Baxter Medical Products, R&D, Baxter Healthcare, Bloomington, IN, USA.
Eur J Pharm Biopharm. 2013 Oct;85(2):236-9. doi: 10.1016/j.ejpb.2013.05.021. Epub 2013 Jul 27.
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.
提出了建立制药冷冻干燥器泄漏率验收标准的科学依据。开发了一种方法来确定在保持 100 级/ A 级微生物条件的情况下，仍有多少空气可以从外部泄漏到任何冷冻干燥器中。在二次干燥过程中，假设冷冻干燥产品最容易受到微生物污染，因为此时产品到冷凝器的水蒸气质量转移最小。使用从已知体积的空气引入时内部压力变化计算出的干燥器的空隙体积，以及泄漏空气的潜在最大生物负荷（基于测量值），可以计算出允许的泄漏空气量、在给定时间内允许该体积进入的空气流量以及在给定测试期间由于泄漏而导致的压力升高。对于本研究中的干燥器，在最坏的空气质量条件下，确定泄漏导致在 30 分钟内压力升高 0.027 毫巴，将允许干燥器在建立的行动水平（即每立方米空气空间一个菌落形成单位）之前保持在二级干燥条件下 62 小时。
