Quality by Design for Biotechnology Products—Part 3

Guidance from the Quality by Design Working Group of the PhRMA Biologics and Biotechnology Leadership Committee on how to apply ICH Q8, Q8R1, Q9, and Q10 to biopharmaceuticals.


The International Conference on Harmonization (ICH) Q8(R2), Q9, and Q10 guidelines provide the foundation for implementing Quality by Design (QbD). Applying those concepts to the manufacture of biotech products, however, involves some nuances and complexities. Therefore, this paper offers guidance and interpretation for implementing QbD for biopharmaceuticals, from early-phase development steps such as identifying critical quality attributes and setting specifications, followed by the development of the design space and establishing the process control strategy; to later stages, including incorporating QbD into a regulatory filing and facilitating efficient commercial processes and manufacturing change flexibility post licensure.

This paper focuses on the factors to consider when applying the Quality by Design (QbD) concepts outlined in ICH Q8(R2), Q9, and Q10 to biotechnology products. Although biologic and biotechnology products often present a higher level of complexity than small molecules in terms of manufacturing process or product structure, the concepts of QbD are the same as those for small molecules. This paper describes the nuances and complexities involved in implementing QbD in the manufacture of biotech products and offers guidance and interpretation for doing so. The scope of this paper is limited to well-characterized protein products, in which the natural molecular heterogeneity, impurity profile, and potency can be defined with a high degree of confidence.

Part 1 of this three-part article, which appeared in the November issue, covered molecular design, the use of laboratory and clinical studies to identify critical quality attributes, setting specifications, and developing the design space. In Part 2, published in the December issue, we addressed the use of design of experiments (DOE) to define the design space, unique considerations for process development for biopharmaceuticals, the establishment of a control strategy, and the placement of QbD information in a regulatory application. Here, in this final Part 3, we discuss continuous verification and postapproval changes, including refining the design space, comparability protocols and expanded change protocols, and our overall conclusions for the three-part article.


Process change is an expected aspect of pharmaceutical manufacturing. Many process changes are made as a result of increased process knowledge to keep pace with advancing technologies and improvements to the manufacturing process. When a product is first approved, its manufacturing process represents the current technology standard for manufacturing and follows the current good manufacturing practices (cGMPs) standard for regulatory compliance. After approval, market demand, technological advances, GMP standards, raw materials (e.g., resins) sourcing or manufacturing experience may require that the approved process be modified. Traditionally, these postapproval changes have required regulatory agency endorsement before implementation. The intent of this section is to propose a path forward that fosters continuous improvement and innovation, and acknowledges the extensive understanding of the manufacturing process and product (process knowledge) gained through the development of the design space or through manufacturing experience. The demonstration of extensive process knowledge in the marketing application, combined with established robust and effective quality systems to monitor manufacturing process performance, provides health authorities the assurance, and thus the allowance, to reduce regulatory oversight and the burden of postapproval change supplements while still meeting legal and regulatory expectations. The future treatment of postapproval changes will be influenced by:

  • in the US, formal integration of change control flexibility and the relationship to registered details, as a part of 314.70 and 601.12; and expanded change protocols used to modify postapproval reporting requirements1
  • changes in the global regulatory landscape, including international regulatory alignment, with respect to the treatment of postapproval CMC changes, driven by a) increased reliance on site-based quality systems change control and reduced requirements for prior regulatory agency approval, and b) the integration of Quality by Design and ICH Q8(R2), 9 and 10 (and presumably Q11 in the future).

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