Finally, the identification of CQAs and understanding the influence certain material attributes exude on the manufacturing
process should be considered a crucial aspect of the process. This is the area where implementing a control strategy and employing
QRM becomes essential; and the concept of design space is introduced into the manufacturing equation. According to Q11, design
space is the multidimensional combination and interaction of two elements: input variables and process parameters (1). Design
space (as defined by the manufacturer) is subject to regulatory oversight by FDA. ICH Q8 (2.4) provides additional detail
on the topic of design space.
The submission process for the enhanced approach: document requirements. There are mandatory submission requirements in support of manufacturing process development that must be considered by drug-substance
manufacturers. The submission must contain sufficient detail to support the claim for product safety and efficacy needed for
eventual commercialization. For example, the expectation is that the following documentation be included as part of the drug-substance
- An overall summary of the development process including: CQAs; description of design stages; description of material attributes;
description of process parameters; and description and development of design spaces should be provided.
- CQAs of the drug substance shall be listed.
- A detailed discussion of the manufacturing process history needs to be provided.
- Manufacturing development studies, including risk assessments employed in support of commercial development, including the
control strategy, must be provided.
Description of process and process controls employed in manufacturing. It is imperative that the manufacturers of drug substances provide a detailed description of the manufacturing process and
the processing controls employed. The most efficient way to adequate delineate processes is through the creation of flow charts.
Flow charts are an inherent requirement, regardless of submission type. In fact, Q11 requires that a flow chart be provided
as part of the submission process.