title: A proposed rationale and test methodology for establishment of acceptance criteria for vacuum integrity testing of pharmaceutical freeze dryers.
abstract: A scientific rationale is proposed for the establishment of acceptance criteria for leak rates in pharmaceutical freeze dryers. A method was developed to determine the quantity of air that could leak into any lyophilizer from the outside while still maintaining Class 100/Grade A microbial conditions. A lyophilizing product is assumed most vulnerable to microbial contamination during secondary drying, when mass transfer of water vapor from product to condenser is minimal. Using the void volume of the dryer, calculated from change in internal pressure when a known volume of air is introduced, and the potential maximum bioburden of the leaked air (based on measured values), calculations can determine the allowable leaked volume of air, the flow rate required to admit that volume in a given time frame, and the pressure rise that would result from the leak over a given testing period. For the dryers in this study, using worst-case air quality conditions, it was determined that a leak resulting in a pressure rise of 0.027 mbar over a 30 min period would allow the dryers to remain in secondary drying conditions for 62 h before the established action level of one colony forming unit for each cubic meter of air space would be reached.
authors.affiliation: Baxter Medical Products, R&D, Baxter Healthcare, Bloomington, IN, USA. Electronic address: lisa_hardwick@baxter.com.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hardwick
authors.forename: Steven L
authors.initials: SL
authors.lastname: Nail
authors.forename: James
authors.initials: J
authors.lastname: Jarman
authors.forename: Kai
authors.initials: K
authors.lastname: Hasler
authors.forename: Thomas
authors.initials: T
authors.lastname: Hense
mesh_terms: D000388:Air; D054796:Drug Dosage Calculations; D004784:Environmental Monitoring / Q000379:methods; D005612:Freeze Drying / Q000379:methods*; D011312:Pressure; D013678:Technology, Pharmaceutical / Q000379:methods*; D013696:Temperature; D014618:Vacuum; D014867:Water / Q000737:chemistry
chemical_list: D014867:Water
keywords: Acceptance criteria; Bioburden; Freeze dryer; Leak rate; Lyophilizaton; Pressure rise test