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Passing the test: Why patient safety is paramount

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Thor Rollins, Piet Christiaens and Matthew R Jorgensen, Nelson Labs, explain why E&L testing offers an expedited path towards enhanced patient safety.

Medical plastics permeate the medical device industry with a remarkable diversity of application. They seem to be everywhere in healthcare: from protective barriers and low-risk device components (eg. instrument housings and handles) to devices of the highest potential risk (eg. permanent implants contacting the central nervous system). The key advantages of plastics include the range of physical and material properties, ease of processing, relatively low costs, and great track record with safety. The benefits of plastics are available for various scenarios because we are able to understand and assess the risk associated on an application by application basis. There are some unique characteristics of plastics that manifest as a challenge in the context of medical devices with regard to protecting patient safety and obtaining regulatory approval.

Introduction of leachables through the manufacturing process

Perhaps the most significant challenge with plastics and biocompatibility is the complexity of the material itself – and how the integrity of the plastics becomes susceptible to possible contamination during the manufacturing process. Consider the manufacturing pathway for a plastic material, with a process flow that may allow introduction of contaminants from several sources:

Each step along the manufacturing pathway has the potential to introduce undisclosed additives and impurities, unknown to those downstream. Because medical device plastics represent such a small share of the market compared with consumer goods, manufacturers may not be concerned or even aware that they can impact patient safety. Upstream processes may change without notice, resulting in a different formulation and leachables profile, while the appearance and functional properties of a plastic remain the same. Upstream processes also remain closely guarded trade secrets, making divination of a material profile impossible without testing.

Risks of the Unknown        

It is precisely the unknown nature of plastics’ formulation and impurity profile that introduces risk from a biocompatibility perspective. What additives or residual catalysts could be present that could leach out slowly over time? If the device in question is high risk like a permanent brain implant, knowledge of whether these compounds are there and, if they are, their toxicity is critical.

There are several options available to medical device manufacturers to address the risk of potentially toxic leachables. One way is to perform a suite of in vivo animal tests. When indirect animal tests are used, samples of the final finished device are extracted separately in saline solution and cotton seed oil and, based on the final application of the device, the animals are exposed to these extracts. The test is concluded when the animals are observed for adverse reactions to the extracts after a specified period of time. Other tests involve implanting the device in an animal for a predetermined period of time, then performing histopathology on the animal. While animal tests have been used for decades as part of the strategy to address biocompatibility and are still generally accepted in the United States, there are questions regarding the sensitivity of animal tests and their applicability to humans. In scientific communities focused on the testing of medical devices, animal tests are sometimes considered as first-generation tests while currently there are second and third-generation options available.

Mitigating unknown risks using E&L testing

One of the more modern options available to address toxicological risks associated with potentially hazardous compounds which may migrate out of medical devices is extractable and leachable chemistry testing. Extractables are the compounds which may migrate out of medical device materials under conditions that are exaggerated (aggressive solvents at high temperatures) compared to clinical exposure. Leachables are those compounds which may migrate out of device materials when effort is made to mimic clinical exposure as closely as possible in terms of temperature, time, and solvents. Solvents used seek to mimic the environment in the body, which is composed of both polar and non-polar liquids. Therefore a polar solvent (water), a non-polar solvent (hexane), and sometimes even a third mid-polar solvent are used as extraction solvents to ensure that leachable compounds across the polarity spectrum are captured. Often an aggressive ‘extractables approach’ is first taken, with the view that if a device is found to be safe under conditions more aggressive than clinical use, then it certainly would be safe as actually used.

The details of the analysis of medical device extracts are a matter of lively scientific debate between industry and regulatory players; however, the key ideas are settled. Analysis of medical device extracts must both identify the compounds contained and measure the amount of compound present with sensitivity sufficient for toxicological assessment. The requirement for simultaneous identification and quantification points towards chromatography with mass-spectrometry methods. Because a range of leachable compounds are possible, a set of analytical methods are needed: headspace gas-chromatography with mass-spectrometry (HS-GC/MS) for volatiles, direct injection GC/MS for medium and heavier compounds up to around 650 atomic mass units, inductively coupled plasma with mass-spectrometry (ICP/MS) for metals, and if large non-volatile molecules are a concern, liquid chromatography with mass spectrometry (LC/MS) for non-volatile compounds will need to be considered.

Modern analytical chemistry coupled with large databases (either developed in-house by the testing laboratory or publically available) provides an excellent ability to identify compounds and measure their concentrations with sensitivity below widely accepted thresholds of toxicological concern. When applied to medical devices, chemistry results provide a level of detail far surpassing the binary results obtained with animal testing. Chemistry studies are followed by a toxicological risk assessment, which is essentially the art of applying knowledge acquired by the chemistry study with past animal studies to the device at hand; the conclusion of the toxicological risk assessment is if the compounds from the device have either a low or high risk of causing negative biological outcomes. In this manner, the animal studies of the past are leveraged to their maximum extent to predict toxicological outcomes, sparing repeat testing.

In addition to sparing animal life and providing more sensitive results, analytical chemistry for medical devices has several other advantages. For example, when a biological test like chronic toxicity fails, it is unknown why it failed and if that failure is truly relevant to the clinical use of the device with humans. However, chemistry results provide a roadmap to discovering the cause of a failure. One of the primary advantages of E&L is that it takes less time, and has the possibility of being expedited, because the time associated with testing and toxicological assessment is dependent mostly on scheduling and logistics, where the turn-around time for biological tests is fixed by the biological system itself. Another advantage is the typical cost of testing, especially in comparison to longer-duration animal tests.

Toxicology considerations beyond E&L testing

While chemistry testing for medical devices in support of biocompatibility has clear advantages when applied to addressing longer-term biological toxicological endpoints, it should be understood that these analytical methods are not an end-all answer that can stand alone to support patient safety. Extractables and leachables chemistry testing does have some challenges and limitations. Testing strategies are designed to capture as many types of concerning compounds as possible, and they do an excellent job, but there can be small groups of compounds that present a potential risk that are not included. For example, analytical tests capable of capturing small anions are not commonly included in testing strategies. Not including anions means that molecules like nitrate, sulfate, and cyanide are not screened. Another gap is the dependence of toxicological impact on crystal structure or morphology.

Plastics in medical devices present an incredible opportunity for innovation that can lead to increased safety and quality of life; they can also present complex challenges from a biocompatibility perspective. The best way to ensure biocompatibility of a plastic containing medical device is to use a set of orthogonal and complimentary testing approaches that includes extractable and leachables chemistry testing. Chemistry testing can replace some of the longer and more burdensome animal tests with analytical results that are more detailed, sensitive, and actionable. In addition to being better from a scientific perspective, extractables and leachables chemistry testing also comes with cost- and time-savings to the manufacturer.

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