Quality by Design for Biotechnology Products—Part 2 - Second in a three-part series that discusses the complexities of QbD implementation in biotech development. - BioPharm International


Quality by Design for Biotechnology Products—Part 2
Second in a three-part series that discusses the complexities of QbD implementation in biotech development.

BioPharm International
Volume 22, Issue 12

A holistic approach to the control strategy helps minimize the probability of a negative impact on product safety and efficacy. In addition, establishing a comprehensive control strategy can further reduce risk by taking the following elements into consideration:

  • procedural controls
  • in-process controls
  • lot release testing
  • process monitoring
  • characterization testing
  • stability testing
  • raw material and excipient controls
  • shipping.

Consider a monoclonal antibody (MAb) that was derived from a Chinese hamster ovary (CHO) cell culture and directed against rheumatoid arthritis. The QTPP for this product indicates that a typical patient needs the product to be delivered in a pen that may be held at room temperature for at least one week. A stable single-use solution drug product using a pre-filled syringe for once-weekly dosing meets the QTPP. The patient population typically has reduced manual dexterity and the pre-filled syringe means there is less need for patients to perform manual product manipulations before dosing (i.e., the product has been designed to meet patient needs). The amino acid sequence for the selected MAb with the greatest efficacy has a methionine in the complimentarity determining region (CDR). Oxidation of this residue in the drug product results in loss of potency, which affects product efficacy. Purity with respect to oxidation, then, is a CQA for this drug product. The formulation design and manufacturing control strategy must be developed for this CQA to minimize the oxidation of the methionine residue during manufacture and shelf storage. Appropriate preformulation and formulation DOE studies must be conducted to define the variables affecting the oxidation of methionine, such as pH or dissolved oxygen (DO), or peroxide or trace metals from raw materials or container closure systems. These studies lead to the identification of the design space where product stability is acceptable. Additional controls define the appropriate control strategy during manufacture as well as for incoming excipients and packaging components. For example, the presence of peroxides in excipients (e.g., surfactants) or potential leachates from packaging components can increase the susceptibility to oxidation and require careful monitoring (e.g., vendor qualification) and control. Controls in manufacturing such as monitoring levels of DO using appropriate in-line process analytical technology (PAT) measurements and temperature controls may be instituted to control the oxidation and stability CQA to obviate an end testing specification. Similarly, processes should be designed such that every batch delivers a safe, efficacious product, consistent with the product design intent outlined in the QTPP.


Development of biotechnology products based on the QbD principles presented in this paper will require modifications to the current application format and content. It is expected that the standard common technical document (CTD) format, for the most part, will be retained in a "QbD" application or supplement but that the content of specific sections in Module 3 will reflect "knowledge rich" information required to support a QbD biological product. The extent of these modifications will depend on how much QbD information individual sponsors may wish to present in their applications. For the purposes of this discussion, we have assumed the sponsor will be maximizing the amount of QbD information to cover manufacture and testing of both the drug substance and drug product. Sponsors may decide to limit QbD to the drug substance, the drug product, or even individual unit operations of either the drug substance or drug product.

There are a number of principles one must consider when preparing and optimizing quality information in the application. In addition to providing a comprehensive "reviewer friendly" data package that meets regulatory requirements, a strong focus on the data required to establish the relationships between the CQAs and the resulting control strategy for drug substance and drug product is essential. This focus should also include the design of key development studies and the risk assessments that were considered in the design of these studies, as well as a summary of the key findings and conclusions. Every effort should be made to avoid the tendency to include every piece of data to support one's conclusions. "Knowledge rich" is not a data dump but a more focused, strategic presentation of the data synthesized into information to allow a comprehensive review and understanding of the product and manufacturing process.

The following section presents a recommendation for incorporating QbD information into a CTD format. A sponsor might choose to apply some or all elements of the recommendation. The regulatory landscape for QbD applications will likely continue to evolve in the future.

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