WHAT IS THE SIGNIFICANCE of a residue or a mixture of residues on an implantable biomedical device? If I perform chemical characterization of materials, do I need risk assessment? With similar processes, historical performance data of the device can provide a level of assurance. However, with new products and new processes, there is the need for a better understanding not only of the identity of the residue but of the significance of the residue. One of the greatest challenges in chemical characterization is performing adequate assessment of biological or toxicological risks from extractables or chemical residuals that can compromise patient safety. ISO-10993-17 has clearly articulated to the medical device community why and how risk assessments are a part of material biocompatibility [1]. But what is not clear is when and if they are absolutely required.

A Decision-Making Tool
Risk assessment is not new, but has only recently been promulgated by international standards and government agencies as a necessary part of chemical characterization and biocompatibility studies. It is really a tool for decision making that has evolved with time. Toxicological risk assessments have a long history with strong ties to the U.S. FDA, EPA, and OSHA. Risk Assessment is important and absolutely necessary to understand the ultimate biological or toxicological human response to materials and chemical processes. It becomes clear that to understand or predict human response to chemicals or materials, there must be close collaboration between the analytical chemist and the toxicological risk assessor.

Risk assessment is a scientific attempt to identify and estimate the true risks, and is the result of considerations of four primary steps. (1) Hazard Identification: identification of adverse health effects associated with exposure to a specific chemical; (2) Hazard Characterization: determination of the quantitative potency of any adverse effect of a chemical; (3) Exposure Assessment: measurement or prediction of the intake a chemical in terms of magnitude, duration, and frequency of exposure; (4) Risk Characterization: the integration of hazard identification, hazard characterization, and exposure assessment to determine the probability of occurrence and severity of risk to human health from the chemical(s).

Protocols for Complex Data
Those who are accustomed to a standard calling out of a specific procedure to identify or quantify a specific analyte may find themselves in unfamiliar territory with ISO 10993-17. Because toxicological data inherently consists of a wealth of complex variables and because the data and supporting studies for a given substance may vary in quantity and quality, a one-size-fits-all standard is impossible.

Instead, ISO 10993-17 is an ambitious, much needed step to define and document consistent protocols for evaluation of the risk factors for specific leachable substances.

This standard provides a systematic method for assessing complex studies. For example, the modifying factor is derived as the product of various component uncertainty factors. One example of a commonly used uncertainty factor is the factor used in extrapolating the effects of animal studies to humans. If only limited long-term exposure studies were available, a higher uncertainty factor leading to a lower acceptable exposure in the human population would be employed. It is noted in the standard that when this factor is combined with other uncertainty factors, modifying factors may be expected to differ by two orders of magnitude. Uncertainty factors and ultimately, the modifying factors, are derived on a case-by-case basis and are highly dependant on the quality of the toxicological database.

A dose or concentration of a chemical substance that does not produce any adverse effect [(i.e., “No-Observed-Adverse-Effect-Level” (NOAEL)] is identified, usually from toxicological studies involving animals, but sometimes from epidemiological studies of human populations. A modifying factor is applied to the NOAEL to derive a Tolerable Daily Intake (TDI), the intake or concentration which is believed that a person can be exposed to daily over a lifetime without deleterious effect.

Higher levels of cleaning, contamination control, and contaminant identification are inherent to the standard. Where only limited toxicological and long-term usage data are available, the modifying factor may be increased by an additional order of magnitude or more. Worker safety and regulatory constraints on cleaning agents and processing agents with known environmental risks as well as outsourcing of manufacturing processes tend to result in a multiplicity of process chemicals. Many of these are complex mixtures, often with poorly-defined toxicological profiles. Cleaning and contamination control processes will become increasingly important because moving from a chemical with well-established risks to a chemical we know less about can make it difficult to define the risk; so a higher risk will be assigned.

Mixtures
Risk assessment of mixtures remains a thorny problem. It is now recognized that significant data gaps exist in the area of mixtures toxicology, and these can preclude accurate risk assessments [2]. Most analytical chemists are acutely aware that leachable residue is likely to be a blend. The assumption is made that compounds with similar metabolic pathways or even with similar structures will have an additive effective. Sometimes, a small change in chemical structure produces sharply different toxicological effects. In addition, there is the possibility that mixtures will have a synergistic effect (i.e. far greater than additive, so that the risk to humans is magnified). Or the effect could be antagonistic, where the various residues cancel each other out.

Conclusions
To be effective, the risk assessment must be well organized, documented, and evidence based for use in support of decision making with respect to product or material safety. The goal is a process that ultimately protects public health and safety of medical devices. If following risk assessment, the conclusion is that there is still an important inherent risk which cannot be reduced, then risk communication and risk management techniques can be used to inform and protect. Decisions on whether to proceed using the material(s) involve a mixture of economic, societal and political factors. Risk assessment is absolutely necessary and must become an integral part of any chemical or material characterization process.

References:
1 ISO 10993-17, Biological evaluation of medical devices – Part 17: Establishment of allowable limits for leachable substances.

2 J.V. Bruckner, D.A. Warren. “Toxic Effects of Solvents and Vapors,” in Casarett & Doull’s, Toxicology, the Basic Science of Poisons, 6th Edition, C.D. Klaassen, editor, (2001) p.871.

Barbara Kanegsberg and Ed Kanegsberg are independent consultants in critical and precision cleaning, surface preparation, and contamination control. They are the editors of “Handbook for Critical Cleaning,” CRC Press.Contact them at BFK Solutions LLC., 310-459-3614; [email protected]; www.bfksolutions.com.

Dr. David Albert has over 25 years of medical device related experience. David has been at NAMSA for 10 years serving as a Corporate Staff Chemist, Manager of the Chemistry Department and most recently as a Senior Scientist. Prior to joining NAMSA, he served as a Senior Scientist at Anatrace, Inc. where he supervised research and development projects involving new and existing medical devices. His primary expertise is in the areas of pharmacology and biochemistry. He can be reached at [email protected].