ICH Q7专家问答（12）原料药和中间体的包装和贴标
Section 9: Packaging and IdentificationLabeling of APIs and Intermediates
第9 章原料药和中间体的包装和贴标
1. Q. What's the minimum amount ofinformation required for the labels on containers of starting materials whenthey are received prior to API manufacturing?
问：原料药生产中，对起始物料容器标签有什么最低要求（需要些什么信息）吗？
Section 7.2, "Upon receipt and beforeacceptance, each container or grouping of containers of material should beexamined visually for correct labeling, including correlation between the nameused by the supplier and the in-house name, if they are different." That'sessentially all that has to be done. That's the only reference in here tomaterial that has to be on the label for incoming starting materials. This isan answer that pertains to what is required with regard to GMPs.
答：第7.2 章节说，“在收到物料而尚未验收，应当目测检查物料每个或每组包装容器的标签是否正确，包括如果供应商所用名称与内部使用名称不一致，应当检查其相互关系。”所有这些工作必须完成是很重要的。这也是对起始物料标签上的内容要求的唯一参考规定。这也是从GMP角度出发的相关要求的答案。
Just to clarify one thing, Section 6 does notdescribe what needs to be on the labels of materials that are coming into you.It does describe what kind of records you need to keep about those materials.
澄清一件事，第6 章节没有描述物料标签上需要有什么信息，这取决于你自己。它只是描述了你必须对这些物料记录些什么。
2. Q. Does the FDA have any objection tostorage and shipment of APIs in polyethylene lined fiber drums?
问：FDA 有没有反对用聚乙烯纤维桶存贮和运输原料药？
I'm not aware of any. I think it's up to themanufacturer to demonstrate that the packaging is suitable for the product andthat they have conducted stability studies to support this container.
答：我不了解。我想这取决于制造商来证明包装适合该产品，并由制造商自己实施稳定性研究来支持这样的包装。
3. Q. 9.2 states that containers shouldnot be additive beyond the specified limits. This imputes the need to evaluatepackaging for interaction with the API. On the other hand, that additive ofpackaging implied is not a concern so long as the API is not altered beyond itsspecification. Please clarify how an API manufacturer might justify not evaluationproduct/packaging interactions.
问：第9.2 章节规定包装材料的加成性不能超过指定的标准。这是由于考虑到包材和原料药之间的相互作用。另一方面，只要原料药在其规格标准之外也不会改变，包材的加成性就不需要考虑了。请阐述原料药制造商如何评估产品和包材之间的相互作用？
That's part of why your stability programputs material up in the same packaging material that it's typically shipped andstored in.
答：这就是你的稳定性研究必须使用和你的贮运和保存相同包材的原因。
4. Q. What kind of ID test is acceptablefor packaging materials, such as polyethylene bags, lined drums? Is theshipping document of packaged material used in lieu of a C-of-A?
问：什么样的包材的鉴定测试可以被接受？例如聚乙烯塑料袋，聚乙烯塑料桶？包材的运输文件是不是必须依据其分析合格证？
If it contains all that information normallyfound on a Certificate of Analysis, then that's probably adequate. If it's justsomething that's saying, we're shipping you a polyethylene bag, or it just saysyou're receiving a truckload of polyethylene bags, it's probably not. In fact,the Certificate of Analysis in reference to the specification and meeting thoserequirements may be adequate.
答：如果在分析合格证上包括了所有信息，那么这可能就足够了。如果仅仅是说，我们用一个聚乙烯塑料袋给你运产品或是说你将收到一车聚乙烯塑料袋，那么这就不可以了。事实上，分析合格证上参引规格标准，并达到那些要求就足够了。
If you look at Section 7.2, the first paragraph, there's a sentence therethat says, "Materials should be held under quarantine until they have beensampled, examined, or tested, as appropriate, and released for use." Thebags may be an example of material that
you just mightsimply examine it before use and determine that it's okay.
如果你看一下第7.2 章节，有一句是，“物料必须在合适的取样、测试或检测，放行之前必须隔离存贮。”袋子可能是你没有办法测试的一种物料；你就只需要在使用前检查一下来决定其是否合格。
At least fiber drums, you probably aren' you're probably examining your drums. Q7A does not specify what kindof ID test you could do on polyethylene bags, but IR is often used.
至少对于纤维桶来说，你不需要测试，你可能只是检查一下你的桶子。Q7A 指南没有制定你对于聚乙烯塑料桶需要做什么鉴定测试，但是一般使用的是红外。
5. Q. A packaging/transport of API outside the facility, can boxes containing API be sealed withtamper-evident tape, or must the inner bottle or container be sealed?
问：包装/标签的问题：把原料药运到室外，装有原料药的盒子必须用胶带封闭吗？或者必须用内装瓶或是容器封口？
The guidance is basically asking that you puta seal so that you can tell whether or not someone opened it and did anythingto the material under normal conditions. The answer, in my opinion, is that'sfine. If you use unique tape and can tell if it had been opened, you've certainlysatisfied the intent of the guidance.
答：指南基本上只是要求你必须有封口，这样你就可以判断是否有人打开过它和对它做过什么。答案是，在我看来，这就可以了。如果你使用特殊的胶带，并可以判断是否被打开过，那么你就满足了指南的要求。
Any measure you can take to ensure theintegrity of that material while it's in transport is most beneficial to youand to your clients. There are many ways of doing that, not only of using sealsthat have specific designs, which may be hard but may not be impossible toimitate. Some companies use some kind of markings that, under normal lightingare not visible, and are only visible under UV lighting or special lightingconditions to mark containers. The persons receiving this material know that ifthey look for those markings in specific locations with special lighting, ifit's missing, that's usually an indicator that that's not their originalmaterial.
为了确保你的物料在运输中的完整性，你可以采取的措施必须最大可能的有利于你和你的客户。有很多方法来做这件事，不单单是使用指定设计的封条，这可能很困难但是并非不可以模仿造假。一些公司使用一些印记，在可见光下不可见，只有在紫外光下或是指定的光线条件下可见，来标记容器。物料接收者知道如果他们在指定的位置使用特殊的光线来检查，如果标记不存在，那么这就是一个信号，表明这已经不是他们原来的物料了。
Don't forget that the Agency is veryconcerned about the potential for counterfeit APIs. So, obviously, if you makeit difficult for somebody to hide a change in the material, you make it muchmore difficult to put something else into your box or your container.
不要忘记药政当局非常关心原料药造假的问题。所以，很明显，如果你让别人很难隐藏物料的改变，你将使往你的盒子或是容器中添加其他东西变得更加困难。
6. Q. Section 11, what do you test forlabeling?
问：第11 章节。你对标签作什么测试？
Section 11 states that "Allspecifications, sampling plans, test procedures should be scientifically sound,appropriate to ensure that . . . and labels conform to established standards ofquality and/or purity." So, whatever you are determining is appropriate,to determine that it's of suitable quality should be in the specifications.Certainly, some that come to mind, depending upon what they are, pre-printed -again, testing and inspection, these are synonymous - it doesn't have to be achemical test, but certainly the label copy, the color of the print, if it's aself-adhesive, that there's adhesive on it. Some of these things which arefairly obvious, but in essence, all the things that you require of yoursupplier to make sure that they get it before you're going to pay them are thethings that you're going to want on your specifications and your acceptancecriteria.
答：第11 章节说“所有的规格标准、取样计划、测试规程必须科学有据，合适于确保…和标签满足已建立的质量标准和纯度。” 所以，无论你决定什么是合适的，都必须决定在规格标准中存在和其相关的合适的质量的规定。当然，必须记住，这取决于他们是什么，是预先打印的（还是其他的什么）。还有就是测试和检查，这是同义词。不用是化学测试，但是当然要有标签的复印件，打印的颜色规定，如果是可以自粘的，上面必须有黏胶剂等等。有些事情很明显，但是是必需的，所有这些事情你必须提前要求你的供应商，确保他们在你向他们付款前知道你的规格标准和要求。
7. Q. With regard to packagingmaterials, Q7A does not make a distinction between inner and outer containers.If you have written procedures for the inner containers that actually come intocontact with the API, do you also need written procedures for the outercontainers, such as fiberboard boxes that do not actually contact the API? An exampleof the inner container might be glass jar or vial.
问：关于包材，Q7A 指南没有明显的区分外包材和内包材。如果你有书面的规程来规定哪些和原料药直接接触的内包材，是不是也必须有书面的规程来规定外包材，例如那些事实上不接触原料药的纤维板盒子？内包材的例子是玻璃瓶或是安培瓶。
If your company is paying good money forsomething, you probably want some sort of acceptance criteria to make sure itis what you want. Packaging material is defined in Q7A as, "materialintended to protect and Intermediate of API during storage and transport."If the material is not being used for that intent, if it is simply being usedto ease the transport and, in fact, you're saying the glass bottle is the thingthat is really protecting the API, then under Q7A, that's not covered andthat's not considered a packaging material. Again, some of these are commonsense
答：如果你的公司为此付了很多钱，你可能希望有一些可以接受的规格标准来确保你所需要的东西质量。Q7A 指南定义的包材概念是，“在保存和运输中，用于保护和中转原料的物质。”如果物料不是这个用途，如果它仅仅用于运输上的方便，（事实上你说的玻璃瓶是保护你的原料药的），那么Q7A 指南中就没有要求也不认为其为包材。另外，这些有些是常识问题。
Section 11.1, under lab controls, tells usthat, "all specifications, sampling plans, test procedures should bescientifically sound and appropriate to ensure." To packaging materials, "thetesting or examination that would be appropriate to ensure" that an outerpackage conforms to what you need will probably be a lot simpler.
第11.1 章节，实验室控制条款中，告诉我们，“所有的规格标准，取样计划，测试规程必须科学有据且有合适的保证。”对于包材来说，最简单的方法是使用那些“测试或是检查可以合适地确保”外包材和你需要的标准一致。
8. Q. Can you perform acceleratedstability studies on an API to extend the retest date if running roomtemperature studies concurrently? And, the statement is made, "Drug productfirms do this routinely, to place a two-year expiry date on the product."
问：如果室温研究同时进行，可不可以通过进行加速稳定性研究来延伸原料药的复检期？然后，得出这样的结论。“制剂公司日常这样操作，产品的复检期为两年。”
Going back to one of those slides, way backin the first session, if Q7A does not prohibit something, it's probably okay todo it. Q7A does not prohibit running accelerated studies. It does notrecommend, or it does not require, it is not an expectation that you'd runthem. And, if the person feels that running those accelerated helps meet therequirement to provide, in terms of retest dates that should be based onevaluation of data derived from stability studies, and that's part of theirstability study, to help them get the data on which they could make a soundjudgment, then it may be appropriate to do it. There's nothing in Q7A thatwould prohibit it or would say that the data generated from that was notscientifically sound and could contribute to the decision.
答：回到前面我们提到的，如果Q7A 指南没有禁止做什么事情，那么就可以做。Q7A 指南没有禁止你进行加速研究。指南本身没有推荐，没有要求，也不期望你做。如果你认为做哪些加速试验可以帮助达到要求，提供复检期所需的稳定性研究数据，而且这也是你的稳定性研究的一部分，帮助你得到一个正确的判断，那么你可以做这些加速试验。Q7A 指南不会禁止也不会说其产生的数据不科学，不能用于判断等等。
But just remember that Part 211 says that anytentative expiration date assigned to a drug product based on accelerated datamust always be verified by shelf-life studies. While this applies for drugproducts, it may be applicable to APIs as well.
但是必须记住在211 法规中任何根据加速实验数据的暂时的有效期数据必须经过货架保存研究。这对于制剂药品适用，当然也适用于原料药。
9. Q. Is that in the GMPs?
问：GMP 中有这样的规定？
211.166(5)b says, "Accelerated studiescombined with basic stability information on the
components, drug products, and containerclosure system, may be used to support tentative expiration date, provided fullshelf-life studies are not available and are being conducted. Where data fromaccelerated studies are used to project a tentative expiration date that is beyonda date supported by actual shelf-life studies, there must be stability studiesconducted, including drug product testing at appropriate intervals, until thetentative expiration is verified or the appropriate expiration datedetermined."
答：法规211.166(5)b 规定，“加速研究结合基本的稳定性信息、组分信息、药物信息、包装密闭系统信息，可以用于在没有办法提供完全的货架稳定性研究或是该稳定性研究正在进行时，支持暂时的有效期数据。当加速研究的数据用于推算暂时的有效期数据，该数据没有真实的货架稳定性支持时，就必须有稳定性研究，包括一定的药物测试间隔，直到暂时的有效期被证实或是合适的有效期数据被建立。”
Again, that is talking about expiry dating.The question related to retests, and the question again, the person talkingabout retest was not saying this would be the only data, and they would nothave any real shelf-life data. This would be in addition to, and help themjustify.
再次重申，这只是对有效期而言的。问题是和复检期相关，人们说到复检期不是说这是唯一的数据，不是说他们没有任何真实的货架数据。应该有这样的数据来做为辅助，支持数据的合理性的。
Q7A tried to address specifically the GoodManufacturing Practices. Typically, the stability development studies are afunction of the filing requirements, which are addressed in Q1, which does talkspecifically about how stability development is done. Since Q7A is a Good ManufacturingPractice document, it is saying you've already done the things you need to do forfiling, and this is what you would do on an ongoing basis. So, the stabilitythat's addressed in the laboratory section of Q7A needs to be the ongoing afterfiling.
Q7A 指南试图明确地说明良好的制造规范。一般来说，文件申报都是需要稳定性开发研究的，在Q1 指南中有详细的解释怎么进行稳定性开发研究。因为Q7A 指南是良好的制造规范的实践性文件，就是说你已经为文件申报做了一些事情，这些就是你不断前进的基础。所以，Q7A 指南实验室部分解释，稳定性试验就需要你在文件申报后不断进行的研究。
Your stability program could be dealt with inyour filings up front. In other words, if you've got a commercial product thatyou've filed for, you could get agreement from the reviewing branch up front toa special approach to a stability program, and that should become then a mootpoint from a GMP perspective. That's your option that you can work ondeveloping.
你的稳定性试验程序可以在你的文档归档最前面进行。也就是说，如果你要申报一个市场化的产品，你可以预先从审核小组那里达成共识，获得审核稳定性程序的特殊方式。这样这就成了GMP检查中的未决关键点。这就是你可以的稳定性开发研究的选择。
10. Q. Would you elaborate on your lastslide in packaging stating if a container seal breach occurs or a label ismissing recipient will be alerted to the possibility of contents being altered?The first question is who should do the alerting? A missing label can occur intransport and originator may not even know it.
问：请您阐明一下您上张幻灯片关于包装的陈述，“ 如果容器的封口发生了破损，或者标签丢失，接收者将警惕可能里面的产品已经被改变”。第一个问题是谁负责报警？标签可能是在运输途中丢失的，操作者可能甚至没有意识到丢失。
You should have a unique seal that isobviously missing or broken. Nobody has to physically alert the party, theyjust have to look at the container upon receipt and see that something is wrong.That was the intention of that expectation in the guidance.
答：你必须有一个独特的封口，它明显的丢失或是损坏了。没有人必须去报警，他们只需要在接收的时候检查容器，看有什么错误。这就是对指南解释的目的。
11. Q. For packaging and labelingissues, is material transferred to and from contract manufacturers stillconsidered control of the API parent firm?
问：对于包装和标签的问题，物料在协议制造商之间运输被认为是在原料药厂的控制范围吗？
The expectation for you, as the primarymanufacturer, is the same whether you are making it or your contractmanufacturer is making it. Transfer to and from each location becomes the ultimateresponsibility of the primary firm.
答：对你的期望，就和主要制造商一样，无论是你制造还是你的协议制造商生产。在每个地址间的运输都是主要制造商的基本责任。
12. Q. If a validated automatedwarehouse is used for inventory control of materials and/or product, does thistype of system provide adequate control or access to labeling material or areadditional controls for separate storage areas required for printed materials?
问：如果一个验证过的自动仓库被用于控制物料/产品的存货管理，是不是这样的系统对控制或接收标签物料也足够了？或者对于印刷的物料需要独立的存贮区域？
Yes, it can, but it really does depend uponhow you operate and what you're doing.
答：对，它可以了。但是实际上这取决于你怎么操作以及你将做什么.
13. Q. I've got a question regarding thelabeling that I discussed for materials that are subdivided in Section 8.1. Forany material with hazardous specification, is Q7A in line with OSHA or othersafety requirements for labeling or how does Q7A deal with the safety?
问：我有一个问题是关于第8.1 章节细分物料的标签的。对于任何有毒有害物料，Q7A 指南的要求符合OSHA 或是对标签有其他要求，Q7A 指南怎么对待安全问题？
Q7A specifically does not address safetyissues. Q7A addresses CGMP issues related to maintaining the identity of thematerial and keeping the information that you need for further use of thematerial. Safety controls are the responsibility of the manufacturer andgoverned by national laws.
答：Q7A 指南没有特别说明安全问题。指南只是解释了关于维护确认物料现行GMP 要求，以及你必须保存的使用物料的信息。安全控制是由制造商和当地政府法律控制监管的。
14. Q. This has to do with inspection ofpackaging and labeling facilities for APIs. Is this intended to be the samelevel as for drug product line clearance? Can production personnel carry outthis check, and does the requirement apply to API only or also to isolatedintermediates?
问：必须检查原料药包装和标签设施。是不是为了保证和制剂产品生产线的清洁在相同水平？生产操作人员可不可以实施这样的检查，是不是仅仅适用于原料药或者还适用于可分离的中间体？
The intent of the EWG here was to assure thatthe procedures exist to prevent the mislabeling or mix-up in the labeling. Anyorganizational unit can actually conduct it. You have that flexibility.
答：专家工作组的目的是保证有规程来防止错误贴标和标签的混合。任何部门都可以负责实际操作，你有灵活性。
15. Q. Why do you have to take allmarkings off a container that you might reuse?
问：为什么你必须将容器（你有可能是需要重新使用这些容器）上的所有标示都拿下来？
The problem is that you may have planned toreuse it in the exact same operation, but then all of a sudden, you don'tconsume it, you put it off to the side, and somebody goes and picks it up andbrings it into a different operation. That's why you need to remove alllabeling and old labeling from every container before you change over.
答：问题是你可能有计划在相同的操作中再次使用它，但是有可能突然，你没有用它，你把它扔在一边，其他人过去把它捡起来带到其它地方去了。这就是你必须在你重新使用前将所有标签从容器上移除。
16. Q. Labeling requirements in Section9 seem excessively complicated where one batch of API requires label performedevery few months. Can this system be simplified, i.e., fill in the blanklabels? So they must be talking about product for clinicals.
问：第9 章节对于标签的要求对于几个月才有一个批号的原料药需要标签的情况，好像过于复杂。可不可以将这个系统简化，例如，直接在空白标签上填写？
Section 9 does not require any complicatedreviews or procedures. It merely establishes the need for procedures.
答：第9部分没有要求任何复杂的审核或是规程，它仅仅是建立了规程的要求。
17. Q. API labeling. For APIsmanufactured, pre-validation for clinical products, is it required to include astatement limited for investigational use like what's required for clinicalproducts?
问：关于原料药的标签的问题。对于原料药制造而言，那些临床用产品的预先验证，必须将仅限于临床研究使用的限制在标签上申明吗？
Section 19.2 states "labeling for APIsintended for use in clinical trials should be appropriately controlled andshould identify the material as being for investigational use."
答：第19.2 部分说，“用于临床研究的原料药的标签必须合适的控制，并且标明物料将用于临床研究。”
18. Q. Someone stated that the qualityunit must inspect packaging materials. Can that be delegated?
问：有人说质量部门必须检查包装材料。这项职能可以被替代吗？
There is no requirement that packagingmaterials be inspected by the quality unit. That is one of those expectationsthat can be delegated.
答：没有要求包装材料需要由质量部门来检查。这是可以被替代的职责。
19. Q. You mentioned that name andmanufacturer and address must be on the label. Would the name and address andthe distributor be acceptable?
问：你提到标签上必须有名称，制造者和地址。只有名称，地址和分销商是不是可以被接受？
No because the intent was traceability. Goback to the Haitian situation.
答：不可以。因为这样做的目的是为了有可追述性。
20. Q. Section 9.3 states that anexample of a printed label needs to be included in the BPR. Does thisrequirement apply to hand printed labels?
问：第9.3 章节说批记录中必须包括一份打印的标签例子。这也适用于手工复印的标签吗？
Yes. How a label is generated makes nodifference. Make a photocopy and attach the photocopy.
答：对。标签是怎么产生的没有关系。复印一份然后将复印件贴上去。
21. Q. Why did Q7A expert work groupallow the option of a retest date being placed on the Certificate of Analysisor the container label?
问：Q7A 专家工作组为什么不允许在分析合格证或是容器标签上的复验期被替代？
The retest date allows for the user to extendthe usability of the product. An expiration date does not allow for extension ofuse. For this reason expiry dates were mandated for label use as C of As arenot always readily available.
答：复检期允许使用者延伸其产品的使用时间。有效期不允许这样的延伸使用。这就是有效期一般不在标签或是分析合格证中使用的原因。
22. Q. Q7A does not seem todifferentiate between intermediate and API labeling. Is there a difference? Canyou use generic labels that operators fill out?
问：Q7A 指南没有区别原料药和中间体的标签。他们之间有区别吗？可以使用普通的标签，然后操作者去填写吗？
If it's not being sold, your ability to labelis really driven by your own procedures. If you're going to be selling theintermediate or the API, than you need to comply with Q7A.
答：如果物料不会去卖，你可以根据你自己的规程去贴标。如果你想把中间体或是原料药卖掉，那么你就必须遵守Q7A 指南的要求了。
23. How do you arrive at your retest orexpiry date?
问：你怎么来获得你的再检验期或是有效期数据？
You define it. Quite frankly, that is yourdecision to make, put it in writing, put it in your procedure and consistentlyuse it.
答：你自己定义这些数据。坦白的说，你必须自己决定，书面决定下来，把它放在你的规程中，并按照它执行。
24. Q. Please clarify reused containerscleaned according to documented procedure. Does this include secondarycontainers?
问：请解释容器根据文件规程清洁后的再使用。这包括那些第二级的包装吗？
25. Q. Does the label information, asdefined in 9.4, apply to starting materials and components used to manufactureAPI as well? Particularly the retest date on a label or CA?
问：标签上的信息，象第9.4 章节定义的那样，适用于起始物料和制造原料药中的所有组分吗？特别是标签或分析合格证上的复检期数据？
If you look at the title of Section 9 itself,you will see it says packaging and identification labeling of APIs andintermediates. Now one of the things that you can bet on is if we mention APIand we say nothing about intermediates, the intent of the expert work group wasit was going to be only for APIs. If we say both, than it is both. Now you willsee this throughout the document. There are sections where we explicitlymention one or the other or both. If we don't say anything about either, itwould probably generally apply to both.
答：如果你看看第9章节的题目，就知道是适用于中间体和原料药的包装和标签。你现在可以肯定的是如果我们说到原料药而没有提到中间体，那么专家组的意思就是只有原料药要遵守。如果我们说到两者，就是两者都要。你可以浏览一下全文，我们都清楚地表明了什么部分适用于什么。如果我们对他们都没有提及，就可能两者都适用。
26. Q. Is Section 9.3 on label issuanceand control, applicable for intermediates?
问：在第9.3 章节中对于标签的发行和控制一样适用于中间体的标签吗？
The answer to that is yes.
答：答案是肯定的。
27. Q. Regarding packaging materials. Towhat standards should they be cleaned?
问：关于包材，他们必须清洁到什么程度？
You have to look at if it's a contactsurface. It certainly has got to be cleaned to comply with the contaminationrequirements of Q7A, not just the requirements of the packaging sections.
答：你必须看它是否接触物料。当然它清洁到必须符合Q7A 指南中关于污染的要求，而不仅仅是在包装部分的要求。
28. Q. Are there any requirements forlabeling of drums of in process materials? These are temporary labels formoving material from one step to another.
问：对于工艺中物料桶的标签有没有要求？这些都是一些用于转移物料的桶的暂时的标签。
There are not specific requirements. It fallsunder the same section of labeling of intermediates and APIs. You define theprocedure in your written procedures.
答：没有特殊的要求。它的要求和中间体和原料药标签的要求一样。你可以在你的书面规程中定义这个过程。
29. Q. Q7A Section 9.4 makes a"requirement to use tamper evident packaging for shipments outside thecompany control." True or false?
问：Q7A 指南第9.4 章节，“对于公司控制范围外的运输，必须使用明确标识的包材”，是真是假？
The intent of the EWG was that you'd be ableto tell whether those containers were tampered with.
答：专家工作组的目的是你必须能够分辨那些包装和什么混杂在一起了。
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