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32 BioPharm International eBook October 2020 www.biopharminternational.com facturing process intended to be validated, and continues through- out the lifecycle according to qual- ity-by-design (QbD) and quality risk management (QRM) princi- ples. This article illustrates the concepts, the approaches, and the tools available to implement this modern vision of PV for pharma- ceutical products, specifically in reference to sterile dosage forms (in particular liquid and freeze- dried products). Freeze-dried and liquid products were selected as they are receiving greater attention in view of the increasing number of biological and biotechnologi- cal products. And yet, despite the progress made on lyophilization technology, there are still several lyophilization cycles not designed/ optimized according to science (e.g., product temperature in pri- mary drying overcomes collapse temperature, the cake has sub-op- timal appearance, cycles are lon- ger than required: unnecessarily long pr imar y dr y ing times are often adopted, and long second- ary drying times can result in drug degradation). QUALITY TARGET PRODUCT PROFILE (QTPP) AND CRITICAL QUALITY ATTRIBUTES (CQAs) The QTPP is a strategic guide to the formulation scientists allow- ing their activities to be focused on the development objectives (1). Therefore, the QTPP is strictly r e l ate d to id e nt it y, s t r e n g t h, purit y, and stabilit y, which are the four pillars of the common technical document (CTD) qual- it y section. Based on the phys- ico c he m ic a l c ha rac te r i st ic s of the drug substance and the gen- e r a l qu a l it y at t r ib ute s of t he drug product, the QTPP for a par- enteral liquid and a freeze-dried product is reported as an example in Table I. Regulatory Sourcebook Process Development QTPP element Target Reference/ Requirement Liquid form Freeze-dried form Dosage form Sterile liquid, clear and clean solution (concentrate for solution for infusion) free from visible particles Sterile powder or cake for reconstitution (sterile powder or cake for concentrate, for solution for infusion) Commercial requirement Route of administration Intravenous infusion Intravenous infusion Commercial requirement Dosage strength Nominal dose (mg/container) or concentration (mg/mL) Nominal dose (mg/container) Clinical requirement Container closure system Single dose, clear Type I glass vial or ampoule, or polymer for blow- fill-seal container, X mL capacity closed with a rubber stopper and sealed with an aluminum metal cap with flip-off or flame sealed, or top mold sealed Single dose, clear Type I glass vial, X mL capacity closed with a rubber stopper and sealed with an aluminum metal cap with flip-off Stability and commercial requirements Composition Precedented and safe inactive ingredients Precedented and safe inactive ingredients Quality and regulatory aspects Drug product quality attributes Appearance Appearance Regulator y requirement Identification Identification Regulator y requirement Assay Assay Regulator y requirement Not applicable Uniformity of dosage units (weight variation or content uniformity) Harmonized requirements for content uniformity Degradation produc ts Degradation produc ts ICH and compendial standards Sterility Sterility Compendial standards Bac terial endotoxins Bac terial endotoxins Compendial standards Osmolality Residual solvents (if relevant) Tolerability and safety requirements pH Water content Regulator y requirement Par ticulate matter Reconstitution time Regulator y requirement Not applicable pH of reconstituted solution Regulator y requirement Appearance of reconstituted solution Regulator y requirement Particulate matter on reconstituted solution Regulator y requirement Shelf-life Variable Variable Commercial requirement Administration instructions Variable Variable Clinical requirement Stability during administration Variable Variable Quality and safety requirements Table I. Quality target product profile (QTPP) examples for liquid and freeze- dried parenteral products. ICH is International Council for Harmonization.