Issue link: https://www.e-digitaleditions.com/i/1302985
Pharmaceutical Technology Regulatory Sourcebook October 2020 7 The definition of the QTPP should be accom- panied by the definition of the CQAs of the drug product. According to International Council for Harmonization (ICH) Q8 (2), a CQA "is a physical, chemical, biological, or microbiological property or characteristic that should be within an appro- priate limit, range, or distribution to ensure the desired product quality." CQAs are generally asso- ciated with the API, excipients, intermediates, and drug product. Therefore, what can be referred to as a CQA for an API or an excipient (e.g., particle size, solid state, purity, etc.) can become a critical mate- rial attribute (CMA) for a unit operation delivering an intermediate or a drug product. Process design Process design is the first stage of the FDA guid- ance for industry on process validation (3). The commercial manufacturing process should be defined in this stage based on knowledge gained through development and scale-up activities. Comprehensive process design is vital to under- stand sources of variability and achieve product and process understanding. In the context of the Table II. Critical quality attributes (CQAs) in process design stage (Contin.). Drug product quality attributes Target Critical (YES/NO) Justification Liquid form Freeze-dried form Closure integrity USP/Ph. Eur. YES* Integrity of closure is critical to safety. However, this CQA is controlled by the use of a validated closure/container configuration. Therefore, this CQA will not be discussed during formulation and process development. This CQA will be monitored during stability of GMP batches. 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. Particulate 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).