WHO发布《使⽤不同⽅法—包括HBEL—建⽴清洁验证限度指南》！Thanks for your attention
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;
怜爱风险评估及风险控制;
技术和组织控制;
农历九月是什么月设定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
教你做冰淇淋
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
碧光环
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 ven appendices. In 2019, the WHO Good manufacturing practices: g
uidelines on validation (2) were updated and republished. Some of the ven 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 u (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)。
还字组词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 discusd during an informal consultation held in Geneva, Switzerland, in July 2019. The outcome of the discussion was prented 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 or
der to describe the current approaches ud 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 the risks. The controls include, for example, technical and organizational
measures, dedicated facilities, clod 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-Bad Exposure Limits {HBEL}) – that could be ud when establishing safe Carryover limits when manufacturing in shared facilities.
公务员年休假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 prents 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 focus on approaches where HBELs tting 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。
故事幼儿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).
心灵的灯
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 expod 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 reprent 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, e 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 bad 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 ud, the decision should be discusd and justified as an alternative to new approaches in tting 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 bad on verifying that a cleaning procedure was effective. However, in many instances, no development work or cleanability studies were performed for the 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-
