Understanding ICH Q11—FDA's Guidance on the Development and Manufacture of Drug Substances - Pharmaceutical Technology

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Understanding ICH Q11—FDA's Guidance on the Development and Manufacture of Drug Substances
The author provides a review of FDA's guidance document, Guidance for Industry: Q11 Development and Manufacture of Drug Substances, and its relation to the International Conference on Harmonization's Q11 document and its application to the industry.

Pharmaceutical Technology
Volume 37, Issue 5, pp. 64-68

Material-selection process

In support of the development and manufacture of drug substances, it is imperative that the quality and physical properties of starting and source materials (note: there is no difference in source versus the starting materials the vernacular used varies by region) be understood (1). Similar to manufacturing process-development requirements, the selection of starting and source materials is also premised on adherence with applicable principles. Principles associated with the material selection process, as delineated within Section 5.1 of Q11 are:

  • Selection of starting materials for synthetic drug substances
  • Selection of starting materials for semisynthetic drug substances
  • The selection of source and starting materials for biotechnical/biological drug substances (1).

Drug substance manufacturers must implement a QRM strategy. Effective implementation of QRM will result in a better understanding of risk and the link between risk and the number of process steps. Also needing to be considered are drug-substance material properties and the management of drug impurities (1). According to Q11, regulatory authorities will assess the controls employed by manufacturers, "including those needed how impurities are formed in the process; how changes in the process could affect the formation, fate, and purge of impurities" (1).

As a point of reference, ICH Q7 is an excellent starting point when it comes to understanding the need for the employment of GMPs needed for managing starting materials (5). Application of ICH 7 has become mandatory in some ICH regions (e.g., the European Union). It should be noted that unlike reagents, starting material should be considered a significant structural fragment of the drug substance. Similar to synthetic drug substances, semisynthetic drug substance starting materials must be understood and adequately described (e.g., "chemical synthesis and elements of biological origin" [1]). When considering the selection of raw materials for biotechnological/biological drug substances, manufacturers should apply the ICH 5 series (6-10) of guidance documents (6).

Submission of relevant information. In support of the submission process, manufacturers are required to provide a list of the raw materials being used and their specifications, supported by written justification as to why these materials are acceptable. This justification is required for synthetic, semisynthetic, and biotechnological/biological drug substances.

Control strategy

A control strategy is the development and implementation of adequate controls to ensure the continued repeatability of process performance and the ongoing assurance of finished product quality. The control strategy and subsequent control steps implemented are premised on a thorough understanding of manufacturing processes, the expected behavioral characteristics of raw materials, and sources of variability associated with a CQA (1). Elements of an effective control strategy typically include:

  • Controls employed for raw materials
  • Controls associated with the design manufacturing process
  • In-process controls (i.e., testing and process control points)
  • Controls placed on the drug substance (e.g., release testing) (1).

Submission of relevant information. In support of the submission process, the control strategy employed must be provided in sufficient detail that includes a detailed description for each of the control-strategy elements. The information can be depicted in a table or through the use of a visual aid (e.g., flow chart delineating control points). As a minimum, the following control-strategy plan elements should be included in the submission:

  • Description of manufacturing-process controls
  • Controls employed for materials
  • Controls for identified critical process steps
  • Controls for the drug substance
  • Container closure systems (5).


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