In November of 2012, FDA issued Q11 Development and Manufacture of Drug Substances (1). The International Conference on Harmonization (ICH) Q11 Expert Working Group developed the FDA guidance (1). Additionally, the term "guidance" is a reflection of the agency's current thinking on this topic and should be considered as nonbinding recommendations only. Current FDA regulations for GMPs do not cover APIs specifically, so the adoption of ICH Q11 as a guidance document was deemed to be a reasonable approach by the agency. In accordance with this guidance, manufacturers can use alternate approaches needed in the development of drug substances. Q11, however, delineates two viable approaches for drug-substance development: traditional and enhanced (2). The traditional approach is premised on establishing set points and specific operating ranges for all process parameters (2). The control strategy for drug substances is predicated on process reproducibility and repeatability and the implementation of an effective program for drug-substance testing against predefined criteria. The enhanced approach entails the employment of risk-management strategies and the application of scientific knowledge to garner a better understanding of process parameters (2). The concept is to develop and implement control strategies and then employ these strategies over the drug-substance lifecycle to support a better understanding of critical quality attributes (CQA) needed to produce safe drug substances and the establishment of design space (as applicable).
To enhance the understanding of Guidance for Industry: Q11 Development and Manufacture of Drug Substances, it is important to have some basic knowledge of ICH and the interrelationship of guidelines published by ICH. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use was founded in 1990. Pharmaceutical industry regulators from the United States, Japan, and Europe were brought together for the succinct purpose of improving global harmonization of regulatory requirements needed to support the design and development for medicines that are safe and effective in their intended use (3). Guidelines developed by ICH Expert Working Groups are divided into four categories: quality guidelines, efficacy guidelines, multidisciplinary guidelines, and safety guidelines (3). Several countries have adopted ICH guidelines as law; however, FDA only considers the guidelines as guidance. Implementation of the guidance provided in Q11 requires knowledge of applicable ICH guidelines referenced specifically in of Guidance for Industry: Q11 Development and Manufacture of Drug Substances.
Manufacturing process developmentOne of the requirements needed for the manufacturer of quality drug substances are validated processes capable of providing repeatable results. In support of accomplishing the task of manufacturing a quality product, manufacturing process development requires adherence with six quality principles delineated within Q11:
Manufacturers are expected to understand the impact of raw-material attributes on drug substances (e.g., CQAs). Additionally, the expectation is that quality risk management (QRM) tools be employed wherever possible (4). Furthermore, manufacturers should focus on the design and development of a fundamentally sound approach for drug development. As delineated in the introduction, a traditional or enhanced approach can be employed or a combination for the two for drug-substance development. It should be noted that the traditional approach has been the preferred method of drug development for years. Q11 and FDA's guidance allows for some flexibility so manufacturers can implement a system that works for them. There are, however, specific elements that need to be implemented: identifying all CQAs, defining the manufacturing process, and defining and implementing a control strategy.