A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 1 - Currently, there is no industry-wide guideline about the process f


A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 1
Currently, there is no industry-wide guideline about the process for establishing specifications for biologicals at different stages of the product lifecycle. The Working Group on Specifications and Formulations of the PhRMA Biologics and Biotechnology Leadership Committee set out to help fill this gap. The first of a three-part article.

BioPharm International
Volume 21, Issue 6

A hypothetical example follows. At the early stage of product development, an anion-exchange chromatography method was developed to evaluate the charge distribution of a MAb. The chromatogram showed a single main peak and two minor peaks. Based on extensive product characterization and clinical experience, a specification was developed around the relative purity of the main peak, with an understanding that the main peak contains multiple components with the same net charge. The limit of minimum purity was set at 85.0%. At the time of commercialization, the ion-exchange column was discontinued by the vendor, and replaced by the drug manufacturer with a new monolithic ion-exchange column. As a result of this technological advancement, a component of the main peak resolved into two peaks, one of which is a separate small peak accounting for a reduction in relative purity of approximately 5%. In such a situation, adopting old limits for the new method would be inappropriate, and a statistical approach used to create limits for the old method may not be applicable in establishing limits for the new method. The peak resolved by the new method was fully characterized as an isoform containing oxidized methionine in the Fc portion of the antibody, with no effect on potency. In addition, it was demonstrated that the level of oxidation in most recent lots ranged from 4% to 5%. In such a case, the manufacturer should request a revision of the specifications for the main peak without an additional specification for oxidized methionine in the Fc portion. An alternative approach would be to sum up two peaks that were not resolved in the original method.

Chromatographic profiles for biopharmaceutical products present a special challenge. Even at the early stages of development, analytical methods are capable of resolving different isoforms. Understanding their structure–function relationships, however, may require several more years. Therefore, at early stages of development, this limited understanding of isoforms and post-translational modifications may lead scientists to establish specifications exclusively with respect to product purity. In such cases, the levels of product-related forms can be inferred from the relative area of the main peak. The fact that specifications are not designed around product impurities should not prevent the manufacturer from tracking individual peaks (likely containing multiple molecular entities) in another system different from specifications. These data can be part of the characterization data collected during the course of development. The data could be very useful at later stages of development.

Precision and Significant Figures

The precision of analytical methods is linked to data reporting, whereas specifications limits are linked to method precision.6–9 Therefore, it is very important to use consistent practices regarding the number of significant figures or decimal places reported by analytical methods that is consistent with the number of significant figures or decimal places in the specification limits (acceptance criteria).

The reporting interval (number of decimal places) should be derived from the standard uncertainty, which can be expressed in the form of standard deviation or coefficient of variation (relative std. dev). Published approaches should be evaluated.7,9 The most commonly adopted is the recommendation from the American Society for Testing and Materials (ASTM), which proposes that the results of analytical measurements should be rounded to a decimal place corresponding to not less than 1/20 of the determined standard deviation.

In the biological and biotechnology industries, precision of methods frequently is assessed during qualification and confirmed during method validation.5,10–11 Therefore, appropriate precision studies should be performed before specifications are established.


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. This Part 1 includes sections 1 to 3 of the paper, covering terminology, the stages of the lifecycle of a product, and components of a biological and biotechnology product specification. Parts 2 and 3 of this article will be published in the next two issues of BioPharm International. Those parts will include section 4, covering current issues related to the development of specifications; and section 5, which suggests an approach for developing and maintaining a total quality system.

Izydor Apostol, PhD, is scientific director, analytical and formulation sciences, at Amgen Inc., Thousand Oaks, CA; Timothy Schofield is senior director, nonclinical statistics, at Merck Research Laboratories, Merck & Co., West Point, PA, and the corresponding author,
215.652.6801; 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.

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