Assessing Biocompatibility for Medical Devices in the U.S.
What is Biocompatibility Testing, Why Does it Matter and How do You do it?
In the United States, individuals or companies that wish to market a Class I, II or III medical devices intended for human use, for which Premarket Approval application (PMA) is not required, must submit a 510(k) to the Food & Drug Administration, unless the device is exempt from such requirements . This is not news to OEMs, but what may be surprising is how many 510(k) submissions are rejected or delayed due to information regarding device biocompatibility.
Biocompatibility is defined as the condition of a material or device being compatible in a biological system. The FDA reports that nearly one-third of 510(k) submissions provide inadequate information regarding device biocompatibility or fail to provide any biocompatible data at all (data indicates that the agency requests additional information with as many as three out of every four submissions it receives) and could explain why manufacturers experience an average wait of more than 175 calendar days from the date they filed their 510(k) submission until they receive final clearance by the FDA. Biocompatibility is also considered for other types of device submissions to the FDA, including:
- Premarket Applications (PMAs)
- Humanitarian Device Exemptions (HDEs)
- Investigational Device Applications (IDEs)
- De Novo Classification Requests
By beginning any necessary material characterization and biocompatibility testing efforts as early as possible, OEMs can address one of the largest barriers in getting their products to market on time and within budget. Providing the FDA with adequate and detailed biocompatibility information (in addition to performance testing, clinical evaluations and other requested information) can also minimize costly delays and submission rejections. With that spirit in mind, we created this resource page to assist product development teams in meeting FDA biocompatibility assessment requirements the first time.
Before we get into more detailed information about biocompatibility assessment requirements, procedures and material selection, here are a few important definitions to keep in mind before we proceed:
- Direct Contact – Term used for a device (or device component) that comes into physical contact with patient or end-user tissue or bodily fluids
- Indirect Contact – A device or component may be said to have “indirect contact” if a fluid or gas passes through it before meeting tissue or bodily fluids
- No Contact – The term “non-contacting” indicates that a medical device (or device component) has neither direct nor indirect contact with tissues or bodily fluids, and is therefore exempt from biocompatibility requirements
To Test, or Not to Test?
Before any testing is considered, there needs to be a thorough review of existing data on the component materials of the device. There may be sufficient clinical history or other toxicological information that can be used to satisfy the biocompatibility assessment of some of the components or the entire device. A good source of information is any component material data that can be provided by your supplier. The next step is to perform material characterization of those components where sufficient data does not exist to support safe use in the specific device. Chemical characterization can be used to identify any chemicals that can be extracted from the component materials and help determine the need for additional in vitro or in vivo testing.
The most important factor in determining what biocompatibility testing is needed is the level of direct or indirect body contact; non-contacting medical devices are not subject to biocompatibility requirements. Contact duration determines which biological endpoints need to be assessed for different categories of devices. The FDA categorizes medical devices based on the following levels of body contact duration:
- Limited (less than 24 hours)
- Prolonged (24 hours to 30 days)
- Permanent (longer than 30 days)
Biocompatibility data of one kind or another is almost always required for devices that have any level of body contact. The FDA may also require determination of safety for modified devices if changes are made to any direct or indirect contacting components or could affect another component that makes contact. Although OEMs can submit data from previous submissions, confirmatory testing will need to be performed if there are significant changes in manufacturing processes, material selection, intended use, etc.
For example, from the actual method of processing (e.g., injection molding vs. machining) to the processing aids used and even the physical location where manufacturing occurs, any changes in the manufacturing process may impact biocompatibility by either changing the chemical structure of the device or creating byproducts that interact differently with materials. In any case, medical device OEMs should consider reevaluating biocompatibility before any planned changes in manufacturing processes, and certainly after any unexpected changes.
Another change that might impact biocompatibility is a change in material formulations and/or suppliers. For example, if your new polymer supplier does not remove all processing solvents, or uses a different polymerization process which could include different residual solvents, the final manufactured device could have unexpected toxicities that were not seen with the original material. Changes in polymer compounds (e.g., additives and colorants) may also result in adverse biological responses and should be assessed for biocompatibility. And it goes without saying that biocompatibility will also need to be assessed if you are manufacturing a device using different materials altogether, such as converting from a metal to plastic medical device.
Biocompatibility Decision Tree
Deciding whether you need to perform biocompatibility testing or request additional biocompatibility data from your suppliers is simply a matter of determining whether all relevant biocompatibility endpoints have been adequately addressed. To this end, there are a series of yes/no questions that can help you determine whether your device has satisfied FDA biocompatibility requirements. Note, this decision tree is based on the FDA’s Biocompatibility Evaluation Flow Chart (Use of International Standards ISO 10993-1) and only intended to provide guidance; it is the sole responsibility of the OEM to determine all necessary tests and data required to evaluate final product safety.
Biocompatibility Testing Endpoints
To assist medical device manufacturers in how to best meet biocompatibility requirements, the FDA has created a biocompatibility matrix that outlines guidelines for biological effects evaluation based on medical device categorization by nature of body contact and contact duration. Thus, the matrix is a framework for the selection of endpoints for and not a checklist of required biocompatibility testing. Design engineers should consult with experienced toxicologists and/or clinical investigators to determine how to best meet the requirements of the materials biocompatibility matrix.
How Your Polymer Supplier Can Provide Biocompatibility Support
OEMs can conduct their own biocompatibility studies in house or outsource to accredited testing labs. However, manufacturers may be able to reduce the amount of testing needed (and the cost associated with testing) by leveraging biocompatibility data provided by their materials suppliers in the form of a Master Access File (MAF).
Master Access Files may include formulation information, sterilization compatibility, recommended processing methods, ISO 10993 test results and other data that can help FDA reviewers assess the biocompatibility, safety and efficacy of the materials used in medical devices subject to 510(k) clearance and premarket approval. These files allow the FDA to review such information without the raw material or component supplier disclosing proprietary material information directly to the medical device manufacturer.
Raw materials suppliers are not required to submit Master Access Files, but many have done so to help bolster their customer’s confidence in using their materials for medical device applications. Well-documented records can also facilitate the design and regulatory application process for medical device OEMS, potentially minimizing additional biocompatibility testing and thereby accelerating time to market.
As a general rule, all studies designed to assess the safety of a medical product in nonclinical models (including biocompatibility studies for medical devices) should be conducted according to Good Laboratory Practice (GLP) procedures. GLP treatment is explicitly required for IDE, 510(k), and PMA submissions. Ask your material suppliers if their biocompatibility studies were done per GLP to ensure that you can use their data in any type of regulatory submission.
Specialty Polymers for Healthcare from Solvay
With over 30 years of experience as a leading materials supplier to the healthcare industry, Solvay understands the technical and regulatory support OEMs need to select medical-grade polymers with confidence. For this reason, we provide FDA Master Access Files for our entire portfolio of high-performance, medical-grade polymers which have been evaluated following the ISO 10993-1 risk-based methodology. We also provide global regulatory support for your medical device submissions, and our global regulatory specialists can assist and support your submissions, petitions and certificate requests.