Stability protocols
A stability study, whether following option 1 or 2 as noted above, should be described in the manufacturer's protocol with
multiple detailed sections, as outlined below.
Objective.
The purpose of conducting a stability study (e.g., to support a new excipient, ongoing evaluation, or to evaluate the impact
of a significant change) should be clearly stated.
Scope.
The protocol should indicate what excipient(s) are covered by the stability study, especially in cases where the protocol
is applied to a "model-product" study.
Selection of the container–closure system.
Stability samples should be stored in a container–closure system that provides equal (not better) protection from temperature
or humidity than the planned commercial packaging. Stability studies for bulk shipments (e.g., barges, railcars) pose particular
problems in design because there is some uncertainty as to how long the excipient may reside in the bulk container. However,
extrapolation from data collected using the methods outlined herein is possible when consideration is given to the risk factors
to excipient stability posed by the transport containers.
Storage conditions.
The stability package should be stored using the specified storage conditions as defined in the protocol or the ambient conditions
found in the manufacturer's warehouse. The experiment should be conducted over the longest period of time that the excipient
maker warrants the product will continue to conform to the specification.
Sampling plan.
The protocol should specify the frequency—schedule from the date of manufacture, which is taken as time zero—of how often
samples are to be taken from the stability package for testing. This type of study is best conducted as a kinetics experiment
in which samples are tested at less frequent intervals as the excipient approaches its re-evaluation interval.
Stability indicating parameters.
If the excipient is known to change during the stated re-evaluation interval, then it should be tested using an appropriate
stability indicating test or test that would demonstrate the changes to the product. When there is no direct measurement of
the purity of the excipient, stability can be quantified by measuring the change in physical or chemical characteristics.
One should also consider comparing the excipient's composition profile at the limit of its re-evaluation interval to that
of the excipient at time zero.
Acceptance criteria.
The protocol should establish the test results that are expected to support the stated re-evaluation interval. Trend analysis
of the data should be used as an indication that the excipient will continue to meet specification through its re-evaluation
interval.
Approval and report.
The protocol should specify the approval process, including an internal review of the data and conclusions. The final stability report should contain an evaluation of the stability data and the conclusion reached.
Conclusion
The study of excipient stability is best conducted under the environmental conditions that will be encountered during warehousing,
shipment, and storage in the market package and a re-evaluation interval should be determined. The new IPEC excipient stability
guide aims to establish expectations using a scientific approach for the stability data in support of excipient retest intervals
that is appropriate to the various packages typically used to store and transport these pharmaceutical ingredients.
Philip H. Merrell, Ph.D., is the technical market manager at Jost Chemical Co., tel. 314.813.1912, phil.merrell@jostchemical.com
, and Irwin Silverstein, Ph.D., is chief operating officer at International Pharmaceutical Excipient Auditing, tel. 732.463.8710, Irwin.s@verizon.net
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