1. INTRODUCTION
1.1 Objectives of the Guideline
This guideline is intended to provide recommendations on how to use stability data, generated in
accordance with the principles detailed in the ICH guideline “Q1A(R) Stability
Testing of New Drug Substances and Products” to propose a retest period or
shelf life in a registration application.
This guideline describes when and how extrapolation can be considered when proposing a retest
period for a drug substance or a shelf life for a drug product that extends
beyond the period covered by “available data from the stability study under the
long-term storage condition”.
1.3 Scope of the Guideline
This
guideline addresses the evaluation of stability data that should be submitted
in registration applications for new molecular entities and associated drug
products. The guideline provides recommendations on establishing retest periods
and shelf lives for drug substances and drug products intended for storage at
or below “room temperature”. It covers stability studies using single- or
multi-factor designs and full or reduced designs.
2. GUIDELINES
2.1 General Principles
The purpose of a stability study is to
establish, based on testing a minimum of
three batches of the drug substance or product, a retest period or shelf
life and label storage instructions applicable to all future batches manufactured
and packaged under similar circumstances. The degree of variability of individual
batches affects the confidence that a future production batch will remain within
acceptance criteria throughout its retest period or shelf life.
A systematic approach should be adopted in the
presentation and evaluation of the stability information. The stability
information should include, as appropriate, results from the physical,
chemical, biological, and microbiological tests, including those related to
particular attributes of the dosage form (for example, dissolution rate for solid
oral dosage forms). The adequacy of the mass balance should be assessed. Factors
that can cause an apparent lack of mass balance should be considered, including,
for example, the mechanisms of degradation and the stability-indicating capability
and inherent variability of the analytical procedures.
The
retest period or shelf life proposed should not exceed that predicted for any
single attribute.
ICH Q1E guideline
mentions about Appendix A and Appendix B guideline, however, in this blog, we
are discussing regarding Appendix A i.e. the decision tree which outlines a
stepwise approach to stability data evaluation and when and how much
extrapolation can be considered for a proposed retest period or shelf life.
2.2 Data presentation
- Data for all attributes should be presented in an appropriate format (e.g., tabular, graphical, narrative) and an evaluation of such data should be included in the application.
- The values of quantitative attributes at all time points should be reported as measured (e.g., assay as percent of label claim).
- If a statistical analysis is performed, the procedure used and the assumptions underlying the model should be stated and justified.
- A tabulated summary of the outcome of statistical analysis and/or graphical presentation of the long-term data should be included
2.3 Extrapolation
Extrapolation is the practice of using a known
data set to infer information about future data. Extrapolation to extend the
retest period or shelf life beyond the period covered by long-term data can be
proposed in the application, particularly if no significant change is observed
at the accelerated condition. Whether extrapolation of stability data is
appropriate depends on the extent of knowledge about the change pattern, the
goodness of fit of any mathematical model, and the existence of relevant supporting
data. Any extrapolation should be performed such that the extended retest period
or shelf life will be valid for a future batch released with test results close
to the release acceptance criteria.
2.4 Data Evaluation for Retest Period or Shelf Life Estimation for Drug Substances
or Products Intended for Room Temperature Storage
For drug substances or products intended for
storage at room temperature, the assessment should begin with any significant change at the accelerated
condition and, if appropriate, at the intermediate condition, and progress through
the trends and variability of the long-term data. The circumstances are delineated
under which extrapolation of retest period or shelf life beyond the period covered
by long-term data can be appropriate. A decision tree is provided in Appendix A
of ICH Q1E as an aid.
2.4.1 No significant change at
accelerated condition
Where no significant change occurs at
the accelerated condition, the retest period or shelf life would depend on the
nature of the long-term and accelerated data.
2.4.1.1
Long-term and accelerated data showing little or no change over time and little
or no variability
- Where the long-term data and accelerated data for an attribute show little or no change over time and little or no variability, it might be apparent that the drug substance or product will remain well within the acceptance criteria for that attribute during the proposed retest period or shelf life.
- In these circumstances, a statistical analysis is normally considered unnecessary but justification for the omission should be provided.
- Justification can include a discussion of the change pattern or lack of change, relevance of the accelerated data, mass balance, and/or other supporting data as described in the parent guideline.
- Extrapolation of the retest period or shelf life beyond the period covered by long-term data can be proposed. The proposed retest period or shelf life can be up to twice, but should not be more than 12 months beyond, the period covered by long-term data.
2.4.1.2 Long-term or accelerated data
showing change over time and/or variability
- Where there are differences in stability observed among batches or among other factors (e.g., strength, container size and/or fill) or factor combinations (e.g., strength-by-container size and/or fill) that preclude the combining of data, the proposed retest period or shelf life should not exceed the shortest period supported by any batch, other factor, or factor combination.
- Alternatively, where the differences are readily attributed to a particular factor (e.g., strength), different shelf lives can be assigned to different levels within the factor (e.g., different strengths).
- A discussion should be provided to address the cause for the differences and the overall significance of such differences on the product. Extrapolation beyond the period covered by long-term data can be proposed; however, the extent of extrapolation would depend on whether long-term data for the attribute are amenable to statistical analysis.
Data not amenable to statistical analysis
Where long-term data are not amenable to
statistical analysis, but relevant supporting data are provided, the proposed retest period or shelf life
can be up to one and-a-half times, but should not be more than 6 months beyond,
the period covered by long-term data. Relevant supporting data include
satisfactory long-term data from development batches that are (1) made with a
closely related formulation to, (2) manufactured on a smaller scale than, or
(3) packaged in a container closure system similar to, that of the primary
stability batches.
Data amenable to statistical analysis
If long-term data are amenable to statistical
analysis but no analysis is performed, the extent of extrapolation should be
the same as when data are not amenable to statistical analysis. However, if a
statistical analysis is performed, it
can be appropriate to propose a retest period or shelf life of up to twice, but
not more than 12 months beyond, the period covered by long term data, when the
proposal is backed by the result of the analysis and relevant supporting data.
2.4.2 Significant change at accelerated condition
Where significant change* occurs at the
accelerated condition, the retest period or shelf life would depend on the
outcome of stability testing at the intermediate condition, as well as at the
long-term condition.
*Note: The following physical changes can be expected
to occur at the accelerated condition and would not be considered significant
change that calls for intermediate testing if there is no other significant
change:
- Softening of a suppository that is designed to melt at 37ºC, if the melting point is clearly demonstrated,
- Failure to meet acceptance criteria for dissolution for 12 units of a gelatin capsule or gel-coated tablet if the failure can be unequivocally attributed to cross-linking.
However, if phase separation of a
semi-solid dosage form occurs at the accelerated condition, testing at the
intermediate condition should be performed. Potential interaction effects
should also be considered in establishing that there is no other significant
change.
2.4.2.1 No significant change at
intermediate condition
If there is no significant change at the
intermediate condition, extrapolation beyond the period covered by long-term
data can be proposed; however, the extent of extrapolation would depend on
whether long-term data for the attribute are amenable to statistical analysis.
Data not amenable to statistical analysis
When the long-term data for an attribute are not
amenable to statistical analysis, the proposed
retest period or shelf life can be up to 3 months beyond the period covered by long-term
data, if backed by relevant supporting data.
Data amenable to statistical analysis
When the long-term data for an attribute are
amenable to statistical analysis but no analysis is performed, the extent of
extrapolation should be the same as when data are not amenable to statistical
analysis. However, if a statistical analysis is performed, the proposed retest period or shelf life can be up to one-and-half
times, but should not be more than 6 months beyond, the period covered by
long-term data, when backed by statistical analysis and relevant supporting
data
Significant change at intermediate condition
Where significant change occurs at the
intermediate condition, the proposed retest period or shelf life should not exceed the period covered by long-term
data. In addition, a retest period or shelf life shorter than the period
covered by long-term data could be called for.
2.5 Data Evaluation for Retest Period or Shelf Life Estimation for Drug
Substances or Products Intended for Storage Below Room Temperature
2.5.1 Drug substances or products intended for storage in a refrigerator
Data from drug substances or products intended
to be stored in a refrigerator should be assessed according to the same
principles as described in Section 2.4 for drug substances or products intended
for room temperature storage, except where explicitly noted in the section
below. The decision tree in Appendix A of ICH Q1E can be used as an aid.
2.5.1.1 No significant change at accelerated condition
If
the long-term and accelerated data show little
change over time and little variability, the proposed retest period or shelf life can be up to one-and-a-half
times, but should not be more than 6 months beyond, the period covered by
long-term data normally without the support of statistical analysis.
Where the long-term or accelerated data show change over time and/or
variability, the proposed retest period
or shelf life can be up to 3 months beyond the period covered by long-term data
if (1) the long-term data are amenable to statistical analysis but a
statistical analysis is not performed, or (2) the long-term data are not
amenable to statistical analysis but relevant supporting data are provided.
Where the long-term or accelerated data show change over time and/or
variability, the proposed retest period or shelf life can be up to
one-and-a-half times, but should not be more than 6 months beyond, the period
covered by long-term data if (1) the longterm data are amenable to
statistical analysis and a statistical analysis is performed, and (2) the
proposal is backed by the result of the analysis and relevant supporting data.
2.5.1.2 Significant change at
accelerated condition
If significant change occurs between 3 and 6 months’ testing at the
accelerated storage condition, the proposed retest period or shelf life should
be based on the longterm data. Extrapolation is not
considered appropriate. In addition, a retest period or shelf life shorter
than the period covered by long-term data could be called for. If the long-term
data show variability, verification of the proposed retest period or shelf life
by statistical analysis can be appropriate.
If
significant change occurs within the first 3 months’ testing at the accelerated
storage condition, the proposed retest period or shelf life should be based on
long-term data. Extrapolation is not considered appropriate. A retest period or
shelf life shorter than the period covered by long-term data could be called
for. If the long-term data show variability, verification of the proposed
retest period or shelf life by statistical analysis can be appropriate. In
addition, a discussion should be provided to address the effect of short-term
excursions outside the label storage condition (e.g., during shipping or handling).
This discussion can be supported, if appropriate, by further testing on a
single batch of the drug substance or product at the accelerated condition for
a period shorter than 3 months.
2.5.2 Drug substances or products
intended for storage in a freezer
For
drug substances or products intended for storage in a freezer, the retest period or shelf life should be
based on long-term data. In the absence of an accelerated storage condition
for drug substances or products intended to be stored in a freezer, testing
on a single batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C)
for an appropriate time period should be conducted to address the effect of
short-term excursions outside the proposed label storage condition (e.g.,
during shipping or handling).
2.5.3 Drug substances or products
intended for storage below -20°C
For drug substances or products intended for storage below -20°C, the
retest period or shelf life should be based on long-term data and should be
assessed on a case-by-case basis.
|
Sr.
no.
|
Storage
Conditions
|
Stability
type
|
Temperature
Conditions
|
Type
of change
|
Shelf
life or Retest period
|
|
01.
|
Room Temperature Storage
|
ACC
|
40°C ± 2°C/75%
RH ± 5% RH
|
Little or no
change
|
The proposed retest period or
shelf life can be up to twice, but should not be more than 12 months beyond
Y=
up to 2X, but not exceeding X + 12 months
|
|
ACC
|
40°C ± 2°C/75%
RH ± 5% RH
|
Significant
change
|
The retest period or shelf life
would depend on the outcome of stability testing at the intermediate
condition, as well as at the long-term condition.
|
||
|
INT
|
30°C ± 2°C/65%
RH ± 5% RH
|
No change
|
The proposed retest period or
shelf life can be up to 3 months beyond the period covered by long-term data,
if backed by relevant supporting data.
|
||
|
INT
|
30°C ± 2°C/65%
RH ± 5% RH
|
Significant
change
|
Should not exceed the period covered by long-term
data
|
||
|
LT
|
25°C ± 2°C/60%
RH ± 5% RH
|
Little or no
change
|
The proposed retest period or
shelf life can be up to twice, but should not be more than 12 months beyond,
the period covered by long-term data.
Y
= up to 2X, but not exceeding X + 12 months
|
||
|
LT
|
25°C ± 2°C/60%
RH ± 5% RH
|
Significant
change
|
The proposed retest period or
shelf life can be up to one and-a-half times, but should not be more than 6
months beyond, the period covered by long-term data.
Y
= up to 1.5X, but not exceeding X + 6
months
|
||
|
02.
|
Refrigerator storage
|
ACC & LT
|
25°C ± 2°C/60%
RH ± 5% RH
&
5°C ± 3°C
|
Little change
|
The proposed retest period or
shelf life can be up to one-and-a-half times, but should not be more than 6
months beyond, the period covered by long-term data normally without the
support of statistical analysis.
Y
= up to 1.5X, but not exceeding X + 6
months
|
|
ACC & LT
|
25°C ± 2°C/60%
RH ± 5% RH
&
5°C ± 3°C
|
Change
|
If there is change in long-term
data, then
Y
= up to X + 3 months.
If there is no change in long-term
data then,
Y
= up to 1.5X, but not exceeding X + 6 months
|
||
|
ACC
|
25°C ± 2°C/60%
RH ± 5% RH
|
Significant
change
|
If significant change occurs
between 3 and 6 months’ testing at the accelerated storage condition, the
proposed retest period or shelf life should be based on the long term data.
|
||
|
03.
|
Freezer
|
LT
|
N.A.
|
N.A.
|
The retest period or shelf life should be based on
long-term data
|
|
04.
|
Below -20°C
|
LT
|
N.A.
|
N.A.
|
The retest period or shelf life should be based on
long-term data and should be assessed on a case-by-case basis
|
ACC- Accelerated stability
INT- Intermediate stability
LT- Long-term stability
N.A.- Not applicable
Note: For drug substances or products intended to be
stored in a freezer, accelerated storage testing should be performed for single
batch at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C) for an
appropriate time period to address the effect of short-term excursions outside
the proposed label storage condition (e.g., during shipping or handling).
References:
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