ABSTRACT

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.

Eli Lilly and Company

The QbD approach can be maintained throughout the lifecycle of the product to facilitate innovation and continuous improvement based on expanded knowledge and new technologies. This knowledge is gained during development and grows with more manufacturing experience through process characterization, scale-up, technology transfer, and manufacture, as well as through increased patient exposure to the product. This approach encourages incorporating prior process and product knowledge and experience-based methodologies (i.e., platform knowledge) into manufacturing throughout the life of the product.

The QbD approach was introduced into the US Food and Drug Administration's chemistry, manufacturing, and controls (CMC) review process in 2004 with the aim of enhancing and modernizing the regulation of pharmaceutical manufacturing and product quality.⁴ The goal of QbD is to develop robust, well-understood processes that 1) deliver a product meeting the QTPP and 2) are controlled by defined steps within the manufacturing process and that allow for manufacturing process changes within an established design space of input variables and operating parameters without negatively affecting process attributes or identified CQAs. When a product is developed using a QbD approach, the impact of raw and starting materials and process parameters on product quality are well understood and the sources of process and product variability are well-known and controlled. In contrast, traditional pharmaceutical manufacturing relies heavily on end-product testing and the process typically lacks the flexibility needed to respond to variables encountered during manufacturing. The outcome is often "quality by conformance" and a rigid, static manufacturing operation that is more susceptible to multiple manufacturing changes post licensure, thus requiring continuous updating of the application through burdensome global regulatory supplements, variations, or amendments.

This paper focuses on the factors to consider when applying the QbD concepts outlined in ICH Q8(R2), Q9, and Q10 to biotechnology products. The paper is intended to capture and reflect both the current and future state of QbD implementation. Therefore, new tools and terminology (e.g., expanded change protocol and the post-approval management plan) have been included with an expectation that the paper will be revised in the future based on new information and experiences, such as the mock biotech common technical document (CTD) sections being developed by the European Federation of Pharmaceutical Industries and Associations (EFPIA) and the CMC Biotech Working Group (formerly Conformia), and the US FDA's CMC Biotech Pilot Program.

This position paper begins by addressing patient needs and product quality attributes, followed by a discussion of characterization development studies and the development of the design space and control strategies. It then addresses how to incorporate QbD into a regulatory filing and finally, how to facilitate efficient, cost-effective commercial processes and manufacturing change flexibility post licensure. 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.