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40 BioPharm International eBook October 2020 www.biopharminternational.com Regulatory Sourcebook Process Development 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 dr ying (time and/or temperature) • Rate of heating too high (produc t temperature exceeds maximum allowable temperature) • Loss of vacuum • Non flat lyo trays (if applicable) • Incomplete dr ying (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-dr yer loading (time and temperature) • Inadequate order of addition of components • Irregular filling • Freezing rate (especially for proteins) • Rate of heating too high (produc t temperature exceeds maximum allowable temperature) • Incomplete dr ying (time and/or temperature) • Incomplete dr ying (time and or temperature) • Temperature too high Degradation produc ts • API degradation during compounding, including freeze-dr yer loading (time and temperature) • Inadequate order of addition of components • Freezing rate (especially for proteins) • Rate of heating too high (produc t temperature exceeds maximum allowable temperature) • Incomplete dr ying (time and or temperature) • Temperature too high Uniformity of dosage units • Incomplete solubilization of the API • Irregular filling No impac t No impac t No impac t Residual moisture Low probability and impac t Low probability and impac t Low probability and impac t • Insuf ficient secondar y dr ying (time and/or temperature) • Produc t water re- adsorption before water content analysis Polymorphism (solid state of the cake) Low probability and impac t • Freezing rate • Annealing ( Yes/No, temperature and ramp rate) • Heating rate • Produc t temperature Reconstitution time and appearance of reconstituted solution • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Freezing rate (e.g., re-cr ystallization) • Temperature and rate of heating too high (produc t temperature exceeds maximum allowable temperature resulting in collapse, melting, crust formation) Low probability and impac t pH of reconstituted solution • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Freezing rate (e.g., pH shif t) Low impac t Low probability and impac t Par ticulate matter • Incomplete solubilization of ingredients (type of stirrer, time, and temperature) • Re-cr ystallization • Freezing rate (e.g., re-cr ystallization) • Temperature and rate of heating too high (produc t temperature exceeds maximum allowable temperature resulting in collapse, melting, crust formation) Low probability and impac t Table VIII. Critical quality attribute (CQA) failure and critical process parameter (CPP) correlation for continued process verification for a freeze-dried product.