Module 9 2024

03/09/2024

When

When are PC and PV typically conducted in the course of mAb development up to BLA/MAA submission?

Marketing authorisation application (MAA)/Biological license application (BLA) Preparation

Clinical Development Phase I

Clinical Development Phase II

Clinical Development Phase III

MAA/BLA Submission

Early Development

Process Validation • Manufacture of at least 3 consecutive PPQ batches • Ideally recommend this is performed prior to Phase III (to avoid risk of process changes and associated comparability studies). • However due to time/budget constraints, it is often performed after Phase III but prior to MAA/BLA submission. • This increases burden on confirmation that the validated process generated material comparable to the clinical supply which is demonstrated by routine comparability studies.

Process Characterisation • Although is an ongoing activity from the start of development. This formally takes place ~9-18 months prior to PPQ.

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Development of the control strategy

• Process development starts by defining the Target Product Profile, which describes the key features of the product under development in terms of quality, safety and efficacy including dosage form, administration route, strength and stability

TPP

• A 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 • CQAs are generally associated with the drug substance, excipients, intermediates (in-processmaterials) and drug product • Critical quality attributes are defined using scientific rationale and risk assessment

CQA

• Process development (PD) usually requires scale up from laboratory scale to pilot scale then establishment of the final commercial scale process • Pilot scale is usually an intermediate scale between development and commercial scale, but should be considered representative of the intended final commercial process. This material is often used as a reference standard and in preclinical evaluations.

Process Develop ment

• Risk assessment tools are used to capture potential material and process risks to the CQAs (CPPs) • PC study planning: CPPs that are identified for further characterisation from the risk assessment should be assessed to determine the acceptable ranges/controls • Scale down models (SDM) should be developed and qualified (where applicable) to allow assessment of process steps using a smaller scale process • Upon completion of PC the CPPs, non-CPPs and associated ranges are defined in a PC report which is used to establish the commercial process control strategy

Process Characte risation

• The control strategy is defined for the commercial manufacturing process. The proven acceptable ranges (PARs) and NOR (normal operating ranges) are described in regulatory dossiers

Control strategy

PPQ • The control strategy is verified through execution of PPQ, and can be adapted to make minor amendments (tightening of ranges for example) following completion

• Continuous process verification: The process performance and product quality is trended and reviewed on an ongoing basis to ensure a state of control is maintained throughout the product lifecycle

CPV

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