The details of Q11
The Q11 expert working group, which is made up of individuals from each of the six ICH parties (that is, the regulatory authorities
and trade associations of the US, European Union, and Japan, plus numerous interested parties and observers), received more
than 1300 comments during Step 3 (which is the regulatory consultation and discussion phase) of the ICH process and spent
last fall working through them. Some of the comments were duplicates or very similar, according to the PhRMA Q11 expert working
group members, and the highest percentage of the comments received requested clarification and revision of the guideline's
process development section.
Q11 states that manufacturing process development should include, at a minimum, the following elements: identification of
potential CQAs associated with the drug substance so that those characteristics having an impact on product quality can be
studied and controlled; defining an appropriate manufacturing process; and defining a control strategy to ensure process performance
and drug substance quality (1).
An enhanced approach to manufacturing process development would additionally include:
- A systematic approach to evaluating, understanding, and refining of the manufacturing process. This process includes identifying
through prior knowledge, experimentation and risk assessment, the material attributes and process parameters that can have
an effect on drug-substance CQAs. It further includes determining the functional relationships that link material attributes
and process parameters to drug substance CQAs.
- Using the enhanced approach in combination with quality risk management to establish an appropriate control strategy (e.g.,
proposed design space(s) and/or real-time release testing) (1).
Q11 asserts that the increased knowledge and understanding obtained from taking an enhanced approach could facilitate continual
improvement and innovation throughout the product lifecycle.
Defining CQAs. CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate
limit, range, or distribution to ensure the desired product quality. Drug-substance CQAs typically include those properties
or characteristics that affect identity, purity, biological activity, and stability, states Q11 (1).
Impurities are an important class of potential drug-substance CQAs because of their potential impact on drug product safety.
For chemical entities, impurities can include organic impurities (including potential genotoxic impurities), inorganic impurities
(e.g., metallic residues and residual solvents). For biotechnological/biological products, impurities may be process-related
or product-related. Process-related impurities include: cell substrate-derived impurities, cell culture-derived impurities,
and downstream-derived impurities (1).
The identification of CQAs for biotechnological/biological products can be particularly challenging because they typically
possess a large number of quality attributes, making it difficult to fully evaluate the impact on for safety and efficacy
of each one, states Q11. The guideline therefore recommends that in such cases risk assessments be performed to rank quality
attributes using prior knowledge and updating that knowledge with development data (e.g., knowledge regarding mechanism of
action and biological characterization).
CQAs for biologics products, therefore, should also include consideration of contaminants, "including all adventitiously introduced
materials not intended to be part of the manufacturing process (e.g., adventitious viral, bacterial, or mycoplasma contamination),"
recommends Q11 (1).