USP:<467>残留溶剂问答

凡例<467>---残留溶剂

Compliance Requirements/Chapter Scope 合规性要求/章节范围

1.What are USP’s expectations relating to General Chapter <467> between now and July 1, 2008 and after July 1, 2008 for all pharmaceutical companies?

USP对于凡例<467>在2008年7月1日之前和之后对所有制药公司的期望是什么？

The USP General Notices require all products to meet the requirements in General Chapter <467> by July 1, 2008. The purpose of the chapter is to limit the amount of solvent that patients receive.

USP凡例要求所有产品到2008年7月1日时均符合凡例<467>中的要求，该章的目的是限制患者接受到的溶剂数量。

2.Are dermatological products and topical products required to comply with <467>?

皮肤用药和局部用药是否要符合<467>？

USP defers to FDA on enforcement questions, but the chapter does include language indicating that in some cases the ICH limit may not be appropriate. This language is not specific to dermatological and topical products.

在执行问题上USP服从FDA要求，但该章指出了在某些情况下ICH限度可能不适合的情况。该说明并不特定于皮肤用品和局部用药。

3.Protein manufacturers do not use solvents in their manufacturing processes. What are the expectations with regards to <467> in proteins?

蛋白质生产商在其生产工艺中并不使用溶剂，关于蛋白质<467>的期望是什么？

The chapter states that no testing is required if you know that solvents are not present. However, it is always prudent to evaluate your starting materials and finished product.

该章声明了如果你已经知道不会有溶剂出现，则不需要进行测试。但是，谨慎的做法还是要评估你的起始物料和最终成品。

4.Is it possible that USP will consider setting standards for residual solvents in packaging components?

USP是否可能考虑设定包材中残留溶剂的标准？

Residual solvents in packaging are not addressed by this chapter. We are aware of extractables and leechables, and we may consider this aspect in the future.

本章中未说明包材中残留溶剂情况。我们知道萃出物和浸出物，我们可能会在将来考虑这方面内容。

5.ICH Q3C does not apply to existing commercial drug product. Please confirm that the USP requirement applies to all existing commercial drug products.

ICH Q3C并不适用于已有商业化药品。请确认USP的要求适用于所有已存在的商业化药品。

That is correct. USP sees no reason to exclude product from the <467> requirements, as the goal is to limit residual solvents in all products.

是的。USP认为任何药品都没有理由例地不服从<467>要求，其目的就是为了限制所有药品中的残留溶剂。

6.Is it accurate to state that <467> applies only to products that are labeled "USP" or "NF", and that if the substance or product is not labeled "USP" or "NF", then <467> is only guidance?

声明<467>仅适用于标示有“USP”或“NF”的药品是否准确，如果药用物质或制剂未标示“USP”或“NF”，那<467>是否仅供指导？

No. If the product or substance is covered by a USP or NF monograph, the monograph standards and the General Notices apply, whether or not it is labeled "USP" or "NF", The General Notices requirement that the substance or product comply with <467> applies to all substances and products covered by USP and NF monographs.

不对。如果制剂或原料药由USP或NF各论所涵盖，各论标准和凡例均适用，而不管是否标示“USP”或“NF”。凡例的要求适用于所由被USP和NF各论涵盖的物质和制剂。

7.<467> applies to the drug product. Are manufacturers of finished products required to test the active ingredient and the excipients?

<467>适用于制剂。制剂生产商是否需要测试其活性成份和辅料？

<467> gives you the option of testing either all of the individual components or the final finished product.

<467>给出了选择，你可以测试所有单个成分或测试最终成品。

8.If we use Water for Injection for dilution of drug substances to make drug products, do we need to test Water for Injection for residual solvents?

如果我们使用了注射用水来稀释药用物质生产制剂，我们是否需要对注射用水检测残留溶剂？

If you don't use any of the solvents listed in the manufacture of Water for Injection, <467> does not require you to test the water for solvents.

如果你在注射用水的生产过程中未使用所列出的任何溶剂，<467>不要求你检测水中的溶剂。

9.How do the <467> requirements apply to animal health items, if at all? Will the chapter apply to veterinary products in the future? If so, when?

<467>如何应用于动物保健产品，是全部吗？该章将来是否适用于兽药？如果是，什么时间开始？

The <467> requirements apply to items for veterinary use. However, the current limits are based on human use and limits for different species of animals probably would need to be different.

<467>要求适用于兽药产品。但是，现行限度是基于人用的，对不同的动物其限度可能会有差异。

10. What about material that is not an API or Excipient, but is a material used in the API, or a salt or hydrochloric acid? Q3C does not address the issue of raw materials used in an API.

如果所用物料并非原料药或辅料，但是在原料药中使用了，或者是一种盐或盐酸该如何处理？Q3C并未说明在原料药生产中使用的原料。

The bottom line is to assure the material that is going out to patients does not harm them. If you do option 1, this test takes care of the solvent issues for these materials. It's up to the manufacturer to make sure the product complies with the limits for solvents.

底线是保证供给患者的物料不会伤害他们。如果你选择了第一种方法，该测试会检查这些物料的溶剂情况。这取决于生产商如何保证产品符合溶剂限度。

11. Do we need to confirm that no solvent contamination occurs during packaging or repackaging?

我是否需要确认在包装或分包装过程中不会发生溶剂污染？

The chapter covers only those solvents used in the manufacturing process. Accidental contamination during packaging, handling, or shipping should be managed through good handling and shipping practices.

该章只包括了用于生产工艺的溶剂。在包装过程，或运输过程中的事故性污染应通过优良处理和运输规范来管理。

Vendor Materials 贸易商物料

12. Do we need to perform a complete residual solvent analysis to verify the information provided by our vendor?

我们是否需要对贸易商提供的物料进行全面溶剂分析以确认其提供的信息？

It is up to the manufacturer to determine whether or not to test. The decision may depend on the confidence and the relationship between the manufacturer and supplier. The manufacturer may choose to audit the vendor.

是否进行检测由生产商来决定。决定可能依赖于信任和生产商与供应商之间的关系。生产商可以选择对贸易商进行审计。

13. If an excipient manufacturer states that class 2 solvents are present in their excipient, but below the option 1 limit, does the drug product manufacturer have to test for these solvents?

如果辅料生产商声明其辅料中存在2类溶剂，但低于选项1限度，制剂生产商是否必须测试其溶剂？

Use good science and prudent behavior in a GMP environment to demonstrate the absence of solvent. If the presence or absence can’t be demonstrated, test the product.

在GMP环境下，采用良好的科学和稳健的方式来证明溶剂是否存在。如果无法证明，那么就对产品进行检测。

USP Methods 药典方法

14. What is the history/source of the USP method? Could the USP make changes to the method in the future?

USP药典方法的历史和来源是怎么样的？USP将来是否会对方法进行变更？

USP's primary source for these methods is the European Pharmacopeia (EP) method. The USP is under continuous revision, and we make changes to the methods to improve existing procedures or to allow the user to obtain better results. USP may revise this chapter in response to additional comments received.

USP方法的原始来潮是EP中使用的方法。USP在持续修订，我们会对方法进行变更以改进现有程序，或使得使用者得到更好的结果。USP可能会对在收到意见时该章进行修订。

15. Chromatographic question: How does USP propose to deal with peak co—elutions in the current proposed chapter?

色谱问题：USP拟稿如何处理现行拟稿中的同时流出峰问题？

There are two procedures, A&B. These procedures provide orthogonal separation. For quantitative analysis, A is preferred, but B should be used if A does not work (for instance, due to co—eluting peaks).

有两个程序，A和B，它们提供矩阵分离。对于定量分析，A更好，但如果A不好用时应该用B方法（例如，由于同时流出峰）。

16. Has the USP method been tested by USP on drug products and excipients?

USP是否对USP方法在制剂和辅料上进行过测试？

The USP method has been tested on some, but not all USP products and active ingredients.

USP方法在一些制剂和辅料上进行过测试，但不是所有USP产品和原料药。

17. What happens to peaks in sample that are non—target solvent peaks?

如果在样品中发现非目标溶剂峰该怎么办？

If you come up with an unexpected peak while looking for a specific solvent, use good science to identify the peak and work with a toxicologist for the acceptable level in that material.

如果你在找指定溶剂时发现异常峰，使用优良科学来鉴别该峰，并与毒理学家一起讨论其在该物料中的可接受水平。

18. During method development, did USP experiment with "salting" agent for the headspace analysis? If so, what did you find as far as efficacy for increasing responses — or "inefficacy"?

在方法研发期间，USP试验是否采用“盐化”试剂用于顶空分析？如果有，关于增加响应时效能方面有什么发现？

USP did not experiment with salting agents because we found that method as written provides acceptable sensitivity.

USP没有采用盐化试剂进行试验，因为我们发现所写的程序具有可接受的灵敏度。

19. How do you suggest testing a product that only has class 3 solvents present that cumulatively are greater than 0.5%? Example:

Ethanol 0.3%

Ethyl Ether 0.2%

1—propanol 0.3%

一个产品仅有3类溶剂，但它们的累积结果超过0.5%，你们对些有何检测建议？例如，乙醇0.3% 乙酸乙酯 0.2% 正丙醇 0.3%。

It is not appropriate to use Loss on Drying (LOD) if the amount of class 3 solvent exceeds 0.5%. In those cases, gas chromatography should be used. If you have process validation information indicating that you can reduce the amount of class 3 solvent to 0.5% or lower in the final product, you can discuss with FDA the possibility of using LOD.

如果3类溶剂的数量超出0.5%，则不适用干燥失重方法。在这种情况下，要采用气相色谱法。如果你的工艺验证信息说明你可以将3类溶剂在成品中的数量降低至0.5%以下或更低，你可以与FDA讨论使用LOD的可能性。

20. If a material has class 3 and Class 1 or 2 solvents in it, what is the USP method, since procedures A, B, and C are only for class 2 solvents and Loss on Drying (LOD) is only for class 3?

如果物料中有3类溶剂，同时有1类溶剂或2类溶剂，USP的方法是什么？在USP方法中，A B C仅适用于2类溶剂，LOD仅适用于3类溶剂。

If you have a Class 3 solvent and either a Class 1 or 2 solvent, use LOD to demonstrate acceptance in class 3 as long as LOD result is not more than 0.5%. If it is more than 0.5%, use gas chromatography to demonstrate compliance.

如果你有一个3类溶剂，另有一个1类或2类溶剂，只要LOD结果不超过0.5%就可以使用LOD证明3类溶剂处于可接受程度。如果超过0.5%，使用气相色谱来证明其符合性。

Harmonization 一致性

21. If USP is working to harmonize USP General Chapters, why doesn't USP completely harmonize <467> with the EP before implementing the chapter?

USP是否正在协调USP凡例一致性？为什么USP不将<467>在实施前与EP保持完全一致呢？

There are only minor differences between the USP and EP methods. The reference standard mixtures are different in the USP. Also, the calculation is different. In the USP, methods A and B are limit tests, method C is a quantitative test. Other than those minor changes, the chapter is harmonized.

在USP和EP方法间只有一些微小的差异。EP的混合对照品与USP不同。还有，计算不同。USP中，方法A和B是限度测试，方法C是定量测试。除上述不同外，整章是一致的。

22. Industry has just finished implementing ICH Q3C to meet European regulatory expectations. Can the USP clarify what is additionally expected to achieve compliance with <467>?

行业刚实施了ICH Q3C以符合欧洲法规期望，USP是否可以解释要符合<467>还有哪些额外的要求吗？

ICH applies only to new products. <467> applies the same requirements to all existing products covered by USP monographs.

ICH仅适用于新产品，<467>将相同的要求适用于所有被USP各论涵盖的已有产品。

Changes to Methods 方法变更

23. The USP method shows less recovery for some of the solvents. Will USP propose recovery correction factor for calculations?

USP方法对有些溶剂回收率较低。USP是否建议在计算中加入回收校正因子？

When using procedure C, a spiked solution will compensate for the differences in recovery.

在使用方法C时，加样溶液会对回收差异进行补偿。

24. Would USP consider separating methods in <467> to a separate chapter?

USP是否考虑将<467>中的方法拆分成一个单独的章节呢？

This has not been discussed internally yet.

内部还没有对此讨论。

Alternative Methods 可替代方法

25. Can USP adopt the ICH language that allows the use of an appropriately validated method?

USP是否采用ICH思路，允许使用经过适当验证的方法？

The General Notices allow for the use of an appropriately validated method.

凡例允许使用经过适当验证的方法。

26. The USP methods still have many drawbacks and may not be able to detect or quantitate certain solvents. How can the industry comply with the requirements if an alternative method has not been developed or validated?

USP方法仍有一些缺点，可能无法检出或定量某些溶剂。如果未开发替代方法或未经验证，行业该如何符合这些要求？

Under the General Notices, manufacturers may use alternative methods if those methods are validated. Ultimately, the solvents known to be present in the product should be controlled before it goes to market. The manufacturer should ensure that appropriate controls are in place and demonstrate that the solvent residues are safe for patients.

根据凡例，生产商可以使用经过验证的替代方法。根本的要求是产品中已知存在的溶剂必须在上市前加以控制。生产商应保证有进行适当的控制，并证明残留溶剂对患者来说是安全的。

27. Can USP add a statement to <467> that will provide companies the flexibility to use the USP method or their own validated procedure?

USP是否可以给<467>增加一个声明，让公司在使用USP方法时有一定灵活性，或使用他们自己的经过验证的方法？

The General Notices also allow for the use of other validated methods.

凡例也允许使用其它经过验证的方法。

28. For a drug to be classified as USP grade, must the manufacturer follow the methods in <467>, or can they use an alternate, validated method?

对于划为USP级别的药品，生产商是否必须遵守<467>方法，还是可以使用经过验证的替代方法？

The manufacturer may use an alternative validated method.

生产商可以使用经过验证的替代方法。

好东东，感谢分享

感谢丹丹楼主分享，不仅找到原文还给出译文，辛苦了！

楼主辛苦了，谢谢分享！很有用

多谢提醒！