1.0 OBJECTIVE
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 enables recommended storage conditions, retest periods, and shelf lives to be established.
2.0 DRUG SUBSTANCE
3.0 GENERAL
Information on the stability of the drug substance is an integral part of the systematic approach to stability evaluation.
4.0 STRESS TESTING
Stress testing helps to determine the intrinsic stability of the molecule by establishing degradation pathways in order to identify the likely degradation products and to validate the stability indicating power of the analytical procedures used.
5.0 FORMAL STUDIES
Primary stability studies are intended to show that the drug substance will remain within specification during the retest period if stored under recommended storage conditions.
6.0 SELECTION OF BATCHES
Stability information from accelerated and long-term testing is to be provided on at least three batches.
The long-term testing should cover a minimum of 12 months duration on at least three batches at the time of submission.
The batches manufactured to a minimum of pilot plant scale should be by the same synthetic route and use a method of manufacture and procedure that simulates the final process to be used on a manufacturing scale.
The overall quality of the batches of drug substance placed on stability should be representative of both the quality of the material used in pre-clinical and clinical studies and the quality of material to be made on a manufacturing scale.
Supporting information may be provided using stability data on batches of drug substance made on a laboratory scale.
The first three production batches of drug substance manufactured post approval, if not submitted in the original Registration Application, should be placed on long-term stability studies using the same stability protocol as in the approved drug application.
7.0 Test Procedures and Test Criteria
The testing should cover those features susceptible to change during storage and likely to influence quality, safety and/or efficacy. Stability information should cover as necessary the physical, chemical, and microbiological test characteristics. Validated stability indicating testing methods must be applied. The need for the extent of replication will depend on the results of validation studies.
8.0 SPECIFICATION
Limits of acceptability should be derived from the profile of the material as used in the preclinical & clinical batches. It will need to include individual and total upper limits for impurities and degradation products, the justification for which should be influenced by the levels observed in material used in preclinical studies and clinical trials.
9.0 STORAGE CONDITIONS
The length of the studies and the storage conditions should be sufficient to cover storage, shipment, and subsequent use. Application of the same storage conditions as applied to the drug product will facilitate comparative review and assessment. Other storage conditions are allowable if justified. In particular, temperature sensitive drug substances should be stored under an alternative, lower temperature condition which will then become the designated long-term testing storage temperature. The six months accelerated testing should then be carried out at a temperature at least 15 C above this designated long-term storage temperature (together with the appropriate relative humidity conditions for that temperature) . The designated long-term testing conditions will be reflected in the labeling and retest date.
| Conditions Long term testing | 25 ± 2 / 60 ± 5% RH | Minimum Tine period at submission 12 Months |
| Accelerated testing | 40 ± 2 / 75 ± 5% RH | 6 Months |
Where “Significant change” occurs during six months storage under conditions of accelerated testingat 40 C ± 2 C / 75% RH ± 5%, additional testing at an intermediate condition (such as 30 C ± 2 C/60 ± RH ± 5%) should be conducted for drug substances to be used in the manufacture of dosage forms tested long term at 25 C / 60% RH and this information included in the Registration Application. The initial Registration Application should include a minimum of 6 months data from a 12-month study.
Significant change at 40 C / 75% RH or 30 C/60% RH is defined as failure to meet the specification. The long. term testing will be continued for a sufficient period of time beyond 12 months to cover all appropriate retest periods, and the further accumulated data can be submitted to the authorities during the assessment, period of the Registration Application.
The data (from accelerated testing or from testing at an intermediate condition) may be used to evaluate the impact of short-term excursions outside the label storage conditions such as might occur during shipping.
10.0 TESTING FREQUENCY
Frequency of testing should be sufficient to establish the stability characteristics of the drug substance. Testing under the defined long-term conditions will normally be every three months, over the first year, every six months over the second year, and then annually.
11.0 PACKAGING / CONTAINERS
The containers to be used in the long-term, real-time stability evaluation should be the same as or simulate the actual packaging used for storage & distribution.
12.0 Evaluation
The design of the stability study is to establish, based on testing a minimum of three batches of the drug substance and evaluating the stability information (covering as necessary the physical, chemical, and microbiological test characteristics), a retest period applicable to all future batches of the bulk 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 until the retest date.
An acceptable approach for quantitative characteristics that are expected to decrease with time is to deter- mine the time at which the 95% one-sided confidence limit for the mean degradation curve intersects the acceptable lower specification limit. If analysis shows that the batch to batch variability is small, it is advantageous to combine the data into one overall estimate, and this can be done by first applying appropriate statistical tests (for example, p values for level of significance of rejection of 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 may depend on the minimum time a batch may be expected to remain within acceptable and justified limits.
The nature of any degradation relationship will determine the need for transformation of the data 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.
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 the circumstances, it is normally unnecessary to go through the formal statistical analysis but merely to provide a full justification for the omission.
Limited extrapolation of the real time data beyond the observed range to extend expiration dating at approval time, particularly where the accelerated data supports this, may be undertaken. However, this assumes that the same degradation relationship will continue to apply beyond the observed data, and hence the use of extrapolation must be justified in each application in terms of what is known about the mechanism of degradation, the goodness of fit of any mathematical model, batch size, existence of supportive data, etc.
Any evaluation should cover not only the assay but the levels of degradation products and other appropriate attributes.
13.0 STATEMENTS/LABELING
A storage temperature range may be used in accordance with relevant national/regional requirements. The range should be based on the stability evaluation of the drug substance. Where applicable, specific requirements should be stated, particularly for drug substances that cannot tolerate freezing. The use of terms such as ambient conditions or at room temperature is unacceptable.
A retest period should be derived from the stability information.
B) Drug Product
1.0 General
The design of the stability program for the finished product should be based on the knowledge of the behavior and properties of the drug substance and the experience gained from clinical formulation studies and from the stability studies on the drug substance. The likely changes on storage and the rationale for the selection of product variables to include in the testing program should be stated.
2.0 Selection of Batches
Stability information from accelerated and long-term testing is to be provided on three batches of the same formulation and dosage form in the containers and closure proposed for marketing. Two of the three, batches should be at least pilot scale. The third batch may be smaller {e.g. 25,000 to 50,000 tablets or capsules for solid oral dosage forms). The long-term testing should cover at least 12 months duration at the time of submission. The manufacturing process to be used should meaningfully simulate that which would be applied to large scale batches for marketing. The process should provide product of the same quality intended for marketing and meeting the same quality specification as to be applied for release of material. Where possible, batches of the finished product should be manufactured using identifiably different batches of drug substance.
Data on laboratory scale batches is not acceptable as primary stability information. Data on associated formulations or packaging may be submitted as supportive information. The first three production batches manufactured post approval, if not submitted in the original Registration Application, should be placed on accelerated and long-term stability using the same stability protocols as in the approved drug application.
3.0 Test Procedures and Test Criteria
The testing should cover those features susceptible to change during storage and likely to influence quality, safety and / or efficacy. Analytical test procedures should be fully validated, and the assays should be stability indicating. The need for the extent of replication will depend on the results of validation studies.
The range of testing should cover not only chemical and biological stability but also loss of preservative physical properties and characteristics, organoleptic and, where required, microbiological attributes. Preservative efficacy testing and assays on stored samples should be carried out to determine the content and efficacy of antimicrobial preservatives.
4.0 Specifications
Limits of acceptance should relate to the release limits (where applicable), to be derived from consider- action of all the available stability information.
The shelf life specification could allow acceptable and justifiable derivations from the release specification based on the stability evaluation and
The use of matrixing or bracketing can be applied, if justified. (See Glossary).
5.0 Packaging Materials
The testing should carried out in the final packaging proposed for marketing. Additional testing of unreported drug product can form a useful part of the stress testing and pack evaluation, as can studies carried out in other related packaging materials in supporting the definitive pack(s).
6.0 Evaluation
A systematic approach should be adopted in the presentation and evaluation of the stability information which should cover as necessary physical, chemical biological, and microbiological quality characteristics, including particular properties of the dosage form (for example dissolution rate for oral solid dose forms).
The design of the stability study is to establish, based on testing a minimum of three batches of the drug product, a shelf life and label storage instructions applicable to all future batches of the dosage form manufactured and packed under similar circumstances.
The degree of variability of individual batches affects the confidence that a future production batch will remain within specification until the expiration date.
An acceptable approach for quantitative characteristic that are expected to decrease with time is to determine the time at which the 95% one sided confidence limit for the mean degradation curve intersects the acceptable lower specification limit. If analysis shows that the batch to batch variability is small, it is advantageous to combine the data into one overall estimate, and this can be done by first applying appropriate statistical tests {for example, p values for level of significance the changes observed on storage. It will need to include specific upper limits for degradation products, the justification for which should be influenced by the levels observed in material used in pre-clinical studies and clinical trials. The justification for the limits proposed for certain other tests such as particle size and/or dissolution rate will require reference to the results observed for batch(es) used in bioavailability and/or clinical studies. Any differences between the release and shelf life specifications for anti-microbial preservatives should be supported by preservative efficiency testing.
7.0 Storage Test Conditions
The length of the studies and the storage conditions should be sufficient to cover storage, shipment, and subsequent use (e.g. reconstitution or dilution as recommended in the labeling).
See Table below for accelerated and long-term storage conditions and minimum times. An assurance that long- term testing will continue to cover the expected shelf life should be provided.
Our storage conditions are allowable if justified.
Heat sensitive drug product should be stored under an alternative lower temperature condition which will eventually become the designated long-term storage temperature. Special consideration may need to be given to products that change physically or even chemically at lower storage conditions, e.g. suspensions or emulsions which may sediment or cream, oils, and semi- solid preparations which may show an increased viscosity. Where a lower temperature condition is used, the six months accelerated testing should be carried out at a temperature at least 15 C above its designated long-term storage temperature (together with appropriate relative humidity conditions for that temperature). For example, for a product to be stored long-term under refrigerated conditions, accelerated testing should be conducted at 250C ± 2 C/ 60% RH ± 5% RH. The designated long-term testing conditions will be reflected in the labeling
and expiration date.
Storage under conditions of high relative humilities applies particularly to solid dosage forms. For products such as solutions, suspensions, etc. contained in packs designed to provide a permanent barrier to water loss, specific storage under conditions of high relative humidity is not necessary, but the same range of temperatures should be applied. Low relative humidity (e .g. 10 to 20% RH) can adverse effect products packed in semi-permeable containers (e.g. solutions in plastic bags, nose drops in small plastic
containers, etc.) and consideration should be given to appropriate testing under such conditions.
| Conditions Long term testing | 25 ± 2 / 60 ± 5% RH | Minimum Time period at submission 12 months |
| Accelerated testing | 40 ± 2 / 75 ± 5% RH | 6 Months |
Where significant change occurs due to accelerated testing additional testing at an intermediate condition e.g. 30 C ± 2 C/60 ± 5% RH should be conducted. Significant change at the accelerated condition is defined as:
1. A 5% potency loss from the initial assay value of a batch;
2. Any specified degradant exceeding its specification limit;
3. The product exceeding its pH limits;
4. Dissolution exceeding the specification limits for 12 capsules or tablets.
5. Failure to meet specifications for appearance and physical properties e.g. color, phase separation, responsibility, delivery per actuation, caking hardness etc.
Should significant change occur at 40 C / 75% RH then the initial Registration Application should include a minimum of 6 months data from an ongoing one-year study at 30 C/ 60% RH the same significant change criteria shall then apply.
The long-term testing will be continued for a sufficient time beyond 12 months to cover shelf life at appropriate test periods. The further accumulated data should be submitted to the authorities during the assessment period of the Registration Application.
The first three production batches manufactured post approval, if not submitted in the original Registration Application, should be placed on accelerated and long- term stability studies using the same stability protocol as in the approved drug application.
8.0 Testing Frequency
Frequency of testing should be sufficient to establish the stability characteristics of the drug product. Testing will normally be every three months over the first year, every six months over the second year, and then annually. 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 in appropriate to combine data from several batches, the overall shelf life may depend on the minimum time a batch may expected to remain within acceptable and justified limits.
The nature of the degradation relationship will determine the need for transformation of the data 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 on all batches and combined batches (where appropriate) to the assumed degradation line or curve.
Where the data shows 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 but only to provide a justification for the omission.
Limited extrapolation of the real time data beyond the observed range to extend expiration dating at approval time, particularly where the accelerated data supports this, may be undertaken.
However, this assumes that the same degradation relation ship will continue to apply beyond the observed data, and hence the use of extrapolation must be justified in each application in terms of what is known about the mechanisms of degradation the goodness of fit of any mathematical model, batch size, existence of supportive data, etc.
Any evaluation should consider not only the assay, but the levels of degradation products and appropriate attributes. Where appropriate attention should be paid to reviewing the adequacy of the mass balance, different stability, and degradation performance.
The stability of the drug products after reconstituting or diluting according to labeling, should be addressed to provide appropriate and supportive information.
The following people have read this SOP and are currently following these procedures in the laboratory.
| Person | Signature | Date |
