延误、抵制、限制或拒绝药品检查的情况（上）

延误、抵制、限制或拒绝药品检查的情况（上） http://www.zjccd.org/exchange/a/ff8080814cb54fd9014cbf86de2b0024.htm

编者按：2014年10月21日FDA发布了关于《延误、抵制、限制或拒绝药品检查的情形》的指南终稿，旨在确保其监管的企业不能在检查期间隐藏问题。根据FDASIA 第707条，如果产品的生产商、加工商、包装商或仓储商“延误、抵制或限制检查，或拒绝允许进入或检查”，FDA可授权将产品视为掺假药。 在此规则通过之前，一些企业已设法拒绝或延迟FDA检查员进入其设施，希望有更多的时间可以用来清理不合规痕迹或准备相关资料。根据FDA的进口警告，现有7家中国企业列入FDA该目录下的红色名单（Red List）中，其产品拒绝进入美国。FDASIA立法者希望，创建一个更加公平的体系，使得FDA能够直接处罚不配合其试图检查设施的企业。 该指南多次强调法律解释的“合理性”，对于企业因合理的理由而延误、抵制、限制或拒绝检查表示理解，愿意做出合理的调整。但指南中并未定义“合理的”这一术语，留给FDA更大的自由裁量权。 值得注意的是，FDA的指南还首次确立了FDA工作人员有权“对认为有效地实施具体检查是有必要的设施区域拍照。” 然而，由于拍照可能涉及侵犯企业的知识产权，检查员在检查过程中如需拍照应做好与企业的沟通协调工作。 中心对《延误、抵制、限制或拒绝药品检查的情形》指南文件进行了翻译，以供检查员在现场检查中参考。由于我国与美国在法律法规上存在较大的差别，检查员在借鉴的同时应结合我国的法律法规以及实际情况，灵活应用。由于译者理解水平的局限，翻译可能存在失误之处，敬请谅解。 工业指南 延误、抵制、限制或拒绝药品检查的情形（上） 2014年10月 I. 介绍 2012年07月09日，美国食品和药物管理局安全与创新法案(FDASIA)(公法112-144)签署成为法律。FDASIA中第707条款使得《食品、药品和化妆品法案》增加了501(j)条款，即“如果药品在一家工厂、仓库或企业生产、加工、包装或存放，该工厂、仓库或企业的所有者、经营者或代理机构延误、抵制、限制检查或拒绝允许进入或检查”，该药品可视为掺假药。FDASIA的第707(b)条款要求美国食品药品管理局（FDA）发布相关指南，为上述501(j)条款定义可能构成延误、抵制、限制或拒绝检查的具体情形。 本指南覆盖了根据FD&C Act法案第704条款需要接受检查的所有企业。该指南定义了501(j)条款中FDA认为构成延误、抵制、限制检查或拒绝允许进入或检查的行为、不作为或情形。本指南中提到的情况不是详尽的清单，而是阐述FDA在准备或执行检查时曾遇到过的最常见的情形以及FDA所能预见到可能发生的情形。延误、否认、限制、拒绝，这四个术语所描述的法律禁止的行为并不一定是互斥的。因此下面情形中所描述的行为可能包含不止一种行为类型。还需要注意的是，本指南中“企业”这一术语包括第 501(j)条款所涵盖的所有的企业、工厂和仓库。     FD&C法案第704条款授权FDA在合适的时间、合适的范围内，采用合适的方式开展检查。虽然FD&C法案没有对“合适”进行特别的定义，FDA长久以来的观点是：FD&C法案第704条款授予的检查权限延伸至“达到检查目的所需的合理范围内”。FDA打算与企业合作开展检查，以获取足够信息，从而达到检查的目的。FDA会考虑这些行为的合理解释，否则将视为延误、抵制、限制或拒绝检查。 包括本指南在内的FDA的指南文件不设立法定责任。相反，指南描述FDA目前对该议题的思考并仅作为参考，除非引用具体法规或法定要求。机构指南中使用“应”这个词语表明着建议或推荐某项内容，但不是必须。 II. 背景 FD&C法案第704(a)条款赋予FDA检查的权利，尤其是赋予FDA雇员或经FDA指定的人员在合理的时间进入企业，并在合理的范围之内以合理的方式对FD&C法案管辖范围的企业进行检查的权力。FDA检查是FDA对企业进行仔细的、关键的、官方的检查以确定是否符合相关的法律法规。FDASIA 第706条对FD&C法案第704(a)条进行了修订，允许FDA在检查前或检查期间，在合理的时间段内、在合理的范围之内、以合理的方式要求企业提供FDA根据第 704(a)条可能会检查到的记录或信息。 根据FD&C法案第510条需要进行注册登记的企业，以及根据FD&C法案第503B条款自愿注册的外包服务企业，需要向FDA提交相关信息。FDA将注册登记信息用于多种用途，包括安排检查计划。根据第510条，药品企业必须注册登记，并且所有注册企业提供相关法令法规所要求的信息，以避免制定检查计划和实施检查中的混淆和混乱。如果在年度注册登记信息上传后企业有变更发生，我们强烈倡导企业以e-mail的形式及时向监管当局提交更新后的信息。 根据FD&C法案第301(e)和301(f)条，拒绝进入或检查、或拒绝获得或复制特定的记录是法律禁止的行为。FDASIA中第707条款使得FD&C Act新增了第501(j)条款，“如果药品在一家工厂、仓库或企业生产、加工、包装或存放，该工厂、仓库或企业的所有者、经营者或代理机构延误、抵制、限制检查或拒绝允许进入或检查”，该药品可视为掺假药。 III. 延误检查 导致延误检查的原因可能有很多，其中一些是企业无法控制的。然而，根据FD&C法案第501(j)条，企业所有者、经营者或代理机构导致检查延误，可能会使得该药品被认为是掺假药。 A.    延误预先通知检查的行程安排 FD&C法案没有要求FDA在检查前预先通知。因而，FDA在进行有因检查和常规监督检查前通常不事先通知。然而，对于许可前和批准前检查，FDA通常在检查员达到检查地点前与企业进行联系，并且绝大多数的境外检查也是预先与企业联系的。虽然不要求提前联系企业，但这样做旨在方便检查的开展，确保企业相关记录和人员能预先到位。 对于预先通知的检查，FDA做好检查安排，通过e-mail向企业方发联系函，如果接受检查的企业为境外企业，则向该企业的美国代理机构发函。FDA根据当地的情况，如天气、安全形势、假期、或其他非工作日、企业生产计划等，做出合理的安排。以下是延误预先通知检查的行程安排并可根据FD&C法案第501(j)条被认为是掺假药的几种情形举例，包括但不限于：? • 企业不同意FDA提议的检查开始日期，也没有对此做出合理的解释。 • 检查时间安排好之后，企业要求推迟检查但没有做出合理的解释。 • 企业指定联系人未给FDA回复。 以下是企业给出了合理解释，根据FD&C法案第501(j)条不会被认为是掺假药的情形举例，包括但不限于： • 企业没有进行连续生产，例如企业每月生产一次，要求FDA更改检查日期，在其进行生产的时间段进行检查。 B. 在检查期间延误检查 FDA检查旨在确保机构对企业的合规情况进行审核。在制药企业，FDA有广泛的权力，对涉及掺假药、冒牌药或其他违反FD&C法案的行为进行调查。企业所有者、经营者或代理机构在检查开始前或开始后，在检查现场以合理的方式阻碍FDA检查员开展检查的行为，都会被视为延误检查。FDA意识到当检查员出现在检查现场时，企业员工最初可能产生一些轻微的困惑和/或不适。企业由于诚实努力地满足FDA的要求而导致的微小延误，通常不会被认为是不合理的。以下是延误检查并可根据FD&C法案第501(j)条被视为掺假药的情况举例，包括但不限于：? • .虽然企业某个区域正处于生产状态且该区域FDA有权进行检查，但企业在未给出合理解释的情况下不允许FDA检查员进入该区域，直到将来某个特定日期或时间才可以进入。 • 企业将FDA检查员留在会议室里，使其在一段较长的时间内无法获得需要的文件或接触到相关责任人，妨碍检查员完成检查。 以下是企业给出了合理解释，根据FD&C法案第501(j)条不会被视为掺假药的情形举例，包括但不限于： • 直到检查员的更衣操作符合企业规定的更衣程序，企业才让FDA检查员进入无菌操作区域， C. 延迟提供记录 FDA在检查准备阶段和开展检查期间的一项关键工作是审核和收集记录复印件、电子记录、文件和纸质文件，以判断该药品是否为掺假药、冒牌药或其他违反FD&C法案的行为。例如，审核记录可核实企业的合规性，也可收集用作偏差、州际贸易、产品标签和推广的证明性文件，以识别这一系列活动的责任主体。尽管FDA认为企业需要一段合理的时间来提供FDA所要求的记录，尤其是当记录保存在不同的地方时，但延迟提供记录给FDA且没有合理解释的情况可视为延误检查。以下是延迟提供记录并可根据FD&C法案第501(j)条被视为掺假药的情况举例，包括但不限于：? • 检查期间，FDA检查员要求企业在特定的合理的时间范围内提供FDA有权限查看的记录，但企业在FDA规定的时间内未能提供所需的记录,且没有合理的解释。 • FDA按照FD&C法案704(a)(4)条的要求查看记录，但企业无法及时提供所需的记录，且没有合理的解释。 以下是企业给出了合理解释，根据FD&C法案第501(j)条不会被视为掺假药的情形举例，包括但不限于： • FDA检查员要求将记录翻译成英文，并且没有现成翻译好的记录。 • 所需的记录当时无法提供，因为其用于正在进行的生产操作。 • 所需的记录数量非常大，以至于需要一定的合理的时间来准备。 在企业就延迟提供记录给出合理解释时，企业还应确保延迟提供的时间在合理的范围内。 英文原文 Guidance for Industry Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection U.S. Department of Health and Human Services Food and Drug Administration Office of Regulatory Affairs (ORA) Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Veterinary Medicine (CVM) October 2014 I. INTRODUCTION 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 adulterated 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 FDASIA 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) This guidance covers facilities that are subject to inspection under section 704 of the FD&C Act.2 This guidance 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; 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 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). Section 704 of the 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 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 be delaying, denying, limiting, or refusing an inspection. FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s 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 that something is suggested or recommended, but not required. II. BACKGROUND Section 704(a) of the FD&C Act provides FDA authority for inspections, specifically providing authority for duly 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 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, and in a reasonable manner, records or information that FDA may inspect under section 704(a). 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 information 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 confusion 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 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 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, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.” III. DELAY OF INSPECTIONS 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. A. Delay Scheduling Pre-announced Inspections 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, FDA’s general practice 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 appropriate records and personnel will be made available. FDA’s efforts to schedule pre-announced inspections include sending correspondence to the facility’s point of contact e-mail address, including the facility’s 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 campaigns. 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: • A facility will not agree to a proposed inspection start date and does not give a reasonable explanation for its failure to do so. • After scheduling an inspection, a facility requests a later start date without giving a reasonable explanation. • A facility fails to respond following FDA’s attempt to contact the facility’s designated contact(s). 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: • 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 agreed to by FDA so that manufacturing will occur during the FDA inspection of the facility. B. Delay During an Inspection An FDA inspection is intended to enable the Agency to review a facility’s compliance with certain 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 facility’s owner, operator, or agent before or after the beginning of an inspection that impede 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 facility’s employees. Minor delays that result from 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: • A facility does not allow 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. • 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 investigator’s ability to complete the inspection. 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: • A facility does not provide the FDA investigator access to aseptic processing areas until the investigator accommodates the facility’s documented gowning procedures. C. Delay Producing Records A critical aspect of FDA’s preparation for inspection and inspection of drug facilities is the review and collection of 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 commerce, 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 producing 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: • During an inspection, the FDA investigator requests, within a specific, 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. • FDA requests records pursuant to 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. Examples of potentially reasonable explanations that might result in the drugs not being deemed adulterated under section 501(j) of the FD&C Act include, but are not limited to: • The FDA investigator requests translation of the records into English, and the translation is not readily available. • The records requested are not available at that time because they are being used for a manufacturing operation that is in progress. • The volume of the records requested is sufficiently large as to require reasonable time to compile. In instances where the facility provides a reasonable explanation for delaying production of records, the facility should also ensure that the resulting delay is of a reasonable duration.

谢谢分享。从风险评估而言，延、抵、限都是最高的风险行为。