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GABRIEL K. KADDU Head, Drug assessment and Registration National Drug Authority Uganda
Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.
Abbreviations Applicable Guidelines Selected definitions Stability Protocol and Reports Stability testing of APIs Stability testing of FPPs Evaluation of results Conclusion
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Abbreviations
API EoI Active Pharmaceutical Ingredient Expression of Interest
GMP Good Manufacturing Practices ICH MA International Conference on Harmonization Marketing Authorization
emphasis
Green
WHO
Blue
ICH
Applicable guidelines
WHO Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms. WHO working document QAS/05.146 - Stability Studies in a Global Environment. ICH guidelines Q1A-Q1F. Stability testing of new APIs and FPPs has been harmonized at global level.
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Applicable guidelines
WHO Guideline on Submission of Documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDS, Malaria and Tuberculosis. Annex 4. Stability requirements for variations and changes to prequalified FPPs Supplement 2 Extension of the WHO List of Stable (not easily degradable ) APIs.
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Selected definitions
Re-test date
The date after which samples of an API should be examined to ensure that the material is still in compliance with the specification and thus suitable for use in the manufacture of a given FPP.
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Selected definitions
Formal stability studies Long term and accelerated (and intermediate) studies undertaken on primary and/or commitment batches according to a prescribed stability protocol to establish or confirm the re-test period of an API or the shelf life of a FPP. Stress testing forced degradation (API) Studies undertaken to elucidate the intrinsic stability of the API. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. Stress testing forced degradation (FPP) Studies undertaken to assess the effect of severe conditions on the FPP. Such studies include photostability testing (see ICH Q1B) and compatibility testing on APIs with each other in FDCs and API(s) with excipients during formulation development.
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Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
Selected definitions
Primary batch
A batch of an API or FPP used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a re-test period or shelf life, respectively. A primary batch of an API should be at least a pilot scale batch. For a FPP, two of the three batches should be atleast pilot scale batch, and the third batch a production batch.
Commitment batches
Production batches of a drug substance or drug product for which the stability studies are initiated or completed post approval through a commitment made in the registration application.
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Selected definitions
Pilot (scale) batch
A batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production scale batch. (For solid oral dosage forms, a pilot scale is
generally, at a minimum, one-tenth that of a full production scale or 100,000 tablets or capsules, whichever is the larger.)
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Selected definitions
Supporting data
Data, other than those from formal stability studies, that support the analytical procedures, the proposed re-test period or shelf life, and the label storage statements. Such data include (1) stability data on early synthetic route batches of API, small-scale batches of materials, investigational formulations not proposed for marketing, related formulations, and product presented in containers and closures other than those proposed for marketing; (2) information regarding test results on containers; and (3) other scientific rationales.
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Selected definitions
Specification - Release
The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of a drug product at the time of its release. The combination of physical, chemical, biological, and microbiological tests and acceptance criteria that determine the suitability of an API throughout its re-test period, or that anFPP should meet throughout its shelf life.
Mass balance
The process of adding together the assay value and levels of degradation products to see how closely these add up to 100% of the initial value, with due consideration of the margin of analytical error.
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stability studies
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Batch number Date of manufacture Site of manufacture Batch size (kg) Primary packing materials Date of initial analysis
The batches should be representative of the manufacturing process and should be manufactured from different batches of key intermediates.
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Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
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To validate the stability indicating power of the analytical procedures. To identify stability-affecting factors such as ambient temperature, humidity and light and to select packing materials, which protect the FPP against such effects.
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Testing period*
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Stability results
A storage statement should be proposed for the labeling (if applicable), which should be based on the stability evaluation of the API. A re-test period should be derived from the stability information, and the approved retest date should be displayed on the container label.
An API is considered as stable if it is within the defined/regulatory specifications when stored at 30 2oC and 65 5% RH for 2 years and at 40 2oC and 75 5%RH for 6 months.
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Testing period*
3 months 3 months according to ICH
* 3 months or 5-15% degradation, whatever comes first ** For API1-API2, or API-excipient, or FPP without packing material, typically a thin layer of material is spread in a Petri dish. Open storage is recommended, if possible.
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Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
Evaluation of results
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3.11.10 Evaluation
A systematic approach should be adopted in the presentation and evaluation of the stability information. Where the data show so little degradation and so little variability that it is apparent from looking at the data that the requested shelf life will be granted, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient. An approach for analysing data on a quantitative attribute that is expected to change with time is to determine the time at which the 95% one-sided confidence limit for the mean curve intersects the (lower) acceptance criterion (95% assay).
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Evaluation
1. Tabulate and plot stability data on all attributes at all storage conditions and evaluate each attribute separately. 2. No significant change at accelerated conditions within six (6) months. 3. Long-term data show little or no variability and little or no change over time.
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Evaluation
4. Accelerated data show little or no variability and little or no change over time. 5. Statistical analysis is normally unnecessary. 6. Proposed retest period or shelf life = double of period covered by long-tem data (X) but NMT X + 12 months 7. A retest period or shelf life granted on the basis of extrapolation should always be verified by additional long-term stability data
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Commitment
For confirmation of provisional (tentative) shelflife, real-time data are required First 3 production batches on stability Follow up stability testing (FUST) one batch per year
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Conclusion
Stability studies should be planned on the basis of pharmaceutical R+D and regulatory requirements. Forced degradation studies reveal the intrinsic chemical properties of the API, while formal stability studies establish the retest date. The shelf life (expiry date) of FPPs is derived from formal stability studies. Variability and time trends of stability data must be evaluated by the manufacturer in order to propose a retest date or expiry date.
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Artemisinin based combined medicines February 23-27, 2009, Kampala, Uganda
THANK YOU
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