Guidelines For Stability of Active Pharmaceutical Ingredient Part-1
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- General
Information on the stability of the API is an integral part of the systematic approach to stability evaluation. Potential attributes to be studied during stability testing of an API are listed in the examples of testing parameters.
The selection of potential attributes and time points to be tested should be justified.
The retest period or shelf life assigned to the API by the API manufacturer should be derived from stability testing data.
- Stress testing
Stress testing of the API can help identify the likely degradation products, which in turn can 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 API and the type of FPP involved.
For an API the following approaches may be used:
–– when available, it is acceptable to provide the relevant data published in the scientific literature to support the identified degradation products and pathways.
–– when no published data are available, stress testing should be performed.
Stress testing may be conducted on a single batch of the API. It should include the effect of temperature (in 10 °C increments (for example, at 50 °C, 60 °C) above the temperature used for accelerated testing), humidity (for example, 75% relative humidity (RH) or greater) and, where appropriate, oxidation and photolysis of the API. The testing should also evaluate the susceptibility of the API to hydrolysis across a justified range of pH values when in solution or suspension.
Assessing the necessity for photo-stability testing should be an integral part of a stress testing strategy.
The objective of stress testing is to identify primary degradation products and not to completely degrade the API. The conditions studied should cause degradation to occur to a small extent, typically 10–30% loss of API as determined by assay when compared with non-degraded API. The target should be chosen so that some degradation occurs, but not enough to generate secondary products. For this reason, the conditions and duration may need to be varied when the API is especially susceptible to a particular stress factor. In the total absence of degradation products after 10 days the API is considered stable under the particular stress condition. However, in this case the stress conditions employed should be justified.
Although examining degradation products under stress conditions is useful in establishing degradation pathways and developing and validating suitable analytical procedures, it may not be necessary to examine specifically for certain degradation products if it has been demonstrated that they are not formed under accelerated or long-term storage conditions.
Results from these studies will form an integral part of the information provided to regulatory authorities.
- Selection of batches
Data from stability studies on at least three primary batches of the API should normally be provided. The batches should be manufactured at a minimum of pilot scale by the same synthesis route as production batches and using a method of manufacture and a procedure that simulates the final process to be used for production batches. The overall quality of the batches of API placed on stability studies should be representative of the quality of the material to be made on a production scale.
Other supporting data can be provided.
- Container-closure system
The stability studies should be conducted on the API packaged in a container-closure system that is the same as, or simulates, the packaging proposed for storage and distribution.
- Specification
Stability studies should include testing of stability-indicating attributes of the API, i.e. those that are susceptible to change during storage and are likely to influence quality, safety and/or efficacy. The testing should cover, as appropriate, the physical, chemical, biological and microbiological attributes.
Validated stability-indicating analytical procedures should be applied. Whether and to what extent replication should be performed will depend on the results from validation studies.
- Testing frequency
For long-term studies, the frequency of testing should be sufficient to establish the stability profile of the API.
For APIs with a proposed retest period or shelf life of at least 12 months, the frequency of testing at the long-term storage condition should normally be every three months over the first year, every six months over the second year, and annually thereafter throughout the proposed retest period or shelf life.
At the accelerated storage condition, a minimum of three time points, including the initial and final time points (e.g. 0, 3 and 6 months), from a six-month study is recommended. Where it is expected (based on development experience) that results from accelerated studies are likely to approach significant change criteria, additional testing should be conducted either by adding samples at the final time point or by including a fourth time point in the study design. 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 and 12 months), from a 12-month study is recommended.
- Storage conditions
In general, an API should be evaluated under storage conditions (with appropriate tolerances) that test its thermal stability and, if applicable, its sensitivity to moisture. The storage conditions and the lengths of studies chosen should be sufficient to cover storage and shipment.
Storage condition tolerances are defined as the acceptable variations in temperature and RH of storage facilities for stability studies. The equipment used should be capable of controlling the storage conditions within the ranges defined in these guidelines. The storage conditions should be monitored and recorded. Short-term environmental changes due to opening the doors of the storage facility are accepted as unavoidable. The effect of excursions due to equipment failure should be assessed, addressed and reported if judged to affect stability results. Excursions that exceed the defined tolerances for more than 24 hours should be described in the study report and their effects assessed.
The following requirements for data at the time of submission are not generally intended to apply to variations. For new APIs, the long-term testing should normally have taken place over a minimum of 12 months for the number of batches at the time of submission, and should be continued for a period of time sufficient to cover the proposed retest period or shelf life. For existing APIs, data covering a minimum of six months may be submitted. Additional data accumulated during the period while the registration application is being assessed should be submitted to the authorities when submitting data in response to outstanding questions. 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 APIs are detailed. The general case applies if the API is not specifically covered by a subsequent section. Alternative storage conditions can be used if justified.
If long-term studies are conducted at 25 °C ± 2 °C/60% RH ± 5% RH and “significant change” occurs at any time during six months’ testing at the accelerated storage condition, additional testing at the intermediate storage condition should be conducted and evaluated against significant change criteria. In this case, testing at the intermediate storage condition should include all long term tests, unless otherwise justified, and the initial application should include a minimum of six months’ data from a 12-month study at the intermediate storage condition.
“Significant change” for an API is defined as failure to meet its specification.
General case
| Study | Storage condition | Minimum time period covered by data at submission |
| Long-term a | 25°C ± 2°C/60% RH ± 5% RH or | 12 months or 6 months |
| 30°C ± 2°C/65% RH ± 5% RH or | ||
| 30°C ± 2°C/75% RH ± 5% RH | ||
| Intermediate b | 30°C ± 2°C/65% RH ± 5% RH | 6 months |
| Accelerated | 40 °C ± 2 °C/75% RH ± 5% RH | 6 months |
a Whether long-term stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is determined by the climatic condition under which the API is intended to be stored (see “Long-term stability testing conditions as identified by WHO Member States”). Testing at a more severe long-term condition can be an alternative to testing condition, i.e., 25 °C/60% RH or 30 °C/65% RH for zone II.
b If 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is the long-term condition there is no intermediate condition.
Active pharmaceutical ingredients intended for storage in a refrigerator
| Study | Storage condition | Minimum time period covered by data at submission |
| Long-term | 5 °C ± 3 °C | 12 months or 6 months |
| Accelerated a |
25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH |
6 months |
- Whether accelerated stability studies are performed at 25 °C ± 2 °C/60% RH ± 5% RH or 30 °C ± 2 °C/65% RH ± 5% RH or 30 °C ± 2 °C/75% RH ± 5% RH is based on a risk-based evaluation. Testing at a more severe accelerated condition can be an alternative to storage testing at 25 °C/60% RH or 30 °C/65% RH.
Data on refrigerated storage should be assessed according to the evaluation section of these guidelines, except where explicitly noted below. If significant change occurs between three and six months’ testing at the accelerated storage condition, the proposed retest period should be based on the data available at the long-term storage condition.
If significant change occurs within the first three months’ testing at the accelerated storage condition a discussion should be provided addressing 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 API for a period shorter than three months but with more frequent testing than usual. It is considered unnecessary to continue to test an API for the whole six months when a significant change has occurred within the first three months.
Active pharmaceutical ingredients intended for storage in a freezer
| Study | Storage condition | Minimum time period covered by data at submission |
| Long-term | −20 °C ± 5 °C | 12 months or 6 months. |
In the rare case of any API of nonbiological origin being intended for storage in a freezer, the retest period or shelf life should be based on the long-term data obtained at the long-term storage condition. In the absence of an accelerated storage condition for APIs 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 or 30 °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.
Active pharmaceutical ingredients intended for storage below −20 °C
APIs intended for storage below −20 °C should be treated on a case-by-case basis.
- Stability commitments
When the available long-term stability data on primary batches do not cover the proposed retest period or shelf life granted at the time of approval, a commitment should be made to continue the stability studies post-approval in order to firmly establish the retest period or shelf life.
Where the submission includes long-term stability data on three production batches covering the proposed retest period or shelf life, 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 three production batches, a commitment should be made to continue these studies through the proposed retest period or shelf life.
–– 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, up to a total of at least three, in long-term stability studies through the proposed retest period or shelf life.
–– 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 or shelf life.
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.
- Evaluation
The purpose of the stability study is to establish – based on testing a minimum of three batches of the API, unless otherwise justified, and evaluating the stability information (including, as appropriate, results of the physical, chemical, biological and microbiological tests) – a retest period or shelf life applicable to all future batches of the API 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 or shelf life.
The data may show so little degradation and so little variability that it is apparent from looking at them that the requested retest period or shelf life will be granted. Under these circumstances it is normally unnecessary to go through the statistical analysis.
One 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% 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 or shelf life 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. As far as possible the choice of model should be justified by a physical and/or chemical rationale and should also take into account the amount of available data (parsimony principle to ensure a robust prediction). 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 long-term data from the long-term storage condition beyond the observed range to extend the retest period or shelf life can be undertaken if justified. This justification should be based 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 existence of supporting stability data. However, this extrapolation assumes that the same degradation relationship will continue to apply beyond the observed data (please refer to ICH Q1E).
Any evaluation should cover not only the assay but also the levels of degradation products and other stability-indicating attributes.
- Statements and labelling
A storage statement should be established for display on the label based on the stability evaluation of the API. Where applicable, specific instructions should be provided, particularly for APIs that cannot tolerate freezing or excursions in temperature. 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.
After this retest period a batch of API destined for use in the manufacture of an FPP could be retested and then, if in compliance with the specification, could be used immediately (e.g. within 30 days) . If retested and found compliant, the batch does not receive an additional period corresponding to the time established for the retest period. However, an API batch can be retested multiple times and a different portion of the batch used after each retest, as long as it continues to comply with the specification. For APIs known to be labile (e.g. certain antibiotics) it is more appropriate to establish a shelf life than a retest period.
- Ongoing stability studies
The stability of the API should be monitored according to a continuous and appropriate program that will permit the detection of any stability issue (e.g. changes in levels of degradation products). The purpose of the ongoing stability program is to monitor the API and to determine that the API remains, and can be expected to remain, within specifications under the storage conditions indicated on the label, within the retest period or shelf life in all future batches.
The ongoing stability program should be described in a written protocol and the results presented in a formal report that should be available on site.
The protocol for an ongoing stability program should extend to the end of the retest period or shelf life and should include, but not be limited to, the following parameters:
–– number of batch(es) and different batch sizes, if applicable;
–– relevant physical, chemical, microbiological and biological test parameters with acceptance criteria or reference to the attached specifications;
–– reference to test methods;
–– description of the container-closure system(s); –– testing frequency;
–– description of the conditions of storage (standardized conditions for long-term testing as described in these guidelines, and consistent with the API labelling, should be used);
–– other applicable parameters specific to the API.
At least one production batch per year of API (unless none is produced during that year) should be added to the stability monitoring program and generally should be tested at least every 6 months in the first year and then annually to confirm the stability.
In certain situations, additional batches should be included in the stability program and may require more frequent testing. For example, a stability study should be initiated after any significant change or significant deviation of the synthetic route, process or container-closure system that may have an impact upon the stability of the API.
Out-of-specification (OOS) results or significant atypical trends should be investigated. Any confirmed significant change or OOS result should be reported immediately to the relevant finished product manufacturer. The possible impact on batches on the market should be considered in consultation with the relevant finished product manufacturers and the competent authorities.
A summary of all the data generated, including any interim conclusions on the program, should be written and maintained and should be available on site. This summary should be subjected to periodic review.
Reference: TRS 1010 Annex 10 2018