MDR新法规对药械组合产品的影响

2019-11-06 14:41 阅读数：3989 标签：

本文讨论了欧盟MDR新法规中关于药械组合产品的关键内容，以及制造商如何规范自己以确保其合规性。作者将针对以下方面展开研究：这类器械的制造商为符合MDR的规定需要了解哪些内容、他们可能面临哪些挑战以及如何克服这些挑战。

欧盟医疗器械法规 (MDR) 和欧盟体外诊断医疗器械法规 (IVDR) 的出台，带来了一系列将会影响所有医疗器械制造商的明显变化。然而，这两项新法规对生产药械组合产品的公司也有影响。由于MDR和IVDR全面施行的最后期限很快就要到来（分别是2020年5月和2022年5月——除非监管机构对其最后期限有所调整，即延期施行），而在最后期限之后，若组合产品中的器械部分不合规，该组合产品将不得不退出市场，因此了解新的法规要求并予以实施至关重要。

欧盟MDR及药械组合产品

欧盟MDR将对目前根据欧盟2001/83/EC指令作为药品进行监管的药械组合产品（其中药物部分的作用，相对于器械部分的作用而言，是主要作用而不是辅助作用）产生影响。这类产品的例子包括胰岛素注射笔和定量吸入器，其中器械部分预期用于药物部分的施用器。

那些长久以来一直属于制药公司，但此后又收购了另一家药械组合产品制造公司的企业，往往会陷入这样一种误区：将新收购的实体仅仅作为制药公司进行评估，而这类企业对21CFR 820和欧盟MDR或IVDR的要求并不了解。通常，制药公司只对一个产品进行三次验证，但对于器械来说，由于生产组合产品所涉及的因素较为复杂，这一验证次数显然不够。

此前，针对器械部分没有明确的法规要求，这意味着许多药品制造商可能并不了解他们需要采取什么措施来确保合规性。这一问题已经变得非常紧迫，尤其是在器械正变得越来越复杂的情况下。为确保器械部分不会逃脱监管审查，欧盟MDR第117条对欧盟2001/83/EC指令附录I进行了修订，其中概述了对器械部分的具体要求。在2020年5月26日（监管机构可能会对其进行调整）之前，制造商必须遵循这些要求。但根据现行医疗器械指令（MDD，93/42/EEC）持有CE标识的药械组合产品可以在过渡期（最迟延长至2024年5月26日）内继续在市场上销售。然而，由于这些产品属于III类器械，除非根据欧盟MDR重新认证，否则不得对产品进行任何变更。

变化

倘若美国FDA或欧盟对某个药械组合产品的生产场地进行检查，该生产场地必须符合针对药品和器械的所有监管要求。针对药品和器械的法规要求大体相似，但在各质量体系要素方面又不尽相同。例如，药品公司对偏差调查的处理方式就不同于器械公司。了解这些差异十分重要，以便根据这两项新法规的要求对质量管理体系进行适当变更。

这两项新的法规较为复杂，正在引起行业内前所未有的动荡。药品制造商不再仅仅就组合产品的上市许可与国家主管当局进行沟通，现在其组合产品的器械部分和药物部分都需接受法规监管。这意味着他们必须针对起辅助作用的器械部分与公告机构进行沟通。截至查询当天，依照欧盟MDR指定的公告机构仅有5家，由于法规变更规模和需要处理的递交文件数量很大，这些机构承受着巨大的压力，因此再怎么强调尽早参与的重要性都不为过。

根据欧盟MDR的规定，每个器械都需要获得新的CE标识才能继续在市场上销售。符合法规要求的一个基本要素就是需要提交最新版临床评价报告，证明该器械的安全性、性能和受益。从未提交过器械符合性申请的药品企业可能无法提供所需数据，因此必须进行新的临床试验。这个过程可能既耗时又要花费很大成本，因此必须确定需要哪些信息、这些信息是否已经可以获取以及获取缺失数据所需采取的步骤。

第一时间投入资源很有必要，从而可以确保顺利完成提交，同时还需要尽早制定标准化程序，以便不断更新相关数据并随时可用。公告机构将寻找正在进行的上市后监督活动的证据，以评估真实世界使用的情况，并对不可预见的风险或并发症实施管理。

强烈建议这些产品的制造商引入外部的器械和组合产品专家；通常情况下，制造商所掌握的专业知识要么限于药品领域要么限于器械领域，因此出现重大合规性问题或质量问题的风险很大。在当今的制造业领域，企业的运作模式是“精益生产”（精益生产就是及时制造，消灭故障，消除一切浪费，向零缺陷、零库存进军），也就是说企业内部很少有合规专家。利用外部第三方支持将是实现监管目标的关键。

陌生领域

为了了解并解读相关法规要求，大多数医疗器械公司已经投入了大量的时间和人力，并制定了必要的程序和文档。相比之下，药品法规团队很可能会发现自己身处一个新的领域，不得不从零开始。制定计划对于赶上法规最后期限和有效管理合规时间表和预期至关重要。制造商必须通过考虑与公告机构的沟通情况和程序以及器械风险水平来适度调整预期。为确保此过程尽可能高效，第三方专家的建议和实际支持对于确保患者安全、避免市场准入发生任何中断以及随后对公司声誉的影响可能是非常宝贵的。

英文原文

The new EU MDR and its impact on drug device combination products

This article discusses the key elements of the EU MDR pertaining to drug device combination products and how life science companies can organize themselves to ensure regulatory compliance is met. The author will work through what manufacturers of these types of devices need to know in order to achieve EU MDR compliance as well as the challenges they could face and how to overcome them.

The EU Medical Device Regulation (MDR) and the EU In Vitro Device Regulation (IVDR) introduce substantial changes that impact all manufacturers of medical devices. However, these regulations also have implications for companies producing drug device combination products. Understanding the new requirements and implementing them is critical as the deadlines for compliance are approaching fast (May 2020 and May 2022 respectively – unless the governing bodies make adjustments to the deadlines for extension), and products containing non-compliant devices after these deadlines will have to be withdrawn from the market.

The EU MDR & Drug Device Combination Products

The EU MDR particularly impacts combination products currently regulated as medicinal products under the EU Medicinal Product Directive 2001/83/EC (MPD), where the drug component is principal to the function of the device. Examples of these products include insulin injector pens and metered dose inhalers, where the purpose of the device is to be the applicator for the integral drug component.

Companies that are historically drug firms and have since acquired another company which manufactures drug device combination products, often fall into the trap of assessing the newly acquired entity solely as a drug company and do not have a grasp of the 21CFR820 and EU MDR or IVDR requirements. Typically drug firms only perform three lots of validation for a product, but for a device this amount is inadequate due to the level of complexities involved in making a combination product.

Previously, there were no clear regulatory requirements for the device element, meaning that many medicinal product manufacturers may not have been aware of actions they needed to take to ensure compliance. The issue has become pressing, especially as devices become ever more sophisticated and complex. To ensure that device components do not escape regulatory scrutiny, Article 117 of the EU MDR provides an amendment to Annex I of the EUMPD, outlining specific requirements for the device component. Manufacturers have until May 26, 2020 – subject to potential adjustments from governing bodies - to comply with these requirements, though drug device combination products already holding a CE Mark under the current Medical Device Directive 93/42/EEC can benefit from an extended transition period up to May 26, 2024. However, as these products are categorised as Class III devices, no changes can be made to the products unless they are re-certified under the EU MDR.

The changes

When the FDA or EU inspect the site of manufacture of a drug device combination product, that site will have to address all regulations that govern both drugs and devices. The regulations for each are similar, but not the same for each quality system component. For example, the handling of deviation investigations is different in a drug company than in adevice firm. It is important that these differences are understood in order for the quality management system to be suitably modified to address both regulations.

The new regulations are complex and are causing unprecedented upheaval in the industry. Instead of liaising solely with national Competent Authorities (CAs) for authorization of their combination products, pharmaceutical manufacturers are now subject to regulatory oversight for both the device and medicinal parts of their combination products. This means that they must liaise with notified bodies for the ancillary device component. To date, only five notified bodies have been designated under the EU MDR putting these organisations under severe pressure due to the scale of there gulatory changes and the number of submissions to be processed, so the importance of early engagement cannot be stressed enough.

Under the EU MDR, every single device needs a new CE mark to remain on the market. An essential element of achieving compliance is submitting updated clinical evaluation reports at testing to the safety, performance and benefits of the device. Medicinal product businesses that have never managed a submission for device conformity may not have the data required and will therefore have to carry out fresh clinical testing. This can be time-consuming and costly, so it is imperative to determine which information is needed, whether it is already available and the steps needed to procure missing data.

It is worth investing resources the first time round to guarantee a smooth and successful submission, and to put standardized procedures in place so that the relevant data is continually updated and always readily available. Notified bodies will look out for evidence of ongoing post-market surveillance activities to assess real world use and to manage unforeseen risks or complications.

It is highly recommended that manufacturers of these products bring in external device and combination product experts; the risk of missing a major compliance or quality issue is huge as expertise is usually siloed into just drugs or just devices. In today's manufacturing world the modus operandi is ‘lean manufacturing’, meaning there are few internal compliance specialists. Harnessing external third-party support will be key to achieving regulatory goals.

Unfamiliar territory

Most medical device companies have already invested time and resources in understanding and interpreting the relevant regulations and developing the necessary procedures and documentation. In contrast, it is likely that pharmaceutical regulatory teams will find themselves in new territory, and will have to start from scratch. Planning is crucial to meet the deadlines in time and efficiently manage compliance timelines and expectations. Manufacturers must adjust expectations by taking into account notified body liaison and procedures, as well as the level of device risk and therefore the level of scrutiny required. To ensure that this process is as efficient as possible, advice and practical support from a third party specialist may be invaluable for ensuring patient safety, avoiding any cessation to market access and the subsequent impact on the bottom line and company reputation.

来源：RAPS

原文链接：https://www.raps.org/news-and-articles/news-articles/2019/10/the-new-eu-mdr-and-its-impact-on-drug-device-combi

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