Lyophilization: the influence of this complex technological process on the regukatory requirements

Lyophilization, or freeze drying, is a crucial development in pharmaceutical manufacturing, because it allows heat-sensitive vaccines, antibiotics, and protein-based drugs to be dried safely. The process results in powders with long shelf lives that can be reconstituted at the point of use. Its strategic importance continues to grow, as injectable biopharmaceuticals become a more prominent part of the overall drug market. Yet, users and the main regulatory Agencies refer to lyophilization as a “complex process” (EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1,Corr.1) associated with the manufacture and control of the final pharmaceutical dosage form. The “Guide to inspections of lyophilization of parenterals” issued by the FDA in 1993 listed some of the critical aspects: formulation of solutions, filling of vials and validation of the filling operation, sterilization and engineering aspects of the lyophilizer, scale-up and validation of the lyophilization cycle, and testing of the end product. Lessons learned from everyday experience underline that the most of these aspects are impacted by a complex combination of both formulation and process factors. Hence, the implementation of the ICH Q8, Q9 and Q10 Pharmaceutical Quality System can be obtained only by advancements in technologies and improvement of the body of knowledge. In other words, innovation will drive the development of a systematic approach to setting inspection expectations to ensure consistency and compliance and simplifying the administrative procedure in case of change in the lyophilization process.