近日，WHO在其技术报告TRS1060中发布了新的《药用辅料GMP》-2025，现将中英文翻译分享给大家： 

 

Annex 3

附录 3

 

WHO good manufacturing practices for excipients used in pharmaceutical products

世卫组织药用辅料良好生产规范

 

Republication of WHO good manufacturing practices for excipients used in pharmaceutical products, WHO Technical Report Series No. 1052, Annex 2, with two appendices.

重新发布WHO关于药用辅料良好生产实践的规定,出自WHO技术报告系列第1052号文件附录2,附有两个附录。

 

Background

背景

 

The WHO guideline Good manufacturing practices: supplementary guidelines for the manufacture of pharmaceutical excipients was published in the WHO Technical Report Series No. 885, Annex 5, 1999.

WHO指南《良好生产规范:药用辅料制造的补充指南》于1999年发布在WHO技术报告系列第885号,附录5中。

 

 

 

As excipients are sometimes used in large quantities in pharmaceutical dosage forms, and may contain impurities, they can affect the quality of a finished pharmaceutical product.

 

由于制剂中辅料有时用量较大,且可能含有杂质,这可能会影响药物成品的质量。

 

The manufacturer of the finished pharmaceutical product is normally dependent on the excipient manufacturer to supply excipients meeting the required specification. An appropriately established and implemented quality management system evaluating and controlling risks in the production and quality control of such excipients is therefore required.

 

通常,药物成品的制造商依赖辅料制造商提供符合要求规格的辅料。因此,需要建立并实施适当的质量管理体系,以评估和控制辅料生产及质量控制过程中的风险。

 

Excipient manufacturers should be required to apply the appropriate principles of good manufacturing practices (GMPs) in producing pharmaceutical excipients. Reports of pharmaceutical products that contain contaminated excipients, or excipients with impurities leading to the death of patients, have further highlighted the importance of reviewing the original guideline. Furthermore, the concept of ongoing improvement, the lifecycle approach, better quality management systems, risk management, and management review should be described in such a guideline, alongside the necessary good storage, good trade and good distribution practices, to ensure quality throughout the supply chain, as applicable.

辅料制造商应遵循适当的良好生产规范(GMP)原则来生产药用辅料。含有污染辅料或因辅料杂质导致患者死亡的药品报告进一步突显了重新审视原始指南的重要性。此外,持续改进的概念、生命周期方法、先进质量管理体系、风险管理以及管理评审应在此类指南中描述,同时还应包括适当的良好储存、良好贸易和良好分销实践,以确保整个供应链的质量。

 

The manufacturer of excipients used in pharmaceutical products should be able to identify risks associated with the production (including stages of manufacturing, route of synthesis) and quality control of its products. This includes the premises, equipment, utilities, storage and distribution. The manufacturer of such excipients should assess those risks and identify appropriate measures to mitigate such risks. The effectiveness of the measures should be evaluated to ensure that they are appropriate.

药用辅料制造商应能够识别与辅料生产(包括制造阶段、合成路线)及其质量控制相关的风险。这包括生产场所、设备、公用设施、储存和分销。辅料制造商应评估这些风险并确定适当的措施来减轻这些风险。措施的有效性应得到评估,以确保其适当性。

 

This document provides information on GMP that should be implemented to assist manufacturers to produce and control excipients used in pharmaceutical products that will meet their intended specifications, in a consistent manner. Risk assessment may be useful in determining which excipient should be manufactured in accordance with this guideline.

本文件提供了应实施的GMP信息,以帮助制造商以一致的方式生产和控制药用辅料,使其符合预期的规格。风险评估可能有助于确定哪些辅料应根据本指南生产。

 

1. Introduction and scope

 

1. 引言与适用范围

 

1.1 The purpose of this document is to provide guidance for the production, control, storage and distribution of excipients used in pharmaceutical products, focusing on good manufacturing practices (GMP) under an appropriate system for managing quality. It is also intended to help ensure that such excipients meet the requirements for quality and purity that they purport or are represented to possess.

本文件旨在为药用辅料的生产、控制、存储和分发提供指导,重点关注在适当的质量管理系统下实施良好生产规范(GMP)。同时,本文件也旨在确保这些辅料符合其声称或代表的质量和纯度要求。

 

1.2 The document does not cover aspects of protection of the environment, or safety aspects for the personnel engaged in the manufacture and control of excipients.

本文件不涵盖环境保护方面的内容,也不包括参与辅料制造和控制的人员的安全方面内容。

 

1.3 Excipients are often used in large quantities in industrial chemistry, as well as in the food and cosmetic industry. Specifications for excipients used in these applications may vary. It may not always be appropriate for use in pharmaceutical products. It is the responsibility of the finished product manufacturer and of the applicant to ensure that the finished product is manufactured using excipients of a suitable grade conforming to its intended use.

辅料在工业化学、食品和化妆品行业中常被大量使用。这些应用中的辅料规格可能有所不同,不一定适用于药品生产。最终产品制造商和申请者有责任确保最终产品使用符合预期用途的适当等级的辅料。

 

1.4 Excipients should be of appropriate quality, as they could affect the safety, quality and efficacy of finished pharmaceutical products.

辅料应具备适当的品质,因为它们可能会影响药物成品的安全性、质量和有效性。

 

1.5 The manufacturer of the finished pharmaceutical product is highly dependent on the excipient manufacturer to provide materials that are homogeneous in chemical and physical characteristics, and of the desired quality.

药物成品制造商高度依赖辅料制造商提供化学和物理特性均一且符合预期用途的辅料。

 

1.6 In general, excipients are used as purchased, with no further refining or purification. Consequently, impurities present in the excipient will be carried over to the finished pharmaceutical product.

通常情况下,辅料按购买状态使用,无需进一步提纯或精炼。因此,辅料中的杂质会转移到药物成品中。

 

1.7 To achieve the objective of ensuring that excipients used in pharmaceutical products are of appropriate quality, an appropriate level of GMP should be established, implemented and maintained during their production, packaging, repackaging, labelling, quality control, release, storage, distribution and other related activities. Additional measures should be taken when manufacturing excipients for which scientific literature, information in the public domain or historical data indicate the presence of higher risk due to potential formation of toxic impurities during manufacturing or contamination during storage and distribution.

为了确保药品中使用的辅料具有适当的品质,应在辅料的生产、包装、重新包装、标签、质量控制、放行、存储、分发及其他相关活动中建立、实施并维持适当水平的GMP。当制造辅料时,如果科学文献、公共领域的信息或历史数据表明存在较高风险,可能会在制造过程中形成有毒杂质或在存储和分发过程中发生污染,应采取额外措施。

 

1.8 Manufacturers of excipients for pharmaceutical use should have a specific analytical testing procedure to ensure suitability for its intended use. Pharmacopoeial and regulatory requirements should be considered by the manufacturers as a reference for these analytical tests. Information in the public domain should also be considered. Risk management principles should be implemented in order to identify and mitigate risks.

药用辅料制造商应具备特定的分析测试程序,以确保其适用于预期用途。药典和监管要求应作为这些分析测试的参考。公共领域中的相关信息也应予以考虑。应实施风险管理原则,以识别和减轻风险。

 

1.9 A thorough knowledge and understanding of the processes and associated risks are required. This includes all unit operations and processing steps, including key steps in the process, critical parameters (such as time, temperature or pressure), the use of recovered solvent or mother liquor, environmental conditions, equipment used, protection from contamination and monitoring points.

需具备对工艺及其相关风险的全面理解和掌握。这包括所有单元操作和加工步骤,包括工艺中的关键步骤、关键参数(如时间、温度或压力)、回收溶剂或母液的使用、环境条件、所用设备、防止污染的措施以及监控点。

 

2. Glossary

 

2. 术语表

 

2.1 The definitions given below apply to the terms used in this document. They have been aligned to the extent possible with the terminology in related WHO guidelines and good practices included in the WHO Quality Assurance of Medicines Terminology Database – List of Terms and related guidelines.⁵ But may have different meanings in other contexts.

下述定义适用于本文件中使用的术语,并在可能的情况下与WHO相关指南和良好实践中的术语保持一致,这些术语和实践包括在WHO药品质量保证术语数据库——术语列表及相关指南中,但其在其他上下文中可能具有不同的含义。

 

acceptance criteria

Numerical limits, ranges or other suitable measures for acceptance of test results.

接受标准-用于接受测试结果的数值限制、范围或其他适当度量标准。

 

adulterated

Pertaining to an intermediate or product (in part or in whole) that is contaminated, unsafe, not shown to be safe, filthy, or produced under unsanitary conditions, or found to have been produced, controlled, stored or distributed not in compliance with good manufacturing practices (such as described in this guideline); or contains any substance that may reduce its quality or purity or render it injurious to health.

掺假-指中间产品或最终产品(部分或全部)受到污染、不安全、未被证明安全、肮脏、或在不卫生的条件下生产,或被发现未按照良好生产规范(如本指南所述)进行生产、控制、存储或分发;或含有任何可能降低其质量或纯度或对其健康有害的物质。

 

auditing

An independent and objective activity designed to add value to and improve an organization's operations by helping it to accomplish its objectives, using a systematic, disciplined approach to evaluate and improve the effectiveness of risk management, control and governance processes.

审计-一种独立且客观的活动,旨在通过帮助组织实现其目标来增加其运营的价值并改进其运营,采用系统且纪律严明的方法评估和改进风险管理、控制和治理过程的有效性。

 

 

 

batch（or lot)

A specific quantity of material produced in a single process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch corresponds to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval.

批(或批次)-特定数量的物料在一个单一过程或一系列过程中生产,预期在指定的限值内保持均匀性。在连续生产的情况下,批次可能对应于生产的一部分。批大小可以通过固定数量或固定时间间隔内生产的数量来定义。

 

batch number (or lot number). A unique combination of numbers, letters or symbols that identifies a batch (or lot) and from which the production and distribution history can be determined.

批号(或批号)-一组唯一的数字、字母或符号,用于标识一批(或一批次),并从中可以确定该批的生产和分发历史。

 

calibration. The demonstration that a particular instrument or device produces results within specified limits by comparison with those produced by a reference or traceable standard over an appropriate range of measurements.

校准-通过与参考标准或可追溯标准在适当量程内进行比较,证明特定仪器或设备产生结果在规定限值内的过程。

 

change control. A formal system by which qualified representatives of appropriate disciplines review proposed actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state.

变更管制-一种正式系统,由相关学科的合格代表审查可能影响验证状态的提议或实际变更。其目的是确定是否需要采取行动以确保系统保持在验证状态。

 

computer system. A group of hardware components and associated software, designed and assembled to perform a specific function or group of functions.

 

计算机系统-一组硬件组件及其相关软件,设计和组装以执行特定功能或一组功能。

 

computerized system. A process or operation integrated with a computer system.

计算机化系统-与计算机系统集成的过程或操作。

 

contamination. The undesired introduction of impurities of a chemical or microbiological nature or of foreign matter into or onto a raw material, intermediate, or excipient during production, sampling, packaging or repackaging, storage, or transport.

污染-在生产、取样、包装或重新包装、储存或运输过程中,非预期地将化学或微生物杂质或外来物质引入或附着于原料、中间体或赋形剂中的过程。

 

critical. Describes a process step, process condition, test requirement or other relevant parameter or item that must be controlled within predetermined criteria to ensure that the excipient meets its specification.

关键-描述必须在预设标准内控制的过程步骤、过程条件、测试要求或其他相关参数或项目,以确保赋形剂符合其规格。

 

cross-contamination. Contamination of a material or product with another material or product.

交叉污染-一种物料或产品被另一种物料或产品污染的过程。

 

deviation. Departure from an approved instruction or established standard.

偏差：偏离已批准的指令或既定标准。

 

excipient for pharmaceutical use. Substance, other than the active ingredient, that has been appropriately evaluated for safety and is included in a drug delivery system: (a) aid in the processing of the drug delivery system during its manufacture; (b) protect, support or enhance stability, bioavailability or patient acceptability; (c) assist in product identification; and (d) enhance any other attribute of the overall safety and effectiveness of the drug during storage or use.

用于制药的赋形剂-除活性成分外的物质,已适当评估其安全性并包含在药物递送系统中,以(a)在药物递送系统的制造过程中辅助处理;(b)保护、支持或提高稳定性、生物利用度或患者接受度;(c)帮助产品识别;以及(d)提高药物在储存或使用过程中的整体安全性和有效性。

 

expiry date (or expiration date). The date placed on the container or labels of an excipient designating the time during which the excipient is expected to remain within established shelf-life specifications if stored under defined conditions and after which it should not be used.

有效期(或失效期)-在容器或赋形剂标签上标注的日期,表明在特定储存条件下赋形剂预期保持在规定货架寿命标准内的期限,之后不应使用。

 

finished pharmaceutical product. WHO: A product that has undergone all stages of production, including packaging in its final container and labelling. A finished pharmaceutical product may contain one or more active pharmaceutical ingredients.

药品成品-WHO:经过所有生产阶段的产品,包括最终容器的包装和标签。成品药品可能包含一种或多种活性药物成分。

 

impurity. An undesired component in an excipient.

杂质-辅料中的非期望组分。 

 

impurity profile. A description of the impurities present in an excipient.

杂质谱-描述辅料中杂质的特征。

 

in - process control (or process control). Checks performed during production in order to monitor, and, if appropriate, to adjust the process or to ensure that the intermediate or product conforms to its specifications.

 

过程控制(或工艺控制)-生产过程中进行的检查,以监控过程,并在适当的情况下调整过程,或确保中间体或最终产品符合其规格。

 

intermediate. A material produced during steps of the processing of an excipient for pharmaceutical use. Pharmaceutical use that undergoes further molecular change or purification before it becomes an excipient for pharmaceutical use. Intermediates may or may not be isolated.

中间体-在辅料用于制药过程中产生的材料,经过进一步的分子变化或纯化后成为可用于制药的辅料。中间体可能或可能不进行分离。

 

lot. See “batch”.

批-见 “批次” 。

 

lot number. See “batch number”.

批号-见 “批次号” 。

 

manufacture. All operations of receipt of materials, production, packaging, repackaging, labelling, relabelling, quality control, release, storage and distribution of an excipient and related controls.

生产-指辅料及其相关控制的接收、生产、包装、重新包装、标签、重新标签、质量控制、放行、储存和分发的所有操作。

 

material. A general term used to denote raw materials (starting materials, reagents, solvents), process aids, intermediates, active pharmaceutical ingredients, and packaging and labelling materials.

物料-用于表示原料(起始材料、试剂、溶剂)、工艺辅助材料、中间体、活性药物成分以及包装和标签材料的通用术语。

 

mother liquor. A concentrated solution from which the product is obtained by evaporation, freezing or crystallization. (Or: The residual liquid that remains after the crystallization or isolation processes. A mother liquor may contain unreacted materials, intermediates, levels of the excipient for pharmaceutical use, or impurities. It may be used for further processing).

母液-通过蒸发、冷冻或结晶从其中获得产品的浓溶液。(或:结晶或分离过程后剩余的液体。母液可能包含未反应的材料、中间体、可用于制药的辅料的水平或杂质。它可以用于进一步的加工)。

 

packaging material. Any material intended to protect an intermediate or excipient for pharmaceutical use during storage and transport.

包装材料-任何用于在储存和运输过程中保护中间体或药用辅料的材料。

 

procedure. A documented description of the operations to be performed, the precautions to be taken and measures to be applied, directly or indirectly related to the manufacture of an intermediate or excipient for pharmaceutical use.

程序-对要执行的操作、应采取的预防措施以及直接或间接与中间体或药用辅料的生产相关的措施进行书面描述。

 

process aids. Materials, excluding solvents, used as an aid in the manufacture of an intermediate or excipient for pharmaceutical use that do not themselves participate in a chemical or biological reaction (for example, filter aid or activated carbon).

辅助工艺材料-除溶剂外,用于制药过程中中间体或辅料制造的辅助材料,本身不参与化学或生物反应(例如,过滤辅助材料或活性碳)。

 

production. All operations involved in the preparation of an excipient for pharmaceutical use, from receipt of materials through processing and packaging of the excipient for pharmaceutical use.

生产-涉及药用辅料制备的所有操作,从原材料接收开始,经过辅料的加工和包装。

 

qualification. Action of proving and documenting that equipment or ancillary systems are properly installed, work correctly and actually lead to the expected results. Qualification is part of validation, but the individual qualification steps alone do not constitute process validation.

确认-证明和记录设备或辅助系统已正确安装、运行正常并确实能产生预期结果的过程。确认是验证的一部分,但单独的确认步骤并不构成过程验证。

 

quality assurance (QA). The sum total of the organized arrangements made with the object of ensuring that all excipients for pharmaceutical use are of the quality required for their intended use and that quality systems are maintained.

质量保证(QA)-为确保所有用于制药的辅料符合预期用途的质量要求,并维持质量体系所采取的组织化安排的总和。

 

quality control (QC). Checking or testing that specifications are met.

质量控制(QC)-检查或测试以确保符合规定要求。

 

quality unit. An organizational unit independent of production that fulfils both QA and QC responsibilities. This can be in the form of separate QA and QC units or a single individual or group, depending upon the size and structure of the organization.

质量单位-一个独立于生产部门的组织单元,负责履行QA和QC职责。这可以是独立的QA和QC部门,也可以是一个单独的个人或团队,取决于组织的规模和结构。

 

quarantine. The status of materials isolated physically or by other effective means pending a decision on their subsequent approval or rejection.

隔离-材料在物理隔离或其他有效手段下隔离的状态,待决定其后续批准或拒绝。

 

raw material. A general term used to denote starting materials, reagents and solvents intended for use in the production of intermediates or excipients for pharmaceutical use.

原料-用于生产中间体或用于制药的辅料的起始材料、试剂和溶剂的通用术语。

 

reprocessing. Introducing an intermediate or excipient for pharmaceutical use, including one that does not conform to standards or specifications, back into the process and repeating a crystallization step or other appropriate chemical or physical manipulation steps (for example, distillation, filtration, chromatography or milling) that are part of the established manufacturing process. Continuation of a process step after an in - process control test has shown that the step is incomplete is considered to be part of the normal process and not to be reprocessing.

重新加工-将中间体或用于制药的辅料(包括不符合标准或规格的)重新引入生产过程,并重复结晶步骤或其他适当的化学或物理操作步骤(例如,蒸馏、过滤、色谱法或粉碎),这些步骤是已建立的制造过程的一部分。在过程控制测试表明某步骤不完整后继续该过程步骤被视为正常过程,而不是重新加工。

 

reworking. Subjecting an intermediate or excipient for pharmaceutical use that does not conform to standards or specifications to one or more processing steps that are different from the established manufacturing process to obtain an intermediate or excipient of acceptable quality for pharmaceutical use (for example, recrystallizing with a different solvent).

 

返工-对不符合标准或规格的中间体或用于制药的辅料进行一个或多个不同于已建立制造过程的加工步骤,以获得可用于制药的合格中间体或辅料(例如,使用不同溶剂重结晶)。

 

shelf-life. The period of time during which an excipient, if stored correctly, is expected to comply with the specification, normally as determined by stability studies. The shelf-life is used to establish the retest or expiry date.

保质期-指如果储存条件正确,辅料在一定期间内预期符合规定要求的时间,通常通过稳定性研究确定。保质期用于确定复检或失效日期。

 

signed (signature). The record of the individual who performed a particular action or review. This record can be in the form of initials, full handwritten signature, personal seal or an authenticated and secure electronic signature.

签署(签名)-执行特定行动或审查的个人的记录。此记录可以是首字母缩写、全名的手写签名、个人印章或经过认证的安全电子签名的形式。

 

solvent. An inorganic or organic liquid used as a vehicle for the preparation of solutions or suspensions in the manufacture of an intermediate or excipient for pharmaceutical use.

溶剂-用于制药中间体或辅料制备溶液或混悬液的有机或无机液体。

 

specification. A list of tests, references to analytical procedures and appropriate acceptance criteria that are numerical limits, ranges or other criteria for the test described. It establishes the set of criteria to which a material should conform to be considered acceptable for its intended use. “Conformance to specification”means that the material, when tested according to the listed analytical procedures, will meet the listed acceptance criteria.

规格-列出的测试、分析程序的参考以及适当的接受标准,这些标准是数值限制、范围或其他测试标准。它确立了一组标准,材料应符合这些标准才能被认为适合其预期用途。“符合规格”-意味着材料在根据列出的分析程序进行测试时将满足列出的接受标准。

 

validation. A documented programme that provides a high degree of assurance that a specific process, method or system will consistently produce a result meeting a predetermined acceptance criteria.

验证-一种文件化的计划,提供高度保证,确保特定过程、方法或系统能够一致地产生符合预定接受标准的结果。

 

validation protocol. A written plan stating how validation will be conducted and defining acceptance criteria. For example, the protocol for a manufacturing process identifies processing equipment, critical process parameters and operating ranges, product characteristics, sampling, test data to be collected, number of validation runs and acceptable test results.

验证计划-书面计划,说明验证将如何进行并定义接受标准。例如,制造过程的验证方案确定了加工设备、关键工艺参数和操作范围、产品特性、取样、需要收集的测试数据、验证运行次数以及可接受的测试结果。

 

verification. The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with established requirements and specifications.

确认(verification)-除了监控外,应用方法、程序、测试和其他评估,以确定是否符合已建立的要求和规定。

 

3. Quality management

 

3. 质量管理

 

3.1 Manufacturers involved in the production, control, storage and distribution of excipients for pharmaceutical use should establish, document, implement and maintain a comprehensively designed and clearly defined quality management system.

生产、控制、储存和分发药用辅料的制造商应建立、记录、实施并维持一个全面设计且定义清晰的质量管理体系。

 

3.2 Senior management should assume responsibility for the quality management system, as well as the quality of the excipients for pharmaceutical use manufactured, controlled, released, stored and distributed.

高级管理层应承担质量管理体系以及所生产、控制、放行、储存和分发的药用辅料质量的责任。

 

3.3 The quality management system should encompass the quality policy, organizational structure, procedures, processes and resources. All parts of the quality management system should be adequately resourced and maintained.

质量管理体系应涵盖质量政策、组织结构、程序、过程和资源。质量管理体系的所有部分都应得到充分资源的支持并得到维护。

 

3.4 The quality management system should cover all activities necessary to ensure that excipients for pharmaceutical use will meet their intended specifications, including quality and purity.

质量管理体系应涵盖所有必要的活动,以确保用于制药的辅料符合其预定规格,包括质量和纯度。

 

3.5 The quality management system should incorporate the principles of good practices, which should be applied to the life cycle stages of excipients for pharmaceutical use. This includes steps such as the receipt of raw materials, production, packaging, testing, release, storage and distribution.

质量管理体系应融入良好实践的原则,这些原则应应用于用于制药的辅料生命周期的各个阶段。这包括原材料的接收、生产、包装、检验、放行、储存和分发等步骤。

 

3.6 All quality-related activities and procedures should be defined and documented manually or electronically.

所有与质量相关的工作活动和程序都应被定义并以手工或电子方式记录。

 

3.7 All quality-related activities should be recorded at the time they are performed.

所有与质量相关的工作活动都应在执行时进行记录。

 

3.8 The quality management system should ensure that:

质量管理体系应确保以下几点:

 

sufficient resources are      available (for example, equipment, personnel, materials);

充足的资源可用(例如,设备、人员、材料);

 

excipients for      pharmaceutical use are produced, controlled, stored and distributed in      accordance with the recommendations in this document and other associated      guidelines, such as good quality control laboratory practices and good      storage and distribution practices, where appropriate;

用于制药的辅料的生产、控制、储存和分发应按照本文件和其他相关指南(如良好质量控制实验室实践和良好储存与分发实践)中的推荐进行;

 

managerial roles,      responsibilities and authorities are clearly specified in job      descriptions;

管理角色、职责和权限在职位描述中应明确指定;

 

operations and other      activities are clearly described in a written form, such as standard      operating procedures and work instructions;

操作和其他活动应在书面形式(如标准操作程序和工作指导书)中清晰描述;

 

appropriate arrangements      are made for the manufacture, supply and use of the correct containers and      labels;

为制造、供应和使用正确的容器和标签作出适当安排;

 

all necessary controls      are in place;

所有必要的控制措施均已到位;

 

calibrations,      verification or validations are carried out where necessary;

必要时进行校准、验证或验证;

 

the excipient for      pharmaceutical use is correctly processed and checked according to the      defined procedures and specifications;

用于制药的辅料根据定义的程序和规格正确处理和检查;

 

deviations, suspected      product defects, out-of-specification test results and any other      nonconformances or incidents are reported,investigated and recorded. An      appropriate level of root cause analysis is applied during such      investigations and the most likely root causes are identified;

偏差、疑似产品缺陷、超出规格的测试结果以及任何其他不符合或事件均被报告进行了调查和记录。在这些调查过程中,适当进行了根本原因分析,并确定了最可能的根本原因。

proposed changes are      evaluated and approved prior to implementation. After implementation of a      change that could impact the quality or the product, an evaluation should      be undertaken to confirm that the quality objectives were achieved and      that there was no unintended adverse impact on product quality;

在实施变更之前,提议的变更应经过评估并获得批准。在实施可能影响产品质量或产品的变更之后,应进行评估以确认是否达到了质量目标,并且没有对产品质量产生意外的负面影响;

appropriate corrective      actions and preventive actions, as well as checks on the effectiveness of      those actions (where appropriate), are identified and taken;

应识别并采取适当的纠正措施和预防措施,并在适当的情况下检查这些措施的有效性;

where required, processes      are in place to ensure the management of any outsourced activities that      may impact product quality, purity and integrity;

如有需要,应有流程确保对外包活动的管理,这些活动可能影响产品的质量、纯度和完整性;

a batch of an excipient      for pharmaceutical use is not released and supplied before it has been      released by the quality unit with the assurance that the batch has been      produced and controlled in accordance with product specifications, and      with the recommendations in this document and any other regulations      relevant to the production, control and release of these products;

在质量部门确认该批次按照产品规格和本文件及任何其他相关法规的要求生产并控制之前,制药用辅料的批次不得被释放和供应;

there is a system for      handling complaints, returns and recalls;

应有处理投诉、退货和召回的系统;

 

there is a system for      self-inspect;

应有自我检查的系统;

 

there is a system for      product quality review.

应有产品质量管理的系统。

 

3.9 The quality unit should be independent of production. The responsibilities of the unit should be clearly defined and documented.

质量部门应独立于生产部门。该部门的职责应明确界定并形成文件。

 

3.10 The person or persons authorized to release excipients for pharmaceutical use should have appropriate qualifications, and be specified.

负责批准用于制药的辅料的人员或人员应具备适当的资质,并明确指定。

 

3.1 Quality risk management

 

3.1 质量风险管理

 

3.11 There should be a system for managing risks (1). The system for quality risk management should be comprehensive and should cover a systematic process for the assessment, control, communication and review of risks in the production, testing, packaging, storage and distribution of excipients for pharmaceutical use. Controls identified should be appropriate, ensure that risks are eliminated or mitigated, and ultimately protect the patient from receiving a pharmaceutical product containing the wrong, contaminated or unsuitable excipients for pharmaceutical use.

应建立风险管理体系(1)。质量风险管理的体系应当全面,应涵盖评估、控制、沟通和审查生产、检测、包装、储存和分发制药用辅料过程中风险的系统性过程。识别出的控制措施应当适当,确保风险被消除或减轻,并最终保护患者免于接受含有错误、污染或不适合使用的辅料的药品。

 

3.12 In order to perform an adequate excipient risk assessment, it would be useful to provide some high-level guidance using an appropriate risk profile or ranking using a question - based risk ranking and filtering system. For example:

为了进行充分的辅料风险评估,使用适当的风险评估或分级系统提供一些高层次的指导是有益的,例如基于问题的风险评估和筛选系统。例如:

 

functionality of      excipient in formulation辅料在配方中的功能

route of administration给药途径

potential for      contamination污染可能性

excipient complexity辅料复杂性

prior knowledge or      experience with excipient对辅料的先前知识或经验

packaging size包装规格

 

3.13 Similarly, a risk score should be calculated for the supply chain (for example, complexity of supply chain, prior knowledge of supply chain, excipient manufacturer performance history, packaging suitability, quality management system standard and certification).

同样,供应链的风险评分也应进行计算(例如,供应链的复杂性、供应链的先前知识、辅料制造商的历史表现、包装的适用性、质量管理体系的标准和认证)。

 

3.14 Note: see WHO guidelines on quality risk management (1).

注意:参见世界卫生组织关于质量风险管理的指南(1)。

 

3.2 Management review

 

3.2 管理评审

 

3.15 There should be a system for regular management review. All elements of the quality management system should be included.

应建立定期管理评审的体系,质量管理体系的所有要素均应纳入评审范围。

 

3.16 Management should ensure that the quality management system achieves its intended objectives and measures managing and performance in areas such as:

管理层应确保质量管理体系实现其预期目标,并在诸如以下方面衡量管理绩效:

 

self - inspections,      inspections, quality audits and supplier's audits

自检、检查、质量审核和供应商审核

 

complaints, returns and      recalls投诉、退货和召回

changes and deviations变更和偏差

rejected batches拒收批次

quality control, out - of      - specification results and out - of - trend results质量控制、超出规格结果和超出趋势结果

maintenance维护

qualification and      validation

资质认定和验证

 

corrective and preventive      actions纠正和预防措施

risk management风险管理

 

3.17 Key performance indicators should be identified and monitored with the view of continual improvement.

应识别并监控关键绩效指标,以实现持续改进。

 

3.18 Records of meetings, discussions and actions should be maintained.

应保持会议、讨论和行动记录。

 

4. Complaints

 

4.投诉

 

4.1 There should be a written procedure describing the recording and investigation of complaints.

应有书面程序详细说明投诉的记录和调查过程。

4.2 All decisions made and measures taken as a result of a complaint should be recorded.

投诉处理过程中作出的所有决定和采取的措施均应予以记录。

4.3 Complaint records should include at least the following:

 

投诉记录应至少包括以下内容：

 

date of receiving the      complaint;

投诉接收日期;

 

name, address and other      relevant details of complainant;

投诉人姓名、地址及其他相关详细信息;

 

details of the complaint,      including name of the excipient and batch number;

投诉详情,包括辅料名称和批号;

 

details of the      investigation and action taken;

调查和采取措施的详细信息;

 

copy of the response      provided;

提供给投诉人的回复副本;

 

final decision based on      the outcome of the investigation.

根据调查结果作出的最终决定。

 

4.4 Where necessary, the appropriate corrective action and follow - up action should be taken after the investigation and evaluation of a complaint.如有必要,应在投诉调查和评估后采取适当的纠正措施和后续措施。

 

4.5 Where necessary, a recall of the batch or batches should be considered.

如有必要，应考虑召回相关批次产品。

 

4.6 Records of complaints should be retained in order to evaluate trends.

应保留投诉记录以评估趋势。

 

5. Recalls

 

5.召回

 

5.1 There should be a written, authorized procedure describing the managing of a prompt and effective recall of an excipient for pharmaceutical use. Where the recall is as a result of a contaminated or adulterated excipient, or any other reason where the excipient could cause harm to a patient, the manufacturer should report this to the relevant authority without delay.

 

应有书面且授权的程序,详细说明药品用辅料的召回管理,确保召回及时且有效。若召回是由于污染或掺假的辅料,或任何其他可能导致患者受到伤害的原因,则制造商应在不延迟的情况下向相关主管部门报告。

 

 

5.2 The recall procedure should indicate the responsibilities of personnel involved in the recall, how the recall should be initiated, who should be informed about the recall and how the recalled material should be handled.

召回程序应明确参与召回人员的职责,召回应如何启动,应通知哪些人员,以及如何处理召回的物料。

5.3 The recall of an excipient for pharmaceutical use should be documented. Records should be kept.

药品用辅料的召回应有记录。应保存相关记录。

 

6. Returns

 

6.回收

 

6.1 There should be a written procedure describing the handling of returned excipients for pharmaceutical use.

应有书面程序描述用于制药的回收辅料的处理方法。

 

6.2 Returned investigational products should be clearly identified and stored in a dedicated area in a controlled manner.

回收的实验用产品应明确标识,并以受控方式存放在专用区域。

6.3 Inventory records of returned products should be kept.

回收产品的库存记录应予以保留。

 

Destruction

 

销毁

 

6.4 The disposition of the returned product should be approved by the quality unit. The conditions under which the excipient for pharmaceutical use had been stored and shipped should be considered when deciding on the fate of the returned product. If the condition of the container itself casts doubt on the safety, quality or purity of the excipient, the product should be destroyed, unless scientific justification can be provided that proves that the product meets the appropriate predefined quality standards.

返回产品的处理应由质量部门批准。在决定返回产品的命运时,应考虑用于制药的辅料在储存和运输过程中所处的条件。如果容器本身的状况对辅料的安全性、质量和纯度产生怀疑,除非能够提供科学依据证明产品符合相应的预定义质量标准,否则应予以销毁。

 

6.5 A certificate of destruction should be available containing the necessary detail to enable traceability of the product, batch and related information.

应提供销毁证明,其中包含必要的细节以实现产品的可追溯性,包括批次和其他相关信息。

 

6.6 Where returned excipient containers are reused, all previous labelling should be removed. The containers should be appropriately cleaned and there should be no risk of contamination from one material to another.

当回收使用返回的辅料容器时,应移除所有之前的标签。容器应进行适当的清洗,并且不应存在一种材料对另一种材料造成污染的风险。

 

7. Self - inspection, quality audits, and supplier’s audits and approvals

 

7.自检、质量审核和供应商审核与批准

 

7.1 There should be written standard operating procedures and programmes for periodic self - inspections, quality audits and supplier audits.

应有书面的标准操作程序和计划,用于定期进行自检、质量审核和供应商审核。

 

7.2 Self - inspections should be performed routinely in accordance with a self - inspection programme.

自检应按照自检计划定期进行。

 

7.3 The team responsible for self - inspection should consist of personnel with the appropriate knowledge and experience. Team members may be from inside or outside the manufacturer, but members of the team should be free from bias.

负责自检的团队应由具备适当知识和经验的人员组成。团队成员可以来自制造商内部或外部,但团队成员应无偏见。

 

7.4 Areas to be covered in self - inspections may include:

 

自检应涵盖的领域可能包括:

 

premises

场所

 

personnel

人员

 

equipment

设备

 

maintenance and      calibration

维护与校准

 

storage conditions of      materials and finished products

原材料和成品的储存条件

 

production and in -      process controls

生产和过程控制

 

quality control

质量控制

 

documentation, data      generation and data integrity

文档、数据生成与数据完整性

 

change control and      deviations management

变更控制与偏差管理 

 

complaints and recalls

投诉与召回

 

qualification and      validation

资质确认与验证

cleaning procedures.

清洁程序

 

7.5 The client's end use should be considered during inspection of excipient manufacturers. It is particularly important to know whether the excipient will be used in the preparation of a sterile dosage form. The excipient manufacturer is responsible for ensuring that excipients are pyrogen free if the manufacturer makes such a representation in specifications, labels or a drug master file.

在检查辅料制造商时,应考虑辅料的最终用途。特别是要了解辅料是否将用于制备无菌制剂。如果制造商在规范、标签或药品主文件中作出此类声明,辅料制造商有责任确保辅料无热原。

 

7.6 Self - inspection should also ensure that appropriate measures are in place to prevent contamination of materials during storage and production.

自检还应确保采取适当措施,防止储存和生产过程中材料受到污染。

 

7.7 The outcome of the self - inspection should be documented, including corrective actions and preventive actions.

自检的结果应予以记录,包括纠正措施和预防措施。

 

8. Personnel

 

8.人员

 

8.1 There should be an adequate number of personnel with appropriate qualifications, training or experience to perform their respective activities.

应有足够数量的具备相应资格、培训或经验的人员,以履行各自的职责。

 

8.2 Responsibilities should be specified in written job descriptions.

职责应在书面岗位描述中明确规定。

 

8.3 Training should be regularly conducted and should include, for example, GMP and the particular operations of the employee. Assessment of understanding of training topics should be done and documented.

应定期开展培训,培训内容应包括,例如,GMP 及员工的具体操作。应对培训主题的理解进行评估,并记录在案。

 

8.4 Records of training should be maintained.

应保存培训记录。

 

9. Sanitation and hygiene

 

9.消毒和卫生 

 

9.1 Excipients for pharmaceutical use should be protected from contamination. A documented risk assessment should identify controls to be implemented to ensure appropriate sanitation and hygiene actions are taken.

药用辅料应防止受到污染。应进行文件化的风险评估,以识别所需实施的控制措施,确保采取适当的卫生与清洁行动。

 

9.2 Written procedures should be followed for cleaning and sanitization, as appropriate, of manufacturing areas, equipment and utilities.

应遵循书面程序对制造区域、设备和公用设施进行清洁和消毒(如需)。

 

9.3 Personnel should practise good hygiene and health habits.

人员应养成良好的卫生和健康习惯。

 

9.4 Personnel should wear clean clothing suitable for their activities. The wearing of appropriate protective clothing should apply to all persons entering production areas where products or materials are handled. Additional personal protective equipment should be worn when necessary.

人员应穿着适合其活动的干净衣物。所有进入处理药品或材料的生产区域的人员均应穿戴适当的防护服。必要时,应穿戴额外的个人防护装备。

 

9.5 Personnel should avoid direct contact with starting materials and excipients for pharmaceutical use.

人员应避免直接接触用于制药的起始物料和辅料。

 

9.6 Smoking, eating, drinking, chewing and the storage of food should not be allowed in production and quality control areas.

生产区和质量控制区不允许吸烟、进食、饮水、嚼口香糖以及储存食物。

 

9.7 Personnel with an infectious disease or who have open lesions on the exposed surface of the body should not engage in activities that could result in compromising the quality of excipients for pharmaceutical use.

患有传染性疾病或身体暴露部位有开放性伤口的人员不应参与可能影响药用辅料质量的活动。

 

9.8 Jewellery and electronic devices such as mobile phones should only be used in authorized areas.

仅在指定区域允许佩戴首饰和电子设备,如手机等。

 

10. Documentation

 

10.文件

 

10.1 Documents such as standard operating procedures, specifications and others related to the production and control of excipients for pharmaceutical use should be prepared, reviewed, updated, approved and distributed according to written procedures.

用于药用辅料生产和控制的标准操作程序、规范及其他相关文档应根据书面程序准备、审核、更新、批准并分发。

 

10.2 The issuance, revision, withdrawal and retention of documents should be appropriately controlled in accordance with good documentation practices.

文档的发行、修订、撤回和保存应根据良好的文件管理实践适当控制。

 

10.3 Documents should be retained for a defined period of time. The retention time of the documents should be justified to ensure availability of information in case of need. This time should be longer than the product retest or expiry date.

文档应保存一段时间。文档的保存期限应经过合理论证,以确保在需要时能够获取相关信息。该期限应长于产品的复检或有效期。

 

10.4 Where documents require the entry of data, these entries should be clear, legible and indelible. Entries should be in compliance with good documentation practices and data integrity requirements.

当文档需要录入数据时,这些数据应清晰、可读且不可擦除。录入的数据应符合良好的文件管理实践和数据完整性要求。

 

10.5 Records should be made or completed when any action is taken and in such a way that all significant activities are traceable to the person making the entry, including signatures and dates. Corrections made to incorrect entries should be dated and signed, with a description of the reason for the change, as appropriate.

应在采取任何行动时记录或完成记录,并确保所有重要活动均可追溯到录入人员,包括签名和日期。对错误录入的修正应注明日期并签名,并在适当情况下说明更改原因。

 

10.6 Electronic documents and records should meet the requirements for good documentation practices, and good practices for computerized systems.

电子文件和记录应符合良好记录实践的要求,并符合计算机化系统的良好实践要求。

 

10.1 Standard operating procedures and records

 

10.1标准操作程序与记录

 

10.7 Standard operating procedures and associated records should be available for at least the following:

 

标准操作程序及相关记录应至少包括以下内容:

 

equipment设备

analytical apparatus and      instruments

分析仪器和设备 

 

out-of-specification      results

不合格结果

 

maintenance and      calibration

维护与校准

 

cleaning and sanitization

清洁与消毒

 

personnel matters, such      as training, clothing and hygiene

人员事务,如培训、着装和卫生

 

qualification and      validation

资质认定与验证

 

self-inspection and      audits

自查与审核

 

complaints

投诉

 

recalls召回

returns

退货

 

10.8 The standard operating procedures for sampling should specify the person or section authorized to take samples and the sampling instructions.

用于取样的标准操作程序应明确规定有权取样的人员或部门以及取样指示。

 

10.9 The standard operating procedures describing the details of the batch (lot) numbering system should ensure that each batch of excipient for pharmaceutical use is identified with a specific batch number.

描述批次(批号)编号系统的详细标准操作程序应确保每批用于制药的辅料都有特定的批号标识。

 

10.10 Records of analytical analysis should be maintained.

分析记录应予以保存。

 

10.11 Written release and rejection procedures should be available.

书面的放行与拒收程序应可供查阅。

 

10.12 Records should be maintained of the distribution of each batch of excipient for pharmaceutical use.

应保存每批用于制药的辅料分发的记录。

 

10.13 Records should be kept for major and critical equipment, as appropriate, of any qualifications, calibrations, maintenance, cleaning or repair operations, including the dates and the identities of the people who carried out these operations.

根据需要,应保存重大和关键设备的相关记录,包括任何资质认定、校准、维护、清洁或修理操作的日期及执行这些操作的人员身份。

 

10.2 Specifications

 

10.2规格

 

10.14 Specifications should be established and maintained for starting materials, packaging materials, excipients for pharmaceutical use, and other related materials where necessary.

应建立并维护起始物料、包装材料、药品用辅料及其他相关物料的规格,必要时应进行此项工作。

 

10.15 Quality attributes, acceptance limits and test procedures should be defined. Relevant pharmacopoeial monographs, when available, should be considered for use or to be used as a basis for the development of internal manufacturer's specifications.

质量属性、接受限值和检验程序应予以定义。当药典中有相关条目时,应考虑使用这些条目,或将其作为制定内部制造商规范的基础。

 

10.16 A positive identification test uniquely applicable to the excipients should be established through analytical technology, such as infrared spectrophotometry and chromatography.

应通过分析技术,如红外光谱法和色谱法,建立一种独特适用于辅料的阳性鉴别试验。

 

10.17 Appropriate limits for impurities should be specified. These limits should be based upon appropriate toxicological data, or limits described in national compendial requirements. Manufacturing processes should be adequately controlled so that the impurities do not exceed such established specifications.

应明确规定杂质的适当限值。这些限值应基于适当的毒理学数据,或参照国家药典要求中的限值。制造过程应得到充分控制,以确保杂质不超出已建立的规格。

 

10.18 Where excipients are extracted from or purified by the use of organic solvents, specifications should include tests and limits for residues of solvents and other reactants.

如果辅料是从有机溶剂中提取或通过有机溶剂进行纯化,则规范中应包括溶剂及其他反应物残留物的检验和限值。

 

10.19 Container specifications should be established for all excipients to ensure consistency in protecting the product during storage and transport, to maintain the stability of the product, and to protect against contamination and infestation.

 

应为所有辅料建立容器规范,以确保在储存和运输过程中产品的一致性保护,维持产品的稳定性,并防止污染和虫害。

 

10.3 Batch documentation

 

10.3批次文档

 

10.20 Procedures such as a master batch manufacturing document with instructions for each excipient for pharmaceutical use should be prepared and authorized (dated and signed).

应准备并授权(注明日期并签字)用于制药用途的主批次制造文档,其中应包含每种辅料的操作指令。

 

10.21 A master batch manufacturing document should include the following:

 

主批次制造文档应包括以下内容

 

the name of the excipient      for pharmaceutical use being manufactured;正在制造的制药用途辅料的名称

a complete list of      materials (formula) and quantities;完整的物料清单(配方)及其数量

the production location;生产地点

equipment to be used;所需使用的设备

detailed production      instructions, in - process controls and flow chart, if needed;详细的生产指令、过程控制和流程图(如需)

where appropriate,      precautions to be followed;如有必要,应注明应遵循的注意事项

labelling and packaging      materials and instructions.

标签和包装材料及其操作指令

 

10.22 A record should be available for the excipient for pharmaceutical use produced. It should contain detailed information relating to the production and control thereof.

应为用于制药用途的辅料生产保留记录,该记录应包含与生产及控制相关的详细信息。

 

10.23 The manufacturing record should provide traceable information, including the following:

 

制造记录应提供可追溯的信息,包括以下内容:

 

the batch number批号       

dates and, when      appropriate, times日期和必要时的时间

identification number of      equipment used使用设备的识别编号-

actual results from      testing测试的实际结果

information regarding any      sampling performed

任何取样的相关信息

signatures of operators      and supervisors

操作员和监督者的签名

records of packaging,      packaging materials and labels

包装、包装材料和标签的记录

records of any deviations      that occurred任何偏差的记录

results of release      testing.

放行测试的结果

 

10.24 The manufacturer should demonstrate that:

 

制造商应证明以下事项:

 

the batch is homogeneous      and compliant with its specification;批次是均匀且符合其规格的;

a capable process is used      to ensure batch-to-batch consistency;使用了能力足够的工艺以确保批次间的稳定性;

a batch has not been      commingled with material from other batches for the purpose of either      hiding or diluting an adulterated substance;批次未与其他批次的材料混合以掩盖或稀释掺假物质;

samples have been taken,      where required, in accordance with a sampling plan that ensures a      representative sample is taken;根据确保取样代表性的取样计划进行了必要的取样;

the batch has been      analysed using scientifically established tests and procedures;批次使用了科学验证的测试和程序进行了分析;

the shelf-life of the      excipient for pharmaceutical use is supported by scientific justification,      including data and literature citations, taking account of the stability      of the excipient in its packaging.

药用辅料的货架期得到了科学依据的支持,包括数据和文献引用,考虑到辅料在包装中的稳定性。

 

10.25 Where computerized systems are used in the production of a batch, the electronic data and records should comply with the guidelines on good practices for computerized systems. The system should be suitable for the intended use.

在使用计算机系统进行批次生产时,电子数据和记录应遵守计算机化系统良好实践指南。系统应适合预期用途。

 

10.26 When computerized systems are in use, aspects such as access and privileges, data integrity, audit trail, and back-up systems should be considered during risk assessment, with appropriate controls identified and implemented.

在使用计算机系统时,应考虑访问和权限、数据完整性、审计追踪和备份系统等方面的因素,在风险评估过程中识别并实施适当的控制措施。

 

10.4 Labels

 

10.4标签

 

10.27 Excipients for pharmaceutical use should be labelled. Labels should be clear, unambiguous and in compliance with national or regional legislation, as appropriate. Procedures for handling incorrect labellingshould be established, covering the investigation, evaluation and treatment of nonconforming products.

药用辅料应进行标注。标签应清晰、无歧义,并符合国家或地区相关法律法规的要求。应建立处理不正确标注的程序,涵盖对不合格产品的调查、评估和处理。

 

10.28 Information on labels should include as a minimum the following:

 

标签信息至少应包括以下内容:

 

the name of the excipient      and grade;辅料的名称及其规格;

the batch number assigned      by the manufacturer;制造商指定的批号;       

the expiry or retest      date, if applicable;有效期或复验日期(如适用);

any special storage      conditions or handling precautions that may be necessary;任何必要的特殊储存条件或处理注意事项;

warnings and any other      appropriate precautions;警告及其他适当的注意事项;

the name and address of      the manufacturer.

制造商的名称和地址。

 

10.29 For further information, see WHO Guideline on data integrity and WHO Good manufacturing practices: guidelines on validation. Appendix 5: Validation of computerized systems (2, 3).

如需进一步信息,请参见WHO关于数据完整性的指南以及世界卫生组织良好生产规范:验证指南。附录5:计算机化系统的验证(2, 3)。

 

11. Premises

 

11.厂房

 

11.1 The premises where excipients for pharmaceutical use are manufactured should provide sufficient space for the production, quality control testing and storage operations.

制备药用辅料的厂房应提供足够的空间以满足生产、质量控制检测和储存操作的需求。

 

11.2 The premises should be located, constructed, cleaned and maintained to suit the operations to be carried out.

厂房应根据即将开展的操作进行选址、建设、清洁和维护。

 

11.3 The layout and design of the premises should aim to minimize the risk of errors, mix-ups, contamination and cross-contamination. In addition, it should allow effective cleaning and maintenance without any adverse effect on the quality of the products.

厂房的布局和设计应旨在最大限度地减少错误、混料、污染和交叉污染的风险。此外,还应便于有效清洁和维护,而不对产品质量产生不利影响。

 

11.4 Only authorized persons should have access to relevant areas.

只有经授权人员才可进入相关区域。

 

11.5 Adequate lighting should be provided.

应提供充足的照明。

 

11.6 The decision to use a separate or dedicated facility for the manufacturing of high-risk excipients used in pharmaceutical manufacturing should be based on the outcome of a holistic risk assessment performed by the excipient manufacturer. The risk assessment should take into account the requirement of health-based exposure limits, as described in the literature (4, 5).

在制药过程中使用独立或专用设施来制造高风险辅料的决定,应基于辅料制造商进行全面风险评估的结果。风险评估应考虑基于健康暴露限值的要求,如文献所述(4, 5)。

 

11.7 Note: The method used to achieve this separation will depend on the nature, extent and risk of the overall operation.

注：实现这种隔离的方法将取决于整体操作的性质、程度和风险。

 

12. Equipment and utilities

 

12.设备与公用设施

 

12.1 Equipment and utilities should be selected, located, designed, constructed and maintained to suit the operations to be carried out.

 

设备与公用设施应根据拟进行的操作进行选择、定位、设计、建设和维护。

 

12.2 The installation and use of equipment and utilities should aim to minimize the risk of errors and contamination, cross - contamination, build - up of dust or dirt and, in general, any adverse effect on the quality of products.

设备与公用设施的安装和使用应旨在最大限度地减少错误、污染、交叉污染、灰尘或污垢的积累以及对产品质量的任何其他不利影响。

 

12.3 Written procedures should be established and followed for repairs, maintenance and cleaning. These operations should not have any adverse effect on the quality of the excipient for pharmaceutical use. Records of these activities should be maintained.

应建立书面程序并遵循维修、维护和清洁操作。这些操作不应对用于制药的辅料质量产生任何不利影响。应记录这些活动。

 

12.4 Equipment and instruments identified as being part of the quality management system should be appropriately controlled. These include those used in production and quality control. The control programme should include standardization, verification, and calibration of reagents, instruments, apparatus, gauges, and recording devices at defined, suitable intervals. Written procedures should contain specific instructions, schedules, acceptance limits and handling of the excursions. Records should be maintained.

应对质量管理体系中识别为组成部分的设备和仪器进行适当控制。这些包括用于生产和质量控制的设备。控制计划应包括在规定的时间间隔内对试剂、仪器、装置、量具和记录设备进行标准化、验证和校准。书面程序应包含具体指示、时间表、接受限度和异常处理方法。应记录这些记录。

 

12.5 Reagents, lubricants, instruments, apparatus, gauges and recording devices that can affect the quality of the product should not be used.

可能影响产品质量的试剂、润滑剂、仪器、装置、量具和记录设备不应使用

 

12.6 Computerized systems that may impact the quality of the excipient for pharmaceutical use should be appropriately validated. Quality data should comply with the requirements for data integrity, including data management, audit trails, access and privileges for users.

可能影响用于制药的辅料质量的计算机化系统应适合其预期用途。这些系统应适当验证。质量数据应符合数据完整性的要求,包括数据管理、审计追踪、用户权限和访问。

 

12.7 An appropriate level of validation should be performed for computerized systems.

应对计算机化系统进行适当水平的验证。

 

12.8 Equipment, utilities and computer systems should be commissioned and qualified, as appropriate.

设备、公用设施和计算机系统应在适当的情况下进行安装和确认。

 

12.9 Utilities such as heating, ventilation and air - conditioning (HVAC), water, nitrogen and compressed air systems should be appropriate for their intended use, should not have any negative impact on either operations or the quality of the excipient for pharmaceutical use, and should not be a source of contamination.

如加热、通风和空调(HVAC)、水、氮气和压缩空气系统等公用设施应适合其预期用途,不应对其操作或用于制药的辅料质量产生任何负面影响,也不应成为污染源。

 

12.10 Where HVAC systems are used, air should be filtered to an appropriate level. The design should ensure that the risk of contamination or cross -contamination is minimized and that specified environmental conditions, where required, are achieved and maintained, at the required grade or class, temperature and relative humidity.

在使用 HVAC 系统的情况下,空气应过滤至适当水平。设计应确保将污染或交叉污染的风险最小化,并在必要时实现和维持指定的环境条件,包括所需的级别或类别、温度和相对湿度。

 

12.11 Water purification systems, where used, should be suitably designed, installed, maintained and operated. Water should be sampled and tested, and should meet its relevant specification.

如果使用水净化系统,应确保其设计、安装、维护和运行符合要求。水质应进行采样和检测,并符合相关规范。

12.12 Compressed air and nitrogen generation systems should be designed and controlled in accordance with the outcomes of risk assessment.

压缩空气和氮气生成系统的设计与控制应根据风险评估的结果进行。

 

12.13 Measuring and control devices requiring calibration should be calibrated at defined intervals.

需要校准的测量和控制设备应按规定的间隔进行校准。

 

13. Materials

 

13.材料

 

13.1 Materials, including raw materials and packaging materials, should be sourced from approved suppliers.

 

材料,包括原料和包装材料,应从已批准的供应商处采购。

 

13.2 A procedure for supplier approval and supplier monitoring should be followed. Records should be maintained.

应遵循供应商审批和供应商监控的程序。应保存相关记录。

 

13.3 Written procedures should be followed for the receiving, sampling, storage, testing and release of materials for use.

应遵循书面程序进行材料的接收、取样、储存、测试和放行,以供使用。

 

13.4 Materials should meet their agreed specifications. Materials that may have a negative impact on the quality of the excipient for pharmaceutical use should not be used.

材料应符合其约定的技术规格。可能对药用辅料质量产生负面影响的材料不应使用。

 

13.5 Materials should be stored in accordance with their status and labelling.

材料应根据其状态和标签要求进行储存。

 

13.6 Specific tests, based on risk assessment of the material and pharmacopoeial requirements, should be done where applicable. Impurities should be identified and appropriately controlled.

根据材料的风险评估和药典要求,在适用的情况下,应进行特定的测试。杂质应被识别并适当控制。

 

13.7 A procedure for handling nonconforming products should be established covering the investigation, evaluation and treatment of nonconforming products. The disposition of nonconforming materials, intermediates and finished products should be approved by the quality unit and recorded.

应建立处理不合格品的程序,涵盖不合格品的调查、评估和处理。不合格材料、中间体和成品的处置需由质量部门批准并记录。

 

13.8 Recovered materials, such as solvents, should only be used if scientifically justifiable, and if they meet their relevant specification. The process of recovery should follow written procedures, and records should be maintained.

回收材料,如溶剂,仅在科学上合理且符合其相关技术规格的情况下方可使用。回收过程应遵循书面程序,并应保存相关记录。

 

13.9 Materials used in batches of excipients for pharmaceutical use should be traceable.

药用辅料批次使用的材料应可追溯。

 

13.10 Materials from waste should be appropriately treated and discarded in a manner that will not have any negative effect on the environment.

废弃物中的材料应适当处理并以不会对环境产生负面影响的方式丢弃。

 

13.11 A procedure for waste management should be followed. Records of waste treatment and disposal should be maintained.

应遵循废弃物管理程序。应记录废弃物处理和处置情况。

 

14. Production

 

14.生产

 

14.1 Raw materials for manufacturing of excipients for pharmaceutical use should be weighed or measured in appropriate areas, under appropriate conditions, using suitable devices.

 

制药用赋形剂的原材料应在适当区域、在适当条件下,使用合适的设备进行称重或测量。

 

14.2 The material to be used in production should be kept in suitable containers bearing labels with required details, such as the name of the material and a traceable control number.

生产中使用的物料应存放在适当的容器中,并附有标签,标签上应包含物料名称和可追溯的控制编号等必要信息。

 

14.3 Equipment in production areas should be labelled, for example, with an asset or other unique identification number and, if applicable, calibration status.

生产区内的设备应进行标识,例如,使用资产编号或其他唯一的标识编号,如适用,还应标明校准状态。

 

14.4 Where appropriate, materials should not be kept for periods longer than the validated hold time.

如有必要,物料不应存放超过验证的保存期。

 

14.5 The extent, stringency and type of testing (for example, in - process), as well as acceptance criteria, should be defined. All tests and results should be fully documented as part of the batch record.

测试的范围、严格程度和类型(例如,在线检测),以及接受标准应明确规定。所有测试和结果应详细记录在批记录中。

 

14.6 The sampling process should not increase the risk of contamination of the material. Samples should be handled with care and their integrity maintained.

取样过程不应增加物料被污染的风险。取样时应小心处理,确保样本的完整性。

 

14.7 Manufacturers should have written procedures and related documents for the production and control of excipients for pharmaceutical use.

制药用赋性剂的生产和控制应有书面程序及相关文件。

 

14.8 Batches should be produced following written procedures or instructions.

批次应按照书面程序或指示进行生产。

 

14.9 The manufacturing process should be described in detail, and risks associated with the production and control of the excipient for pharmaceutical use should be appropriately controlled. This includes requirements specified in the recognized pharmacopoeia, transmissible spongiform encephalopathy (TSE) or bovine spongiform encephalopathy (BSE), and impurities.

制药用赋形剂的制造过程应详细描述,并应适当控制与生产及控制赋形剂相关的风险。这包括被认可药典中规定的各项要求,可传播海绵状脑病(TSE)或牛海绵状脑病(BSE),以及杂质。

 

14.10 Batches should be produced using suitable equipment in an appropriate environment, and should be protected from possible contamination and cross-contamination.

生产批次应使用合适的设备在适当的环境中生产,并应防止可能的污染和交叉污染。

 

14.11 In - process sampling and testing should be done in accordance with written instructions. Records should be maintained.

中间体的取样和检测应按照书面指令进行。应保存记录。

 

14.12 Checks and maintenance operations should not affect the quality of the excipient for pharmaceutical use.

检查和维护操作不应影响制药用辅料的质量。

 

14.13 Changes and deviations in production should be managed through the relevant procedures.

生产中的变更和偏差应通过相关程序进行管理。

 

14.14 Blending operations should be controlled to ensure homogeneity of the final batch. A blended batch should be assigned a unique batch number, and batches used in the blend should be traceable.

混合操作应受控以确保最终批次的均匀性。混合批次应分配唯一的批次编号,并且用于混合的批次应可追溯。

 

14.15 A sampling procedure should be followed to ensure that a sample collected from the blend is representative of the batch.

应遵循取样程序，以确保从混合物中采集的样品代表整个批次。

 

14.16 Each batch of product to be mixed should be produced in accordance with the batch manufacturing document, be tested separately, and meet the corresponding specifications. The mixed batch should be tested and should be in compliance with its specified.

每个待混合的产品批次应按照批次生产文件生产,单独检测,并符合相应的规格。混合批次应进行检测并符合其规格。

 

14.17 Blending or mixing of batches should be controlled and validated. Procedures and records should be maintained. Blending of batches to salvage out-of-specification batches or adulterated material is not an acceptable practice.

混合或混合批次的操作应受控并进行验证。应保存操作和记录程序。将批次混合以挽救不合格批次或掺假材料的做法是不可接受的。

 

14.18 Manufacturers should regularly review the capability of the process and ensure batch-to-batch consistency of the excipient for pharmaceutical use, meeting its specification.

药用辅料的生产过程应定期进行能力评估,并确保批次间的一致性,符合其规格。

 

14.19 Written procedures should be followed for the receipt, identification, quarantine, sampling, examination or testing, and release/rejection, and handling of packaging and labelling materials. Records should be kept.

应遵循书面程序接收、识别、隔离、取样、检验或测试、放行/拒收以及处理包装和标签材料。应保存记录。

 

14.20 Packaging materials such as containers should provide adequate protection against deterioration or contamination of the excipient for pharmaceutical use. They should be clean and dry, and should not be reactive, additive or absorptive.

包装材料如容器应提供足够的保护,防止制药用辅料的退化或污染。它们应清洁干燥,且不应具有反应性、添加剂性或吸湿性。

 

14.21 Printed packaging materials such as labels should be in the prescribed format.

印刷包装材料如标签应符合规定格式。

 

14.22 Access to printed packaging material storage areas should be controlled.

打印包装材料存储区的访问应受到控制。

 

14.23 Stock should be reconciled at periodic intervals, including received, issued, and returned quantities. Discrepancies found should be investigated.

库存应在定期间隔进行核对,包括收货、发放和退货的数量。发现的差异应进行调查。

 

14.24 Batch coded labels not used for the specified batch, and obsolete and outdated labels, should be destroyed. Reconciliation should be done. Records should be maintained.

对于未用于指定批次的批次编码标签,以及过时和过期的标签,应予以销毁,并进行核对和记录。

 

14.25 Written procedures should be followed for packaging operations. Controls should be in place to prevent any mix - ups during packaging. These should include line opening and line closing checks, segregation between packaging lines, and verification of materials on the packaging line prior to the start of packaging.

 

应遵循书面操作程序进行包装操作。应实施控制措施,防止包装过程中出现混淆,这些措施应包括生产线开启和关闭检查、包装生产线之间的隔离,以及在开始包装前对包装线上的材料进行验证。

 

14.1Rework

 

14.1返工

 

14.26 Reworking should only be undertaken when the outcome of a risk assessment indicates that this is acceptable and approved by the quality unit.

仅在风险评估结果表明这是可接受的并通过质量部门批准的情况下,才能进行返工。

 

14.27 Batches that have been reworked should be subjected to appropriate quality control testing and stability testing, if required. A reworked batch should be released by the quality unit when it has been determined, by applying the relevant analytical testing procedures, that the specification has been met.

经返工的批次应接受适当的质量控制测试和稳定性测试(如需)。返工的批次应由质量部门在通过相关分析测试程序确定符合规定后批准放行。

 

14.28 Records should be maintained.

应进行记录。

 

14.2 Reprocessing

14.2 重新加工

 

14.29 Reprocessing should only be undertaken if this activity and process have been evaluated internally and found to be acceptable.

只有在对该活动和过程进行内部评估并确认其可接受后方可进行。

 

14.30 Records should be maintained.

应当建立并维护记录。

 

15.Qualification and validation

15. 确认与验证

 

15.1 The scope and extent of qualification and validation should be determined based on risk management principles.

确认与验证的范围和程度应基于风险管理原则来确定。

 

15.2 Manufacturers should be able to provide documented evidence to show that premises, equipment, utilities, procedures and processes are appropriate and are consistently rendering the specified outcome.

 

制造商应能够提供文件证明,表明设施、设备、公用设施、程序和过程是合适的,并且能够持续地产生预期的结果。

 

15.3 Authorized procedures, protocols and records should be maintained for qualification and validation performed.

应维护批准的程序、方案和记录,以记录所进行的验证和确认工作。

 

15.4 The extent of qualification and validation may be further justified when considering the data from development and scale - up, process capability studies, and product quality reviews.

验证和确认的程度可进一步通过考虑开发和放大生产、工艺能力研究以及产品质量评审的数据进行论证。

 

16.Quality control

 

16.质量控制

 

16.1 The layout of the quality control section should be appropriate.

质量控制部分的布局应适当。

 

16.2 Personnel should be suitably qualified and trained.

人员应具备适当的资质并经过培训。

 

16.3 Materials, including raw materials, packaging materials (as applicable) and excipients for pharmaceutical use, should be tested for compliance with their current specifications by following authorized procedures, as described in pharmacopoeias, if available, or by validated in - house procedures.

原辅料(包括原料、包装材料和药品使用的辅料),应按照现行标准要求,通过授权程序进行测试,如药典中有相关标准,则应遵循药典规定;否则,应使用经过验证的内部程序进行测试。

 

16.4 Laboratory equipment and instruments should be appropriate for their intended use. These should be suitably designed, installed, labelled, used, maintained, qualified and calibrated (where so determined), according to written procedures. Records should be kept.

实验室设备和仪器应适合其预期用途。这些设备应设计合理、安装正确、标识清晰、使用正确、维护得当,并根据书面程序进行合格验证和校准(如需)。应保留相关记录。

 

16.5 Equipment and instruments that are out of order or out of calibration should be clearly identified to indicate that they are not to be used.

出现故障或未校准的设备和仪器应明显标识,以表明不得使用。

 

16.6 Authorized procedures should be used for activities including sampling, operation of equipment and instruments, and analysis.

应使用授权程序进行包括取样、设备和仪器操作以及分析在内的各项活动。

 

16.7 Analytical test procedures should be developed and validated to control potential and actual impurities that have been identified following a risk assessment and used routinely to ensure that each batch meets the specification.

分析测试程序应根据风险评估识别的潜在和实际杂质进行开发和验证,并定期使用,以确保每批产品符合标准。

 

16.8 To facilitate traceability of each analysis, a record of analysis should be maintained. This includes a certificate of analysis.

为了便于追溯每项分析,应记录分析过程。这包括分析证书。

 

16.9 Records of analysis should normally include at least the following:

 

分析记录通常应包括以下内容:

 

name of the excipient for      pharmaceutical use;药用辅料的名称;

batch number;批号;       

test results and      reference to any specifications (limits) and test procedures;

测试结果及任何标准(限值)和测试程序的参考;

date and reference number      of testing;测试日期及编号;

date and initials of the      persons who performed the testing and the person who verified the testing      and the calculations, where appropriate;测试人员及验证测试和计算人员的姓名及签名日期;

a clear statement of      release or rejection (or other status decision) and the date and signature      of the designated responsible person.

明确的放行或拒收(或其他状态决定)声明及指定负责人的日期和签名。

 

16.10 Test results should be incorporated into a certificate of analysis.

测试结果应纳入分析证书中。

 

16.11 Out-of-specification results should be thoroughly investigated and documented as per defined procedures. Appropriate actions should be taken.

出现超出规格的结果应进行彻底调查并记录,按照定义的程序进行。应采取适当的措施。

 

16.12 Reference and retention samples should be kept in a secure, suitable location under appropriate conditions. An appropriate quantity should be kept to allow investigation and testing, when these are required.

参考样品和保留样品应存放在安全且适合的地点,并在适当条件下保存。应保留足够的样品数量,以便在需要时进行调查和测试。

 

16.13 Where stability testing is indicated, a procedure and programme should be followed. The procedure and programme should include:

如需进行稳定性测试,应遵循相应的程序和计划。程序和计划应包括:

 

a written schedule that      is reviewed at least annually;

书面的时间表,至少每年审查一次;

reference to the number      of batches and frequency of a batch to be placed on stability;

关于进行稳定性测试的批次数量和批次频率的说明；

type of containers to be      used;使用的容器类型;

conditions of storage,      including stress conditions (such as elevated temperature, light, humidity      or freezing), where appropriate;存储条件,包括可能的应力条件(如高温、光照、湿度或冷冻）；

use of stability -      indicating test procedures, as applicable.如适用,使用指示稳定性的测试方法。

 

16.14 The results from stability testing should be reviewed and trended. An expiry or retest date should be allocated based on scientific data.

应对稳定性测试结果进行审核和趋势分析。应根据科学数据确定有效期或复验期。

 

16.15 Storage conditions should be specified on the label if these are identified (for example, protection from light, temperature).

如果确定了存储条件(例如,防光、防温),应在标签上标明存储条件。

 

17.Life cycle and continuous improvement principles

 

17.生命周期和持续改进原则

 

17.1 Manufacturers of excipients for pharmaceutical use should implement the life cycle approach and continuous improvement philosophy. These principles should be applied, in the relevant areas of the premises, to equipment, instruments, utilities, products and processes.

药用辅料制造商应采用生命周期方法和持续改进理念。这些原则应在相关场地区域内应用于设备、仪器、公用设施、产品和工艺过程。

 

17.2 Manufacturers should implement measures to continuously improve the quality management system, manufacturing and testing procedures, andthe quality of their products. These measures may include the review of root causes of nonconformances, quality complaint investigations and outcomes, and results from self - inspections, audits and other trends.

制造商应采取措施持续改进质量管理体系、制造和检测程序以及产品质量。这些措施可能包括对不符合项根本原因的审查、质量投诉调查及其结果、自我检查、审核及其他趋势的结果。

 

18.1Storage and distribution

 

18.1储存与分发

 

18.1 Storage areas should be appropriately designed, constructed and maintained. They should be kept clean and dry. There should be sufficient space and suitable ventilation.

储存区域应适当设计、建造和维护。应保持清洁和干燥,并有足够的空间和适当的通风。

 

18.2 Storage areas should normally be under cover with sufficient space. Where excipients for pharmaceutical use are stored outside buildings, risk assessment should be done to determine the necessary controls to protect the products from contamination and deterioration.

储存区域通常应有遮盖,并有足够的空间。如果药品辅料存放在建筑物外,应进行风险评估,以确定必要的控制措施,以防止产品受到污染和变质。

 

18.3 Excipients for pharmaceutical use should be stored in suitable containers, under appropriate storage conditions. Where special storage conditions are required, these should be provided, controlled, monitored and recorded.

药品辅料应存放在合适的容器中,并在适当的储存条件下存放。如果需要特殊的储存条件,应提供并控制这些条件,进行监控并记录。

 

18.4 There should be a written programme for pest control in storage and other relevant areas.

应有书面的害虫控制计划,适用于储存和其他相关区域。

 

18.2 Distribution

18.2 分发

 

18.5 Excipients for pharmaceutical use should be distributed through traceable routes. Product, batch, container identity and integrity should be maintained at all times. All labels should remain legible.

药品辅料应通过可追溯的路线进行分发。产品、批次、容器的身份和完整性应在所有时间保持。所有标签应保持清晰可读。

 

18.6 Excipients for pharmaceutical use should be transported in accordance with the conditions stated on the labels.

药品辅料应按照标签上规定的条件进行运输。

 

18.7 Distribution records should be sufficiently detailed to allow traceability in case of a recall.

分发记录应详细到足以在召回时进行追溯。

 

18.8 Note: for further information, see WHO Good trade and distribution practices for pharmaceutical starting materials (6).

注:更多信息,请参见世界卫生组织关于药品起始材料的优良贸易和分销实践(6)。

 

来源：Internet

关键词： 药用辅料