PDA TR15_切线流过滤_Tangential Flow Filtration_1992

Industrial Perspective on Validation of Tangential Flow Filtration in Biopharmaceutical Applications对生物制药应用中切向流验证的工业透视PARENTERAL DRUG ASSOCIATION 注射药物协会Table of Contents 目录PageI. Forward 前言S3II. Introduction 简介S3III.Validation of Generic TFF Equipment 验证一般TFF设备S4A.Initiating Validation Projects 开始验证项目S4B.Overall Approach 整体法S4C.IQ 安装确认S4D.OQ 运行确认S6IV.Generic Concepts of Process Validation 工艺验证的一般概念S6A.Prospective vs. Concurrent Validation 预期验证vs.同步验证S6B.Worst Case Conditions 最坏情况条件S7C.Number of Replications 重复试验数量S7D.Prerequisites to Initiating Process Validation 开始工艺验证的先决条件S7E.Design and Execution of Process Validation 工艺验证的设计和执行S7 V. Critical Elements of TFF Process ValidationTFF工艺验证的关键要素S7patibility相容性S7B.Retention 滞留S8C.Integrity 完整性S9D.System and Membrane Cleaning 系统和膜清洗S9E.Sterilization/Sanitization 灭菌/.消毒SI0F.Membrane Re-Use 膜再使用SI0G.Process Scale Changes 工艺规模变更SI0H.Qualifying Alternate Vendors 审核选择的供应商SI0I. Miscellaneous Issues其他问题S11VI. Specific Applications 具体应用S11A.Endotoxin Removal 内毒素去除S11B.Protein Concentration/Diafiltration蛋白质浓度/过滤S11C.Cell Debris Removal细胞碎片移除S12D.Bacteria Harvesting 细菌捕获S12E.Mammalian Cell Separation哺乳动物细胞分离S12VII. Summary 总结S13 VIII. References参考S13I. Foreword 前言The Purification and Scale-Up Task Force of the PDA's Biotechnology Sub-committee has sought to address how the FDA's 1987 Guideline on General Principles of Process Validation may be applied to the validation of specific operations in the manufacturing of parenteral products by the Biotechnology industry. PDA生物技术委员会的净化和扩大规模工作小组已力求说明工艺验证一般原理的1987年FDA指南如何应用到生物技术工业的注射用药物生产的特定操作验证中。

Two major categories of separation used in purification and downstream processing are chromatography and tangential flow filtration (TFF). This article focuses on the validation of tangential flow filtration processes as it relates to the 1987 FDA guidelines. In preparing this document, we assumed the reader would be familiar with the technical aspects of tangential flow filtration and its application in biopharmaceutical processes. We have positioned this article to provide the knowledgeable user some insight into the process of validating TFF applications. Readers seeking additional background information on TFF are referred to the references (1-5) listed at the end of the article. 用于提纯和下游工艺的两种主要分离方法是色谱分析和切向流过滤（TFF）。

本文侧重于切向流过滤工艺的验证，因为它与1987年的FDA指南有关。

在准备本文件时，我们假设读者都熟知切向流过滤的技术验证及其在生物制药工艺上的应用。

我们将该文件定位于向有见识的用户提供一些验证TFF应用工艺的见解。

探求有关TFF的附加背景知识，请读者参阅本文件末尾所列的参考文献（1-5）。

II. Introduction 简介Validation is "establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its predetermined specifications and quality attributes" (6). Process validation is a requirement of the Current Good Manufacturing Processes 21 CFR Parts 210 and 211 where the end product is to be used in clinical trials or for commercial sale. To assist the pharmaceutical manufacturer in complying with this requirement, the FDA issued a guideline in 1987 (6) which “outlines general principles ... consider(ed) to be acceptable elements of process validation...”. In this document we are giving an industrial perspective of the general principles outlined in the FDA's guideline as applied to the specific problem of validating a Tangential Flow Filtration (TFF) process. 验证是“建立提供高度保证的文件证明，以保证某一特定工艺将持续生产满足其预先确定的说明和质量属性”（6）。

工艺验证是现行良好生产工艺21CFR第210和211部分的要求，终端产品用于临床试验或商务销售。

为了帮助制药生产商遵照要求，FDA在1987年发布了“概述一般原则...认为工艺验证原理可以接受”的指导方针。

本文件我们给出了FDA指导方针所概述的一般原则的工业观点，该观点应用于验证切向流过滤（TFF）工艺的特定问题。

Tangential flow filtration, a term synonymous with crossflow filtration, is filtration in which the driving force for flow (transport) of fluid across the filter (membrane) is provided by a pressure source which is usually a mechanical pump. In TFF the pump is also used to drive fluid flow parallel (tangential) to the membrane surface which removes materials at the membrane surface to reduce concentration polarization of the filter (Fig. 1). Only a portion of the fluid passes through the membrane as the fluid recirculates through the system. The exact mechanisms and equations which describe the polarization process and subsequently the mode of action of TFF have been extensively researched and discussed in the chemical engineering literature (7) and will not be discussed in this document. TFF is a versatile technique which hasproven effective in a wide variety of Biopharmaceutical applications including:removing or concentrating whole cells or insoluble lysed cell components, concentration of macromolecules, buffer exchange, and depyrogenation. 术语切向流过滤和交叉流过滤同义，其中，压力源提供的驱动力使液体流（运输）穿过过滤器（薄膜），压力源通常是一个机械泵。