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2014-01-29 Lachman CONSULTANTS

虚拟企业请注意—《FDA安全和创新法案》调高热度

2012年，《FDA安全和创新法案》（Food and Drug Administration Safety and Innovation Act, FDASIA）在食品药品与化妆品法案501(a)(2)(B) 一节中增加了如下表述，扩展了现行药品生产质量管理规范 (current good manufacturing practice, cGMP) 的涵义： “在 (a)(2)(B)款范围内，术语‘现行药品生产质量管理规范’包括为确保质量而对药品生产实施的监督与控制，其中包括对原辅料以及用于生产药品和成品的物料的风险管理与安全性确证。”这一补充，是自1962年以来，首次强化了现行药品生产质量管理规范的含义。在有关《FDA安全和创新法案》的新闻中，并未对此大量报道，这一补充的全部影响也尚未充分显现。

纵观美国食品药品管理局安全和创新法案的立法历史，一大意图是要求药品生产商对其所购物料进行充分管理。该法案的提案人，参议员Tom Harkin (D-IA)在其发言中敦促道，“《FDA安全和创新法案》使得FDA对药品供应链权威的目标得以现代化……这一法案强化了我们这个国家药品供应链从获得原辅料到生产产品确保完整性的能力。”有道理。大多数人认同不安全物料的危害为要求生产商有效控制与监督提供了正当理由，大多数企业也意识到它们有监督用于生产的物料的安全性与质量的义务。

FDA在说明《FDA安全和创新法案》的网页上，对501(a)(2)(B) 一节所增加的要求将在修订版cGMP法规中得以体现作出了承诺。FDA 2014年监管日程计划于11月发布一份拟议规章。然而，执法行动已经开始，虚拟企业正是其中一个目标。

FDA在 2013年5月《药品合同外包生产安排：质量协议》的指南草案中，引用了《FDA安全和创新法案》对501(a)(2)(B) 一节所增加的描述作为该指南的依据。该指南草案对企业提高对合同外包方的质量监督带来了挑战，但面临最大挑战的还是虚拟企业。此类企业可能拥有新药申请，但并无生产设施，也不具体拥有任何药品。此外，对于签订合同并销售第三方所生产药品，但未能设立符合cGMP以对合同方开展充分监督与控制的质量体系，进而将掺杂使假的药品引入州际间贸易的情况，FDA 将追责虚拟企业。根据这一理念，合同外包商（事实上的生产商）是否完全符合cGMP已无关紧要 — 但因未能建立提供质量保证所需的体系，虚拟企业将会肯定不合规。

FDA以不同渠道表达了他们明确的预期，即虚拟企业（在指南中被定义为“所有者”）应与合同生外包产组织（CMO）分担合规责任。按照联邦法规第21章200.10节的表达，合同外包生产设施长期以来被视为“生产商自身设施的扩展”，但事实上，这一定义对于虚拟企业而言并不确定。很明显，虚拟企业需要一个具有充分权威与责任的质量管理部门，对于所有者（虚拟企业）的最低要求就是最终放行每一批次产品至市场。正如FDA在指南草案中所解释，所有者应对特定的供应商开展专门的风险评估，以估计对特定供应商所需控制的程度。这应包括决定认为受控所需的关键效能指标，以及建立监督所需的体系。对于虚拟公司而言，这包括对合同生产组织的定期合规审计，以及特定批次以及工艺文件记录的审查与批准；例如，批记录与分析报告单，生产偏差与实验室调查，变更控制，连续工艺验证以及年度产品回顾。很明显，就虚拟公司而言，需要具备充分的技术资源以及产品知识。

FDA 在2012年给一家虚拟企业的警告信中展示了其理念，FDA在警告信中表达了其立场，虚拟企业通过参与合同外包生产商的设计、实施以及质量监督来证明有效的质量领导能力的最终责任。尽管就现在的讨论而言，对FDA指南草案的分析可能过于复杂，但一些针对草案的意见中所反映的争论的关键点有必要提及。在FDA指南草案中，无论新药申请是否覆盖药品，所有者均被表述为引发或造成药品进入州际间贸易的一方。在一些评论者看来, 这一表述过于宽泛。评论者指出，例如，“所有者”一词不应涵盖在受食品药品与化妆品法案303(c) 一节所提供的担保情况下善意接受产品的并不具备产品知识与专门知识的分销商（包括自有品牌分销商）。如果FDA接受了这一意见，最终的指南必须找到定义所有者的方法，以将纯粹的分销商与虚拟公司以及其他可能的指南受众区别对待。另一条有趣的意见，指出《食品、药品与化妆品法案》赋予了FDA对药品生产、加工、包装或放置的设施开展检查的职能，似乎并不包含没有任何此类事项发生的虚拟企业。但这一事实显然不能阻止FDA对虚拟企业办公室开展cGMP检查。

所有评论均未涉及到一项扭曲之处，即FDA 在联邦法规第21编第200.10节中的长期政策表明，FDA并未考虑验证研究可能是仅有合同外包生产设施所持有的商业机密，但在实践中，FDA允许某些特定的验证信息，以所有者不可获得的药物主文件不公开部分的形式提交。对获得药物主文件中保密部分的限制，将使指南草案的实施进一步复杂化，例如，所有者将与合同外包实验室就确保该方法得到验证共同担责。

Lachman CONSULTANTS - Edmund Fry先生 2014-01-24
校译：识林-Kapok 2014-01-27

Virtual Companies Beware – FDASIA Ratchets Up the Heat
Written by Edmund Fry • January 24, 2014

In 2012, the Food and Drug Administration Safety and Innovation Act (FDASIA) inserted a statement into Section 501(a)(2)(B)of the Food, Drug and Cosmetic Act that expanded the meaning of current good manufacturing practice (cGMP): “For purposes of paragraph (a)(2)(B), the term 'current good manufacturing practice' includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.” This insertion, which enhanced the meaning of cGMP for the first time since 1962, wasn't widely acknowledged in trade press coverage of the FDASIA and the full implications of the insertion aren't yet readily apparent.

FDASIA's legislative history tells us that one intention was to require drug manufacturers to employ adequate controls over the materials they purchase. FDASIA's sponsor Sen. Tom Harkin (D-IA) said in his remarks urging passage, “[FDASIA] modernizes FDA's goal of drug supply chain authority ... this bill enhances our ability to ensure the integrity of that drug supply chain from where they get the raw materials to where they put it together in this country.” Fair enough. Most would agree that the hazards of unsafe materials justify the need for effective controls and oversight by manufacturers, and most companies are well aware of their responsibility to oversee safety and quality of materials used for manufacturing.

FDA's web page describing FDASIA promises that requirements of the enhanced 501(a)(2)(b)will be reflected in revised CGMP regulations. FDA's 2014 Regulatory Agenda targets November for issuing a proposed rule. However, enforcement has already begun, and virtual companies are a target.

FDA's May 2013 Draft Guidance on Contract Manufacturing Arrangements for Drugs: Quality Agreements (here) cited FDASIA's enhanced 501(a)(2)(B)wording as authority for the guidance. This draft Guidance challenges companies to improve quality oversight for contractors, but none are more challenged than virtual companies. Such a company may hold an NDA, but have no manufacturing facilities and may never physically possess any article of drug. Nevertheless, FDA will hold a virtual company responsible for having caused the introduction of an adulterated drug into interstate commerce if it contracts for and markets a drug product made for it by a third party, but does not operate a quality system in compliance with cGMP to provide adequate oversight and control over the contractor. Under this concept, it would make no difference whether or not the contractor (that is, the actual manufacturer) happens to be in full compliance with cGMP – the virtual company would be out of compliance simply for failing to have the systems needed to provide the assurance.

FDA's clear expectation, expressed in a number of ways, is that the virtual company (the Owner, in the terminology of FDA's Guidance) shares responsibility with the contracted manufacturing organization (CMO) for compliance. Contracted facilities have long been considered “an extension of the manufacturer's own facility” as expressed in 21 CFR 200.10, but what this requires in practice for virtual companies is somewhat uncertain. A virtual company clearly is expected to have a quality unit with adequate authority and responsibility, and a minimum requirement is for the Owner (virtual company) to perform final release to market of each batch. As the FDA draft Guidance explains, the Owner should conduct a risk review that evaluates the extent of controls required for the particular supplier. This should include determining the key performance indicators it believes necessary to control, and to develop systems for oversight. For a virtual company, this would include use of periodic compliance audits of CMOs, as well as review and approval of certain batch and process documentation; for example, batch records and certificates of analysis, manufacturing deviation and laboratory investigations, change control, continuous process verification, and annual product reviews. Obviously, this requires adequate technical resources and product knowledge on the part of the virtual company.

FDA revealed its philosophy in a 2012 Warning Letter to a virtual company, in which FDA expressed its position that a virtual company has ultimate responsibility to demonstrate effective quality leadership by participating with contract manufacturers in the design, implementation, and monitoring for quality.

Although analysis of FDA's draft Guidance would be too complex for this discussion, some key points of contention as reflected in comments to the draft are important to mention. In the FDA draft Guidance, the Owner is described as the party that introduces or causes the introduction of the drug into interstate commerce, whether or not the drug is covered by an NDA. This definition appeared overly broad to some commenters. Comments suggested, for example, that the term "Owner" should not include distributors (including private-label distributors) who may have no product knowledge or expertise and who may receive products in good faith under a guarantee as provided in Section 303(c) of the Food, Drug and Cosmetic Act. If FDA accepts this input, a final Guidance must find a way to define Owner in such a way that pure distributors are treated differently from virtual companies and others that were (we believe) the intended audience for the Guidance. Another interesting comment pointed out that the Food, Drug and Cosmetic Act provides FDA authority to conduct inspections of facilities where drugs are manufactured, processed, packed, or held, which would seem not to include virtual companies where none of those things take place. That fact apparently will not stop FDA from conducting cGMP inspections at virtual company offices.

A twist not addressed by any comment is the inconsistency between FDA's long-standing policy in 21 CFR 200.10 that FDA doesn't consider validation studies to be trade secrets that may be withheld by a contracted facility, versus FDA's practice of allowing certain validation information to be filed in the closed sections of DMFs where it is not available to Owners. The limitation on access to closed portions of DMFs will further complicate implementation of the draft guidance which says, for example, that the Owner is jointly responsible with the contracted laboratory for assuring that methods are validated.