WHO发布《使用不同方法—包括HBEL—建立清洁验证限度指南》！

近日，WHO发布了新的清洁验证指南——《不同方法——包括HBEL——建立清洁验证的残留限度以确定共用设施生产污染风险的考量》，该指南解读如下：

传统的方法是进行清洁验证并基于GMP文件中建议的接受标准来判断清洁程序的适用性。这种做法可能不再是可以接受的和合理的，因为没有考虑到HBEL。

鉴于污染和交叉污染的风险，应毫不拖延地实施下文所述的新方法。

新的清洁验证方法包括：

  • 清洁能力研究;

  • 风险评估及风险控制;

  • 技术和组织控制;

  • 设定HBELs

  • 分析程序;及

  • 清洁确认，并通过统计学评价证实清洁能力。

设备图纸应保持更新，准确和可用。在计算设备表面积时应使用。应有这些计算的源数据。计算的数值应应用于清洁验证的计算。

难以清洁的设备和部件，如筛子、筛网和袋子，也应包括在清洁验证和计算中。

关于取样，应使用至少两种或三种取样方法的组合。包括擦拭取样、冲洗取样和目视检查的组合。

应当选择适当的取样程序和技术来收集样品。应在程序和规程中加以明确说明。收集样品的地点(擦拭取样)及方式应清楚说明，并具科学理据支持。

淋洗水取样应有详细的描述。规程应清洗明确。

收集的样品进行分析的方式应适当，并详细说明。

在验证清洁程序并日常使用之前，应进行清洁能力研究，以确定物料、产品残留、清洁剂和微生物的清除程序是否合适。

关于清洁能力研究，对于不同结构材料上的不同物料、中间体和产品，应确定通过清洁程序能够除去的物质的最低浓度。该浓度可用mg/m2表示。

清洁能力研究应在批准的文件中进行描述，例如规程和程序。该方法应具有科学性，可包括对不同结构材料进行涂布。可以使用所谓的烧杯法或其他适当的方法。

应制定和执行程序，说明如何获取关于HBEL的科学数据和毒理学信息。

关于HBEL报告，数据和信息应收集并呈现在报告中。这些数据应没有偏差。如此服务外包，应采取适当措施，以确保所获得的数据可靠。应考虑GMP要求，如供应商确认、协议和其他相关方面。

HBEL的确定，应形成报告，包括以下内容：

  • 化学结构;

  • 危害识别

  • 作用方式;

  • 关键影响识别;

  • 建立无可见不良作用水平(NOAELs);

  • 调整因子;

  • 临床前、临床及非临床资料;

  • 药代动力学及药效学;

  • 专家评估;

  • 关键影响识别;

  • 调整系数(AF)的分配;

  • 论证选定的HBEL;

  • 给药途径;

  • 偏离点(POD);

  • POD 的关键影响论证;以及

  • 因子的论证。

全文翻译如下：

Working document QAS/20.849

工作文件QAS/20.849

May 2020

二零二零年五月

DRAFT WORKING DOCUMENT FOR COMMENTS:

工作文件草案:

Points to consider on the different approaches – including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities

不同方法——包括HBEL——建立清洁验证的残留限度以确定共用设施生产污染风险的考量

1. Introduction and background

介绍及背景

2. Scope

范围

3. Glossary

术语

4. Traditional approach

传统方法

5. New approaches

新的方法

6. References

参考资料

1. Introduction and background

介绍及背景

The World Health Organization (WHO) has published the guideline entitled Good Manufacturing Practices for pharmaceutical products: main principles in the WHO Technical Report Series, No. 986, Annex 2, 2014 (1).

WHO 于 2014 年 TRS 986 附录 2 发布了题为“药品 GMP：主则”的指南。

The WHO Supplementary guidelines on good manufacturing practice: validation were published in 2006 and were supported by seven appendices. In 2019, the WHO Good manufacturing practices: guidelines on validation (2) were updated and republished. Some of the seven appendices were also individually updated between 2013 and 2019:

WHO 的“GMP 补充指南：验证”于 2006 年发布，有 7 个附录作为支持文件。2019 年， WHO 的“GMP：验证指南”进行了更新并重新发布。7 个附录中有几个分别于 2013 年和 2019 年进行了更新。

  • Appendix1. Validation of heating, ventilation and air conditioning systems (3).

  • 附录1  HVAC 系统的验证(3)

  • Appendix2. Validation of water systems for pharmaceutical use (4).

  • 附录2  制药用水系统的验证(4)。

  • Appendix3. Cleaning validation (5).

  • 附录3  清洁验证(5)。

  • Appendix4. Analytical procedure validation (6).

  • 附录4。分析方法验证(6)。

  • Appendix5. Validation of computerized systems (7).

  • 附录5计算机化系统验证)。

  • Appendix6. Guidelines on qualification (8).

  • 附录6  确认指南(8)。

  • Appendix7. Non-sterile process validation (9).

  • 附录7  非无菌工艺验证(9)。

Appendix 3, relating to cleaning validation (5), was not updated at that time. Its revision, however, was discussed during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of the discussion was presented to the WHO Expert Committee on Specifications for Pharmaceutical Products (ECSPP) meeting in October 2019. The ECSPP acknowledged the importance of harmonization in regulatory expectations with regards to cleaning validation approaches. The Expert Committee recommended a “Points to consider” document be prepared in order to describe the current approaches used in cleaning validation and highlighting the complexities involved in order to establish a common understanding. A revision of the relevant appendix would then be considered by the Expert Committee thereafter.

与清洁验证有关的附录 3 当时未更新。但在 2019 年 7 月瑞士日内瓦的非正式沟通期间对其修订进行了讨论，讨论结果于 2019 年 10 月提交给了 ECSPP 会议。ECSPP 了解清洁验证方法的监管要求保持一致的重要性，因此专家委员会建立起草一份“考量要点”文件，以阐述当前清洁验证中所用方法，强调其所涉及的复杂性，以求对此达成共识。鉴于此，专家委员会随后考虑要对相关附录进行修订。

Many manufacturers produce products in multi-product facilities where there is a risk of contamination and cross-contamination. Some of the main principles of good manufacturing practices (GMP) include the prevention of mix-ups and the prevention of contamination and cross-contamination. It is therefore important that manufacturers identify all risks for contamination and cross-contamination and identify and implement the appropriate controls to mitigate these risks. These controls include, for example, technical and organizational measures, dedicated facilities, closed systems, cleaning and cleaning validation.

许多生产商会在多产品设施中生产多个产品， 这时就会存在污染和交叉污染的风险。优良生产规范（GMP）的一些重要原则包括有防止混淆和防止污染与交叉污染，因此生产商识别所有污染与交叉污染，识别实施适当控制措施以降低这些风险就非常重要。这些控制措施包括例如技术和组织措施、使用专用设施、封闭系统、清洁和清洁验证

2. Scope

范围

The scope of this document is to discuss the different possible approaches – including methods that account for pharmacological and toxicological data (Health-Based Exposure Limits {HBEL}) – that could be used when establishing safe Carryover limits when manufacturing in shared facilities.

本文件的范围是讨论不同的方法，包括考虑药理学和毒理学数据的方法(基于健康的暴露限度{HBEL})，以确定共用设施生产的安全残留限值。

This document further provides clarification on cleaning validation and presents points to consider when reviewing the current status and approaches to cleaning validation in multiproduct facilities. It reflects the current regulatory guidance and expectations. It further focuses on approaches where HBELs setting need to be considered in cleaning and cleaning validation approaches.

本文件进一步厘清了清洁验证，并提出了在审查多产品设施清洁验证的现状和方法时需要考虑的要点。它反映了当前的监管指导和期望。它进一步侧重于在清洁和清洁验证方法中需要考虑HBELs设置的方法。

The principles should be applied in manufacturing facilities with active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs).

这些原则适用于活性药物成分(API)和制剂(FPP)的生产设施。

This document should be read in conjunction with the main GMP text and supplementary texts on validation (1-10).

本文件应与GMP主文本和验证补充指南(1-10)一起阅读。

3. Glossary

术语

cleaning validation. Documented evidence to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.

清洁验证：证明清洁方法可将残留清除至预定的可接受水平的文件化证据，同时考虑的因素有如批量、给药剂量、毒性和设备尺寸。

contamination. The undesired introduction of impurities of a chemical or microbiological nature, or of foreign matter, into or on to a starting material or an intermediate or pharmaceutical product during handling, production, sampling, packaging, repackaging, storage or transport.

污染：起始物料或中间体或药品在处理、生产、取样、包装、重新包装、存贮或运输期间引入的不希望存在的化学或微生物杂质，或异物。

cross-contamination. Contamination of a starting material, intermediate product or finished product with another starting material or product during production.

交叉污染：起始物料、中间体或成品与另一起始物料或产品在生产期间相互污染。

margin of safety. The margin of safety is the distance between a calculated acceptance limit and the actual residues after cleaning. It indicates the probability that a patient has to be exposed to the API residues resulting from cleaning.

安全空间：安全空间是计算出的可接受限度与清洁之后实际残留之间的差距。它显示的是患者必须暴露于清洁引起的 API 残留的可能性。

maximum safe Carryover (MSC). Mathematically calculated quantity of residue from a previous product when carried over into a different product that can represent potential harm to the patients.

最大安全残留（MSC）：算术方法计算得到的上一产品携入下一不同产品，可能会对患者带来潜在伤害的残留量

maximum safe surface residue (MSSR). The maximum safe surface residue is mathematically calculated dividing the quantity of residue on a contact surface by the total area of contact (Maximum Safe Carryover/Total Equipment Surface Area).

最大安全表面残留（MSSR）：最大安全表面残留是将接触表面的残留量除以总接触面积（最大安全残留/总设备表面积）

verification. The application of methods, procedures, tests and other evaluations, in addition to monitoring, in order to determine compliance with GMP principles.

确认：在常规监测以外，使用方法、程序、检测和其它评估确定是否符合 GMP 原则。

4. Traditional approach

传统方法

For details on the traditional approaches in cleaning validation, see the WHO Technical Report Series, No. 1019, Annexure 3, Appendix 3, 2019 (5).

有关清洁验证的传统方法的详细信息，请参阅WHO技术报告，第1019号，附录3，附录3,2019(5)。

One traditional approach is that cleaning validation is performed and the appropriateness of the cleaning procedure was based on acceptance criteria suggested in GMP texts. This approach may no longer be acceptable and justifiable as HBELs were not considered.

一种传统的方法是进行清洁验证并基于GMP文件中建议的接受标准来判断清洁程序的适用性。这种做法可能不再是可以接受的和合理的，因为没有考虑到HBEL。

Where traditional acceptance limits are used, the decision should be discussed and justified as an alternative to new approaches in setting acceptance criteria.

在使用传统的接受限度时，作为确定接受标准新办法的合理性。

In view of the risks of contamination and cross-contamination, the new approaches, as described below, should be implemented without delay.

鉴于污染和交叉污染的风险，应毫不拖延地实施下文所述的新方法。

5. New approaches

新的方法

Traditional cleaning validation approaches were often based on verifying that a cleaning procedure was effective. However, in many instances, no development work or cleanability studies were performed for these cleaning procedures.

传统的清洁验证方法通常基于验证清洁程序是否有效。然而，在许多情况下，没有为这些清洁程序进行开发工作或清洁能力研究。

Manufacturers should ensure that their cleaning is effective and appropriate and that their cleaning validation provides scientific evidence that identified products can be manufactured in shared facilities

制造商应确保其清洁是有效和适当的，并且其清洁验证提供了科学证据证明产品可以在共用设施中生产。

– with control measures implemented to mitigate the risks of contamination and cross-contamination.

-采取控制措施以减轻污染和交叉污染的风险。

This approach should include at least the following points which are further described in the text below:

这种办法至少应包括下文中进一步阐述的以下几点:

  • cleanability studies;

  • 清洁能力研究;

  • risk assessment and riskcontrol;

  • 风险评估及风险控制;

  • technical andorganizational controls;

  • 技术和组织控制;

  • HBELs setting;

  • 设定HBELs

  • analytical procedures;and

  • 分析程序;及

  • cleaning verificationwith proven capability through statistical evaluation.

  • 清洁确认，并通过统计学评价证实清洁能力。

Manufacturers should describe their policy and approaches, including the points mentioned above, in a document such as a master plan.

制造商应在文件（如主计划）中说明其方针和方法，包括上述要点。

It is strongly recommended that manufacturers review their existing technical and organizational measures, suitability of cleaning procedures and appropriateness of cleaning validation. Genotoxic and carcinogenic substances, degradants and other contaminants should be identified and the appropriate action should be taken in order to ensure that materials and products are not contaminated when produced in shared facilities.

强烈建议制造商审查其现有的技术和组织措施、清洁程序的适用性和清洁验证的适当性。应识别基因毒性和致癌物质、降解产物和其他污染物，并应采取适当措施，以确保在共用设施生产的物料和产品不受污染。

5.1       Documentation

5.1文件

Risk management principles, as described in other WHO guidelines on quality risk management (10), should be applied to assist in identifying risks and controls to mitigate contamination and cross-contamination.

应使用风险管理原则来帮助确定风险和控制以减少污染和交叉污染。

Procedures, protocols, reports and other related and supportive documentation should be prepared, used and maintained.

程序、方案、报告和其他相关的和支持性的文件应准备、使用和保存。

The policy and approaches in cleaning and cleaning validation may be described in a Cleaning Validation Master Plan. Experiments and validation should be performed in accordance with predefined, authorized standard operating procedures, protocols and reports.

清洁和清洁验证的方针和方法可在清洁验证主计划中描述。测试和验证应按照既定的、经批准的标准操作程序、方案和报告进行。

The design and layout of documents, and the reporting of data and information, should be in compliance with the principles of good documentation practices (11) and should also meet data integrity requirements (12).

文件的设计和布置以及数据和信息的报告应符合良好文件规范的原则(11)，并应符合数据完整性的要求(12)。

5.2       Equipment

5.2设备

Consideration for cleaning validation should cover contact surfaces, as well as non-contact surfaces, where the latter have been identified as areas of risk.

清洁验证的考虑应包括接触表面，以及非接触表面，如后者已被确定为危险区域。

Authorized drawings of equipment should be current, accurate and available. These should be used when equipment surface areas are calculated. Source data for these calculations should be available. The calculated values should be used in the calculations in cleaning validation.

设备图纸应保持更新，准确和可用。在计算设备表面积时应使用。应有这些计算的源数据。计算的数值应应用于清洁验证的计算。

Equipment and components that are difficult to clean, such as sieves, screens and bags, should also be included in the cleaning validation and calculations.

难以清洁的设备和部件，如筛子、筛网和袋子，也应包括在清洁验证和计算中。

5.3       Detergents and solvents

5.3清洁剂和溶剂

Solvents and detergents used in cleaning processes should be selected with care. They should also be appropriate for their intended use. The selection of the relevant solvent and detergent should be justified.

应谨慎选择清洁过程中使用的溶剂和清洁剂。它们也应该适合其预期用途。选择的溶剂和洗涤剂应合理。

There should be proof of effectiveness and appropriateness of the selected solvent and detergent.

应有所选溶剂和洗涤剂的有效性和适当性的证明。

Other points to consider include the concentration in which these are used, their composition, and removal of their residues after cleaning.

其他需要考虑的要点包括使用浓度、试机组成以及清洁后残留物的去除。

The use of solvents and detergents should be included in cleanability studies.

清洁能力研究应包括溶剂和清洁剂的使用。

5.4     Sampling

5.4取样

Traditionally, cleaning validation included the sampling of equipment and other areas in order to determine whether or not there was any residue remaining on the surfaces. The focus was mainly on contact surface areas. Non-contact surface areas were sometimes considered by some manufacturers.

传统上，清洁验证包括对设备和其他区域进行取样，以确定表面是否有残留物。焦点主要集中在接触面积。一些制造商有时会考虑非接触表面。

A combination of at least two or three sampling methods should be used. These include a combination of swab samples, rinse samples and visual inspection.

应使用至少两种或三种取样方法的组合。包括擦拭取样、冲洗取样和目视检查的组合。

The appropriate sampling procedures and techniques should be selected and used to collect samples. These should be clearly described in procedures and protocols. The location (swab sample) and the manner in which the samples are collected should be clearly described and be scientifically justifiable.

应当选择适当的取样程序和技术来收集样品。应在程序和规程中加以明确说明。收集样品的地点(擦拭取样)及方式应清楚说明，并具科学理据支持。

The manner in which a rinse sample is collected should be described in detail. The procedure should be clear and unambiguous.

淋洗水取样应有详细的描述。规程应清洗明确。

The manner in which samples collected are prepared for analysis should be appropriate and described in detail.

收集的样品进行分析的方式应适当，并详细说明。

5.5       Cleanability studies

5.5清洁能力研究

Before a cleaning procedure is validated and adopted for routine use, a cleanability study should be performed in order to determine the appropriateness of the procedure for removing material, product residue, cleaning agents and microorganisms.

在验证清洁程序并日常使用之前，应进行清洁能力研究，以确定物料、产品残留、清洁剂和微生物的清除程序是否合适。

The lowest concentration of a substance that can be removed by following the cleaning procedure should be established for different materials, intermediates and products on different materials of construction. The concentration can be expressed in mg/m2.

对于不同结构材料上的不同物料、中间体和产品，应确定通过清洁程序能够除去的物质的最低浓度。该浓度可用mg/m2表示。

Cleanability studies should be described in authorised documents, such as protocols and procedures. The method should be scientific and may include spiking on coupons made from different materials of construction. The so-called beaker method, or other appropriate method, may be used.

清洁能力研究应在批准的文件中进行描述，例如规程和程序。该方法应具有科学性，可包括对不同结构材料进行涂布。可以使用所谓的烧杯法或其他适当的方法。

Consideration should be given to all substances and different procedures where different processes or solvents are used, including different surface materials.

应该考虑所有的物质和不同的程序，使用不同的工艺或溶剂，包括不同的表面材料。

The results should be documented in authorized reports and used in further determinations, such as Maximum Safe Residue.

结果应记录在经批准的报告中，并用于进一步的决定，如最大安全残留。

5.6       Risk assessment and risk control

5.6风险评估及风险控制

Risk identification should be performed with a focus on the assessment of risks and defining and implementing controls to mitigate the risk of contamination and cross-contamination.

应进行风险识别，并评估风险，制定并实施控制措施，以减少污染和交叉污染的风险。

These should include technical and organization controls, including but not limited to, premises, equipment, utilities, containment, closed systems, cleaning and cleaning validation.

这应包括技术和组织控制，包括但不限于，厂房，设备，公用系统，隔离器，密闭系统，清洁和清洁验证。

5.7       Technical and organizational controls

5.7技术和组织控制

The appropriate technical and organizational controls should be defined and implemented.

应确定和实施适当的技术和组织控制。

Their appropriateness and effectiveness should be evaluated. Note: Cleaning and cleaning validation are considered additional and supplementary controls to technical and organizational controls.

应评价其适当性和有效性。注:清洁和清洁验证被认为是技术和组织控制的附加和补充控制。

Technical and organizational controls should be justifiable and clearly documented.

技术和组织控制应合理，并有明确的文件记录。

Technical controls, such as the design of the premises and utilities (e.g. heating, ventilation and air-conditioning {HVAC}, water and gas), should be appropriate for the range of products manufactured (e.g. pharmacological classification, activities and properties).

技术控制，例如厂房和公用系统(例如空调系统（HVAC）、水和气体)的设计，应适用于所制造的产品范围(例如药理分类、活动和特性)。

Organizational controls, such as dedicated equipment, procedural control, and campaign production, should be considered where appropriate as a means to reduce the risk of cross-contamination.

组织控制，例如专用设备、程序控制和错峰生产，应酌情考虑作为减少交叉污染风险的一种手段。

5.8       Health Based Exposure Limits (HBELs) setting

5.8健康暴露限值(HBEL)设定

Manufacturers should establish, document and implement a company-wide policy on HBELs setting for shared facilities.

制造商应该建立、记录和实施一个公司范围内的关于设置共享设施的HBELs的政策。

APIs and products manufactured in shared facilities should be reviewed based on scientific evidence in order to determine whether production and control activities in shared facilities may be considered acceptable or whether dedicated facilities are required for the production and control of identified products.

应根据科学证据对共用设施生产的API和产品进行审查，以确定共用设施的生产和控制活动是否可以接受，或者是否需要专门的设施用于特定产品的生产和控制。

This is applicable to legacy products as well as the introduction of new products introduced into a facility through a change control procedure.

这适用于在产产品以及通过变更控制程序引入的新产品。

Procedures should be established and implemented describing how scientific data and toxicological information on HBELs should be obtained.

应制定和执行程序，说明如何获取关于HBEL的科学数据和毒理学信息。

Data and information should be gathered and presented in a report. The data should be free from bias. Where this service is outsourced, the appropriate measures should be put in place in order to ensure that the data obtained are reliable. GMP requirements, such as vendor qualification, agreements and other related aspects, should be considered.

数据和信息应收集并呈现在报告中。这些数据应没有偏差。如此服务外包，应采取适当措施，以确保所获得的数据可靠。应考虑GMP要求，如供应商确认、协议和其他相关方面。

The report should include scientific detail, including information on:

报告应包括科学细节，包括以下方面的信息:

  • chemicalstructure;

  • 化学结构;

  • hazardidentification;

  • 危害识别

  • modeof action;

  • 作用方式;

  • identificationof critical effects;

  • 关键影响识别;

  • establishingNOAELs (no-observed-adverse-effect level);

  • 建立无可见不良作用水平(NOAELs);

  • adjustmentfactors;

  • 调整因子;

  • pre-clinical,clinical and non-clinical data;

  • 临床前、临床及非临床资料;

  • pharmacokineticsand pharmacodynamics;

  • 药代动力学及药效学;

  • expertassessment;

  • 专家评估;

  • identificationof the critical effect;

  • 关键影响识别;

  • assignmentof adjustment factors (AF);

  • 调整系数(AF)的分配;

  • argumentationfor the selected HBEL;

  • 论证选定的HBEL;

  • routesof administration;

  • 给药途径;

  • pointof departure (POD);

  • 偏离点(POD);

  • justificationfor critical effect of POD; and

  • POD 的关键影响论证;以及

  • justificationfor factor.

  • 因子的论证。

The Permitted Daily Exposure (PDE) should be calculated based on the data and information obtained. For example:

每日允许暴露量应根据所获得的数据和资料计算。例如:

Where NOAEL is no-observed adverse event level, and

其中 NOAEL 为无明显不良作用水平

F represents various factors. The value selected should be justifiable.

F表示不同的因子。选择的值应合理。

The report should be reviewed by the manufacturer’s in-house team for completeness and appropriateness. Team members should have the appropriate qualifications and experience in the field of toxicology. A summary report should be prepared for each product and contain information on the PDE value, genotoxicity and carcinogenicity (13).

生产商的内部团队应审核报告的完整性和恰当性。团队成员应具备适当的毒理学领域资质和经验。应为每个产品制作一份总结报告，在其中包括 PDE 值、毒性和致癌性方面的信息。

These scientific reports should be used when considering the cleaning validation control measures.

在考虑清洁验证控制措施时应使用这些科学报告。

Manufacturers should periodically review and update PDE reports. The appropriate action should be taken where such a report needs to be updated.

生产商应定期审核并更新其 PDE 报告。在需要对此类报告进行更新时应采取适当措施。

5.9       Acceptance criteria

5.9可接受标准

Limits established in cleaning validation should be justifiable.

清洁验证中建立的限度应可论证。

Manufacturers often specified acceptance limits based on historical GMP texts. These traditional limits may no longer be acceptable as HBELs (PDE) and cleanability studies were not performed in many cases.

生产商通常会根据历史的 GMP 要求规定可接受限度。这种传统的限度可能不再可以接受，因其在很多情况下未使用 HBEL 和清洁能力研究。

Criteria such as Margin of safety, Maximum Safe Carryover (MSC) and Maximum Safe Surface Residue (MSSR) values should be calculated. Calculations and data should be available and comply with data integrity principles. The calculation should include values of PDE, maximum daily dose, batch size and equipment surface areas.

应计算出标准值如安全空间、最大安全残留（MSC）和最大安全表面残留（MSSR）值。应可提供计算过程和数据，并应符合数据完整性要求。计算应包括 PDE 值、最大日给药剂量、批量和设备表面积。

Maximum Safe Surface Residue (MSSR) should be calculated and presented, for example, in table form listing preceding and following product values. The cleanability value obtained should be considered in determining the acceptability of the procedure(s) and whether other controls including separate, dedicated facilities are required. (See Annex 1 as an example.)

应计算并列明最大安全表面残留（MSSR） ，例如在表格中，写明前一产品和后一产品的各值。在确定清洁方法是否可接受，以及是否需要采取其它控制措施，包括分开生产设施或使用专用设施时， 应考虑研究所得的清洁能力值（参见附录 1 作为例子） 。

5.10 Grouping by therapeutic use

5.10根据治疗用途分组

The risk associated with contamination and cross-contamination from one product to another product in one therapeutic group, and between products in different therapeutic groups in shared facilities, should be considered. For example, due to the risk, certain products should be manufactured in dedicated or segregated self-contained facilities, including certain antibiotics, certain hormones, certain cytotoxics and certain highly-active drugs – even though these are in the same therapeutic class.

应考虑共用设施中污染和同一治疗组和不同治疗组之间的一个产品到另一个产品中的交叉污染相关风险。例如，由于该风险，应在专用或分开的自我封闭设施中生产特定产品，包括特定的抗生素、特定的性激素、特定的细胞毒性产品和特定高活性药品—即使它们归属同一治疗类别。

The risk assessment should include, for example, PDE values, batch size, maximum daily dose of the next product, as well as other criteria associated with cleaning.

风险评估应包括例如 PDE 值、批量、下一产品的最大日给药剂量，以及与清洁有关的其它标准。

The higher the PDE value, the lower the risk. The products and therapeutic groups considered for manufacturing should be plotted based on an identified scale of risk (14, 15). An illustration is presented in figure 1 where hazard is plotted against risk

PDE 值越高，则风险越低。应根据所识别的风险规模规划产品和治疗组的生产。图 1中展示的是风险与危害的关系图

5.11 Analytical procedures

5.11分析程序

Samples obtained in cleaning validation should be analyzed by using specific, validated procedures. The procedures should be developed, validated and appropriate for their intended use.

清洁验证中所取样品应采用经过验证的特定方法进行验证。检验方法应根据其既用途开发、验证，并适合其既定用途。

Specific methods, such as HPLC, should be used where possible. Non-specific methods including UV spectrophotometry should only be used where specific methods cannot be employed.

应尽可能使用专属方法例如 HPLC。只能在没有专属性方法可用时方可使用非专属性方法包括 UV 分光光度法。

Testing for total organic carbon (TOC) may be used where indicated and where justified.

如经说明并论证，可使用总有机碳（TOC）检测。

Analytical procedures validation should be done on-site. Where analytical procedures were developed and validated off-site, the scope and extent of validation should be defined and justified. This includes procedures that are transferred from research and development laboratories to site laboratories. (For analytical procedure validation, see reference 6).

分析方法应在工厂进行验证。如果分析方法不在工厂开发和验证，则应规定和论证验证范围和程度。其中包括将方法从研发实验室转移至工厂实验室。（分析方法验证参见参考文献 6）。

Manufacturers should ensure that the procedures remain in a validated state.

生产商应确保清洁方法保持经过验证的状态。

5.12 Data integrity

5.12数据完整性

Data, information and results pertaining to, for example, HBELs, PDE reports, results obtained from cleaning validation and calculations should be scientific and should be in compliance with the principles as contained in data integrity guidelines (12).

关于例如 HBEL、 PDE 报告、清洁验证的结果和计算过程之类的数据、信息和结果应具有科学性，应符合数据完整性指南中的原则。

5.13 Cleaning validation and cleaning verification

5.13清洁验证和清洁确认

The cleaning procedure should be validated after the cleaning procedure had been developed and the cleanability study had been done.

清洁方法在开发之后以及完成清洁能力研究之后应进行验证

Cleaning validation should include proof of, for example, the applicability of the procedure to clean equipment that:

清洁验证应包括证明清洁方法对以下设备状态的适用性：

  • had been kept in an unclean state for a period of time (dirty equipment hold time);

  • 待清洁状态的保持时间（脏的保持时间）;

  • are used after product change-over;

  • 更换产品后;

  • are used in a campaign, where multiple batches of a product are produced one after the other; and/or

  • 连续生产的设备，一个产品的多个批次连续生产;及/或

  • are stored in a clean state for defined periods of time (clean equipment hold time).

  • 洁净状态下存放一定时长（干净的保持时间）

Cleaning validation should include consideration of HBELs when the appropriate method used in establishing Carryover limits. Where HBELs are not used, scientific justification should be provided.

如果在建立残留限度时使用了适当的方法，则清洁验证应包括对 HBEL 的考量。如果未使用 HBEL，则应提供科学论证。

The company should describe the policy and approach to cleaning verification. The effectiveness of the validated cleaning procedure should be routinely verified. The approach may include swab or rinse samples. The results obtained from testing on a routine basis should be reviewed and subjected to statistical trending.

公司应阐明清洁确认的方针和方法。已验证清洁方法的有效性应有常规确认。确认方法可包括擦拭取样或淋洗取样，常规检测的结果应进行审核，并进行统计学趋势分析。

5.14 Visually clean

5.14目视清洁

Visually clean is an important criterion in cleaning validation and should be one of the acceptance criteria used on a routine basis.

目视清洁在清洁验证中是一个重要标准，应该在日常工作中用作可接受标准。

Visible residue limits (VRLs) should be determined. The process to determine the limit should be appropriately described in procedures and protocols including concentrations, method of spiking, surface areas, material of construction and other conditions such as light and angles.

应确定目视残留限度（VRL）。确定该限度的过程应在程序和方法中应的适当描述，包括浓度、加标方法、表面积、结构材料和其它条件如照明和角度。

VRLs should be quantitatively established for APIs, excipients, detergents and pharmaceutical products.

API、辅料、清洁剂和药品应建立定量 VRL。

Visual Detection Index (VDI) may be calculated using MSSR.

可使用 MSSR 计算目视检测指数（VDI）。

5.15 Cleaning verification and process capability

5.15清洁确认和工艺能力

The cleaning procedure should remain in a validated state. Cleaning verification and process capability may be used to provide data to support this. For example, the results from cleaning verification sample analysis could be statistically trended. The capability of the cleaning process is then calculated through an appropriate statistical process.

清洁方法应保持处于经过验证的状态。清洁确认和工艺能力可用于提供数据支持该状态。例如，清洁确认样品分析的结果可进行统计学趋势分析。清洁工艺的能力可通过适当的统计学过程进行计算。

The presentation of individual results and data used in the calculation, such as with a Central Processing Unit (Cpu) and acceptable daily exposure (ADE) base limit, should meet ALCOA principles.

计算中所用单个结果和数据，如集中处理单元（CPU）和可接受日暴露量（ADE）基本限度的表现形式应符合 ALCOA 原则。

Data should be presented, for example, in graph form, and the capability of the process in relation to control limits and the margin of safety should be discussed as part of continuous improvement.

数据应以例如图形方式呈现，与控制限度和安全空间有关的工艺能力应作为持续改进一部分进行讨论。

5.16 Personnel

5.16人员

Personnel should be trained in the principles of cleaning validation, with an emphasis on contamination and cross-contamination control, HBELs setting, equipment disassembly, sampling, testing and statistical calculations.

人员应接受清洁验证原则的培训，重点要强调污染与交叉污染控制、 BEL 设置、设备组装、取样、检测和统计学计算。

5.17 Quality metrics and performance indicators

5.17质量量度和性能指标

Aspects of HBELs setting, cleanability studies, cleaning validation and cleaning verification, as well as process capability, should be considered in quality metrics, with performance indicators identified and to be monitored.

HBEL 设置、清洁能力研究、清洁验证和清洁确认，以及工艺能力各方面均应在质量量度范畴内考量，同时识别出性能指标并进行监测。

5.18 Life cycle

5.18生命周期

HBEL reports, protocols, cleaning validation and cleaning verification should be included in a company policy and life cycle approach in preventing cross-contamination in shared facilities.

HBEL 报告、方案、清洁验证和清洁确认均应包括在公司防止共用设施的交叉污染的方针和生命周期方法中。

公众号

GMP办公室

  • 专业的GMP合规性研究组织

  • 国内外（FDA、EMA、MHRA、CFDA、WHO、PIC/S等）GMP法规解读；

  • 国内外制药行业GMP监管动态；

  • GMP技术指南（ISPE、PDA、ISO、ASTM等）分享

赞 (0)

相关推荐