Our 22nd Year of Publication
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Cover Story

Biocompatibility Testing Of Medical Devices: The Manufacturer’s Perspective

Dr. S.S. Murugan
MSc., PhD
Managing Director
GLR Laboratories Pvt.Ltd.

Dr. T.S. Kumaravel
Founding Chairman
GLR Laboratories Pvt. Ltd.

Biological risk assessment should be conducted on all medical devices before marketing to assure its safety. This assessment should include consideration of all toxic endpoints. It should be noted that biological safety cannot be demonstrated adequately using a “checklist” approach. A systematic analysis of biological risks is required. Attention is drawn to the general principles applying to the biological evaluation of materials and devices set out in Clause 3 of EN/ISO 10993-1. Unfortunately, the matrix in EN/ISO 10993-1 is often used as a checklist to perform a standard set of tests.

What is actually needed is a qualified toxicologist trained and experienced in risk assessment, developing an evaluation programme based on the specifics of the device. It might well be that data is already available from other sources that allow evaluation of the hazard without the need for further tests. It should be kept in mind that individual considerations of the device might lead to a need to assess toxic end points over and above the ones listed in the table. Such “individual considerations” include, but are not limited to, the site of exposure of the device and the duration of exposure. For example regarding exposure duration, long-term exposure can be obtained via a single device application (e.g. implants), or via repeated use of new single use devices (e.g. contact lenses, colostomy bags). In the first case, the effects of degradation products need to be assessed in addition to the exposure to the device materials. In the second case, longterm exposure to the device materials still needs to be assessed, but individual device exposure might be short enough that the exposure to breakdown products could be negligible.

The guidance on the specific tests in different parts of EN/ISO 10993 only discusses the test and sample methods, it does not specify pass/fail criteria. It is not possible to comply with the Essential Requirements by listing the tests done according to 10993 and indicating a “pass” behind each test. The results of the tests should be interpreted in the context of the overall risk assessment to know whether a specific outcome indicates acceptable risk or not. This once again emphasises the need for an overall, scientifically valid risk assessment.

The three basic types of information required for a toxicological risk assessment are identified in Annex C of EN/ISO 14971, i.e.

  • The chemical nature of the materials (including the toxicity of ingredients);

  • prior use of the materials; and

  • biological safety test data.

Toxicological hazard is a property of the chemical constituents of the materials from which a medical device is made and should be considered in relation to the hazard identification steps of EN/ISO 14971 (Steps 1 and 2). The latter two types

of data listed above are dependent upon exposure to a particular material or device and thus predominantly address the risk of an adverse reaction occurring, rather than hazard.

Hazard Identification

The toxicity of a compound or material is investigated using basic toxicology studies which provide information on the nature of toxic effects elicited by a test material, the dosages at which the effects occur and the no-effect levels. There is a widespread misconception that ‘medical grade’ materials (or “surgical grade” or “implant grade”) exist. In the EU there is no regulation or standard that defines what a medical grade material would be and indeed, considerations to achieve acceptability for implantation in an orthopaedic implant would be quite different for a vascular stent. Compliance of a material with a Pharmacopoeial requirement does confer some reassurance insofar as that is a wellrecognised starting point.

EN/ISO 14971 requires that relevant characteristics that could affect safety are listed and, from these, possible hazards are identified. For a biological safety assessment, the first step comprises characterisation of materials. Data relating to formulations, additives, processing aids, degradation products, effects of processing, residue levels, etc. allow the chemical nature of the material(s) to be fully characterised.

Toxicological hazards can be identified from a knowledge of the toxicity of the chemicals or materials listed.

Risk Evaluation

The probability that an adverse effect will arise from exposure to a chemical depends not only on its inherent toxicity, but also on the amount to which a subject is exposed and the route of exposure. This means that information on the identity and toxicity of materials, residues, degradation products, etc. must be considered in relation to quantitative data on the amount present in the final product, its leachability and systemic availability. This analysis is analogous to the requirements of Clause 4.4 of EN/ISO 14971. In practice this means that in many cases an exposure assessment will already provide sufficient justification for limiting the number of toxic end points that need to be addressed in more detail.

Where significant risks arising from hazardous residues are identified by this procedure, their acceptability should be assessed in line with established toxicological principles. Additional information from biocompatibility tests or prior use of materials may be used to provide a basis for further assessment of

Dr. S.S. Murugan is a UK and EU Registered Toxicologist with more than 20 years experience in industry. Dr. Murugan obtained his Bachelors, Masters as well as Doctoral degree in Toxicology from University of Madras and MGR Medical University. He has worked with major contract research organizations (CRO) in India - Head of Genetic Toxicology at IIBAT, Toxicology and Quality Assurance Manager at SGS and Scientific Director at RCC India. He has extensive operational and quality assurance experiences. He has been instrumental in obtained GLP certification and has turned around the business at 2 Indian CROs. He has successfully faced several GLP, ISO17025 and FDA audits. Additionally, he has faced several national and international client audits. He was also a member of CPCSEA guidelines committee, which over sees the animal experimentation in India. He has experience in Toxicology as well as Quality Assurance. This two types of experience helps in understanding QA requirement for the regulatory submission and organizing the studies in alignment to the required quality system. Also he has vast experience in Toxicology and specialized in Genetic Toxicology.

Dr. T.S. Kumaravel is American Board certified and UK/Eurotox Registered Toxicologist with more than 20 years experience in industry as well as in academia. He is a pioneer in conducting Biological Safety Assessments and Biocompatibility studies on Medical Devices. Dr. Kumaravel obtained his Bachelor’s degree in Medicine and Surgery from Stanley Medical College, Doctoral degree in Pharmacology/Toxicology from University of Madras and finally obtained PhD in Genetic Toxicology/Cancer Genetics from MGR Medical University, Chennai. He then carried out toxicology research at Hiroshima University, Japan; National Institutes of Health, USA and Princess Margaret Hospital, Canada. Subsequently, he has worked with world leading contract research companies such as Covance Laboratories and Huntingdon Life Sciences, where he worked with various international medical devices clients. He has extensive experience running and supervising Biocompatibility studies, advising clients on their requirements to comply with national and international guidelines such as ISO10993. Additionally, he has experience of managing regulatory submissions. He has authored several confidential reports, 40 peer-reviewed publications and has 50+ conference papers to his name.

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