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
Page
I. Forward 前言S3
II. Introduction 简介S3
III.Validation of Generic TFF Equipment 验证一般TFF设备S4
A.Initiating Validation Projects 开始验证项目S4
B.Overall Approach 整体法S4
C.IQ 安装确认S4
D.OQ 运行确认S6
IV.Generic Concepts of Process Validation 工艺验证的一般概念S6
A.Prospective vs. Concurrent Validation 预期验证vs.同步验证S6
B.Worst Case Conditions 最坏情况条件S7
C.Number of Replications 重复试验数量S7
D.Prerequisites to Initiating Process Validation 开始工艺验证的先决条件
S7
E.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S7
patibility相容性S7
B.Retention 滞留S8
C.Integrity 完整性S9
D.System and Membrane Cleaning 系统和膜清洗S9
E.Sterilization/Sanitization 灭菌/.消毒SI0
F.Membrane Re-Use 膜再使用SI0
G.Process Scale Changes 工艺规模变更SI0
H.Qualifying Alternate Vendors 审核选择的供应商SI0
I. Miscellaneous Issues其他问题S11
VI. Specific Applications 具体应用S11
A.Endotoxin Removal 内毒素去除S11
B.Protein Concentration/Diafiltration蛋白质浓度/过滤S11
C.Cell Debris Removal细胞碎片移除S12
D.Bacteria Harvesting 细菌捕获S12
E.Mammalian Cell Separation哺乳动物细胞分离S12
VII. Summary 总结S13 VIII. References参考S13
I. 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 has
proven 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。

在TFF中，该泵也用于推动液体流与薄膜表面相平行（相切），从而移除了膜表面的物质，以减少过滤器浓度的极化（图表1）。

液体通过系统再循环时，只有部分液体穿过薄膜。

精确的原理和方程式式描述了极化工艺，随后，TFF的运行模式已经过广泛研究并在化学工程文献中进行论述。

TFF是一种多用途技术，多种生物制药的应用有效证明了这点，包括：移除或浓缩整个细胞或不可溶解的细胞成分、大分子浓缩液、缓冲液交换和去除热源。

III. Validation of Generic TFF Equipment一般TFF设备的验证
A.Initiation of a Validation Project 启动验证项目
The first step in any task is to assign responsibility for the design, planning, execution, and final approval for the project. The roles performed by groups and individuals in validation projects will vary among organizations depending on the organization's overall validation experience as well as the specific expertise existing within the organization's groups at the time the project is initiated. Typically, there will be a validation manager who draws upon appropriate expertise from Engineering, Quality Control, Regulatory, Production and Process Development to assist in the various phases of a validation program. Often vendor expertise is used to complement in-house expertise in developing a validation program. 首先，任何任务要分配项目设计、计划、执行和最终批准的职责。

团体和个人在验证项目中所起的作用会因不同组织机构而变化，这取决于组织结构的整体验证经验和在项目开始时组织团体的特定专业技能。

通常，会有验证负责人采用相关的工程、质量控制、管理、生产和工艺研发等专门技术来协助验证程序的各个阶段。

供应商的专门技术常用于补充开发验证程序中的内部技术。

The nomenclature used in this article is also likely to differ from what the reader is using depending on the affiliation of the reader. Each organization may place a given activity into a different phase (installation qualification, operational qualification, process qualification) of the project or may use entirely different nomenclature (process validation, process qualification, performance qualification) for similar tasks. The reader should not be put-off by these incidental differences, but needs to look to the integrity and soundness of the whole program. The viability of the program resides in the capability of the program to execute the requirements of validation as defined in the FDA's guidelines regardless of semantics or job titles. 本文件中使用的术语也可能和读者使用的不同，这取决于读者的隶属关系。

每个组织可能将一个已知活动放到项目不同阶段（安装确认、运行确认、工艺确认），或者可能在相似工作中使用完全不同的术语（工艺验证、工艺确认、性能确认）。

读者不应该被这些偶然差异困扰，但是需要注意整个程序的完整性。

执行FDA指南中所指定的验证需求的程序可行性，而不追究语义学或职称。

B.Validation: Overall Approach 验证：整体法
Any device or system designated for use in a pharmaceutical application must receive proper scrutiny during set-up and start-up in the manufacturing area. To guarantee its proper operation and performance, three stages of qualification of the device are normally followed: installation qualification (IQ); operational qualification (OQ); and process qualification (PQ). During each stage, a thorough plan or protocol specifying a set of procedures is designed, reviewed and approved by the validation manager or designees. The approved validation protocol is executed and the successful completion of the various tasks are documented and reviewed by qualified personnel. 在生产区进行设定和启动期间，在制药应用中指定使用的任何设备或系统必须接受相关检查。

为了保证正确的运行和性能，设备的三个确认阶段通常按照：安装确认（IQ）；运行确认（OQ）以及工艺确认（PQ）。

在每一阶段中，验证负责人或特派员设计，审核和批准描述一套程序的详细计划或方案。

授权人员执行已批准的验证方案，并记录和审核成功完成的各种任务。

The complexity of the documentation can vary dramatically. A simple, non-automated apparatus would retesting and documentation than a completely automated system which includes automated cleaning and sterilization. In a complex system, completed installation qualification protocols may be warranted for the controller and/or software before the system is operationally qualified. Whether the membrane device is simple or complex, the goals are the same: 1. to provide assurance that the system operates reproducibly; 2. to demonstrate that the process yields product which consistently meets established specifications; and 3. to record and document these facts. 文件的复杂性会发生显著变化。

与一个全自动化系统包括自动清洁和灭菌系统相比，一个简单的非自动器械会进行再测试和记录。

在复杂系统中，在系统运行确认前完整的安装确认方案会为控制器和/或软件提供保证。

不管薄膜装置是简单还是复杂，目标都是一样的：1.提供系统可重复运行的保证；2.证明工艺生产的产品将一直满足所建立的说明；3.记录这些事实并存档。

C. Installation Qualification 安装确认
Installation Qualification (IQ) refers to the procedure by which the user verifies that the device or system is assembled and installed, plumbed and wired appropriately and according to the proper local building codes, user's design specifications and manufacturer's recommendations. When carried out properly, the procedure also insures that the device or system is compatible with the facility and that maintenance and calibration schedules are set-up to insure the equipment's consistent operation. Although not necessarily all inclusive, the following information is usually contained in the installation document. 安装确认（IQ）指用户确认设备或系统已正确组装和安装，检测和布线，且符合地方建筑法规，用户设计说明和生产商建议的程序。

当正确执行时，程序也保证设备或系统与设施相兼容，且设定维护和校准时间表以保证设备一致运行。

虽然没必要包含所有信息，以下信息通常包含在安装文件中。

System or Equipment Description: This section of the IQ document consists of a detailed written description of the system or device outlining the primary critical components and their unique characteristics. In addition, the specific application or intended use of the TFF system should be described in detail. For many
membrane systems, the application dictates many of the procedures to be tested and may require specification of materials of construction. As an example, the individual components of a cell harvesting system should be described separately including the pump(s), piping, instrumentation and controllers, holding vessels and the membrane (type, manufacturer, etc.). In this case, the type of organism and rate of harvest are important parameters to be specified. A schematic of the system is essential. The description may include design criteria for the equipment, such as whether it is meant to be sanitary or non-sanitary, what the hold up volume is meant to be, whether or not the system is meant to provide product containment for recombinant organisms under NIH Guidelines, etc. (8, 9). Input from groups who specified or approved the purchase/ design of the equipment is valuable at this stage. For example, Process Development may list requirements for process performance (type of fluids being processed, requisite processing times, etc.), while Engineering may define physical and mechanical features (e.g., resistance to corrosion and NEMA rating for the electrical elements). 系统或设备描述：这部分的IQ文件包含概述主要关键组件及其特性的系统或设备的详细书面描述。

另外，TFF的特定程序或预期用途应该具体描述。

对许多薄膜系统来说，应用程序指出了许多待测试的程序，而且可能需要结构材料的说明。

例如，单个的细胞采集系统组件应该分别描述包括泵、管道、仪器和控制器、储存容器及薄膜（型号、生产商等）。

在这种情况下，微生物类型和采集量是重要的特定参数。

系统原理图是必不可少的。

描述可能包括设备的设计标准，比如，是否是消毒或未消毒的，容量意味着什么，系统是否可在NIH指导方针下为重组有机物提供产品密封等等（8，9）。

来自指定或批准设备采购/设计团体的信息在该阶段有很大的价值。

例如，工艺开发可能列出工艺性能的要求（经过加工的液体类型，必需的工艺时间等），而工程可能定义物理和力学特征（例如，耐腐蚀和电气元件的NEMA等级）。

Equipment Information Summary: For any system, information on the individual components is documented and compiled. The information includes each item's manufacturer, model number, serial number, and the composition of parts of each component which contact or could potentially contact product. For example, in a basic crossflow system, the materials of composition (316L SS, teflon, polypropylene, etc.) and surface finishes of wetted surfaces of the components of the pumps, the membrane packet or filter module, the valves, tubing connections, and holding tanks can be separately described. This information is necessary to completely define the system being validated, to evaluate the potential impact of future modifications or repairs on the process, and to initiate an evaluation of compatibility (discussed in detail in a later section). 设备信息概要：对任何系统来说，都应记录有关单个组件的信息并对其进行汇编。

信息包括每个元件的生产商、型号、序列号，以及接触或可能接触产品的每个组件的部件构成。

例如，在基本的交叉流系统中，可以单独描述构成材料（316L SS，聚四氟乙烯，聚丙烯等）和泵组件的润湿表面的表面抛光，薄膜包或过滤器组件、阀门、管道连接点和存储灌。

的信息是必要的，该信息对完整定义验证系统，评估工艺的未知更改或修改的潜在影响，并开始对相容性机械能评估（在后面部分有具体论述）。

Manual Listing/Documentation: A complete list of the technical documents for the TFF system and its components, and the location of the documents should be compiled. Such a list, which would also include piping and instrumentation drawings (P&ID) and schematics, serves as a ready reference source of information necessary for equipment installation or subsequent equipment maintenance or repair. 手写列表/文件：应编辑TFF系统及其组件的技术文件的完整列表和文件位置。

这种列表也应包括管道和仪表图（P&ID）以及图表，为设备安装或随后的设备维护或修理提供现成的信息参考源。

Spare Parts/Service Requirements: After the manuals have been collected and listed, they serve as a reference for compiling a spare parts list as part of the IQ document in anticipation of future maintenance. The IQ document should also list and review maintenance procedures to assure that prescribed maintenance can be performed without negative impact on the process or product. 备用零件/服务要求：在收集并列出手写文件后，他们为编辑备用零件列表提供参考，作为未来预期维护的IQ文件的一部分。

IQ文件也应该列出并审核维护程序，以确保规定的维护能够在对工艺或产品无不利影响下进行。

Product Contact Chemicals/Agents: The chemical additives and compounds used to maintain the system's performance such as pump lubricants, and membrane storage, shipping, and cleaning solutions, should be identified. If these compounds could possibly contact the product, during process validation, these items must be shown to be removed from the process fluid path to an adequate level by a validated wash procedure before being considered acceptable in the manufacturing process. The determination of what is meant by "removed to an adequate level" is a matter of judgement, usually involving input from scientific (particularly clinical and toxicology) and regulatory parts of the organization. Frequently, the limit of detection of the assay method is used. Obviously, the importance of meeting a specification of "none detectable" for a residual chemical should be dependent on the toxicity of the compound. For example, sodium azide residues are likely to be more problematic than traces of ethanol. 产品接触的化学品/试剂：应识别用于维护系统性能的化学添加剂和混合物，如泵润滑剂，膜存储、运送和清洁溶剂。

在工艺验证期间，如果混合物能够接触产品，这些元件必须在生产工艺可接受前通过验证清洗程序从工艺流体通道转移到适当等级。

“转移到适当等级”的意思通常包括科学信息（尤其是临床和毒性学方面）和组织的管理部分。

经常使用分析法来检测局限性。

明显地，满足残留化学品的“不可检测”的重要性应取决于混合物的毒性。

例如，钠叠氮化物残渣很可能比乙醇的痕迹更难处理。

Utility Requirements: The IQ for the TFF system should list the utility requirements. In addition, the document should ensure that the utilities are available and are actually delivered to the equipment as specified. This should be verified by actual measurements prior to installation of the equipment or more commonly by referencing the IQ/OQ validation package for the facility's utilities. As a practical matter, verification of utility requirements may help avoid unexpected schedule delays by identifying problems prior to equipment installation. Typically, the utilities include: Electrical requirements(Voltage, phases, and circuit breaker
ratings), Room Air Quality(Temperature, humidity, and classification),Compressed air or other compressed gasses (Pressure, temperature, humidity, classification, oil content, and cuft per minute), Sterilization steam (temperature, pressure, pounds per hour, purity requirements, and condensate requirements), Cooling by Chilled Water or Glycol (coolant temperature and flow), Drain requirements (sanitary vs. contained). 公用设施需求：TFF系统的IQ应列出公用设施需求。

另外，文件应保证公用设施可用，且确实按规定递交设备。

应在设备安装之前通过实际测量证实，或通过参照公用设施的IQ/OQ验证包来使用更常见的方法。

作为一个实际问题，通过确定设备安装前的问题，确认公用设施需求可能帮助避免意外的计划延迟。

通常，公用设施包括：电气需求（电压、相位和断路器额定功率），房间空气质量（压力、温度、湿度和等级），压缩空气或其它压缩气体（压力、温度、湿度、等级、油含量和立方英尺/分），灭菌蒸汽（温度、压力、磅/时、纯度要求和浓度要求），通过冷冻水或乙二醇冷却（冷却剂温度和流动），排水管要求（消毒vs.密封）。

Process Instrumentation: Calibration of all instrumentation against standards traceable or comparable to the National Institute of Standards and Technology (NIST) is essential for a validatable system. The installation document should call out the type, manufacturer, and nature (critical or non-critical) of those instruments that require regular calibration. The IQ should also list the SOP's which describe the calibration procedures. Critical instruments are those which are required to run the system in a controlled fashion and whose failure may affect product quality or safety. In a membrane separation system, the instrumentation may include pressure gages, pressure transducers, flow meters, level indicators, temperature probes, and data logging equipment. 工艺仪表：对于验证系统来说，根据可追溯标准或对比国家标准技术协会（NIST）标准，校准所有仪器是很重要的。

该安装文件应该说明那些需要定期校准的仪器型号、生产商和性质（关键的或不关键的）。

IQ也应该列出描述校准程序的SOP。

关键仪表是需要在控制下运行系统，而且其故障可能影响产品质量或安全。

在薄膜分离系统中，仪器可能包括测压计、压力传感器、流量计、液位指示器、温度探测器以及数据记录设备。

Instrumentation Control Packages: In the event that the membrane system has been supplied with an automation package, the ability of the control hardware to run reproducibly must be shown. For such a control package a separate more detailed installation qualification document is desirable, and validation of these control systems should be similar to that of other automated systems (10). 仪表控制包：如果薄膜系统已提供有一个自动包，则必须显示控制硬件可重复运行的能力。

对这种控制包来说，需要一个单独的更详细的安装确认文件，而且这些控制系统的验证应与自动化系统的验证相似（10）。

Safety, Caution, and Warning Information: Situations where the system may be damaged or where there is danger to operating personnel should be enumerated. System alarms, either internal or external, should be listed in the IQ document with alarm limits, alarm locations, and status of the installation. For example, steam-in-place sterilizable systems should have set alarm limits for over pressurization of the system which may be externally monitored and alarmed. Alarm function should be tested as part of the IQ or OQ, and SOP's should describe
operator's responses to alarm situations. If the alarm signals an event which is not part of normal operations (e.g., over pressure situation due to equipment malfunction) then these responses may be considered process deviations and may not be considered as part of the validation effort. 安全、警告和报警信息：应列举系统可能损坏或运行人员危险的情况。

系统警报，不论是内部还是外部，都应该列在IQ文件中，包括报警限、警报地点和安装情况。

例如，在线蒸汽灭菌系统应对可能超出外部监测并报警的系统压力设置报警限。

报警功能应作为IQ或OQ的一部分重新测试，SOP应描述运行员对警报情况的回应。

如果警报表明其不是正常运行的一部分（例如，设备故障导致的过压情况），那么这些回应可能考虑工艺误差，且可能不作为验证成果的部分考虑。

Operating Logs and Pertinent Procedures: Logs should document the use of the individual membrane modules, pieces of equipment or systems, and the calibration of the electronic components and mechanical gages. The logs should reference the procedures (SOP's) that are used for installation, cleaning, or calibration. 运行日志和相关程序：日志应该记录单个膜组件的使用、设备或系统零件及电气组件和机械测量仪校准等。

该日志应参考用于安装、清洗或校准的程序（SOP）。

D. Operational Qualification 运行确认
Upon completion of the Installation Qualification the membrane system should be tested. The Operational Qualification (OQ) documents the detailed tests to be performed which demonstrate that the components of the system function as specified and that taken together, these components operate as a system. The detailed protocols and documented results make up the final document. 安装确认一完成就应测试膜系统。

运行确认（OQ）记录了具体执行的测试，其证明按指定的系统功能组件且这些组件作为一个系统运行。

具体方案和记录结果组成最终文件。

The following topics should be covered in an Operational Qualification Document regardless of the type of membrane (RO, ultrafiltration, microporous) or system configuration (hollow fiber, spiral wound, plate and frame). 以下话题应涵盖在运行确认文件中，忽略薄膜型号（RO、超滤膜口、多微孔膜）或系统配置（中空纤维、螺旋口，金属板和框架）
Checking Manual Elements and System Alarms: The manual elements such as check valves, hand-operated valves, and traps should be checked either physically or visually to insure proper operation. Solenoid and actuated valves should be shown responsive to external signals. Each instrument or monitoring device should be tested and shown to be functional. Alarm situations should be simulated and the proper signals from the alarms verified. For example, if placed in sufficiently warm liquid, a pump's high temperature limit switch should activate.
检查手动元件和系统警器：手动元件比如止回阀，手动阀和疏水器应进行物理或外观检查以保证正常运行。

螺线管和控制阀应对外部信号做出响应。

每件仪器或监测设备应进行测试并能运行。

应模拟报警情况，并确定正确的报警信号。

例如，如果放置在足够热的液体中，应激活泵的高温限制开关。

Checking Critical Components: In any membrane system, the more important components should be separately tested as per vendor recommendations to insure proper operation. For example, tanks, gages, and valves may be individually checked and demonstrated to be functioning properly. Pumps should also be operated independently of the whole system and, in some cases, be calibrated to establish flow rates versus pump setting at specific back pressures to measure pump efficiency and seal integrity. It is difficult to evaluate the membrane filters themselves outside of the assembled system. However, vendor certification can give some assurance that minimum performance standards will be met. Because membranes can be susceptible to damage by careless handling, the integrity of the membranes should be tested after the system is assembled (see below). 检查关键组件：在任何薄膜系统中较重要的组件应按照每个供应商建议单独测试，以保证正常运行。

例如，容器、测量仪和阀门可以单独检查，并表明其功能正常。

泵也应该在整个系统中单独运行，在一些情况下，泵应校准以确定泵在特定背压下的流量来测量泵的效率和密封完整性。

很难在组装系统外评估薄膜过滤器本身。

但是，供应商合格证能够保证满足最低性能标准。

由于薄膜易受粗心操作造成的损坏影响，在系统组配完后应测试薄膜的完整性（如下）。

Checking System Integrity: The system as a whole should be checked to insure it is integral, i.e., that it does not leak across the filter membrane nor leak past seals, O-rings, or through piping connections. For example, simple pressure hold tests on the components and piping can identify leaks before attempting operation. Vendors of the TFF membranes or modules may be consulted to obtain recommended test procedures and specifications suitable for verifying integrity of filters once installed in the system; pressure hold or, more accurately, air flow tests are frequently specified to verify filter integrity. If the system is designed to provide biological containment for recombinant organisms, tests should be designed to address this issue prior to introduction of viable organisms to the system.检查系统完整性：作为一个整体，应检查系统以确保它是完整的，即系统穿过过滤膜时没有渗漏，在密封处、O形环或管道连接点也无渗漏。

例如，组件和管道上的的简单压力保持测试可以在尝试运行前识别渗漏。

一旦安装在系统中，TFF 薄膜或模块的供应商可咨询获得所推荐的测试程序和适合验证过滤器完整性的说明；压力保持，或更准确地说，空气流动测试常被指定用于验证过滤器完整性。

如果系统设计用来为重组生物体提供生物密封，把活性微生物引入系统前，测试应设定以处理该问题。

Checking System Operating Procedures and Automated Sequences: Before use in a manufacturing process, the procedures associated with the cross-flow device's operation (e.g., concentration, cleaning, sterilization, etc.) should be run using water or buffer to insure a logical sequence of tasks exists for the manufacturing operators. Automation of any particular function should be tested in practice runs, and the actual timed sequence of events should be compared to those which were anticipated. 检查系统操作程序和自动排序：在生产工艺中使用前，与交叉流装置运行有关的程序（例如，浓缩、清洁、灭菌等）应使用水或缓冲
液运行，以保证生产操作员按工作的逻辑顺序操作。

任何特殊功能的自动运行都应在实际运行中测试，而且项目的实际时间顺序应对比那些预期顺序相对比。

System Operating Procedures: A list of the procedures describing the operation of the system (i.e., SOP's) should be included for reference purposes in the Operational Qualification Document. 系统操作程序：描述系统操作的程序列表（如SOP）应该包括在运行确认文件中，仅供参考。

IV. General Concepts of Process Validation 工艺验证的一般概念
A. Prospective Validation vs. Concurrent Validation 预期验证vs.同步验证
Since the goal of validation is to gather scientific evidence that the process actually accomplishes what it is purported to do, the most scientifically valid data comes from the actual process carried out at the intended scale of operation and on the authentic process equipment by the actual operators. However, this scenario is an idealistic goal which is often unattainable. In the biopharmaceutical industry the cost of the manufactured product leads to the use of concurrent validation. In concurrent validation one performs an expanded testing program during the early (validation) production runs to gather data on the process and the product. The tests are designed to document process performance including reproducibility. The product made during these runs is intended for clinical use (assuming satisfactory test results). Prospective validation is performed in advance of actual full scale production. Prospective validation may involve testing the full scale equipment during a simulation of production processes, or it may involve small scale experiments which model the production process. Clearance studies using infectious agents (virus) or toxic reagents (radiolabeled DNA or proteins) are usually performed prospectively at small scale for reasons of safety and costs. 由于验证的目的是收集科学证据，证明工艺实际实现的预期结果，最科学有效的验证数据来自以预期规模进行的实际工艺和操作员操作的真实工艺设备。

但是，这种方案是理想目标，很难达到。

在生物制药业中，所生产的产品成本将导致使用同步验证。

在早期（验证）生产运行期间，在同步验证中进行扩大测试程序以收集有关工艺和产品的数据。

测试旨在记录工艺性能，包括可再生性。

这些运行期间生产的产品将用于临床使用（假设测试结果令人满意）。

在实际大规模生产之前应进行预期验证。

预期验证可能包括测试模拟生产工艺期间的大规模设备，或模拟生产工艺的小规模实验。

使用传染剂（病毒）或有毒试剂（放射性同位素标记的DNA或蛋白质）进行的余隙研究，出于安全和成本原因，通常以小规模进行。

A closely related issue is identifying which experiments may be done at small scale on laboratory equipment and which studies must be performed on actual production equipment. Examples of experiments which are legitimately carried out on non-production equipment were discussed above (see Prospective Validation). However there are other validation tests which will have value only when the tests are conducted on the actual production equipment. In these cases the aspects of the process being validated are intrinsically associated with equipment design. As an example, cleaning and sanitization procedures are very dependent on the actual design of the processing equipment, the types of connectors, the number and length。