This contradiction has fostered strategies that protect against stability OOS results that have little or negative impact
on product quality. A minimalist approach to stability testing is engendered during development, because frequent measurements
may result in early OOS results that shorten the apparent shelf life of the product. Often, companies file shelf life limits
(which should contain stability measurements through shelf life) that are artificially wide because of adjustment for statistical
multiplicity (i.e., the increased probability of failure, with multiple testing; one adjusts for multiplicity by making the
interval wider), and are thus unable to capture meaningful changes in product stability. As with release testing, the current
environment discourages enhanced designs to study the stability of the final product or to monitor the stability of product
on the market. Stability data should be analyzed in a way that promotes data collection to achieve better product understanding.
This risk is likewise borne in validation studies. Samples are taken from multiple locations of the production process, or
at multiple levels of a process parameter, and subject to specifications. As with stability testing, in which multiple samples
are taken over time, validation samples are subject to excess risk of OOS due to multiplicity, which acts as a disincentive
to collecting data for better process understanding.
The purpose of this paper, which has been developed by the Biologics and Biotechnology Working group on specifications of
the Pharmaceutical Research and Manufacturers of America (PhRMA), is to provide guidance on a lifecycle approach to setting
global specifications for biological and biotechnology-derived products.
Part 1 of this article, published in the June issue of BioPharm International, included three sections: Terminology, Stages of the Lifecycle of a Product, and Components of a Biological and Biotechnology
Product Specification. This part 2 covers the next section, Current Issues Related to the Development of Specifications. The
final section, the Suggested Approach for Developing and Maintaining a Total Quality System, will be published in Part 3,
in the August issue.
Timothy Schofield is senior director, nonclinical statistics, at Merck Research Laboratories, Merck & Co., West Point, PA, and the corresponding
215.652.6801; Izydor Apostol, PhD, is scientific director, analytical and formulation sciences, at Amgen Inc., Thousand Oaks; Gerhard Koeller, PhD, is vice president, quality and compliance biopharmaceuticals, at Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany;
Susan Powers, PhD, is biotech quality technology leader, Wyeth Pharmaceuticals, Collegeville ,PA; Mary Stawicki is associate director, regulatory affairs biopharm CMC, at GlaxoSmithKline, Collegeville, PA, and Richard A. Wolfe, PhD, is director and team leader, biopharma operations, at Pfizer Global Manufacturing, Chesterfield, MO.
12. International Conference on Harmonization (ICH). Q1E, Evaluation of stability data. Geneva, Switzerland; 2003.
13. ICH. Q6A, Specifications for new drug substances and products. Geneva, Switzerland; 1999.
14. US Food and Drug Administration. Guidance for Industry: Investigating out of specification (OOS) test results for pharmaceutical
production. Rockville, MD: 2006.
15. Foust L, Diener M, Gorko MA, Hofer J, Larner G, LeBlond D, Lewis J, Sandell D, Schofield T, Vukovinsky K, Warner E.
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