欧盟QP协会关于EU GMP附录1《无菌产品生产》的问答！
Q&As at the Live Online QP Forum 2020
欧盟QP协会-2020问答
1. Can you explain a little bit moreof negative pressure isolators?
可以再解释一下负压隔离器吗?
Negative pressure isolators should be avoided.However, especially when working with CMR-Substances this might not be possible.
应避免使用负压隔离器。然而，特别是在使用CMR（致癌、致突变、致畸）物质时，这可能是不可避免的。
2. Chapter 6: hydraulic systems:could you please give an example?
第六章:液压系统：可以举个例子吗?
6.21 Major items of equipment associated withhydraulic, heating and cooling systems, e.g. such as those associated withBlow-Fill-Seal equipment should, where possible, be located outside the fillingroom. Where they are located inside the filling room there should beappropriate controls to contain any spillage and/or cross contaminationassociated with the hydraulic system fluids. Hydraulic systems are often usedfor lifting and also are often found as pressure tools with Blow-Fill-Sealequipment.
与液压、加热和冷却系统有关的主要设备，如与吹-灌-封有关的设备，应尽可能放在灌装室的外面。如在灌装室内，应该有适当的控制措施来控制与液压系统相关的任何泄漏和/或交叉污染。液压系统经常用于提升，也经常被用作吹灌封设备的压力工具。
3. Is there any plan to revise the'aseptic/sterile process' sections of the ATMP-Guideline and to alignit with Annex 1?
是否计划修订ATMP指南中的“无菌/无菌工艺”部分，使其与附录1一致?
Currently not.
暂无
4. If decided, based on a rationale,not to perform PUPSIT (for simple buffer not likely to mask filter flaws),would it then be normal practice to submit the rationale to the authorities forapproval before initiating the production?
如果基于某种理由决定不进行PUPSIT（灭菌后使用前完整性测试）(对于简单的缓冲液不太可能掩盖过滤器缺陷的过滤器)，那么在开始生产之前，是否应该向有关部门提交理由以获得批准?
Most probably this has to be decided on a caseby case basis. The document available is still a draft.
很可能这要根据具体情况来决定。目前该文件仍是草案。
5. My colleagues from Manufacturingproposed the following cleaning approach of the floor in grade C and B whenthey are idle. Grade C: 1/week, Grade B: 1/month. Shouldn't Grade B be also1/week?
我的生产部同事提出了以下C级和B级地板闲置时的清洁方法。C级:1周，B级:1月。B级不也应该是1/周吗?
Grade B cleaning should certainly be morefrequent than Grade C. However when idle things are different. I suggest adecision based on principles of QRM is what you should do in first instance andthen implement a plan.
B级的清洁当然应该比C级的频繁，但是当闲置时，则是不同的。建议首选基于质量风险管理原则的决策实施计划。
6. Should CCIT performed on everybatch?
CCIT（容器密封完整性测试）是否应每批执行?
In general yes. Samples should be taken andchecked for container closure integrity (CCI) using validated methods. Thefrequency of testing should be based on the knowledge and experience of thecontainer closure system being used. A scientifically valid sampling plan shouldbe utilized. The sample size should be based on information such as supplierapproval, packaging component specifications and process knowledge. Remember:visual inspection alone is not considered as an acceptable integrity testmethod.
一般来说是的。应采用经过验证的方法对样品进行取样和容器密封性(CCI)检查。测试的频率应基于所使用的容器密封系统的知识和经验。应采用科学有效的抽样方案。样品的大小应基于供应商评估，包装元件的说明和工艺知识等信息。记住：仅凭目测不能被认为是可接受的完整性测试方法。
7. Should the MAH QP have access tothe record mentioned (sterilization record), even though the manufacturing ofthe sterile product is outsourced to a CMO where the CMO QP is certifying thebatch for partial manufacturing?
MAH QP是否有权查阅所提到的记录(灭菌记录)，即使无菌产品的生产外包给了CMO, CMO QP负责批次部分生产的认证?
Of course Annex 1 won’t be in contradiction toAnnex 16.
当然，附录1与附录16并不矛盾。
8. Is vial and stopper combinationconsidered as “closed by fusion”?
玻璃瓶和胶塞的组合是否被认为是“熔合密封”?
The following examples are given for closed byfusion:
下面给出了熔合密封的例子:
8.21 […]e.g. Blow-fill-seal (BFS),Form-Fill-Seal (FFS), Small and Large Volume Parenteral (SVP & LVP) bags,glass or plastic ampoules […]
8.21[…] 吹灌封(BFS)，成灌封 (FFS)，小容量注射、大容量注射(SVP & LVP)袋，玻璃或塑料安瓿[…]
→vial and stopper combination is NOT considered as closed by fusion.
玻璃瓶和胶塞的组合不被认为是熔合密封。
9. Will be CCS a formal auditabledocument?
CCS（污染控制策略）是一个正式的可审核文件吗?
As the document(s) are requested by the currentdraft, CCS is considered as a formal auditable / inspectable document.
正如当前草案所要求的，CCS被认为是一个正式的可审核/可检查的文件。
10. Are there any real changes madeto the requirements in Annex 1 or is it more clarification and expansion ofalready stated requirements?
附录1的要求有什么实际的变化，还是对已经陈述的要求做了更多的澄清和扩展?
Both.
都有
11. Regarding PUPSIT, most of thepharmaceutical Companies are not implementing it because it could induceadditional risk for the product. Is it acceptable to justify it on a positionpaper? What’s your though?
关于PUPSIT（灭菌后使用前完整性测试），大多数制药公司还未实施，因为它可能会导致产品的额外风险。是否接受在一份立场文件上进行评估?
Most probably this has to be decided on a caseby case basis. The document available is still a draft.
很可能这要根据具体情况来决定。该文件目前仍是草案。
12. Will the new version of Annex 1also contain details about VHP sterilization?
新版的附录1是否也包含VHP灭菌的细节?
VHP sterilization is mentioned as an example in4.39 and 10.8.
VHP灭菌是4.39和10.8中提到的一个例子。
13. What are your thoughts on oralvaccines manufactured as sterile products following Annex 1? Any waiver fromAnnex 1 could be acceptable ? (e.g. no visual inspection, no endotoxin testing,any other...?)
你对按照附录1生产的无菌口服疫苗有何看法?附录1的任何豁免都可以接受吗?(例如，没有目视检查，没有内毒素测试，任何其他…?)
2.2 Processes, equipment, facilities andmanufacturing activities should be managed in accordance with QRM principles toprovide a proactive means of identifying, scientifically evaluating andcontrolling potential risks to quality. Where alternative approaches are used,these should be supported by appropriate rationales and risk assessment andshould meet the intent of this Annex.
2.2工艺、设备、设施和生产活动应按照质量风险管理原则进行管理，为识别、科学评价和控制潜在的质量风险提供前瞻性的措施。在采用其他方法时，应提供适当的理由和风险评估，并应符合本附录的目的。
14. What do you propose to use as a documentedQP evaluation of the impact of changes of the new annex, a gap assessmentsigned by the QP in charge? Or is a global update of the QMS sufficient?
你建议用什么作为QP对新附录变化影响的书面评估，由QP负责人签署的差距评估?还是一个全面的质量管理体系更新就足够了?
Both of these approaches are good. I would addthat a top level Change Control be opened to manage the various strands ofactivity and that it get closed when the strands are closed, also ensure youput a time limit on completion dates for the strands! Do not let the strands ofactivity drag on indefinitely. Timeliness is always key.
这两种方法都很好。我想补充的是，可以使用一个最高级别的变更控制来管理活动的各个链条，当链条关闭时，它就关闭了，还可以确保你为链条设定一个完成日期的时限! 不要让这些活动无限期地拖延下去。及时总是关键。
15. When you are a non-sterilemanufacturer but using the principles of Annex 1, would you advise documentingthe elements utilised in a position paper or inherently documented into QMSSOPs?
如果你是一个非无菌的制造商，但使用了附录1中的原则，你是否建议将所使用的元素记录在立场文件中或上记录在质量管理体系sop中?
Both seems to make sense.
两者都可以。
16. In a MA it is written,'filling has to be under Annex 1 class A conditions' However it isn'tclear, if missing those should be handled as a deviation to the process or OOSrelated to the product (thus releasing the batch under an OOS), what do youthink?
在一个MA中写着，“灌装必须在附录1的A级条件下”，但是它不清楚，如果遗漏了这些，应作为工艺偏差或与产品相关的OOS(从而放行该批OOS)处理，你怎么认为?
In general compliance with the MA is a legal requirement.However this is an equipment GMP matter not a release specification matter. Isuggest a deviation is appropriate.
一般而言，遵循MA是一项法律规定。然而，这是一个设备GMP问题，而不是放行规范问题。我认为偏差是适当的。
17. Is Annex 1 applicable to QCtesting labs like sterility testing, micro lab? What is the concept?
附录1是否适用于无菌测试、微生物实验室等QC测试实验室?
Annex 1 concepts should be applied to sterilitytesting arrangements. It makes sense that the testing arrangements in terms ofAir Quality are at least as good if not better than the manufacturingarrangements, otherwise we cannot argue that the test is more reliable than themanufacturing. I suggest Annex 1 is not applicable to other micro related testssuch as TVC counting, MLT etc.
附录1的概念应适用于无菌检测活动。就空气质量而言，测试环境应至少与生产环境一样好，这是有道理的，否则我们不能说测试比生产更可靠。建议附录1不适用于其他微生物相关测试，如TVC（细菌总数）计数，MLT（微生物限度测试）等。
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