Setting limits for final drug product is part of an overall quality strategy that includes the control of raw materials, excipients,
in-process testing, and good manufacturing practices. Quality cannot be tested into the product.
Likewise, process understanding cannot be achieved by holding quality attribute measurements to specifications. Strategic
studies such as process validation, as well as development and post-licensure stability studies, should be adequately designed
and analyzed to obtain relevant and reliable information. Over-interpretation of measurements from these studies creates a
disincentive for collecting valuable process and product information. A proper evaluation of the data will yield information
that can be used to develop a total quality system to control the process and protect the customer.
A rational approach to setting specifications for biological and biotechnology-derived products involves a clear understanding
of the purposes of the limits, as well as recognition of risks to both the customer and manufacturer. A primary goal of specifications
is to ensure that only quality product is released to the market. When a quality attribute has been demonstrated to have clinical
impact, the release limits should acknowledge release assay variability and product stability. The purpose of the release
limit is to guarantee that a released lot will have a clinically acceptable level of quality through the end of shelf life.
When a quality attribute is unlikely to have clinical impact, the information generated by the assay should be used to monitor
the process. The control limit should acknowledge the process distribution, which is composed of product variability and release assay variability. An adequate number and variety of representative lots is necessary to characterize that distribution
and establish control limits.
Control limits on a clinically meaningful quality attribute should be used in conjunction with specifications to monitor product
for shifts or trends. Control limits should ideally fall within release limits, to maintain satisfactory process capability.
When release limits are set to coincide with control limits, satisfactory lots will be OOS because of small process fluctuations
or chance alone. In such a scenario, manufacturing improvements are difficult to implement because of either the increased risk of yielding OOS results or the
risk of being required to set tighter limits. Practices such as setting release limits to coincide with control limits or
narrowing release limits after a process improvement has been implemented may increase product cost without providing added
quality, and thus fail to serve the best interest of the customer.
Post-licensure stability studies are an additional tool to study shifts or trends in a product profile. Post-licensure studies
should not be viewed as a study of the lot on stability, but rather as a control of the stability characteristics of the product.
Control limits on stability properties of the product such as the slope can be used to help control the overall product profile
throughout the lifecycle of the product.
A common understanding and acceptance of these principles by industry and regulators will enhance the quality and availability
of biological and biotechnology-derived products.
16. Montgomery DC. Introduction to Statistical Quality Control. New York: John Wiley & Sons; 1991.
17. Fairweather WR, Mogg R, Bennett PS, Zhong J, Morrisey C, Schofield TL. Monitoring the stability of human vaccines, J
Biopharm Statistics. 2003;13,395–413.
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.