Risk assessment and design space
ICH Q9 Quality Risk Mangement indicates that,
The manufacturing and use of a drug product necessarily entail some degree of risk... The evaluation of the risk to quality
should be based on scientific knowledge and ultimately link to the therapeutic benefit to the patient. The level of effort,
formality and documentation of the quality risk management process should be commensurate with the level of risk (5).
Performing a risk assessment before pharmaceutical development helps manufacturers decide which studies to conduct. Risk assessments
are often driven by knowledge gaps or uncertainty. Study results determine which variables are critical and which are not,
which then guide the establishment of control strategy for in-process, raw-material, and final testing. There were questions
during the workshop about how risk-assessment processes should be described and included in regulatory submissions.
ICH Q8(R1) defines design space as,
The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that
have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change. Movement
out of the design space is considered to be a change and would normally initiate a regulatory post-approval change process.
Design space is proposed by the applicant and is subject to regulatory assessment and approval (1).
Because design space is potentially scale- and equipment-dependent, the design space determined at the laboratory scale may
not be relevant to the process at the commercial scale. Therefore, design-space verification at the commercial scale becomes
essential unless it is demonstrated that the design space is scale-independent. Currently, generic-drug sponsors obtain information
about acceptable ranges for individual CPPs and CMAs at laboratory or pilot scales. Sponsors may occasionally conduct these
studies with appropriate design of experiments, including multivariate interactions, which will create a design space at the
laboratory or pilot scale. Such a design space, however, will have limited regulatory flexibility because the regulatory scientists
will be unable to determine whether the design space is still valid at the commercial scale unless sponsors can provide additional
information that shows the design space is scale-independent or actual verification data at the commercial scale.
Workshop discussions demonstrated that there is confusion among industry and regulatory scientists about the connection between
design space and QbD. Many believe design space and QbD are interchangeable terms. This is incorrect. For generic-drug applications,
design space is optional. QbD can be implemented without a design space because product and process understanding can be established
without a formal design space (6). It should be pointed out that implementation of QbD is strongly encouraged by FDA. For
some complex drug substances or drug products, implementation of QbD is considered a required component of the application.