FDA国外制药企业检查指南中英文对照-Part 1
2016-10-04 23:42阅读：
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GUIDE(1)
TO INSPECTIONS
OF FOREIGN PHARMACEUTICAL MANUFACTURERS
FDA国外制药企业检查指南
BACKGROUND
背景
There has been a significant increase in the number of
foreign inspections of pharmaceutical manufacturing plants in the
past few years. This trend is attributable mainly to the increase
in the number of pre-approval inspections although the increase has
been noted in other areas such as routine GMP inspections and
compliance follow-up activities. Considering the
resource-intensive nature of the foreign inspection program, it has
become clear that effective and efficient inspectional coverage is
crucial to the successful management of the program and that can be
achieved only through maintenance of consistency and uniformity of
inspection and enforcement activities.
过去几年对于国外制药企业检查的数量显著增加，虽然在日常的GMP检查和后续的回顾性检查活动也有增加，但这种趋势主要是还是由预先批准的检查数量增加所引起的。国外检查的资源密集型的本质使得有效和高效的检查覆盖范围对于成功的计划管理很重要，而且只能通过维持检查的持续性和一致性以及强制行动来达到上述目的。
Whenever possible, the agency tries to utilize only highly
qualified Investigators and Analysts for the foreign inspection
program who have extensive experience in conducting drug
inspections with demonstrated track records of working effectively
in a tight time frame and under considerable pressure. However, it
has become increasingly evident that a formal guidance is necessary
to address the issues specific to the foreign drug inspection
operations as the agency needs to broaden the cadre of personnel to
meet the objective of the program. Through this guide, the agency
strives to ensure that it continues to realize the consistency and
the uniformity in the overall inspectional/enforcement activities
and, furthermore, informs the prospective inspection staff of the
differences in the foreign vs. domestic drug inspection
programs.
FDA会尽可能的在国外检查计划中使用具有高素质的检查员和分析师，这些高素质的检查员和分析师指的是拥有丰富药品检查并且拥有能够表明他们能在时间较紧、压力较大的情况下有效完成检查计划的记录。然而为了扩大相应的人事储备来满足日益增加的国外检查的需要，FDA认为有必要确立一个专门针对于国外检查计划的正式指南。通过本指南，FDA能够保证所有的检查或者强制活动都能够延续一贯的连续性和一致性，而且可以为未来的检查员展示国内和国外检查计划的差异。
This guide was prepared by FDA's Office of Regulatory Affairs
(ORA) with the assistance of the Center for Drug Evaluation and
Research (CDER) and the Center for Veterinary Medicine
(CVM).
本指南是由FDA的法规事务办公室（ORA）在药品审评研究中心（CDER）和兽用药中心（CVM）的协助下完成的。
PURPOSE
目的
This document is not intended to provide guidance on how to
perform an inspection at a foreign drug establishment. Rather, it
is intended to address logistical and technical aspects specific to
foreign drug inspections. With diminishing resources and increasing
responsibilities in this program, efficient utilization of
available time and information is a key to affording an adequate
inspectional coverage abroad. This means that the investigator or
the inspectional team will need to start preparing for the
inspections as soon as the inspection itinerary is
set.
本指南不是一个关于如何在国外药品公司执行检查的指南，而是一个旨于解决针对国外药品检查活动后勤和技术方面问题的指南。因为FDA针对于国外检查计划的资源越来越少且责任越来越重，因此如何高效的利用有限的时间和信息对于执行一个覆盖足够范围的国外检查计划就显得非常重要。这也就意味着检查员或者检查组需要在确定了检查行程之后就立即着手准备检查活动。
The guidance provided in this document is intended to
establish greater consistency and uniformity in inspectional
activities at both domestic and foreign drug manufacturers.
Additionally, this document is intended to strengthen the foreign
inspection program at all levels through greater utilization of the
resources available in the field and the Centers.
本文件中提供的指导旨在为FDA的国内和国外药品检查活动确立更广泛的连续性和一致性。此外，本文件也可以使得FDA能够通过更好的利用现有资源来全方位地强化国外检查计划。
This document outlines the types of information and documents
that the inspection team is expected to review prior to the foreign
inspection trip. It sets forth the roles played by members of the
inspection team and the staff in the Office of Regional Operations.
It explains the communication process and the flow of work among
field offices, the Office of Regional Operations, and respective
Centers, namely, Center for Drug Evaluation and Research (CDER) and
Center for Veterinary Medicine (CVM) bearing in mind that there are
changes taking place in how the program is managed
administratively. It sets forth guidance for inspection teams
regarding communications with officials of the regulated
industry.
本文件概括了检查组在开展国外检查之前应该审核的信息和文件类型，并为检查组成员和FDA区域性运行办公室员工进行了角色定位；同时本文件也对现场办事处、区域运行办公室和（FDA）各个中心的沟通过程和工作流程进行了说明，也就意味着CDER和CVM需要记住关于检查计划行政管理方面的发生的变化。
For guidance on specific inspectional areas or technical
subjects, the investigator should continue to refer to existing
inspection guides, appropriate sections of the Compliance Program
Guidance Manual, and Compliance Policy Guides.
对于特定检查区域或技术主题，检查员需要继续参考已有的检查指导、合规性项目指导手册和合规性政策指南中适用的章节。
OVERALL PROGRAM ADMINISTRATION AND
MANAGEMENT
检查计划的总体行政管理
The foreign inspection program is under the management and
direction of the International and Technical Operations Branch
(ITOB) headquarters staff of the Division of Emergency and
Investigational Operations/ORO. This branch schedules all foreign
inspection trips and provides all the resources necessary for the
program activities. ITOB also performs liaison activities with
CDER, CVM, field offices, and the regulated industry. In addition,
headquarters staff of the branch is responsible for resolving
logistical difficulties that may arise during inspection
scheduling, in-transit changes, and pre-inspection document
support, and other issues.
国外检查计划是由应急和调查管理部门/ORO总部下属的国际业务和技术运营分部（ITOB）管理和指导的。ITOB负责所有国外检查的行程安排并提供所有检查活动所需的必要资源，同时ITOB也负责与CDER、CVM、现场办公室以及受管辖行业之间的联络工作；此外ITOB总部还负责解决可能在已安排的检查过程中和检查途中可能发生的后勤保障问题，支持预检查所需文件和其他的事务。
The field offices evaluate and endorse establishment
inspection reports (EIRs) and forward them to ITOB. Inspections
performed by the ITOB staff or the Center personnel are evaluated
and endorsed by the branch headquarters staff. ITOB forwards EIR
packages and any recommendations to the appropriate Center and
coordinates all follow-up activities. As mentioned earlier, the
policy regarding compliance review and follow-up activities is
under review and is subject to change.
Field offices are expected to ensure that assignments are
completed on schedule; and to ensure reports and decisions
regarding follow-up activities are submitted to ITOB in a timely
manner. Field offices are accountable for the work identified in
the ORA field workplan covering foreign inspections assigned to
their districts and regions.
FDA现场办公室负责工厂检查报告（EIRs）的评估和签署，并将EIR转交给ITOB。ITOB员工或者（FDA某相关）中心人员执行的检查是由ITOB总部评估和签署的。ITOB负责将EIR报告以及任何建议打包转发给合适的（FDA）中心并协调所有的后续活动。如前面所提到的，关于合规性审查以及后续活动的政策目前正在审查当中且会有变化。
PROCEDURES AND CONCEPTS
程序和概念
Inspections at foreign drug facilities are expected to be
approached in the same manner as domestic inspections. One main
difference that poses a significant challenge to the inspection
team abroad is the logistics borne by the program itself. The
majority of foreign inspections are pre-set and relatively tight
time-framed. Unless the inspection is prepared in advance and
sharply focused, it is difficult to meet the objectives of the
program satisfactorily.
针对国外药品企业的检查应该以和国内药品企业的检查差不多的方式进行，两者之间最主要的区别是国外检查本身的后勤负担将会给检查组带来非常大的挑战。绝大多数的国外检查都是预先设定的，并且检查时间相对较紧；因此如果不能在事先准备好并且明确重点的话，那么便很难使检查计划的达到让人满意的目标的。
Another factor to keep in mind is that the authority to
inspect foreign drug facilities does not come from Section 704 of
the Food, Drug and Cosmetic Act (the Act,) but from the agency's
ability to exercise Section 801 of the Act and commitments made by
the sponsors of applications, if applicable.
另一点需要注意的是FDA对国外药品企业进行检查的授权并不是来自于食品、药品和化妆品法案704章节，而是FDA对上述法案第801章节的运用以及申请发起人的承诺（如果适用的话）。
For that reason, the agency is not required to provide
stringent documentary evidence to establish violations of the Act.
However, the inspection team is expected to collect sufficient
records to substantiate its findings and to aid in the further
review process by the agency.
因此FDA在确定违规行为时是不需要提供严格的书面证据的，但是检查组需要收集足够多的记录来支持检查结果并协助FDA的进一步的审查。
The inspection team should consult appropriate sections of
the Compliance Program Guidance Manual (CPGM) to determine the
level and the area of coverage. The team should also refer to
pertinent sections of the Compliance Policy Guides (CPGs),
Regulatory Procedures Manual (RPM), and various inspection guides
when preparing for and conducting foreign inspections.
检查组需要通过查阅合规性项目指导手册中（CPGM）适用的章节来确定检查所应该达到的层次和覆盖的范围，检查组在准备和执行国外检查的时候还需要参考合规性政策指南（CPGs）、管理程序手册（RPM）和其他检查指南中有关的章节。
As a general rule, sample collection is not required during
inspections at foreign facilities. However, some compliance
programs, such as the drug pre-approval and post-approval programs,
may require sample collection as part of the inspection process. Be
guided by the respective compliance program.
通常在国外工厂进行的检查是不需要收集样品的，但是对于某些合规性计划，比如针对药品的预先批准和批准后的回归性计划的检查，样品的收集工作可能是作为检查活动一部分的。（因此）样品采集要针对不同的合规性计划进行个案处理。
The inspection team leader is responsible for contacting the
assigned Center application reviewers and discussing the need for
sample collections. When significantly violative conditions are
observed during an inspection, the team leader should alert ITOB
with its findings either by phone or FAX for timely evaluation of
the situation. At the end of each inspection, the inspection team
leader is expected to communicate the result of the inspection to
ITOB, if possible, by FAX, (301) 443-6919, transmission of the form
FDA 483, a brief summary of findings, and a proposed
recommendation.
检查组组长负责联系指定的（FDA）中心的申请审评员并与其讨论是否需要在检查中收集样品，当在检查中发现了重大的违规行为时组长需要通过电话或者传真向ITOB通报检查发现的情况以便ITOB能够及时的违规情况进行评估。
每次检查结束之后，检查组需要与ITOB就检查结果进行沟通，沟通方式尽可能使用传真-（301）443-6919，同时还要向ITOB转发FDA
483表格、检查过程中发现的情况小结和提出的建议。
INSPECTION SCHEDULING
检查行程安排
ITOB headquarters staff is responsible for scheduling all
foreign inspectional activities. When requests for inspection from
various components of the agency are received by ITOB, it schedules
and assigns inspections to foreign inspection cadre members
according to their specialties and availability. Geographical
factor also influences the assignment of the inspections; i.e.,
ITOB tries to assign inspections to the lead investigator of the
home district where the sponsor firm is located. This proximity to
the sponsor firm will provide the inspection team some advantage in
dealing with the US representative at all stages of the
inspection.
ITOB总部负责所有国外检查活动的行程安排，当ITOB接收到不同FDA各部门的检查请求之后，ITOB将根据外国检查组成员的专长和时间来安排和分配检查。地理因素也会影响到检查的分配，比如说ITOB会设法将检查分配给与被检查公司同一地区所在的首席检查员，这种安排可以为检查组在检查全程中与美国代表打交道时带来优势。
At the initial stage of inspection planning, ITOB
headquarters staff contact the domestic sponsor of an application
to obtain any pertinent information necessary for preparation of
the inspection scheduling. If any documents or data regarding the
facility to be inspected need to be obtained, ITOB will arrange
with the sponsor to have them forwarded directly to the inspection
team leader in sufficient time prior to the trip departure
date.
在检查计划制定的初期，ITOB总部会联系该申请在美国国内的发起人来获取任何对检查行程安排和准备所必须的相关信息。如果检查组需要任何跟待检查工厂有关的文件或数据的话，ITOB会与申请发起人商议在检查组启程之前将相关文件/数据直接发给检查组组长并预留有充分的时间让检查组去查阅相关的文件/数据。
ITOB will coordinate the collection and the routing of
documents and information from various headquarters offices to the
team leaders. When deemed appropriate, a briefing may be held at
the headquarters office prior to the trip. For those who are
travelling abroad on an inspection trip for the first time, they
are required to be briefed at the headquarters office.
ITOB会协调从各个总部发给检查组的文件、信息的收集和信息/文件传递方式。如果合适的话，可以在启程前在总部办公室举行一个简报会。对于那些第一次出国进行检查的检查员来说，他们会被要求在总部办公室做一个简单的介绍。
REVIEWING DOCUMENTS PRIOR TO TRIP AND WHILE AT THE
FIRM
在检查启程前和检查中需要审阅的资料
Responsibility of the inspection team is to evaluate the
foreign facility's compliance with cGMPs and its adherence to
application commitments and DMF information, if applicable. The
inspection team is expected to review background documents and
records whenever possible and prepare for the inspection prior to
travelling abroad. This is necessary due to the tight time-frame
usually assigned to each inspection; without advance preparation,
an adequate inspectional coverage cannot realistically be attained
in most cases. At this stage of planning, the inspection team will
have to determine tentatively those issues needing attention during
the on-site inspection.
检查组的职责是对国外工厂的cGMP合规性、申请承诺和DMF信息（如果适用的话）进行评估。只要有可能的话，检查组在启程前往国外检查之前应该阅读背景文件和记录，这是因为每一次出国检查的时间都是很紧的，如果没有事先准备的话，大多数情况下的检查就无法覆盖足够的范围。在准备阶段，检查组必须先暂时性的确定好在现场检查时需要格外注意的问题。
DMFs, (A)NDAs, (A)ADAs, and (A)NADAs filed with the agency
are accessible to the inspection team through ITOB. Copies of the
above are sometimes available at district offices with NDA
managers. For an application product, the inspection team should,
at least, obtain and review the chemistry, manufacturing and
controls (CMC) section of the application prior to the
inspection.
检查组可以通过ITOB获得任何在FDA登记过的DMFs,
(A)NDAs, (A)ADAs, and
(A)NADAs，而复印件有时可以在区域办公室的NDA管理者那里获得。对于一个产品申请，检查组最少应该在检查之前获得并查阅相应申请中有关CMC的章节。
This section contains information regarding bio-batches,
process and controls, analytical methods, and supporting analytical
data. Also worth reviewing are reviewers' comments and
correspondence between the sponsor and the agency (deficiency
letters and written responses). They usually contain
application-specific issues, but occasionally provide indications
of GMP concerns to focus on. For an approved application, annual
reports should be reviewed to identify any potential problems. For
bulk drug substances, most of which are covered by DMFs, the
inspection team should review the section describing the final
purification steps of the manufacturing process.
CMC章节应该包含生物批次、工艺、控制、分析方法以及支持性的分析数据，另外需要仔细查阅（FDA相关中心）审评员对申请的评论和FDA与申请发起人之间的通信（缺陷信和书面回复），虽然在一般情况下这些通信中只包含了申请有关的特定问题，但是偶尔也会提供一些GMP关注点方面的信息。对于一个已经批准了的申请，必须审阅相应的年报来识别任何潜在的问题；对于原料药而言，大部分的申请都是以DMF形式存在的，检查组需要审核工艺描述中最后的纯化步骤。
Sometimes, it becomes necessary to review the documents that
are not part of data filed with the agency prior to the scheduled
inspection. Either ITOB or the inspection team may request those
data from the domestic sponsor or the foreign facility. They are
documents that would be routinely inspected, but may be too bulky
or lengthy to cover during the limited on-site inspection. Examples
of such documents are manufacturing process validations, cleaning
validations, and stability data.
While at the firm the inspection team should evaluate all
process failures, product failures, failures in laboratory tests,
and process changes. Process failures and process changes are
important because they have a significant impact on the adequacy of
process validation. Attention should be given to all reports of
failure investigations of any batches requiring rework or
reprocessing.
有些时候检查组需要在计划检查行程之前查阅那些已在FDA登记材料以外的文件，这时不论是ITOB还是检查组都可以向该申请在美国国内的发起人或者是国外的工厂要求提供，虽然这类文件通常也会在现场检查的时候进行审核的，但是因为这些文件数量繁多而无法在有限的现场检查时间内完全覆盖，所以可能会在现场检查之前就要求工厂提供（这些文件）给检查组以便事先审核。这类文件包括工艺验证资料、清洁验证资料和稳定性数据。检查组在公司检查的时候必须查阅所有的过程失败案例、产品失败案例、实验室分析失败案例和工艺变更。工艺失败和工艺变更之所以很重要的原因是因为它们对于工艺验证的充分性有重大的影响。必须关注到任何重加工和返工批次的所有失败调查报告。
For sterile products, the following should be reviewed:
microbial test results for all batches; all initial positive
sterility test results and reports of investigation; all organisms
isolated and source; environmental monitoring results and
investigations; monitoring of Water for Injection (WFI) systems for
microbial and endotoxin qualities. For aseptic processes, media
fills need to be reviewed. Also, keep in mind that dosage forms
other than injectables may have microbiological
requirements.
对于无菌类产品需要审评下面几点：所有批次的微生物检测结果；所有的原始阳性无菌测试结果和调查报告；所有孤立的有机体和它们的来源；环境监测结果和调查；注射用水系统（WFI）的微生物和细胞内毒素监测。对于无菌工艺，需要审核培养基灌装；此外需要记住除注射用之外的其他剂型也可能有微生物方面控制的需要。
Complaint files should be reviewed for all products being
covered.
需要审核覆盖所有产品的投诉文件
Determine and report all products that the firm manufactures,
which products of those are shipped to the United States, and the
amounts being shipped to the USA since the last inspection or over
the last two years.
确定并报告被检查公司自上一次检查之后或者上一个两年周期内该公司所生产的所有产品和输入到美国的产品以及（相应的）数量。
TEAM INSPECTION
团队检查
A large number of foreign inspections today are performed by
teams of Investigators and Analysts. There is no question about the
importance of close cooperation between the two groups for the
success of the program. The lead Investigator is responsible for
making the pre-inspection preparation and identifying the areas of
focus for each member.
目前大量的国外检查是由检查员和分析师组成的团队完成的，这两组人员之间的紧密合作对于检查活动的成功的重要性是毫无疑问的，首席检查员负责预先检查准备和确定检查组内各个成员所负责的区域。
The lead Investigator is also responsible for providing the
Analyst with any records or data that need to be reviewed prior to
the inspection. During the inspection, he or she leads the
direction of the investigation and determines the types of records
or operations to be examined by the team. However, keep in mind
that the ultimate objective is to maximize the inspectional
coverage by working together as a team and the role played by each
team member should be flexible. In fact, the team members often
need to operate independently at different locations.
首席检查员也负责在启程出国检查前为分析师提供所需要的任何记录或者数据，在检查过程中首席检查员引领检查方向和确定检查组需要检查何种类型的记录或者操作。不过需要记住的是检查的终极目的是在检查组各个成员的通力合作下尽可能的使检查的覆盖更广的范围，因此检查组内各个成员的工作是需要弹性处理的；事实上检查组成员通常需要独立检查不同的位置。
Investigators and Analysts are expected to communicate
inspectional strategies and findings at all times during the
inspection. Strategy discussions outside the inspectional hours are
encouraged. The team should avoid giving any appearance of discord
or disagreement in the presence of the firm's
personnel.
检查员和分析师应该在检查过程中就检查策略和调查结果持续保持沟通，鼓励检查组成员在检查时间之外就检查策略问题进行沟通。检查组成员应避免在有被检查公司的员工存在的情况下发生任何意见不一致和/或者争论的行为。
INSPECTIONAL GUIDANCE
检查指导
Foreign drug inspections will generally involve bulk
pharmaceutical chemicals (BPCs) or dosage forms. The end product
may be sterile or non-sterile. Contract processors or contract
laboratories may also be assigned. The Investigators/Analysts will
inspect these facilities in the same manner as domestic facilities.
The inspection team should be guided by the appropriate Compliance
Programs and Compliance Policy Guides. Also, there are several
inspectional guides that may be useful to review and understand
prior to conducting the inspection. The inspection team may wish to
carry copies of pertinent programs and guides to be used as
inspectional tools and also to have available for copying by the
firms being inspected.
国外的检查一般会涉及到原料药和制剂，最终产品可能是无菌的也可能是非无菌的，也可能会有合同处理商和委托实验室，检查员/分析师需要按照国内检查一样的方式对这些设施进行检查。检查组（的检查）应该由合适的合规性计划和合规性政策指导原则来指导，另外也有一些如果（检查组）能在执行检查前就进行阅读和理解从而会给检查带来益处的检查指导。检查组有时也需要（在出国检查的时候）携带有关的检查计划/指导原则的复印件并当作检查工具使用，同时也能够让被检查的公司能够获得这些（资料的）复印件。
There are numerous sources of information regarding
inspectional guides, Compliance Programs, policy guides, etc. These
include FDA-on-Disk (FDA personnel have access to this on ORA's CD
ROM Gold Disk), FDA's Electronic Bulletin Boards, FDA's Internet
Home Page, CDER staff, CVM staff, and staff in the Investigations
Branch of the Division of Emergency and Investigations Operations.
It is recommended that the inspection team be prepared to provide
the appropriate telephone number or Internet addresses to firms to
assist them in obtaining the various inspectional
guides.
（检查组）有很多种途径来获得这些相关的检查指导、合规性计划、政策指导等，这些途径包括FDA-on-Disk（FDA的员工可以在ORA’s
CD ROM Gold
Disk获得）、FDA电子布告栏、FDA网站主页、CDER的员工、CVM的员工以及应急和调查管理部门下属的调查分部的员工。建议检查组准备好合适的电话或者网址提供给被检查的公司以帮助他们获得各种检查指导。
Refer to Attachment A for a listing of pertinent Compliance
Programs, Compliance Policy Guides, and inspectional
guides.
有关的合规性计划、合规性政策指导和检查指导请参考附件A。
FDA World Wide Web Home Page address:
FDA网址如下：
http://www.fda.gov
