By Jim Kasic, Boulder iQ
Most medical device developers know that biocompatibility testing for medical devices is complex, time-consuming, and expensive. When you are laser-focused on speeding a novel device to market, those three factors can determine whether your device — and often, your company — will succeed or fail.
But there are ways to mitigate those factors. With careful foresight and expertise, you can use a smart approach to biocompatibility testing and maintain your critical path to market.
The Biocompatibility Bible: ISO 10993
Briefly, biocompatibility testing is a regulatory safety requirement that assures a device and its components are compatible with the biologic environment in which the device will be used. Biocompatibility data is almost always required for devices that are designed for human use, specifically for any devices (or components of devices) that may have any human contact. The primary goal of any biocompatibility testing is to determine whether use of the device may have any potentially harmful physiological effects.
ISO Standard 10993 is the starting point for understanding biocompatibility requirements. Regulatory bodies in Europe and Asia follow ISO 10993 as the main source for guidance on testing requirements. In the United States, the FDA has substantially adopted ISO 10993, although for some testing, its requirements go beyond those of ISO. The agency also has issued its FDA guidance document, Use of International Standard ISO 10993-1, Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process (2020), for its perspective on using the standard.
Note that ISO 10993 does not prescribe a specific battery of tests for any particular medical device. Rather, it provides a framework a device development company can use to design a biocompatibility testing program. Testing requirements are not secrets. The standard provides a tremendous amount of detail, and device developers who become very familiar with it will benefit tremendously. As such, it is surprising to find many development companies do not take the time to understand the standard or take the guidelines to heart.
At the same time, some of the information is subject to interpretation, so developers can ensure maximum productivity by working with regulatory experts with applicable experience. Further, ISO 10993 has seen a number of upgrades and modifications over the last few years, especially as in-vitro lab tests are approved to replace previous animal lab testing. It’s important to work with regulatory experts who keep up with the latest developments.
Importance Of The Risk Analysis
While the ISO 10993 standard will outline specific tests to perform, the biocompatibility testing process starts with the risk analysis, which determines if a device carries any risk to any user or any operator or the environment in all aspects of use. Complete the analysis carefully and thoughtfully, as it will serve as your guide for development of the actual biocompatibility test plan. In fact, the plan will include a section for the risk analysis so that the FDA, intent on assessing device risk, will understand the reasons for completing or not completing a specific test.
Keep in mind that the FDA will ask for assessment of the biocompatibility of the entire device, not just the component materials. It does not clear individual materials, only a device in final form. Therefore, the risk assessment must evaluate more than just the materials used in the device. It must also evaluate the processing of the materials, the manufacturing methods (including the sterilization process), and any residuals from manufacturing aids used. It is worth reading and fully understanding the agency’s specific guidance on this issue, stated in the ISO 10993 standard:
“This guidance considers the assessment of biocompatibility to be an evaluation of the medical device in its final finished form, including sterilization, if applicable. However, sponsors should understand the biocompatibility of each device component and any interactions between components that could occur. This is particularly important when the combination of device components could mask or complicate interpretation of a biocompatibility evaluation. For example, if a metal stent has a polymer coating that may separate over time, then the results of a final device biocompatibility assessment may not fully reflect the longer-term clinical performance of the device, and biocompatibility evaluation of the stent with and without the coating may be needed. Similarly, for an in situ polymerizing and absorbable sealant, where the materials present will change over time, separate evaluations of the pre-polymerized, polymerized, and degrading sealant may be needed.”
Testing, Step By Step
When the risk analysis is complete and you are ready to develop the actual biocompatibility test plan, one of the first steps in making the process easier and faster is to see if you can obtain a Chemical Abstract Services (CAS) Registry Number for each component you’ll be testing. Every CAS number is a unique identifier that links to a wealth of information about the substance. Doing what you can to leverage work already done will save you tremendous time.
Then, refer to Table A.1 – Biocompatibility Evaluation Endpoints in the ISO 10993 standard. You’ll find that tests are listed by categories, with an X or an O indicating the level of requirement. An X indicates a “recommended endpoint for consideration,” while an O indicates an “additional FDA recommended endpoint for consideration.” With some exceptions, the tests marked with an X should be considered required unless clinical data and a sufficient rationale can be provided.
A quick scan of the matrix’s X marks shows that almost every medical device must go through three biocompatibility test categories. Sometimes referred to the Big Three, these are cytotoxicity, sensitization, and irritation tests. Based on the category of the device, additional testing categories, as defined in Table A1, may be required.
To assist in deciding exactly what you need to test, and how, refer to the standard’s Attachment D: Biocompatibility Evaluation Flow Chart. This detailed chart walks you through, in a clear, step-by-step manner, every question you must ask yourself for every material. Many engineers do not use this flow chart as a guiding tool, and they then get tripped up in testing down the line. You’ll find many, if not most, of your questions on what you need to test — and what you don’t need to test — answered here.
Keeping Costs Down
One simple rule of thumb in biocompatibility testing is that, whenever possible, the best place to start is with the lowest-cost tests. In doing so, you’ll decrease time and significantly reduce costs, sometimes to the tune of several hundred thousand dollars.
Referring back to the Biocompatibility Evaluation Endpoints matrix, you’ll find that the Big Three tests are the least expensive to complete at the very beginning of the testing process. Within them, the first to do is almost always cytotoxicity. Why? If you don’t pass cytotoxicity tests, you won’t pass anything else. Generally, if your device is using known materials, this testing will be enough. But if your device is using novel materials, you will often need to do leaching and extractable tests. These tests are in-depth studies of the chemical interactions between a device and the human body (or between a device and a drug). They look to identify any chemicals that can be “pulled out” using stress conditions or that can leach out under normal conditions of exposure. Leachables and extractables testing is incredibly time-consuming and expensive; it can easily cost more than $300,000 per device. And with high demand working against supply constraints in the current economy, long lead times are not uncommon.
By planning and working smartly, though, you can complete these tests for a fraction of the cost by, once again, starting with the least-expensive pathway.
Tests for key leachables — neutral, polar, and non-polar (commonly saline, alcohol, and hexane) — are all easy to do in your own laboratory. Once you complete these, send the results to a gas chromatography–mass spectrometry (GC-MS) lab. Typically, for around $1,000, they can run your samples, and in just a few days you will know, at a qualitative level, if you’ll have any issues with your device. At that point, you can either continue to the full required good manufacturing practices (GMP) testing with confidence or go back to the drawing board and figure out your issues. In other words, troubleshoot any issues before spending the money and time on the official testing.
Lost Revenue Exacerbates Financial Impact
The impacts of not following the process described above can mean hundreds of thousands of dollars in out-of-pocket costs. But perhaps more importantly, they can mean millions of dollars in lost revenue.
In a recent example with one of our clients, the FDA had cleared a previous version of the company’s device several years ago. A new version contained materials that were almost identical to those used in the original, but the FDA still required extraction testing. Feeling confident that there would be no issues because of the similarity, the company skipped the inexpensive testing and moved right into GMP testing — at a cost of $350,000.
To their surprise, due to the results of the extraction testing, the device did not receive clearance. While there was no issue with a novel polymer the new device version used, some of the common materials were considered “dirty,” including one that came from a vendor with a problem.
Testing The Process
The issue in the above example turned out to be in the mineral oils in the production equipment used to create a high molecular-weight polyethylene thread. This illustrates the importance of testing how materials behave in the manufacturing process, not only testing materials themselves. The number of factors that impact a material in manufacturing, from how it is delivered to how well it is cleaned, can be significant.
In this particular situation, had the company followed the process suggested above (run tests in its own lab, then send out to a GC-MS lab), the cost would have been around $10,000. They could have identified the issues, modified the production process, and then completed the required official testing — still expensive at $350,000, but without incident. If that wasn’t enough, the company encountered a delay of almost a year in getting the device to market, and that delay cost several million dollars.
Biocompatibility testing is a critical requirement in medical device development. Taking some basic but often-overlooked steps will save device developers time and money. Utilize the ISO 10993 standard as a comprehensive guide, conduct sound risk analysis, and develop a testing plan that meets the standard’s directions. Follow a few logical steps to save costs and cover all bases, and you’ll be doing what you can to get your device to market as quickly as possible.
About the Author:
Jim Kasic is the founder and chairman of Boulder iQ. With more than 30 years of experience in the Class I, II, and III medical device industry, he holds more than 40 U.S. and international patents. His career includes experience with companies ranging from large multinational corporations to startups with a national and international scope. Kasic has served as president and CEO of Sophono, Inc., a multinational manufacturer and distributor of implantable hearing devices, which was acquired by Medtronic. He also was the president of OrthoWin, acquired by Zimmer-BioMed. He received a B.S. in physics and an M.S. in chemical/biological engineering from the University of Colorado, and an M.B.A. from the University of Phoenix. He can be reached at firstname.lastname@example.org or on LinkedIn.