首页 > 资讯 > FDA发布组合产品CGMP要求定稿指南

出自识林

2017-01-30

美国FDA于1月11日发布《组合产品的现行生产质量规范要求》定稿指南，提供了关于组合产品制造商如何能够符合现行生产质量规范（CGMP）要求的FDA建议。指南遵循并严格遵守2013年最终规定（收编在21 CFR Part 4中），该最终规定阐述了药品、器械或生物制品的哪些CGMP要求适用于组合产品。定稿指南提供了有关制造商可以如何实施简化质量管理体系的更多详细信息。

指南涉及对组合产品CGMP要求的一般考虑，以及对21 CFR Part 4中特定条款的目的和内容阐述。指南还讨论了牵头的组合产品审评中心以及与组合产品CGMP问题相关的其它FDA组成部分的作用。另外指南还提供了三个假设情形以期澄清针对具体类型的组合产品的合规性考虑如何符合某些要求。

简化方法：FDA的期望

指南重申了一个对于理解FDA对组合产品的方法至关重要的概念，即“组合产品的组成部分在组合之后保留其监管状态（例如，作为药品或器械）。”然而，这一概念并不意味着对组合产品各组成部分特定的单独质量体系是必要的。相反，指南阐述了制造商可以建立充分的“CGMP操作体系”的两种方式。一方面，药品/器械组合产品的制造商可以证明符合对产品各组成部分适用的所有CGMP规定。或者制造商可以选择“简化方法”，简化方法允许制造商证明符合药品CGMP（21 CFR. Part 210和211）或器械质量体系规范（QSR）（21 CFR Part 820），以及符合其它一些CGMP具体规定。

例如，组合产品制造商可以通过遵循所有药品CGMP要求和来自QSR的特定条款来实施基于药品的CGMP体系，或者制造商可以通过遵循所有器械QSR要求和来自药品CGMP的特定条款来实施基于器械的CGMP体系。最终规定确定了必须在任一体系中实施的CGMP条款，指南阐述了FDA对于实施这些规定的期望。QSR条款包括管理层责任、设计控制、采购控制、纠正和预防措施以及安装、检修，而药品CGMP条款包括收率计算、稳定性试验、有效期、留样要求等等。

简化方法通常限于单个实体和共同包装的组合产品；指南重申了跨标签组合产品的各组成部分仍需满足该特定部分的CGMP要求（例如，对于药品组成部分应满足Part 211，对于器械组成部分应满足 Part 820）。然而，如果跨标签组合产品的组成部分在同一设施内制造，FDA表示将不反对实施简化CGMP体系。值得注意的是，组合产品的“主要作用模式”（确定对组合产品具有管辖权的FDA中心），不决定制造上必须实施哪个基础CGMP体系。

在药品/器械组合产品之外，FDA还提供了当组合产品包括生物制品或人体细胞和组织产品（HCT/Ps）时制造商必须遵循的具体CGMP条款的指南。

实践：三种组合产品假设情形

为了说明简化方法的实施，指南为三种类型的组合产品提供了假设情形。这些情形包括：

• 预填充注射器：基于药品的CGMP体系，与特定器械QSR条款
• 药物洗脱支架：基于器械的QSR体系，与特定药品CGMP条款
• 药物涂层网：在药品组成部分与器械组合后符合器械CGMP条款

合规注意事项：特定CGMP要求

FDA建议制造商确认证明符合21 CFR Part 4的文件或证明为什么不需要合规性的文件。制造商的质量体系文件应确定CGMP体系的类型（即，基于药品、基于器械或基于生物制品），并应在检查开始时提供给FDA检查员。

指南具体讨论了对于其组合产品使用基于药品的CGMP系统的制造商对采购控制（21 CFR第820.50节）的实施，采购控制是器械QSR特有的条款。当然，药品制造商并不熟悉采购控制，尤其是在国外供应原料药的背景下，但制造商可能必须增加其现有程序以满足21 CFR第820.50节的要求。例如，QSR明确要求制造商评估潜在供应商，记录评估并在可能的情况下与供应商达成变更通知协议。

FDA还预期在涉及组合产品生产的多个制造商之间的协作。组合产品所有者对产品承担责任，包括CGMP合规，即使他们不直接参与制造过程。FDA建议所有者通过，例如与合同制造商的质量协议和对设施的常规审计，来确保合规性。

计划销售组合产品的药品制造商应了解QSR设计控制条款（21 CFR第820.30节）的行政和技术要求。重要的是，虽然设计控制要求不适用于所有器械，但在适用的情况下，甚至在研究阶段也适用。例如，组合产品器械组成部分适用设计控制的制造商必须创建设计历史文档（DHF） — 产品开发的历史文档。除其它内容外，DHF包括定期设计审查以及核实和验证检测结果的文件。指南建议制造商可以利用现有产品的开发文件来满足DHF要求，但可能不熟悉核实或验证检测的药品制造需要仔细考虑对确保其产品满足设计控制要求所必需的检测。

编译：识林-椒
原文作者：盛德国际律师事务所Nancy K. Stade、Allison Fulton和Parker D. Kasmer律师
感谢Anya Zhang（张晓鹏）女士推荐
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英文原文
FDA Describes Streamlined Approach to Good Manufacturing Practice Requirement for Combination Products
原文地址

On Jan. 11, the Food and Drug Administration (FDA) published a final guidance document entitled “Current Good Manufacturing Practice Requirements for Combination Products url,” which provides the FDA’s recommendations on how manufacturers of combination products can comply with current good manufacturing product (cGMP) requirements. The guidance follows – and closely adheres to – a 2013 final rule (codified at 21 C.F.R. Part 4) that describes which cGMP requirements — i.e., drug, device or biological product — apply to combination products. The final guidance provides greater detail about how manufacturers can implement a streamlined quality management system.

A Streamlined Approach: FDA Expectations

The guidance reiterates a concept that is central to understanding the FDA’s approach to combination products, namely that “[t]he constituent parts of a combination product retain their regulatory status (as a drug or device, for example) after they are combined.” This concept does not mean, however, that separate quality systems specific to each constituent part of a combination product are necessary. Rather, the guidance describes two ways manufacturers can establish an adequate “cGMP operating system.” On one hand, a manufacturer of a drug/device combination product can demonstrate compliance with all cGMP regulations applicable to each of the product’s constituent parts. Or a manufacturer can opt for a “streamlined approach” that allows the manufacturer to demonstrate compliance with either the drug cGMPs (21 C.F.R. Part 210 and 211) or the device quality system regulation (QSR) (21 C.F.R. Part 820) as well as compliance with several specific provisions from the other set of cGMPs.

For example, a combination product manufacturer can implement a drug-based cGMP system by following all drug cGMP requirements and specific provisions from the QSR, or a manufacturer can implement a device-based cGMP system by following all device QSR requirements and specific provisions from the drug cGMPs. The final rule identifies the cGMP provisions that must be implemented in either system, and the guidance elaborates on the FDA’s expectations for implementing those provisions. The QSR provisions include management responsibility, design controls, purchasing controls and corrective and preventive actions, while the drug cGMP provisions include calculation of yield, stability testing, expiration dating, requirements for reserve samples and more.

The streamlined approach generally is limited to single-entity and co-packaged combination products; the guidance reiterates the principle that each constituent part of a cross-labeled combination product remains subject to the cGMP requirements for that particular part (e.g., part 211 for a drug constituent part or part 820 for a device constituent part). However, if constituent parts of a cross-labeled combination product are manufactured at the same facility, the FDA states it will not object to the implementation of a streamlined cGMP system. Notably, the “primary mode of action” of the combination product, which determines the FDA center that has jurisdiction over the combination product, does not dictate which base cGMP system the manufacturer must implement.

Outside of drug/device combination products, the FDA also provides guidance on specific cGMP provisions that manufacturers must follow when their combination products include biological products or human cell and tissue products (HCT/Ps).

In Practice: Hypotheticals for Certain Combination Products

To illustrate implementation of the streamlined approach, the guidance offers hypothetical scenarios for three types of combination products. The scenarios include:

• Prefilled syringe: drug-based cGMP system, with device-specific QSR provisions
• Drug-eluting stent: device-based QSR system, with drug-specific cGMP provisions
• Drug-coated mesh: compliance with device cGMP regulations after a drug constituent is combined with a device

Compliance Considerations: Specific cGMP Requirements

The FDA suggests that manufacturers identify documentation to demonstrate compliance with 21 C.F.R. Part 4 or document justification why compliance is not necessary. The manufacturer’s quality system documentation should identify the type of cGMP system (i.e., drug-based, device-based or biological product-based) and should be provided to FDA investigators at the initiation of an inspection.

The guidance specifically discusses implementation of purchasing controls (21 C.F.R. § 820.50), which is a provision specific to the device QSR, for manufacturers using a drug-based cGMP system for their combination product. Certainly purchasing controls are not unfamiliar to drug manufacturers, particularly in the context of foreign-supplied active pharmaceutical ingredients, but manufacturers may have to augment their existing procedures to meet the specific requirements of 21 C.F.R. § 820.50. For example, the QSR explicitly requires manufacturers to evaluate potential suppliers, document the evaluations and obtain change notification agreements with suppliers where possible.

The FDA also expects coordination across multiple manufacturers involved in the production of a combination product. Combination product owners assume responsibility for the product, including cGMP compliance, even if they are not directly engaged in the manufacturing process. The FDA recommends that the owner ensure compliance through, for example, quality agreements with contract manufacturers and routine audits of their facilities.

Drug manufacturers that plan to market a combination product should be aware of the administrative and technical requirements of the QSR design control provision (21 C.F.R. § 820.30). Importantly, although design control requirements do not apply to all devices, when applicable, they apply even at the investigational stage. For example, manufacturers of combination products with a device constituent to which design controls apply must create a design history file (DHF), a historical file of a product’s development. A DHF contains, among other things, documentation of periodic design reviews and results of verification and validation testing. The guidance suggests that manufacturers can leverage existing product development documentation to satisfy DHF requirements, but drug manufacturers — which may not be familiar with verification or validation testing — may need to carefully consider the testing necessary to ensure their products meet design control requirements.