What should be the accelerated stability testing and shelf-life calculation is explained in the 21 CFR part 211.137- Expiration dating.
As a result of the publication of 21 CFR Part 211 – Current Good Manufacturing Practice for Finished Pharmaceuticals, requirements were outlined concerning the expiration date of a drug product and the stability testing needed to ensure that that date was appropriate.
A drug product may be unique due to, among other factors, differences in (i) chemical and physical properties of the active ingredients or excipients, (ii) manufacturing procedures, (iii) formulations, (iv) containers and closures, (v) proposed storage conditions and (vii) the stability of the product to maintain its quality or purity through the use of antioxidants or preservatives.
A set of rules that can apply to all drug products is virtually impossible due to the unique nature of each drug. The CGMPs were specifically written to allow for such unique differences.
Accelerated Stability Testing And Shelf-Life Calculation:
A: Absence of expiration date:
Any drug product packaged after September 29, 1979, except for those specifically exempt by 211.137 (e), (f), and (g), is subject to regulatory action against the product and/or the responsible firm if no expiration date is included.
For OTC products meeting the exemption of 211.137 (g), accelerated testing programs may be used to demonstrate that they have been stable for 3 years or longer. It may also be useful to analyze information obtained from old stock, which has not previously been studied for stability.
C: Products Intended for Reconstitution:
A drug product intended for reconstitution that does not bear an expiration date for the unreconstituted product and additional expiration date for the reconstituted product is considered to be out of compliance with 211.137 (c). Each expiration date must be supported by a separate stability study.
Stability Testing (21 CFR 211.166):
A: Written Stability Testing Program:
If there is no written protocol for stability testing, regulatory action may be initiated against the product and/or the responsible firm.
B: Supportive Stability Data:
i. Number and size of batches:
An initial stability test may be performed on a smaller batch than the normal production size as long as the batch is produced on the same equipment as the regular run.
To determine the expiration date, an initial batch of three should be placed in the long-term stability program to assure batch uniformity.
A dosage form is a complex unit, and there are many variables in the production process, including personnel, raw material suppliers, and equipment, so it is imperative that ongoing stability studies are not limited only to initial production batches, but a portion of the annual production batches as well.
ii. Accelerated Studies:
When accelerated stability studies are conducted, one batch may be sufficient to establish a tentative expiration date. Since the purpose of an accelerated test is not to determine batch uniformity, but to determine kinetic degradation, this is acceptable.
The use of accelerated testing data to establish a tentative expiration dating period exceeding three years is discouraged when it is based solely on accelerated testing data. Based on the combination of data collected at room temperature and at accelerated temperature, it is possible to justify an expiration dating period of over two years.
As an example, accelerated temperature conditions can be applied by taking a sample that has been at room temperature for one year and subjecting it to those conditions. The expiration date used would be the sum of the dates justified individually at each storage condition.
Performing accelerated tests at very high temperatures for a very short time and extending results to a very long expiration dating period is not appropriate because the actual mechanism of degradation may be different at high temperature than at room temperature.
iii. Test Intervals:
In general, stability testing is recommended to be performed initially, then every three months for the first year, then every six months for the second year, and then annually after that.
However, more frequent testing near the end of the expected expiration date may provide more information regarding the actual stability of the finished product.
However, compliance with CGMPs requires testing at least once a year.
For economic reasons, some manufacturers test all stability samples of a given product at random dates. A test performed at least once a year can be quite satisfactory under this approach.
iv. Storage Conditions:
The actual conditions of storage should be recorded if a product was kept under controlled conditions (temperature and humidity). In order to evaluate a product’s stability, it is not enough to state that it was stored at room temperature.
According to the USP, controlled room temperatures should range between 15°C and 30°C (59 and 86 F).
In a nutshell, a product stored at or near 15° C may have quite a different quality profile at its expiration date than a product stored at or near 30° C.
According to published data, a reasonable temperature range for thermal exposure at room temperature is 24-25° C.
A stability study should be conducted on a product stored under normal storage conditions or, preferably, under exaggerated conditions.
It is recommended that products susceptible to degradation by light or moisture are stored in a lighted area or in conditions of high humidity, unless the packaging demonstrates that it will prevent degradation by that condition.
In general, products susceptible to light degradation need not be kept in an area with lighting if they are usually packaged and stored for use in opaque containers.
v. Test Methods:
While 211.166 (a) (3) merely requires that test methods be reliable, meaningful, and specific, section 211.165 (e) gives even more guidance by requiring that the accuracy, sensitivity, specificity, and reproducibility of the test methods employed by the firm be established and documented.
According to Section 211.194 (a) (2), all testing methods must be verified under actual operating conditions.
The testing procedures must include a stability indicator test that will distinguish the active ingredient from any degradation products and be able to calculate the quantity of any degradation products.
Assay methods for determining product strength do not necessarily include the stability indicator test.
Manufacturers who contract analytical labs to perform end product testing or stability studies or who produce under contract for other firms are ultimately responsible for the quality of their products and must retain copies of all analytical procedures employed and appropriate documentation to support their validity on file.
Additionally, repackers relying on stability studies conducted by the manufacturer must have copies of all analytical data required to support the date of expiration.
In order to determine a product’s stability, specific methods must be employed, but there is no need for any specific technique. Analyses such as thin layer chromatography, where limits are known, may be satisfactory in situations such as these.
Despite the fact that many USP tests are specific to the drug or its degradation products and may be used for stability testing, some USP monographs lack stability indicators.
Additionally, it may be unreasonable to expect a manufacturer to develop specific methods for each component of some multi-component drugs containing ingredients of botanical origin, for example, benzoin, Peruvian balsam, or tolu balsam.
vi. Container Closure System:
The requirement that stability testing be performed in the same container-closure system as that in which the drug product is marketed has been interpreted differently.
U.S. vs. Kaybel ruled that when a “new drug” was repackaged, the repacker did not have to get pre-market approval for the repackaged product or for its repacking procedures. Repackers, however, are subject to current good manufacturing practices.
Although stability studies were performed on the dosage unit in the original manufacturer’s container, putting the dosage unit into a different storage container may and often does affect its shelf life.
Center for Drugs and Biologics policy is to allow repackaging into container-closure systems that can be demonstrated to be as protective or more protective than the original system without conducting new stability studies.
A satisfactory comparison of container-closure systems can be done several ways, such as by referring to the literature for information on the permeation properties of different container materials, performing moisture permeation tests, or comparing the properties of the original system to the new one by stress testing. (A stress test refers to testing a product after it has been stored under extreme conditions. This will likely involve high temperatures and high humidity).
Firms are also allowed to repackage solid dosage units in glass containers instead of plastic containers, since glass has been shown to be a superior moisture and gas barrier. Liquid drugs are not covered by this policy due to pH problems caused by the alkaline nature of glass.
Compliance Policy Guide 7132b.11 contains information on the expiration date of unit dose repackaged drugs. Repackaging from bulk containers is also not covered by this policy.
vii. Container Size to be Tested:
If the same product is marketed in more than one size, e.g., bottles containing 100 tablets and bottles containing 1,000 tablets, or bottles containing 4 oz of syrup and bottles containing 16 oz of syrup, it can be demonstrated that the ratio of the surface area to the internal volume of small containers is higher than that of larger containers.
In terms of contributing to product degradation, the smallest marketed container is the most critical. In other words, moisture or oxygen permeation through a 4 oz bottle is more critical than that through a 16 oz bottle of similar construction.
Due to this, when studying the stability of a product marketed in different sizes of similar containers, it is extremely important to test it in the smallest container size to ensure compliance with CGMPs.
FDA recommend that all other container sizes be tested for stability, but some may not, which is not necessarily a violation of CGMPs.
In order to ensure the effectiveness of the preservative system, products that contain preservatives to inhibit microbial growth must be monitored throughout their shelf life. A chemical test for the preservative(s) may be performed once a minimally effective level of preservative has been established. It’s important to monitor the preservative system at the same times as other ingredients.
Viii. Bulk Drug Substances (Bulk Pharmaceutical Chemicals):
It is feasible and valuable to expect manufacturers of bulk drug substances to ensure that their product is stable for the intended period of use, even if the CGMP regulations do not specifically require expiration dating.
The following features should be included in a bulk drug substance stability testing program:
- The program must be in writing.
- At least one commercial-sized batch should be included in the program; thereafter, one batch should be included every year.
- Samples should be stored in containers that approximate market containers; if that is not practical, samples can be stored in other similar containers, provided that data indicate that they will yield results comparable to those obtained with market containers.
- The samples should be stored at room temperature; an additional sample stored at elevated temperatures or under other stress conditions may be used if appropriate.
IX. Sterility Testing:
When sterilized products are kept unopened and stored according to label instructions, they must maintain that quality throughout their labeled expiration dates. Container-closure systems determine whether or not a product can retain its sterility.
Sterility tests need to be performed initially and at the end of the expiration date period when qualifying the container-closure system.
When any particular container-closure system is demonstrated to maintain sterility throughout the expiration date period, it is unnecessary to revalidate its ability to maintain sterility for other ingredients that may be placed in the same container-closure system.
As part of the stability testing program, products sterilized in glass ampuls are not required to undergo sterility testing.
These are the factors that help to define accelerated stability testing and shelf-life calculation.
- Requirement for conducting stability study in pharma
- Electronic codes of federal regulations (E-CFR)
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- Practices to avoid data integrity issues
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- Laboratory investigation of aberrant results
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