By Michael Alabran, President of PSN Labs
Characterizing the risks of medical devices has always been a challenge. Materials are at the core of this challenge, especially as supply chain disruptions have led to the need to alter materials to continue production of critical devices. The understanding of toxicology and the effect of chemistry on the human body is evolving in real-time. When you combine all these factors into an industry that is classically slow to alter the charted course, it leads to a perfect storm. This article will explore what this means to the industry based on the belief that engineering, material selection, and biocompatibility must be considered in concert and effectively balanced throughout the entire development process.
Biological response and safety is a complicated subject, but at its core requires adherence to basic engineering and scientific principles with material selection ultimately driving the impact of the device to the patient. Biocompatibility is not just a series of material tests, but rather a test on the entire device which includes a plurality of materials and conditions that must be accounted for in order to ensure that final testing be done on the final finished form of a medical device. This can be a complicated area as there are a variety of sources for misinformation along the way including manufacturers with vested interests, a lack of understanding for the device being developed, or even a lack of understanding regarding the basic materials of construction. To make this even more challenging, regulation of these devices is continually evolving as well as the advancement of the science being implemented to assess these devices. Equipment and methods have evolved over the past ten to twenty years and the industries’ understanding of chemical hazards and their toxicological risk, as well as the impact of bioaccumulation has improved. As a result, common knowledge that was appropriate ten, five or even one year ago may not necessarily be the most appropriate for a device being developed today. In other words, just because it’s been accepted historically doesn’t mean that the standard and/or burden of proof of safety will remain the same.
The key point here is that knowledge evolves in real-time along with regulation, but of paramount importance is patient safety. Patient safety is at the center of all biocompatibility efforts, and therefore the effects of biological risks need to be assessed at each stage of the development process. To do this effectively, it requires a well-rounded and multidisciplinary team that may not be commonly found within a single organization. The ideal team would include a multitude of disciplines such as biomedical engineers, mechanical engineers, material scientists and toxicologists to wholistically evaluate how the device realistically works versus how it was intended to work, how the materials behave during use, and to determine what the ultimate risk is to patient safety. It is keenly important to approach the subject from the perspective of assessing actual risk versus simply getting the device to work from a toxicological perspective. Specifically, there needs to be a mindset shift in the industry from the concept of informatory testing (i.e. we don’t know what to expect) to the concept of confirmatory testing (i.e. we’ve done the work and have a good idea and just need to confirm what we believe).
The entire development process begins with implementing sound engineering principles which starts with a thorough understanding of the device being developed. There is no one size fits all solution that exists as each device or class of devices, requires their own unique considerations from design to material selection to processing. In addition, device operating parameters or use conditions should be established within a range that is appropriate for the given material, and manufacturing conditions and techniques must be scrutinized along the way to ensure they do not introduce opportunities for biological risks. Arguably, the most important aspect of medical device development from a biocompatibility standpoint is material selection. Most, if not all, devices that fail, do so as a function of the basic materials of construction. In general, a bare bones or medical grade polymer is an excellent starting point and understanding that additives incorporated for a particular purpose may have unintended consequences. For example, adding plasticizers to a material to make it more soft or rubbery often utilizes organic molecules that are detrimental to biocompatibility. Something as seemingly simple as adding color to the material can deleteriously impact the biocompatibility of a device as many colorant packages use metallic constituents that are not appropriate for patient contact. All too often materials are selected based on familiarity, cost, or availability. The next generation of medical devices demands that quality and vetted materials be used, however there is often a lack of knowledge regarding polymers in medical devices. This gap underscores the need for a multifunctional team during the development process.
The end goal of any device on the market must be to focus on accurate and carefully cultivated data during the development stages. The data required should be generated iteratively through testing and analysis using realistic parameters or boundary conditions appropriate to the specific device in question. The process should allow the team to iterate quickly, appropriately, and efficiently and buy-in should be solicited along the way from all appropriate parties so that processes, designs, and performance windows can be identified and discussed, which will help to mitigate scaling issues and expedite the product to market. From form, fit, and function considerations to biocompatibility concerns, the industry demands iterative testing to best understand the impact of the device and to mitigate risks to all critical-to-quality parameters for the device; test, validate, and repeat should be the development model. Only when proper material selection, design, and informed engineering are implemented, will the process truly shift from an informatory mindset to a confirmatory process that validates what the team already believes and has data to substantiate.
An area that is often overlooked during the development cycle is the manufacturing process. Clay models, rapid machining/prototyping or 3D printing are excellent tools from an ergonomics or aesthetics perspective, but often do not use the same materials or capture key manufacturing attributes that may impact part performance or biocompatibility concerns. Instead, functional prototypes that capture the nuances of the injection molding process that contribute to residual stresses in the part and use the same materials is highly recommended to ensure production worthy processes and materials along with performance windows are captured. In general, polymer processing is not typically well understood by biocompatibility teams and proves to be an underestimated source of concern in medical devices. Even good or marginal materials can be hazardous to the patient if processed poorly. Degradation through residence times or shearing, molded-in residual stresses, or part dimensional interferences will impact the performance of the device. Poor molding practices negatively impact a device and as a result, outside material suppliers and manufacturers should be thoroughly vetted to ensure their protocols for material handling, raw material sourcing, process development practices and control are done in a manner that mitigates the risk to the device. A good approach for any medical device development is to follow the clauses outlined in ISO 13485 which clearly identifies the need for a risk-based approach to engineering and focuses heavily on utilizing design and process failure mode and effects analyses (DFMEA and PFMEA) as a core mechanism to ensure devices are suitable for the intended application. However, all too often, manufacturers will do what was historically done which can undermine regulation and advancements in science. Selecting suppliers based on cost and/or availability should be secondary to performance and safety of the device to avoid failures and costs down the road.
Biocompatibility must be brought to the forefront of the entire process. The development team must not live in a vacuum as the bridge to successful biocompatibility demands quality materials, sound engineering and processing principles, as well as iterative testing and validation be implemented to ensure a device is engineered properly to interface with the patient. Biological evaluation follows the principles of ISO 10993 and keeps in mind predicate devices and performance, patient contact and clinical risk, and worst-case use scenarios, and use conditions. Through this process, biocompatibility evaluation plans are developed based on device classification and mitigation strategies to address endpoints using custom test protocols unique to a particular device. With this data, a wholistic evaluation of the device, including complete toxicological and biocompatibility risk assessments, can be developed which enables the process to shift towards a confirmatory mindset. In addition, developers would be well advised that additional information (AINN) is commonly required from regulatory bodies to ensure patient safety. This should be recognized, and the work put in upfront to justify why the device is truly safe versus having serious gaps/risks that need addressed downstream. Incorporating flexibility into the project schedule to allow for this in real-time will substantially help to alleviate the pains associated with the development process across all interested parties.
In conclusion, change is inevitable. Be prepared to adapt. Regulation bodies such as the FDA and EMA, are not a roadblock, but are there to ensure patient safety is maintained. Be willing to accept that and understand that CROs, device manufacturers, and the regulatory bodies must work in harmony to ensure patient safety is maintained. Proper engineering, material selection and manufacturing can reduce or eliminate most biological safety risks. Be advised that this process takes time but doing it right from the onset will drastically reduce the headaches on the backend such as developing complicated mitigation strategies and justifications that cost even more time and money. Lastly, ask an expert that is well experienced and is vested in the success of your device.
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