While sterility testing can be cumbersome and time consuming, there are FDA-approved options regarding container and closure system integrity testing. In fact, the Food and Drug Administration (FDA) recently released a guidance document on container and closure system integrity testing in lieu of sterility testing as a component of the Stability Protocol for Sterile Products. The document offers an alternative approach, if the approach satisfies the requirements of the applicable statutes and regulations.
Aimed at manufacturers, the guidance offers alternative testing methods
other than sterility testing to confirm container and closure system
integrity as a part of the stability protocol for sterile biological
products, human and animal drugs, and medical devices.
The purpose of stability testing is to provide evidence on how the
quality of a substance or product varies with time under the influence
of a variety of environmental factors such as temperature, humidity and
light. Products labeled as sterile are expected to be free from viable
microbial contamination throughout the product's entire shelf life or
dating period. This enables manufacturers to establish or modify
recommended storage conditions, retest periods and shelf life or dating
period, as the case may be.
Currently, manufacturers of drugs and biologics purporting to be sterile
are required to test each batch or lot, to ensure that the product in
question conforms to sterility requirements. They must also maintain a
written testing program designed to assess stability characteristics and
meet stability testing requirements.
Manufacturers of medical devices are required to validate processes,
including sterilization, for a device purporting to be sterile, although
stability testing should be part of the design validation of such
devices. Also, in vitro diagnostic products for human use are required
to be labeled with stability information.
The minimum sterility testing generally performed as a component of the
stability protocol for sterile products is at the initial time point
(release) and final testing interval (i.e., expiration). Additional
testing is often performed at appropriate intervals within this time
period (e.g., annually).
Alternatives to sterility testing as part of the stability protocol,
such as replacing the sterility test with container and closure system
integrity testing, might include any properly validated physical or
chemical container and closure system integrity test (e.g., bubble
tests, pressure/vacuum decay, trace gas permeation/leak tests, dye
penetration tests, seal force or electrical conductivity and capacitance
tests, etc.), or microbiological container and closure system integrity
tests (e.g., microbial challenge or immersion tests).
Such tests may be more useful than sterility testing in demonstrating
the potential for product contamination over the product's shelf life or
dating period. The advantages of using such container and closure
system integrity tests in lieu of sterility tests in the stability
protocol for sterile products include: detecting a breach of the
container and/or closure system prior to product contamination;
conserving samples that may be used for other stability tests; requiring
less time than sterility test methods which require at least seven days
incubation; and reducing false positive results with some alternative
test methods when compared to sterility tests.
To implement container and closure system integrity testing as an
alternative to sterility testing, the FDA recommends manufacturers
consider the following: a container and closure system integrity test
may replace sterility testing in a stability program at time points
other than the product sterility test prior to release; container and
closure system integrity tests do not replace sterility testing methods
for product sterility testing prior to release; any validated container
and closure system integrity test method should be acceptable provided
the method uses analytical detection techniques appropriate to the
method and is compatible with the specific product being tested.