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

Early-Stage Development

Early-stage development involves predicting relevant quality attributes (and their parameters), methods, and acceptance criteria for the class of molecules based on preclinical characterization, industry experience, published scientific literature, and guidance from regulatory agencies. At early stages of development, selected quality attributes and corresponding limits (acceptance criteria) should be focused on well defined expectations related to product safety (e.g., DNA, Limulus amebocyte assay (LAL), and host cell proteins), and allow clinical experience to define other quality attributes such as product-related substances and impurities. The predicted specifications may be able to take advantage of the knowledge base of other well characterized products and prior research experience.

Specifications are ultimately used to protect the patient from receiving product that is not fit for use. The basis for defining fit for use derives from the preclinical and clinical development experience with drug product, which ultimately is tied to specifications in the product license application. Unless quality attributes can be linked to preclinical and clinical experience, there is no rational basis for establishing specifications. Thus, in early development, measurements of product quality should be made to reliably identify potential quality attributes of the product. The relationship between the level of a quality attribute (such as potency) and its clinical impact is best understood when the attribute is allowed to vary rather than be constrained by narrow limits. This information can then be used to determine which attributes forecast clinical outcomes, and to set limits that ultimately (i.e., during commercial manufacture) predict fitness for use.

Because of this, it is unreasonable to set restrictive specifications for quality attributes that are not directly linked to product safety. Early development data should be unrestricted and thereby scientifically informative. Fit-for-use specifications may be set from these data, and verified in late-stage development.

Late-Stage Development

In late-stage development, selected quality attributes should be based on a biochemical and biophysical understanding of the product that is linked to manufacturing experience and clinical relevance. The selection of analytical methods and corresponding acceptance criteria should be based on sound scientific judgment and an appropriate statistical analysis using knowledge coming from clinical, preclinical, and nonclinical development experiences.

Attributes that are not related to product quality may be either eliminated or reserved for characterization after a manufacturing process change. Such process changes are frequently associated with the preparation for commercialization. Attributes that are redundant with other quality attributes may be eliminated. In principle, the test with the greatest sensitivity and/or reliability should be reserved for conformance testing.

Early-Stage Manufacturing

Process performance attributes that are used to monitor consistency rather than fitness for use require adequate experience to reveal the process distribution. This involves a sufficient number of lots manufactured across a representative range of process conditions. Because this is not the primary objective of product development, specifications that are developed to monitor product consistency require data acquired during full-scale manufacture, under normal operating conditions, over a range of changes in process parameters.

Continued Manufacturing

Limits related to process consistency may evolve with extended experience in manufacturing. Process control limits should reflect the current state of the process. Thus, if an improvement has been made that has no impact on quality attributes related to safety or efficacy, but results in a shift or change in the distribution of a consistency parameter, process monitoring limits should be amended to reflect the change.


As described in ICH Q6B,1 specifications are the list of quality attributes, methods, and limits. However, for biological and biotechnology-derived products, some quality attributes may have several parameters. For example, purity of a monoclonal antibody (MAb) typically has three parameters related to its size, charge, and molecular integrity. Consequently, specifications for the purity of protein products have four components:

1. Quality attribute (e.g., purity)

2. Parameter (e.g., size, charge, molecular integrity)

3. Analytical method (e.g., size-exclusion chromatography [SEC], ion exchange chromatography, capillary electrophoresis–sodium dodecyl sulfate [CE-SDS])

4. Limit or acceptance criteria (e.g., main peak relative purity for SEC).

It is important to stress that protein products are not structurally homogeneous, such that a single peak on a chromatogram, electropherogram, or in a spectrum may not represent a single molecular entity (as is typically seen with small molecules). No single analytical method can define product purity; therefore, a combination of orthogonal analytical methods typically is used to properly describe a single quality attribute such as purity.

Another quality attribute that is unique to biological and biotechnology-derived products is potency. Potency reflects activity in a biologically relevant system, usually expressed as relative potency to a standard or specific activity. While there is scientific debate regarding the relevance of potency to clinical effectiveness, potency assays typically are considered a link to the mechanism of action of a biological or biotechnology-derived product, which potentially can bridge changes in biophysical characteristics to biological activity.

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