MEDICAL DEVICE TESTING - Chemical Characterization & the Non-Targeted Analysis of Medical Devices

INTRODUCTION

At Medical Engineering Technologies Ltd. (MET), we are con­ducting a variety of Medical Devices Testing. Chemical Charac­terization is vital for new medical devices released on the market. When a new medical device (MD) is developed, it is mandatory to know the potential effects that this can have on the patient. In addition to the materials of construction there are other products that can be used during cleaning, processing, and sterilization of the devices. These materials can be easily missed from further in­vestigations; the focus is mainly on the materials of construction. Any contaminants or impurities are referred to as Non-Target Ma­terials (NTMs). When chemical analysis is performed, it is impor­tant that screening methods are developed to detect all potential extractables and leachables, rather than only target materials.

The scope of the medical devices is to monitor, diagnose, or treat an injury or medical condition, or to prevent and monitor a disease. There are many medical devices being designed every day, such as insulin pumps, syringes, oxygenators, diabetic pens, heart valves, brain implants, dental implants, etc.

At MET, we are specialized in developing bespoke ISO 10993-18 extractables and leachables studies for a whole range of these devices. Medical Devices can be categorized by the du­ration of body contact (eg, =1day, >1 to 30 days, or >30 days), frequency of body contact (eg, continuously versus intermittently), and type of body contact (eg, surface contact with intact skin, mu­cosal contact, implantation in tissue, or intravascular implanta­tion) according to ISO 10993.

The investigation of the potential risks is developed based on the information provided by the manufacturer of the device, components, and materials.

INFORMATION GATHERING

Information Gathering is the crucial first step in testing MDs, and this is covered by the Biological Evaluation Plan (BEP), which is a risk assessment and gap analy­sis (as per ISO 10993-1 Biological evalu­ation of medical devices – Part 1: Evaluation and testing within a risk man­agement process), detailing all the mate­rials that the medical device is composed of and the potential risks that the patient could be exposed to. The BEP includes a review of the existing scientific information, and it can lead to new testing to determine if the device is safe for the intended use. Based on the information provided in the BEP, the testing study is designed.

Depending on the contact route of the MD, further tests covered by ISO 10993: Biological Evaluation of Medical Devices for direct contact devices or ISO 18562: Biocompatibility evaluation of breathing gas pathways in healthcare applications are recommended.

CHEMICAL ANALYSIS

This is performed in accordance to ISO 10993 series and involves a broad range of studies, designed specifically for each product. Extractable and leachable studies are mostly used to assess direct-contact MDs. For example, implant de­vices, due to their permanent duration of contact in the tissue, and where any po­tential degradation is possible must be evaluated for any potential degradation, and the degradation products must be an­alyzed. Extractable and Leachable studies are designed according to ISO 10993 parts 12 & 18, whilst degradation studies follow parts 13, 14, and 15, depending of the materials of construction.

Extractables are materials that can be extracted from the MD during exaggerated and accelerated conditions. The acceler­ated conditions are simulated by increas­ing the temperature of the extractions, eg, for an MD with an intended use at body temperature, the exaggerated extraction will be performed at a higher temperature, such as 50°C. Extractable compounds can be forced out from the MD using aggres­sive solvents. The extraction vehicles are chosen considering the intended use, ex­aggerating the polarity of the solvent, tem­perature, and extraction time, without dissolving the product. When choosing the extraction vehicles, ISO 10993 suggests that the scope is not to dissolve or com­promise the device, so the selection of the extraction conditions must be well-evalu­ated prior to testing and the selection jus­tified.

Leachables are the compounds that can leach from the device under normal use conditions; this process is generally performed by simulating the normal use of the MD. When it comes to assessing the leachable compounds, it is important to recreate the biological environment of use and, if formulations are present, to use the drug vehicle or fluid that the device will be contacting during use. It is mandatory to assess the MDs for leachable compounds, as these possess a high risk to the patient. Leachable compounds are transferred in the body by the drug and could lead to re­actions that can harm the patient.

In addition to extractable and leach­able testing, implant devices, where there is a potential for degradation, must be as­sessed for any degradation products. The degradation studies are intended to simu­late the complex environment in the body; they are performed using hydrolytic and oxidative solutions.

It is important to know that the accel­erated degradation uses high tempera­tures, and the extraction solutions must be analyzed over specific periods of time (given in the standard or justified in the testing protocol). However, it can be chal­lenging to use this approach to identify all the hazards present and released by the devices, due to the complexity of the ma­terials and different manufacturing processes. For example, complex devices can introduce chemicals that are not ac­counted for by formulation information solely.

To cover the gaps, MET is conducting targeted and non-targeted screening analysis using a variety of analytical tech­niques in order to investigate any residual impurities that could be volatile, semi-volatile, non-volatile, organic, or inorganic that are present at concentrations above the AET (Analytical Evaluation Threshold).

The studies are developed bespoke for each product. They consider worst-case scenarios of release of materials by the de­vice. The selection of extraction media and conditions and the instrumentation used is based on sample proprieties, the chemical make-up, and the application of the de­vice.

At MET, we have a broad range of an­alytical techniques available:

• Head Space-Chromatography coupled with Mass Spectrometry (HS-GC-MSD) is used to screen and identify any po­tential volatile organic impurities or residual solvents released by the MD or from the manufacturing process that could harm the consumer. HS-GC-MS may be performed on an aqueous ex­tract or directly on a solid test article.
• Gas chromatography coupled with Mass Spectrometry Detection (GC-MSD) methods are developed to search for a multitude of potential semi-volatile impurities that could be released by the device. These may derive from the manufacture and storage of polymers and precursors or be added (purposely or inadvertently) during the manufactur­ing, sterilization, or any other treat­ments of the raw materials, components, or device. The extract media is normally introduced into the analytical equipment by direct injection.
• High Performance Liquid Chromatog­raphy methods with Photodiode Array Detection coupled with Mass Spectrom­etry (HPLC PDA-MSD) detection are de­veloped based on the material of construction of the MD and the poten­tial non-volatile residuals that could harm the user. The dual detection method PDA and MS is designed to have a higher sensitivity, as it has the capability to detect organic compounds that do not ionize and contain chro­mophore groups (such as colorants or monomers added to the devices) and molecules that can ionize.
• Inductively Coupled Plasma Optical Emission Spectroscopy (ICP-OES) is used to search for any potential non-or­ganic (metallic) residuals left behind from manufacturing machinery or from any metals or pigments associated with the MD.

Materials can be quantified by using either targeted (fully quantitative) or non-targeted (semi-quantitative) methods. Tar­geted quantification refers to the analysis of a specific analyte or a group of analytes of interest using pure reference standards within a defined concentration range. To evaluate analytical suitability for use in quantification, a calibration curve is pro­duced with 5 to 6 non-zero calibration points.

System suitability is the assessment that is used to determine the performance range of the analytical instrumentation prior to testing. The system suitability as­sessment determines whether the method has been implemented properly, maintains its performance at the same level as dur­ing qualification, and performs acceptably throughout its use. System suitability for NTM work has been proposed to include the use of blanks, pooled samples such as matrix controls, and multi-analyte-spiked (with reference/control materials added) samples. The selection of the reference or target materials is based on prior informa­tion and is used to perform calibration and system suitability analysis.

Analytical Evaluation Threshold is de­fined as the level below which quantifica­tion of a material is not required; the analyst doesn’t need to identify, quantify, or report peaks for toxicological risk as­sessment. The AET was adapted for MDs in the 2020 edition of ISO 10993-18. The calculation of the AET considers the dose-base threshold (DBT), which depends on the frequency and duration of a patient’s exposure to a device, as described in ISO/TS 21726:2019. It should be noted that, according to ISO 10993-18:2020, AET is not applicable to substances named as “cohorts of concern.” These materials are considered highly toxic at very low concentrations, such as volatile organic compounds and non-organic compounds. Therefore, AET is only valid for semi-volatile and non-volatile organic compounds and is calculated as AET = (DBT x (A/(B x C)))/UF.

A is the number of devices extracted, B is the extract volume, C is the number of devices that contact the body divided by 1 day, D is the dilution factor, and UF is the uncertainty factor of the analytical method. The value of the UF depends on the ana­lytical method and accounts for variation in the response factors (RFs) of individual analytes.

As most of the time the test extract fluid sample goes through multi-step preparation, including concentration and dilutions, a D factor must be considered (D<1 where the sample is concentrated and D>1 for diluted samples).

Once extracts of the devices are ob­tained, the solutions prepared (diluted, concentrated, etc) are injected into the sys­tems; analysis involves separation of the molecules extracted using the aforemen­tioned methods.

EXTRACTIONS

The extraction process is intended to transfer mobile chemical constituents from the MD into a liquid phase/solvent. The extractions can simulate the real-life or worst-case scenarios, with respect to clini­cal use.

The selection of the solvents is made from a broad range of candidate organic solvents. The goal is to cover all the polarities that are clinically relevant. The extractions are conducted on patient-contacting de­vices/components to result in a worst-case scenario, with respect to the clinical use.

Solid-liquid extraction is not the only possibility; liquid-liquid extraction applies when the device is in a liquid form and gas to solid phase extraction (followed by re­turn release to gas for analysis) applies for breathing components.

The extraction process is controlled by the interaction of the device or material with the extraction vehicle (solvent) and is governed by the solubility, diffusion of the chemical into the solvent, and partitioning of the chemical between the solvent and the material, extraction temperature, ex­traction duration, and surface area. The goal of the extraction is to facilitate migra­tion of chemical constituents that could po­tentially leach out of the device during clinical use without changing their chemi­cal identities or physically destroying the device.

In some cases, exhaustive extraction is required (for example: in the case of im­planted devices). This is defined as repeti­tive extraction, performed until the amount of material extracted in a subsequent ex­traction step is less than 10% (by gravimet­ric analysis of that determined in the first extraction step). The most common method for checking is to assess the Non-Volatile Residue (NVR) analysis.

This method is relatively simple; how­ever, the approach is limited by the sensi­tivity of gravimetric analysis and is insensitive to volatile and some semi-volatile compounds.

When a device is invasive but not per­manent, exaggerated extraction may be appropriate. This is performed by the use of solvents and temperatures that repre­sent a worse case than the conditions of the clinical use (temperatures chosen above 37°C and extraction duration longer than the duration of the device use).

Because clinical use of a device can extend over a considerable time period, accelerated extraction is used to allow analysis to be performed in a reasonable timescale. This is defined as an extraction with a duration shorter than the duration of the clinical use, whilst not causing degradation, chemical, or physical changes to the substances being extracted. The accelerated extraction is usually achieved by increasing the temperature used.

When selecting materials and compo­nents for use in an MD, designers will pay attention to the biocompatibility of these items. However, final proof of biocompat­ibility must be given for the device pre­sented to the patient. Therefore, the selection of the test article for the study is very important. The study aims to replicate the real use of the product and it must, therefore, be representative of the final product (as opposed to a raw material, resin, or unfinished medical device).

In targeted analysis, the chemistry of the extractable of interest is known, allow­ing extraction optimization. In NTAs, how­ever, the chemistry of each potential extractable is typically unknown and varies. Therefore, to maximize the extrac­tion of chemicals having a broad range of chemistries, non-targeted extraction con­ditions usually include the use of polar, semi-polar, and non-polar solvents, ele­vated temperature, and longer extraction times.

The polarity selection of the solvent is performed as per Table D.1 of ISO 10993-18:2020. The selection of polar, semi-polar, and non-polar solvents is recommended for devices intended for long-term use (>30days). The selection of the solvent must also consider the tissue the device will contact, in order to simulate the worst-case scenario.

One example would be alcohol-water mixtures that can have polarities in the semi-polar to non-polar range. Extractions using alcohol-water mixtures can result in lower concentrations of extractables and can underestimate their presence in com­parison to extractions purely using alcohol.

Another important parameter in ex­traction study design is the solvent volume-to-sample size ratio. Concentration or dilution of the extract is performed with consideration of the reporting limit and the sensitivity requirements of the analytical techniques used for extractable profiling .ISO 10993-12:2021 contains recom­mendations for various ratios of the device surface area or mass-to-solvent volume, depending on the device characteristics, and ISO 10993-18:2020 contains recom­mendations to use these ratios as potential starting points in planning an extractables study. However, the final solvent volume determination is based on factors that in­clude the properties of a device/material and the extraction techniques used. For ex­ample, absorbent materials will require additional extraction fluid.

It is important that extracts, once gen­erated, are compatible with the analytical methods. The analytical methods must be adequately sensitive and achieve the nec­essary reporting limit can support a bio­compatibility evaluation. In many cases, extracts can be directly analyzed using GC and liquid chromatography (LC) tech­niques without further sample processing. However, further processing of the sam­ples is often required for analytical instru­ment compatibility and reliable analytical outcomes. For example, sample dilution, sample concentration, liquid-liquid extrac­tion (solvent exchange), and solid phase exaction (SPE) are some of the techniques used to process the sample extracts prior to injection in the analytical systems.

The need of chemical characterization and toxicological risk assessment for eval­uating and supporting the biocompatibility of MDs is constantly increasing. The design and performance of the suitable chemical analysis depends on the collaboration of the team of experts in areas including MD manufacturing, analytical chemistry, and toxicology.

Medical Devices industry is in contin­uous growth, and the development of new reliable and accurate approaches in order to assess the safety of the products is con­stantly reviewed.

REFERENCES

1. Chemical Characterization and Non-targeted Analysis of Medical Device Extracts: A Review of Current Approaches, Gaps, and Emerging Practices – Eric M. Sussman,* Berk Oktem, Irada S. Isayeva, Jinrong Liu, Samanthi Wickramasekara, Vaishnavi Chandrasekar, Keaton Nahan, Hainsworth Y. Shin, and Jiwen Zheng.
2. ISO10993-1 ISO 10993-1:2018: Biological evaluation of medical de­vices — Part 1: Evaluation and testing within a risk management process.
3. ISO 10993-18:2020: Biological evaluation of medical devices — Part 18: Chemical characterization of medical device materials within a risk management process.
4. ISO10993-12: Biological evaluation of medical devices: Part 12: Sample preparation and reference materials.
5. ISO 10993-17:2002: Biological evaluation of medical devices — Part 17: Establishment of allowable limits for leachable substances.
6. ISO 10993-13:2010: Biological evaluation of medical devices — Part 13: Identification and quantification of degradation products from poly­meric medical devices.

Luminita Moraru is the Analytical Chemistry Manager at Medical Engineering Technologies Ltd, has more than 6 years of experience in Medical Devices Testing. She is a committee member of ISO10993: CH/194 Biological evaluation of medical devices and ISO18562: CH/121/09 Lung Ventilators & Related Equipment having insight knowledge for in the applications of those on medical devices to meet the requirements, ensuring the data is generated in appropriate form to be risk assessed in Toxicological Risk Assessments. She earned her Masters in Chemistry at the University of Bucharest.