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.
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.
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.
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.
COMPONENTS OF A BIOLOGICAL AND BIOTECHNOLOGY PRODUCT SPECIFICATION
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.