等待ICH Q3D（步骤4）：修订和国家法规的执行情况

清歌一曲月如霜

Waiting for ICH Q3D (Step 4): Revision and Implementation of national Regulation


对于在过去3年，金属杂质的检测一直是ICH的有关协调工作的主题。该委员会是负责创建的制药和原料药行业所使用的准则 - 完成时 - 在这三个经济区欧洲，美国和日本。最终指引公布通过4个步骤;在第五和最后一步，该文件是合并（即“领养”）到相应的指导方针基金的三个合作伙伴。
截至2011年底，Q3D ICH指导原则的草案已作为它首先对含有金属杂质的医药产品和API测试要求的预步骤2中的文档。在2013年7月结束，该草案达成共识指引“指引元素杂质”（步骤2b文件）被释放，并开放供评论6个月之久。在考虑所有收到的意见，内容及其发布相应的调整应在2014年6月，那是至少在meetingwhich发生了从5月31日至ICH的议程提出了ICH专家工作组的工作计划6月5日在明尼阿波利斯。它指出：“非物质文化遗产Q3D指引第4步，预计在2014年6月”。如果这个期限不能得到尊重，采纳落实指引今年预计只会在秋季。
在ICH Q3D指南（第4步）的验收和出版的延迟也对在这三个地区非物质文化遗产的一些重要国家的法规修订的后果。
EMA的2008年“关于规范限值金属催化剂或金属试剂残留指引”包含的杂质，通过14金属在不同剂型的测试，以及分类为这些金属的规定。本指南的范围包括新开发的，以及已经批准的药品。对于后者，有5年的过渡期已经设置的止2013年9月1日，由于在这个时候，ICH的Q3D草案达成共识指引的公布日期无法确定，EMA的指南的有效期为“遗产“药品被暂停。因此，它仍然适用 - 直到出版ICH Q3D（步骤4） - 只对医药产品的事先授权。
5.20章“金属催化剂或金属试剂残留”欧洲药典包括EMA的指南的完整的需求，并在2034专着引用因为这个交叉引用在一般的专着，第一章5.20变为绑定。此外，作为专着2034的实施日期为2014年4月1日，第一章5.20（如因而EMA的指南的规定）将被应用自该日起。欧洲药典委员会找到了解决办法摆脱这种困境，并暂停欧洲药典的出版。补充8.1其中包含了专着2034与交叉参考第二章5.20。这种方法已经被称义了EDQM的发表于2013年8月29日（也见我们的新闻日期为2013年9月26日）的新闻稿。
美国药典通则<232>元素杂质 - 限制与<233>元素杂质 - 程序发表在经修订的形式在2014年3月1日在药典论坛40（2）用90天的评议期。美国药典发布了一个详细的时间表章节的每一步修改<232>和<233>。据“美国药典修订和实施计划”，这两章应适用于药典专着为2015年12月1日，这个日期也对应于“通用声明部分5.60.30”，这将实现章节的有效期。一个Q＆A文档提供了关于修改程序的更多细节。
现在的情况是不理想的医药行业，因为它目前还不清楚不同的预期最终Q3D ICH指导原则是去年公布的草案（步骤2）。此外，长期的准备（在技术和资源投资）是困难的。特别是，仍然存在不确定性对于大容量注射并列入已上市销售药品。另一个问题是在非物质文化遗产和非ICH区域，当最后的ICH Q3D将结合将会出现采用了不同的标准。应该如何全球制药业以及监管及发牌当局管理的？回答这个问题，目前仍处于打开状态。

For over the past 3 years, the testing of metallic impurities has been the subject of ICH's efforts on harmonisation. The committee is responsible for the creation of guidelines for the pharmaceutical and APIs industry to be used - when finalised - in the three economic zones Europe, USA and Japan. The publication of a final guideline goes through a 4-step process; in the fifth and last step, the document is incorporated (i.e. "adopted") into the respective guidelines fund by the three partners.
At the end of 2011, the draft of a ICH Q3D guideline was published as a pre-step 2 document which first contained the requirements on the testing of metallic impurities in medicinal products and APIs. At the end of July 2013, the Draft Consensus Guideline "Guideline for Elemental Impurities" (step 2b document) was released and open for comments 6 months long. After considering all the comments received, the corresponding adaptation of the content and its publication should take place in June 2014. That was at least the working plan presented by the ICH Expert Working Group in the agenda of the ICH meetingwhich took place from 31 May till 5 June in Minneapolis. It stated: "Step 4 of the ICH Q3D Guideline is expected in June 2014". If this deadline can't be respected, the adoption of the finalised guideline would be expected only in autumn this year.
The delay in the acceptation and publication of the ICH Q3D guideline (step 4) also has consequences on the revision of some important national regulations in the three ICH regions.
EMA's "Guideline on the Specification Limits for Residues of Metal Catalysts or Metal Reagents" from 2008 contains provisions about the testing of impurities through 14 metals in different dosage forms as well as a classification for those metals. The scope of this guideline includes newly developed as well as already authorised medicinal products. For the latter, a 5-year transition period had been set which ended on 1st September 2013. As at this time, the publication date of the ICH Q3D Draft Consensus Guideline couldn't be determined, the validity period of EMA's guideline for "legacy" medicinal products was suspended. It thus still applies - until the publication of the ICH Q3D (step 4) - only to medicinal products prior authorisation.
Chapter 5.20 "Metal Catalysts or Metal Reagents Residues" of the European Pharmacopeia includes the complete requirements of EMA's guideline and is referenced in the monograph 2034. Because of this cross-reference in a general monograph, Chapter 5.20 becomes binding. Moreover, as the implementation date of the monograph 2034 was the 1st of April 2014, Chapter 5.20 (as thus the provisions of EMA's guideline) would have been applying since that date. The European Pharmacopeia Commission found the solution out of this dilemma and suspended the publication of Ph. Eur. Supplement 8.1 which contains the monograph 2034 with the cross-reference to Chapter 5.20. This approach has been justified in a press release of the EDQM published on 29 August 2013 (see also our News dated 26 September 2013).
USP's General Chapters <232> Elemental Impurities - Limits and <233> Elemental Impurities - Procedures were published in their revised form on 1st March 2014 in the Pharmacopoeial Forum 40(2) with 90-day comment period. The USP released a detailed schedule for each revision step of the Chapters <232> and <233>. According to the "USP Revision and Implementation Plan", both chapters should apply to the pharmacopoeial monographs as of 1 December 2015. That date also corresponds to the validity date of the "General Notices section 5.60.30" which will implement the chapters. A Q&A document provides more details about the revision procedure.
The current situation is unsatisfactory for the pharmaceutical industry as it is not clear how different the expected final ICH Q3D guideline is from last year's published draft (step 2). Furthermore, long-term preparation (investments in technology and resources) is difficult. In particular, uncertainties remain with regard to large volume parenterals and the inclusion of already marketed medicinal products. Another issue concerns the different standards used in ICH and non-ICH regions which will emerge when the final ICH Q3D will be binding. How should global pharmaceutical industry as well as supervisory and licensing authorities manage that? The answer to that question is currently still open.

syhorchid

经典的洋泾浜：The answer to that question is currently still open.回答这个问题，目前仍处于打开状态。

hongwei2000

USP好像比Q3D更早就提出了