Insights & Intelligence for Regulatory Leaders

The International Organization for Standardization (ISO) is the largest body in the world publishing standards. In fact, it is a conglomeration of standards bodies from over 160 countries working together to harmonize standards. As such, ISO 10993 is the international standard that is practically used globally for testing and determining the biocompatibility of medical devices. So it’s critical for medical device manufacturers to understand all 23 parts of ISO 10993 for the success of 510(k), pre-market authorization (PMA), and other device submission projects for regulatory authorities worldwide. As an example, the FDA has issued guidance on the Use of International Standard ISO 10993-1.

What is biocompatibility?

According to ISO 10993-1:2018, the current version of part 1 of the standard, biocompatibility is the ability of a medical device or material to perform with an appropriate host response in a specific application. Any device that comes into direct or indirect contact with the skin must be tested for biocompatibility. A medical device that makes indirect contact with the skin is one that encounters a liquid, gas, or another medium, that makes direct contact with the patient or user.

Categorizations for medical devices according to ISO 10993

When testing the biocompatibility of a device, it is broken down into two categories; one based on its type of contact with humans, and the other based on the duration of contact.

The categorizations for types of contact are:

• Non-contacting medical devices: These are medical devices that do not make direct or indirect contact with patients. Examples include in-vitro diagnostics devices, blood collection tubes, and petri dishes.
• Surface-contacting devices: Surface-contacting medical devices are ones that touch the skin, in-tact mucous membranes, and breached or compromised surfaces. Examples of these devices are catheters, contact lenses, and bronchoscopes.
• Externally communicating devices: Externally communicating devices are those that are partially or wholly external and come into contact with bodily fluids. These devices are usually intended to deliver or draw fluids to or from the body and are attached to an external delivery or withdrawal system. Examples include dialyzers and dialysis tubing accessories, transfer and transfusion sets, and arthroscopes.
• Implantable devices: Implantable devices are the riskiest type for medical devices because they are embedded within human tissue. Pacemakers, artificial larynxes, and heart valves are all implantable devices.

The categorizations for times of duration are:

• Limited exposure – Medical devices whose cumulative sum of single, multiple, or repeated duration of contact is up to 24 hours.
• Prolonged exposure – Medical devices whose cumulative sum of single, multiple, or repeated contact time is likely to exceed 24 hours but does not exceed 30 days.
• Long-term exposure – Medical devices whose cumulative sum of single, multiple, or repeated contact time exceeds 30 days.

Determining biocompatibility

Medical devices are most commonly made of metals, plastics, and fabrics, which are composed of chemicals with varying properties. Manufacturers must gather physical and chemical information about the device, which is vital to its biological and material evaluation and characterization.

For devices with components that are made of or utilize novel chemicals or materials, or those known to cause adverse effects, ISO 10993 requires rigorous risk assessment and management according to the standards of ISO 14971. Furthermore, there are prescribed data endpoints that set the foundation for determining the biocompatibility of medical devices and their intended uses and components.

The main things manufacturers must consider when determining the biocompatibility of medical devices and their components are listed below:

• Complete chemical characterization – ISO 10993 requires manufacturers to describe the chemical and material makeup of the medical device and its components, as well as the use of chemicals in the manufacturing of the device. Sometimes, a test of extractable and leachable chemicals is required to determine the safety of the medical device.
• Toxicological assessment – Toxicological assessment serves to determine and mitigate the risk of medical devices when they come into contact with patients and users. There are four pillars of toxicology assessment: hazard identification, hazard characterization, exposure assessment, and risk characterization.
• Biocompatibility testing – Biocompatibility testing is the process of testing the local and systemic effects of a medical device on the tissues it comes into contact with. Oftentimes a favorable toxicological assessment by a qualified individual, based on the facts of the thorough chemical characterization, can rule out the possibility of adverse effects and the need for biocompatibility testing.

ISO 10993 compliance

Biocompatibility assessment is a vital part of risk management according to ISO 14971. Ensuring compliance with risk management and biocompatibility assessment standards requires buy-in from all departments, from marketing and design to quality assurance and regulatory affairs.

It is vital that you begin considering ISO 10993-1:2018 in the early stages of product design. Part 1 of the standard will refer to additional parts, as listed in the following section. Completing your complete chemical characterization and toxicology assessment early in the process will help ensure the biocompatibility of your medical device during the design phase and expedite your device registration and time to market.

Also, it’s important to note that many regulatory authorities around the world have their own variation of ISO 10993. While these varying standards have the same foundation and are similar in many ways, you must understand their nuances if you plan to offer your medical device internationally.

ISO 10993 sections

ISO 10993 is made up of 23 different sections or parts, each of which is maintained and updated separately. Previews of the standard can be viewed on the ISO website, but full versions of the standard need to be purchased.

• ISO 10993-1:2018 – Evaluation and testing within a risk management system
• ISO 10993-2:2022 – Animal welfare requirements
• ISO 10993-3:2014 – Tests for genotoxicity, carcinogenicity, and reproductive toxicity
• ISO 10993-4:2017 – Selection of tests for interactions with blood
• ISO 10993-5:2009 – Tests for in vitro cytotoxicity
• ISO 10993-6:2016 – Tests for local effects after implantation
• ISO 10993-7:2008 – Ethylene oxide sterilization residuals
• ISO 10993-8: - Withdrawn (Selection of reference materials for biologic tests)
• ISO 10993-9:2019 – Framework for identification and quantification of potential degradation products
• ISO 10993-10:2021 – Tests for skin sensitization
• ISO 10993-11:2017 – Tests for systemic toxicity
• ISO 10993-12:2021 – Sample preparation and reference materials
• ISO 10993-13:2010 – Identification and quantification of degradation products from polymeric medical devices
• ISO 10993-14:2001 – Identification and quantification of degradation products from ceramics
• ISO 10993-15:2019 – Identification and quantification of degradation products from metals and alloys
• ISO 10993-16:2017 – Toxicokinetic study design for degradation products and leachables
• ISO 10993-17:2002 – Establishment of allowable limits for leachable substances
• ISO 10993-18:2020 – Chemical characterization of medical device materials within a risk management process
• ISO 10993-19:2020 – Physico-chemical, morphological, and topographical characterization of materials
• ISO 10993-20:2006 – Principles and methods for immunotoxicology testing of medical devices
• ISO 10993-22:2017 – Guidance on nanomaterials
• ISO 10993-23:2021 – Tests for irritation

How can we help?

Many manufacturers endure longer and more costly paths to market than necessary because they do not have systems and tools designed specifically for their regulatory teams. Furthermore, a lack of visibility and collaboration from departments that see regulatory teams traditionally as the “department of saying no” leaves ample room for human error in regulatory, quality management, and even marketing processes and activities. Read more about why we believe regulatory teams need to be considered revenue functions, not cost centers.

The resulting inefficiencies lead to problems such as marketing products with expired certificates, missing certificates, inaccurate and/or incomplete submissions, and even non-compliance with current regulatory requirements. Having a holistic RIM system is central to staying in compliance with standards, regulations, and guidance in the many markets around the world. Rimsys is the only RIM system of its kind built specifically for the medtech industry.

To learn how Rimsys can help your company get its regulatory ducks in a row, click here to schedule a demo.

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What is STED?

The STED, or Summary of Technical Documentation, format was created originally by the Global Harmonization Task Force (GHTF), the precursor to the current International Medical Device Regulators Forum (IMDRF). The original STED format, defined in 2007, was the first attempt to harmonize medical device submission information and standardize the information required under the EU MDD and regulations in other countries.  

As medical devices and corresponding regulations developed more stringent regulations that defined their market access submissions, regulators found that this original harmonized format did not require sufficiently detailed technical information, nor did it provide enough structure. As a result, more recent regulations have replaced STED with expanded requirements. Note that some in the industry may refer to “STED” when discussing the newer requirements that have replaced it.

Is STED still valid?

Technical documentation formatted using STED may come close to meeting current requirements in some cases. However, many major markets have updated their regulations and requirements for technical documentation, or they have standardized on MDR. EU notified bodies expect MDR technical files, which may have specific requirements depending on the notified body that a manufacturer is using.  

In addition to MDR in the EU, we have seen other countries over the past few years make changes to their regulatory systems and requirements, including:

• New regulations in China based on IMDRF in June, 2021 (Order #739)
• Emerging regulations in Canada and Brazil that are currently based on the IMDRF ToC
• New Regulations for Saudi Arabia that closely resemble EU MDR 
• Massive regulatory restructuring in ASEAN market

What has replaced STED?

STED has been replaced by the IMDRF Table of Contents (ToC) submission dossier. This submission template has more defined requirements than STED and we are seeing countries update their regulations to adhere closely to the IMDRF ToC. There are a few additional benefits to the IMDRF ToC:

• Additional Flexibility - The IMDRF ToC has a specific numbering structure for technical requirements that allow authorities to “pick and choose” requirements based on submission type and risk classification.
• Efficiency – Countries that use the IMDRF ToC will have a matrix structure for their submissions to note what is required (R), Conditionally Required (CR), Not Required (NR) or optional (O). This can cut down on extraneous information that does not need to be in a submission. Canada already has draft guidance in place with their matrix submission style.  
• Standardization – each country that follows the IMDRF ToC will number their submission document requirements with the same Table of Contents.

There are also other markets that are using alternative pathways to STED. The ASEAN market uses ASEAN CSDT (common submission dossier template), which is similar to the IMDRF ToC format, but uses different numbering. There are also two versions of the CSDT – one for standard medical devices and one for in vitro diagnostic devices.

Note that Singapore HSA has good information and is considered the “gold standard” for regulatory submission processes in the ASEAN market.

Expectations for future medical device submission requirements

We expect requirements to only get more complex and burdensome as countries move to further improve patient safety and address the needs of increasingly complex medical devices. A well-defined submission template strategy is critical to managing your device types. Within Rimsys, you can not only access standard IMDRF, NMPA, and other templates - you can design customized templates as needed for your holistic regulatory strategy.  

Additional resources

• IMDRF ToC IV
• IMDRF ToC n-IVD
• Health Canada ToC Matrixes
• NMPA Submission Matrixes (in Chinese)

Would you like to learn more about how Rimsys handles submission templates? Schedule a conversation with our experts now.

There’s no question that the medical device market is global, and the United Kingdom (England, Scotland, Wales, and Northern Ireland) is one of the world’s most viable and vital markets. It’s certainly one that you want your medical device in if you hope to make a global impact. The Medicines and Healthcare products Regulatory Agency (MHRA) is the gatekeeper of that market and one of the world’s most influential regulatory bodies.

Knowing who the MHRA is and understanding their role in ensuring that only safe, effective, high-quality medical devices enter the market is vital to your success in the UK. In this brief article, we’ll tell you more about who the MHRA is, their authority and responsibilities, and even some of the requirements you must meet to get your medical device into this market.

What is the MHRA?

The MHRA is an executive branch of the Department of Health and Social Care. It’s the UK’s equivalent of the US Food and Drug Administration (FDA), meaning that they set the quality and regulatory standards for medical devices in Great Britain.  

Because the UK used to be part of the European Union, products required a CE marking to enter the UK market. Since Brexit, the MHRA has been the sole regulatory authority in Great Britain (England, Scotland, and Wales) and the gatekeeper to its robust medtech market.

What does the MHRA do?

As you know, medical devices must meet specific requirements before they can be sold in most markets around the world. Generally, the more developed the nation and its healthcare and medical device industries, the more complex its healthcare regulations are.  

The MHRA is responsible for:

• Monitoring and regulating post-market surveillance of all medical devices currently on the market and creating regulations and requirements for medical devices entering the UK. They also enforce regulations, ensure medical devices meet the necessary safety, efficacy, and quality standards, and have the power to pull noncompliant products from the shelves.  

• Making sure that supply chains for medical devices and the materials that comprise them are safe and secure. This includes everything from the facilities where products are made and stored, to their packaging and the systems and logistics applied in their transport.  
• Educating the general public, healthcare professionals, and manufacturers about the risks and health benefits of medical devices.  
• Engaging in harmonization efforts with other countries to develop standardized pathways to global markets. They influence international regulatory standards, best practices, and frameworks to support this effort.  

How do you register a medical device with the MHRA?

Registering a medical device in the UK is different than in years past due to Brexit, which was the British exit from the European Union. Before Brexit, the UK adhered to the EU regulatory requirements as put forth in the EU MDD/IVDD, which Regulation EU 2017/745 (MDR) and Regulation EU 2017/746 (IVDR) eventually replaced. However, the MHRA will be instituting its new regulations currently set to be in force in July 2024.

One of the first steps of registering a product in the UK is getting the UK Conformity Assessment (UKCA) marking on your device and packaging. Manufacturers of Class I (lowest-risk classification) devices and general In Vitro diagnostic devices can self-certify against UKCA marking if these devices are non-measuring and non-sterile.  

Class II and III devices must go through conformity assessment by a UK approved body. Approved bodies are the UK’s equivalent of Notified Bodies in the EU. These organizations have the authority to perform conformity assessments and apply UKCA markings on medical devices. UK approved bodies also perform post-market surveillance of devices currently on the market to ensure they’re safe and compliant for as long as they’re in use.  

The process is a little different for device manufacturers outside of the UK who want to market their medical devices. Foreign manufacturers must designate a single person based in the UK to serve as their authorized representative (or UK Responsible Person). The UK Responsible Person acts as a liaison between the manufacturer and the relevant approved regulatory bodies, and handles the task of registering that company’s products with the MHRA.  

The MHRA and Northern Ireland

When registering a device in Great Britain and Northern Ireland, you’ll notice that there are different procedures even though both were part of Brexit. According to the Northern Ireland Protocol (Northern Ireland’s response to Brexit), Northern Ireland applies Regulation EU 2017/745 (MDR) and Regulation EU 2017/746 (IVDR) to its own regulatory framework, whereas Great Britain has decided to implement its own regulations over the next couple of years.

For instance, as Northern Ireland still adheres closely to  Regulation EU 2017/745 (MDR) and Regulation EU 2017/746 (IVDR), UK approved bodies cannot provide conformity assessments for them. In fact, if a manufacturer based in Great Britain wants to put a medical device on the market in Northern Ireland, they must designate an EU Authorized Representative to register the product for them.  

Furthermore, an EU Notified Body must provide a conformity assessment according to Regulation EU 2017/745 (MDR) and Regulation EU 2017/746 (IVDR) for the device to receive UKNI marking (Northern Ireland’s conformity assessment mark). Likewise, Northern Ireland Authorized Representatives cannot represent Northern Irish or other foreign manufacturers in Great Britain, nor can Northern Ireland Notified Bodies provide UKCA marking for medical devices. In short, Northern Ireland has decided to continue to abide by EU medical device and in vitro diagnostics regulations as set forth by the European Medicines Agency, whereas Great Britain has not.  

How to achieve compliance

The MHRA is firmly positioned as one of the foremost regulatory authorities in the world. They’re responsible for creating, implementing, and enforcing regulations for medical devices and IVDs in the UK while also providing research and education to promote the safety and efficacy of devices worldwide.  

Adherence to UK regulations is essential to getting your medical device on that market and keeping it there. Medical devices entering the Great Britain market must adhere to the MDR/IVDR (until June 30, 2023) or UK MDR 2002, whereas Northern Ireland still abides by EU regulations.  

Manufacturers based outside of Great Britain that want to put their devices on the market there must designate a UK Responsible Person (UKRP) to represent their interests and a UK-approved body to perform conformity assessments and apply UKCA marks. At the same time, Northern Ireland still adheres to EU regulations, requiring foreign manufacturers to utilize EU and NI responsible persons and notified bodies to assess medical devices, documentation, and manufacturing facilities while requiring the EU’s CE marking.

Bringing your device to market in the UK requires a dynamic regulatory strategy that enables you to optimize your projects and processes, ensuring your medical devices hit the mark for both the GB and NI markets. Also, it’s vital that you do your due diligence to ensure conformity with the regulations of both markets while also avoiding conflating their processes and regulatory requirements. Ultimately, getting your medical devices compliant with both markets could set your medtech company up to be a mainstay in the UK.  

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When we think of medtech regulatory affairs it’s easy to focus in on pre-market activities: the identification of market entrance requirements and the submission process to obtain market clearance for a new device. This is an important aspect of the work that RA teams do, but it’s definitely not all they do.

The reality is that regulatory work is never done because products are never done. Medtech companies are consistently making product updates, whether optimizing manufacturing or supply chains, adding accessories, working with new materials, or releasing software updates. This is normal, but in a highly-regulated industry, any of these changes can have an impact on a product’s license or market clearance status.

Impact assessments of new regulations, product or manufacturing changes, or standards updates are a core RA activity and one that we’ve focused on automating within Rimsys. Our unique “product-centric” data structure allows registrations, submissions, standards, and technical files to be linked to individual products. This association means that any RA team member can instantly pull a list of products that may be impacted by a standards change, or, conversely, a list of registrations that may be impacted by a product change.

Now we’ve enhanced Rimsys’ impact assessment capabilities by allowing teams to survey registration owners or country managers and collect their individual feedback about the impact of pending changes.

Feedback is a critical element of impact assessments

Communication and feedback within a broader regulatory team is a critical component of any impact assessment. In larger organizations, different teams often have responsibility for different regions, whether those are dedicated RA teams, consultants, or in-country representatives. A product or manufacturing change can impact any number of country registrations in different ways, so to properly assess the regulatory workload needed to process the change, teams need to gather and document input across the extended RA team.

Traditionally this activity has involved a flurry of emails, some shared spreadsheets, and no clear tracking or management, making it time-consuming and difficult to effectively collect this information.The new impact survey feature from Rimsys automates this task and centrally collects all of the necessary feedback within a consolidated project plan.

How it works

Impact surveys are included in the projects module in Rimsys. Now, when you start a new project request you can automatically send a survey to all of the owners for registrations that are associated with the project. Owners are notified to log into Rimsys, review the product details and any linked documentation, and fill out a short form to document whether they think their particular registration will be impacted by the proposed project, the remediation required (registration update, audit, etc.), and the expected time required.

Registrations where the owner indicates an impact are automatically flagged, and a progress bar provides an at-a-glance view of the survey status (completed responses, pending responses, % of registrations impacted).  When the project request is approved, all impacted registrations and timeline are carried over to the active project plan.

Automated impact assessments deliver more than efficiency

The new survey feature is another key piece in our goal to streamline and automate as many regulatory activities as possible. Centralizing the surveys within the Rimsys platform ensures that everybody has access to the information they need to assess the impact of proposed changes on specific markets and registrations. It allows surveys to be completed more quickly and ensures that all of the potential impacts are incorporated into a project plan.

This allows RA teams to work more quickly, but more importantly, it ensures that all potential impacts are properly identified, preventing project delays and eliminating noncompliance risks. If a product design change unexpectedly invalidates a license in a particular country, companies may have no choice but to withdraw that product until it can be recertified. Regulatory automation isn’t just about increasing efficiency, it can also have a significant revenue impact.

Want to learn more about automated impact assessments in Rimsys? Contact us today for a custom demo.

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The energy sector, the financial sector, and the healthcare sector are some of the most heavily regulated sectors out there due to the possibility of significant risk to consumers in those industries. In particular, the healthcare sector is regulated to ensure that only the highest quality care is provided to patients and that medical devices are optimized for safety and efficacy.

In the world of Regulatory Affairs, words such as “standards” and “regulations” are used frequently. While they can be rather similar, they do have different meanings in different situations. Let’s explore their definitions and meanings when being used by medical device regulatory affairs professionals.

In general, legislative bodies pass laws, government agencies develop regulations to implement the laws, and industry groups and organizations create and approve standards. ‍

Medical Device Standards

Standards refer to industry standards that device manufacturers use to design, develop, and manufacture safe medical devices. Standards help to demonstrate safety, manage risk, and to achieve regulatory compliance. Harmonized standards are used, when possible, to make working across borders easier.

Example: ISO, IEC, and UL are all examples of industry standard organizations that develop standards to help guide manufacturers on safe design, development, and manufacturing of quality products.

Standards are:

• Technical documents
• Driven by the need for a consensus
• Crafted by experts
• Approved by peers within the industry ‍

Medical Device Laws

Laws are created by the government, as are regulations, but the two are different. Regulations are the practices which need to be followed to ensure that the law are followed.  
Example: Criminal laws, civil laws, federal laws, international laws, etc.

Laws are:

• Rules created by the government
• Designed to regulate commercial and business transactions
• Legal rules that apply to all members of society and/or institute
• Not changed frequently

Medical Device Regulations

Regulations are the process of monitoring and enforcing established government rules and laws.

‍Example: The EU implemented the Medical Device Regulation (MDR)  Regulation EU 2017/745 for all its member states. This regulates the clinical investigation and sale of medical devices for human use. If you want to sell a medical device in the EU, it must be designed, developed, and manufactured according to this regulation.

Regulations:

• Define processes for the monitoring and enforcing the laws
• Provide a consistent method to ensure laws are followed
• Are known to change often and without notice  

‍Medical Device Directives

In Europe, Directives are legal acts of the European Union. Directives comply with the EU's desire for subsidiarity and acknowledges that different member states have different legal systems, allowing each member state the leeway to choose its own statutory wording.

Directives:

• Are legal acts set up by the European Parliament and Council .
• Require member states to uphold the acts without dictating specific processes.
• Allow member state to have flexibility as to how the rules are to be adopted.

Medical Device Guidance

Guidance documents are designed by federal and/or regulatory agencies, such as the FDA and European Union, and are meant to help further explain or provide clarity on existing rules.   

Example: The FDA provides many guidance documents to help medical device manufacturers better understand the rules and regulations governing the safe design, development, and manufacturing of medical devices.

Guidance documents are:

• Designed by federal and regulatory agencies
• Intended to help people better understand legal rights and obligations
• Not designed to be enforceable under law

Medical Device Policies

A policy defines how an institution should execute a regulation. While it’s not against the law to not follow policy, failing to follow the policy can result in situations that cause an organization to operate outside of the law. The government creates regulatory policies to ensure that industries operate in a sustainable manner and that any risks are minimized (i.e., foreign policy, economic policy, ethics policy, environmental policy, etc.).

A Policy is:

• How an institution interprets and implements regulations.
• Is meant to execute a regulation, depending on an institution’s size, complexity, location, and other factors.
• Helpful in providing people with guidelines for making day-to-day decisions.  

As you can see, there are many different rules, regulations, etc. that need to be considered and followed, and they can sometimes be intertwined. When developing and selling medical device equipment, it’s very important for regulatory affairs teams to understand how each needs to be followed. You also need to be aware of the constant changes, especially when doing business in more than one country. A regulatory information management system is a great place to start to ensure the security of your products – no matter where they are being distributed and sold.

Learn how Rimsys can help your regulatory team keep track of each product and related regulations, standards, and more!

The Council of the European Commission has concluded their December 9^th meeting meant to address member states’ concerns over the challenges and issues in meeting current MDR deadlines. MDD certificates for medical devices will continue to be accepted for an additional three to four years beyond current MDR deadlines, with limited exceptions.  

While not all details are available, it is believed that the following changes will be adopted:

• An extension of the transitional period, allowing medical devices to continue to be marketed under MDD certifications through 2027 for class IIb and class III devices, 2028 for class IIa and class I devices that require an external conformity assessment, and 2028 for class 1 devices that are sterile or have a measuring function.
• An extension of the validity of certificates issues under the MDD.
• Some restrictions will be put in place under the new extensions. Devices not eligible for extended deadlines will include those devices presenting an unacceptable risk, those that have undergone significant changes since being certified, and devices for which the manufacturers are already in the process of obtaining certification under the MDR.
• The removal of the existing “sell off” provision.

It is expected that the MDCG will release a guidance to address bridging the gap for expiring MDD certificates within the coming days and that the full legislative proposal will be introduced in January, 2023.  

Stay tuned for additional information as we learn exactly how this will be implemented and what restrictions will be in place.

Additional articles and information:

• MDCG 2022-18: MDCG Position Paper on the application of Article 97 MDR to legacy devices for which the MDD or AIMDD certificate expires before the issuance of a MDR certificate
• New extension to implement MDR (MDlaw.eu)
• Summary of the EU Commission Meeting – including video (Easy Medical Device LinkedIn post)
• Jan 6 update - EC adopts proposal
• 6 reasons medtech companies shouldn't delay MDR certification

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