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Regulatory requirements on Medicine Stability Guidelines relevant for Stability testing

Regulatory requirements on Medicine Stability Guidelines relevant for Stability testing. Sultan Ghani. Focus of The Presentation. Regulatory Considerations Guidelines relevant for stability testing Highlights of new WHO Stability Guidelines . Regulatory Considerations.

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Regulatory requirements on Medicine Stability Guidelines relevant for Stability testing

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  1. Regulatory requirements on Medicine Stability Guidelines relevant for Stability testing • Sultan Ghani

  2. Focus of The Presentation • Regulatory Considerations • Guidelines relevant for stability testing • Highlights of new WHO Stability Guidelines

  3. Regulatory Considerations • Regulatory requirements in various countries • Pre- and post-marketing requirements • Guidelines vs Regulations

  4. Regulatory Considerations (cont’d) European Regulatory Agency • Adopted ICH guidelines, but practical implementation may differ • Wide range of other guidelines generated by the CPMP included in the EU Directives and Regulations (65/65 EEC, 75/318 EEC, 91/507 EEC)

  5. Regulatory Considerations (cont’d) European Regulatory Agency (cont’d) • CPMP Guidelines – Stability testing of existing active substances and related finished product • Apply to chemically active substance previously approved in EU and product, except radio-pharmaceuticals or biological • Refer to ICH guidelines on stability testing of new active substances and products • Consideration on pharmacopoeial monographs with respect to stability data requirements of active ingredients

  6. Regulatory Considerations (cont’d) European Regulatory Agency (cont’d) • CPMP Guidelines – Stability testing of existing active substances and related finished product • Two options when data is required: • Two industrial-scale batches • Accelerated 40°C ± 2°C 75% RH ± 5% 6-month data • Long-term 25 °C ± 2°C 60% RH ± 5% 6-month data • Three pilot-scale batches, same synthetic route (6-month accelerated, 12-month long- term) • For dosage form 6-month accelerated 6-month long-term

  7. Regulatory Considerations (cont’d) European Regulatory Agency(cont’d) • Other Guidelines • CPMP Guidelines: Dry Powder Inhaler • Declaration of storage conditions for medicinal products in product particulars • European Union Requirements for Variations (changes) related to stability

  8. Regulatory Considerations (cont’d) European Regulatory Agency (cont’d) • Requirements for variations (changes) related to stability • Three types of variation: • Minor or type 1 (notification) • Major or type 2 (assessment and approval) • Significant changes requiring a new marketing authorization • Data requirements depend on particular circumstances. Normal extrapolation of data will be allowed (e.g. up to two times of real time data up to a limit of 3 years)

  9. Regulatory Considerations (cont’d) European Regulatory Agency(cont’d) • Requirements for variations (changes) related to stability • Specific Examples: • Modification to one or more steps of the same route of synthesis • 3 months of comparative accelerated and long-term data • Change in synthetic route • 3 batches of at least pilot manufacture for 6 months • Changes to the composition of the finished product • 6 months data from two pilot-scale batches (LT and accelerated) • Changes to the immediate packaging of the finished product • 6 months data from three pilot-scale batches (LT and accelerated)

  10. Regulatory Considerations (cont’d) FDA • Stability Testing for Abbreviated New Drug Application (21 CFR 31492 – 31499) • Consideration for a reduction in the amount of stability required for an ANDA as compared to an NDA • Dosage forms are classified as simple or not simple • For “simple” dosage forms, the requirement is liberal • For “not simple” dosage forms, the requirements are less liberal

  11. Regulatory Considerations (cont’d) FDA(cont’d) • Drug Substance (stability submission) • Appropriate referenced DMF • Stability data on pilot-scale batch (restriction on design, equipment, process with exception of capacity) • For fermentation product, three production batches, two of which should be generated from different starter cultures • Stress-testing if not performed previously • Same composition and type of container, closure and liner, but smaller in size

  12. Regulatory Considerations (cont’d) FDA (cont’d) • Drug Product • The ANDA data package is based on various factors, such as complexity, existence of sufficient information, etc. • ANDA data package recommendations are • For simple dosage form • 0, 1, 2, 3 months at controlled room temperature 25ºC • Accelerated stability 0, 1, 2 and 3 months • 24-month expiry period granted based on satisfactory accelerated data • A minimum of one batch pilot-scale • Additional stability studies (12 months at intermediate or long-term data through proposed expiry date) if significant change in 3-month accelerated data, expiry date will be determined based on the available data

  13. Regulatory Considerations (cont’d) FDA (cont’d) • For complex dosage forms • Requires a modified ICH Q1A stability data package • 3-month accelerated stability studies • Long-term stability studies • Expiry date will be determined on long-term stability data • Minimum three batches according to ICH Q1A batch size • Additional stability studies (12-month intermediate or long-term stability) through proposed expiration date (change in accelerated condition) • Other supportive data • Extension of expiration date is based on at least three production batches according to the approved protocol

  14. Regulatory Considerations (cont’d) Canadian Requirements for Generic Drugs • The stability testing requirements for generic drugs are the same as for innovator products. All ICH guidelines are fully endorsed by Health Canada.

  15. Regulatory Considerations (cont’d) Recommendation • Considering the differences in the regulatory requirements, it is recommended to develop and design stability studies according to ICH, so as to meet all requirements.

  16. GUIDELINES RELEVANT FOR STABILITY TESTING

  17. Other Reference Documents • In addition to the applicable Regulations and GMP documents, following are some of the Quality documents that should be consulted for Stability requirements: • Health Canada (www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_drugs_information_e.html): • (stay tuned) • FDA (www.fda.gov/cder/guidance/index.htm): • Stability Testing of Drug Substances and Drug Products (draft, 1998) • Drug Substance - CMC Information (draft, 2004) • Drug Product - CMC Information (draft, 2003) • SUPAC series (IR, MR, SS) (and Q&A Document) • Changes to an Approved NDA/ANDA (04/2004) (and Q&A Document)

  18. Other Reference Documents • In addition to the applicable Regulations and GMP documents, the following are some of the Quality documents that should be consulted for Stability requirements: • EU EMEA (www.emea.eu.int/Inspections/QWPhome.html):

  19. Highlights of new WHO Stability Guidelines

  20. 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 propertiesAssay of each API: ±10% of the label claim possible at the end of shelf-lifeAssay of degradation productsAssay of antioxidants and chemical preservatives, check also for their efficacyDissolution testing (limits should remain unchanged to release)Microbial contamination, sterility, bacterial endotoxins • In-use stability data (if applicable)

  21. Quality dossier / Section 3Finished 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 30°C/65% RH and 6 months accelerated 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

  22. Climatic Zone IV • Zone IVa: 30oC and 65% RH (hot & humid condition). • Zone Ivb 300C and 75% RH (hot & very humid conditions). • Store at temperature not 30oC in a dry place. Protect from light.

  23. Thank youSultan GhaniDirectorBureau of Pharmaceutical SciencesTherapeutic Products Directorate (TPD), Health CanadaPhone: 1-613-941-3185Fax: 1-613-957-3989E-mail: sultan_ghani@hc-sc.gc.ca

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