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10 Pharmaceutical Technology Regulatory Sourcebook October 2020 P h a r mTe c h . c o m Process Development Finally, Table V summarizes the most important formulation development studies for a solution and freeze-dried product. The final output of the design and experimental phase is the update of the risk assessment as a con- sequence of the results of development studies: If there are some gaps, the mitigation actions should be defined, implemented, and verified to define the manufacturing batch record to be used during process qualification. Moreover, an initial defini- tion of the control strategy might be developed; although, this initial hypothesis will be confirmed during stage 2. Process performance qualification (PPQ) The new concept of the process qualification (stage 2) starts with process design and contin- ues for the entire lifecycle of the product (stage 3). PPQ shows that the process, operating within established parameters, can be performed effec- tively and reproducibly to produce a medicinal product meeting its QTPP. Another aim is to pro- vide evidence that (at least) the identified risks, as described in the risk analysis, are controlled by means of suitable actions. The PPQ protocol should at least describe the following topics: • Validation approach (i.e., traditional, hybrid, or continuous, according to references [6] and [7]) • CQA, CPP, and other parameters (e.g., yield) to be investigated including acceptance criteria • The number of batches to be manufactured • Bracketing/matrixing approaches, if applicable • Process for release and certification of batches, if applicable (prospective validation, concur- rent validation) • The number of batches for which additional monitoring is proposed. At the end of the activities, data must be col- lected and reviewed against predetermined accep- tance criteria of the validation protocol and fully documented in PV reports. Table III. Initial risk assessment of the manufacturing process of a lyophilized product for injection. DP is drug product and CQAs are critical quality attributes. DP CQAs Manufacturing process steps Manufacture of the solution to be freeze- dried Sterilizing filtration Filling and pre-stoppering Freeze-dryer loading Lyo cycle -freezing Lyo cycle -primary drying Lyo cycle -secondary drying Stoppering and capping Assay Medium High High High Low Low Medium Low Degradation products High High High High Low Medium High Low Appearance of freeze-dried cake Low N/A N/A N/A Low Medium Low Low DP water content N/A N/A N/A N/A N/A Low Medium Low DP residual solvents N/A N/A N/A N/A N/A Low Medium N/A Sterility Low Medium Medium Medium Low Low Low Medium Reconstitution time Low N/A N/A N/A Low Low Low Low Appearance (primary reconstituted solution) Low Low N/A N/A Low Low Low Low pH (primary reconstituted solution) Low N/A N/A N/A N/A N/A N/A N/A