A Rational Approach for Setting and Maintaining Specifications for Biological and Biotechnology–Derived Products—Part 2

The Biologics and Biotechnology Working Group on specifications of the Pharmaceutical Research and Manufacturers of America presents new approaches to analyzing development and manufacturing data.


This paper discusses an approach for the establishment and lifecycle management of biological and biotechnology-derived product specifications. The views presented are consistent with the concept of Quality by Design (QbD), in which critical quality attributes (CQAs) are distinguished from parameters used to monitor process consistency. Specifications and the corresponding limits as applied to CQAs serve to ensure that the product is fit for use, whereas control limits are a manufacturer's tool to monitor shifts and trends in the manufacturing process. In the current paradigm, inappropriate use of specifications creates a disincentive for continuous process understanding; more suitable approaches to analyzing development and manufacturing data are discussed. Statistical methods are presented for deriving and interpreting data against specifications that better manage the risk to the customer of receiving product with diminished safety or efficacy, as well as the risk to the manufacturer of earmarking a satisfactory lot as unacceptable. The recommendations are presented as a rational approach to setting and maintaining specifications, while recognizing that their applicability may not be suitable in all cases, given the heterogeneity of types of regulated biological and biotechnology-derived products and their unique challenges.

The purpose of this paper, which has been developed by the Working Group on Specifications and Formulations of the Pharmaceutical Research and Manufacturers of America (PhRMA) Biologics and Biotechnology Leadership Committee, is to provide guidance on a lifecycle approach to setting global specifications for biological and bio technology-derived products. In the pharmaceutical industry, specifications are legally binding criteria that a product must meet in order to be marketed. They ensure the consistency and quality of the product and help ensure that it is safe and efficacious over the shelf life of the product. Specifications evolve during product development and ideally should embrace future process capability. This is true for biological and biotechnology-derived products for which there may be limited experience at the time of regulatory filings (including the marketing application), and for which early commercial production often is necessary to gain a better understanding of product quality attributes, methods, and limits.

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.


Several issues require resolution to implement a rational approach for setting specifications. These issues relate to the interpretation of measurements relative to limits, and the meaning and use of various types of limits.

Current strategies for developing and maintaining specifications and for interpreting data against specifications do not adequately acknowledge the risks to both the customer and the manufacturer. Although most manufacturers strive to attain an acceptable quality level for their processes and products, a common understanding of the business risks as well as the risks to the customer is necessary to achieve a 21st century vision of quality. Many practices for setting limits are arbitrary and fail to factor in these risks. Some practices strive to achieve unattainable goals, such as guaranteeing that every dosage unit will meet specifications. Other practices are overly restrictive, leading to either disincentives for collecting data or hardships on the part of the manufacturer to investigate and explain apparent out-of-specification results. Still other practices, such as adopting control limits as specifications, hinder process understanding and improvement. The following is a discussion of the practices impeding a rational approach to setting and maintaining specifications for biological and biotechnology-derived products.

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