PDATR-29清洁验证中英对照（第一章—简介）

1. Introduction
介绍
1.1 Background
背景
In recent years, cleaning has achieved a position of increasing importance in the pharmaceutical industry. The current good manufacturing practices (CGMP) regulations recognize that cleaning is a critical issue to ensure product quality. Virtually every aspect of manufacturing involves cleaning, from the initial stages of bulk production to the final dosage form.
近年来清洁作业逐渐在制药界占有重要的地位。

现行的GMP法规也指出清洁作业是保证产品质量的关键性工作。

自大宗原料的生产以迄最终剂型的制造作业，几乎每一个制造工序均含有清洁作业。

The CGMPs in the United States, Europe and other parts of the world have provided the pharmaceutical industry with general guidance for cleaning requirements. For example, in the U.S., section 211.67 of part 21 of the Code of Federal Regulations (CFR) states that "Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements." Section 211.182 of part 21 of the CFR identifies that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established. In addition to CGMPs, various inspectional guideline documents published by the FDA contain expectations regarding cleaning in the pharmaceutical industry. Cleaning is also addressed in the PIC recommendations on cleaning validation and in the SFSTP Commission report "Validation desprocédés de nettoyage."
美国、欧洲及全球其他地区均有制药界清洁作业的通则性指南。

例如，美国联邦法规21章211.67小节描述设备和器具应每隔适当的时间予以清洁、维护消毒处理，以防止其故障或污染而可能造成药品安全性、效价、质量或纯度超购法定或其他既定的标准。

美国联邦法规21章211.182小节明确指出清洁程序应适当的文件化，并应建立清洁作业方法及使用日志。

除了CGMP之外，FDA亦颁布各种包含FDA对于制药业清洁作业之期许的检查指南。

另外，在PIC对于清洁验证的建议以及SFSTP委员会报告"Validation desprocédés de nettoyage"中，低于清洁作业亦有所规定。

It has always been the responsibility of the regulated industry and the regulatory agencies to interpret the CGMPs and to create programs and policies which establish the general requirements as specific practices. Recognizing the importance of the relationship between cleaning and product quality, regulatory agencies are demanding greater evidence of cleaning effectiveness through validation or verification.
对CGMPs的解释以及制定计划与建立特定作业之通则性规定的政策，一直是受法规约束之业者与管理当局的职责。

基于对清洁作业与产品质量的重要关系型的认知，管理当局乃要求必须经由确效或查核证实以获致大量有关清洁有效性的证据。

1.2 Purpose
目的
The purpose of this publication is to identify and discuss the many factors involved in the design, validation, implementation and control of cleaning programs for the pharmaceutical industry.
本刊物的目的在于讨论制药工业清洁程序的设计、验证、执行与控制的许多重要事项。

The document does not attempt to interpret CGMPs but provides guidance for establishing a cleaning validation program. It identifies the many factors to be considered for all segments of the pharmaceutical industry. It also identifies specific points to be considered by dosage form manufacturers, manufacturers of clinical trial materials (CTMs) and manufacturers of bulk pharmaceutical chemicals and biochemicals. The report covers the different approaches which may be appropriate for the different stages of product development from the early research stages to the commercially marketed product.
本文件并不是要解释CGMPs，而是在于作为建立清洁验证程序的指南。

它确定制药行
业的所有环节考虑的很多因素，也指出药品制剂制造企业、临床试验用原料制造企业及原料药与生物制品制造企业个别所应考虑的特定问题点。

本报告覆盖了各种不同的方案，能适用于自早期研究阶段至商业化上市的产品研发过程的不同阶段。

1.3 Scope
适用范围
This paper applies to biopharmaceutical, bulk pharmaceutical and finished dosage form operations; liquid, dry, solid and semi-solid dosage forms are covered in both sterile and non-sterile presentations. Both clinical and marketed product cleaning validation programs are identified.
本文件适用于生物制药、原料药及最终剂型：液体、干品、固体及半固体剂型，包括其无菌与非无菌两种形态，及临床试验与已上市两类产品的清洁验证程序
The manufacture of modern pharmaceuticals is a complex process involving highly technical personnel, complex equipment, sophisticated facilities and complicated processes. Individuals responsible for all aspects of the production, approval and validation of products, such as quality control, quality assurance, engineering, validation, production, research and development, contractors and vendors and regulatory affairs personnel may use this document as a resource for establishing or reviewing the cleaning programs within their facilities.
现代药品的制造是一种需要高技术人员、复杂设备、精密且复杂的设施及复杂的工艺的复合式程序。

负责质量、质量保证、工程、验证、生产、研发、接受委托加工、供应商及法规事务等所有有关药品生产、审核及验证方面的人员均可参照使用本文件以建立或复核其工厂内的清洁计划。

The validation programs described herein assume that an overall validation program with appropriate controls is already in place for the facility, utilities, equipment and processes. The cleaning of the environment is not specifically covered, however many of the same concerns that are considered for the cleaning of process equipment also impact the cleaning of the environment. The monitoring of microbiological and endotoxin contamination and steps for their elimination are mentioned in several sections and should be part of the cleaning validation program. However this document is not intended to be a comprehensive treatise on microbiological control, or endotoxin limitation. Other documents have addressed microbiological programs and methods for the environmental monitoring which can be applied to cleaning.
本文件内所描述的验证程序是以其场所、公用设施、设备及工艺均已经过确认与适当的控制为准。

虽然本文件并未特别包含环境清洁，但环境清洁可参考引用许多已应用于制药设备的清洁方法。

在部分章节提及的微生物及内毒素污染的监控与清洁步骤，也必须成为完整的清洁验证程序的一部分。

然而，本文件并能拟成为微生物控制和内毒素限度的综合论著，清洁程序也可参照其他专著及微生物与环境监测方法的文件。

1.4 Report Organization
本报告的组织架构
Each of the major topics of this document starts with a general section which applies to all segments of the pharmaceutical industry. Points to be considered for specific industry segments such as biopharmaceuticals, bulk pharmaceutical chemicals, clinical products may vary, depending on the specific product type. A glossary is provided at the end of the report. 本文件的每一个主题的开始都有一个适用于各种类型制药企业的通则性章节。

对于诸如生物药品、原料药、临床试验用药等特点药物类型所需的个别考量点，择依其产品形态而有所不同。

于本文件末列有词汇表供参考。

Finished Pharmaceuticals
药物成品
Finished pharmaceuticals represent solid formulations, semi-solid formulations, liquid and aerosol formulations with various routes of administration. Over-the-counter and prescription pharmaceuticals for both human and veterinary use are included in this category.
药物成品系指具有多种给药途径的固体制剂、半固体制剂、液体及喷雾剂。

本类别制剂包括人用及动物用处方药与非处方药。

The common characteristics shared by finished pharmaceuticals are their manufacture by combining raw materials and active ingredients to create the final dosage form.
药物成品所具有的共同特征是其制造方法是将原料与火星成分组合以制造出最终剂型。

Pharmaceutical manufacturers often make a large number of product types in one facility; often there are several different strengths prepared of the same product. The cleaning problems include the large number of processes and product types manufactured within one facility. The number of cleaning methods, assays and types of equipment to be tested are
often staggering. This is complicated by the issues surrounding the use of non-dedicated equipment. Thus, the establishment of a cleaning validation policy which is applicable to all products is often very difficult.
制药企业通常在一个工厂内生产大量不同剂型产品，而且一种产品常常有多种不同效价。

其清洁作业的困难包括在一个场所内有大量不同形态的工艺和产品。

其清洁方法与含量测定方法得种类，及需要加以检测的是被的类别时常重叠。

在使用非专用性设备时，情况会更加复杂。

因此，要建立一个适用于所有产品的清洁验证方法，通常十分困难。

Biopharmaceuticals
生物制剂
Bioprocess manufacturing, starting with microbial, animal or insect cells, or DNA derived host cells or other cells modified to make a specialized product, can be performed in several ways. Indeed, new methods for bioprocessing are constantly being developed. The most common method is through large scale fermentation (such as bacterial cell culture or mammalian cell culture) followed by highly specific purification steps. Other methods include the development of an antibody in host animals (such as ascites), cloning of cells or tissues, or transgenic generation of cellular components, namely, proteins. Many in the biopharmaceutical industry consider the stages of fermentation to be similar to other pharmaceutical industry processes. For example, the initial stages of the large scale fermentation have a striking similarity to bulk pharmaceutical chemical production. Later, harvest and purification steps find more in common with pharmaceutical processes. It is important to remember however, that other bioprocessing methods used in the biopharmaceutical industry differ greatly from traditional pharmaceutical processes.
所谓生物科技方法得制造方法是将微生物、动物或昆虫细胞，或DNA衍生宿主细胞（DNA derived host cells）、或其他细胞，改造成特殊化的产品，此等方法可以利用多
种途径进行。

事实上，事务科技的新方法一直持续不断地被开发出来。

最常见的方法是经过大量的发酵（例如细菌细胞培养或哺乳动物细胞培养），再经过高度专一的纯化步骤。

气氛方面包括在宿主细胞（如ascites）产生抗体、细胞或组织的无性或细胞成分（即所谓的蛋白质）的基因转移（transgenic generation）。

许多生物制剂工厂认为发酵的步骤与其他只要工厂的工艺相似。

例如，大量发酵的初始步骤就明显的与原料药的生产相似。

其后的收集和纯化步骤则更与制剂的工艺具有相同性。

然而很重要的是，要记得其他生物制品所使用的方法与传统的制剂工艺有很大的差异。

Cleaning for biopharmaceuticals presents special concerns due to the large number of impurities such as cellular debris, waste products of cellular metabolism, media constituents and buffer salts generated or added during manufacture which must be eliminated from the equipment. In the case of mammalian cell cultures, due to the nature of the source material, microbial contamination is of great concern. Identification of the residues is often quite difficult because they may vary from batch to batch. The large variety of proteinaceous materials present in the residue make differentiation of the contaminants from one another a challenge.
由于生物药品的清洁作业必须将大量不纯物（诸如细胞残骸、细胞代谢废弃物、培养基成分及制造过程中添加或产生的缓冲剂类）从设备清除，所以须特别关注清洁程序。

在
哺乳动物细胞培养的场合，由于基源物质的本质应特别关心微生物的污染。

其残留物会逐批不同，所以残留物的鉴别通常相当困难。

残留物中的蛋白质物质会有很大的变异，，所以污染物的区别是一项挑战。

Due to the nature of the biopharmaceutical production, multi-product facilities represent an area of regulatory concern. In order to control the production within a multi-product facility, it is necessary to ensure that special precautions are taken which preclude product to product carryover. Cleaning is an integral part of the strategies designed to ensure that there is no cross-contamination in these facilities. The terms cleaning and cleaning validation in multi-product facilities often include the facility itself, and therefore emphasis is placed on changeover validation.
由于生物制品生产作业的本质，使多种产品制造场所在管理上个具有相当的重要性。

为了控制多种产品在制造场所内的生产操作，需保证有特别的预防措施以防止产品与产品之间的残留物转移。

清洁规程是一个保证场所内无交叉污染而设计的完整策略的一部分。

在多种产品的制造场所，清洁程序与清洁验证两个名词通常也包括场所本身，因此应强调产品更替方面的验证。

Cleaning for biotechnology products has been described in "Cleaning and Cleaning Validation: A Biotechnology Perspective," PDA, Bethesda, MD, 1996.
生物制品的清洁规程在"Cleaning and Cleaning Validation: A Biotechnology Perspective," PDA, Bethesda, MD，1996文件中有所描述。

Bulk Pharmaceutical Chemicals
原料药
Bulk pharmaceutical chemical processes are typically biochemical or chemical syntheses carried out on a relatively large scale. The bulk pharmaceutical chemicals may be provided to pharmaceutical manufacturers as active or inactive ingredients for eventual inclusion in a finished dosage form pharmaceutical. The bulk pharmaceutical chemical manufacturing process for active ingredients is typically enclosed in large tanks with direct transfer of materials from tank to tank after a particular chemical reaction has occurred. The initial stages of the bulk pharmaceutical chemical drug development are reminiscent of the chemical industry. At some point during the process, the manufacturer must, in accordance with CGMPs have identified a process step after which the process will strictly comply with the CGMPs.
原料药的工艺通常为相当大量的生化或化学合成。

原来药可为活性或非活性成分，而供应给制剂生产商使用，经制作程序而被包含于最终剂型的制剂中，活性成分的原料药工艺通常将原料置于大型罐中，直接于罐与罐之间转移知道产生特定的化学反应。

原料药药物研发阶段的初始步骤会令人怀念往昔的化学工业。

制药企业必须依照CGMPs的规定，在其所指定的工艺中某一阶段以后的操作均需完全的符合CGMPs规范。

Bulk pharmaceutical chemical production, due in large part to the scale of manufacture and its use of strong reagents and chemicals, is often performed in closed systems which may use automated or semi-automated Clean-In-Place technologies. The difficulties in the validation
of cleaning processes often stem from the inaccessibility of many areas to direct sampling. The contaminants to be removed include precursor molecules, intermediates, byproducts, impurities or other physical forms such as isomers or polymorphs, which exist from early stages in the process.
由于是以较大规模制造以及使用强烈的化学试剂，使得合成原料药的工艺通常于密闭系统执行（该系统可以使用自动化或半自动的CIP技术）。

其清洁验证程序的困难是因为许多不易接近而无法直接取样的部位。

其应该清除的污染物包括前药、中间产物、副产物、杂质、或诸如异构体或多晶型体等物理结构物（自工艺初期即以存在）。

Clinical Products
临床试验用药
In this document, clinical products identify those products which are currently registered as an investigational status due to their involvement in clinical trials. The Clinical Products category identifies the special care that must be taken with these products which may not be as fully characterized as marketed materials. Both pharmaceutical and biopharmaceutical drug products and drug substances are included in this category.
本文件中临床产品是指尚在临床试验中，通常以研究中的身份提交申请登记的产品。

由于本类产品未如上市产品的全面特性化，所以有其应特别注意的事项。

本类产品包括一般制剂、生物制剂和原料药。

Cleaning in a clinical manufacturing setting is often complicated by the use of small scale manually cleaned equipment. Clinical manufacturing may represent a period during which process improvements are made, and therefore the same equipment may not be used each time the product is made. Also, since clinical products are often manufactured in development facilities, the subsequent products may not be known. The next materials manufactured may be research products, development products, placebo products or other clinical products. Our intent is to address cleaning of equipment in Phase III and later, but it may be appropriate to consider the same approaches in earlier phases as well. Typically, assays for low level detection of the active ingredient and its excipients will need to be developed and validated. Verification of cleaning effectiveness, as opposed to traditional validation, is prevalent since information on the material is not readily available.
生产临床试验用药时，往往使用小型手工设备，使得清洁操作复杂化。

临床试验用药的生产会有工艺改善的可能，因此同一产品不一定每次都使用相同的设备。

而且，由于临床试验用药往往在药品的开发阶段所使用的制造，而随后要在该场所所生产的产品也是未知的。

下次要在该场所生产的产品可能是研究中的产品、开发中的产品、空白对照品或其他临床试验用药。

我们的目的是针对三期及其以后阶段设备的清洁操作，但应采用于较前阶段。

通常应开发出活性成分及其赋形剂的低浓度定量检测方法并进行验证。

相对于传统的验证，因为本类产品较缺乏可用的信息，所以确认其清洁的有效性就显得较为重要。