Planning a biological evaluation of your medical device? Then you need to be familiar with ISO 10993-1. This primer covers the fundamentals.
The International Organization for Standardization (ISO) develops and publishes a wide range of proprietary, industrial and commercial standards – including standards for the biological evaluation of medical devices. As a medical device manufacturer, you’re probably aware of ISO 10993 and its twenty-some parts. However, these parts are highly detailed and ever-changing – and up for regulatory interpretation.
What do you – the manufacturer – really need to know?
Let’s start at the beginning with ISO 10993-1: “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.”
What is ISO 10993-1?
ISO 10993-1 is the first part of a series of standards to evaluate the biocompatibility of medical devices. Biocompatibility, as defined by the FDA, is the ability of a device material to perform with an appropriate host response in a specific situation. In other words, manufacturers need to ensure that the various materials and manufacturing processes used in a device or a device delivery system support safety or do not pose risks to patients or clinicians.
The overall purpose of ISO 10993-1 is to provide a framework in which to plan a biological evaluation – as a part of the overall evaluation and development of each medical device. It sets the stage to thoroughly identify potential risks resulting from the product’s materials as well as manufacturing processes. Generally, this starts with a complete chemical characterization.
Why is ISO 10993-1 Important?
While ISO 10993-1 sets the stage and the remaining parts of ISO 10993 dig into the details, Part 1 should by no means be overlooked. This is because the 2018 update of ISO 10993-1 indicated a significant shift in the approach to supporting preclinical medical device safety. Instead of a checklist-based approach, the standard moved towards a risk-based approach that starts with understanding the materials and the chemical constituents in those materials.
With increased emphasis on chemical characterization, biocompatibility testing alone cannot always be relied on to support medical device safety. A thorough understanding of the materials and manufacturing process (as mentioned, most often addressed with chemical characterization) should precede any biological testing. This will also help to refine the biological test plan.
How Do Regulatory Authorities Approach ISO 10993-1?
Every region has different interpretations and preferences for what they want to see in the application process. Not to mention, while the EU for the most part accepts ISO standards without exceptions, the U.S. FDA does not recognize all ISO 10993 standards. So, simply following ISO standards may not result in the acceptance of your biocompatibility evaluation.
The good news is that ISO 10993-1 is recognized by both the FDA and EU Medical Device Regulation (MDR). However, both regulatory bodies differ in their approach to assessing quality and overall risk profile, device classifications and clinical testing procedures.
In 2020, the FDA published their own guidance to provide further clarification regarding the use of ISO 10993-1. While the standard has not been harmonized across all EU countries, the MDR considers it “state of the art,” as it is the most recent published version of an accepted standard.
When Should Medical Device Manufacturers Consider ISO 10993-1?
ISO 10993-1 is applicable fairly early in the medical device testing and risk management process. This is because it actually helps medical device manufacturers understand their product testing requirements by classifying medical devices according to the nature and duration of contact with human tissues when in use.
So, once a manufacturer identifies this information, they can use it as a guide to identify the biological endpoints that need to be addressed to support safety for your device according to the standard. This will also help fill in some of the gaps with their timeline for regulatory submission.
ISO 10993-1 should also be considered when there is a change in the medical device’s manufacturing process, material or supplier. These changes can have unintended consequences for safety and may require testing to demonstrate equivalence to the initially approved or cleared product.
What Do Medical Device Manufacturers Need to Do to Comply?
There are generally three phases involved in evaluating biological risk as part of a biological evaluation under ISO 10993-1: complete chemical characterization, toxicological risk assessment, and biocompatibility testing, ideally in that order.
- Complete Chemical Characterization: Identifies the chemicals and the quantity of those chemicals per device. Additional data often needs to be generated through extractables/leachables (E/L) testing. E/L testing can provide sufficient data to support some biological endpoints, including genotoxicity and systemic toxicity, helping you avoid costly and time-consuming biological testing.
- Toxicological Risk Assessment: Considers each chemical and the quantity, and derives a margin of safety based on patient population and intended use.
- Biocompatibility Testing: Covers local effects (e.g., irritation) and any systemic effects specific to the device that could not be addressed in the toxicological risk assessment (e.g., pyrogenicity), or need to be conducted to mitigate potential concerns identified in the toxicological risk assessment (e.g., genotoxicity or subacute/subchronic toxicity).
Once all of the data have been gathered, ISO 10993-1 requires a qualified individual, usually a toxicologist, to review the data and develop a weight of evidence argument called a biological evaluation.
Historically, device manufacturers have been able to reach successful submission with biocompatibility testing alone. However, more often than not, this is no longer the case. Beginning with biocompatibility testing is no longer a best practice because complete chemical characterization followed by a favorable toxicological risk assessment can often address several biocompatibility endpoints.
Key Takeaways for Compliance
- Use a risk-based approach to support the safety of your product.
- Use chemistry data and risk assessment to develop a biocompatibility test plan. This can often save unnecessary use of animals in testing and costly test articles.
- Outsource testing to an experienced laboratory partner that offers a full range of preclinical device testing services. This can be instrumental in accelerating the process and getting your device to market before others.
- Work with qualified scientists, chemists and toxicologists. ISO 10993-1 also includes ensuring that qualified individuals carry out the biological evaluation, so it matters whom you choose to work with. Many regulators request credentials of the medical device evaluation staff to determine credibility and gauge the quality of resulting data.
Can Device Manufacturers Manage 10993-1 Testing In-House?
The above best practices for ISO 10993-1 compliance beg the question: Can medical device manufacturers actually conduct medical device testing themselves?
To answer this, you have to ask another question: Do you have the capability, qualifications and experience to conduct complete chemical characterization and the corresponding data analysis, toxicological risk assessments and GLP compliant in vitro and in vivo biocompatibility testing?
If the answer is no to any or all parts of that question, you may have to resort to piecemeal testing. This may result in a number of challenges, including:
- Longer timelines
- Higher costs
- Miscommunications between parties
- Loss of information altogether
- Insufficient information to support your submission (often by way of incomplete chemical characterization due to unidentified compounds)
While all of these problems are serious, the last one poses the most risk to your submission success. Reporting unknowns may cause regulators to reject your submission or issue requests for additional information (AIs). Unknowns are expensive. On average, repeat testing can cost more than $75,000 and 27 weeks of time.
So, what other options are available to a device manufacturer?
Working with a Medical Device Testing Partner
Reading through and understanding ISO 10993-1 is one thing. Following it according to regulatory guidance – including the necessary vertical guidances for specific product groupings – is another. This is true for a few reasons:
- Language used in regulatory standards can be vague and subject to interpretation
- A common practice in one region may not be recognized in another
- Interpretations evolve as regulators receive additional data when reviewing submissions
Because of these evolving interpretations, it’s critical to stay informed and current to ensure medical device submissions are aligned accordingly with guidance. This in and of itself is a challenging and time-consuming endeavor.
However, these challenges inherent to global submissions should not dissuade medical device manufacturers from the financial and healthcare opportunities available. Those who prioritize patient safety – in lockstep with the priorities of the regulatory landscape – and take special care when setting project expectations and timelines will better navigate global submissions. Especially if they don’t do it alone.
Manufactures that turn to experienced laboratory patterns to develop a regulatory submission strategy (and have the infrastructure and experience to support testing) will help achieve regional compliance and get their medical devices everywhere they need to be.
WuXi AppTec has a state-of-the-art analytical chemistry laboratory and experienced scientists, chemists and toxicologists – focused on ensuring the biological evaluation strategies and testing you require meet the latest regulatory standards. Our chemistry experts understand that unknowns are unacceptable™. We guide our clients’ test plans based on our industry knowledge, regulatory collaboration and the extensive number of products we have assisted through product clearance.
Our technical and regulatory experts serve as active participants and hold leadership positions with international regulatory standards committees. This allows us to track regulatory trends and even anticipate regulatory changes ahead of the published standards and guidances.
Talk to an expert about your upcoming project to see how we can help.
As a global company with operations across Asia, Europe, and North America, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable global pharmaceutical and healthcare industry to advance discoveries and deliver groundbreaking treatments to patients. Through its unique business models, WuXi AppTec’s integrated, end-to-end services include chemistry drug CRDMO (Contract Research, Development and Manufacturing Organization), biology discovery, preclinical testing and clinical research services, cell and gene therapies CTDMO (Contract Testing, Development and Manufacturing Organization), helping customers improve the productivity of advancing healthcare products through cost-effective and efficient solutions. WuXi AppTec received AA ESG rating from MSCI in 2021 and its open-access platform is enabling more than 5,800 collaborators from over 30 countries to improve the health of those in need – and to realize the vision that “every drug can be made and every disease can be treated.”