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8 Pharmaceutical Technology Regulatory Sourcebook October 2020 P h a r mTe c h . c o m Process Development new paradigm of the 2011 FDA guidance on pro- cess validation, an additional quality level is incor- porated into the concept of product quality. Not only must all drug product batches manufactured for clinical studies and subsequently for the mar- ket comply with established specifications, but the process must also be in a permanent state of con- trol and product performance must be consistent from batch-to-batch and unit-to-unit. Prior knowledge with similar processes and risk management can be used as the first step to iden- tify a list of potential CQAs. Prior knowledge can also be useful to identify a list of process param- eters and material attributes potentially impact- ing the CQAs. Using risk management (4), the risk of these parameters and materials impacting the CQAs can be ranked. Based on these evaluations, experimental activities are prioritized, ultimately leading to a list of CMAs and critical process pa- rameters (CPPs). Another goal is the identification of the most appropriate immediate packaging to ensure the consistency of the identified CQAs. The stage 1 output is as follows: • QTPP (at the beginning of stage 1) • CQAs • Product and process design • CMAs and CPPs and their limits • Knowledge of process variables, enabling the establishment of control strategy (raw materi- als, in-process controls, finished product) • Design space (if applicable) • Process design report. The iterative approach leading to the above- mentioned outputs is illustrated schematically in Figure 1. At the early stages of formulation development, pre-formulation studies are typi- cally conducted, aimed at selecting compatible excipients and immediate packaging, generating stability data, and identifying preliminary man- ufacturing process. It is clear from Figure 1 that product and process design are closely related. After completion of the pre-formulation program, product and process optimization studies are conducted. Rather than using the traditional Target product profile and quality target product profile API characteristics (from preformulation and prior knowledge) Proposed formulation and manufacturing process Determine the functional relationships that link MAs and PPs to product CQAs Risk evaluation Parameters to investigate (risk reduction) Product and process design Control strategy Product and process understanding (re-evaluation and understanding) Monitoring and continuous improvement Figure 1. Scheme for pharmaceutical development and risk management to construct design space and control strategy. MAs are material attributes, PPs are process parameters, and CQAs are critical quality attributes. Comprehensive process design is vital to understand sources of variability and achieve product and process understanding. FIGURES ARE COURTESY OF THE AUTHORS.