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Safe & Compliant: Mitigating Risks After Device Modifications

Safe & Compliant: Mitigating Risks After Device Modifications

The medical device regulatory environment is continuously evolving. As regulatory body expectations become more demanding, manufacturers need to evaluate the safety implications of changes to their devices and processes.

Manufacturing modifications are one example that can affect a medical device’s compliance and possibly end-user safety. Changes to supply chains and manufacturing processes may pose more than just logistical challenges—they can potentially alter a product’s chemical makeup, impact toxicological risk assessments (TRAs) and even put a device’s regulatory approval at risk.

Whether changes to a manufacturing process are planned or reactive, it is critical to understand the implications they may have on a medical device’s material composition and what that means for evaluating biological safety concerns. When modifications to the device or the process occur, ensure your team takes the right steps to protect the end-user and meet or maintain regulatory approval.

Keeping an Eye on Potential Pitfalls

The manufacturer is responsible for identifying, addressing and eliminating potential risks before implementing modifications to the device design or a manufacturing process. There is always the possibility that adjustments may go wrong and cause obstacles or delays. Companies must be intentional in identifying challenges that can affect a device’s chemical makeup at all stages of the product lifecycle.

When design changes occur, there may also be new materials or processes at play. These changes can affect the outcome of chemical characterization and toxicological risk assessments – and could potentially lead to retesting a device altogether. Evaluating device toxicity is critical to gauging potential patient safety risks and assists in gaining regulatory approval. 

It is essential to consider the various regulations that device or material modifications could fail to satisfy – as well as new standard updates that may soon come into effect. For example, the updates to ISO 10993  should always be considered when making changes to a device or process.

Even when no red flags from the manufacturing process arise, a modified device may contain new unknown risks. Ensure your team assesses new device risks that could be associated with the changes and undergo further testing when necessary to protect end-user safety. Your testing partner can help you determine when additional testing is needed.

Recognizing the Common Link

For many established products, one variable that sticks out as the most volatile to change is material choice. When an element in your device makeup changes, differences in raw material composition and quality can falter when it’s time to evaluate toxicity.

When proven safe through testing and risk assessment, a device’s material and chemical composition allow it to function accurately and consistently. But, even altering just one component can put the compatibility of these selections in flux, and the impact on your end-user may be unclear. Laboratory testing partners are more than willing to provide their perspective in determining the necessary next steps when there are material changes in a device. They may suggest additional testing such as material characterization, validation testing, biocompatibility and risk assessments to prove the device is still safe and meets regulatory standards.

Innovate While Playing It Safe

Protecting patient safety and maintaining regulatory compliance is the top priority, so it is essential to consider the risks associated with manufacturing and chemical changes and take the necessary precautions to minimize potential hurdles. Addressing obstacles before they arise can support safer products and successful regulatory submission. Modifications aren’t just manageable—they’re an opportunity to strengthen your understanding of a medical device’s chemical composition through purposeful planning and connection with the right partners.

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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. 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.”

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/

Webinar: Biocompatibility Evaluation of Medical Devices for Global Registration

Webinar: Biocompatibility Evaluation of Medical Devices for Global Registration

When preparing your medical device for a global submission, there are many factors to consider from developing a testing plan to keeping up with regulatory standards and much more. While it can be daunting to move forward with a global submission, there are resources and partners that can support you from start to finish, ensuring you are taking the right steps to achieve success.

In this webinar, Dr Bob Przygoda, Research Fellow at Adventure Biocompatibility Consulting, takes a deep dive into the global submission process. As an active member of ISO committees in addition to extensive experience in the medical device industry, Przygoda brings a wealth of knowledge and a unique perspective to this topic and provides valuable considerations for anyone considering a global filing strategy. 

Przygoda explores how data and test plans are utilized, leveraged, and adjusted for regulatory bodies, as standards and regulations continue to evolve. He also walks through a global submission case study, starting from initial submission, and going all the way through to the first round of required changes and updates. Following the product cycle provides an opportunity to learn about potential challenges that may face your device and how to avoid or overcome them.

If you are considering a global filing or anticipate adjustments to your current strategy, this webinar will provide insights to help guide plan design, and decision-making, to support your submission. Watch the webinar here.

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 3,900 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/

Webinar: Biocompatibility Evaluation of Medical Devices for Global Registration

Extraction Techniques: Designing the Right Studies to Get the Answers You Need

Having a clear understanding of the chemistry required for regulatory submission is not an easy feat. Chemistry background knowledge is crucial when making decisions regarding study design and preparing a device for submission. With this insight, you can gain more value out of your next extractables/leachables (E/L) tests and avoid over- or under-testing.

It is essential to design an extraction technique tailored to your device. Every device is unique and will require a customized approach. Incorrect testing will not yield proper results and could delay timelines by months. You can only accurately access risks after identifying a device’s materials through appropriate testing.

Sandi Schaible, Senior Director of Analytical Chemistry and Regulatory Toxicology at WuXi AppTec Medical Device Testing, walks through the different extraction types and more in our webinar: “Extraction Techniques: Designing the Right Studies to Get the Answers You Need.”

Schaible starts by diving into the various factors and challenges with:

  • Exhaustive extractions
  • Exaggerated extractions
  • Simulated use extractions
  • Leachables

She also discusses the current expectations of different regulatory bodies and provides two case studies using different extraction techniques. Additionally, Schaible explores the updates of ISO 10993-18:2020, while providing insight on how to apply the revision to your testing plan.

In this webinar, you will learn more about the different techniques, the challenges associated with them and much more to help familiarize yourself with the chemistry process and how to determine the method most compatible with your device.

Watch now.

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 3,900 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”.

What’s the Future of Biocompatibility?

What’s the Future of Biocompatibility?

A risk-based approach that tailors test requirements to the specific risks of each device.

 

As the medical device industry continuously evolves and processes become more streamlined, others, like biocompatibility, becomes more complex. In the past, biocompatibility standards have been more black-and-white, but changing regulatory requirements are shifting the methodology and processes for manufacturers to adhere to. Historically, the typical checklist to address risks with biocompatibility tests was sufficient, but recent and upcoming regulatory changes require a more thoughtful approach to medical device testing.

 

Underlying Forces

The primary force behind changing methodology lies in the purpose of various testing methods and the answers they can provide. Ideally, addressing the biological safety of medical devices is facilitated by a program that is risk-based and has the appropriate data, whether through biological testing or chemistry, to address the recommended biological endpoints of concern. Biocompatibility testing on medical device extracts may provide evidence of a potential adverse effect, but chemical characterization provides specific information on the possible chemical hazards which can be further assessed for toxicological risk.

 

While biocompatibility testing is necessary to address some biological endpoints, like local tissue effects and hemocompatibility, it does not typically address all biological endpoints indicated in ISO 10993-1 specific to the nature and duration of exposure to medical devices. For example, though some biological endpoints, like genotoxicity, may be addressed by either methodology, biocompatibility testing or chemical characterization and risk assessment, the latter is a sharper tool for detection of potential mutagens in medical devices.

 

Chemical characterization tends to be more practical and potentially more specific in addressing other endpoints like carcinogenicity, reproductive and developmental toxicity with a toxicological risk assessment. It’s clear that chemistry and biocompatibility testing each resolve different questions pertaining to device risks.

 

Even though a risk-based approach to biological evaluations is a significant focus of ISO 10993-1:2018, an additional focus is a reduction in unnecessary in vivo testing. In vitro models and chemical characterization testing are preferred to in vivo in “situations where these methods yield equally relevant information to that obtained from in vivo models.”

 

Regulatory bodies have been increasingly accepting the use of alternative in vitro models. Yet, the approach and speed of implementation differ between the U.S. and the EU. Balancing varying expectations can be difficult and result in differing degrees of in vivo testing, so taking the time to familiarize yourself with each regulatory body’s approach is essential.

 

The EU’s Swift Approach

With the EU’s transition to the Medical Device Regulation (MDR), the overhaul in submission requirements accelerates the pace of changes in biocompatibility testing. Manufacturers should only pursue in vivo testing when alternative methods cannot mitigate the risk. For example, in vivo testing might be appropriate when local effects at the implant site are a concern due to significant device design changes or when complaints indicate there are patient safety concerns with a product.

 

To avoid overuse of in vivo testing, EU regulators recommend creating stopping points in the testing process to prevent replicate or unnecessary studies. Unnecessary in vivo testing can put submissions in a negative light to regulators, so whenever possible, taking a proactive approach to using alternative methods is essential. Thus, there may be a noticeable shift to in vitro testing to resolve unanswered questions from the limited use of in vivo testing.

 

The U.S. Approach

In the U.S., in vivo testing will not decrease as noticeably compared to the EU. The key focus for U.S. submissions is meeting the recommendations of the FDA Guidance on the Use of ISO 10993-1:2016, which is primarily based on ISO 10993 principals with some differences. This guidance has been implemented consistently now for several years, meaning currently, there is less of a learning curve for manufacturers.

 

To satisfy these recommendations, testing labs will no longer run through a predetermined list of tests. Scientists will need to have a deeper understanding of devices to determine relevant risks and choose appropriate tests.. Regulators hope this approach will minimize the amount of testing required for submissions and support the shift away from using in vivo testing, when possible.

 

Adjustments Across the Board

As labs change their approach to biocompatibility evaluations, the order in which many labs perform their testing will likely become more consistent with ISO 10993-1, enhancing the importance of chemical characterization. Because the exact certainty of device materials is unknown until the completion of chemical characterization, delaying this step or using unverified information could misdirect testing.

 

To accomplish addressing risks, scientists start by determining any gaps that need to be addressed by biocompatibility testing. ISO 10993-1:2018 requires a description of the medical device chemical constituents, and consideration of material characterization, including chemical characterization, before proceeding to any biological testing. Completing chemistry testing sooner in the testing process helps to minimize potential setbacks. Additionally, facilitating communication between engineers that select materials and toxicologists and biocompatibility experts can increase the lab’s understanding of your device and the likelihood of success with your submission.

 

Building relationships and having regular discussions with suppliers is also essential. Consistent communication about material selection and materials used in manufacturing processes is critical. If suppliers make any changes, you need to know in advance, as it could affect device safety and delay manufacturing while the change is evaluated. Therefore, developing proactive communication practices can help you get ahead of issues and risks.

 

Patient safety drives changes in medical device regulations, which may impact biocompatibility evaluations. As the approach to biological evaluations continues to evolve, it is critical to develop partnerships across the industry to collaborate and stay apprised of coming changes.

 

Discover more on the importance of chemical characterization and identifying unknowns in chemical makeup in Unknowns are Unacceptable.

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 3,900 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://www.wuxiapptec.com