FDA关于PFS组合产品的cGMP要求介绍

当前越来越多的生物药采用PFS（预充式注射器）作为包装容器，其与传统的西林瓶作为包装容器相比，存在特殊的组合产品（Combination Product）的概念。FDA指南文件"Current Good Manufacturing Practice Requirements for Combination Products, 2015"规定了组合产品生产的cGMP要求，包括PFS组合产品，本文作简要介绍。

组合产品定义：

采用预充式注射器（PFS）作为包装形式的生物制品属于典型的组合产品，从美国21 CFR 3.2(e)章节中有相关定义：

A product comprised of two or more regulated components, i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic, that are physically, chemically, or otherwise combined or mixed and produced as a single entity (a “single entity” combination product, such as a prefilled syringe or drug-eluting stent).

PFS组合产品的场景举例：

A drug manufacturer (Manufacturer A) plans to sell a drug in a prefilled syringe presentation.Manufacturer A already has marketing approval for the drug product andintends to apply for marketing approval for the prefilled syringe presentation. No changes to thedrug formulation will be made. Manufacturer A will buy off-the-shelf syringe components from a supplier (Manufacturer B) who also manufactures finished syringes using the same components. Manufacturer A will assemble the syringe components, prefill the syringe at a facility it operates, and then package, label, and distribute the prefilled syringe from this facility.举例一个典型的场景：药厂A的某个药物已经获批上市，计划更换为PFS的包装形式（药液配方不变），从企业B采购PFS，药厂A进行灌装、组装、贴签、包装等。

Manufacturer A’s facility has an existing drug CGMP operating system. As the prefilled syringe is a single-entity combination product under 21 CFR 3.2(e)(1), Manufacturer A must demonstrate compliance with both the drug CGMPs and device QS regulation. To do so, Manufacturer A opts to establish a CGMP operating system using the drug CGMP-based streamlined approach in accordance with 21 CFR 4.4(b)(1). While Manufacturer A must ensurethat its operating system fully complies with the drug CGMPs for this product, taking into account all of the issues raised by inclusion of the device constituent part, this example focuses on considerations for demonstrating compliance with the provisions from the device QS regulation specified in21 CFR 4.4(b)(1).药厂A拥有合规的CGMP体系，所使用的PFS应满足21 CFR 3.2(e)(1)法规的要求。药厂A必须证明所注册申报的PFS组合产品同时满足药品的CGMP法规要求和器械的法规要求。因此，药厂A依据21 CFR 4.4(b)(1)的法规要求，以药品CGMP为基础的简化方法，建立CGMP体系。

设计控制

Manufacturer A is buying the syringe components from Manufacturer B, another manufacturer, which uses the same components to manufacture finished syringes. As a result, Manufacturer A may be able to leverage syringe-specific design control documentation from the design controls Manufacturer B uses for its finished syringes. Because no changes are to be made to the drug other than being put into the syringe, the drug comes into the design control process as an input to the design ofthe syringe to ensure that the syringe’s design reflects adequate consideration of the drug’s characteristics.药厂A可以借鉴企业B的PFS设计控制文件，把药物特性作为输入，评估PFS的设计控制需求。

An appropriate first step for Manufacturer A would be to review Manufacturer B’s design control data to determine what new questions are raised by the use of the syringe with the drug, and to assess what additional design control activities may be needed as a consequence. It may be the case, for example, that Manufacturer A can demonstrate that the only new design questions that are raised concern the performance of the syringe as a container/closure to store the drug and the extent to which the contact between the syringe and the drug may affect its performance as a delivery system. Regardless, Manufacturer A must ensure that all design considerations for the combination product are addressed in accordance with 21 CFR 820.30.药厂A应评估输出药物特性对于PFS性能的影响，比如药物储存期间的容器密封完整性、启动力/滑动力等。具体如下：

The table below includes illustrative examples of design inputs and user needs andrelated design outputs for this prefilled syringe. PFS的设计输入和设计输出

Once Manufacturer A has established design outputs for all design inputs, it must perform design verification and validation activities to ensure that the combination product meets design input requirements, including user needs and intended uses. Examples of appropriate testing of the prefilled syringe include:基于PFS的设计输出开展设计确认和验证，包括：

• Bench testing of the delivery of the drug from the syringe to ensure repeatable and accurate drug delivery;台架测试

• Shock and vibration testing of the packaged prefilled syringe to ensure no damage or loss of integrity in shipping;运输验证

• Validation that expected users can adequately follow the instructions for use;用户使用

• Other human factors studies;人体因素研究

• Biocompatibility testing;生物相容性测试

• Drug and syringe compatibility studies;药物和注射器的相容性研究

• Leachables and extractables testing; E＆L研究

• Verification that the prefilled syringe works with all expected delivery methods (i.e., needle, needleless).按照预期递送方式的使用确认

These activities would be documented in the DHF (Design History File) pursuant to 21 CFR 820.30(j) and would be subject to design change and review requirements pursuant to 21 CFR 820.30(e) and (i).设计文件相关的法规要求。

Manufacturer A should identify risks associated with the prefilled syringe design, its manufacturing processes, and intended uses, and also reduce or mitigate any unacceptable risk(s). The table below lists some potential risks associated with prefilled syringes andpotential mitigations for these risks.对PFS的设计进行风险评估。

PFS风险评估示例

Manufacturer A must also have procedures in place to ensure that any changes to design requirements are identified, documented, validated and/or verified, reviewed, and approved prior to implementation. Activities should include review of the original risk analysis, review and approval of the revised design inputs and outputs, and review and approval of the design change. For example, before changing a material used in the syringe that comes into contact with thedrug, Manufacturer A should conduct verification activities to ensure that no degradation of performance characteristics will occur before the expiration date for the combination product as a result of the change of materials. Likewise, any change to the formulation of the drug should include design control activities such as verification to confirm that the new formulation does not degrade performance of the syringe. All of this information would need to become a part of the DHF.需要有PFS设计变更相关的控制程序。

The DHF may include references or point to information residing elsewhere so long as the reference or pointer is precise enough to allow the necessary information to be readily accessed as needed, including for inspections. For example, elements of the syringe component manufacturer’s design documentation may be relied upon to support the combination product DHF. Such information on the syringe may reside at Manufacturer B’s (syringe component manufacturer) facility, so long as the necessary documentation can be accessed in a reasonable time during inspection of Manufacturer A. Manufacturer A should ensure access to such documentation through supplier agreements with Manufacturer B under its purchasing controls (21 CFR 820.50). Documentation of development of the drug product that preceded the design effort to incorporate the drug product into a prefilled syringe may be referenced in the DHF and become an input to the combination product design effort (though such drug-only development is not itself subject to design controls).药厂A应该在与企业B签订供货协议时要求其提供完整的PFS设计资料，以协助完成组合产品的注册申报。

采购控制：

Manufacturer A is required to control its purchasing activities, including for the syringe components, in accordance with 21 CFR 820.50. For example, if the syringe barrel and plunger material is critical to ensuring that there is no adverse reaction with the drug,Manufacturer A should structure purchasing agreements with Manufacturer B to ensure that Manufacturer A is notified of any changes to this material prior to implementation of the change.药厂A应通过采购协议规定当企业B针对PFS的任何变更均应在实施前通知药厂A。Similarly, if Manufacturer A uses an outside facility for terminal sterilization of the prefilled syringe, Manufacturer A must also have appropriate controls over that sterilization service provider.如果药厂A将采购的PFS委托其他机构进行灭菌，则对该机构进行适当的管理控制。

CAPA：

Manufacturer A is required to establish and maintain CAPA procedures for the combination product. Following are two examples of issues that might arise and exemplary steps for addressing them:

• Manufacturer A has implemented in-process manufacturing verification procedures to confirm that the syringe is being filled with the correct amount of the drug, and the data from this verification are analyzed for potential nonconformities. Manufacturer A notes an increase in nonconformities relating to the volume of drug being put in the syringe and in turn opens a CAPA to investigate the problem. Upon investigation of the cause of the improper fill volume, Manufacturer A determines that maintenance procedures on the filling equipment are the cause of the incorrect fill volume. Manufacturer A updates the maintenance procedures and performs verification/validation testing to confirm that the changes correct the problem and do not cause new ones.举例装量过程控制相关的CAPA。

• Manufacturer A begins receiving an increased number of customer complaints related to holes or other damage to the syringe’s sterile package and opens a CAPA to investigate the issue. The CAPA reveals that Manufacturer B has made changes to a syringe component such that there are sharp edges that can damage the sterile pouch during shipping. Manufacturer A works with Manufacturer B to eliminate the sharp edge or finds a new supplier. Manufacturer A also augments purchasing specifications and acceptance test steps to perform visual inspection of the syringe components. Manufacturer A repeats related design verification testing to ensure that the new syringe meets all design requirements and does not result in pouch damage during shipping.举例药厂A收到关于PFS质量投诉的处理CAPA。

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