Bergmann D G
SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Bioprocess Technol. 1990;10:417-49.
A successful manufacturing scale cell culture process has as its basis a well-designed process. However, even the best designed large-scale process can become unreliable if not managed properly. The primary element to successful management of all large-scale processes is the careful attention to the details, especially the most important ones. The second element that requires serious consideration is the operation of that process within the confines of current regulatory environments. The major considerations are: 1. Adequate raw material specifications and testing. 2. Facility and equipment design that maximizes operational success and meets current regulatory requirements. 3. Thoroughly written procedures covering all aspects of operation and maintenance, and supported by a thorough documentation and review system. 4. A dedicated staff with a thorough understanding of systems and the importance of operational details. 5. Continual training and retraining programs. 6. Sound process and facility validation programs. 7. Comprehensive preventive maintenance programs. 8. Thorough understanding of process and facility trends, and the expected and acceptable ranges of results. 9. Development of sound procedures and practices that minimize batch losses and permit operation within current regulatory requirements. 10. Thorough and continual monitoring of all critical process parameters. 11. Process scheduling to minimize batch jeopardy or loss while maximizing throughout. 12. Maintenance of the appropriate environmental conditions of the plant and general cleanliness of plant and equipment. 13. Adequate batch loss prevention programs. 14. Adequate troubleshooting programs. 15. Adequate support organization and facilities both internally and externally to plant operations. With the appropriate application of sound process design and management principles, and with operational experience, large-scale cell culture process plants can be operated at success rates that exceed 95%.
一个成功的规模化细胞培养生产工艺，其基础是精心设计的流程。然而，即便设计得再好的大规模工艺，如果管理不当也可能变得不可靠。成功管理所有大规模工艺的首要因素是对细节的密切关注，尤其是最重要的细节。第二个需要认真考虑的因素是该工艺在当前监管环境范围内的运行情况。主要考虑因素包括：1. 足够的原材料规格和检测。2. 设施和设备设计，以最大限度地提高操作成功率并符合当前监管要求。3. 全面编写涵盖操作和维护各个方面的程序，并辅以完善的文件记录和审核系统。4. 一支对系统以及操作细节的重要性有透彻理解的专业团队。5. 持续的培训和再培训计划。6. 完善的工艺和设施验证计划。7. 全面的预防性维护计划。8. 对工艺和设施趋势以及预期和可接受的结果范围有透彻的理解。9. 制定完善的程序和做法，以尽量减少批次损失并允许在当前监管要求范围内运行。10. 对所有关键工艺参数进行全面且持续的监测。11. 进行工艺调度，以在最大限度提高产量的同时尽量减少批次风险或损失。12. 维持工厂适当的环境条件以及工厂和设备的总体清洁度。13. 足够的批次损失预防计划。14. 足够的故障排除计划。15. 为工厂运营提供足够的内部和外部支持组织及设施。通过合理应用完善的工艺设计和管理原则，并借助操作经验，大规模细胞培养生产工厂的运行成功率可超过95%。
