How To Meet Biocompatibility Needs Of Polymeric Medical Components
By Dr Vinny Sastri
This article was originally published in Medical Plastics Data Service, Sep—Oct, 2016.
Medical device manufacturers need to ensure that their products are safe and effective. Safety considerations should include usability, energy, operation, informational, and chemical and biological hazards. Biological hazards can be extensive and complex. When materials come in contact with human skin or tissue, their biocompatibility should be evaluated. The importance of patient safety with respect to biocompatibility continues to be an important area that regulatory bodies continue to focus on.
The international standard ISO 10993-1Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process, updated in 2009, added the risk management process based on ISO 14971 in the selection and evaluation of biocompatible materials. In 2016, the United States FDA published its final guidance titled Use of International Standard ISO 10993-1, Biological evaluation of medical devices — Part 1: Evaluation and testing within a risk management process. This guidance document covers the use of the standard including specific requirements that the agency expects in selection, testing, evaluation and documentation. In June 2016, the European Parliament and the Council of the European Union published its draft proposal on its new Medical Device Regulation. Section 7 of Annex 1 details the requirements for a medical device and material chemical, physical and biological properties.
In September 2016, the Center for Devices and Radiological Health (CDRH) in the USA published the CDRH Regulatory Science Priorities (FY2017). One of the top 10 priorities for 2017 is to “Modernize biocompatibility and biological risk evaluation of device materials”. The report states that “it is critical to perform biocompatibility evaluation to assess the risk of adverse events” “to determine the safety profile of implantable or patientcontacting medical devices” The report emphasizes that “less burdensome approaches that are more patient-centric and predictive of realworld device performance are needed to modernize and transform biocompatibility evaluation of medical devices and their materials.”
The medical device manufacturer is ultimately responsible for the safety and effectiveness of the final device. The device, its components and raw materials that come into contact with human tissue must all be evaluated for biocompatibility. As a result, suppliers of parts, components and resin that are used to build the device should also do their part in ensuring that the products or processing conditions do not adversely affect the biocompatibility of those products. Figure 1 illustrates the raw material to finished device value chain with respect to plastic materials and components. There may be instances where the resin manufacturer directly supplies the raw material to the medical device manufacturer who does their own processing and converting.
The steps involved the selection of materials and their evaluation and testing is as follows:
1. Risk Assessment
The intended use and application of the final device is first identified. The initial design concepts can be used to conduct an initial risk assessment of the device design, the material and component characteristics, the manufacturing processes including sterilization, the clinical use of the device, and the nature and duration of contact with human tissue.
The nature of contact falls into three categories per the standard.
- Surface contacting devices — Those devices contacting skin, mucosal membranes or breached and compromised surfaces (broken skin)
- External contacting devices — Those devices that contact blood paths indirectly, tissue/bone/dentin and circulating devices
- Implantable devices — Those devices that come into long term contact with tissue and bone, and blood
The durations of contact are:
- Limited exposure — Contact up to 24 hours
- Prolonged exposure — Contact between 24 hours and < 29 days
- Permanent contact — Contact > 30 days
This information should be used to identify potential risks with respect to biocompatibility and the types of biocompatibility tests that need to be conducted. The standard and the guidance document allow for the use of historical data and information to make informed decisions before committing to extensive biocompatibility testing.
2. Identification of Potential Risks and Exposure Assessment
The physical and chemical characteristic of the materials under evaluation should be listed. Before conducting any biocompatibility tests the potential risks can be evaluated using methods like literature and historical data.Sources of information on potential biocompatibility risks can include previous experience with the same material(s) that have been used in the same or similar devices in the same anatomical location. In addition post market data for similar devices and applications can also provide a rich source of data as an initial risk assessment for biocompatibility.
3. Material selection
When selecting materials to be used in a specific device design, manufacture and use, consideration should be given to the fitness for the device’s intended use with respect to chemical, toxicological, physical, electrical, morphological and mechanical properties. With respect to the biological evaluation of the device, the following should be considered:
i. The properties of the base resin
The choice of the base resin can be constrained by the application and process needs of the device. For example, hydrolytically unstable resins cannot be used in implants. Highly porous materials may not be suitable under ethylene oxide sterilization because unremoved residuals from ethylene oxide could impact patient safety. Thermally unstable grades cannot be used in applications where high temperature autoclave sterilization is required. In addition to physical and mechanical instability, degradation products could affect the material’s biocompatibility.
ii. The material formulation
Additives, catalysts, colorants, fillers, nanoparticles, plasticizers and other materials either alone or by interactions with each other can significantly affect biocompatibility. If each individual component of the formulation is claimed to be biocompatible, it does not automatically mean that the complete, formulated material is biocompatible. Compounders should evaluate the breadth of additives and a range of levels in their formulations to gain maximum flexibility of biocompatible materials in their portfolio.
iii. Manufacturing Processes — Degradation and Residues
Excessive heat and shear during the manufacturing of plastic parts can change the levels of extractables and leachables in the final part and thus significantly affect biocompatibility. Joining and cleaning of parts and residues from materials used in facilitating production (e.g. mold release) can also change a product’s biological properties. Processors should define the process ranges that will not affect biocompatibility.
iv. Master Files
In the case where formulations are proprietary, Device Master Files (MAF) of the product can be used. Material suppliers can submit a Device Master File that is privy only to the FDA for review and evaluation of final device submissions. Device Master Files typically contain the name of the product, its formulation (ingredients and levels), manufacturing conditions, sterilization compatibility, physical and mechanical properties, known impurities and chemical characterization. Included are also biocompatibility screening studies.
4. Biological Evaluation
In order to reduce unnecessary testing, including animal testing, manufacturers should first consider all available relevant information from literature and test data. For example, in some circumstances, a chemical analysis can demonstrate that the extractables and leachables using a specific solvent have not changed compared to a baseline material, eliminating the need for additional biocompatibility testing using that type of solvent. In addition, chemical analyses can be used to assess the toxicological risk of the chemicals that elute from devices. For example, chemical analysis using exhaustive extraction techniques can also be helpful to evaluate long-term toxicity endpoints such as potential carcinogens.
It is critical that test articles are prepared using the proper methods and solvents and also using representative configurations of the end product. Both polar and non-polar solvents should be used. Extraction conditions based on the device application and use should also be employed. Justification of the selected extraction conditions should be provided.
Developing “finger prints” of the extractables and leachables can help in decisions for additional biocompatibility testing if there are changes to materials and manufacturing conditions. If the “finger prints” match the rationale not to conduct additional biological tests can be made.
When biocompatibility tests are required, the decision on the applicable tests can be identified using the Table A.1 in Annex A of the standard. The evaluation tests described should be considered and carried out where necessary tocomplete the data sets needed for the biological evaluation of the particular medical device or its materials and components.
Considerations should be made for testing like cytotoxicity, sensitization, hemocompatibility, pyrogenicity, implantation, genotoxicity, carcinogenicity, reproductive and developmental toxicity and degradationassessments.
5. Biocompatibility Documentation
Due to the diversity of medical devices, not all biocompatibility tests identified in a category will be necessary or practical. Documentation of biocompatibility evaluation and testing should include:
- The strategy, plan and content for the biological evaluation of the medical device, part or material
- The criteria for determining the acceptability of the material for the intended purpose using risk-based methodology
- The adequacy of the material characterization
- The rationale for selection of methods used
- The interpretation of existing data and results of testing
- The need for any additional data to complete the biological evaluation
- The overall biological safety conclusions for the material component and the medical device
6. Changes to Product or Process
When there are changes to an existing, approved and tested material, component or device, biocompatibility should be reevaluated if there is:
- Any change in the source or in the specification of the materials used in the manufacture of the product
- Any change in the formulation, processing, primary packaging or sterilization of the material or product
- Any change in the manufacturer’s instructions or expectations concerning storage, e.g. changes in shelf life and/or transport
- Any change in the intended use of the product
- Any evidence that the material or product may produce adverse effects when used in humans
In order for plastics processors and resin manufacturers to understand the critical characteristics and application of the final device their products go into, the lines of communication between medical device manufacturer and their suppliers should be seamless and effective. Processors of the components and parts should control their production processes so as not to affect or change the biocompatibility of the material provided by the resin supplier. Resin suppliers (virgin or compounded) should provide the basic biocompatibility characteristic to both the processor and the finished medical device manufacturer. Any changes to material or process should be communicated to the medical device manufacturer, as the medical device manufacturer is ultimately responsible to ensure safety, effectiveness and biocompatibility of their finished device.