Risk Assessment, Toxicity of Residues in Implantable Biomedical Devices
Barbara Kanegsberg, Ed Kanegsberg and David Albert, October 2005
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 cleaning, 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; info@bfksolutions.com; 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 dalbert@namsa.com.
