European Medicine Agency (EMA) and the US FDA have issued their  responses to the industry on nine aspects of Quality by Design (QbD) elements on design space verification. It would facilitate the implementation of QbD specifically on design space verification in both US and Europe.

Early this year, two regulators, launched a pilot programme to allow joint evaluation of QbD elements. As a result of this pilot programme, the EMA and FDA reached agreements on a wide range of QbD elements.

The nine factors which required detailed explanation by both EMA and FDA were related to harmonization on some QbD aspects on design space verification which is a combination of input process parameters and material attributes that are capable of manufacturing quality product at commercial scale.

Delving on the need for design space be verified during the product lifecycle, both the regulators said that in their experience design space verification needed to occur right through the product life cycle. Initial design space verification often occurs solely at or near the target operating ranges. However, movements from one area to another area within the design space like re-establishing the Normal Operating Ranges (NOR) within the approved design space in an unverified area could pose unknown risks due to potential scale –up effects.

On the purpose of design space verification, the regulators pointed out that within specific boundaries scale-up effects are under control and do not adversely affect the expected product quality at commercial scale.

Both Agencies acknowledged that when a design space is established at early stages of product development, it is typically developed based on experiments conducted at laboratory or pilot scale.

On the verification of design space at a commercial scale, the regulators said that it was not necessary to repeat the experiments initially conducted to define a design space at lab or pilot scale. The approach to design space verification over the product lifecycle could be guided by the results of risk assessment on the potential effect of changes to scale dependent parameters on product quality.

If the verification studies prove the process did not meet the predefined product quality attributes in a new region of the approved design space, it could indicate an underlying issue with the design space or a flaw in the assessment or verification plan.

US FDA and EMA indicated that design space verification should not be confused with process validation. Both take into consideration prior knowledge and development conclusions which are conducted at commercial scale. However the scope of the studies are not the same.

FDA recommends that companies have a written plan for when and how to evaluate the need for design space verification under their pharmaceutical quality system at the manufacturing site as it could be beneficial during review of the application.