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6 Pharmaceutical Technology Regulatory Sourcebook October 2020 P h a r mTe c h . c o m Process Development Table II. Critical quality attributes (CQAs) in process design stage. Attributes denoted with an asterisk (*) indicate that the CQA can be effectively controlled by the quality management system of the manufacturing facility. Therefore, these CQAs will not be investigated and discussed in detail in the pharmaceutical development. However, the CQA remains a target element of the drug product profile and will be addressed. (To be noted: the list should not be considered as exhaustive and should be adapted to the considered drug product.) USP is United States Pharmacopeia and Ph. Eur. is European Pharmacopoeia, CQAs are critical quality attributes, ICH is International Council for Harmonization, and NMT is not more than. Drug product quality attributes Target Critical (YES/NO) Justification Liquid form Freeze-dried form Appearance Clear and clean solution, free from visible particles No visual defects observed YES* Appearance is not directly linked to safety and efficacy. Therefore, in principle it is not critical (provided that neither visual defects nor foreign particles are observed). Identification Positive YES* Though identification is critical for safety and efficacy, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. Formulation and process variables do not impact identity. Therefore, this CQA will not be discussed during formulation and process development. Assay Within limits YES Assay variability will affect safety and efficacy. Process variables may affect the assay of the drug product (this attribute is strictly linked to degradation products). Thus, assay will be evaluated throughout product and process development. Uniformity of dosage units (weight variation or content uniformity) Conforms to USP/Ph. Eur. YES* Variability in uniformity of dosage units can potentially affect safety and efficacy. As the distribution into vials process step is from a true solution, it is unlikely that variability in uniformity of dosage units occurs, provided that an appropriate control strategy (in-process check of filling weight) is in place. Therefore, this CQA can be effectively controlled by the quality management system and will be monitored at drug product release. For this reason, this CQA will be marginally discussed during formulation and process development. Extractable volume Conforms to USP/Ph. Eur. Not Applicable YES* Extractable volume is a CQA of a parenteral solution, but this parameter is not being evaluated during development studies. Degradation products Based on ICH guidelines and toxicology qualification YES Degradation products can impact safety and must be controlled based on ICH requirements and/or API toxicological qualification and/or reference listed drug characterization (for a generic product). This is of particular significance with poorly stable drugs. Formulation and process variables can impact degradation products. Therefore, degradation products will be assessed during product and process development. Sterility Sterile YES* Lack of sterility will impact patient safety. Therefore, sterility is a key attribute of any parenteral dosage form. However, this CQA will not be discussed during formulation and process development as sterility is to be built in the product/process by adopting an appropriate quality management system (sterile filtration and aseptic filling technique). This CQA will be monitored at drug product release and during stability of GMP batches. Bacterial endotoxins Within limits YES* Non-compliance with bacterial endotoxins limits will impact patient safety. Therefore, bacterial endotoxin is a key attribute of any parenteral dosage form. However, this CQA will not be discussed during formulation and process development as compliance with endotoxins limit is to be built in the product/process by adopting an appropriate quality management system. This CQA will be monitored at drug product release of GMP batches. Residual solvents (if relevant) Not applicable Based on ICH guideline YES Non-compliance with the specification limit can impact patient safety. Thus, residual solvents will be evaluated throughout product and process development. Water content Not applicable Variable YES Water content may affect drug degradation both at release and during storage. This CQA will be assessed during product and process development.