A Whitepaper by Dr. Nancy J Stark and Dr. Dan McLain
There are commonly three scenarios in which manufacturers call on CDG for biocompatibility help: a) FDA has raised questions about the safety tests you performed, b) you disagree that you need sensitization, genotoxicity, or carcinogenicity tests, or c) you have a new device and don't have a clue as to what tests to do. Can an expert opinion help?
Materials and the manufacturing process
We usually think about biological safety when selecting the materials for a new device. Many materials may be under consideration for a particular component. The mechanical properties, manufacturability, availability, aesthetics cost, as well as biological safety issues, are all considerations in the material selection process.
Often manufacturers believe they are using "common" material in their medical devices, but when challenged by FDA to give reasonable assurance of the material's safety they cannot offer specifics. You must establish the material is comparable after your manufacturing process. This is why biological safety tests are performed on final manufactured product. Some companies use final manufactured devices, others run a coupon of the material through the manufacturing process to get a material that is representative of the final process.
Back in the day—when one of us started working in the device industry—there were no recognized standards for device biological safety testing. Manufacturers floundered around looking for tests that seemed applicable. I once used US Pharmacopoeia (USP) tests for drug containers when developing a new syringe. Even today, suppliers and manufacturers sometimes assume that materials which meet USP Class V or VI requirements are sufficiently safe for device applications. (1 USP)
Step Two: "The Matrix"
Because of its long history, most manufacturers base their biological safety testing on "The Matrix". In 1986, regulators from FDA, the UK, and Canada published the Tripartite Biocompatibility Guidance. The guidance built upon standards that had previously been published by AAMI, ANSI, ASTM, and others. It looked at materials based on the type of tissue the material contacted and the duration of that contact. Then a testing category was recommended for each combination of contact and duration. The problem with the Tripartite Guidance was that nearly every category of biocompatibility test was recommended for nearly every combination of material contact and duration (198 out of a possible 240 categories were recommended.) (2 Tripartite) There were other problems too: it didn't tell you how to handle whole devices, and it didn't apply to metals or ceramics.
In 1992, the International Standards Organization (ISO) published ISO 10993 Part 1 "Guidance on selection of tests". The standard was part of a series of biological safety standards, but Part 1 included a matrix similar to the contact and duration matrix of the Tripartite Guidance. The major difference was that far fewer categories of tests were recommended (117 out of 240). (3 ISO 19003-1 Selection of Tests) This matrix was not accepted by FDA.
1995 brought us The Matrix as American manufacturers know it today. It is found in FDA's General Program Memorandum G95-1. (4 G95-1) With clairvoyance and foresight FDA modified the matrix presented in a version of the ISO 10993-1 standard that would not be published for another two years. (5 ISO 10993-1 Testing and Evaluation) The goal was to harmonize the agency's biological safety policy with the expectations of the international community. In the modified matrix, an additional 36 categories of tests are "suggested" for manufacturers to consider (for a total of 153 out of 240).
Step One: ISO 10993 Part 18 'Chemical characterization of materials' (2005)
A more ethical and efficient practice is to chemically characterize materials and compare them to materials in existing clinical use before performing animal tests. This is done in conformance to ISO 10993-18 'Chemical characterization of materials' (2005) and it should be done before the matrix is even consulted. (6 ISO 10993-18)
To put it in context, the chemical characterization of materials justify the performance or omission of animal biocompatibility tests, just as clinical evaluations justify the performance or omission of human clinical investigations.
Chemical characterization is the accepted method for comparing one finished, manufactured material to another in order to make the argument that they are clinically equal or that one material is no worse than a currently used material. The methodology has been developing over the years and was described in detail in a book by Dr. Stark in 2003. (7 Stark) The characterization is done in the following manner.
 Qualitative information
Describe the material and its intended purpose within the device. The description includes qualitative information such as supplier name, common name, chemical name, batch or lot number, visual and physical characteristics such as color, hardness, flexibility, and chemical family, and other specifications. The intended use of the material (type of tissue contact, duration of contact, and function) are also described.
 Material equivalence
The new material is compared to an existing material that is used in a device with the same clinical exposure; the device can be a commercial device from your own firm or it can be from your competitor. You can readily visualize a spreadsheet or database listing each material in the device and comparing it to another known material. If you have sufficient information for an expert to make a toxicological risk assessment you can stop here.
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Expert Opinions and Consultation for Biological Safety
Dr. Dan McLain, is an internationally renowned medical device toxicologist. His position as convener of ISO 10993-11 is evidence of his global stature. Dan is available to assist with pre-clinical strategies and chemical risk assessments for your materials and devices. Our style is to work collaboratively with a point-person on your side so that you are involved in the process every step of the way. Phone or email us at 773-489-5721 or firstname.lastname@example.org.
 Quantitative data
Quantitative data will be needed if a sound risk assessment cannot be made purely on qualitative information. This means a thorough knowledge of the chemical composition, additives, manufacturing residues, and leachables must be obtained through analytical and physical chemistry. The goal is to determine the amount of identified chemicals (such as monomers, anions, radioactive elements, and the like) that are present in the final, manufactured material.
 Quantitative risk assessment
In the quantitative risk assessment the amount (in µg, Gy for radiation, or other unit of exposure) of identified chemicals are compared to existing toxicological information, rather than to another material. The objective is to determine which, if any, of the chemicals in the material might be harmful at the calculated exposure.
 Estimate clinical exposure
Finally the amount of potentially harmful chemicals, the 'dose', is compared to the clinical dose a patient might receive in a lifetime, a procedure, or other unit of time. Such a comparison seeks to show that the maximum dose of a chemical one might receive is acceptable in light of the lowest dose that could case medical problems. Detailed methods for risk assessments are discussed in ISO 14155-17 'Methods for the establishment of allowable limits for leachable substances' (2008). (8 ISO 10993-17)
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"The Matrix" Is Available as a Mousepad/Notepad
CDG's talented graphic artists have reconfigured The Matrix and printed it on a high-quality mouse-grade paper pad. Now you can always have The Matrix at your workstation, in plain sight where you can find it. You can quickly look up the test categories needed while the boss is quizzing you on the phone. And at ten sheets to the pad, you can take notes on the conversation (or doodle), tear off the sheet, and keep it safe in the technical file.
Consider these examples, they are intended to illustrate the kind of issue you'll be addressing: a) Let's say you have a metallic implant that you clean by washing with perchloroethylene. Known to be highly volatile, but also highly toxic, you must ask if enough perchloroethylene remains on the metal implant to preclude its use as a cleaning agent; b) Let's say you make a wound dressing that contains a potassium salt. You know that potassium affects cardiac function and in sufficiently high concentrations could put a patient into cardiac arrest. You must ask if sufficient potassium can leach out of the dressing and into the wound to affect cardiac function.
(1 USP) United States Pharmacopeia.
(2 Tripartite) Tripartite Biocompatibility Guidance G87-1, (1987).
(3 ISO 10993-1 Selection of tests) ISO 10993-1 Biological evaluation of medical devices: Selection of tests (1992).
(4 G95-1) "Use of International Standard ISO-10993-1 Biological Evaluation of Medical Devices: Evaluation and Testing", G95-1 (1995).
(5 ISO 10993-1 Evaluation and Testing) ISO 10993-1 Biological evaluation of medical devices: Evaluation and testing (1997).
(6 ISO 10993-18) ISO 10993-18 Biological evaluation of medical devices: Chemical characterization of materials (2005).
(7 Stark) "Biocompatibility Testing & Management" Fourth Edition, Nancy J Stark, Clinical Device Group Inc, 2003.
(8 ISO 10993-17) ISO 10993-17 Biological evaluation of medical devices: Methods for the establishment of allowable limits for leachable substances (2008).
Questions or Comments?
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