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www.biopharminternational.com October 2020 BioPharm International eBook 35 At the early stages of formulation development, pre-formulation stud- ies are typically conducted, aimed at selecting compatible excipients and immediate packaging, generat- ing stability data, and identifying preliminary manufacturing pro- cess. 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 'one-factor-at- a-time' approach, design of experi- ments is most typically deployed in this stage, allowing the identifica- tion of interaction effects between variables. Table II summarizes the quality attributes of a parenteral product (solution and freeze-dried). This table has been adapted to a ster- ile product starting from what is reported in the FDA document on quality by design for ANDAs (5). It indicates which attributes are classified as drug product CQAs in Regulatory Sourcebook Process Development Drug product quality attributes Target Critical (YES/NO) Justification Liquid form Freeze-dried form Reconstitution time Not applicable Variable (generally NMT 2 minutes) YES Reconstitution of the freeze-dried product must provide a clear and clean solution. The target of NMT 2 minutes is a generally accepted value for lyophilized products. Thus, reconstitution time will be evaluated throughout product and process development. Osmolality Preferably in the 280- 330 mOsm/Kg range Not applicable YES Osmolality is a CQA as it can impact product tolerability. Thus, osmolality will be evaluated throughout product and process development. pH Variable Reconstituted solution: variable YES pH of a parenteral solution is a CQA as it can impact product tolerability and drug stability. Thus, pH will be evaluated throughout product and process development. Appearance of reconstituted solution Not applicable The solid dissolves completely, leaving no visible residue as undissolved matter YES The presence of undissolved matter upon reconstitution of a lyophilized product may affect patient safety. Therefore, this CQA will be evaluated throughout product and process development. Par ticulate matter Conforms to USP/ Ph. Eur. Reconstituted solution: conforms to USP/Ph. Eur. YES* The presence of particulate matter may affect patient safety. However, this CQA can be effectively controlled by the quality management system and by selecting the appropriate primary packaging. Formulation variables will not likely impact this CQA. Therefore, this CQA will not be discussed during formulation and process development. This CQA will be monitored at drug product release and during stability of the GMP batches. Stability of reconstituted solution Not applicable Variable YES* This is a critical requirement for both regulatory and marketing perspectives. This attribute, however, is strictly related to the API stability in aqueous solution. Therefore, this CQA will not be discussed during formulation and process development. Table II has been sourced from FDA's document on quality-by-design for Abbreviated New Drug Applications (5). Table II. Critical quality attributes (CQAs) in process design stage (Contin.). Visit Our Archive Sign up for our quarterly regulatory newsletter Stay Current with Global Regulatory Updates