Manufacturers typically use QBD as a science and risk-based approach to pharmaceutical development and manufacturing to help ensure product quality. The concepts are described in the international guidelines, including ICH Q8, Q9, Q10 and Q11.
What the regulators’ Q&A terms “design space verification,” is a demonstration that the combination of the process parameters and material attributes established at pilot scale during pharmaceutical development are capable of delivering a product of appropriate quality on a commercial scale.
Movements from one area to another area within the design space, for example re-establishing the Normal Operating Ranges within the approved design space in an unverified area, may pose higher or unknown risks due to potential scale–up effects and/or model assumptions.
“It is important that these risks are understood and evaluated utilizing an appropriate control strategy…It is understood that when an applicant demonstrates that a design space is scale independent, then additional risk mitigation steps are not necessary for design space verification,” the FDA and EMA say.
The agencies also clarify how design space should be verified on the commercial scale.
“It is not necessary to repeat at commercial scale the experiments initially conducted to define a design space at lab or pilot scale,” according to the Q&A. “Furthermore, it is neither necessary to verify entire areas of design space nor to identify the edge of failure. In principle, more than one area of a design space may be verified at the time of submission but the design space can, as appropriate, also be further verified over the product lifecycle.”
As far as how design space verification and process validation should be delineated, the regulators warn that design space verification “should not be confused with process validation.
“Both take into consideration prior knowledge and development conclusions and are conducted at commercial scale, however the scope of the studies are not the same. Whereas process validation demonstrates consistency of the process at normal operating ranges, design space verification demonstrates that scale effect and or model assumptions are under control in the new area of design space and do not affect product quality.”
In March 2011, the EMA and US FDA launched a three-year pilot programme for the parallel assessment of certain quality or chemistry manufacturing and control (CMC) sections of applications that are relevant to QBD. Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) is participating as an observer in the programme.
The objective of the parallel assessment is to share knowledge, facilitate a consistent implementation of the international guidelines on the implementation of QBD throughout the EU and US.
The EMA and FDA said they will publish further conclusions on other QBD-related topics as the pilot programme continues and more parallel assessments are conducted.