ICH Q7A问题解答（验证部分）

Q7A US Based Training Seminars, 2002 Q7A US Based Training Seminars, 2002 Section 12: Process Validation 验证 1. Q. Does Q7A address the need for product-specific Master Plan or the Validation Master Plan? 问：Q7A 指南有没有要求针对产品的主或是验证主计划？ A written validation protocol should be established that specifies how validation of a particular process will be conducted. The protocol should be reviewed and approved by the quality unit(s) and other designated units. Q7A doesn't address product-specific or Master Validation plans. It's really the company's judgment what you do with the Master Plan. The Master Plan could be for an Intermediate or API, a class of API, or for an entire facility. (Section 12.2) 答：必须建立书面的验证方法来进行特定工艺的验证。质量部门和其他相关部门必须审核和批准。Q7A指南没有说到产品相关或主验证计划。这是由公司决定你的主计划有什么。主计划可以是为一个中间体或原料药，一类原料药，或者是整个厂的验证。（第12.2部分） 2. Q. Is the need for Design Qualification (DQ) addressed in Q7A? 问：Q7A指南是不是有要求要进行设计确认（DQ）？ Section 12.3 defines Design Qualification, as "documented verification that the proposed design of the facilities, equipment, or systems is suitable for the intended purpose." Q7A is probably one of the first GMP documents where you see design qualification. The EWG had a reason to put it in there - to send the message that process validation really begins with the design of an adequate manufacturing facility. 答：指南的第12.3部分定义了设计确认，“确认设施，设备或是系统的设计适合于所使用的用途的归档文件记录。”Q7A指南可能是第一个提及设计确认的概念的GMP文件。专家工作组把这个概念提出来的原因是传递一个信息，那就是工艺验证实际上在设计生产设施的时候就开始了。 3.Q. Are charging operations, even of non-critical materials, considered as critical steps that must be documented and verified? 问：投料操作，即使是对与非关键物料，是不是都被认为是关键步骤必须归档记录和证实？ Section 8.1 states, "Critical weighing, measuring, or subdividing operations should be witnessed or subjected to an equivalent control. Other critical activities should be witnessed or subjected to an equivalent control." Due to the nature of API manufacturing, when you're charging liquids or solids, usually a printout out from a flow meter or weight-cell would suffice as an indicator that you charged the appropriate amount of reagent, or catalyst, etc. Alternate means may also be appropriate. 答：Q7A指南第8.1部分说，“关键的称量，测量，或是细分操作必须证实或是用等效的手段控制。其他的关键活动必须证实或是有等效的手段控制。”考虑到原料药制造的特性，当你投料的时候，一般会有一个流量表或是称量表会打印出一个单证，这就足够证明你有投入合适数量的试剂或是催化剂等等了。替代的方法只要合适就可以。 4．Q. Can approval of the IQ/OQ protocols be delegated if the template document has been approved by quality? 问：如果模版文件被质量部门批准后，具体的设备IQ/OQ方案的批准可以被替代吗？ Section 2 is very specific. Reviewing and approving validation protocols and reports are listed as activities that should not be delegated. Someone in the quality unit should review the protocol. Would the questioner like to clarify "template?" 答：第2部分写得很明确了。审核和批准验证方案和报告是不能被替代的活动。质量部门一定要有人审核方案。提问者可以明确一下什么是“模版”吗？ 5．Q. (Audience) We have generalized templates and from there we will take that and add the specific information for the equipment to those templates. We're wondering if the original templates are signed off after the additional information has been added to the templates, do we need to have an additional review by quality prior to the execution of the IQ? 问：（听众）我们有一般的模版，我们在这个模版中添加设备所需的特殊的信息成为特定设备的方案。我们想知道如果原始的模版在添加了信息后被签发，我们需要在实施安装确认的前进行额外的质量部门的审核吗？ It depends. If you have a standard format that you use every time you are writing a validation protocol, you don't have to reinvent what section goes where. If you've got that much information in the template, then signing the template probably meets the expectations in Q7A 答：那要看了。如果你有一个的格式来用于你每次起草验证方案，你就不需要每次重新填写重复的部分。如果你的模版中有足够的信息，那么签发模版可能就可以满足Q7A的要求了。. 6. Q. What are the expectations for qualifying equipment? For instance, does the OQ need to go to the limit that the piece of equipment is capable of running, or can it just go to the typical operating conditions, i.e., temperature, pressure, etc.? 问：质量合格的设备有什么期望要求？例如，运行确认是不是要达到设备的运行极限？或是考察它是否可以达到典型的运行条件，例如温度，压力等等？ Section 12.3 defines Operational Qualification (OQ) as documented verification that the equipment or systems, as installed or modified, perform as intended throughout the anticipated operating ranges. 答：第12.3 部分定义了运行确认（OQ）就是设备或系统（安装或是修改后），在期望的运行范围内够可以运行满足其使用目的的要求。 7. Q. Drug Product Manufacturers may produce placebo product during the PQ-phase to demonstrate the process and equipment are functioning prior to manufacturing commercial product. What is expected in performing a PQ in an API facility? 问：药物产品制造商可能会在性能确认阶段为了证实工艺和设备有足够生产商业批号产品的功能，会在正式生产之前生产一些安慰剂产品。对于原料药制造的设施对于性能确认有没有特殊的要求？ It may be difficult to run a "placebo" batch in API processes. Many companies may run solvents or a water batch to simulate the API process. In other instances, a company may go directly to a validation phase after IQ/OQ, without the benefit of a true PQ. 答：很难在原料药制造中使用所谓的“安慰剂”批号。很多公司可能会运行溶剂或是水批号来模仿原料药工艺。在其他的一些情况下，公司可能直接在IQ/OQ后进入验证阶段，而没有真实的性能确认。 8. Q. What is the difference between "witness" and "verify" in Q7A? 问：Q7A指南中“目击证明”和“证实”有什么区别？ Generally, the term "witness" means a second person present at the time the operation occurred. In comparison, verify is usually conducted after-the-fact through review of supporting documentation. For example, a weight can be verified through review of a scale printout, but one cannot confirm which material was charged without witnessing the act. But, Q7A is actually silent in defining "witness" and "verify". 答：一般来说，“目击证明”是指第二个人在现场证实操作的发生。相对比，“证实”一般是操作发生后的审核性的支持文件。例如，称量操作可以通过审核量具的打印单来证实，但是如果没有人目击看到整个过程，没有人可以证实投入的是什么物料了。但是实际上，Q7A指南没有定义“目击证明”和“证实”。 9. Q. Can you give examples of appropriate documentation or other alternate means to indicate the status of equipment? 问：您是不是可以举例解释合适的文件或是其他替代的方式来标识设备的状态？ (Section 5.1) Major equipment (e.g., reactors, storage containers) and permanently installed processing lines used during the production of an intermediate or API should be appropriately identified. In addition, Section 5.2 indicates "Equipment should be identified as to its contents and its cleanliness status by appropriate means." Major equipment should have a unique equipment number on it, for example, your reactors may be numbered R40, R41. In your batch record or on your control panel in the control room, if you have a distributed control system as referred to, an Operator should be able to see what's happening with R40 and what is in it at any particular moment 答：（第5.1部分）生产中间体或是原料药的主要设备（例如反应罐，储罐）和永久性安装的工艺管道必须合适的标识。另外，第5.2部分说“设备必须用合适的方法表明其中的物料和清洁状态”。主要设备上必须有一个唯一的设备编号，例如你的反应罐可能有R40,R41这样的编号。在你的批记录或是你的控制室的控制台上要有标记表明这些设备，如果你有相对应的分销控制系统，操作者必须能够看到反应罐R40发生了什么，在指定的时间R40中有什么东西。 10. Q. Does Q7A address process development reports? 问：Q7A指南没有提到工艺开发报告？ Q7A does not specifically address the need for process development reports. In Section 6.1, it does indicate that summary reports be available regarding the development history, scale-up and technology transfer of the API process. 答：Q7A指南没有特别的说需要有工艺开发报告。在第6.1部分中，有规定要求有开发历史的总结报告，包括扩产，和原料药工艺的技术转移。 Generally, during development of the API, the R&D group writes a report that includes all the fundamental information that drives your eventual manufacturing on a commercial scale and your process validation. Regardless of what you call those reports, (they may have different names in the industry), the bottom line is that a company should have some level of documentation showing that the process has been fully developed and transferred to the commercial facility. 一般来说，在原料药开发阶段，研发小组必须写一个报告，表明所有的你最终在制造商业批号产品和你的工艺验证中的基本信息无论你怎么叫这些报告（在工业中，他们可能有不同的名称），底线就是公司必须有一些文件可以证明工艺被充分开发和转移了，适合进行商业化生产了。 11.Q. Does the quality section need to signoff/approve the validation reports in addition to validation protocols? 问：质量部门是不是在验证方案之外还必须签名或是批准验证报告？ Yes. This is discussed in Section 2.2, item 10. The Quality Unit's responsibilities should include "Reviewing and approving validation protocols and reports." 答：对。这在第2.2部分，第10条中有要求。质量部门的职责必须包括“审核和批准验证方案和报告。” 12.Q. Could you elaborate on section 12.6? Would a change in the source of an API starting material require revalidation? 问：您能不能阐述一下第12.6部分？原料药起始物料的变更是不是需要再验证？ Section 12.6 states, "Systems and processes should be periodically evaluated to verify that they are still operating in a valid manner. Where no significant changes have been made to the system or process, and a quality review confirms that the system or process is consistently producing material meeting its specifications, there is normally no need for revalidation." 答：第12.6部分说，“系统和工艺必须周期性的评估来证实他们仍然是按照证实的行为在运行。系统或工艺中如果没有重要的变更，且质量审核确证系统或是工艺可以继续生产符合规格标准的物料，那么一般就没有再验证的必要。” Revalidation of an API process may be warranted if the change in the API starting materials is deemed significant. If the Impurity Profile of the Starting Material is significantly different from that previously validated, this may warrant additional validation studies to ensure that the API process can eliminate any increase in or new impurities in the API. 如果原料药起始物料的变更是被认为是重要的，那么原料药的再验证将是必须的了。如果起始物料中的杂质状况和早先验证过的有很大的区别，那么这将导致额外的验证研究来确保原料药工艺可以减少任何增加的或是新的原料药中的杂质。 13.Q. A company wants to manufacture a blend of chemical actives, where no chemical synthesis extraction occurs. This blend is then sold for use in the manufacture of a consumer product. Is this blend considered an API or does API starting material manifest itself? 问：公司希望制造化合物的混合物，工艺中没有化学合成，提取等。这样的混合物最后被用做制造化妆品。这样的混合物是原料药吗？或者本身就是原料药起始物质？ This example goes beyond API manufacturing. What you're doing is you're combining various actives for purposes of manufacturing a drug product or some consumer product. For example, if you are in fact taking various actives and combining those in order to produce a consumer product, that's formulating. 答：这个例子不在原料药制造范围内。你所做的是将不同的活性物质混合在一起来制造一个药物产品或是化妆品。例如，如果你实际上使用了不同的活性物质，然后把这些物质结合在一起来制造化妆品，这就是配方了。 14.Q. In Section 8D in your presentation, is validation data required in support of blending? 问：在您演讲的第8D部分，为了支持混粉需要验证数据吗？ Section 8.4 states, "Where physical attributes of the API are critical, APIs intended for use in solid oral dosage forms or suspensions, the blending operation should be validated to show homogeneity of the combined batch. Validation should include testing of critical attributes (e.g., particle size distribution, bulk density, and tap density) that may be affected by the blending process." If it is for a liquid, it's generally not an issue. But, if you know it's going for a solid oral dosage form or a suspension, those physical attributes could be critical to the performance of the drug product. 答：第8.4部分说，“当原料药的物理性质是很关键的时候，例如原料药用于固体口服制剂或是悬混剂，混粉操作必须验证其均一性。验证必须包括混粉工艺可能影响的关键性质的测试（例如，颗粒度分布，松密度和堆积密度）。”如果是液体，就不存在这样的问题了。但是，如果你知道它将被用于固体口服制剂或是混悬剂，那些物理性质是对药物产品功效有关键作用的了。 15. Q. If the only specification not met is expected yield, is blending still acceptable? 问：如果规格标准中唯一没有达到的是期望产率，混粉是不是可以被接受？ Although not addressed by Q7A, a blend not meeting the expected yields may be acceptable. Typically, if you're starting a campaign and charging to a clean blender, you may experience low yield on the first batch due to material adhering to equipment surfaces. After that first batch, an investigation would be expected into why the yield is low 答：虽然没有在Q7A指南中解释，但是没有达到预期产率的混粉是可以被接受的。一般情况下，如果你刚刚开始一个产品的生产，是使用干净的混粉器，你的第一批产率一般都比较低，因为物料会吸附在设备表面。第一批次后，产率还是低就需要调查原因了。 16．Q. Is it acceptable to blend multiple lots that do not have a physical property specification to meet a blended lot physical property specification, example bulk volume particle size? If the material is out of specification for physical properties, can it be blended with other lots to meet these specifications? In all cases, appropriate validation would be conducted. 问：混粉那些没有物理性质规格标准的多批产品来达到一个混粉批号的物理性质规格标准是不是可以接受？例如堆积体积颗粒度？如果物料杂物理性质上超标，是不是可以和其他的批号来混粉达到规格标准？或者是在任何情况下，都必须实施合适的验证？ As an example, a manufacturer may have an API that they're selling to multiple customers, and a particular customer for some reason has provided you a particle size specification. So, this is now a customer-defined specification that you get when the order comes in and is within the range of particle size distribution of the process. Thus, to meet the new, tighter criteria, selected batches chosen and blended. This results in a batch that meets the desired specification of the customer. 答：作为一个例子，制造商可能有一个原料药产品，他们把它卖给多个顾客，且其中一个顾客有一些特殊的理由要求你提供颗粒度的规格标准。所以，这是客户定义的规格标准。当你接到这样的定单的时候你就要判断工艺产品的颗粒度分布范围是不是在此之内。这样，为了可以满足新的，更加严格的规格标准，选择一些批号来混粉。这样的批号结果就可以达到客户要求的规格标准。 This appears to be within the expectations of Section 8.4 of Q7A, provided the individual batches selected are within the manufacturers initial specifications. While the justification for doing such a blending would need to be carefully developed, it does not appear to represent dilution of a known quality problem for the materials that would not be permitted under Q7A. 这显然在Q7A指南第8.4部分的期望之内，只要每个单独选择的批号都在制造商原来的规格标准之内。但是进行这样的混粉必须特别仔细，这不是代表去稀释一个有已知质量问题的批号物料，这是Q7A指南所不允许的。 17. Q. In the presentation on Section 12.4: Approaches to Process Validation, the expectation of having at least one validation batch completed at the time of the Pre-Approval Inspection was mentioned. Is this stated in Q7A? 问：在第12.4部分的演讲中：工艺验证的方法，期望在批准前检查时，至少有一个验证批号的生产完成。这是Q7A指南所要表述的吗？ While not specifically discussed in Q7A, section 12.4 states, "Prospective validation of an API process should be completed before the commercial distribution of the final drug product manufactured from that API." Thus, validation of both the API process and the Drug Product process should be completed prior to commercialization of the Drug Product. 答：虽然没有在Q7A指南中特别讨论，第12.4 部分说到，“原料药工艺的前瞻性验证必须在使用该原料药制造的最终药物产品市场化销售之前完成。”这样，原料药工艺和药物产品的工艺验证都必须在药物产品的市场化销售前完成。 During the Pre-Approval Inspection, a key focus of the inspection is the evaluation of technology transfer. As such, production experience at a particular site provides some level of confidence that the process has been adequately transferred and will operate as described. Production and Inspectional history at the site may also play an important role in reinforcing this confidence. 在批准前检查中，一个关键的检查焦点就是对技术转移的评估。例如，生产的经验就是一个特别的地方可以提供足够水平的自信，该工艺已经被足够的转移可以按照描述的进行运行了。该地址的生产和检查历史可能也会在强化这种自信上扮演重要的角色。 18.Q. What kinds of validation work need to be done for a validated API process that stopped producing for five years and produces again? No process or equipment changes are made. Do we need to do stability tests again? 问：对于停止生产五年又要进行生产的一个已经验证过的原料药工艺需要进行什么类型的验证工作？没有工艺或是设备的变更。我们需要重新做稳定性测试吗？ Q7A would not expect revalidation if you haven't changed anything. Your change control system should still be operating. If you've made no changes to what you're going to do, and it's the same facility with the same equipment, Q7A does not mandate another series of extra work. Now, if you're a conservative manufacturer, you may want to do some additional work, additional testing to assure that the process will still produce API in a consistent manner. But, by no means does this guidance require that additional work if nothing has changed. 答：Q7A指南没有期望重新进行验证如果你没有改变任何事情的话。你的变更控制系统应该还在运行。如果你没有变更，还是同样的设施和同样的设备，Q7A指南没有命令进行另一系列的特殊工作。现在，如果你是比较保守的制造商，你可能想要进行一些额外的工作，额外的测试来确保工艺仍然可以按照原来的方式制造原料药。但是，本指南对于这样没有任何变更的情况没有要求任何额外的工作。 19. Q. Should process parameter ranges used during validation be tighter than the filed parameters applied to routine commercial production operation, e.g., the full range supported by development? 问：在验证阶段的工艺参数范围是不是必须比日常市场化生产运行的参数严格？例如，有发展数据支持的全范围。 Section 12.1 of Q7A states, "The critical parameters/attributes should normally be identified during the development stage or from historical data, and the necessary ranges for the reproducible operation should be defined." Normally, the full range of processing parameters that are listed in the filing are wider than those challenged during validation. These ranges are normally established in the development lab or in the pilot plant to show that acceptable product can be manufactured. Many companies chose to operate within tighter ranges (e.g., target process parameters, typical ranges, etc.) during routine production. 答：Q7A指南第12.1部分说“关键的参数/性质必须在开发阶段或是有历史数据确认，必须定义重生产运行的必须范围。”一般来说，在文档中罗列的工艺参数的全范围比在验证中考核的那些参数范围要广。这些范围一般是建立在开发实验室或是中试车间的数据上的，是可以接受的生产该产品的。很多公司选择在日常生产中使用更加严格的范围（例如，目标工艺参数，典型的范围等等）。 20. Q. One of the most critical words used in Q7A is "critical." Is it not essentially implied in Q7A that there be documented bases for identifying critical materials, critical steps, critical operating parameters, etc., whether or not it be called a product development report? 问：Q7A指南中最重要的一个术语就是“关键”。在Q7A指南中是不是没有隐含必须有确认关键物料，关键步骤，关键操作参数等等的文档，无论其是不是被叫做产品开发报告？ With respect to validation, Section 12 of Q7A says that you should validate critical process steps. Each company is responsible for defining what steps are considered critical. During an inspection by a regulatory agency of a company's validation packages, it would be reasonable for the investigator to ask you how you determined which of the steps in your eight-step synthesis are critical, and how you determined the critical process parameters. It is expected that data are available to show that the critical process steps are in fact critical and support by the range of critical process parameters. 答：对于验证，Q7A指南第12部分说你必须验证关键工艺步骤。每一个公司都必须定义什么步骤是关键的。在药政管理当局进行检查一个公司的验证的时候，检查官问你你是怎么来决定在你的八步合成步骤中哪一个步骤是关键的，你是如何决定什么是关键工艺参数的。希望有数据表明关键工艺步骤确实关键且有关键的工艺参数范围所支持。 21. Q. Can process deviations be used to expand the validation critical process parameter ranges, for one deviation, multiple deviations? 问：工艺偏差（用一次偏差或是多次偏差）可不可以用来扩展验证关键工艺参数的范围？ Q7A does not specifically address this issue. In some cases, deviating batches may suggest the need to expand the previously validated ranges. Data from these batches may supplement the available information and allow the company to define what additional validation work may be necessary. 答：Q7A指南没有特别的解释这个问题。在一些情况下，有偏差的批号可能建议对先前的验证范围进行扩展。从这些批号获得的数据可能是对已获得信息的补充，允许工艺定义需要进行那些额外的验证工作。 22.Q. What is an acceptable mechanism for confirming the suitability of an alternate source of a starting material? 问：起始物料的替代来源必须有什么可以被接受的机制来确保其适用性？ Section 7.1 of Q7A states, "Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control." Section 13 states," The potential impact of the proposed change on the quality of the intermediate or API should be evaluated." 答：Q7A指南第7.1部分说，“对关键物料的供应商来源的变更必须根据第13部分变更控制的规定来控制。”第13部分说。“变更对中间体或是原料药质量的潜在影响必须评估。” 23．Q. It's not uncommon for a company to have two suppliers of a starting material. They're now going to validate the process and they want to make sure that their validation encompasses material from both suppliers. What do they need to consider. 问：公司有两个起始物料的供应商是一件不寻常的事情。他们必须验证相关的工艺，必须确保他们的验证包括两个供应商提供的物料都合适。他们需要考虑什么？ Assuming that the company has done some preliminary work to show that their two suppliers are delivering material to the same specification, and that both will work in the company's API process, it would be prudent to use material from both suppliers in their demonstration batches. With the criteria that the starting materials from both suppliers met the same specifications and all quality attributes are satisfactorily met for the API, this should support the use of either supplier. 答：假设公司先前有进行一些调查工作表明他们的两个供应商提供的物料是相同的规格标准，两者都是适合公司原料药制造工艺的，在他们的验证批号中使用两个供应商的物料就是很精明的了。两个供应商的起始物料的质量标准都达到了同样的规格标准，所有的质量特征都适合原料药的要求，这就支持了可以使用两个供应商中的任何一个。 24. Q. Are requirements for GMP compliance, in fact, less stringent for API manufacturers versus dosage form manufacturers: less validation, less cleaning validation, less detailed documentation? Is there any basis for individuals to interpret Q7A this way? 问：GMP对原料药制造的要求是不是比制剂产品的制造要低？验证要少，清洁验证少，详细的记录少？有没有什么解释Q7A指南的底线？ Q7A recognizes that there are fundamental differences between the manufacturing processes for API and Drug Products. GMPs are no less important in API processing. GMPs are applied differently to APIs because of the nature of API manufacturing and the differences in API manufacturing. 答：Q7A指南认识到原料药和制剂产品的制造在工艺上有明显的区别。在原料药工艺中GMP并非不重要。只是GMP的实施因为原料药制造的不同特性决定了要求不同。 25．Q. In Q7A there are lots of definitions provided in the back. Why are there no specific de