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Abbreviations
API EoI FDC FPP GMP ICH MA DRA Active Pharmaceutical Ingredient Expression of Interest Fixed-Dose Combination Finished Pharmaceutical Product Good Manufacturing Practices International Conference on Harmonization Marketing Authorization Drug Regulatory Authority
Green WHO Blue ICH
Yellow emphasis
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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 (draft) Supplement 2 [for use from July 2005 (CPH25)] Extension of the WHO List of Stable (not easily degradable ARV) APIs. Further potential APIs are e.g., amodiaquine, mefloquine, and so on.
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4.
5. 6. 7.
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STABILITY STUDIES
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. See also Notes Page
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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 at least 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. See also Notes Page
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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.
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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INTERCHANGEABILITY
STABILITY EQUIVALENCE
Interchangeability (IC)
Interchangeability (IC) of multisource FPPs =
(Essential similarity with innovator FPP) =
IC = PE + BE
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Pharmaceutical equivalence
FPPs meet same or comparable standards
(pharmacopoeia, marketing authorization)
Same API (chemical and physical equivalence) Same dosage form and route of administration Same strength Comparable labeling WHO-GMP (batch-to-batch uniformity of quality) STABILITY EQUIVALENCE
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APIs and FPPs are not official in the internationally used major pharmacopoeias WHO guides/SOPs apply to multisource FPPs. ICH guides should be used for evaluation. Require particular attention by national DRA as regards assessment of applications for marketing authorization
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Low-risk APIs
1. Certificate of suitability (DRA)
2. Drug Master File
Open part (APPLICANT) Closed part (DRA) Literature evidence of stability Synthesis impurities are controlled by monograph (toxicology of additional impurities) Class1 solvents excluded, class2 solvents controlled
3. Pharmacopeia monograph
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ICH Q1A(R2) Stability Testing of New Drug Substances and ICH Q1B ICH Q2B ICH Q3A(R) ICH Q3B(R)
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Photostability Testing of New Drug Substances and Products Validation of Analytical Procedures: Methodology Impurities in New Drug Substances Impurities in New Drug Products
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Prequalification experience
Results Deceptive Predictive Comments Degradation level is good (<15%) but no relevant degradants are observed Degradation level is good (<15%) and at least one or all relevant degradants are observed Between 15 and 100% degradation but no relevant degradants observed
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Testing period*
2 weeks
2 weeks 2 weeks
24 hours
* Storage times given or 5-15% degradation, whatever comes first See also Notes Page
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Accelerated: 402
Intermediate: 302 Long term: 252
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Stability Room
1. A special cabinet for each condition
2. Design, construction, qualification, monitoring 3. Costs of operation including R + D failures 4. Time
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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 302oC and 655% RH for 2 years and at 402oC and 755%RH for 6 months.
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Pitfall
The assay value is still within the limits but the change during stability is more than 5.0% Example
Release assay limit: 95.0 105.0% Stability assay limit: 92.5 105.0% Release assay: 101.0% (within spec) 24-Month assay: 93.0% (within spec) Loss in potency: 8.0%. This is a significant change.
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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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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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variability"?
change over time suggests potential problem with accuracy/precision of analytical method.)
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Variability is taken to be reflected by the spread of data around the previously derived regression line. The standard deviation about the regression line SY/X is a measure of this spread.
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UCL - LCL
6*
UCL - LCL =
process capability
6 SY/X
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Commitment
For confirmation of provisional (tentative) shelf-life, real-time data are required
First 3 production batches on stability Follow up stability testing (FUST) one batch per year
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THANK YOU
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