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EMA/FDA Paper on Design Space Verification

On the 4th November the EMA and FDA published a second Q&A paper resulting from their joint review of QbD submissions. This document is on the subject of ‘Design Space Verification’. A design space is established at early stages of product development, it is typically developed based on experiments conducted at laboratory or pilot scale. This document has been issued as movements from one area to another within the design space (eg, re-establishing the Normal Operating Ranges (NOR) 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. Design space verification demonstrates that within design space boundaries scale-up effects are under control and do not adversely affect the expected product quality at commercial scale.

The approach to design space verification over the product lifecycle can be guided by the results of risk assessment on the potential effect of changes to scale dependent parameters on product quality. A design space verification protocol should be drawn up and this could include the following:

• a list of scale dependent parameters, whose impact on the CQAs has not been verified at commercial scale
• definition of the potential scale-up risks to the CQAs
• discussion of whether the control strategy can address these risks and
• a description of any additional controls required.

The expectation as to how Design Space Verification is handled is different for EMA and FDA. The EMA’s expectation is that a protocol for design space verification be submitted in section 3.2.R of the application. At the time of submission, a proposed design space not verified at commercial scale should be accompanied by an appropriate verification protocol.

FDA’s expectation is that any plans for design space verification should be available at the manufacturing site as an element of the change control, validation, and/or knowledge management strategy. Providing data for initial design space verification and a high-level overview of the plan for design space verification over the product lifecycle can be beneficial to the review of the application.

If the verification studies prove the process does not meet the predefined product quality attributes in a new region of the approved design space, this may require changes to the boundaries or description of the design space, which will then require the submission of Variations.

There follows detailed guidance, as two appendices, on the approaches to be followed in the EU and the US.