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ISO 10993-1 Primer: Medical Device Testing for Risk Management

ISO 10993-1 Primer: Medical Device Testing for Risk Management

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.

  1. 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.
  2. Toxicological Risk Assessment: Considers each chemical and the quantity, and derives a margin of safety based on patient population and intended use.
  3. 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:

  1. Language used in regulatory standards can be vague and subject to interpretation
  2. A common practice in one region may not be recognized in another
  3. 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.”

E/L Testing Isn’t What It Used to Be

E/L Testing Isn’t What It Used to Be

Medical device biological safety evaluations have advanced significantly over the last ten years, and regulatory requirements are quickly evolving as well. Turnkey evaluation of testing requirements has progressed into a more device-specific evaluation of risks. It is essential for manufacturers to consider how the changes put in place by ISO 10993-18 will impact their product’s testing needs and any historical compliance of chemical characterization studies.

Complying with the new standard requires a variety of highly sensitive and selective analytical equipment, robust databases and, above all, the expertise to sift through data and identify all chemical constituents. Manufacturers are reevaluating their products to ensure past testing strategies still hold up to current regulatory expectations. To understand how the industry got to this point and forecast where it is headed, we need to start from the beginning.

E/L Gains Momentum

When E/L testing first gained a foothold with medical devices in the early 2000s, methods were focused on qualitative measures. Testing did not generally attempt to quantify the amount of specific chemical constituents present but rather verify major materials present and evaluate total extractable residue.

As certain products were facing public litigation, such as pelvic mesh and breast implants, renewed scrutiny around the risks presented by implantable devices quickly caused the expectations for chemical characterization to be more rigorous, selective and quantitative.

As the decade progressed, even more analytically selective and sensitive techniques emerged, and chemical characterization requirements tightened. Regulators responded with an increased focus on testing device materials and a growing interest in customizing testing to better suit medical devices. In 2016, the US FDA Draft Guidance on ISO 10993-1 reaffirmed the value of chemical characterization when evaluating medical devices.

Recent E/L Testing Trends

Expectations grew along with advanced test methods and equipment that could accommodate increasing regulatory requirements. The 2016 US FDA guidance on the use of ISO 10993-1 required two to three solvents per instrumentand three replicates, thus increasing the investment that companies made during biological safety evaluations.

Around 2017, regulatory agencies began requiring exhaustive extractions (that is, multiple extractions on the same device) for permanent implants. Then in 2018, regulators published a revised version of ISO 10993-1, putting new guidance in place. Specifically, it made chemical characterization and the subsequent risk assessment fundamental components in assessing device safety.

This expectation meant submissions must examine chemistry information and risk assessment to drive their biocompatibility test strategy, and manufacturers must provide justification to support final submissions. Additionally, reviewers examined the training and qualifications of the expert personnel performing these tests. 

Internally, the U.S. FDA showed increasing alignment around chemical characterization and toxicological risk assessments, asking how those play into evaluating a device’s biological safety. By 2019, reviewers began requiring exhaustive extraction on prolonged devices as well as permanent devices, which extended the timeline needed to perform testing and increased associated costs.

E/L Testing Today & Going Forward

The publication of ISO 10993-18:2020 marked a significant milestone for the medical device industry. The 2020 revision continued to push expectations and the subsequent approach forward.

This revision provided increased guidance for tailoring chemical characterization to each device by establishing thresholds based on device size, duration and type of patient contact, and the target patient population. For example, reviewers began expecting confidence intervals for identification and implemented the analytical evaluation threshold (AET) as a common baseline for chemistry studies. The AET is essential to achieving an accurate risk assessment. It also helps avoid regulatory scrutiny by requiring qualified chemists to work alongside toxicologists.

The methodologies that laboratories employ today are evolving rapidly, perhaps even faster than the standards themselves. Thus, the concept of “state-of-the-art” procedures is gaining attention as regulators’ expectations grow in tandem with the industry’s capabilities. This is evident with the September 2020 release of International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process.” As we near the upcoming publication of ISO 10993-17, toxicological risk assessments are positioned next to advance the practices in place. Still, manufacturers may find these latest regulations challenging to keep up to date with the continuously evolving regulatory landscape.

Keeping Up with Chemistry

If you have not conducted E/L testing in recent years, it may be time to consider retesting to satisfy the evolved science and regulations. For many products, testing conducted prior to the publication of ISO 10993-18:2020 may need reevaluation according to the new guidance.

Given the new role that chemical characterization has taken in testing and the new expectations to identify biological concerns, it is critical to consider E/L testing as an essential ingredient in preparing a successful medical device submission. Looking to dive further into the details? Check out a detailed recap about ISO 10993 in “Planning and Predicting for ISO 10993: Part 18 & Part 17.

To stay up to date on the latest industry news and regulatory changes, follow us on LinkedIn.

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WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions – and has received ESG (Environment, Social and Governance) A Ratings from Morgan Stanley Capital International since 2019. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,200 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”

For more information, please visit: http://medicaldevice.wuxiapptec.com/

3 Regulatory Red Flags with Medical Device Changes

3 Regulatory Red Flags with Medical Device Changes

Consideration of regulatory approval should be top of mind when making minor changes to current devices on the market to mitigate potential setbacks. The industry approach to chemistry testing is evolving rapidly, and any adjustments could put a device’s approval at risk. Whether a manufacturer alters a device’s nature or changes a material supplier, consider reviewing past biological evaluation data for potential gaps. 

With the increased requirements for chemical characterization following ISO 10993-18:2020, regulators may view alterations as a chemical constituent concern. Changes to your device could likely require retesting to reduce future risk. Keep your device on track for approvals and in compliance by bringing in your testing partner when making any adjustments that could affect the material composition of the product.

A New Approach to Chemistry

Chemical characterization and toxicological risk assessments evaluate devices based on the nature and duration of device contact with the end-user. Devices face more scrutiny from regulators than ever before to meet the latest revision requirements to ISO 10993-18, which was released in early 2020.

To determine testing parameters and support a chemical characterization program to meet ISO 10993-18:2020, laboratories need an in-depth perspective on the production process, use scenarios and many other details to paint a clear picture of the device’s chemical constituents. That said, results may identify everything down to the mold release agents during extractable/leachable (E/L) testing. If previous data did not investigate to this same level, comparing past and present medical device risks might be inaccurate.

For example, if a lab identifies a carcinogenic, mutagenic or reproductive toxicant (CMR) substance, or the level of unknowns is above the AET (analytical evaluation threshold), the device will likely need additional chemical characterization. Rather than risk receiving this feedback in an additional information request, manufacturers need to resolve their potential concerns before submission approval. Medical device companies should be aware of the signals that could show that their device may present a risk.

Red Flags for Reviewers

In some cases, companies may not realize the impact of altering their device’s nature or duration. In others, they may not recognize the impact a minor adjustment can have on device composition. Looking for these red flags for reviewers takes practice and a cross-functional approach to planning.

New Patient Populations

Expanding patient populations for clinical use could also put device compliance at stake. Devices intended for pediatric patients require lower body weight assumptions and CMR substances may be considered a more significant concern. For instance, many low-risk devices with high volume, single patient use are constructed using PVC containing phthalates, which typically is a cost-effective option. Regulators are vigilant in reviewing the risks of this material and ensuring the exposure levels are safe for the intended patient populations. If a device’s original population resulted in an acceptable margin of safety for such chemicals, but the new one does not, past chemical characterization data may not be sufficient to support product safety.  

Extended Duration

Any changes to exposure duration, specifically extending it in a manner that puts it into a new contact category, will likely require extensive chemical characterization. For example, initial chemical characterization testing on a limited duration device may have been done in an exaggerated study, utilizing a higher dose-based threshold (DBT) for the AET. If the device is now considered to have long-term contact, the initial extractable/leachable testing may no longer be appropriate for the new duration of contact, and further chemistry testing may be recommended. An exhaustive extraction with a lower DBT would then be expected based on the requirements of ISO 10993-18:2020.

New Suppliers

When adding or changing suppliers, proceed with caution and consider testing the material even if the previously used material is an exact match. Like-materials are not all interchangeable or created equally. Often, a material that appears to have the same chemical profile can have significantly different impurities or additives that can produce drastically different chemical characterization profiles.  Analyzing these materials is essential to maintaining compliance – and laboratories are eager to play a larger role in material selection.

Bring in Partners Sooner

Rather than making it through the design phase without understanding potential biological risks, bring your testing partner in early for guidance and support. If there are necessary changes to your device, intended population, duration or suppliers, check with your lab testing partner about how this may impact previous or upcoming biological evaluation strategy. Identifying these red flags and addressing the potential hurdles can help consolidate timelines, save money and decrease the likeliness of additional information requests.

Understanding how changes like material modifications, production adjustments or patient population expansions can impact your device will ultimately set you up for a smoother regulatory process. For additional background on the thinking behind medical device chemistry testing, read our blog, “Extraction techniques: Designing the right studies to get the answers you need.”

WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient, socially responsible and sustainable solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated.”

For more information, please visit: http://medicaldevice.wuxiapptec.com/

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Behind the Curtain: How ISO 10993 Impacts Testing Labs

Behind the Curtain: How ISO 10993 Impacts Testing Labs

Manufacturers are not the only ones facing challenges due to the updates to ISO 10993 and other recent regulatory changes. The evolving standards are also affecting testing labs. Previous industry projected timelines and costs are becoming less feasible with today’s regulatory requirements and capacity constraints. These circumstances have left manufacturers asking important questions, such as why timelines have increased and why testing partners now advise companies to provide additional information or retest.  

These questions are all valid, and it is time for testing labs to pull back the curtain to address them. To put it simply – the answers boil down to changes in expectations, process and availability.

Expectation Changes

Most lab testing partners and manufacturers generally knew what to expect from the ISO 10993-18:2020 updates, but it was a waiting game to see how the U.S. Food and Drug Administration (FDA) would interpret them. Part 18 was published in January, and the FDA has been communicating additional expectations through presentations at various venues such as conferences and scientific forums. However, they have not formally documented expectations in guidance as of yet, and shifts in expectations continue as new information is submitted. The dust has yet to settle with the latest update to the standard and FDA expectations.

Manufacturers that have performed testing recently (as recent as late 2019) are seeing gaps in their testing compared to what the FDA is requesting. The FDA website states it will accept testing from the previous standard until July 10, 2022, but reality may prove otherwise. There may be additional information that can be provided to bring your testing up to FDA standards, but in many scenarios, it may be best to start testing from scratch.

In 2020, the FDA increased the expectations of chemical characterization. They are now probing deeper and asking for more technical evidence than ever before. For a submission to be successful, laboratories and manufacturers will need to justify everything – why they chose particular solvents, why they conducted the extraction in a specific way, why they selected a particular method of preparation, and what documentation supports each decision. Ensuring you have the justification to back up your testing takes time and resources. It’s essential to build this into your timeline and budget.

Shifting Process

With increased regulatory expectations comes more responsibility for lab partners. Regulatory bodies are demanding that labs identify all compounds found above the analytical evaluation threshold (AET). If they cannot identify the compounds or provide details to inform the chemical structure, it could negatively impact your timelines, as retesting may be your only option.

No matter the stage of the medical device, pre-clinical to post-submission, manufacturers will need to plan accordingly for shifting expectations. You may receive more submission questions from the FDA than in the past and will need to change your process and timeline accordingly when entering the regulatory review process. Prepare to get additional information requests and allocate time to answer them. Depending on how long ago you performed the testing, responding to an additional information request may mean further testing and require a substantial amount of time.

If you’re still in the testing stage, be sure you’re partnering with a testing lab well-versed in what these process changes mean to your budget and timelines. Quality testing procedures may cost more initially but will save time on unexpected delays or additional testing down the road. It’s crucial to give the lab time to reflect and provide thoughtful, scientifically-sound justifications and recommendations.

Limited Availability

Labs are filling up, and fast, due to the shifting regulatory expectations and delays raised in 2020. Additionally, the medical device industry is transitioning to the E.U. Medical Device Regulation (MDR) requirements. The increased effort to achieve this is putting a significant amount of stress on the labor market. More rigorous testing means less capacity of analysts, laboratory techs and data analysts. Expediting your testing is rarely an option in the current climate. The longer you wait to communicate your submission strategy and timeline with testing labs, the longer it will take to secure a spot in line.

What You Can Do

Testing partners are sympathetic to what these changes mean to manufacturers, and they are doing everything they can to make the testing and submission process as streamline as possible. The best way to establish a productive partnership is to plan accordingly. Trust your well-vetted laboratory’s experience, and build time for additional information requests into your timeline. Try to avoid rushing to the finish line. Design testing plans to produce data with longevity.

Achieving the level of quality necessary to earn regulatory approval may mean larger budgets and extended timelines, but in the long-term, it will save time and money. By understanding the challenges that can compound into timeline delays – expectation, process and availability changes – and taking them into account when you approach your lab testing partner, you can work together to achieve successful studies. 

Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. As an innovation-driven and customer-focused company, WuXi AppTec helps our partners improve the productivity of advancing healthcare products through cost-effective and efficient solutions. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,100 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.

For more information, please visit: http://medicaldevice.wuxiapptec.com/

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Preparing Biocompatibility Risk Assessments for International Registration

Preparing Biocompatibility Risk Assessments for International Registration

With many factors to consider, preparing a global submission may seem daunting, and adhering to the varying testing requirements and interpretations of standards of regional regulatory organizations adds to the chaos. But when you know the different interpretations and preferences for specific tests and standards, it is easier to see the best way to approach submission for your device.

It is crucial to be up to date on the current ISO standards and understand how regulatory bodies are interpreting them. ISO 10993 standards provide a framework for the biological evaluation of medical devices within a risk management process. They are not a rigid set of test methods or evaluation procedures but are a series of standards that provide information to help identify the biological risk associated with a medical device. By bringing risk to the surface, changes to the device can mitigate said risk.

Because interpretations of ISO 10993 standards vary by each region’s regulatory body, it can be challenging to determine a regulatory approval strategy. Understanding the various interpretations by regulatory bodies, such as the European Union (Notified Body), United States Food and Drug Administration (U.S. FDA), Ministry of Health, Labour and Welfare of Japan (MHLW) and China’s National Medical Products Administration (NMPA) can help guide your submission plans.

European Union: MDR

The newest – and arguably most complex – regulation is the Medical Device Regulation) MDR. The regulatory environment in the EU is changing with the transition from Medical Device Directive (MDD) to MDR. Due to COVID-19, the new date for MDR application is May 26, 2021, and the compliance date, which was not delayed, remains the same (May 26, 2024). You can learn more about MDR here.

The EU accepts ISO standards without exceptions, so if your device is compliant with current versions of ISO 10993 standards, it is likely compliant with MDR or will require minimal additional documentation. However, it is critical to confirm with your testing partner to avoid the removal of any devices from the EU market.

In approaching your submission strategy, be aware that Notified Bodies (N.B.s) prefer a risk-based approach and alternatives to replace in vivo testing, including chemical characterization, previous testing, literature, in vitro tests and safe clinical history. If you absolutely require in vivo testing, there is a preference to only perform it after chemical characterization and in vitro testing.

Any evaluations or tests that follow older versions of the ISO standards require a gap analysis. You will need a risk assessment if any carcinogenic, mutagenic or toxic reproduction substances, phthalates, or endocrine disrupters have concentrations at or above 0.1 percent.

An MDR submission will require you to review test reports for compliance to current standards, prepare gap assessments and justify any deviations.

United States: FDA

Unlike the EU, the U.S. FDA does not recognize all ISO 10993 standards; some standards are only partially recognized. Manufacturers should review the U.S. FDA website to determine if, and to what extent, a standard is recognized. Also, the FDA provides guidance for the manufacturer on the use of ISO 10093-1. Obtain additional guidance by contacting testing partners with experts on their team who are members of ISO committees and have legacy knowledge from experience with previous device submissions. At the end of the day, it comes down to the individual reviewer’s discretion on the acceptability of ISO compliance.

A device that contains a novel material (a material not previously used on a medical device and not already evaluated by the U.S. FDA) will require additional in vivo cytogenetic testing as part of a genetic toxicity test battery. In addition, the U.S. FDA has a preference for MEM elution cytotoxicity test.

The best approach is to use the risk assessment and tests performed for EU submission, as well as include a MEM elution cytotoxicity test.

Japan: MHLW

In February 2020, the Japanese MHLW published Notification No.1006-1, which revises a previous notification from 2012. The notification recommends the use of the most current version of ISO 10993 standards and expands the expectations of biological evaluations. Most of the expectations are consistent with ISO standards, such as the requirement of the same endpoints for evaluation, as listed in ISO 10993-1 (2018). Furthermore, all biocompatibility tests must comply with Good Laboratory Practices (GLPs).

MHLW expects detailed information on patient contacting materials that do not meet recognized standards. For those that do not, you will need material composition and physical test information. There is also a data integrity review to confirm the reliability of the data submitted. The MHLW may also ask for raw data for any particular biocompatibility test. If the requested data is not available or deemed insufficient, the submission could be at risk of rejection.

Japan requires two different extraction strategies: one for the evaluation of sensitization and the other for the evaluation of genotoxicity. These extraction strategies attempt to deliver sufficient extractable materials to be representative of the whole device.

Using available information to address the required endpoints sets you up for success when preparing the MHLW application.

China: NMPA

The NMPA has significantly expanded in size over the last ten years. Due to this there is the perception that China requires testing and does not accept risk-based evaluations. In reality there are cases in which NMPA has accepted risk-based evaluations and it currently does accept these assessments; however, acceptability is at the reviewer’s discretion. NMPA is making an extensive effort to train their reviewers and to accept more risk-based evaluations.

The NMPA evaluates medical devices with C.E. mark and/or 510(k) clearance using alternative procedures which facilitate the review. However, the NMPA may not accept current versions of ISO standards (currently accepted versions of the standards are posted by the organization on their website and can be translated into English) and may prefer conformance to older versions on the standards. Furthermore, they often request that the biocompatibility evaluations reference the Chinese standards that are equivalent to ISO standards.

By delaying submission until the EU and the U.S. clear the device, you can streamline the submission process for the NMPA since devices previously in the U.S. or EU follow an abbreviated review process. However, to avoid unnecessary delays, it is important to provide a risk assessment referencing the ISO equivalent Chinese standards.   Your testing partners can help in providing appropriate information needed for a successful submission to NMPA.

The regulatory environment is consistently changing due to periodic standard revisions and new guidelines from regulatory agencies. While ISO 10993 standards are recognized globally, every region has different interpretations and preferences for what they want to see in the application process. Simply following ISO 10993 standards may not result in the acceptance of your biocompatibility evaluation. Having a thorough understanding of regulatory expectations in the regions where you plan to submit devices for review can guide endpoint selection, test design and more. Preparing sooner than later can help ensure your device’s success no matter where in the world you are submitting for review.

To learn more about how to approach each regulatory body, and follow an example of a product through regulatory approvals, check out this webinar, “Biocompatibility Evaluation of Medical Devices for Global Registration.”

To stay up to date on the latest industry news and regulatory changes, follow us on LinkedIn.

Established in December 2000, WuXi AppTec provides a broad portfolio of R&D and manufacturing services that enable companies in the pharmaceutical, biotech and medical device industries worldwide to advance discoveries and deliver groundbreaking treatments to patients. With industry-leading capabilities such as R&D and manufacturing for small molecule drugs, cell and gene therapies, and testing for medical devices, WuXi AppTec’s open-access platform is enabling more than 4,000 collaborators from over 30 countries to improve the health of those in need – and to realize our vision that “every drug can be made and every disease can be treated”.

For more information, please visit: https://medicaldevice.wuxiapptec.com/