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Stability Studies: Gabriel K. Kaddu Head, Drug Assessment and Registration National Drug Authority Uganda
Stability Studies: Gabriel K. Kaddu Head, Drug Assessment and Registration National Drug Authority Uganda
Stability Studies: Gabriel K. Kaddu Head, Drug Assessment and Registration National Drug Authority Uganda
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
2.
Applicable Guidelines
3.
Selected definitions
4.
5.
6.
7.
Evaluation of results
8.
Conclusion
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Abbreviations
API
EoI
Expression of Interest
MA
Marketing Authorization
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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
Supplement 2 Extension of the WHO List of Stable (not
easily degradable ) APIs.
5|
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.
6|
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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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
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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Standard
ICH Q1A(R2)
ICH Q1B
ICH Q2B
ICH Q3A(R)
ICH Q3B(R)
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Testing period*
pH 2, room temperature
2 weeks
pH 7, room temperature
2 weeks
2 weeks
24 hours
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Accelerated: 402
755
Intermediate: 302
655
12
605
12 (6)
Storage temperature
(C)
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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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appearance
friability
dissolution time
assay
hardness
moisture content
degradants
microbial purity
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Testing period*
3 months
3 months
according to ICH
Stability studies
API and FPP
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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THANK YOU
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