The pending ICH Q11 guideline incorporates risk management and a science-based approach for the development and manufacture of drug substances.
ICH Q11, the pending guideline from the International Conference on Harmonization titled Development and Manufacture of Drug Substances, may be one of the most anticipated guidelines in the global pharmaceutical industry in recent years (1). Since 2004, the industry has been working to reshape its approach to drug manufacturing based on FDA's Pharmaceutical CGMPs for the 21st Century initiative, which were cemented between 2005 and 2008 by the so-called ICH Quality trio guidelines (2). These globally harmonized guidelines, which include ICH Q8 Pharmaceutical Development, Q9 Quality Risk Management, and Q10 Pharmaceutical Quality System, detailed quality-by-design (QbD) concepts for pharmaceutical manufacturing and redefined the industry lexicon with terms such as quality target product profile, critical quality attributes and critical process parameters (CQAs and CPPs), knowledge management, product life-cycle management, and control strategy (3–5). The Q11 guideline, which was published as a draft in May 2011 and is expected to be adopted by the ICH steering committee this year, both complements and enhances these concepts by offering industry guidance and clarity "regarding the description and justification of development and manufacturing processes for drug substances and the type and extent of information to be submitted in regulatory dossiers" (6).
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Q11 is one of the longest ICH quality guidelines at 26 pages and specifically addresses the drug-substance manufacturing process for chemical entities and biotechnological/biological entities.
Although the ICH Quality trio guidelines apply to drug substance as well as drug product, industry and regulators felt there was a need to clarify QbD or "enhanced" concepts for drug-substance manufacture. "There are fundamental scientific differences in the process for drug-substance manufacture and the process for drug-product manufacture, including impurity control and removal and chemical transformations," according to the Pharmaceutical Research and Manufacturers Association (PhRMA) representatives on the ICH Q11 expert working group. These representatives include: Betsy Fritschel, Johnson & Johnson and the PhRMA Topic Lead for ICH Q11; Timothy Watson, PhD, Pfizer; and Steven R. Mendivil, Amgen.
The ideas behind Q11
The quality of a drug product is linked to the quality of its drug substance. ICH Q11 therefore seeks to take into consideration and provide examples as appropriate for describing the principles and concepts which are included in ICH Q8, Q9, and Q10. ICH issued a concept paper for Q11 in April 2008 to identify these elements and to detail the goals of the proposed guideline. While defining differences between a "traditional" and an "enhanced" approach to drug-substance manufacture, Q11 states clearly that "Traditional and enhanced approaches are not mutually exclusive. A company can use either a traditional approach or an enhanced approach to drug substance development or a combination of both" (1). In the traditional approach, "set points and operating ranges for process parameters are defined and the drug substance control strategy is typically based on demonstration of process reproducibility and testing to meet established acceptance criteria" (1).
Q11 defines an enhanced approach for drug-substance manufacture as using risk management and extensive scientific knowledge to select process parameters and unit operations that impact CQAs "for evaluation in further studies to establish design space and control strategies applicable over the lifecycle of the drug substance" (1). The guideline provides illustrative examples and approaches for demonstrating product and process understanding that is gained during the process development of drug substances. It also outlines the information recommended for describing the manufacturing process and control strategy as well as considerations for selecting starting materials for synthetic and semisynthetic entities and source materials for biotechnological/biological entities and the related justification. In addition, Q11 addresses the elements and development of a control strategy; process validation and evaluation; and the regulatory evaluation process of drug-substance manufacturing, including the harmonization of common technical document (CTD) submissions (see sidebar on CTD submissions).
How to fill out the common technical document when using an enhanced approach
According to FDA members of the ICH Q11 working group, "identifying what is common and what is different between the development and manufacturing of chemical entities and biotechnological/biological drug substances was one of the key goals" in developing Q11 as well. These ICH Q11 working group members include: John Smith, PhD, CDER (ONDQA) and FDA Topic Lead; Patrick Swann, PhD, CDER (OBP), and FDA Deputy Topic Lead; Steve Wolfgang, PhD, CDER (OC), and Working Group Expert; Chris Joneckis, PhD, CBER, and Working Group Expert.