The new Medical Devices Regulation (2017/745/ EU) (MDR) and the In Vitro Diagnostic Medical Devices Regulation (2017/746/EU) (IVDR) bring EU legislation in line with the technological advances and changes in the field of medical science. This document emphasizes more on the chemical nature of medical devices, influencing the safety aspect. The MDR will also provide increased transparency, with information on devices and studies being made public. The new European Database for Medical Devices – EUDAMED – will play a central role in making data available and increasing both the quantity and quality of data. In contrast to the above MDR regulation, one of the essential components of establishing biological safety is the characterization of medical devices based on its chemical and material nature. Medical device materials present a unique challenge to chemists (for Identification of extractable) and toxicologists (to provide adequate toxicological risk assessment). Historically, assessing the safety evaluation of a new medical device has been performed primarily through in-vivo bio compatibility testings. This testing looks at whether device components or extracts, have the probability to pose hazard in a biological system. After the product is in extensive use, sometimes unforeseen problems can lead to recall from the market. In recent times several medical devices have been withdrawn from the market. The recall of the medical device can happen due to various reasons like, a reasonable chance that a product might pose serious health problems or fatalities. Currently, there are sophisticated, sensitive analytical equipment’s and more robust analytical methods are available. The regulatory bodies like the US FDA, EU MDR and other bodies are asking for the data on the material/chemical components of the medical device to complement in-vivo biocompatibility studies. By analysing the device components, by looking at the type of chemical and its level that migrate from the device to patient’s body during the usage the associated risks can be evaluated. Devices that fall into the more critical category (class III devices like, implants) of use, require exhaustive extraction followed by robust analysis to identify and quantify the extracted chemicals. Exhaustive extractions are generally recommended for the evaluation of materials intended to be implanted into the body. Thus, characterization studies are performed to gain a thorough understanding of the device and risk associated with it, if any. This also explains why the FDA and MDR regulations are placing a greater emphasis on chemical and material characterisation studies to ensure patient safety.
Material Characterization vs. Chemical Characterization (Leachable/Extractables)
Material characterization refers to identifying all the component materials of a device. This can include colorants, plasticizes, specific metals, and ceramics. In general, the specific information or data on the device components can be obtained from the manufacturers. The ISO 10993 set entails a series of standards for evaluating the bio compatibility of medical devices and recommends gathering the information or data as much as possible from the device manufacturers. Pre-existing data may offer a reasonable substitute, which will reduce the characterization testing.
The following are the reliable methods for identification of polymers in the medical device:
- Fourier Transform Infrared Spectroscopy (FTIR): This testing technique is used to identify organic substances in a given material or to prepare a product fingerprint.
- Differential Scanning Calorimetry (DSC): Identify critical thermal properties of a given material, thermal history and purity of a polymer
Chemical characterization (extractables/leachable): A device is submerged in a polar and non-polar solvent—like water, hexane, or alcohol—and kept for an appropriate time and temperature (e.g., human body temperature or greater) for extraction. The extract is then analysed, which yields quantitative, semi-quantitative and/or qualitative data depending on the test method. Four common types of analytical methodologies for extractables and leachables are as follows:
- Gas Chromatography-Mass Spectrometry (GC-MS): Provides quantitative data for volatile and semi-volatile organic compounds of small molecular weight.
- Liquid Chromatography-Mass Spectrometry (LC-MS): Provides quantitative data by analysing extracts for non-volatile molecules .
- Inductively Coupled Plasma-Mass Spectrometry (ICP-MS): Specific to identify and quantify metallic compounds such as heavy metals that do not generally metabolize in the body and may lead to toxicity .
- Gravimetric Assays: This test detects two types of gross contaminant non-volatile residue: surface and leachable .
As indicated, the user of the device can be exposed either by locally and /or systemically to the chemicals, and it is important that the potential user to know whether the use of the device may yield harmful effects. Once the composition of the device is known, the qualified toxicologist can conduct the toxicological risk assessment and identify the risk associated with the use of the device.
The degree of the chemical and material characterization required based on tissue contact and duration:
|Nature of contact and tissue type||Duration of contact||Types of Devices||Degree of material characterisation|
|Surface: Skin and mucous membranes||Limited||Gloves, tape, blood pressure cuff, dental dams and endoscope etc.||Minimal|
|External communication: Blood, indirect contact||Prolonged||Dialysis, Cardiopulmonary bypass||Intermediate|
|Implant: Blood, direct tissue contacts||Permanent||Stunts or grafts
ISO 10993 Standards for material and chemical Characterization Studies:
Several sections of the ISO 10993 standard cover aspects of characterization studies:
ISO 10993-9: Framework for identification and quantification of potential degradation products
ISO 10993-12: Sample preparation and reference materials
ISO 10993-13: Identification and quantification of degradation products from polymeric medical devices
ISO 10993-14: Identification and quantification of degradation products from ceramics
ISO 10993-15: Identification and quantification of degradation products from metals and alloys
ISO 10993-17: Establishment of allowable limits for leachable substances
ISO 10993-18: Chemical characterization of materials
ISO 10993-19: Physico-chemical, morphological and topographical characterization of materials
The below two medical devices have been recalled due to the improper material characterisation.
1. Case study 1:
Recalled Product: The SpF® PLUS-Mini (60μA/W) & SpF® XL IIB Implantable Spinal Fusion Stimulators
- Serial numbers:
- SpF-XL IIB: 224595, 224598, 224607, 224608, 224610, 224613, 224615, 224621, 224622, 224623, 224624, 224625, 224626, 224644, 224649, 224651, 224655, 224656, 224658, 224659, 224666, 224667
- SpF-PLUS: 410093, 410094, 410096, 410103, 410111, 410115, 410119, 410148, 410151, 410158, 410171
- Reason for recall:
- “Zimmer Biomet is recalling the SpF PLUS-Mini and SpF XL IIb Implantable Spinal Fusion Stimulators due to higher than allowed levels of potential harmful chemicals, which may be toxic to tissues and organs (cytotoxicity) and that were found during the company’s routine monitoring procedure. A cytotoxicity test is a part of the biological evaluation of medical devices to ensure compatibility with the device and the human body. A positive cytotoxicity test (failed result) can indicate that a device contains potential harmful chemicals at amounts or levels that could be dangerous to the patient.
- “The use of affected product may cause serious adverse health consequences, including but not limited to chronic infections, long-term hospitalization due to additional surgical procedures, paralysis, and death”.
- Who May be Affected:
- “Health care providers using the SpF PLUS-Mini and SpF XL IIb Implantable Spinal Fusion Stimulators”.
- “All patients undergoing spinal fusion procedures involving the SpF PLUS-Mini and SpF XL IIb Implantable Spinal Fusion Stimulators”.
2. Case Study 2:
Recalled Product: “In 2016, FDA recalled Becton Dickison (BD) Vacutainer® EDTA Blood Collection tubes.
- Recalled products
- “BD Vacutainer® EDTA Lavender, Tan, and Pink Top Tubes”
- “BD Vacutainer® Lithium Heparin Green Top Tube”
- Reason for recall:
“Due to a chemical in the rubber tube stopper that interferes with the accuracy of the Anodic Stripping Voltammetry (ASV) testing methodology. ASV is the methodology used in Magellan Diagnostics’ LeadCare Testing Systems. The tube stoppers contain a substance called Thiuram that can sometimes release sulfur-containing gases, which may dissolve into the blood sample and bind the lead particles. This chemical reaction makes it difficult for the Magellan lead tests to detect the correct amount of lead in the sample and may cause falsely lower test results. Falsely lower test results may lead to improper patient management and treatment for lead exposure or poisoning. The use of affected product may cause serious adverse health consequences. The FDA has identified this as a class I recall, the most serious type of recall. Use of these class may cause serious injuries or death and hence recalled from the market” .
- Who may be affected:
- “Patients being tested with assays using ASV methodology (i.e. Magellan Lead Care Diagnostics’ Testing Systems) whose blood is drawn in the affected BD blood collection tubes”.
- “Laboratory personnel who perform clinical testing using patient samples drawn in the affected BD blood collection tubes and running assays using ASV methodology (i.e. Magellan Diagnostics’ Lead Care Testing Systems)”.
- “Health care providers who interpret these clinical test results”
A poorly directed approach to safeguard against product failure can damage manufacturers’ reputation for sustaining products in the market and it may even call for a withdrawal of the product from the market. Bio compatibility is an important aspect of the overall safety of medical devices. A thorough safety evaluation looks at all the potential effects on a human body that can result from contact with a device. An important step in the process is that of characterizing the material and identification of chemicals that can migrate or extract from the polymer components. Such basic information is critical to understand the biological response and toxicological risk of the device since adverse effects caused by materials are generally by chemical effects.
- European Commission: Regulatory frame work, On 5 April 2017