Setting Specifications for a Biotech Therapeutic Product in the Quality by Design Paradigm - Manufacturing using meaningful, science-based specifications will ensure that we attain the optimal balance
Setting Specifications for a Biotech Therapeutic Product in the Quality by Design Paradigm
Manufacturing using meaningful, science-based specifications will ensure that we attain the optimal balance between manufacturing flexibility and product safety.
Figure 2. Ratio of the product quality and clinical design spaces for a hypothetical monoclonal antibody product. The quality
attributes shown have been chosen from Table 1.
Figure 2 presents an illustration of the data presented in Table 1 with the ratio of the product and clinical design spaces
plotted against the clinical lot number. A ratio of 1 would mean that the specification is the same as the variability in
product quality seen in the clinic. It can be seen that product-related impurities such as percent purity by high performance
size exclusion chromatography (HP SEC) and percent purity by ion exchange chromatography (IEC) are at ratios <2. In contrast,
process related impurities such as HCP and DNA are at ratios >10. This reflects our knowledge about how a particular attribute
affects the safety, efficacy, and consistency of the product. The less knowledge we have, the more we must depend on the clinical
experience of the product to justify a specification.3
Establishing Specifications for Product-Related Quality Attributes
Figure 3. Illustration of clinical and product design spaces for a few chosen product related quality attributes from Table
1
Product-related quality attributes fall into two categories.2 The first is product-related variants, which include species such as deamidation that are related to the product and have
potency, clearance, immunogenicity, and safety properties similar to the product. The second group covers product-related
impurities such as aggregation, which differ in the above-mentioned properties from the product. Figure 3 illustrates the
comparison between the clinical and product quality design spaces for two product-related impurities. It is seen that the
product quality design space as defined by the specifications is only slightly broader than the clinical experience for percent
purity by HP SEC (specification: ≥98%; clinical experience: 99.1–99.8%) and percent purity by IEC (specification: ≥95%; clinical
experience: 97.5–100.0%). The broader product design space in these cases would still need to be justified by nonclinical
studies evaluating the safety and efficacy of these impurities or by clinical and nonclinical studies related to these impurities
with other platform molecules.
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
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