Q7A问答

Section 1A: Background and History

Based on FDA changing of the meaning of "should," does this mean that Q7A will be applied differently in the US than in the EU?

基于FDA改变了“should”的意思，那是否意味着Q7A在美国的应用与欧盟将不一样？

No. The change was made by FDA's attorneys to comply with Good Guidance Practices. There was no change in meaning intended. The change in the definition of "should," was not intended to have any impact on how the guidance is applied either domestically or abroad. Remember, Q7A is a guidance document, but it is not legally binding to either the FDA or the public.

不是。这是FDA的律师为了符合优良指导规范而做的改变。意思上没有变化。它对本指导原则在国内或国外的应用没有任何影响。记住，Q7A是一个指导文件，它对FDA或公众都没有法律的约束。

How do you define a "significant structural element" in an API starting material?

你如何定义API起始物料的“主要结构元素”？

A significant structural fragment is that portion of a molecule that contributes to or is responsible for the molecule's pharmacological activity. The original definition talked about an important element. In Q7A the term "element," was changed to "fragment" to avoid confusion with the chemical understanding of "element."

主要结构片段是分子中贡献或负责分子药理活性的一部分。最初的定义是一个重要的元素。在Q7A中，为了避免与化学上的元素混淆，“元素”被换成“片段”。

How close can you get to the API and still call it an API starting material?

API起始物料和API可以有多近？

The company should document the rationale for the designated API starting material. Where in a given process the designated regulatory API starting material comes will vary with each process. One of the difficulties was trying to cover all possible situations, because that's nearly impossible. The decision to designate an API starting material is based on more than chemical logic. It is a pharmaceutical consideration as well. Remember, there is a patient at the very end of every API process who is suffering from a disease, and the goal to provide something to get rid of his illness in a safe and reliable manner.

公司应该证明指定API起始物料的合理性。在一个特定的工艺过程中，特定的API起始物料在每一步都会变化。难点之一就是试图覆盖所有的可能情况，这几乎是不可能的。指定API起始物料不仅要基于化学逻辑，它也是一个制药学上考虑的问题。记住，每一个API过程的终点都有受疾病折磨的患者，目的是要保证祛除其疾病的药物是安全可靠的。

When you're developing a new chemical process or API process you should be discussing your choice of API starting material with the review division. At some point, you should come in and talk to the reviewers and say, 'this is what I consider to be my API starting material, this is where I consider my API process begins." The reviewers are either going to agree with you or disagree, and they might think that it's further back in the process. But, this is something that you should agree on early with the FDA review divisions, because it's absolutely critical that you have agreement with the Agency as to what you define as your API starting material and where your API process begins.

当你开发一个新的化学工艺或API的工艺，你应该和审评部讨论API起始物料的选择。你应该告诉审评人：“这是我考虑指定的API起始物料，API的合成过程从此处开始。”审评人要么同意，要么反对。但你应当在早期和FDA的审评部达成一致，因为你和行政部门在确定API起始物料的达成一致是绝对必要的。

How early should a company discuss with FDA the company strategy, rationale and what we consider to be an API starting material for filing?

公司应多早和FDA讨论公司的策略和原理？我们要将API起始物料的那些内容整理成档案？

Q7A does not address filing issues. However, you should meet with the review division as early as feasible, to get early input from the reviewers in defining the API starting materials.

Q7A不针对档案问题。但你应尽早和审评部接触，在确定API起始物料上获得较早的回复。　

If you identify an API starting material vendor, does that vendor need to be audited or qualified?

如果确定了API起始物料的供应商，该供应商需要审计或评估吗？

Section 7.1 states "Manufacturers of intermediates and/or APIs should have a system for evaluating the suppliers of critical materials." The API Starting Material would typically be critical to the process, so you should have assurance of the quality of that API Starting Material. For purchased API Starting Materials, this involves establishing the reliability of the supplier's analysis through qualification of the supplier's test results at appropriate intervals, as described in Section 7.3. API manufacturers may choose to audit the manufacturer of the API starting material, but this is not mentioned in nor is it an expectation in Q7A.

7.1节指出“中间体和/或API的生产商应该对关键物料的供应商有一个评估系统。”API起始物料是典型关键物料，因此，对API起始物料的质量应有保证。象7.3所描述的，在适当的间隔评估供应商的测试结果，以此来确定供应商分析的可信度。API生产商可以选择对API起始物料制造商的审计，但在Q7A中未提到或着说Q7A未期望。

Are internal audit reports mentioned in Section 2.4 subject to FDA review during an inspection?

2.4节提到的内部审计报告在检查中要提交给FDA检查吗？

FDA does not generally review internal audits unless just cause exists. FDA has the authority to look at them, under the statute, if they chose to do so. But they generally do not. Such a request is rare, and actually, by policy, has to be approved at very high management levels within the FDA.

除非有原因，FDA一般不检查内审报告。按照法规，FDA有权看该报告。但他们一般不要求。这样的要求很少，实际上，根据政策，还需FDA内的高层批准。　

Concerning the distinction that you made between ICH versus VICH for APIs for veterinary products, which standards do the FDA inspectors use in the plants producing APIs for US vet products? Are there any differences seen during a PAI, and which standards should a plant follow?

考虑到ICH和VICH（兽用药物指南）的区别，FDA检查官在美国兽用药物API上所用标准是哪个？它们之间有哪些不同，工厂按哪个标准执行？

Since the VICH at this point has not adopted Q7A, FDA investigators may use Q7A in inspecting manufacturers of APIs for veterinary drug use. Any issues or deficiency findings will be brought to the attention of their office of compliance, the Center for Veterinary Medicine. They will then apply what is commonly referred to as regulatory discretion with respect to those APIs for vet use. To summarize, since we lack GMP guidance specifically for APIs for vet use, the best guidance investigators could use is Q7A.

因为VICH目前没有采用Q7A，FDA检查官在检查兽药API生产商时可能采用Q7A。任何问题或不足将会引起执行部门－兽药中心的注意。然后他们会将普遍提到的调整标准应用到兽药检查。总之，因为我们没有专门的兽药API的GMP规范，检查官能用的最好的指南就是Q7A。

You said that the WHO has now decided to compare the Q7A document with its 1992 API GMPs., I heard previously that the WHO was adopting Q7A with no mention of this evaluation. Is this just a standard procedural issue at WHO or do they have specific concerns, doubts, problems with Q7A?

你们说WHO正决定将Q7A和1992 API GMPs比较，我以前听说WHO没有考虑该评估，正在采用Q7A。这是WHO的标准程序问题，还是他们对Q7A有特殊的关心、疑问和问题呢？

The World Health Organization (WHO) was an observer/participant during the development of Q7A and agreed that it's more scientifically sound, it's updated, and so forth. The WHO also is a public health agency with a heightened degree of concern for developing countries.

 

The WHO wants to ensure that this guideline is practical for use by regulators in developing countries where resources are very stretched or even non-existent.

WHO在Q7A的发展过程中充当了观察员，他认同Q7A是更科学，最新的文件。WHO还是一个公众健康机构，致力于提高对发展中国家的关注。

WHO希望这个指导原则对资源紧张甚至没有资源的发展中国家的管理者是实际可用的。

To my knowledge, China, Australia, and India have not had official (observer or participant) status in previous ICH guidance processes. By participating in Q7A, do they agree to be bound by it?

据我所知，中国，澳大利亚和印度在以前的ICH发展中没有官方的身份（观察员或参与者）。随着Q7A的多方共享，他们同意受之约束吗？

China's representation was spotty during EWG deliberations; sometimes an industry person and sometimes a government person. The regulators in China would have to specifically agree or adopt this document.

 

India did not have regulator representation. There was a conference in Hyderabad that was the first conference to discuss the document. Even at the point where Q7A drafts were not supposed to be distributed, officials in India had a copy of the Q7A document and it was the subject of the conference. However, the regulators in India have not yet agreed to adopt Q7A.

中国的代表在EWG研讨期间不定；有时候是厂方代表，有时候是政府部门代表。中国的管理者务必明确同意或采用Q7A。

印度没有管理者代表。在海得拉巴召开了一个会议，也是第一次讨论这个文件的会议。即使在Q7A草案不被分发的地方，印度官员也有Q7A的复印件。Q7A也是会议的主题。但是，印度的管理者还没有同意采用Q7A。

As a clarification to this question, will the Indian and Chinese regulators be enforcing Q7A on their domestic manufacturers?

简单的讲，中国和印度的管理者对国内的生产商强制执行Q7A吗？

 

The FDA or their European or Japanese counterparts will definitely be using Q7A in China and India for materials being imported into the ICH regions. Any intermediate or API imported into any of the ICH regions would be expected to comply with Q7A, no matter where it originated. However it is not currently expected that Indian or Chinese regulators will be enforcing Q7A on APIs intended for consumption in India or China.

对中国和印度进口到ICH地区的原料，FDA、欧洲或日本明确采用Q7A。任何中间体或API进口到ICH 的任何地区，不论产自何地，均希望符合Q7A。尽管目前不能期望印度或中国的管理者对国内使用的API强制执行Q7A。

Since most APIs are manufactured outside the US (80 percent or so), and the FDA's moving to the MRA for inspections, what training is being given to government inspectors outside the US, and what about FDA foreign inspection teams?

因为大多数API（大约80％左右）在美国以外生产，并且FDA正向检查的MRA靠拢，美国以外的政府检察官受到什么培训？FDA的国外检察官又怎么样？

 

We intend to have the same training in Europe as we have outlined here. Nearly all of the associations, including the European inspectors and the European Commission, who are supporting or co-sponsoring this event, are participating. It will be a big move forward for European inspectors and for some parts of the industry, in understanding how GMPs are applied to this aspect of the industry.

我们打算在欧洲举办和这里略述的同样的培训。几乎所有的协会，包括欧洲检察官，欧洲委员会正支持或共同发起这件事，并参与其中。这将会大大提高欧洲检察官和部分工厂在GMP如何应用到相关工业的理解。

Just confirming, the definition of "should" could vary from country to country in the final version, for instance the US FDA versus the EU version. What would you recommend for companies that are international/global? Another person also wanted some practical, down-to-earth words around what "should" should mean. In other words, in here, the person asks, is "should" in ICH similar to "must," is "should" in FDA similar to "good to do?" In other words, I think there's a little confusion around "should."

想确认，在最后版本中“should”的定义可能在国与国之间改变，例如，FDA版本和欧盟版本之间。对跨国公司你们有何建议？另有一人还希望对“should”的含义用实际的词语解释。换言之，这个人问，是否ICH中的“should”类似“应该”，FDA中的“should”类似“最好这样做”？我认为关于“should”这里有一些含糊。

At least in the United States, the "should" language in any guidance is a safe harbor. If you follow it, you should be found in GMP compliance. If you do something different than what is mentioned in Q7A, then you should have information to demonstrate to an investigator that what you're doing is reasonable. If you're doing what the guidance says, the presumption is you're in compliance and you're doing something reasonable.

至少在美国，任何指导原则中的”should”是一个安全的海港。如果你按他做，你应该被发现服从GMP。如果你做了一些和Q7A不一样的事，你应该有信息给调查者，你所做的是合理的。如果你在做指导原则说的，可以推测你服从它，你在做的合情合理。

The intent of the expert working group was that the definition would be the same in different parts of the world. Both the EU version and the FDA version talk about alternative methods and identify recommendations. The language is quite clear in both versions. Q7A identifies GMP expectations or recommendations for API manufacturing. When we talk about GMP requirements, that's usually referring to a regulation, which is legally binding. So, if something is spelled out in the GMP regulation, 21 CFR 211, that's a requirement, that's legally binding.

专家工作组的意图是这个含义在不同的地方是一样的。欧盟和FDA的版本都提到替换的方法并明确了意见。两个版本的语言非常清楚。当我们谈及GMP的要求，那通常是指有法律约束力的法规。因此，如果说的是GMP法规，21CFR211，那是必需的，有法律效应的。

Q7A's expert work group provided a lot of examples to help identify what we were looking for. It was not meant to be the only way. If we said, "should," our intent was that it's something that should be done, but you could do it in a different way if there was another option and you would be able to justify it. The guidance has a lot of flexibility in it to recognize the real world.

Q7A的专家工作组提供了许多例子来帮助鉴别我们期望的是什么。他不代表唯一的方法。如果我们说“should”，我们的意图是必须做，但你可能通过别的方法做，只要有另外的选择，并且你能证明他是适当的。这个指导原则认识现实世界有许多的弹性。

What are the main differences between the FDA's March 1998 API draft and Q7A?

FDA 1998年3月的API草案和Q7A的主要区别是什么？

There are several major differences between the two documents. FDA's March '98 draft guidance covered chemical synthesis manufacturing processes and the later isolation and purification steps of APIs produced by biotech and fermentation processes. The scope of Q7A is broader.

这两个文件有几个主要的区别。FDA1998年3月的指导原则涵盖了化学合成过程和生物、发酵过程的后期分离和纯化。Q7A的范围更广。

In addition, Q7A has a chapter on agents, brokers, distributors, and all those other organizations. There's also a chapter in Q7A related to biotech and fermentation. Q7A only covers APIs intended for human drug products not veterinary drug applications. There were other issues, such as validation issues, that were either removed or clarified. There were purchasing requirements. There were a number of issues that, quite frankly, made the Q7 negotiation worthwhile for both the regulators and industry.

另外，Q7A有一章是关于代理商，经纪人，经销商等所有其它机构。还有一章关于生物和发酵。Q7A仅包含人用药的API，不包括兽药。还有其他问题，比如验证的问题，或者被删掉，或者被澄清。还有采购要求。坦白的讲，有一系列的问题，值得管理者和厂方商讨。

The new ICH guideline is a major step forward in ensuring the quality of APIs. How does the FDA plan to ensure that they are applied and interpreted consistently by field investigators, and who, when, and how it will be applied to overseas suppliers? Additionally, it is really encouraging to see the support and participation of FDA in this important series of workshops. How does the Agency plan to carry through this commitment within its own organization, for example, training of field staff, key review personnel in the application of Q7A to API manufacturing?

新的ICH指导原则将保证API质量向前迈了一大步。FDA如何保证领域调查者一贯采用和解释他们？谁，什么时间，怎样应用于海外供应商？另外，看见FDA在这系列重要工作里的支持和参与，的确令人鼓舞。行政部门如何在组织内部计划执行委托事项，例如，Q7A现场检查人员和主要审评人员的培训？

With Q7A in mind, FDA is planning to update its compliance program for APIs, 7356.002F. However, changes in FDA's inspectional or enforcement policies with respect to APIs are not anticipated.

 

FDA personnel have attended previous sessions of these agency/industry workshops. In addition, FDA held a one-week session training course for 40 or more FDA investigators in December 2001 and is planning a second course in May of 2003. The training includes interpretation of Q7A and how to conduct API inspections.

由于Q7A，FDA正计划更新API的检查程序，7356.002F。但是，FDA有关API的检查和执行政策没打算变。

FDA官员已经参加了以前的行业会议。另外，FDA在2001年12月举办了40多FDA调查员参加的，为期一周的培训。正计划在2003年5月举办第二次。培训包括对Q7A的解释及如何执行API检查。

 

 

FDA plans to revise its September 1991 guide to inspection about pharmaceutical chemicals and why the need to revise? Does Q7A not replace the 1991 guide?

FDA计划修订1991年的化学药物制品的检查指导，为什么需要修订？Q7A不取代1991年的指导吗？

Since FDA's publication of the Notice of Availability for Q7A, there's been some talk of revising the September 1991 BPC inspection guide. However, no decision has been made to proceed with this revision since some in the FDA still question the rationale for doing this. .

因为FDA发布了Q7A可用的通知，有些关于修订1991年9月BPC检查指导的谈论。但是，没有决定继续的修订，因为FDA部分人仍在怀疑这样做的合理性。

What does Q7A mean?

QA7的意思是什么？

 

Q stands for quality, which is one of the four sections within ICH consultation, 7 is the seventh topic considered under Quality, it's the first GMP topic, but it's the seventh topic considered, and A indicates the first document under the topic of GMP.

Q代表质量，也是ICH讨论的四方面之一，7是质量讨论的第7个主题，它是GMP的第一个主题，但是考虑过的第七个主题，A表示它是GMP主题的第一个文件。

USP requires water used in the manufacture of parenterals to be water for injection, WFI. Does Q7A conflict with this?

美国要求用于生产注射用药物的水是注射用水，Q7A和这矛盾吗？

 

No. If you go back to the scope of Q7A, it clearly states that the sterilization and aseptic processing of sterile APIs are not covered by this guidance

不。如果你回头看Q7A的这方面内容，它明确说明不包括无菌原料药的灭菌和无菌过程。

Now that we have Quality System Inspections and Q7A, can you describe what you envision as a typical FDA inspection of an API plant?

 

既然我们有质量体系检查和Q7A，作为一个典型的FDA 的API工厂的检察官，你能描述你的展望吗？

The concepts embodied in Q7A grew from concepts used for years. It will not substantially change FDA's audits and inspections of API manufacturers. It does establish clearer guidelines to assist all parties.

Q7A的具体概念来自使用多年的概念。它将不实质上改变FDA审计和检查API生产商。它将建立更清楚的指导原则来帮助所有单位部门。

Any background, history on why the accountability for lab records was not included in Q7A? For example, numbered pages in a lab bound notebook or sequential lab sheets that cannot be duplicated.

 Q7A里没有实验室记录的责任规定，对此有何背景或历史？例如，实验室的装订笔记本有页码编号或连续的实验室记录不能被复制。

The accountability of lab records stems from the Barr decision and the falsification of laboratory data. Q7A is an international document; it is not just a U.S. document. It provides good, sound guidance on documentation practices, but it does not specify sequential numbered sheets or the level of documentation that has come to be used in the U.S. for lab records since the Barr decision. Q7A allows flexibility in meeting documentation practices.

实验室记录的责任源于Barr决定和试验记录的伪造。Q7A是一个国际性的文件；它不仅仅是美国的文件。它在文件规范上提供好的，合理的指导，但Barr决定以后，它不详细说明连续编号的记录或美国的实验室记录的水平。Q7A在会议文件规范上允许灵活性。

If the raw material is commercially available, and if this raw material is the API only after purification, so we're basically one step removed, does the raw material manufacturer fall under Q7A?

如果原料是市场可购买的，并且如果该原料只是纯化后即是API，我们主要进行一步过程，那原料制造商归入Q7A吗？

It sounds like you're bringing an API into your facility and just further purifying it. Does Q7A apply? Yes, because, basically, you're bringing in the active ingredient in an unpurified form and subjecting it to the purification. So, the manufacturer of the crude API would probably fall under Q7A.

听起来你们买API到你们工厂，只是进行了进一步的纯化。要采用Q7A吗？要。因为，你们基本上购买了未纯化的活性物质将它纯化。因此，API粗品的生产商或许将归入Q7A。