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.

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.