Professional Documents
Culture Documents
STABILITY STUDIES
Assessment experience
Jnos Pogny, pharmacist, Ph.D.
consultant to WHO
Guilin, China, 9 January 2006
E-mail: pogany@t-online.hu
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Abbreviations
API
EoI
FDC
FPP
GMP
ICH
MA
DRA
Yellow emphasis
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Green WHO
Blue ICH
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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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2.
Interchangeability of FPPs
3.
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)
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Low-risk APIs
1. Certificate of suitability (DRA)
2. Drug Master File
3. Pharmacopeia monograph
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ICH Q1B
ICH Q2B
ICH Q3A(R)
ICH Q3B(R)
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Prequalification experience
Results
Comments
Deceptive
Predictive
Useless
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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
Minimum time
period covered by
data at submission
(months)
6
Intermediate: 302
655
12
605
12 (6)
Storage temperature
(C)
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Relative
humidity
(%)
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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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appearance
friability
dissolution time
assay
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hardness
moisture content
degradants
microbial purity
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Pitfall
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Testing period*
3 months
3 months
according to ICH
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Stability studies
API and FPP
Evaluation of results
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"?
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process capability
UCL - LCL
=
6*
acceptance limits
Cpk =
process capability
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UCL - LCL
=
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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