Inside IPEC–Americas: Evaluating Excipient Stability

The International Pharmaceutical Ex-cipients Council (IPEC) is in the final stages of developing an Excipient Stability Program Guide to provide an alternative approach to the International Conference on Harmonization's Q1A(R2) guideline on Stability Testing of New Drug Substances and Products. The ICH guideline, harmonized in 2003, describes the controlled conditions used to evaluate the stability of drug substances and products that rely on long-term, intermediate, and accelerated testing. Because excipients are marketed in packages ranging from 10 kg or less to 55-gallon drums as well as totes, supersacks, bulk trucks, railcars, or even barge vessels, stability testing under controlled storage conditions is impractical. In addition, the excipient is likely to be exposed to a broad range of temperatures and humidity conditions before reaching the pharmaceutical customer. The new guide is meant to establish a scientific basis for creating data that supports the shelf life or re-evaluation date of excipients.

Guide overview

The new IPEC guide defines normal and ambient excipient storage conditions as being within the general range of 4–40 °C and 20–90% relative humidity, as well as being protected from light (if applicable). Where excipients require more restrictive storage conditions to preserve their quality during the re-evaluation interval in the market package, the storage conditions should be specified on the label. Data should be available from the manufacturer to support the effectiveness of these conditions. Three excipient stability categories (very stable, stable, and limited stability) form the basis of a suitable program that can develop such data.

Very stable. Excipients considered to be "very stable" according to the IPEC guide have a demonstrated history of stability (as supported by literature or actual stability studies) that deems they will meet specification in the specified packaging for at least five years. It is also possible to predict the stability of very-stable excipients based on their known attributes. Their stability is not expected to be altered by a change in the manufacturing process or a change in the package. Many inorganic salts, for example, are considered to be very stable

For very-stable excipients with sufficient literature citations or stability studies to show they remain unchanged for ≥ 5 years, an ongoing stability testing program is unnecessary. A summary report supporting the classification should be available to the user upon request.

Stable. Excipients defined as "stable" in the IPEC guide have a re-evaluation interval of < 60 months to ≥ 24 months. Such excipients have been demonstrated to be stable through stability studies and, in general, their stability is more sensitive to a significant change in the manufacturing process or product packaging compared with very-stable excipients.

Limited stability. Excipients defined as having "limited stability" have a re-evaluation interval of < 24 months. Storage is typically under specified conditions in suitable packaging. This class of excipients has a much higher risk of of instability from a change to the manufacturing process or product packaging. Limited-stability excipients typically include compounds that are subject to hydrolysis, thermal degradation, oxidation, or are otherwise adversely affected by environmental conditions.

Stability studies

The primary purpose of an excipient stability study is to provide evidence that the excipient will continue to meet quality standards from the point at which manufacture has been completed until the package is opened by the customer. Compendial or specification testing is usually used to monitor excipient stability when there is no stability indicating test method.

There are two excipient stability-test design options. One can conduct a study using the excipient packed in the commercial package or packaging of equivalent composition and stored in an area under normal warehouse conditions. Or, one can follow ICH Q1A(2R), which designates controlled temperature and humidity conditions for storage of drug- substance test sample packages for stability studies in support of the shelf life. Specified ranges are provided for accelerated, intermediate, or long-term drug-substance stability studies.

Option 1 demonstrates stability of the excipient in the supply chain from warehousing to customer receipt. Generating data using the actual commercial packaging and storage conditions is ideal, especially as storage conditions are often uncontrolled with regard to humidity and temperature.

Running stability studies under carefully controlled conditions is only relevant to excipients that require specified storage conditions. For most excipients, normal warehouse conditions are sufficient for storing stability samples as long as the temperature and relative humidity are monitored. Stability studies for excipients with physical or chemical characteristics whose packaging determines their stability should be conducted under environmental conditions that challenge the protection provided by the packaging.

Option 2, following Q1A(R2), therefore is generally only necessary for novel and new excipients which require registration with the authorities or which require data for marketing authorization applications.

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