Marcus-Sekura C J
Center for Biologics Evaluation and Research, Food and Drug Administration, MD.
Dev Biol Stand. 1991;75:133-43.
Validation of virus removal during product manufacture is one of several techniques which can be used to help establish product safety. The usefulness of the validation technique will be illustrated for the manufacture of immunoglobulins by the Cohn-Oncley ethanol fractionation procedure in which the partitioning and inactivation of HIV were studied, and for the manufacture of Factor VIII. In the case of Factor VIII which was contaminated with HIV and transmitted infection to product recipients, several manufacturers explored means of eliminating infectious virus by using a validation procedure involving a scaled-down manufacturing process and the spiking of individual steps to determine the extent of removal from the product and the inactivation of virus during manufacture. Assays for virus remaining after each step were performed in tissue culture. Some products were also tested in chimpanzees. Results of tissue culture assays could be correlated with safety testing in animals, and also with subsequent retrospective analysis of actual product use in patients. Correlation was good, suggesting that process validation is useful. Current use of virus validation to assess virus removal from products made from continuous cell lines such as human hybridomas which could potentially contain viruses infectious for humans, as well as some limitations of these validation techniques are also discussed.
在产品生产过程中验证病毒清除是可用于帮助确立产品安全性的多种技术之一。将通过科恩 - 昂克利乙醇分级分离法生产免疫球蛋白（其中研究了HIV的分配和灭活情况）以及生产凝血因子VIII来说明验证技术的实用性。在凝血因子VIII被HIV污染并将感染传播给产品接受者的情况下，几家制造商探索了通过使用一种验证程序来消除传染性病毒的方法，该程序包括按比例缩小的生产过程以及对各个步骤进行加样，以确定生产过程中从产品中去除病毒的程度和病毒的灭活情况。在组织培养中对每个步骤后残留的病毒进行检测。一些产品还在黑猩猩身上进行了测试。组织培养检测结果可以与动物安全性测试相关联，也可以与随后对患者实际使用产品的回顾性分析相关联。相关性良好，表明工艺验证是有用的。还讨论了当前使用病毒验证来评估从连续细胞系（如可能含有对人类有传染性的病毒的人杂交瘤）制成的产品中去除病毒的情况，以及这些验证技术的一些局限性。
