMIPERMEABLE containers • It is up to the applicant to decide the tem/RH for long term. • If 302C / 35% RH  5% RH is the long term, then NO INTERMEDIATE cond. • Aqueous-based products packaged in semipermeablecontainers should be evaluated for potential water loss in addition to physical, chemical, biological, and microbiological stability. • 5% loss of water(after 3 months) is considered significant change.

29. Typical storage condition and study duration [d] Drug products intended for storage in a REFRIGERATOR [e] Drug products intended for storage in FREEZER [f] Drug products intended for storage BELOW-20 C Drug products intended for storage below -20°C should be treated on a case-by-case basis.

30. THE SIGNIFICANT CHANGES

31. THE SIGNIFICANT CHANGE IS DEFINED AS

32. Example of Failed stability • The assay value is still within the limitsbut the change during stability is more than 5.0% • Example • Release assay limit: 95.0 – 105.0% • Release assay: 101.0% (within spec) • 6-Month assay: 95.5% (within spec) • Loss in potency: 5.5%. • This is a significant change.

33. Stability Data and Report

34. Stability Data and Report

35. Additional or New Stability Data is Required if; • Change in the route of synthesis of an API • Change in composition of the FPP • Change in immediate packaging of the FPP • In case of failed stability, (chemical, instrumental, regulatory) • using raw material from different manufacturer, • excepients  type/ratio change • manufacturing procedure  modified. • change of  package, closure.

36. و الحمد لله رب العالمين Thank you