(仅供参考)制药厂设备维护部门经常发生的十个GMP问题

白皮书：制药厂设备维护部门经常发生的十个GMP问题

小编按：本白皮书列举了十个药厂设备维护部门最常发生的GMP合规性问题。在检察官进行现场检查时，这十个问题经常给企业带来很大的麻烦。建议您在检察官下次进行检查之前，预先找出这些问题，并展开调查，尽早将问题先行解决。

问题一

A risk-based approach to maintenance is not used

在维护工作中没有使用基于风险的方法

It's common to treat every piece of equipment within a pharma plant equally when it comes to maintenance.

A better way is to use a risk-based approach that classifies each piece of equipment in terms of its impact on product quality.

在药厂中，通常所有设备接受的都是同等维护。但是，更好的方法是使用基于风险的方法，根据每个设备对产品质量的影响，对设备的维护进行划分。

We recommend a simple four-category system for equipment:

我们建议将设备分为了四类：

1.Direct Impact (Product Critical Equipment)直接影响（关键设备）

关键设备是指直接影响产品质量的设备。例如：冻干机

2.Indirect Impact (Process / System Critical Equipment) 间接影响（工艺/系统关键设备）

工艺/系统关键设备是指对工艺或系统性能有间接影响的设备，这些设备的故障可能影响成品的质量或安全。例如：高压灭菌器内的温度监控器

3.No Impact Equipment 无影响

这些设备是指对最终产品质量、安全或环境没有影响的设备。例如：厂房入口处的安全水栅门。4.Safety/Environmental Impact System 安全/环境影响系统

这类设备是指对安全或环境有直接影响的设备。例如：锅炉。

This categorization system is detailed in the ISPE Baseline Guideline on Qualification and Commissioning, Volume 5, Impact Assessment. The Direct, Indirect, No Impact and Safety categories are sometimes referred to as the D.I.N.S. system.

设备的这种分类体系在国际制药工程协会的《确认和调试基本指南》中第五卷“影响评估”中有详细说明。上述设备的四种分类体系也简称为D.I.N.S.体系。

Using a risk-based approach such as DINS can dramatically impact the amount of work facing a maintenance department. For example, your maintenance schedule may require that all temperature transmitters be calibrated annually. This is the same frequency for an autoclave as for the ambient air temperature measurement in a warehouse. Which one is more likely to impact product quality? The frequency of calibration should be determined during the validation or re-validation project phases. Using the risk-based categorization approach, the temperature transmitter in the autoclave may need calibration every three months, but the warehouse temperature transmitter may need calibration only once every two years.

采用这种基于风险的方法，例如DINS，可以显著减少维修部门的工作量。例如：维修计划可能要求所有温度传感器每年都要进行校准。也就是说高温灭菌器中的传感器和仓库环境空气温度测量器中的传感器校验周期相同。究竟哪个传感器对产品质量的影响更大呢？校验周期应在验证或复验阶段规定。根据基于风险的方法，高温灭菌器中的传感器需要每三个月校验一次，而仓库温度传感器只需要两年校验一下。

问题二

Computerized Maintenance Management Systems (CMMS) are not utilized, are under-utilized or are not

validated

没有使用信息化的设备维护管理系统（CMMS），或使用程度不足，或CMMS系统未验证

A CMMS typically performs five GMP-critical tasks:

信息化设备维护管理系统CMMS通常执行下列五项重要的GMP工作：

1.Allocating a Unique Identifying Number(UINs) to each piece of equipment

为每个设备分配独一无二的标识码（UINs）

2.Describing the validated plant configuration

说明已验证厂房布局

3.Being the repository of maintenance plans

汇总维护计划

4.Holding records of maintenance activities

保存维护活动的记录

5.Scheduling maintenance activities

安排维护活动

As consultants to the industry, we often see hybrid management systems within maintenance departments. 作为顾问，我们通常会发现企业维护部门使用的是混合管理系统（纸质管理系统和计算机系统）。

These hybrid systems may keep the UIN list in a spreadsheet, store the plans and records as paper files and schedule maintenance activities with a computer system.

这样的混合管理系统就是把UIN清单转化为电子表格，把计划和记录保存为纸质文件，用计算机系统安排维护活动。

Whenever hybrid system exists, the computer system gets preference because it’s easier. Paper systems are neglected and maintenance job sheets get lost. An auditor will target this area because it’s often difficult for companies to get right. Our advice? Use a validated CMMS system.

计算机系统在混合管理系统中更受青睐，因为这样会使工作便捷，纸质系统往往被忽略，维护工作单会丢失。检察官检查的重点也在此，因为企业往往会犯错误。我们的建议是使用已验证的全信息化的CMMS系统。

Validation should be included in the budget for any CMMS. When using a risk-based approach to validation, you need to validate only the five GMP-critical tasks listed above– not the whole system. An unvalidated CMMS is not defendable during an audit, so if you can’t afford validation you may as well forget the whole thing.

在规划CMMS项目时，一定要包括计算机系统验证的预算。如果使用基于风险的方法实施计算机系统验证，只需要验证CMMS系统的上述五项GMP重要功能及其他GMP相关功能，而不一定是验证整个CMMS系统。在检查时，没有被计算机系统验证过的CMMS是没有合理性与说服力的，如果你无法保证CMMS系统能被合理的验证过，也许就不该考虑实施CMMS系统。

问题三

Maintenance plans are not updated as part of new equipment introduction

新设备进厂后，维护计划没有更新

Buying a new piece of hi-tech machinery is very exciting. All the engineers scramble to be the first one to stroke its gleaming steel. Amongst all that excitement, the fact that this newbie has to be maintained is often neglected. Updating the maintenance plan should be included as an activity in the procedure covering new equipment installation.

购置新的高端设备是令人兴奋的，所有工程师都想成为第一个使用的人。但是在兴奋之中，新设备的维护却往往被忽略。如果购置安装了新设备，需要更新维护计划。

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问题4

Maintenance staff and contractors are not trained properly

维护人员和维护承包商没有接受适当培训

Do your maintenance workers and contractors know the impact of changing a setting on a piece of production equipment? Do they understand the concept of a validated state? Do they know when to involve QA?

维护人员和维护承包商是否知道变更生产设备的某个设置会造成什么影响？他们是否理解已验证状态的意义？什么时候需要QA参与？

Let’s face it –maintenance staff would rather watch 15 hours of snail racing on TV than complete paperwork. It’s hard enough to get them to complete maintenance records, let alone Change Control forms. Yet simple maintenance activities such as changing filters or adding lubricant can dramatically impact product quality.

事实上，维护人员更愿意看15个小时的蜗牛赛跑节目，而不是完成纸质文件。维护人员很难完成维护记录，更不用说变更控制表单了。然而简单的维护工作，例如换装过滤器或添加润滑油，都可能对产品质量造成很大影响。

The GMP regulations require all contractors to be trained appropriately before they enter GMP areas. Developing tight, long term relationships with your contracting suppliers is critical. Their HR systems should trigger GMP training for every new hire. You could request that small contracting companies use a simple check list when a new hire commences work. “GMP training" could be on that check list.

GMP法规要求所有维护承包商在进入GMP区域前必须接受适当的培训。与维护承包方建立紧密且长期的合作关系至关重要。维护承包方的人力资源系统会为所有新员工自动安排GMP培训。在维护承包商的新员工上岗前，企业可以要求小型维护承包商准备新员工的检查清单，企业可以依据这份检查清单，判断维修承包商的新员工是否接受了相关GMP培训。

问题5

The GMP impact of lubricants is not considered

润滑油的影响没有被考虑

When we ask the question, “What affect do your lubricants have on product quality?”, we frequently get a puzzled look and a shrug. Lubricants are often ignored in terms of their GMP impact. Yet they can have direct contact with the product and, as such, are considered GMP-critical. Make sure that lubricants are on your criticality assessment list. The assessment and impact of lubricants on product quality should be documented. The introduction of new lubricants should be assessed and documented. Bottom-mounted or indirect drive systems used in plant design are strongly recommended.

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如果被问到“润滑油对产品的质量有什么影响？”企业往往会感到迷惑。润滑油对产品质量的影响通常会被忽略。润滑油其实对产品质量有直接影响，所以应被重点关注。确保润滑油在危险程度评估的清单上，并且评估结果和相关影响应被记录下来。新的润滑油被使用前也要经过评估和记录。强烈建议厂房设计时采用间接驱动系统。

A plant lost a batch worth half a million dollars after an uncontrolled filter change. Maintenance replaced the filter during scheduled maintenance. Due to poorly documented maintenance plans, it was not checked. Product was filtered and packed, and only later was it found that the filter's pore size was 2 μm, not 0.2 μm. the error was found before release and distribution. The batch was disposed of. A simple error, but easy to prevent.

不受控的过滤器更换很可能导致企业损失了价值50万美元的产品。虽然替换过滤器的工作是按照维护计划进行的，但由于维护计划没有被恰当记录，并没有相关人员检查维护计划，在产品过滤和包装后，发现过滤器的孔径大小为2 μm，而不是0.2 μm，在放行和销售前发现了错误，最终批次被销毁，而企业可以轻易避免这样的低级错误。

问题6

Maintenance of utilities and supplies falls between departmental cracks

一些设备的维护职责没有清楚说明到底属于哪个部门

The not-so-glamorous end of the maintenance activity list includes:

通常不引起工作人员注意的维护事项包括：

1.chemicals 化学品

2.power supplies 电源供给

3.fire protection systems消防系统

4.security systems 安全系统

5.HVAC 通风和空调设备

6.water and gas supplies. 水气供应设备

Make sure it’s clear who manage s all this non-production equipment. Too often these items fall into the cracks between departments. The finger pointing starts when things go wrong and the cracks are revealed. 明确说明哪些人员是负责管理这些非生产设备。由于这些非生产设备的维护职责不明确，所以出现问题时，就出现部门见互相推脱责任。

We recommend that "who is responsible for what" be documented in the quality system.

建议明确说明人员的责任。

问题 7

Maintenance activities are undocumented

没有记录维护工作

Policies, procedures and work instructions should exist for all maintenance activities. These documents form an essential training resource for maintenance staff and contractors. This documentation will also be requested by auditors, who know that maintenance is a GMP-risk. They will ask to see documentation that describes the what, when and how of maintenance. Make sure that you have it and that it’s followed. It’s worth while to get a professional technical writer to produce this documentation; this will ensure that the documents are useful and understandable.

所有维护工作都应有相关的方针、规程和工作指令。这些文件对维护人员和维护承包方的培训都非常重要。这些文档也是审计人员所要求的，因为审计人员认为维护工作可能带来风险。在审计时，审计人员会查看这些文档，确认是否有维护的内容、时间和方式。企业应制定并遵循这些文件。需要有专业的技术文档撰写人制定这些文档，这样能够保证文档的有效性和可读性。

Use a risk-based approach to prioritize the documentation needed. The highest risk occurs during times of change, including projects and annual shutdowns. Start by documenting how these are handled.

使用基于风险的方法判断文档的必要性等级。项目终止和系统每年的停止等变更，可能引起最高限度的风险，应有文件记录如何处理这些风险。

The documentation system must be kept simple. Say what you are going to do and do what you said. The auditors will ask staff to “show me,”so if the documentation says that you do it, they will ask to see proof of it. They have a practiced eye to detect impractical systems and drill down. You don’t want to be at the bottom of the drilling.

文档系统应该尽量简单，员工的工作计划和已完成的工作应能够被一目了然地显示出来。审计员要求有文件证明员工所执行的工作。审计员能够检查到系统不合理的地方。

问题 8

Modern maintenance management techniques are not used

没有使用先进的维护管理技术

It’s easy to keep doing things the way you’ve always done them – particularly with daily pressures to manage. With a few exceptions, we’ve seen little adoption by pharmaceutical plants in Australia and New Zealand of maintenance best-practice techniques. Total Preventative Maintenance (TPM) is one we recommend, as well as Condition Based Monitoring (CBM) and Lean Maintenance. With both GMP and your

company’s expectation that you are continuously improving your processes, we recommend that you get some training in these techniques or call in a consultant to help.

按部就班是再简单不过的了，对于每天承受过大压力的人员来说更是如此。当然也有例外，澳大利亚和新西兰的制药厂就很少采用按部就班的技术。这里我们推荐全面预防维护（TPM）、基于条件的监管（CBM）和精细维护。考虑到企业的前景和GMP合规性，企业需要不断完善工艺，我们建议对上述维护技术进行培训，或是寻求顾问的帮助。

问题9

Equipment documentation is not readily accessible

设备文档使用不便

所有设备使用前，有关文档都发放至相关技术人员。如果技术人员已经查阅，那么应做记录。设备的有关文档包括：

?操作手册

?安装手册

?维修手册

?设备验证状态的说明，例如：所使用的设置

?维修记录

?设备的相关工作指令或规程

?设计图纸

?工艺和仪器图表

系统应保存所有文档的受控电子副本，确保技术人员能够从台式机，笔记本电脑，或平板电脑上查看。实际上，目前厂房内大多数使用的还是纸质文件。

建议指定人员不断更新文档，并确保文件便于网页搜索和下载。指定人员可以复印文件，发放质量文件的复印件，但是不允许维护人员持有原件。

在电脑上保存下每个设备制造商网站上的相关维护网页，这样就方便技术人员在遇到问题是能够快速找到设解决问题的方法。

审计员通常会选择三个重要的产品生产设备进行审计，并检查相关的维护记录。如果记录内容为“预防维护依据生产者的建议进行”，那么审计员可能要求查看这些意见的具体内容。这时最好确保生产者的文档都是近期更新的内容。

问题10

Maintenance is not considered during equipment purchases

在购买设备时没有考虑维护问题

在选择新设备时，维护部门往往做得最不到位。产品生产工程师和产品开发人员依据物料通过量和清洁难易程度选择新的设备。事实上，维护的难易程度和影响也需要考虑在内。

假设有两种洁净室产品供选择，它们的选择标准基本相同。其中一个完全安装在洁净室内，另一个产品的可维修部件在洁净室外，产品接触部门在受控区域。那么该选择哪种产品呢？当然是第二个产品，因为维修工作在洁净室外进行，就不会影响洁净室的验证状态，而且维护工作会更简单、更迅速，所以对比而言，应选择第二种产品。