FDA国外制药企业检查指南中英文对照-Part 2
2016-10-04 23:46阅读：
PRE-APPROVAL INSPECTIONS
预先批准检查
Pre-approval inspections (PAIs) requested by CDER and CVM for
approval of specific NDAs/ANDAs/NADAsA constitute a major segment
of FDA's foreign pharmaceutical inspection activities. When a PAI
inspection is scheduled at a given facility, ITOB may, at its
discretion, request the inspection team also cover other product
applications needing priority handling. District NDA program
managers should keep track of and advise ITOB headquarters staff of
any significant issues pending at the facility that must be
resolved before an application can be approved even if CDER or CVM
has not completed its review of the application.
CDER和CVM所要求的针对特定NDAs/ANDAs/NADAsA的预先批准检查（PAIs）是FDA国外检查活动很重要的一部分。当对某个规定工厂的检查已经安排好了的时候，ITOB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。区域办公室的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 relatively short deadlines. They must
be given the highest priority and handled in a timely
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 (if one is issued), a brief
summary of findings, and proposed recommendations. Subsequently,
the EIR is expected to list all of the applications covered during
the inspection and the status of each application. Be guided by
appropriate Compliance Programs and Compliance Policy Guides for
making endorsements and recommendations.
最快在检查结束的时候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（如果有的话）、检查结果的小结和检查组建议传发给ITOB。接下来需要在EIR报告中列清楚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。
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 we conduct
ourselves abroad may well determine how much information we bring
back from the firms we inspect on which to base our regulatory
decisions.
现在越来越多的检查是在与美国文化不同的地方进行，（有时）甚至是在拥有与美国相同文化特质的地方FDA也经常在被检查的工厂观察到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的公司带回多少按照我们自己的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、记录文件中的任何缺陷和差异。
The mission of the inspection team is, as is true in the
domestic inspections, to gather as much information as possible to
allow the agency to make an informed decision. Avoid a
confrontational approach, if at all possible. Yet, be assertive and
clear about what information and/or documentation the firm should
provide to the team.
检查组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/文件给检查员一事非常自信和清楚。
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. Regulatory processes 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。
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 through the
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 to discuss issues or concerns regarding the
specific application. As mentioned in the 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 in transit. 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候就特定的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、行政或者其他事情保持联系；在途中的时候ITOB有时也会通知检查组任何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 findings warrant
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), a brief 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。
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 for its 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.
区域（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.
对于预先批准申请的检查，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 as soon 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。
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 a manufacturer 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 manufactured
for years employing an established process for many years and is
not expected to 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 of batch production
records. If the process needs to be constantly fine-tuned from
batch 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。
DOCUMENTATION OF VIOLATIONS OF
cGMPs
cGMP违规的文件资料
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 of the law exist to
warrant restricting importation of the commodity and/or
non-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
The following list shows some of the references to be used by
travelers. This list is not all inclusive. Travelers should use
whatever resources available to them to keep this list updated and
adapted for their needs.
下面的表格列出了那些对出国进行检查的人员有用的参考（文件），但应注意这些文件不是包罗万象的，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。
COMPLIANCE PROGRAMS
合规性计划
1. 7356.002
Drug Process Inspections
2.
7356.002A Small Volume Parenterals
3.
7356.002B Drug Repackers and Relabelers
4.
7356.002C Radioactive Drugs
5.
7356.002F Bulk Pharmaceutical Chemicals
6. 7346.832
Pre-Approval Inspections
7. 7346.843
Post-Approval Audits
8.
COMPLIANCE POLICY GUIDES
合规性政策指导
CHAPTER 4 - 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/Test Requirements
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 to
Stability/Expiration
6. CPG
7132c.08: Process Validation Requirements for Drug Products Subject
to Pre-Market Approval
7. CPG
7150.16: Status and Responsibilities of Contract Sterilizers
Engaged in the Sterilization of Drugs and Devices
8. CPG
7151.02: FDA Access to Results of Quality Assurance Program Audits
and Inspections
CHAPTER 2 - BIOLOGICS
CHAPTER 3 - DEVICES
CHAPTER 6 - VETERINARY MEDICINE
REGULATORY PROCEDURES MANUAL
管理程序手册
CDER GUIDELINES
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-Product Endotoxin Test,
12/87
14.Sterilization Process Validation:
Recommendations for Information to be Submitted to CDER/CVM
Applications, 1/93
15.Guidance to Industry on the Packaging of Test
Batches, 2/95
16.Various SUPAC Documents
17.
INSPECTION GUIDES
检查指南
1. Guide to
Inspections of Oral Solid Dosage Forms Pre/Post Approval Issues for
Development and Validation, 1/94
2. uide 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 Control
Laboratories, 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.Guide to Inspections of Oral Solutions and
Suspensions, 8/94
11.Guide to Inspection of Computerized Systems
in Drug Processing, 2/83
12.Guide to Inspections of Dosage Form Drug
Manufacturers - CGMPs, 10/93
13.Preapproval Inspection Guide for Laboratory
Analysts, 3/91
14.Software Development Activities Technical
Report, 7/87
15.Interim Guide to Inspection of Validation of
Filters for Sterilizing Liquids, 1995
16.ORA Stability Guidance for Preapproval
Inspections, 3/92
17.Inspection of Bulk Chemical Substances,
3/92
18.
HUMAN DRUG CGMP NOTES
人用药CGMP注释
INTERNATIONAL CONFERENCE ON HARMONIZATION
GUIDELINES
ICH指南
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 for Human 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 Aseptic Drug Powder Filling
Processes
b.
Validation of Steam Sterilization Cycles
c.
Validation of Aseptic Filling for Solution
Products
d. Aspects
of Container/Closure Integrity
e. Design
Concepts for the Validation of a Water for Injection
System
f.
Validation of Dry Heat Processes Used for Sterilization and
Depyrogenation
8.
Sterility and Pyrogen Requirements for Injectable Drug
Products (CVM)
9. Various
AAMI Documents
10.Various trade association
publications
TEXTBOOK REFERENCES
参考教科书
There are a number of textbooks available related to
pharmaceutical production which serve as valuable reference
sources. Consult with the FDA Medical Library, National Experts,
DEIO/ Investigations Branch, or other places for these references.
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. Aseptic
Pharmaceutical Manufacturing I & II
2. Computer
Systems Validation for the Pharmaceutical and Medical Device
Industries
3. Design
and Operation of Pharmaceutical Bio-Cleanrooms and Aseptic
Areas
4. Drug
Stability Principles and Practices
5. Failure
Mode and Effect Analysis
6. Good
Manufacturing Practices for Pharmaceuticals
7.
Guidelines for Laboratory Quality Auditing
8.
Industrial Sterilization
9.
Introduction to Pharmaceutical Dosage Forms
10.Isolator Technology
11.Juran's Quality Control Handbook
12.Parenteral Products
13.Parenteral Quality Control
14.Pharmaceutical Dosage Forms: Parenteral
Medications Vols 1,2, & 3
15.Pharmaceutical Dosage Forms: Tablets Vols 1,
2, & 3
16.Pharmaceutical Process Validation, Second
Edition
17.Pharmaceutical Statistics Practical and
Clinical Applications
18.Pyrogens
19.Remington's Pharmaceutical Sciences, 18th
edition
20.Sterile Pharmaceutical Manufacturing Vols 1
& 2
21.Sterilization of Medical
Products
22.The Merck Index
23.The Pharmaceutical Quality Control
Handbook
24.The Theory and Practice of Industrial
Pharmacy
25.Validation of Aseptic Pharmaceutical
Processes
26.USP/NF
1.
1 Note: This document is
reference materials for Investigators and other FDA personnel. The
document does not bind FDA, and does not confer any rights,
privileges, benefits, or immunities for or on any
person(s).
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。
