MHRA博客：共用设施/设备交叉污染问题 20200818
Cross Contamination Control in Shared Facilities and Equipement.
Reflection on common deficiencies and expectations as seen in recent PIC/S guidance.
共用设施与设备中交叉污染控制
常见缺陷以及最近PIC/S指南中提出的要求
Posted by:Graeme Mc Killigan,
Posted on:18 August 2020 –
Categories:Compliance matters, Good manufacturing practice
During this period where MHRA hasbeen conducting predominantly remote inspections, we have reflected on some ofthe common factors in critical deficiencies we have been seeing in control strategies for cross contamination between products in shared facilities.Requirements and expectations have been refreshed with Inspectors with a particular focus of attention on sites handling products with lower level Health Based Exposure Levels (HBELs), those with products around the red area of the continuum seen in the PIC/S Q&A document,
在MHRA主要执行远程检查的期间，我们发现了关键缺陷中常见的一些问题，是关于共用设施中交叉污染控制策略的问题。我们已提醒检查员新的要求，特别要求关注工厂对那些低HBEL限度的药品的处理，即那些PIC/S问答文件中显示的连续条中红色区域附近的产品。
As a result, we would make Industry aware of the following elements of their control strategy that they should ensure they are addressing:
为此，我们想让企业明白其控制策略中的以下要素应能确保解决：
Health Based Exposure Limits (HBELs) completed for all products by experienced professional Toxicologists
由具备经验的毒理学专家对所有产品完成HBEL评估
So what is going wrong?
那么什么地方出问题了呢？
HBELs are being generated by company personnel without adequate and appropriate experience in developing HBELs. Q4in the PIC/S Q&A document explains the expectations. It is important thatHBEL values are of the appropriate magnitude to ensure cross contamination control strategies are establish based on the relevant hazard level, this can only be achieved by personnel with extensive relevant toxicology knowledge and experience.
问题在于HBEL是由公司里不具备足够和适当HBEL计算经验的人员计算出来的。PIC/S问答文件第4问说明了这点要求。HBEL值对于确保交叉污染控制策略是基于相关危害水平而建立的非常重要，而这点只能由具备广博相关毒理学知识和经验的人员才能达成。
The HBEL value and hazard knowledge should be used to set the context and the reference for conducting Quality Risk Management development of Organisational and Technical controls
应使用HBEL值和危害性知识来设定环境，作为执行组织和技术控制质量风险管理开发的基准。
So what is going wrong?
那么什么地方出问题了呢？
Many companies are conducting risk assessments without any reference to the HBEL level they are required tocontrol to. Risk assessments are thus conducted without consideration of the magnitude and nature of the hazards they are trying to control so are unlikely to be effective. The only use that some companies are making of HBEL is to set cleaning validation acceptance criteria.
问题在于许多公司在执行风险评估时并没有参考其所需控制达到的HBEL水平。如此一来，风险评估在执行时并未考虑其试图控制的危害的严重程度和属性，所以是不可能有效的。有些公司对HBEL的使用仅仅是用来设置清洁验证可接受标准。
As described in Q3 in the above PIC/SQ&A, input to a Quality Risk Management study to develop Organisational and Technical controls (or critically assess existing controls) is a key use of theHealth Based Exposure Limit studies. Risk Management requires a focus and a perspective as well as knowledge and data. QRM is a team activity and all teammembers should be clear on what level of residue they are trying to control atboth batch and unit dose levels – the HBEL allows this context to be established. Pictorial representation of these critical HBEL values may be helpful, and patient safety should be a core focus to control risks of failure through design of controls and minimisation of human error. Critical control points should be established, these may include key parts of equipment to dismantle, retention points of contamination, primary control/containment systems. QRM team members may have inherently different risk perception and acceptance so expectations of how the risk is assessed and controlled should be clearly defined in a documented process.
正如上述PIC/S问答文件第3问所述，将其作为质量风险评估研究的输入，制定组织和技术控制措施（或批判性地评估现有控制）是HBEL研究的关键用途。风险管理要有重视和深刻认识，以及知识和数据。QRM是一个团队活动，所有团队成员均应明白他们试图控制的批次和单位剂量残留水平—HBEL可用于建立该条件。用图片来呈现这些关键HBEL值可能会有所帮助，患者安全应该是通过控制设计和最小化人为错误控制失败风险的核心关注点。应建立关键控制点，其中可包括要拆卸的关键设备部件、污染存留点、初步控制/封闭系统。QRM团队成员可能会存在不同的风险观点和可接受度，所以应该有书面流程明确规定如何评估和控制风险。
Sole reliance on visual inspection for cleanliness at changeover between products following cleaning validation should only be made when there is clear and safe evidence that residues can be consistently and readily seen at the acceptance criteria level.
清洁验证之后，更换产品的清洁度检查单单依赖于目视检查时，必须要有明确安全的证据证明残留量恒定，且可接受标准水平的残留量很容易目检看到。
So what is going wrong?
那么哪里出问题了呢？
Having completed basic cleaning validation many companies are ceasing analytical testing at product change overand applying a visual inspection only. In some cases, the allowable residue limits that safely meet HBEL cannot be seen at the visual threshold of the product contaminant. As a result, there is no discerning test of success of the cleaning activity post validation. Where manual cleaning is used, this is a high-risk strategy that has been found to be unjustifiable in some manufacturers. Visual inspection is always regarded as a minimum requirement for confirmation of cleaning but Q7 and Q8 in the PIC/S Q&A describe circumstances where sole reliance may be placed on visual inspection.
许多公司在完成了基本的清洁验证之后即停止在更换产品时进行分析检测，使用仅目视检查取而代之。很多情况下，满足HBEL要求的允许残留限度并不能达到该产品污染物的目视阈值。如此一来，在验证之后其实并没有使用具备辨识能力的测试来证明清洁活动是否成功。当使用人工清洁时，我们发现许多生产商其实无法给出这种高风险策略的正当理由。目视检查一直以来被认为是清洁确认的最低要求，PIC/S问答的第7和8问说明了仅依赖目视检查的情形。
Manufacturers should ensure compliance with cross contamination control requirements and consult the PIC/S Q&A for further clarification of expectations. Manufacturers should also consider if their cleaning validation can truly be considered reproducible and consistent, particularly where manual cleaning is conducted.
生产商应确保符合交叉污染控制要求，并参考PIC/S问答中对要求的进一步阐述。生产商还应考虑其清洁验证是否真的可认为是可重复的和一致的，特别是使用人工清洁的时候。
Regulatory action has been required as a result of failures at several sites in the last year, so don’t be caught out and reassess your controls.
去年在几个工厂所发现的问题我们已经提出了监控措施要求，所以，请不要被发现同样的问题，请重新评估你们的控制措施。
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