The ICH Q11 guideline on the development and manufacture of drug substances may be one of the most  awaited regulatory guidelines in recent harmonization history. The concept for this guideline was developed in May 2008, and at the end of last month, June 2011, FDA published the Step-2 consensus document as draft guidance for industry comment. In general, the document aims to provide guidance on how industry can develop process and drug-substance (that is, chemical and biological entities) understanding. This guidance is important because of its focus on APIs—perhaps the most important component of any drug product—and because it addresses biopharmaceutical manufacturing, an area that is growing like wildfire in terms of R&D but has been somewhat stifled when it comes to global regulatory guidance. The document is also of great interest to industry because of its attention to “understanding”—a key concept of quality by design. Understanding of a drug-product’s materials and their functionality and characteristics is becoming more important and, in fact, is critical for any quality- or risk-based approach to bio/pharmaceutical manufacturing today. These types of approaches, promise the authorities, are meant to provide regulatory flexibility for manufacturers.

Q11 is quite long (26 pages) compared with other ICH guidelines—even the Q10 guideline on pharmaceutical quality systems is only 17 pages. But as a result, it provides a great amount of detail. According to a notice in the Federal Register about the drug guidance, Q11 applies to drug substances as defined in the “Scope” sections of ICH guidances Q6A Specifications: Test Procedures and Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances and Q6B Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products.

The document includes sections on selecting and qualifying starting materials, identifying critical quality attributes, developing a control strategy (including key considerations such as downstream factors for biologics manufacture), process validation, life-cycle management, and more. The technical part of the guidance includes several practical examples that may benefit industry implementation (e.g., how to present a design space for a biotech product, and how to link material attributes and process parameters to drug substance critical quality attributes). Both traditional and enhanced (i.e., risk-based) approaches are provided.

The Q11 draft document also keys industry into what they are supposed to include in their Common Technical Document (CTD) submissions regarding process descriptions and justifications for the development and manufacture of their drug substances (CTD sections 3.2.S.2.2 through 3.2.S.2.6). The draft guidance notes, for instance, that the role of experimental studies, risk assessments, and prior knowledge in establishing the process and control strategy should be reported. Q11 further states that the CTD Description section should include a diagram and sequential procedural narrative of the manufacturing process, as well as any information about how the applicant will manage postapproval movements within an approved design space.

Finally, Q11 aims to clarify some key concepts tied to the existing Quality Trio guidelines (Q8 on pharmaceutical development, Q9 on quality risk management, and Q10 on pharmaceutical quality systems). For example, the concepts of design space and Quality Target Product Profiles noted in Q8, the risk assessments noted in Q9, and the knowledge-management expectation noted in Q10 are all incorporated into Q11, with given examples.

Industry should take time to review this important document and provide feedback to FDA. Once finalized, Q11 will be a crucial part of any bio/pharmaceutical manufacturing strategy.