When surveying the myriad of pre-clinical testing required to bring your medical device to market, we understand it can be daunting. Not only you are tasked with comprehending the minute details of these pre-clinical evaluations, but you must also implement them appropriately. Understanding your product’s biocompatibility requirements, however, doesn’t have to become a headache. In this blog series, we will breakdown how to determine your biocompatibility requirements and what each biological evaluation entails.
What are Biocompatibility Requirements?
Biocompatibility refers to the interaction between a medical device and its material components and the host tissue. The purpose of biocompatibility testing is to determine the safety and efficacy of a device’s material components in surrogate animals prior to use in humans. The required testing for your device is largely based on your device’s nature and duration of body contact.
ISO 10993 and the FDA
International standard ISO 10993 is the backbone of biocompatibility testing. Through this consensus standard, your device’s necessary biological evaluations are determined through a risk-based approach. Once the biological risks of a product’s finished form are identified and relevant existing information is evaluated, you can appropriately identify the biocompatibility testing needed to bring your device to market.
Using ISO 10993-1: Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process and Its FDA Guidance
We want you to be able to tackle your biocompatibility testing requirements with confidence! The first step to make that happen is to determine which biocompatibility evaluations are right for your device. This process is broken down in ISO 10993-1 and its respective FDA Guidance (Use of international Standard ISO 10993-1, “Biological evaluation of medical device—Part 1: Evaluation and testing within a risk management process”). Here, we will walk you through the risk analysis, device categorization, and biological endpoint determination for your new device.
1. Risk Analysis
ISO 10993-1 uses a risk management process to determine your device’s biocompatibility testing requirements in its finished form. This means the systemic analysis of your new device shows that the benefits provided outweigh the potential risks produced. How is this determined? Consider the following:
- Chemical characteristics of the device materials
- Physical properties of the of the device
- Nature and degree of exposure to the body
- Frequency and duration of exposure to the body
Another key component of the risk analysis process is the review of existing information to not only identify and mitigate potential risks, but also determine the relevant biological endpoints for your device. Knowing what prior data is available, you will be able to identify the biocompatibility endpoints that can be leveraged or waived, mitigation strategies, and the knowledge gaps that remain. You can find a lot of this information in the following sources:
- Literature and other publicly available information
- Clinical experience
- Animal study experience
- Medical device standards
- Devices previously reviewed by FDA
The FDA recommends that you provide your new device’s risk assessment at the beginning of your submission’s biocompatibility section. You can follow the risk assessment flow chart below to determine if biological endpoints can be waived/leveraged for your device. Often, deviations in material/formula selection, manufacturing, processing, intended use, and/or storage requirements from existing, marketed devices warrant biocompatibility re-evaluation.
2. Device Categorization
Based on the risk management process outlined by ISO 10993-1, your device is primarily categorized based on its duration and nature of body contact.
The duration of body contact is broken down into 3 categories:
A. Limited Exposure – devices whose cumulative single, multiple, or repeated use is < 24 hours.
B. Prolonged Exposure – devices whose cumulative single, multiple, or repeated long-term use or contact is between 24 hours and 30 days.
C. Permanent Contact – devices whose cumulative single, multiple, or repeated long-term use contact is > 30 days.
The nature of body contact is also used to classify based on contact point, as outlined in the table below. While some contact points might be easy to identify (e.g., skin and bone), others are a little less straight forward. For instance, the Mucosal Membrane contact point refers to the layer of cells surrounding organs and orifices that secrete protective mucus. Mucosal Membranes can be found within the ears, eyes, digestive system, respiratory system, and reproductive system. The Blood Path (indirect) contact point refers to devices that contact the blood path at one point and serve as a conduit for entry into the vascular system.
3. Biological Endpoint Determination
Once you’ve determined the categorization of your device, you can then decide the specific biological endpoints appropriate for your new device using ISO 10993-1 and the corresponding FDA Guidance (Use of international Standard ISO 10993-1, “Biological evaluation of medical device—Part 1: Evaluation and testing within a risk management process”). The recommendations in the table below, in combination with the existing data determined during risk assessment, establish the biocompatibility testing requirements for your device. Biological endpoints include:
- Delayed-type hypersensitivity
- Systemic toxicity
- Subacute and subchronic toxicity
- Chronic toxicity
- Reproductive and developmental toxicity
- Toxicokinetic studies
X = ISO 10993-1:2009 recommended endpoints for consideration*
O = Additional FDA recommended endpoints for consideration*
Note * All X's and O's should be addressed in the biological safety evaluation, either through the use of existing data, additional endpoint-specific testing, or a rationale for why the endpoint does not require additional assessment.
Note + Tissue includes tissue fluids and subcutaneous spaces
Note ^ For all devices used in extracorporeal circuits
Note # Reproductive and developmental toxicity should be addressed for novel materials, materials with a known reproductive and developmental toxicity, device with relevant target populations (e.g., pregnant women), and/or devices where there is the probability for local presence of device materials in the reproductive organs.
Note @ Degradation information should be provided for any devices, device components, or materials remaining in contact with tissue that are intended to degrade.
With your biological endpoints decided, it’s now time to start testing! Follow along as we breakdown and guide you through each of the biological endpoint evaluations in this blog series.