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
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
- 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.
- 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 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.
- 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.
- 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.
- 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 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.
- 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 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.
- 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.
- 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.
- 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:
- The program shall be in writing.
- The program should include samples from at least one commercial-size
batch; thereafter, one batch each year should be entered into the program.
- 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
similar containers, provided that data show that such containers will yield
results comparable to those obtained with market containers.
- 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.
- 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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