Setting Drug Substance and Drug Product Specifications
Figure 2. Illustration of an approach towards setting specifications for product quality attributes.
Drug substance and drug product specifications are two components of the control strategy that enable delivery of the QTPP
and represent the ranges within which the product is considered to meet the desired product quality. It should be pointed
out that there is not a one-to-one correspondence between a list of CQAs and specifications. Although some CQAs will have
specifications (i.e., acceptance criteria) associated with them, there may be others (such as host cell proteins or DNA) that
will not have associated specifications if it has been demonstrated that the process has satisfactory clearance through multi-log
removal validation carried out in small-or large-scale studies.
Product specifications can be proposed using a combination of approaches, consistent with the guidance in ICH Q6B (Figure
2).20 Where appropriate, certain attribute specifications are based on existing regulatory guidance. For other attributes, relevant
limits or ranges are established based on several sources of information that link the attributes to the safety and efficacy
of the product, similar to the way this information is used to assess the criticality of these attributes. These sources include
but are not limited to:
clinical experience with the product
nonclinical studies with the product or the isolated variant or impurity such as binding assays, in vivo assays, and cell-based assays
clinical and nonclinical studies with similar platform products
published literature on other similar products, variants, or impurities
the process control strategy and the extent of variability observed in the manufactured lots.
Figure 3. Illustration of differences between clinical experience and filed specifications for a product-related impurity
(% purity by ion exchange chromatography, or IEC) and a process-related impurity (host cell protein, or HCP) for a typical
monoclonal antibody product
The difference between actual experience in the clinic and product specifications depends on our level of understanding of
the impact that the attribute under consideration can have on the safety and efficacy of the product. This is illustrated
in Figure 3 for two attributes, purity by IEC and host cell proteins. In the case of purity, the proposed specifications of
>95% compared to the clinical experience of >98% would require either nonclinical studies relating the impurity or impurities
to safety and efficacy, or clinical or nonclinical data on these species from another similar platform molecule or the literature.
The proposed specification for host cell proteins (<100 ng/mg) is significantly broader than the clinical experience (<10
ng/mg). This may be justified based on our understanding of the host cell proteins or data from other molecules within a platform,
as it is recognized that the types of host cell proteins present can be as important as the level of host cell proteins.
In summary, identifying the CQAs and setting appropriate specifications and acceptable limits (or validating removal if applicable)
are the foundational activities of implementing QbD for biologics. The former requires a risk assessment process to estimate
the criticality of each quality attribute. Both activities depend heavily on prior knowledge from the sources listed above.
Anurag S. Rathore, PhD, is a consultant, Biotech CMC Issues, and a member of the faculty in the department of chemical engineering at the Indian Institute of Technology. Rathore is also a member of BioPharm International's Editorial Advisory Board.
Articles by Anurag S. Rathore, PhD
John Towns is the senior director of global CMC regulatory affairs at Eli Lilly and Company. Towns is also the chair of the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee
Articles by John Towns
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