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Pharmaceutical Technology Regulatory Sourcebook October 2020 19 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 has not to 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 and ICH is International Council of Harmonization. Drug product quality attributes Target Critical (YES/NO) Justification Powder Granule Tablet Appearance No visual defect observed No visual defect observed No visual defect 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 Positive 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 d rug 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 Within limits 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. Conforms to USP/Ph. Eur. Conforms to USP/Ph. Eur. YES Variability in uniformity of dosage units can potentially affect safety and efficacy. Blending, intermediate product transfers and tableting may impact on the drug product content uniformity. Therefore, this CQA will be evaluated throughout product and process development. Degradation products Based on ICH guidelines and toxicology qualification Based on ICH guidelines and toxicology qualification 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. Microbial load Conforms to USP/Ph. Eur. Conforms to USP/Ph. Eur. Conforms to USP/Ph. Eur. YES* Solid oral forms must comply with specific microbial purity properties. Non-compliance may impact patient safety. However, this CQA will not be discussed during formulation and process development as compliance with microbial purity will be effectively controlled by the quality management system and will be monitored at drug product release and during stability of good manufacturing practice (GMP) batches. Residual solvents (if relevant) Based on ICH guidelines Based on ICH guidelines Based on ICH guidelines YES Non-compliance with the specification limit can impact patient safety. Thus, residual solvents will be evaluated throughout product and process development. Water content Within limits Within limits Within limits YES Water content may affect drug degradation both at release and during storage. This CQA will be assessed during product and process development. Closure integrity USP/Ph. Eur. USP/Ph. Eur. 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. Dissolution Within limits Within limits Within limits YES Dissolution time is critical for safety and efficacy. This CQA provides drug release information and will be monitored throughout product and process development. Table II has been sourced from FDA's document on quality-by-design for Abbreviated New Drug Applications (4).