Expiration Dating and Stability Testing for Human Drug Products
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`Expiration Dating and Stability Testing for
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`DEPT. OF HEALTH, EDUCATION, AND
`WELFARE PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`*ORA/ORO/DEIO/IB*
`Date: 10/18/85 Number: 41
`Related Program Areas:
` Drugs
`
`ITG SUBJECT: EXPIRATION DATING AND STABILITY TESTING FOR HUMAN
` DRUG PRODUCTS
`
`BACKGROUND
`
`Publishing of 21 CFR Part 211 - Current Good Manufacturing Practice for Finished
` Pharmaceuticals established requirements concerning the expiration date on a drug
` product and stability testing to assure the appropriateness of that date. Each drug
` product may be a unique article because of, for instance, differences in (1) chemical
` and physical properties of the active ingredients or the excipients, (2) manufacturing
` procedures, (3) formulations, (4) containers and closures, (5) proposed storage
` conditions, and (6) the stability of the article to maintain its quality or purity through
` the use of antioxidants or preservatives. Because of the uniqueness of each drug
` product, it is virtually impossible to provide one set of rules that can apply to all
` situations. The CGMPs were purposely written broadly to allow for such unique
` differences.
`
`EXPIRATION DATING (21 CFR 211.137)
`
`A. Absence of an Expiration Date
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`Expiration Dating and Stability Testing for Human Drug Products
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`The absence of an expiration date on any drug product packaged after September 29,
` 1979, except for those drugs specifically exempt by 211.137 (e), (f), and (g), is cause
` to initiate regulatory action against the product and/or the responsible firm.
`
`B. Exemptions
`
`OTC drug products meeting the exemption of 211.137 (g) may utilize accelerated
` testing programs to support the requirement that they are stable for at least three
` years. Information obtained from old stock, not previously the subject of stability
` studies, may also be utilized.
`
`C. Products Intended for Reconstitution
`
`Any drug product intended for reconstitution and not bearing an expiration date for the
` unreconstituted product and another expiration date for the product after
` reconstitution is considered to be out of compliance with 211.137 (c). There must be
` separate stability studies to support each expiration date.
`
`STABILITY TESTING (21 CFR 211.166)
`
`A. Written Stability Testing Program
`
`The absence of a written protocol for stability testing is cause to initiate regulatory
` action against the product and/or the responsible firm.
`
`B. Supportive Stability Data
`
`1. Number and Size of Batches
`Initial stability testing by accelerated testing may be performed on a batch smaller
` than the normal production size as long as the batch is produced by similar
` equipment as would be used for regular production.
`Generally, the placing of three initial batches into the long term stability program
` is considered minimal to assure batch uniformity for establishing an expiration
` date. Since a dosage form is a complex unit and there are continued variables in
` the production process, such as change in personnel, raw material lots and
` suppliers, and equipment, it is imperative that stability studies are not limited only
` to initial production batches but a portion of annual production batches be the
` subject of an ongoing stability program.
`2. Accelerated Studies
`When accelerated stability studies are performed, one batch may be adequate in
` order to establish a tentative expiration date. This is acceptable since it is not the
` purpose of an accelerated test to determine batch uniformity but rather to test for
` kinetic degradation.
`The use of accelerated testing data to establish a tentative expiration dating
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` period of greater than three years is discouraged when it is based solely on
` accelerated data. Combining data compiled at room temperature and at
` accelerated temperature is possible to justify an expiration dating period of over
` two years. This can be done, as an example, by taking a sample product that
` has been at room temperature for one year and subjecting that sample to
` accelerated temperature conditions. The expiration dating period used would
` then be the sum of that justified individually at each storage condition.
`We do not believe it is reasonable to perform accelerated testing at very high
` temperatures for a very short time and expect to extrapolate results to a very
` long expiration dating period since the actual mechanism of degradation at high
` temperature may be different than at room temperature.
`3. Test Intervals
`It is commonly recommended that stability testing be performed initially, than
` every three months for the first year, then every six months for the second year,
` and then annually thereafter. However, more frequent testing near the end of the
` anticipated expiration date is often likely to give better information about the
` actual stability of the finished product. Nonetheless, testing at least annually is
` considered minimal for compliance with CGMPs. Some firms have chosen, for
` economical purposes, random dates to test all stability samples of a given
` product. As long as there is at least one test performed annually, this approach
` can be quite satisfactory.
`4. Storage Conditions
`If a product was stored under controlled conditions, those actual conditions
` (temperature and humidity) should be recorded. Merely stating that a product
` was stored at room temperature is not sufficient for purposes of determining
` stability. The USP defines controlled room temperature as being between 15 and
` 30 C (59 and 86 F). A product stored for stability 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. Based on published information, it appears that 24-25 C is a reasonable
` reference for thermal exposure at room temperature.
`Stability studies should be conducted on product stored under normal storage
` conditions or, preferably, under exaggerated conditions. Products liable to
` degradation by light or moisture should be stored either in a lighted area or
` under conditions of high humidity unless it can be demonstrated that the
` packaging will prevent deterioration by that condition of interest. For example, a
` product liable to degrade by light need not be stored in a lit area if it is normally
` packaged and stored for use in an opaque container.
`5. Test Methods
`While 211.166 (a) (3) merely requires that test methods be reliable, meaningful,
` and specific, section 211.165 (e) gives more guidance by stating that the
` accuracy, sensitivity, specificity, and reproducibility of test methods employed by
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` the firm shall be established and documented. Section 211.194 (a) (2) further
` requires that all testing methods used shall be verified under actual conditions of
` use. Testing procedures must include a stability indicating test which will
` distinguish the active ingredient from any degradation products and be able to
` make a reliable estimate of the quantity of any degradate. The stability indicating
` test does not have to be the assay method used to determine product strength.
`Manufacturers, who contract with analytical laboratories to perform either end
` product testing or stability studies, or who produce product under contract for
` other firms are ultimately responsible for the quality of the product and must
` have copies of all analytical procedures employed and the appropriate
` documentation to assure their validity on file. Likewise, repackers who rely on
` stability studies performed by the manufacturer must have copies of all analytical
` data necessary to support the expiration dating period.
`Although specific methods are critical to determine product stability, they do not
` have to employ any specific technique. The use of quantitative analysis, where
` limits are known, such as thin layer chromatography, may be satisfactory. While
` many USP tests are specific for the drug or its degradates and may be used for
` stability testing, some USP monographs do not incorporate stability indicating
` tests. Additionally, it may be unreasonable to expect a manufacturer to develop
` specific methodology for each component of some multi-component drugs
` containing ingredients of botanical origin such as benzoin, Peruvian balsam or
` tolu balsam.
`6. Container-Closure Systems
`The requirement that stability testing be performed in the same container-closure
` system as that in which the drug product is marketed has been subject to
` interpretation. The courts ruled in U.S. vs. Kaybel that when a "new drug" was
` repackaged, the repacker did not have to obtain pre-market approval of the
` repackaged product or the firm's repacking procedures. However, the repacker is
` subject to applicable current good manufacturing practices.
`Although stability studies were performed on the dosage unit in the original
` manufacturer's container, the event of placing the dosage unit into a different
` storage unit may and often does affect the product's shelf life. It is the policy of
` the Center for Drugs and Biologics to allow repacking into container-closure
` systems that can be demonstrated to be at least as protective or more protective
` than the original system without performing new stability studies prior to
` marketing.
`Satisfactory comparison of container-closure systems may be done by several
` methods, i.e., literature reference to permeation properties of different container
` materials; performance of moisture permeation testing; or comparing the
` properties of the original container-closure system to a new system by stress
` testing. (Stress testing refers to testing the product after storage under
` exaggerated conditions. This will usually involve high temperature and high
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` humidity.)
`It is also current policy to allow firms to repackage solid dosage units from plastic
` containers into glass containers because glass has been shown to be a superior
` moisture and gas barrier. This policy does not apply to liquid drugs because of
` pH problems resulting from the alkaline nature of glass. Policies relating to the
` expiration dating of unit dose repackaged drugs may be found in Compliance
` Policy Guide 7132b.11. This also does not apply to repacking from bulk
` containers.
`7. Container Sizes to be Tested
`When 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, by
` comparing the ratio of the surface area of the container to the internal volume,
` that smaller containers have a higher ratio than larger containers. This indicates
` that the smallest marketed container is the most critical in terms of the container
` properties contributing to product degradation. Thus, moisture or oxygen
` permeation through a 4 oz bottle is more critical than through a 16 oz bottle of
` similar construction. For this reason, when studying stability of the product
` marketed in several sizes of similar containers, testing of the smallest container
` size is imperative to be in compliance with CGMPs. While we recommend that all
` other container sizes be subjected to stability testing, the fact that some may not
` is not necessarily a violation of CGMPs.
`8. Preservatives
`Products formulated to contain preservatives to inhibit microbial growth should be
` monitored throughout their shelf life to assure the effectiveness of the
` preservative system. Once a minimally effective level of preservative is
` established, chemical testing for the preservative(s) may be performed. The
` preservative system should be monitored at the same stability testing times as
` other ingredients are monitored.
`9. Bulk Drug Substances (Bulk Pharmaceutical Chemicals)
`While expiration dating is not required specifically for bulk drugs in the CGMP
` regulations, it is feasible and valuable to expect the manufacturer of bulk drug
` substances to assure that their product is stable for the intended period of use.
`A stability testing program for bulk drug substances should contain, at the
` minimum, the following features:
`
`a. The program shall be in writing.
`b. The program should include samples from at least one commercial-size
` batch; thereafter, one batch each year should be entered into the program.
`c. Samples should be stored in containers that approximate the market
` containers; if it is not practical to do so, samples may be stored in other
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` similar containers, provided that data show that such containers will yield
` results comparable to those obtained with market containers.
`d. Samples should be stored at room temperature; an additional sample stored
` at elevated temperatures or under other stress conditions may be used if it
` is appropriate to do so.
`10. Sterility Testing
`Products manufactured as sterile must maintain that quality throughout the
` labeled expiration dating period as long as the product is unopened and stored
` according to labeled instructions. The ability of the product to retain its sterile
` condition is a function of the container-closure system. When qualifying the
` container-closure system, sterility testing should be performed initially and at the
` end of the expiration dating period. Once any particular container-closure system
` can be demonstrated to maintain sterility throughout the expiration dating period,
` it is unnecessary to revalidate its ability to maintain sterility for other ingredients
` that may be placed into the same container-closure system.
`Products sterilized in glass ampuls need not be subjected to sterility testing as
` part of the stability testing program.
`
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