Stability Testing of New Drug Substances
The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions.
The choice of test conditions defined in this guidance is based on an analysis of the effects of climatic conditions in the three regions of the EU, Japan, and the United States.
The mean kinetic temperature in any part of the world can be derived from climatic data, and the world can be divided into four climatic zones, I-IV.
This guidance addresses climatic zones I and II.
The principle has been established that stability information generated in any one of the three regions of the EU, Japan, and the United States would be mutually acceptable to the other two regions.
Scope of the Guidance
The guidance addresses the information to be submitted in registration applications for new molecular entities and associated drug products.
This guidance does not currently cover to be submitted for abbreviated or abridged applications, variations, or clinical trial applications.
Specific details of the sampling and testing for particular dosage forms in their proposed container closures are also not covered in this guidance.
A. Drug Substance
1. General
Stability of the drug substance is an integral part of the systematic approach to stability evaluation.
2. Stress Testing
Stress testing of the drug substance can identify the degradation products, which can in turn help establish the degradation pathways and the intrinsic stability of the molecule and validate the stability indicating power of the analytical procedures used.
The nature of the stress testing will depend on the individual drug substance and the type of drug product involved.
Stress testing is to be carried out on a single batch of the drug substance.
The testing should include the effect of temperatures (in 10°C increments (e.g., 50°C, 60°C) above that for accelerated testing), humidity (e.g., 75 percent relative humidity or greater) where appropriate,oxidation, and photolysis on the drug substance.
The testing should also evaluate the susceptibility of the drug substance to hydrolysis across a wide range of pH values when in solution or suspension. Photostability testing should be an integral part of stress testing.
For details of photo-stability testing please refer ICH Q1B Photo-stability Testing of New Drug Substances and Products
Examining of degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures.
Results from these studies will form an integral part of the information provided to regulatory authorities.
3. Selection of Batches
Data from formal stability studies should be provided on at least three primary batches of the drug substance. The batches should be manufactured to a minimum of pilot scale by the same synthetic route as production batches and using a method of manufacture and procedure that simulates the final process to be used for production batches.
The overall quality of the batches of drug substance placed on formal stability studies should be representative of the quality of the material to be made on a production scale.
4. Container Closure System
The stability studies should be conducted on the drug substance packaged in a container closure system that is the same as or simulates the packaging proposed for storage and distribution.
5. Specification
Specification, which is a list of tests, references to analytical procedures, and proposed acceptance criteria
Stability studies should include testing of those attributes of the drug substance that are susceptible to change during storage and are influence quality, safety, and/or efficacy.
The testing should cover the physical, chemical, biological, and microbiological attributes (As applicable).
For details Refer ICH Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances)
Please refer for Specification for degradation products in a drug substance is discussed in ICH Q3A Impurities in New Drug Substances).
6. Testing Frequency
long-term condition: Frequency of testing should be sufficient to establish the stability profile of the drug substance.
For drug substances with a proposed retest period of at least 12 months, the frequency of testing at the long-term storage condition should normally be
Every 3 months over the first year,
Every 6 months over the second year, and
Annually thereafter through the proposed retest period.
Accelerated storage condition, a minimum of three time points, including the initial and
final time points (e.g., 0, 3 months and 6 months), from a 6-month study is recommended.
Where an expectation (based on development experience) exists that the results from accelerated studies
are likely to approach significant change criteria, increased testing should be conducted either by
adding samples at the final time point or including a fourth time point in the study design.
Intermediate storage condition
When testing at the intermediate storage condition is called for as a result of significant change at
the accelerated storage condition,
a minimum of four time points, including the initial and final time points (e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.
7. Storage Conditions
A drug substance should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and its sensitivity to moisture (if applicable).
The storage conditions and the lengths of studies chosen should be sufficient to cover storage, shipment, and subsequent use.
The long-term testing should cover a minimum of 12 months’ duration on at least three primary batches at the time of submission and should be continued for a period of time sufficient to cover the proposed retest period.
Additional data accumulated during the assessment period of the registration application should be submitted to the authorities if requested.
Data from the accelerated storage condition and, if appropriate, from the intermediate storage condition can be used to evaluate the effect of short-term excursions outside the label storage conditions (such as might occur during shipping).
Long-term, accelerated and where appropriate, intermediate storage conditions for drug substances are as follow. Alternative storage conditions can be used if justified.
A. General case 
If long-term studies are conducted at 25°C ± 2°C/60% RH ± 5% RH and significant change occurs at any time during 6 months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria.
Testing at the intermediate storage condition should include all tests,unless otherwise justified.
The initial application should include a minimum of 6 months’ data from a 12-month study at the intermediate storage condition.
Significant change for a drug substance is defined as failure to meet its specification.
B. Drug substances intended for storage in a refrigerator
Data from refrigerated storage should be assessed and evaluate, except where explicitly noted below.
If significant change occurs between 3 and 6 months’ testing at the accelerated storage condition,the proposed retest period should be based on the real time data available at the long-term storage condition.
If significant change occurs within the first 3 months’ testing at the accelerated storage condition, a discussion should be provided to address the effect of short-term excursions outside the label storage condition (e.g., during shipping or handling).
Also supported,if appropriate, by further testing on a single batch of the drug substance for a period shorter than 3 months but with more frequent testing than usual. It is considered unnecessary to continue to
test a drug substance through 6 months when a significant change has occurred within the first 3 months.
c. Drug substances intended for storage in a freezer
For drug substances intended for storage in a freezer, the retest period should be based on the real time data obtained at the long-term storage condition.
In the absence of an accelerated storage condition for drug substances 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).
d. Drug substances intended for storage below -20°C
Drug substances intended for storage below -20°C should be treated on a case-by-case basis.
8. Stability Commitment
When available long-term stability data on primary batches do not cover the proposed retest period granted at the time of approval, a commitment should be made to continue the stability studies post-approval to establish the retest period.
Where the submission includes long-term stability data on three production batches covering the proposed retest period, a post-approval commitment is considered unnecessary.
Otherwise, one of the following commitments should be made:
· If the submission includes data from stability studies on at least three production batches, a commitment should be made to continue these studies through the proposed retest period.
If the submission includes data from stability studies on fewer than three production batches, a commitment should be made to continue these studies through the proposed retest period and to place additional production batches, to a
total of at least three, on long-term stability studies through the proposed retest period.
If the submission does not include stability data on production batches, a commitment should be made to place the first three production batches on long term stability studies through the proposed retest period.
The stability protocol used for long-term studies for the stability commitment should be the same as that for the primary batches, unless otherwise scientifically justified.
9. Evaluation
The purpose of the stability study is to establish, based on testing a minimum of three batches of
the drug substance and evaluating the stability information (including, a results of the physical, chemical, biological, and microbiological tests), a retest period applicable to all future batches of the drug substance manufactured under similar circumstances.
The degree of variability of individual batches affects the confidence that a future production batch will remain
within specification throughout the assigned retest period.
The data may show so little degradation and so little variability that it is apparent from looking at the data that the requested retest period will be granted. Under these circumstances, it is normally unnecessary to go through the formal statistical analysis; providing a justification for the omission should be sufficient.
An approach for analyzing the data on a quantitative attribute that is expected to change with time is to determine the time at which the 95 percent, one-sided confidence limit for the mean curve intersects the acceptance criterion.
If analysis shows that the batch-to-batch variability is small, it is advantageous to combine the data into one overall estimate. This can be done by first applying appropriate statistical tests (e.g., p values for level of significance of rejection of more than 0.25) to the slopes of the regression lines and zero time intercepts for the individual batches.
If it is inappropriate to combine data from several batches, the overall retest period should be based on the minimum time a batch can be expected to remain within acceptance criteria.
The nature of any degradation relationship will determine whether the data should be transformed for linear regression analysis. Usually the relationship can be represented by a linear, quadratic, or cubic function on an arithmetic or logarithmic scale.
Statistical methods should be employed to test the goodness of fit of the data on all batches and combined batches
(where appropriate) to the assumed degradation line or curve.
Limited extrapolation of the real time data from the long-term storage condition beyond the observed range to extend the retest period can be undertaken at approval time if justified. This justification should be based, for example, on what is known about the mechanism of degradation, the results of testing under accelerated conditions, the goodness of fit of any mathematical model, batch size, and/or existence of supporting stability data.
However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the
observed data.
Any evaluation should cover not only the assay, but also the levels of degradation products and other appropriate attributes.
10. Statements/Labeling
A storage statement should be established for the labeling in accordance with relevant national/regional requirements.
The statement should be based on the stability evaluation of the drug substance. Where applicable, specific instructions should be provided, particularly for drug substances that cannot tolerate freezing. Terms such as ambient conditions or room temperature should be avoided.
A retest period should be derived from the stability information, and a retest date should be displayed on the container label if appropriate.
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Reference:Guidance for Industry Q1A(R2) Stability Testing of New Drug Substances and Products
