Life Sciences

设计吸入药物的设备以确保患者合规性

Vectura设备开发总监Andreas Meliniotis描述了如何设计吸入设备,以确保通过使此类设备易于使用来确保患者递送药物的递送,还可以使患者遵守给药方案。

一些药物最好通过吸入提供,通常是因为它们正在治疗影响肺部的疾病,但是随着这种交付途径,需要适当的设备。传统的吸入器和雾化器可能难以操作,并要求患者在药物的释放中呼吸灵感。此外,设备可能不适合所有患者,例如儿科医生,也可能不适用于患有敏捷性问题的人,例如骨关节炎患者。

因此,开发新的,改进的设备有很大的机会,以确保广泛的患者可以使用吸入药物,这也可以有效地治疗各种疾病和疾病。设计新设备的起点是定义其目标市场,用户需求以及可能的监管途径。创新者需要与工程师和设计师合作,以专注于药物和患者群体的需求。

First steps

作为第一步,通常会提出许多不同的概念,这些概念在收益和缺点方面被排名。那些紧密匹配要求的人将被提出到更详细的设计阶段,在该阶段中,评估了诸如制造性和可伸缩性之类的实际考虑。

下一步是采用这些详细的设计概念,并使用3D打印或其他快速原型制作方法制作样品设备。图纸不能代替物理原型,该原型可以进行彻底的评估,并真正了解该设备如何在患者手中工作。拥有塑料设备还可以在早期阶段进行测试,以减少较晚的时间。

These prototype devices also allow the performance of laboratory tests to determine how the formulated drug is likely to behave in the device, as well as mechanical tests against the key functional parameters defined at the programme’s outset. These assessments will allow the definition of a list of critical quality attributes (CQAs) for the device.

变成塑料

If, after these initial studies, the proposed device looks to be promising, a more robust prototype will be made. Computer-aided design (CAD) and rapid mould tools allow this to be completed typically within six weeks. Having a prototype allows the user needs to be compared against actual functional specifications of a device, which are both testable and can be concept-specific. Table 1 shows examples of how functional specifications relate to user needs.

用户需要 功能规范
The device shall be operable by the patient population 该设备应需要不超过10n的力才能操作按钮
The device shall be portable 该设备的重量小于500克
该设备应保护药物免受水分的侵害 剂量应包含在单独密封的铝水泡中

Table 1. How inhaler device functional specifications relate to user needs.

下一步是设备验证,再次将其与功能规范进行比较。这将允许创建一个可追溯性矩阵,该矩阵将整理出符合功能规范和用户需求列表的证据。

人类方面

人为因素研究在设计中尤为重要。最初,这些主题将与相对较少的受试者进行,以及最有可能显示用户错误的用户群体,其中可能包括老年人,可能存在敏捷问题或幼儿,他们可能没有力量或协调以有效操作设备。

在此类研究中,招募健康的志愿者(除了这些敏捷问题外还健康的志愿者)通常更容易,并且这些通常在开发过程的早期突出了潜在的问题。这允许更快地消除问题,而费用要小于将项目进展到后期临床试验中,只是因为该设备不合适而失败。

Inhaled drugs exacerbate the challenges with patient compliance because if there is a difficulty in using a device effectively, a patient may think they are taking their medicine, but, in reality, the intended dose of drug is not reaching the lungs properly. The consequence of this, and for all issues around patient compliance, is that potential treatments for patients are stopped or altered because of a perceived lack of efficacy. For device developers, ensuring that a patient is able to use a device both effectively and consistently is vital for improving compliance.

人为因素研究突出了患者如何与设备进行观察和互动,设计师必须确保通过良好的产品设计尽可能降低依从性差的可能性,这在人为因素研究中的成功必须再次支持。

测试的结果被馈回设备设计人员,他们可以在新设备上重复测试之前先完善设计。这种迭代的设计测试反馈 - 强烈反馈过程可能会延长开发的早期阶段,但最终可以通过从药物开发开始建立有效的设备来节省货币和时间。

Understanding how successful the device is in delivering a dose is key, but what human factor studies can also show is whether the devices are being used correctly by patients. What is perhaps most useful is the fact that the studies can indicate exactly how they may be misused, and this could be for reasons such as a minor error or slip by a patient (‘operator error’), a disconnect between a designer’s view on patient intuition when handling a device, or on fundamental misunderstanding of the device concept. Instructions for use (IFU) are provided with the marketed devices, however there is no guarantee that patients will read these, and therefore testing without the IFU can be useful to determine how intuitive the design is and how likely errors are to occur in the market.

因此,该设备开发过程通常指出lows a stage gate process, where the project is reviewed with a board of representatives from across the relevant disciplines. The development is structured so that initially the target product profile (TPP) and user requirements, including the user needs and intended uses, are reviewed at the first stage gate, followed by the concepts at the second stage gate, formal designs, device verification, manufacturing equipment, validation and finally preparation for market. The performance of the device continues to be monitored by post-market surveillance to assess whether lifecycle management activities are required. The reviews are conducted with representatives from a number of different disciplines to ensure that every relevant aspect is reviewed prior to continuation through the phases.

Regulatory compliance

Obviously, any device development process must align with the requirements of the regulators, and sufficient evidence of suitability must be included in the registration package. Following the waterfall diagram in the FDA’s 21 CFR Part 820.30 (Figure 1) is a good place to start, and although different regulatory bodies have slightly different requirements, it is important to include an assessment of whether it will meet the demands of the regulators in all the regions where the device is likely to be launched.

Figure 1. FDA-recommended design control parameters for medical device manufacture.

Source: Schematic from 21 CFR 820.30 FDA Design Controls Guidance for Medical Device Manufacturers (March 11, 1997)

降低风险

在理想的情况下,新产品将利用现有的交付平台,因为这提供了一定程度的证明,即该产品将可扩展到商业流程,并且规模上的问题较小。使用实验室规模的制造在大规模生产之前探索产品的设计空间可以帮助确保有效的成本和时间表,并有助于在相对较早的阶段将产品转移到诊所,而无需投资昂贵的设备和商业产品所需的设施。

将统计分析应用于测试数据,一旦设备在商业阶段制造和填充,就可以预测任何问题。如果可以预见任何问题,那么此分析将允许提前采取措施,以减少大量收益的潜力,以及伴随不良宣传和声誉丧失的相关成本。

Various different methods can be applied to reduce the risk. Paper-based exercises such as tolerance analysis can be used to assess the risk, while processes such as failure mode and effects analysis can also help, whether from the manufacturing, design or human factors perspective. Using these outputs to guide development allows risks to be navigated and reduced as a project moves from an idea to a product that is ready for clinical trials and subsequent commercialization.

Validation: a necessary step

针对特定于概念的规范验证产品是一回事。因此,可以预期可以生成可以进行统计分析的清晰值。但是,验证需要一路回到原始用户需求列表,并证明该设备满足所有原始需求,而不仅仅是用于建立的规格。

人为因素的研究提供了验证,但应根据患者指导传单中的指示使用患者使用它。临床试验也可能构成验证,即它应有的一切。

最终,重要的是要记住为该设备创建的人:病人。设备显然需要坚固,并运送产品。但是,不是以患者为中心的设计不太可能成功。

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