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14 Pharmaceutical Technology Regulatory Sourcebook October 2020 P h a r mTe c h . c o m Process Development Table VIII. Critical quality attribute (CQA) failure and critical process parameter (CPP) correlation for continued process verificatIion for a freeze-dried product. CQA failure CPP to be monitored Compounding and filling Freezing Primary drying Secondary drying Appearance of the cake • Incomplete solubilization of ingredients (type of stirrer, time and temperature) • Irregular filling • Incomplete solidification (time and/ or temperature) • Non flat lyo trays (if applicable) • Freezing rate • Incomplete drying (time and/or temperature) • Rate of heating too high (product temperature exceeds maximum allowable temperature) • Loss of vacuum • Non flat lyo trays (if applicable) • Incomplete drying (time and/or temperature) • Rate of heating too high (for amorphous systems) Assay • Incomplete solubilization of the API (type of stirrer, time and temperature) • API degradation during compounding, including freeze-dryer loading (time and temperature) • Inadequate order of addition of components • Irregular filling • Freezing rate (especially for proteins) • Rate of heating too high (product temperature exceeds maximum allowable temperature) • Incomplete drying (time and/or temperature) • Incomplete drying (time and or temperature) • Temperature too high Degradation products • API degradation during compounding, including freeze-dryer loading (time and temperature) • Inadequate order of addition of components • Freezing rate (especially for proteins) • Rate of heating too high (product temperature exceeds maximum allowable temperature) • Incomplete drying (time and or temperature) • Temperature too high Uniformity of dosage units • Incomplete solubilization of the API • Irregular filling No impact No impact No impact Residual moisture Low probability and impact Low probability and impact Low probability and impact • Insufficient secondary drying (time and/or temperature) • Product water re- adsorption before water content analysis Polymorphism (solid state of the cake) Low probability and impact • Freezing rate • Annealing (Yes/No, temperature and ramp rate) • Heating rate • Product temperature Reconstitution time and appearance of reconstituted solution • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Freezing rate (e.g., re-crystallization) • Temperature and rate of heating too high (product temperature exceeds maximum allowable temperature resulting in collapse, melting, crust formation) Low probability and impact pH of reconstituted solution • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Freezing rate (e.g., pH shift) Low impact Low probability and impact Particulate matter • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Re-crystallization • Freezing rate (e.g., re-crystallization) • Temperature and rate of heating too high (product temperature exceeds maximum allowable temperature resulting in collapse, melting, crust formation) Low probability and impact