問：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對于凡例<467>在2008年7月1日之前和之后對所有制藥公司的要求是什么？

 

答：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凡例要求所有產品到2008年7月1日時均符合凡例<467>中的要求，該章的目的是限制患者接受到的溶劑數量。

 

問：Are dermatological products and topical products required to comply with <467>?

皮膚用藥和局部用藥是否要符合<467>？

 

答：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.

在執行問題上USP服從FDA要求，但該章指出了在某些情況下ICH限度可能不適合的情況。該說明并不適用于皮膚用品和局部用藥。

 

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

蛋白質生產商在其生產工藝中并不使用溶劑，關于蛋白質<467>的要求是什么？

答：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.

該章聲明了如果你已經知道不會有溶劑出現，則不需要進行檢驗。但是，謹慎的做法還是要評估你的起始物料和最終成品。

 

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

USP是否可能考慮設定包材中殘留溶劑的標準？

答：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.

本章中未說明包材中殘留溶劑情況。我們知道提取物和浸出物，我們可能會在將來考慮這方面內容。

 

問：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并不適用于已有商業化藥品。請確認USP的要求適用于所有已存在的商業化藥品。

 

答：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認為任何藥品都沒有理由不執行<467>要求，其目的就是為了限制所有藥品中的殘留溶劑。

 

問：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?

聲明<467>僅適用于標示有“USP”或“NF”的藥品是否準確，如果藥用物質或制劑未標示“USP”或“NF”，那<467>是否僅做為指導？

答：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.

不對。如果制劑或原料藥由USP或NF各論所涵蓋，各論標準和凡例均適用，而不管是否標示“USP”或“NF”。凡例的要求適用于所有被USP和NF各論涵蓋的物質和制劑。

 

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

<467>適用于制劑。制劑生產商是否需要測試其活性成份和輔料？

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

<467>給出了選擇，你可以測試所有單個成分或測試最終成品。

 

問：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?

如果我們使用了注射用水來稀釋藥用物質生產制劑，我們是否需要對注射用水檢測殘留溶劑？

答：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產過程中未使用所列出的任何溶劑，<467>不要求你檢測水中的溶劑。

 

問：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>如何應用于動物保健產品？該章將來是否適用于獸藥？如果是，什么時間開始？

答：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>要求適用于獸藥產品。但是，現行限度是基于人用的，對不同的動物其限度可能會有差異。

 

問： 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藥或輔料，但是在原料藥中使用了，或者是一種鹽或鹽酸該如何處理？Q3C并未說明在原料藥生產中使用的原料。

答：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.

目的是保證供給患者的物料不會對他們造成傷害。如果你選擇了第一種方法，該測試會檢查這些物料的溶劑情況。這取決于生產商如何保證產品符合溶劑限度。

 

問： Do we need to confirm that no solvent contamination occurs during packaging or repackaging?

我是否需要確認在包裝或分包裝過程中不會發生溶劑污染？

答：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.

本章只包括了用于生產工藝的溶劑。在包裝過程、運輸過程中的污染應通過良好的操作和運輸規范來管理。

 

Vendor Materials 供應商物料

 

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

我們是否需要對供應商提供的物料進行全面溶劑分析以確認其提供的信息？

答：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.

是否進行檢測由生產商來決定。決定可能依賴于信任和生產商與供應商之間的關系。生產商可以選擇對供應商進行審計。

 

問： 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?

如果輔料生產商聲明其輔料中存在2類溶劑，但低于選項1限度，制劑生產商是否必須測試其溶劑？

答：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環境下，采用良好的科學和穩健的方式來證明溶劑是否存在。如果無法證明，那么就對產品進行檢測。

 

USP Methods 藥典方法

 

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

USP藥典方法的歷史和來源是怎么樣的？USP將來是否會對方法進行變更？

答：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方法的原始來潮是EP中使用的方法。USP在持續修訂，我們會對方法進行變更以改進現有程序，為使用者得到更好的結果，USP可能會根據收到的意見對該章進行修訂。

 

問：Chromatographic question: How does USP propose to deal with peak co-elutions in the current proposed chapter?

色譜問題：在本章節中USP對色譜圖中的共流出峰建議如何處理？

答：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).

有兩個程序，程序A和程序B，它們提供兩個分離程序。對于定量分析，建議用程序A，但如果程序A不適用應該用程序B方法（例如，由于共流出峰）。

 

問： Has the USP method been tested by USP on drug products and excipients?

USP是否對USP方法在制劑和輔料上進行過測試？

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

USP方法在一些制劑和輔料上進行過測試，但不是所有產品和原料藥。

 

問：What happens to peaks in sample that are non—target solvent peaks?

如果在樣品中發現非目標溶劑峰（未知峰）該怎么辦？

答：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.

如果測定指定溶劑時發現異常峰，使用優良科學來鑒別該峰，并與毒理學家一起討論其在該物料中的可接受水平。

 

問： 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"?

在方法開發期間，USP試驗是否使用“鹽”試劑用于頂空分析？如果有，它對增加相應是否有效？ 

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

USP沒有使用鹽進行試驗，因為我們發現程序具有可接受的靈敏度。

 

問： 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%

一個產品僅有3類溶劑，但它們的累積結果超過0.5%，你們對些有何檢測建議？例如，乙醇0.3%； 乙酸乙酯 0.2%； 正丙醇 0.3%。

答：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類溶劑的數量超出0.5%，則不適用干燥失重方法。在這種情況下，要采用氣相色譜法。如果你的工藝驗證信息說明你可以將3類溶劑在成品中的數量降低至0.5%以下或更低，你可以與FDA討論使用LOD的可能性。

 

問：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類溶劑，同時有1類溶劑或2類溶劑，USP的方法是什么？在USP方法中，A B C僅適用于2類溶劑，LOD僅適用于3類溶劑。

答：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.

如果你有一個3類溶劑，另有一個1類或2類溶劑，只要LOD結果不超過0.5%就可以使用LOD證明3類溶劑處于可接受程度。如果超過0.5%，使用氣相色譜來證明其符合性。

 

Harmonization 藥典協調

 

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

USP是否正在協調USP通則一致性？為什么USP不將<467>在實施前與EP保持完全一致呢？

答：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方法間只有一些微小的差異。EP的混合對照品與USP不同。計算不同，USP中，方法A和B是限度測試，方法C是定量測試。除此之外，整章是一致的。

 

問：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>?

行業剛實施了ICH Q3C以符合歐洲法規期望，USP是否可以解釋要符合<467>還有哪些額外的要求嗎？

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

ICH僅適用于新產品，<467>將相同的要求適用于所有被USP各論涵蓋的已有產品。

 

Changes to Methods 改變方法

 

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

USP方法對有些溶劑回收率較低。USP是否建議在計算中加入回收校正因子？

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

在使用方法C時，溶劑標準添加法會對回收差異進行補償。

 

問：Would USP consider separating methods in <467> to a separate chapter?

USP是否考慮將<467>中的方法拆分成一個單獨的章節呢？

答:This has not been discussed internally yet.

內部還沒有對此討論。

 

Alternative Methods 可替代方法

 

問：Can USP adopt the ICH language that allows the use of an appropriately validated method?

USP是否采用ICH思路，允許使用經過適當驗證的方法？

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

凡例允許使用經過適當驗證的方法。

 

問： 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方法仍有一些缺點，可能無法檢出或定量某些溶劑。如果未開發替代方法或未經驗證，行業該如何符合這些要求？

答：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.

根據凡例，生產商可以使用經過驗證的替代方法。根本的要求是產品中已知存在的溶劑必須在上市前加以控制。生產商應保證有進行適當的控制，并證明殘留溶劑對患者來說是安全的。

 

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

USP是否可以給<467>增加一個聲明，讓公司在使用USP方法時有一定靈活性，或使用他們自己的經過驗證的方法？

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

凡例也允許使用其它經過驗證的方法。

 

問： 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?

對于劃為USP級別的藥品，生產商是否必須遵守<467>方法，還是可以使用經過驗證的替代方法？

答：The manufacturer may use an alternative validated method.

生產商可以使用經過驗證的替代方法。