A. Norlin-Weissenrieder and S. Board
St. Jude Medical, St. Paul, Minnesota, USA
Take an integrated route
There are significant benefits in utilising advanced material selection and testing strategies in new product development (NPD) projects. These include reduced completion time, submission risks and development costs and improved performance and safety of the device. Through careful design of dynamic test strategies throughout the entire NPD process and by involving subject experts, who work closely with design engineers and regulatory personnel, project success is improved.
Most medical device companies utilise some sort of NPD process to ensure that their devices are developed in a cost efficient, controlled and quantifiable environment.
Methodologies that divide the NPD process into phases are frequently employed. One method is the so-called phase gate development process, which has five phases:
- Concept phase in which the device idea or concept is evaluated to determine its feasibility.
- Plan phase when the project plan is outlined and teams are organised.
- Design phase during which the device reaches its final design through a series of iterative design steps.
- Verification phase when the performance of the final design is reported and documented.
- Release phase when the product is released to the market.
The execution of various test protocols is of great importance during the first four phases of this NPD process. Tests are necessary for evaluating novel technologies, making appropriate design decisions and gathering data to support submission to regulatory bodies. To reduce the complexity in projects, tests are typically treated as independent, separate entities and the responsibility for each is allocated among different team members. However, by treating material selection, biocompatibility and device testing as an integrated entity that includes understanding fundamental scientific fields such as material science, chemistry and biology, more powerful and effective test strategies will be designed.
When the scientific level on which the tests are based increases, it is necessary to involve subject experts to define and outline test strategies. To ensure successful completion of the project, experts need to work closely with design engineers and regulatory personnel. Using real life examples, it is illustrated below how poorly designed test strategies can obstruct NPD projects and how advanced testing strategies have the potential to improve the success rate of projects.
To ensure project success, it is important to identify and evaluate potential clinical risks such as device failure and biocompatibility issues as early as possible in the NPD process. Because of the inherent unpredictable nature associated with failure, this is of course easier said than done. It requires highly skilled and experienced personnel to predict complex failure modes and design tests that can expose inherent device weaknesses prior to failure.
Failure modes are, in general, closely related to some aspect of the materials in the device. Material-related failures are multifaceted and include, but are not limited to, mechanical failure, corrosion, material interactions, material chemistry and biocompatibility. Many design engineers have a background in mechanical engineering and therefore the mechanical aspects of the device are usually included in testing protocols. However, fundamental material properties are often neglected or treated in a general manner, which greatly increases the risk of failing to identify material–design incompatibilities, as shown in the first example below from the concept phase. Even simple failure modes may cause major disruptions to a project if left unaddressed or discovered too late.
Case study one
Figure 1: Severe corrosion of the device after an accelerated mechanical ageing test illustrates the importance of involving a material scientist in the concept phase.
(click image to enlarge)
A permanently implantable device was designed that comprised moving components in contact with each other. The design team selected passivated stainless steel 316 LVM as the construction material. The mechanical adequacy of the device was evaluated in atmosphere and the device was successfully implanted in animal studies. Accelerated mechanical ageing in simulated body fluid was evaluated as part of the final verification testing. The test showed severe corrosion of the device (Figure 1).
This was surprising to the team because they knew 316 LVM is approved for implant applications (ASTM F138-139) and has a long history of permanent clinical use.
The reason for the corrosion of the 316 LVM was the combined mechanical wear action and the corrosive environment; wear or fretting corrosion can occur on stainless steel implants subjected to wear.1,2 Corroding steel releases nickel and chromium ions, which are locally cytotoxic and may cause adverse effects in adjacent tissue.3,4 Therefore, a corroding material may compromise the mechanical performance as well as the biocompatibility of the implant. This example highlights the importance of evaluating material–device compatibility for the specific device design and the in vivo environment. The lesson learned here is just because a material is allowed to be used for implants, does not mean it is an appropriate choice for all device designs.
Parallel material–device design
The standard approach in many NPD projects is to give the design engineer responsibility for both device design and material selection. However, it is advocated here that an increased success rate will occur if specialists provide guidance on material selection. Material science is a complex scientific field and it is not reasonable to expect a design engineer to be familiar with advanced material technologies, material-related failure modes and current standards. Apart from the obvious advantage of reducing the risk of material–design incompatibility, there is more to be gained by involving subject experts. The material scientist can screen different material technologies and select the best solution for the device. This allows more tailored material solutions and the device will be introduced to the market with an extra competitive edge.
Interactive and parallel material–device design strategies are advantageous in the concept phase. The example in case study one shows that stainless steel 316 LVM was unsuitable for chronic applications in a device where the components were subjected to mechanical wear. Yet, 316 LVM is easy to machine, relatively cheap and has the (acute) mechanical properties the device requires. It could have been used to construct the first devices for animal feasibility studies. While the performance of the provisional 316 LVM device was evaluated in its intended application, the material scientist could simultaneously have evaluated suitable material technologies for the final commercial device.
Animal feasibility studies are of great value in evaluating device concepts at an early state and can expose unknown weaknesses that are not always predicted by bench tests. A correctly designed feasibility animal study can provide pilot input data and greatly reduce device design iterations in the NPD project. The initial data is also useful in establishing discussion points with regulatory bodies as well as for developing future animal models for verification testing.
Planning reduces cost, time and risk
Testing standard and regulatory guidelines are purposely written in a general manner to provide the flexibility needed to select correct test methods and parameters for the specific device under investigation. This flexibility makes the initial selection and design of tests more difficult, but it also offers an opportunity for effective test planning in the NPD process.
The regulatory bodies in various geographies have different requirements and different approaches to specific tests. However, it is often possible to identify a global submission strategy that can, at least partially, be used for several regulatory geographies. This is outlined in the second example from the plan phase. If biocompatibility and materials testing protocols are adjusted to meet the requirements of all geographies where the device will be marketed, the project cost, time and submission risks can be significantly reduced. It is particularly important to interact with regulatory personnel to stay up to date on current regulatory requirements.
Case study two
Figure 2: Establishing an effective test design in the plan phase can reduce costs, time and submission risks when seeking to market globally.
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Biocompatibility, good laboratory practice (GLP) animal, material and shelf-life tests are planned for a device with a metal component (>30 days) and a delivery system (<24 h). The strategy is to market the device first in the European Union (EU) and the United States (US) then in Japan and finally in China. US Food and Drug Administration (FDA) standards are continuously updated. To ensure the tests are designed to comply with current regulations, the most recent FDA guidelines must be used. For this particular device there is a requirement to provide specific information on thrombosis. Therefore, the distal organs from the GLP animal study are saved for complementary thrombus evaluation (Figure 2a), something that was not required in the past. Recently, the EU has adopted stringent limitations on sensitising compounds. Although these currently apply to exposure from materials in contact with the skin, quantification of selected ions is performed during the corrosion evaluation to address possible future questions on ions leaching from the implant (Figure 2b).
Figure 3: Minuscule design alterations can create significant device weakness and the recommended approach is to incorporate material–device compatibility during the design phase.
(click image to enlarge)
Many NPD teams know the regulations set by EU and US regulators, but are less familiar with other geographies. If the test results that are approved in the EU and US are submitted to the Japanese regulatory authorities, they will reject biocompatibility data because they do not accept all ISO 10993 test methods and extract conditions. If those specific test conditions are not addressed in the protocol during the testing regime for EU and US requirements, they must be performed separately (Figure 2c). Also, Japan has specific requirements for the use of drugs during GLP animal tests. For example, the antithrombogenic drug Plavix is approved in the EU and the US, but not in Japan. Consequently, Japan does not accept GLP animal studies that use Plavix. If the initial test design did not use a drug acceptable in all geographies, additional studies with appropriate drugs must be conducted (Figure 2d). Finally, Japan requires real-time ageing studies for shelf life and rejects accelerated testing conditions unless they have been related to real time data (Figure 2e). This takes a long time and should be initiated as soon the device manufacturer even considers submitting to Japan. Finally, China is reluctant to accept rationale for thrombosis testing and demands that this is addressed in in vivo studies (Figure 2f).
Results of knowledge gaps in NPD
The NPD process provides a method to develop medical devices in an efficient, controlled and measurable environment. Unfortunately, no matter how solid the method, the quality of its output is dependent on the knowledge, skills and experience of the project team members. Knowledge gaps in the project team during NPD directly influence the quality and efficiency of its deliverables.
It is crucial to ensure the team is composed of individuals with the appropriate variety of skills and experiences. If there is a gap in the project team’s knowledge and a failure mode falls within this area, there is a high probability that the team will be unable to identify the risk. This is illustrated in the next example from the design phase. It is important to be aware that even small changes in design can introduce weaknesses into the device, even when all materials are kept the same.
Case study three
The design team was tasked with reducing the diameter of an implantable lead that came into contact with blood. The team proposed to change the round filar conducting coil wires (Figure 3a) to flat filars (Figure 3b), which provides a thinner lead with minimal design modifications. No material was changed, thus the risk of material failure modes was assumed to be zero. During the design review the material engineer asked the team if they had evaluated the risk of crevice corrosion in their proposed design. The flat filar wire in contact with the inner side of the connector ring creates a long narrow crevice between the two components (CoCr-alloy). Crevices of critical sizes locally deplete the electrolyte of oxygen and through a series of mechanisms the corrosion resistance of the material is reduced in the crevice. The corrosion behaviour of the two designs was compared. The new design with the flat filar coil exhibited significant lower corrosion resistance. The material engineer suggested a modified design whereby ridges were introduced on the inside of the connector ring to reduce the crevice length (Figure 3c). The corrosion tests proved that the new design had acceptable corrosion resistance.
Chemical characterisation in NPD
The material composition of medical devices means that they can be comprehensively characterised by various analytical methods. These methods are capable of providing detailed quantitative and qualitative results, in contrast to biological testing, which is more empiric in character. The chemical profile of the device, for example leachables, can be identified by selected analytical methods. Because the biological reactions following implantation largely depend on the amount and character of the leachable compounds that are released from the device, the chemical profile can be used to predict its biological response. The chemical profile can also be used to establish chemical equivalence of a new device to a clinically approved device.
Chemical characterisation was recently adopted into ISO 10993, Part 18, and this can be used as a tool throughout the entire NPD process.5 It is particularly useful in the verification phase because it is has the potential to replace or complement the more expensive biological testing, as demonstrated in the example below from the verification phase. This approach greatly reduces the project cost and time line.
Case study four
The biocompatibility of a second generation catheter that came into contact with circulating blood (<24 h) is evaluated. The biological testing required by ISO 10993 are cytotoxicity, sensitisation, irritation, acute systemic toxicity and haemocompatibility. The testing costs approximately US$20000, takes 60 days and requires 28 catheters and three control devices. If the first generation (predicate) device is clinically approved, other methods are viable. Rationales, which claim equivalence of the new device to the predicate device, can be used to justify leverage of previous biocompatibility data. It is difficult to justify biological equivalence with no supportive testing and it is highly likely that the regulatory body will not approve the rationale. Chemical characterisation (ISO 10993-18) can establish equivalence of new devices to predicate devices. If the chemical "fingerprint" of the new device is equivalent to a predicate device, it supports the rationale that biological requirements will be met. One approach is to identify and measure all leachables from the device by a series of analytical tests using gas chromatography with mass spectrometer and inductively coupled plasma. This method of chemical characterisation on the above catheter will cost US$2000–4000, take 5–10 days and require 12 catheters. This is a significant reduction of cost and time compared with the biological evaluation path.
Implementing advanced material selection and testing strategies in NPD projects has the potential to reduce the time it takes to complete the project, submission risks and development costs. Allowing personnel who are knowledgeable in material science, chemistry and biocompatibility to take an active part in the design ensures material–device compatibility and reduces the risk of unpleasant surprises in verification testing. Inclusion of a materials expert does not diminish the importance of the design engineer, but instead promotes collaboration between team members with different expertise and provides for a more holistic attitude to product design. Project success rate is further increased by defining test strategies that span the entire NPD process and combine a global submission approach.
Eva Micski, Andreas Örnberg, Jeff Sturm, Deanna Porter, Darren Schwede are acknowledged for their contributions to the examples in this article.
1. S.A. Brown and J.P. Simpson, "Crevice and Fretting Corrosion of Stainless-Steel Plates and Screws," J. Biomedical Materials Research, 15, 6, 867 (1981).
2. K.C. Dee at al., "An Introduction to Tissue-Biomaterial Interactions," ch. 1, John Wiley & Sons, Hoboken, New Jersey, USA (2002).
3. H.F. Hildebrand and J.–C. Hornez, "Metals as Biomaterials," ch. 9, Eds. J.A. Helsen and H.J. Breme, John Wiley & Sons Ltd, Chichester, UK (1998).
4. P. Combrade, "Corrosion Mechanisms in Theory and Practice," 2nd ed., ch. 11, Ed. P. Marcus, Marcel Dekker Inc., New York, New York, USA (2002).
5. ISO 10993-18:2005(E), Biological Evaluation of Medical Devices, Part 18: Chemical Characterisation of Materials, International Organisation for Standardisation, Geneva, Switzerland (2005).
Anna Norlin-Weissenrieder Ph.D. is Senior Scientist and Stephanie Board is Manager, Analytical Development and Materials Technology, St. Jude Medical, 117 East County Road B, St. Paul, Minnesota 55117, USA, tel. +1 651 481 7722, e-mail: email@example.com, www.sjm.com