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.


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 biotechnology-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.

Currently, there is no industry-wide guideline about the process for establishing specifications for biological and biotechnology-derived products at different stages of the product lifecycle. The International Conference on Harmonization (ICH) Q6B document provides detailed guidance for commercial products and refers to specifications as a list of tests, references to analytical procedures, and appropriate acceptance criteria with numerical limits, ranges, or other criteria to describe the result of the test. Specifications establish a set of criteria to which a drug substance (DS), drug product (DP), or materials at other stages of manufacture should conform to be considered acceptable for use. Conformance to specifications means that the drug substance or drug product, when tested according to the listed analytical procedures, will meet the acceptance criteria. However, this definition may be too restrictive for some applications, such as stability testing or process validation, for which more appropriate means of establishing product quality might be considered.

This paper is laid out in five sections. We will first provide some terminology and definitions. This terminology is not necessarily common throughout the industry, but we hope it will cover all aspects of setting specifications and provide a basis for discussion throughout the paper. The second section of the paper outlines the stages of the lifecycle of a biological or biotechnology-derived product, with emphasis on the level of product information at each stage. The third section describes the components of a product specification, including parameters and components that are unique to this class of products. The fourth section highlights some unresolved issues that must be addressed before setting specifications. The last section proposes a strategy for developing a quality system for biologicals and biotechnology-derived products that helps ensure safety and efficacy to the customer throughout the shelf life of the product, and provides the manufacturer with a powerful set of tools to monitor the manufacturing process.

Sections 1 to 3, covering terminology; the stages of the lifecycle of a product; and components of a biological and biotechnology product specification, appear below, as Part 1 of this article. Section 4 (current issues related to the development of specifications) and section 5 (the suggested approach for developing and maintaining a total quality system), will be published as Parts 2 and 3, in the next two issues of BioPharm International.

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