逆向思维——跟FDA对内GUIDE学习如何迎接现场检查-1

编者注：随着越来越多国内企业到美国进行产品申报，FDA的检查官们也越来越频繁地造访国内各医药企业的实验室和车间。

为了让大家慢慢不要再谈FDA Inspection而色变，小编决定跟大家一起从FDA检查官的角度来学习:

1. FDA工作人员为他国现场检查都做了哪些具体工作?

2. 除了cGMP我们还有哪些需要准备的工作和需要学习的内容?

该系列文章由多篇构成，主题与FDA Inspection相关，内容主要是FDA对现场检查官们的指南文件。后期逐步分期发布，欢迎留言交流。

第一期

《Inspection Guides： Foreign Pharmaceutical Manufacturers》

现场检查指南：外国制药企业

（仅对重点和主要内容进行了翻译整理）

原文：https://www.fda.gov/ICECI/Inspections/InspectionGuides/ucm075021.htm

也可点击文末“阅读原文”获取中英文对照版

专业术语：

1.CDER（Center for Drug Evaluation andResearch）FDA药物评价与研究中心

2.CVM（Center for Veterinary Medicine）兽药中心

3.PAIs（Pre-approval inspections）批准前检查

4.ITOB（International and TechnicalOperations Branch）国际业务与技术运营部

5.PDUFA（Prescription Drug User Fee Act）处方药用户收费法案

6.ORA(Office of Regulatory Affairs) 法规事务办公室

1.  PRE-APPROVAL INSPECTIONS

批准前检查

Pre-approval inspections (PAIs) requested by CDER andCVM for approval of specific NDAs/ANDAs/NADAsA constitutea major segment of FDA's foreign pharmaceutical inspection activities. When aPAI inspection is scheduled at a given facility, ITOB may, at its discretion,request the inspection team also cover other product applications needingpriority handling. District NDA program managers should keep track of andadvise ITOB headquarters staff of any significant issues pending at thefacility that must be resolved before an application can be approved even ifCDER or CVM has not completed its review of the application.

CDER和CVM所要求的针对特定NDAs/ANDAs/NADAsA的批准前检查（PAIs）是FDA国外检查活动很重要的一部分。当对某个工厂的检查已经安排好了的时候，ITOB（International and TechnicalOperations Branch）可以根据需要，自行决定去要求检查组在检查的时候覆盖其他需要优先处理的产品申请。区域的NDA管理员应该就任何待检工厂需要在申请批准前解决的待定的重大问题（即使CDER或者CVM还没有完成申请的审评）与ITOB总部检查保持联络并提供建议。

Many of the PAI assignments are generated as a result of the Prescription Drug User Fee Act (PDUFA). These assignments are identified as such and bear relativelyshort deadlines. They must be given the highest priority and handled in atimely manner.

大部分的PAI检查任务都是PDUFA法案的结果，这些检查任务被视为是需要在相对较短的时间内完成，因此必须把这些任务安排到最优先的位置并且及时的处理完成。

At the earliest time after completion of an inspection, the team leader should  notify ITOB headquarters staff of the outcome of the inspection. He or she should transmit to ITOB via FAX the Inspectional Observations, Form FDA 483 (ifone is issued), a brief summary of findings, and proposed recommendations.Subsequently, the EIR (Establishment Inspection Reports) is expected to listall of the applications covered during the inspection and the status of each application. Be guided by appropriate Compliance Programs and Compliance PolicyGuides for making endorsements and recommendations.

在检查结束后最短时间内，检查组组长就应该将检查结果通知ITOB总部并通过传真将检查观察项、FDA 483表（如果有）、检查结果的小结和检查组建议传发给ITOB。接下来需要在EIR报告中列清所有被检查的申请以及这些申请所处的状态，检查组在做推荐和建议的时候需要遵循适用的合规性计划和合规性政策指南。

2.CULTURAL ASPECTS

文化差异

More and more inspections are being performed at places outside of our own cultural boundaries. Even in places that share common cultural traits, we often observe big disparities in regulatory climates in the industry being inspected. How weconduct ourselves abroad may well determine how much information we bring back from the firms we inspect on which to base our regulatory decisions.

现在越来越多的FDA检查需要在与美国有着不同文化背景的地区进行，（有时）即使在一些与美国有相同文化的地方，也经常会在被检查的工厂观察到与美国截然不同的监管环境。因此，我们在国外的行为可能会决定我们能够从被检查公司带回多少按照FDA监管决策所要求的信息。

The inspection team is there to make an assessment of each foreign facility on FDA's terms. Foreign firms are under no obligation to comply with the U.S.regulations except for their commitments in applications filed with the agency and/or for their desire to market their products in the U.S.A. In dealing with  a foreign firm, therefore, it is important not to impose our views on it during the inspection. Observe its manufacturing operations and verify them with the filed processes. Review the production records and document any deficiencies and discrepancies.

检查组去国外进行检查，是按照FDA的要求对国外工厂进行评估，除非国外的公司在给FDA的申请中有相应的承诺或者是他们希望出口他们的产品到美国市场，否则他们没有义务遵守美国的法规。在检查过程中与国外公司打交道时很重要的一点，是不能把我们的观点强加给他们，只需要观察工艺操作和核查申报的工艺、查阅产品记录、记录文件中的缺陷和差异。

The mission of the inspection team is, as is true in the domestic inspections, togather as much information as possible to allow the agency to make an informed decision. Avoid a confrontational approach, if at all possible. Yet, beassertive and clear about what information and/or documentation the firm should provide to the team.

检查组再国外检查的任务跟国内的检查是一样的，那就是收集尽可能多的信息来让FDA作出明智的决定。检查的时候要尽一切可能地避免（与被检查公司）对抗的方式，因此检查组需要对被检查公司应提供哪些信息/文件给检查员要非常自信和清楚。

Views of the inspection team (or of the agency) and inspectional findings should be discussed with the firm during the exit interview in a constructive manner. Regulatoryprocesses of other countries are usually different from ours, and the inspection team may need to explain to the firm the implication of the findings and ways to remedy the problems, including possible corrective actions.

在末次会议的时候，检查组（或者代理）要以建设性的方式和被检查公司就检查中的发现项进行讨论，一般来说其他国家的监管过程是跟美国不一样的，因此检查组有时需要向被检查公司解释检查中发现项的含义、纠正方式和可能的纠正措施。

3.COMMUNICATIONS

沟通

Prior to the inspection trip, the inspection team may contact the domestic sponsor directly by phone or by visit when deemed necessary and expeditious. However,as a rule, contact ITOB first to see if the information may be obtained throughthe Branch.

在启程之前，检查组可能需要通过电话与（相应申请在）美国国内的发起人进行联系，必要时还可以直接拜访发起人，不过通常情况下检查组应该先联系ITOB来确认是否可以通过ITOB获取（检查组想要的）信息。

The inspection team is encouraged to contact the CDER reviewers at any time todiscuss issues or concerns regarding the specific application. As mentioned inthe previous section, Center reviewers may provide some information valuable for determining the direction of the inspection.

During the trip, the inspection team is expected to keep in touch with ITOB at all times for technical, administrative, or any other matters. ITOB sometimes needs to keep the team apprised of any additional information or changes while intransit. With regards to technical support during travel, ITOB will try to tap available resources within the Agency, including the National Experts and appropriate Center personnel to respond to the request in a timely manner.

支持检查组在任何时间就特定的与申请有关的问题和关注点联系CDER审评员进行讨论，正如前面章节提到过的，CDER审评员也许可以为检查方向的确定提供一些有价值的信息。在检查行程中检查组需要全程与ITOB就技术、行政或者其他事项保持联系；在途中的时候ITOB有时也会通知检查组一些额外的信息或者是变化。ITOB会充分利用机构内部已有的资源—包括国内专家和适用的FDA某个中心的人员，来及时的回复行程中的（检查组所需的）技术支持。

When the inspection team finds significant GMP violations or data integrity problems at the foreign facility that may require additional attention, such findings should be immediately communicated to ITOB either by phone or FAX. On rare occasions, the inspection schedule may have to be amended if the finding swarrant extensive evidence documentation. At the conclusion of each inspection,the team leader will notify ITOB with the result of the inspection by FAX including the Inspectional Observations, Form FDA 483 (if one is issued), abrief summary of findings and the team's recommendation.

一旦检查组在国外工厂检查时发现了严重违反GMP的情况或者数据完整性问题就可能需要额外的关注，而且检查组需要立即通过电话或者传真与ITOB（就此类问题）进行沟通。在极少数情况下检查安排会进行调整，如在检查中发现的情况需要大量的证明性文件资料。在检查结束的时候检查组组长需要将检查观察项、FDA 483表（如果有的话）、检查结果的小结和检查组建议包括在内的检查结果通过传真的方式向ITOB通报。

4.REVIEW AND ENDORSEMENT OF INSPECTION RESULTS

检查结果的评估和认可

The District (field) offices are responsible for review of all inspection findings and for proposing appropriate endorsements and recommendations consistent with the current policy applicable to domestic facilities. Follow the time-frames specified in the various Compliance Programs.

Current procedure requires that the District office forward the EIR package to ITOB forits evaluation of the District's endorsement and recommendation for consistency and uniformity. Then, ITOB headquarters staff will route the EIR package to the appropriate Center for their concurrence. The District office should be aware of changes in procedures regarding the routing of inspection reports,recommendations, compliance review, and other post-inspectional activities.

现场办公室负责复核所有的检查发现并按照现行的应用于国内工厂的政策提出适当的背书和建议。（检查组需要）遵循各种合规性计划中规定的时间期限。现行的程序要求区域办公室提供EIR包给ITOB以便ITOB能够在一致性和均一性方面对区域办公室的背书和建议进行评估，接着ITOB总部会将EIR包发给合适的FDA中心以寻求他们的赞同。区域办公室需要知道跟检查报告、建议、一致性审评的去向和批准后检查活动流程方面的变化。

For the inspections performed by the staff of ITOB or headquarter's employees (ORA,CDER, or any other Center) shall continue to be forwarded to ITOB for its review and endorsement. ITOB is considered to be the home district for these employees.

对于那些有ITOB员工或者总部员工（ORA，CDER或者其他中心）执行的检查也仍旧需要转给ITOB以便ITOB审查和认可，ITOB应该被视作为这些员工的本部。

For pre-approval inspections, Investigators and Districts should be guided by the current policy, particularly as it relates to District responsibilities regarding approval or withhold recommendations, compliance activities, and correspondence to the appropriate Center offices and applicants.

Written responses to FDA 483 observations and other correspondence received in ITOB will be copied to members of the inspection team for their review and comment.

对于批准前检查，检查员和区域办公室需要按照现行政策的指导，尤其是那些跟区域办公室职责（对申请应该批准或者保留的建议、合规性活动、与FDA适用中心的办公室和申请人之间的通信）有关的情况。（被检查公司）对FDA483表格中观察项的书面回复以及其他ITOB收到的函件应该复印给检查组成员以供他们审核和发表意见。

The inspection team is expected to provide any comment in writing back to ITOB assoon as possible. The inspection team leader is responsible for coordinating the manner in which the comment is provided.

ITOB headquarters staff is responsible for coordinating with the Centers, when applicable, in determining the need for any inspectional follow-up at the foreign facilities. ITOB should always coordinate the follow-up activities with the appropriate Center if the inspection request was initiated by that Center.

检查组需要尽快以书面形式向ITOB提供所有的评论，检查组组长负责协调提供评论的方式。ITOB总部员工负责协调（FDA）各个中心（如果适用的话）来确定任何的针对国外工厂的后续检查。IPOB需要一直与发起检查要求的（FDA）中心就任何后续的活动进行协调。

5.VALIDATION POLICY

验证政策

All drug manufacturing processes are expected to have been validated prior to shipping. (Refer to HFC-133 memo dated November, 1995) This may mean that amanufacturer is not required to have documentation of a validated manufacturing process at the time of the inspection. However, this should not deter the inspection team from making an assessment of the firm's manufacturing process(es). Especially, for a bulk drug substance that has been manufacturedfor years employing an established process for many years and is not expectedto change, the firm should have had sufficient experience with the respective process to have their critical process parameters under control to attain reliable and consistent product quality.

所有地药品生产工艺都需要在发货之前完成验证（参考1995年11月的HFC-133备忘录），这也就意味着在检查的时候，生产商可能不一定需要有某个已验证工艺的文件资料。但这并不是要阻止检查组对被检查公司的生产工艺进行评估，尤其是对于那些已经持续生产了很多年且没有预期变更的原料药生产工艺，这一类公司应该对他们制定的用来需要控制药品质量的可靠性和一致性的关键工艺参数有足够的工艺经验。

During the inspection, the inspection team should attempt to evaluate if there are any significant variations in critical process parameters by examining a series ofbatch production records. If the process needs to be constantly fine-tuned frombatch to batch, that is a sign of an invalidated process.

检查时检查组应该尝试通过检查一系列的批生产记录的方式来评估工艺中关键参数是否有重大变更。如果批与批之间的生产工艺一直有调整的话，那么就说明这是一个未经验证的工艺。

For the majority of bulk drug processes, the single most important quality attribute is the substance purity. Therefore, particular attention must be paid to the evaluation of final purification processes.

Even in the case of finished dosage form drugs, the inspection team should determine if the product has been already manufactured for the local market. For many applications submitted by foreign sponsors, the products have been marketed outside the U.S.A. for years and their processes usually established. The inspection team should first determine if the product and the process being inspected are new at the time of the inspection. If the application process is substantially similar to the existing process, the inspection team should attempt to find out if the firm has validation data and if other available production data support a validated process.

即使是在对制剂的检查当中，检查组也应该确定被检查公司生产的产品是否已经为当地市场生产过。对于很多国外发起人递交的申请，他们的产品其实已经在美国之外的市场上市很多年了而且他们的工艺通常都早已确立。检查组应该首先判定被检查的产品和工艺在检查时是否为新产品/工艺。如果申请的工艺大体上与已有工艺是相似的话，检查组应尝试查明被检查公司是否有验证数据和是否有其他用来支持某个已验证工艺的产品数据。

When and if the inspection team notes on the FDA 483 the lack of a validated process, the observation should be supported by a detailed account of how the inspection team came to that conclusion. The concept of validated processes and documenting such evidence is not yet a widely accepted one outside the U.S.A.Being specific about what the observation implies will not only help the foreign firm to understand the issue, but also allow the agency to make an appropriate informed compliance decision.

如果最后有签发FDA 483表格并且在上面注有“工艺缺乏验证”缺陷项的话，那么检查组需要提供详细的解释来说明检查组是如何得出‘工艺缺乏验证’这一结论的。（因为）在美国以外的地方，验证工艺和记录工艺验证证据的概念还没有被广泛接受，因此详细的检查观察项不仅能够帮助被检查的外国公司理解问题所在，而且也可以让FDA做出恰当且明智的合规性决定。

6.DOCUMENTATION OF VIOLATIONS OF cGMPs

cGMP违规文件

During the inspection of a foreign drug manufacturer, it is not necessary to obtain the same level of documentation expected from a domestic inspection to establish evidence of GMP violations or data integrity problems. The agency has the authority under the FD&C Act to administratively restrict the importation of a product without demonstrating the adulteration of the product.The burden of proof is placed on the importing party.

在针对国外药品生产商的检查中，没有必要去取得跟国内检查一样水平的用来确认GMP违规或者数据完整性问题的文件资料。根据FD&C法案，FDA有权通过管理来限制某个产品的进口而不用证明这些产品是掺假药，（毕竟）举证的责任方是进口商。

However,the inspection report should contain sufficient information and documentation to support a conclusion by the reviewing office that significant violations ofthe law exist to warrant restricting importation of the commodity and/ornon-approval of affected application(s). Where data integrity problems are suspected,an attempt should be made to establish a pattern of practice. If the inspection team determines that extensive evidence documentation is required and fears that the evidence might be destroyed, ITOB should be contacted at the earliest possible time so as to develop a prompt logistical support plan.

但是检查报告还是应该包含足够多的信息和文件，用来支持审核办公室作出的（因为）存在严重违反法律而需要限制产品进口和/或者不批准受影响申请的结论。当数据完整性问题存在嫌疑的时候，应该建立起一个实践模式。如果检查组确定需要大量的证明性文件而又担心这些证据可能会被破坏的时候，检查组应该尽可能早的联系ITOB以便他们能够制定一个迅捷的后勤保障计划。

ATTACHMENT A

附件A

下面列出了一些对FDA出国检查人员有用的参考文件，但应注意这些文件不是包括所有的，检查人员应根据需要以及任何可以获得的资源来更新和采纳列表中的参考文件。

附1. COMPLIANCE PROGRAMS

合规性计划

1. 7356.002Drug Process Inspections

2. 7356.002ASmall Volume Parenterals

3. 7356.002BDrug Repackers and Relabelers

4. 7356.002CRadioactive Drugs

5. 7356.002FBulk Pharmaceutical Chemicals

6. 7346.832Pre-Approval Inspections

7. 7346.843Post-Approval Audits

附2.COMPLIANCE POLICYGUIDES

合规性政策指导

CHAPTER4 - HUMAN DRUGS

1.CPG 7132a.06: Finished Dosage Form Drug Products in Bulk Containers -Applications of cGMPRs

2.CPG 7132c.04, CPG 7132.05, & CPG 7132a.01: All related to Compendial/TestRequirements

3.CPG 7132a.17, CPG 7132.a.12, CPG 7132a.15, CPG 7132a.07, & CPG 7132a.08:All related to computers

4.CPG 7132.13: Repacking of Drug Products - Testing/Examination Under cGMPs

5.CPG 7132a.04, CPG 7132b.11, & CPG 7132a.10: All related toStability/Expiration

6.CPG 7132c.08: Process Validation Requirements for Drug Products Subject toPre-Market Approval

7.CPG 7150.16: Status and Responsibilities of Contract Sterilizers Engaged in theSterilization of Drugs and Devices

8.CPG 7151.02: FDA Access to Results of Quality Assurance Program Audits andInspections

CHAPTER2 - BIOLOGICS

CHAPTER3 - DEVICES

CHAPTER6 - VETERINARY MEDICINE

附3. REGULATORY PROCEDURESMANUAL

管理程序手册

CDERGUIDELINES

CDER指导方针

1.Bulk Pharmaceutical Chemicals, 9/91

2.Preparation of IND Products, 3/91

3.Sterile Drug Products - Aseptic Processing, 6/87

4.General Principles of Process Validation, 5/87

5.Limulus Amebocyte Lysate Test, 10/89

6.The various 13 guides related to NDA/ANDAs

7.Format and Content for the CMC Section, 9/94

8.Stability Testing of New Drug Products, 9/94

9.Validating Laboratory Automation Systems, 10/94

10.Validation of Chromatographic Methods, 11/94

11.Sterilization Process Validation in Applications, 11/94

12.Validation of Computerized Liquid Chromatographic Systems, 8/92

13.Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-ProductEndotoxin Test, 12/87

14.Sterilization Process Validation: Recommendations for Information to beSubmitted to CDER/CVM Applications, 1/93

15.Guidance to Industry on the Packaging of Test Batches, 2/95

16.Various SUPAC Documents

附4.  INSPECTION GUIDES

检查指南

1.Guide to Inspections of Oral Solid Dosage Forms Pre/Post Approval Issues for Developmentand Validation, 1/94

2.Guide to Inspections of Topical Drug Products, 7/94

3.Guide to Inspections of High Purity Water Systems, 7/93

4.Guide to Inspections of Validation of Cleaning Processes, 7/93

5.Guide to Inspections of Microbiological Pharmaceutical Quality ControlLaboratories, 7/93

6.Guide to Inspections of Lyophilization of Parenterals, 7/93

7.Guide to Inspections of Sterile Drug Substance Manufacturers, 7/94

8.Guide to Inspection of Solid Oral Dosage Form Validation Activities, 3/93

9.Guide to Inspections of Pharmaceutical Quality Control Laboratories, 7/93

10.Guideto Inspections of Oral Solutions and Suspensions, 8/94

11.Guideto Inspection of Computerized Systems in Drug Processing, 2/83

12.Guideto Inspections of Dosage Form Drug Manufacturers - CGMPs, 10/93

13.PreapprovalInspection Guide for Laboratory Analysts, 3/91

14.SoftwareDevelopment Activities Technical Report, 7/87

15.InterimGuide to Inspection of Validation of Filters for Sterilizing Liquids, 1995

16.ORAStability Guidance for Preapproval Inspections, 3/92

17.Inspectionof Bulk Chemical Substances, 3/92

附5. HUMAN DRUG CGMP NOTES

人用药cGMP注释

INTERNATIONALCONFERENCE ON HARMONIZATION GUIDELINES

ICH指南

附6. OTHER

其他

1.Federal Standard 209E

2.ISO 9000 Documents

3.Review of Procedures for the Detection of Residual Penicillins in Drugs

4.Inspection Technical Guide #41: Expiration Dating & Stability Testing forHuman Drugs, 10/85

5.Federal Register on ETO Residues, 6/78

6.Drug Stability Guideline for Veterinary Drug Products, 12/90

7.Various Technical Reports and Monographs from the Parenteral Drug Association

a.Validation of AsepticDrug Powder Filling Processes

b.Validation of SteamSterilization Cycles

c.Validation of AsepticFilling for Solution Products

d.Aspects of Container/ClosureIntegrity

e.Design Concepts forthe Validation of a Water for Injection System

f.Validation of Dry HeatProcesses Used for Sterilization and Depyrogenation

8.Sterility and Pyrogen Requirements for Injectable Drug Products (CVM)

9.Various AAMI Documents

10.Various trade association publications

附7.  TEXTBOOK REFERENCES

参考教科书

Thereare a number of textbooks available related to pharmaceutical production whichserve as valuable reference sources. Consult with the FDA Medical Library,National Experts, DEIO/ Investigations Branch, or other places for thesereferences. The following is a partial list that may prove helpful:

有很多对于制药生产有关的教科书也是有价值的参考资料，可以咨询FDA医学图书馆、国内专家，DEIO/研究调查部门或者其他地方来获得这些参考教科书。下面的清单只是部分可能有用的教科书清单：

1.AsepticPharmaceutical Manufacturing I & II

2.ComputerSystems Validation for the Pharmaceutical and Medical Device Industries

3.Designand Operation of Pharmaceutical Bio-Cleanrooms and Aseptic Areas

4.DrugStability Principles and Practices

5.FailureMode and Effect Analysis

6.GoodManufacturing Practices for Pharmaceuticals

7.Guidelinesfor Laboratory Quality Auditing

8.IndustrialSterilization

9.Introductionto Pharmaceutical Dosage Forms

10.IsolatorTechnology

11.Juran'sQuality Control Handbook

12.ParenteralProducts

13.ParenteralQuality Control

14.PharmaceuticalDosage Forms: Parenteral Medications Vols 1,2, & 3

15.PharmaceuticalDosage Forms: Tablets Vols 1, 2, & 3

16.PharmaceuticalProcess Validation, Second Edition

17.PharmaceuticalStatistics Practical and Clinical Applications

18.Pyrogens

19.Remington'sPharmaceutical Sciences, 18th edition

20.SterilePharmaceutical Manufacturing Vols 1 & 2

21.Sterilizationof Medical Products

22.TheMerck Index

23.ThePharmaceutical Quality Control Handbook

24.TheTheory and Practice of Industrial Pharmacy

25.Validationof Aseptic Pharmaceutical Processes

26.USP/NF

注：本文件只是作为FDA调查员和其他工作人员的参考资料，该文件不约束FDA，也不授予任何人任何权利、特权、利益和豁免权。

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