構(gòu)成拖延、否認、限制、拒絕藥品檢查的情況

1、Contains Nonbinding Recommendations 包括無約束力的建議Guidance for Industry工業(yè)指南Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection構(gòu)成拖延、否認、限制、拒絕藥品檢查的情況U.S. Department of Health and Human Services 美國衛(wèi)生與人力資源服務(wù)部Food and Drug Administration 食品藥品監(jiān)督管理局Office of Regulatory Affair

2、s (ORA) 藥政事務(wù)辦公室(ORA)Center for Drug Evaluation and Research (CDER) 藥物評價與研究中心(CDER)Center for Biologics Evaluation and Research (CBER)生物制劑評價與研究中心(CBER)Center for Veterinary Medicine (CVM) 動物藥物中心(CVM)October 2014 2014年10月TABLE OF CONTENTS目錄I. INTRODUCTION 簡介2II. BACKGROUND 背景5IIIDELAY OF INSPECTIONS 拖

3、延檢查6IVDENIAL OF INSPECTION 拒絕接受檢查11VLIMITING OF INSPECTION 限制檢查12VIREFUSAL TO PERMIT ENTRY OR INSPECTION 拒絕允許進入或檢查15Guidance for Industry工業(yè)指南Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection組成拖延、否認、限制、拒絕藥品檢查的情況This guidance represents the Food and Drug Administ

4、rations (FDAs) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discus

5、s an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance.本指南體現(xiàn)了FDA當(dāng)前對于此話題的見解，它不為任何人創(chuàng)造或提供任何權(quán)利，也不約束FDA 或公眾。如果有可替代的滿足相關(guān)法律和法規(guī)要求的方法，則可以選用這種方法。如果需要對替代

6、的方法進行討論，請聯(lián)系負責(zé)實施本指南的FDA官員。如果無法確定相關(guān)的FDA的官員，請撥打在本指南標(biāo)題頁中列出的相關(guān)電話號碼。I . INTRODUCTION 簡介On July 9, 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) (Public Law 112-144) was signed into law. Section 707 of FDASIA adds 501(j) to the Food, Drug, and Cosmetic Act (FD&C Act) to deem adu

7、lterated a drug that “has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.” Section 707(b) of FDA

8、SIA requires the Food and Drug Administration (FDA) to issue guidance that defines the circumstances that would constitute delaying, denying, or limiting inspection, or refusing to permit entry or inspection, for purposes of section 501(j).2012年7月9日，F(xiàn)DA食品藥品管理局安全創(chuàng)新法（FDASIA)）（公法112-144）簽署成為法律。FDASIA的7

9、07部分加入501(j)到食品、藥品、化妝品法案（FD&C Act）來將摻假藥物定義為“在任何工廠、倉庫或企業(yè)生產(chǎn)、處理、包裝或保存的，且這些工廠、倉庫或企業(yè)的所有者、操作人員或代理機構(gòu)對藥品檢查進行拖延、否認或限制，或者拒絕允許進入或進行檢查”。FDASIA的707（b）部分要求FDA 頒布指南來規(guī)定構(gòu)成拖延、否認、限制或拒絕藥品檢查的情況，這就是501（j）部分的目的。This guidance covers facilities that are subject to inspection under section 704 of the FD&C Act.2 This guidance

10、 defines the types of actions, inaction, and circumstances that the FDA considers to constitute delaying, denying, or limiting inspection, or refusing to permit entry or inspection for the purposes of section 501(j).3 The examples used in this guidance are not intended to serve as an exhaustive list

11、; rather, they illustrate the most common situations that FDA has encountered in preparing for and conducting inspections as well as situations that FDA anticipates may occur. FDA does not interpret the four terms describing prohibited behavior (delay, deny, limit, refuse) necessarily to be mutually

12、 exclusive. Therefore, the behaviors described in the following scenarios may be examples of more than one type of prohibited behavior. Also note that, for purposes of this guidance, the term facility is intended to include all establishments, factories, and warehouses covered by section 501(j).本指南包

13、括所有需要按照FD&C Act 704部分進行檢查的設(shè)施。本指南定義了FDA 認為會構(gòu)成為實現(xiàn)501(j)部分的目的而進行的藥品檢查的拖延、否認、限制或拒絕進入或檢查的情況、行為及不作為。本指南中舉出的例子并不是有關(guān)這些情況的詳細清單，但它們卻是在FDA準備或進行檢查時最常遇見的情況，也是FDA 認為可能會出現(xiàn)的情況。FDA 也不將這4中描述禁止行為的項目（拖延、否認、限制或拒絕）解釋為互不相關(guān)的，因此，在下面章節(jié)中舉出的例子有可能不只屬于某一類禁止行為。還要注意的是，本指南中的“設(shè)施（facility）”一詞包括了501(j)部分所囊括的所有企業(yè)、工廠及倉庫。Section 704 of t

14、he FD&C Act authorizes FDA to conduct inspections at reasonable times, within reasonable limits, and in a reasonable manner. Although the FD&C Act does not specifically define “reasonable,” FDA has long maintained that the inspectional authority under Section 704 of the FD&C Act “extends to what is

15、reasonably necessary to achieve the objective of the inspection.”4 FDA intends to work with facilities to conduct inspections and procure the information necessary to achieve the objective of the inspection. FDA will consider reasonable explanations for behavior that may otherwise be considered to b

16、e delaying, denying, limiting, or refusing an inspection.FD&C Act 704部分授權(quán)FDA 在合理的范圍內(nèi)、以合理的方式、進行適當(dāng)次數(shù)的檢查。雖然FD&C Act 并沒有對“合理的”進行定義，當(dāng)FDA長期以來將FD&C Act 704部分下的檢查權(quán)限維持為“擴展到為實現(xiàn)檢查的目的而需要的合理的程度”。FDA 意圖與企業(yè)一起進行檢查以及獲取為實現(xiàn)檢查的目的所需要的信息。FDA 會對被認為是對藥品檢查進行拖延、否認或限制，或者拒絕進行檢查的行為進行合理的解釋說明。FDAs guidance documents, including th

17、is guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agencys current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means t

18、hat something is suggested or recommended, but not required.FDA 的指導(dǎo)性文件，包括本指南，并不會建立強制執(zhí)行的責(zé)任。相反，這些指南描述了FDA當(dāng)前對某一主題的見解，除另有法律或法規(guī)引證外，應(yīng)作為建議。在FDA的指南中，使用“應(yīng)當(dāng)（should）”一詞時，表示建議或推薦，而不是要求。II . BACKGROUND 背景Section 704(a) of the FD&C Act provides FDA authority for inspections, specifically providing authority for d

19、uly designated officers or employees of the FDA to enter, at reasonable times, and inspect, at reasonable times and within reasonable limits and in a reasonable manner, facilities subject to regulation under the FD&C Act.5 An FDA inspection is a “careful, critical, official examination of a facility

20、 to determine its compliance with certain laws and regulations administered by the FDA.”6 Section 706 of FDASIA amended section 704(a) of the FD&C Act by adding 704(a)(4), which allows FDA to request, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits,

21、 and in a reasonable manner, records or information that FDA may inspect under section 704(a).FD&C Act中704(a)部分授權(quán)FDA進行檢查，特別是授權(quán)為按照要求指定的FDA官員或雇員進入受FD&C Act監(jiān)管的設(shè)施適當(dāng)?shù)拇螖?shù)及以適當(dāng)?shù)姆绞健⒃谶m當(dāng)?shù)南薅葍?nèi)，對受FD&C Act監(jiān)管的設(shè)施進行適當(dāng)次數(shù)的檢查。FDA 檢查是一次“對設(shè)施的仔細、關(guān)鍵、正式的檢查以確定其與確定的FDA的法律和法規(guī)的符合性”。FDASIA的706部分修訂FD&C Act 的704(a)部分，通過增加704(a)(4)，以

22、允許FDA在合理的時間范圍和限度內(nèi)、以適當(dāng)?shù)姆绞皆跈z查前索要704(a)部分規(guī)定的FDA可能會檢查的記錄和信息，或以索要704(a)部分規(guī)定的FDA可能會檢查的記錄和信息來代替檢查。Facilities that are required to register under section 510 of the FD&C Act7 and that voluntarily register as outsourcing facilities under section 503B of the FD&C Act8 are required to submit certain informatio

23、n to FDA. FDA uses registration information for many purposes, including scheduling inspections. It is imperative that drug facilities register under section 510 when required, and that all registered facilities provide the information required by statute and our regulations to avoid creating confus

24、ion or complicating the scheduling and conduct of inspections. We also strongly encourage facilities to update point of contact e-mail information submitted to the Agency promptly if a change occurs after an annual registration submission.9根據(jù)FD&C Act 510部分要求進行注冊的設(shè)施和根據(jù)FD&C Act 503B 部分自愿注冊為外包的設(shè)施，被要求向F

25、DA提交確定的信息。FDA將注冊信息用于不同目的，包括對檢查進行計劃。極為重要的是，根據(jù)510部分注冊的藥品設(shè)施，在被要求時，所有已注冊的公司要提交我們的法律和法規(guī)要求的信息以避免造成困惑或使計劃或進行檢查變得復(fù)雜。我們強烈建議如果在年度注冊資料提交后進行了變更，公司能夠立刻對提交給FDA的聯(lián)系郵件信息點進行更新。It is a prohibited act under sections 301(e) and 301(f) of the FD&C Act to refuse to permit entry or inspection or refuse to permit access to

26、or copying of certain specified records.10 New section 501(j) of the FD&C Act, as added by FDASIA section 707, now deems a drug to be adulterated if “it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, wa

27、rehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.”在FD&C Act 301(e) 和 301(f)部分規(guī)定拒使進入或檢查，或拒使查看或備份指定的記錄是違法的。由FDASIA 707 部分添加的FD&C Act中的新部分501(j)將摻假藥物定義為“在任何工廠、倉庫或企業(yè)生產(chǎn)、處理、包裝或保存的，且這些工廠、倉庫或企業(yè)的業(yè)主、操作人員或代理機構(gòu)對藥品檢查進行拖延、否認或限制，或者拒使進入或檢查”。III DELAY OF INS

28、PECTIONS 拖延檢查Delays may occur for many reasons, some of which are beyond the control of the facility. However, where an owner, operator, or agent causes the delay of an inspection, this may cause the drugs to be adulterated under section 501(j) of the FD&C Act.拖延有很多原因，有些超出了企業(yè)了控制。但是，如果企業(yè)所有者、操作人員或代理機構(gòu)

29、造成檢查的延遲，這就有可能導(dǎo)致藥品根據(jù)FD&C Act中501(j)部分被定義為摻假藥品。A. Delay Scheduling Pre-announced Inspections 延遲預(yù)先公布的檢查的日程The FD&C Act does not require FDA to pre-announce its inspections. Therefore, FDA usually does not pre-announce for-cause and routine surveillance inspections. It is, however, FDAs general practice

30、 to contact the firm before an investigator arrives at the inspection site for pre-approval and pre-license inspections, and most inspections of foreign facilities of drug products. This pre-announcement, although not required, is intended to facilitate the inspection process and ensure that appropr

31、iate records and personnel will be made available.FD&C Act不要求FDA預(yù)先公布檢查。因此，F(xiàn)DA 通常不會預(yù)先公布“有原因”和日常監(jiān)督檢查。然而，F(xiàn)DA的總原則是在調(diào)查人員到達檢查現(xiàn)場進行批準前和許可前檢查前以及對大多數(shù)外國藥品生產(chǎn)公司進行檢查前會聯(lián)系被檢查公司。 這種預(yù)先公布，雖然沒有要求，但卻是為了便于檢查過程和確保能夠接觸到適當(dāng)?shù)挠涗浐腿藛T。FDAs efforts to schedule pre-announced inspections include sending correspondence to the facilit

32、ys point of contact e-mail address, including the facilitys U.S. agent if the facility is a foreign facility. FDA will make reasonable accommodations for local conditions, such as weather or security situations, holidays, and other non-work days, and, where appropriate, scheduled manufacturing campa

33、igns. Examples of delay in scheduling a pre-announced inspection that may cause drugs to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:FDA安排預(yù)先公布的檢查，包括向被檢查公司的聯(lián)系郵件地址發(fā)送信件，如果被檢查公司為外國公司，則還會向該公司在美國的代理機構(gòu)發(fā)送信件。FDA 會根據(jù)當(dāng)?shù)氐臈l件，例如天氣或安全狀態(tài)、假期、其他非工作日，以及如果適當(dāng)?shù)脑挘a(chǎn)安排等進行合理的調(diào)整。因延遲進行預(yù)

34、先公布的檢查而可能導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的例子，包括但不僅限于： A facility will not agree to a proposed inspection start date and does not give a reasonable explanation for its failure to do so.被檢查的公司不同意被提議的檢查開始日期，但并沒有給出合理的解釋。 After scheduling an inspection, a facility requests a later start date without giving

35、a reasonable explanation.在安排檢查后，被檢查的公司要求一個較晚的開始日期，但并沒有給出合理的解釋。 A facility fails to respond following FDAs attempt to contact the facilitys designated contact(s).被檢查的公司未能夠根據(jù)FDA的要求使其與被指定的聯(lián)系人取得聯(lián)系。An example of a potentially reasonable explanation that might result in the drugs not being deemed adultera

36、ted under section 501(j) of the FD&C Act includes, but is not limited to:可能不會導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的合理解釋，包括但不僅限于： Manufacturing at the facility is not on-going, for example running only one manufacturing campaign per month and the facility requests a different date than that proposed by or ag

37、reed to by FDA so that manufacturing will occur during the FDA inspection of the facility.被檢查的公司沒有進行生產(chǎn)活動，例如，每月僅生產(chǎn)一次，被檢查的公司申請的檢查日期與FDA提議的檢查日期不同，并被FDA 批準以便在進行檢查時有生產(chǎn)活動在進行。B. Delay During an Inspection在檢查過程中的拖延An FDA inspection is intended to enable the Agency to review a facilitys compliance with certa

38、in laws and regulations. In a drug facility, FDA has broad authority to inspect things that bear on whether the drugs are adulterated, misbranded, or are otherwise in violation of the FD&C Act. Actions by a facilitys owner, operator, or agent before or after the beginning of an inspection that imped

39、e an FDA investigator at the inspection site from performing the inspection in a reasonable manner may be considered delaying the inspection. FDA is aware that its appearance on-site may initially cause some minor confusion and/or inconveniences to the facilitys employees. Minor delays that result f

40、rom good faith efforts by the facility to comply with FDA requests generally would not be considered unreasonable. Examples of delays during an inspection that may cause drugs to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:FDA檢查的目的是為了能夠讓監(jiān)管當(dāng)局審核生產(chǎn)設(shè)施與確切法律和法規(guī)的符合性。

41、在一個制藥廠內(nèi)，F(xiàn)DA 有廣泛的權(quán)限來檢查所有判定藥品是否摻假、是否錯誤標(biāo)示或是否違反FD&C Act的事物。被檢查公司的所有者、操作人員、或代理機構(gòu)在檢查開始前或檢查開始后所采取的阻礙在現(xiàn)場的FDA調(diào)查員進行適當(dāng)?shù)臋z查的措施，可能會被認為是拖延檢查。FDA意識到，當(dāng)FDA檢查官出現(xiàn)在檢查現(xiàn)場后，剛開始時會引發(fā)一些小混亂和/或給現(xiàn)場的員工帶來一些不便之處。由于公司真誠的努力來滿足FDA的要求而導(dǎo)致的一些不重要的拖延，一般不會被認為是不合理的。由于在檢查過程中的拖延而可能導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的例子，包括但不僅限于： A facility does not a

42、llow the FDA investigator access to an area of the facility until a specific future date or time even though the area is operational and is an area of the inspection site that FDA has authority to inspect, without giving a reasonable explanation.被檢查公司不允許FDA調(diào)查員在指定的日期或時間之前進入到廠房區(qū)域，即使該區(qū)域有操作在運行以及該區(qū)域是FDA有

43、權(quán)限進行檢查的區(qū)域之一，卻沒有給出合理的解釋。 A facility leaves the FDA investigator in a conference room without access to necessary documentation or responsible individuals for an unreasonable period of time that interferes with the investigators ability to complete the inspection.在一段不合理的時間內(nèi)，將FDA調(diào)查員留在會議室中，卻不讓其接觸到必要的文件或

44、相關(guān)責(zé)任人員，影響了調(diào)查員完成檢查。An example of a potentially reasonable explanation that might result in the drugs not being deemed adulterated under section 501(j) of the FD&C Act includes, but is not limited to:可能不會導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的合理解釋，包括但不僅限于： A facility does not provide the FDA investigator acces

45、s to aseptic processing areas until the investigator accommodates the facilitys documented gowning procedures.在FDA調(diào)查員能夠根據(jù)公司規(guī)定的更衣程序進行更衣前，不讓其進入無菌生產(chǎn)區(qū)域。C. Delay Producing Records 延遲出示記錄A critical aspect of FDAs preparation for inspection and inspection of drug facilities is the review and collection of

46、hardcopy and electronic records, files, and papers bearing on whether the drugs are adulterated, misbranded, or are otherwise in violation of the FD&C Act. For example, records may be reviewed to verify compliance, but may also need to be collected to document evidence of deviations, interstate comm

47、erce, product labeling and promotion, and to identify the party or parties responsible for a variety of actions. Although FDA recognizes that facilities require a reasonable amount of time to produce records requested, especially if the records are maintained at a different site, a delay in producin

48、g records to FDA without reasonable explanation may be considered delaying the inspection. Examples of delays in producing records that may cause drugs to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:FDA為檢查所做的準備或?qū)λ幤飞a(chǎn)廠房進行檢查的一個關(guān)鍵方面是審核和收集可以判定藥品是否摻假、是否錯誤標(biāo)示或是否違反FD&

49、C Act的記錄、文件和資料的硬拷貝和電子版。例如，審核記錄可能是為了證實法規(guī)符合性，但也可能將記錄收集作為偏差、州際貿(mào)易、產(chǎn)品標(biāo)示和銷售的記錄證據(jù)，以辨別一系列措施中一方或多方的職責(zé)。盡管FDA意識到被檢查的公司需要一段合理的時間來準備被要求出示的記錄，特別是當(dāng)這些記錄保存在另一個地方時，但當(dāng)延遲向FDA出示記錄卻沒有合理的解釋時，也會被認為是拖延檢查。由于延遲向FDA 出示文件而可能導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的例子，包括但不僅限于： During an inspection, the FDA investigator requests, within a s

50、pecific, reasonable timeframe, records that FDA has authority to inspect, but the facility fails to produce the requested records within the timeframe requested by FDA, without reasonable explanation.在檢查過程中，在一定的合理的時限內(nèi)，被檢查公司無法在規(guī)定的時限內(nèi)出示FDA調(diào)查員要求提供的、其據(jù)有檢查權(quán)限的記錄，而沒有給出合理的解釋。 FDA requests records pursuant t

51、o section 704(a)(4) of the FD&C Act, but the facility fails to produce the requested records in a timely manner, without reasonable explanation.FDA根據(jù)FD&C Act 704(a)(4)部分的規(guī)定索要文件，但被檢查公司沒有及時提供這些文件，也沒有給出合理的解釋。Examples of potentially reasonable explanations that might result in the drugs not being deemed

52、 adulterated under section 501(j) of the FD&C Act include, but are not limited to:可能不會導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的合理解釋，包括但不僅限于： The FDA investigator requests translation of the records into English, and the translation is not readily available.FDA調(diào)查員要求將記錄翻譯為英文，但翻譯件不是現(xiàn)成的。 The records requested are

53、not available at that time because they are being used for a manufacturing operation that is in progress.無法出示被要求出示的文件，因為此文件正在被使用。 The volume of the records requested is sufficiently large as to require reasonable time to compile.被要求出示的文件體積很大，需要合理的時間來匯編。In instances where the facility provides a reas

54、onable explanation for delaying production of records, the facility should also ensure that the resulting delay is of a reasonable duration.假如被檢查的公司對于延遲出示記錄有合理的解釋，那么也應(yīng)當(dāng)確保這種延遲是在合理的時限內(nèi)的。IV DENIAL OF INSPECTION 拒絕接受檢查FDA interprets the word deny to include active behavior by the owner, operator, or age

55、nt of a drug facility to prevent an authorized representative of the FDA from conducting an inspection or to prevent FDA from completing an inspection. This includes statements or physical actions intended to avoid inspection or to mislead, deceive, or impede the investigator. Examples of behavior t

56、hat may constitute a denial that may cause drugs to be adulterated under section 501(j) of the FD&C Act include, but are not limited to:FDA將“拒絕（deny）”一詞解釋為制藥設(shè)施的所有者、操作人員或代理機構(gòu)的主動行為以阻止FDA的授權(quán)代表進行檢查或完成檢查。這包括意圖避免檢查或誤導(dǎo)、欺騙或阻礙調(diào)查員的聲明或形體動作。由于可能構(gòu)成拒絕而可能導(dǎo)致藥品根據(jù)FD&C Act 501(j)部分被定義為摻假的行為，包括但不僅限于： A facility rejects

57、 FDAs attempt to schedule a pre-announced inspection.被檢查的公司拒絕讓FDA 進行預(yù)先公布的檢查。 Upon arrival at the facility, the facility does not allow the FDA investigator to begin the inspection.在到達被檢查公司后，該公司不允許FDA調(diào)查員開始檢查工作。 A facility does not allow the FDA investigator to inspect the facility because certain sta

58、ff members are not present, without a reasonable explanation.被檢查公司由于某些員工不在現(xiàn)場而不允許FDA調(diào)查員對廠房進行檢查，但卻沒有合理的解釋。 A facility does not allow the FDA investigator to inspect the facility by falsely alleging the facility does not manufacture, process, pack, or hold drugs.被檢查公司通過虛假的聲稱沒有在生產(chǎn)、處理、包裝或儲存藥品而不允許FDA調(diào)查員進行檢查。 A facility sends staff home for the day and tells the FDA investigator that the facility is not producing any product.被檢查公司在檢查當(dāng)天給員工放假，然后告知FDA調(diào)查員公司內(nèi)沒有生產(chǎn)活動在進行。Examples of potentially reasonable explanations that might result in t