Professional Documents
Culture Documents
STABILITY STUDIES
Assessment experience
Jnos Pogny, pharmacist, PhD
consultant to WHO
Tanzania, 21 August 2006
E-mail: pogany.janos@chello.hu
2006.08.21.
1/60
Abbreviations
API
DRA
EoI
FDC
FPP
GMP
ICH
MA
PQIF
Yellow emphasis
2006.08.21.
Green WHO
Dr. Pogny - Tanzania
Applicable guidelines
WHO Guidelines for stability testing of
pharmaceutical products containing well
established drug substances in conventional
dosage forms
See Notes page
WHO amendment of the above guideline in TRS
937 (2006).
See Notes page
ICH guidelines Q1A-Q1F. Stability testing of new
drug substances and products has been
harmonized at global level.
2006.08.21.
3/60
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. 2.7 Stability testing
Supplement 2 Rev.1 [for use from May 2006 (CPH31)]
Extension of the WHO List of Stable (not easily
degradable ARV) APIs.
Annex 4 Stability requirements for variations and changes
to prequalified FPPs in Guidance on variations to a
prequalified dossier
2006.08.21.
4/60
5/60
STABILITY STUDIES
Selected definitions
Re-test period
The period of time during which the drug substance is expected
to remain within its specification and, therefore, can be used in
the manufacture of a given drug product, provided that the drug
substance has been stored under the defined conditions.
Shelf life (expiration dating period, conformance period)
The time period during which an API or a FPP is expected to
remain within the approved shelf-life specification, provided
that it is stored under the conditions defined on the container
label.
See also Notes Page
2006.08.21.
7/60
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
2006.08.21.
8/60
Selected definitions
Primary batch (called also exhibit 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
2006.08.21.
9/60
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 .)
10/60
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.
2006.08.21.
11/60
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.
2006.08.21.
12/60
INTERCHANGEABILITY
STABILITY EQUIVALENCE
Interchangeability (IC)
Interchangeability (IC) of multisource FPPs =
(Essential similarity with innovator FPP) =
Pharmaceutical equivalence (PE) +
Bioequivalence (BE)
IC = PE + BE
2006.08.21.
14/60
Pharmaceutical equivalence
FPPs meet same or comparable standards
(pharmacopoeia, marketing authorization)
2006.08.21.
15/60
Batches tested
General information
Container/closure system
Literature and supporting data
Stability-indicating analytical methods
Testing plan
Test parameters
Test results
Other requirements (post-approval commitments)
Conclusions
Result sheets must bear date and responsible person signature / QA approval
2006.08.21.
17/60
20
100
100
18/60
19/60
ICH Q1B
ICH Q2B
ICH Q3A(R)
ICH Q3B(R)
2006.08.21.
21/60
2006.08.21.
22/60
Prequalification experience
Results
Comments
Deceptive
Predictive
Useless
2006.08.21.
23/60
24/60
Testing period*
3 months
3 months
according to ICH
25/60
Testing period*
pH 2, room temperature
2 weeks
pH 7, room temperature
2 weeks
2 weeks
24 hours
26/60
Conditions
Observations
Temperature
Humidity
Light
Oxidation
Acid
Base
Metal ions
Other
2006.08.21.
27/60
Relative
humidity
(%)
Minimum time
period covered by
data at submission
(months)
755
IVa 655
IVb 755
12 (6)
605
12 (6)
28/60
29/60
Stability Room
1. A special cabinet for each
condition
2. Design, construction,
qualification, monitoring
3. Costs of operation including
R + D failures
4. Time
5. Do we need new standard
conditions?
2006.08.21.
30/60
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.
2006.08.21.
31/60
2006.08.21.
33/60
appearance
friability
dissolution time
assay
2006.08.21.
hardness
moisture content
degradants
microbial purity
34/60
2006.08.21.
35/60
36/60
37/60
Pitfall
2006.08.21.
38/60
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).
2006.08.21.
40/60
2006.08.21.
41/60
42/60
variability"?
43/60
44/60
45/60
46/60
acceptance limits
process capability
UCL - LCL
6*
Cpk =
acceptance limits
process capability
2006.08.21.
UCL - LCL
6 SY/X
47/60
2006.08.21.
48/60
2006.08.21.
49/60
50/60
2006.08.21.
51/60
2006.08.21.
52/60
2006.08.21.
53/60
54/60
55/60
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
2006.08.21.
56/60
2006.08.21.
57/60
58/60
59/60
THANK YOU
2006.08.21.
60/60