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.
Parts 1 and 2 of this article, published in the June and July issues of BioPharm International, included four sections: Terminology; Stages of the Lifecycle of a Product; Components of a Biological and Biotechnology Product
Specification; and Current Issues Related to the Development of Specifications. This final section describes a suggested approach
for developing and maintaining a total quality system.
A SUGGESTED APPROACH FOR DEVELOPING AND MAINTAINING A TOTAL QUALITY SYSTEM
A rational approach to setting and maintaining specifications should incorporate the following fundamental principles:
- A total quality system should seek to minimize risks to the customer and manufacturer alike. When in conflict, however, practice
should err on the side of minimizing customer risk.
- If possible, specifications should be established from sound scientific data and reflect fitness for use.
- Specifications should be established to guarantee that the product is fit for use throughout the shelf life of the product.
- Control limits are a manufacturer's tool to monitor shifts and trends in the manufacturing process, and to study the effect
of process improvements.
- Specifications should be set to control the average lot attribute rather than individual dosage units or measurements. This
approach reflects current industry practice of mapping average quality attributes to population clinical response during product
- A lifecycle approach should acknowledge that material and substantial information is necessary to establish specifications,
and thus restrictive limits should not be set during development. In some cases, it may not be possible to set limits until
post-licensure, after early product manufacture and test method experience have captured information adequate to set meaningful
- Product limits provide a basis for assessing product quality attributes at significant points in time, such as at release
and at the end of shelf life. Limits should not be overused in studies that aim to explore process or product stability.
On the basis of these principles, the following guidance is recommended for setting limits for biological and biotechnology-derived
1. Capture scientific data during development to set limits that reflect fitness for use throughout the shelf life of the
With the goal of setting specifications that reflect fitness for use, development studies should be performed to identify
quality attributes that may be linked to clinical outcomes, and to set release limits that guarantee the quality of the product
throughout its shelf life. Setting specifications in this way requires a coordinated effort among the preclinical, clinical,
and nonclinical development teams. The goal of identifying quality attributes that may be linked to fitness for use may be
accomplished by using sound scientific judgment and by evaluating the historical performance of products with similar quality
Preclinical studies in animals or cell culture can help assess how changes in quality attributes may affect clinical outcome.
These studies form the beginning of our understanding about which quality attributes may be clinically meaningful, and also
can provide a basis for setting preliminary or final limits on those attributes. Clinical studies in target populations may
be designed to explore or support ranges for meaningful quality attributes, which together with preclinical experiments form
the basis of specifications. Nonclinical studies on final product should be designed to explore and define the properties
of the product and analytical methods under conditions that are likely to occur during manufacture, testing, handling, and
product shelf life.