Biocompatibility regulatory requirements

Medical grade plastics are discussed with reference to biocompatibility and the tests that the end-product manufacturer should perform in order to ensure the safety of the material. Regulatory requirements are described, and tabulated data is presented on mostly European suppliers of medical grade plastics. The data shows that most companies rely onUSP Class VI certificates to demonstrate the suitability of their materials for the medical industry. However, it is argued that most manufacturers of medical devices would benefit more from tests carried out according to ISO 10993. 6 refs. 

Collaborating with a laboratory that specializes in these types of tests and is familiar with the regulatory requirements will generally produce the best data to demonstrate biocompatibility. 

Polymers have been extensively used both as biomaterials, which are constituents of medical devices, and as constituents of drug-delivery systems. Many regulatory requirements must be met in order to use materials in the domain of human health. For instance, sterility is mandatory concerning materials in direct contact with living tissues in the absence of a barrier such as the intact skin. In addition, both polymers and devices have to be biocompatible, and their biocompatibility has to be evaluated by in vitro and in vivo tests. 

In fact, the term biocompatibility is so widely used that people have stopped thinking about what it means. For a reader of text in which this term is used, it is required to define what the term means. A definition that fits well with the regulatory requirements is The quality of not having toxic or injurious effects on biological systems [1]. 

As previously noted, medical devices are developed and marketed under strict regulatory requirements to ensure safety and efficacy. The transcutaneous nature of the minimally invasive CGM systems on the market and in development creates additional requirements on the materials, processes, packaging, and delivery of the devices. In vitro diagnostic devices are considered to be a subclass of medical devices, and a separate EU regulation (98/79EC) applies. In contrast to in vitro diagnostic devices, medical devices need, e.g., a biocompatibility assessment, and for invasive sensors also sterilization, disinfection requirements apply. As such, the materials used in the constmction of the transcutaneous part of the sensor, and the complete sensor itself, must be biocompatible in the sense that the sensor exhibits no toxicity toward the surrounding tissue. 

The regulatory requirements for biocompatibility and sterihty increase the time and cost of product development for CGM sensors, as all materials and sensors to be used in any experimental programs or clinical trials must be evaluated and satisfy the requirements of the standards. 

Noncontact devices These are devices that do not contact the patient s body directly or indirectly in vitro diagnostic devices). Regulatory agencies rarely require biocompatibility testing for these devices. X ISO evaluation tests for consideration. 

The extract dilution type of cell culture assay requires a solvent extraction of the biomaterial under consideration and testing of this extract, most commonly at various dilutions, for evidence of cytotoxicity and cellular interaction. This type of cell culture assay finds its most common use in providing information for regulatory compliance. As identified in the preceding Materials for Medical Devices section and in Table 1, low-molecular-weight extractables are of concern regarding biocompatibility. The extraction assay, carried out with a series of solvents that are hydrophilic and hydrophobic, permits examination of the potential cytotoxicity of extracts and the identification of materials within a biomaterial that may be cytotoxic. These types of assays ultimately permit identification and characterization of cytotoxic materials within biomaterials or the lack of cytotoxicity, as well as providing correlation with in vivo assays such as sensitization, irritation, intracutaneous (intradermal) reactivity, and other tests where the in vivo injection of extracts is required. 

There are a wide variety of tests in the literature addressing these various requirements. Protocols for many of these tests have been issued as ISO standards. The American Society for Testing and Materials (ASTM) has also developed protocols for demonstrating biocompatibility. Since these standard protocols are recognized by many regulatory agencies, their use will often aid in the device approval process. 

It is unknown which of the proposed devices presented in this chapter will overcome the regulatory and commercial barriers and be accepted into the marketplace. However, the literature not only shows promise in future SMP biomedical devices, but several working devices proven in regards to biocompatibility and animal studies. Future proposed SMP devices will likely require multiple functionalities including triple shape-memory, remote actuation, therapeutic agents, tailored degradation rates, surface modifications, and more. 

Although the range of textile materials is very large, focusing on implantable devices narrows the scope. Chemical biocompatibility is an essential requirement. A close look reveals that only about 50 materials are commonly used compared to more than 1.5 Mio materials that exist. This shows how necessary it is to take into account chemical constraints of implantable medical devices to meet the requirements of standards and regulatory processes (Table 13.3). 

For instance, equiatomic nickel-titanium alloy (nitinol) is a very attractive material for biomedical applications. However, the high nickel content of the alloy and its potential influence on biocompatibility is an issue for nitinol-composed devices. Corrosion resistance of nitinol components from implantable medical devices should be assessed according to regulatory processes and standard recommendations. It is now well known that nitinol requires controlled processes to achieve optimal good life and ensure a passive surface, predominantly composed of titanium oxide, that protects the base material from general corrosion. Passivity may be enhanced by modifying the thickness, topography, and chemical composition of the surface by selective treatments [46]. 

Biocompatibility should be considered for each ionic liquid and in the context of its application. For that reason, several views of their biocom-patibility may arise. General understanding of biocompatibility is a quality of not having toxic or injurious effects on biological systems (Dorland s medical dictionary). This term is now essentially applied to materials used for medical devices (ISO 10993). Biocompatibility evaluation can however be analyzed accordingly to different areas of research and application, and discussed within regulatory and environmental requirements. 

Materials intended for use inside the body have to be approved by regulatory agencies. The minimal requirements of biomaterials for medical applications include nontoxicity, effectiveness, and sterilizability (Table 27.1). Although many currently available biomaterials meet these requirements, most of them lack biocompatibility. 

To mitigate the risk of applying a device to the human body, a series of tests such as those guided by the International Organization of Standards (ISO), are required to be performed on the device prior to human use. Biocompatibility evaluation of medical devices, based on the ISO 10993, is performed to determine the potential harmful effects from contact of the component materials with the body. BiocompatibiUty tests also evaluate the fitness and function of the devices under an implant environment. It should be noted that requirements of biocompatibility vary considerably based on the device function and design, so most regulatory evaluations are device-orientated rather than material-orientated. Usually, materials that have been proven to be biocompatible in one device have to be reevaluated for a different application. 

It is very important to note that it is considered unethical to intentionally determine biocompatibility or biostability in human clinical trials. These parameters are to have been established before regulatory submission and the first human implant. Of course, should any untoward result be found clinically, or in prior preclinical tests, it must be reported according to FDA regulations. The clinical study is to determine the human safety and reliability of the new product, not its biocompatibility or biostability. The requirements for the development of clinical study plans can be found in the FDA Guidance [29]. 

Biocompatibility testing is an essential requirement for regulatory approval of medical devices such as medical textile products, and it is important to follow strict testing protocol in order to avoid potential pitfalls that could delay a product launch. During the product development process, it would be sensible to start the process early enough to allow for thorough and complete testing. As with any business or scientific endeavor, it is important to communicate all details accurately and be as up to date as possible on all test requirements. It is often necessary to consult qualified professionals to provide the expertise that is required for the successful completion of the various tests. 

---