欧洲QP协会问答集(之一)：关于原料药和其它起始物料的答疑

Q: Raw material for API production: are on-site audits required for all suppliers?

问：原料药生产用原料：是否需要对所有供应商都做现场审计？

A: No; however a risk based supplier quality audit programme should be established. It is important to perform a risk analysis to determine whether a supplier needs to be audited.

答：不需要，但是要建立基于风险的供应商质量审计程序。重要的是要实施风险分析来决定是否需要对一个供应商进行审计。

Q: A batch of an API has been released before all testing and final approval was completed. How do I handle this in the certification of the final product?

问：一批原料药在所有检测和最终批准完成前即被放行。我在对制剂成品出具证书时要怎么办？

A: Within the EU shipment of unapproved API is not be acceptable under EU law. For shipments outside of the EU the local laws would have to be checked. It would be necessary to check what is stated in the API producer’s SOP with reference to shipping unapproved material and whether that contravened any regulatory laws. The quality agreement between the API producer, the contract manufacturer and the MA holder should also be looked at to see if there is any reference to the movement of unapproved material being acceptable. It is not good practice to ship unapproved materials and as such this should have been picked up by the quality person releasing the API. Further, a deviation should have been raised and a full investigation carried out as to the root-cause. In addition the contract manufacturer should have quarantined this material on receipt and also raised a deviation to find out what went wrong. If this was a one-off incident and not a fundamental break down of the API’s manufacturers and/or the contract manufacturers Quality System, then as long as the API was formally approved, you should reference the deviation report and as long as everything else was in order, certify the final drug product. However, if this incident was part of a systematic failure of the Quality System would recommend not to certify the drug product as the potential for other GMP non-conformances would be too great. The follow-up to the deviation could involve an audit of the API producer initiated by the MA holder.

答：根据欧盟法律，在欧盟境内发运未经批准的原料药是不能被接受的。如果是发生在欧盟境外，则要检查当地法律是否允许发运。需要检查原料药生产商的SOP中关于发运未经批准物料的条款，看是否违反了法规规定。要查看合同生产商和上市许可持有人与原料药生产商之间的质量协议，看看是否有条款规定未经批准的物料转移是可以接受的。发运未经批准的物料是不好的方式，因此需要由原料药放行质量人员进行挑选。另外，要启动偏差程序，进行全面调查，找出根本原因。还有，合同生产商要在接收时暂扣该物料，也需要启动偏差调查找出是什么地方出问题了。如果这只是一次性的偶然事件，而不是原料药生产商或合同生产商的质量体系基础崩溃，则只要该原料药经过了正式批准，你可以引用偏差报告，只要保证其它所有事情都正常，就可以批准最终制剂。但是，如果该事故是一个质量体系系统性的失效事件，则建议不要批准制剂，因为潜在的其它GMP不符合性可能是很严重的。在偏差跟踪时，上市许可持有人可以启动对原料药生产商的现场检查。

Q: How far down the manufacturing supply chain (finished API – intermediate – starting materials) has the QP to place consideration when preparing a GMP API declaration?

问：QP在准备原料药GMP声明时，要考虑生产供应商多远（成品原料药---中间体---起始物料）？

A: Based on a risk-assessment of the process the QP must evaluate the critical materials or critical steps. The QP can base his decisions on statements of authorised persons within a QA-System.

答：根据对工艺的风险评估，QP必须评估关键中间体或关键步骤。QP可以根据QA体系内授权人的声明做出决定。

Q: API-supplier audit: If a big company is purchasing the API in bulk and then repackaging it and doing the QC testing and release, do I as the final QP need to audit the bulk manufacturer?

问：原料药供应商审计：如果一个大公司采购散装原料药，然后分装并进行QC检测后放行，作为最终QP，我是否需要审计散装原料药生产商？

A: It is the responsibility of the QP for the MAH to assure that each step in the supply chain from the starting material onwards has been manufactured in accordance with GMP. In this example it would be necessary for the final QP to either audit, or have an approved auditor carry out an audit of the bulk manufacturer. This would be in addition to having a Quality Agreement in place between the bulk manufacturer and the drug product producer.

答：MAH的QP有责任保证从起始物料起的供应链中每一步生产均符合GMP要求。在此例中，最终QP需要进行现场审计，或由经过批准的审计人员对散装原料药生产商进行审计。上外，散装原料药生产商和制剂生产商之间要有一份质量协议。

Q: Is a QP responsible to release an API?

问：QP要负责放行原料药吗？

A: No. The EU Guidelines to Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use; Part II Basic Requirements for Active Substances used as Starting Materials does not contain a reference to a Qualified Person. It is the Quality Unit that has this responsibility.

答：不要。欧盟人用和兽用药品GMP指南第二部分原料药基本要求并不包括对QP的要求。质量部门承担该项职责。

But the QP is required to confirm in an EU marketing application that the API has been manufactured in accordance with Part 2 of EU GMP. It is important to emphasise that it is the QP who is certifying the final drug product and who has to give the assurance that the API has been made in accordance with the relevant GMPs. Hence the QP must have access to appropriate documentation including supplier audits (not necessarily by the QP themselves) together with a Quality Contract (Agreement) signed by both parties, to assure her-/himself that the API does comply with the valid standards.

但是，QP要确认欧盟上市许可所用的原料药是按照EU GMP第二部分生产的。要强调的是放行最终制剂成品的QP必须保证原料药根据相关GMP生产。因此，QP必须可以有适当途径来对审查适当的文件，包括供应商审计（不一定是由QP自己审计）与双方签字的质量合同（协议），从而他/她自己能保证原料药符合有效的标准。

However, some Member States may have differing national regulations that might require QPs for certain APIs, e.g. in Germany those APIs derived from a human, animal, microbiological source, and manufactured by biotech methods.

但是，有些成员国的国家规定可能不同，可能要求QP对特定的原料药，例如，在德国对人体、动物、微生物来源生产的原料药，生物技术生产的原料药，进行放行。

Q: How are APIs covered under the MRA? Do APIs from non-MRA states have to be retested?

问：MRA如何能覆盖API？非MRA国的原料药必须要重新检测吗？

A: An API has to be re-tested on receipt no matter where it comes from. In this case the MRA is irrelevant. Testing can only be reduced or eliminated (but the ID still must be done) until the supplier has been fully qualified and has provided materials over a period of time with no issues. An on-site audit of the supplier would also have to be undertaken to ensure the supplier is meeting the required standards.

答：不管原料药从何而来，必须在接收时重新检测。MRA与此完全不相关。只能在供应商被确认后，且供货超过一定时长都没问题发生时，才对可以减少检测项目或免检（但鉴别还是要做的）。还必须对供应商进行现场审计以保证供应商符合要求的标准。

Q: What is the minimum requirement/ expectation for supplier qualification of excipients? Are on-site audits required?

问：辅料供应商最低要求/期望是怎样的？是否需要进行现场审计？

A: The minimum requirement is that starting materials (including excipients and others) and packaging materials are only purchased from approved suppliers. There is no regulatory requirement for on-site audits for excipient suppliers, this is only mandatory for APIs that are manufactured under GMPs. Nevertheless, own audits or qualified third party audits or joint audits should be considered as a part of the qualification programme for suppliers and distributors of excipients besides quality and delivery history, full analysis and performance based tests.

答：最低的要求是起始物料（包括辅料和其它物料）和包装材料只能从批准的供应商那里采购。没有法规要求必须对辅料供应商进行现场审计，只有在GMP条件下生产的原料药生产商是必须进行现场检查的。不管怎样，在对辅料的供应商和分销商进行资格确认时，除质量和发运历史，全面分析及检测结果评估外，还是要要考虑自己进行现场检查或由第三方或联合检查。

Q: Does the manufacture and purchase of raw materials represent an activity governed by Chapter 7 of the EU GMP Guide?

问：生产和采购原料是否要遵守EU GMP指南的第7章要求？

A: In principle, Chapter 7 covers all outsourced activities. Therefore, the general requirements for supplier selection, approval and performance management apply equally to raw materials as to other outsourced activities. There may not be a need for Quality/Technical Agreements (QTA) with the supplier; this will depend on the nature of the arrangement between the parties. For example, if the purchaser contracts the supplier to manufacture raw materials for them, then the arrangements would need to be covered by a Quality/Technical Agreement. However, if the purchaser simply buys raw materials from the supplier a QTA would not be required.

答：原则上来说，第7章包括了所有外包活动。因此，该供应商选择、批准和表现管理的通则性要求同等适用于原料及其它外包活动。可能这些情况下不需要与供应商签署质量/技术协议（QTA），这取决于双方安排的情况。例如，如果采购方与供应商订有合同要该供应商为其生产原料，则该安排需要订立质量/技术协议。但是，如果采购方只是从供应商处采买原料，则不需要QTA。

Q: The notice to applicants requires the submission of a declaration signed by the Qualified Person (QP) that the active substance used is manufactured in accordance with GMP. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration?

问：申请人需知里要求提交一份由QP签署的声明，声明活性物质是根据GMP生产的。我产品中的活性物质应用范围非常广泛，但一般并不作为药用物质，我在符合性方面遇到一些困难。我要怎么样来完成这份要求的声明呢？

A: Full compliance with GMP for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products, the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business. Alternative sources should normally be sought, but in exceptional circumstances the manufacturing authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation. The declaration provided by the QP should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach, which can be used as a basis for discussion on related amendments to guidelines in the future. (source: EMA Q&A)

答：制剂和原料药全面符合GMP是生产许可持有人的法定义务。我们知道对于少数药品，活性物质的基本用途并不是用在药品中，因此其生产可能并不符合药用客户的特定要求，这些药用客户的用量并不大。这时通常要寻求替代的来源，但在例外情况下，生产许可持有人应评估和记录符合GMP的程度，对于接受任何降低的要求需提供基于风险的评估。由QP提供的声明应详细说明其所实施标准可以提供与GMP相同水平的质量保证。EMA会收集该方法的经验，用于讨论在将来对相关指南的修订。

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