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Navigating European Medical Device Premarket Submissions

Navigating European Medical Device Premarket Submissions

Navigating the tricky waters of regulation can be frustrating and challenging for any medical device manufacturer. When those regulations change, the prospect becomes even more daunting. This post breaks down the regulatory path for medical device submissions in the European Union (EU) and explains the hurdles manufacturers may encounter. 

In May 2021, the European Union belatedly implemented its Medical Device Regulation (MDR) path for medical devices after being delayed a year due to the pandemic. But nearly a year later, expectations associated with MDR are still unclear. 

Challenges in the EU Regulatory System 

Manufacturers Face a Mountain of Work 

Manufacturers need to ensure their products comply with EU health, safety and environmental regulations. They must work with notified bodies to perform conformity assessments, create technical files, write EU declarations of conformity when necessary and ensure CE marks accompany their products. It takes a large team of experts to bring a device to market in the EU. Still, manufacturers are ultimately held wholly accountable for the accuracy of the technical file and the device’s compliance with safety guidelines. 

Notified Bodies are Struggling to Keep Up 

The 28 notified bodies operating in the EU struggle to keep up with demand, resulting in significant backlogs for manufacturers. Many of these notified bodies operate with limited scope, fewer resources, and conflicting information about regulatory requirements. Many have stopped accepting MDR applications for specific categories of devices altogether.  

Switching to the New Regulatory Route is Difficult  

Attaining MDR certification for devices approved under the previous Medical Device Directive (MDD) is also complicated. If a device was approved under MDD and it is currently in market, the CE mark remains valid. If a notified body reviews a new product and confirms that the product is compliant with current EU specifications (i.e., MDR), the manufacturer may add the CE mark.

The entire process can take a long time—up to a year with potentially six months added on to attain the CE mark. That timeline assumes that all documentation is prepared perfectly and the safety data are acceptable. When existing chemistry and biocompatibility data are not compliant with current accepted standards, additional time is required to address the data gaps. The amount of time will depend on which biocompatibility endpoints need to be addressed.

Confusion in European Countries 

Since Brexit, the United Kingdom has chosen its regulatory requirements for medical devices. Instead, the country does not use a CE mark but a CA (conformity assessment) mark. A product with a CE mark can go on the UK market until June 2023, assuming the manufacturer can write a declaration of conformity. Northern Ireland is even more complex. As part of the UK but sharing a land border with the Republic of Ireland, Northern Irish notified bodies can certify EU devices, but the certificates issued are only valid in Northern Ireland.

Switzerland is also challenging. The Swiss failed to reach a mutual recognition agreement with the EU before the MDR’s implementation in May 2021. This means existing Swiss certificates of conformity and certificates issued in the EU for Swiss devices are invalid. 

All these challenges mean device manufacturers need to treat the MDR certification process as though they are starting from the beginning. Even if they once held MDD certification, they cannot expect preferential treatment and may be asked to prove well-known or scientific principles about their devices. They must also fully understand how MDR applies to their product specifically.

Risk Management Requirements 

Anyone planning on selling a medical device in the EU must address “physical and/or chemical information” as outlined by the ISO 10993-1:2018 standard. This is often achieved through chemical characterization data that complies with ISO 10993-18:2020. The standard has not been harmonized across all EU countries, but MDR considers it “state of the art,” as it is the most recent published version of an accepted standard. 

ISO 10993-18:2020 is deemed particularly strict because of the analytical evaluation threshold (AET) and the emphasis on exaggerated and exhaustive extractions. The AET is a threshold for chemicals that requires chemists to identify and quantify compounds at or above a specific concentration to ensure all compounds of potential toxicological concern are reported for subsequent evaluation in the toxicological risk assessment (TRA).

Knowing Who Does What 

Journeying through the EU regulatory pathway means dealing with many local, national and continental organizations and individuals. Knowing who is responsible for which part of the process is critical for regulatory success. 

  • European Authorized Representative: When a medical device manufacturer does not have a registered place of business in the EU, it must appoint an “EU Rep” to liaise between themselves and the competent authority. 
  • Harmonized Standard Consultant: HAS Consultants work with manufacturers to clarify a device’s legal definition and determine the best category for it.  
  • Notified Body: The notified body must review and approve a medical device before receiving market approval. They are independent organizations designated by EU member states to ensure devices adhere to MDR regulations. 
  • Competent Authority: These are usually government agencies within an EU member state. They monitor medical device safety after products go to market and are responsible for ensuring EU regulations become national legislation. 
  • European Medicines Agency: The EMA evaluates human veterinary medicine’s quality, safety, and efficacy. Competent Authorities usually regulate medical devices, but the EMA gets involved in certain circumstances. 

All of this makes the emerging regulatory landscape in the EU daunting. Still, if manufacturers stay vigilant and wait out the collective uncertainty, they can gain or maintain access to a gigantic market. The rules may be demanding and complex, but an experienced laboratory testing partner can play a critical role in helping manufacturers achieve their goals. 

Complete this short form to speak to a WuXi AppTec scientist about your EU submission.

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 5,700 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.”

Overcoming Obstacles to Tissue Sterilization Validation: What Manufacturers Need to Know

Overcoming Obstacles to Tissue Sterilization Validation: What Manufacturers Need to Know

Sterilization validation is necessary to bring tissue-based products to market. The U.S. FDA requires it, whether the device functions in vivo or in vitro, so understanding how to ensure sterility is critical. When it comes to living tissue, the process carries an even bigger imperative because sterility level could mean the difference between life and death.

A 100% sterile device is neither realistic nor possible, so manufacturers must ascertain and set an appropriate sterility assurance level (SAL) to assess bioburden. SAL measures the probability of a single living microorganism surviving after sterilization, and a SAL of 106 is the acceptable standard. This SAL threshold means no more than one microorganism in one million is present after sterilization. There can be no margin for error when dealing with tissue-based products, so understanding bioburden is mandatory.

Methods of Tissue Sterilization Validation

Sterilization validation requires strict timelines for bioburden testing to verify the proper sterilization method. Tissue is typically sterilized using heat, irradiation, or chemicals, and each requires its own process. Gamma irradiation is a common sterilization method that has a long and successful track record of reducing bioburden. Radiation dosage follows Association for the Advancement of Medical Instrumentation (AAMI) guidelines to reach the lowest SAL.

Electron beam (e-beam) is an alternative to gamma irradiation and has been used for decades to sterilize sutures, gloves, gowns, masks, etc. It is only just starting to be used in tissue sterilization. While researchers cannot sterilize as much material as they can when using gamma, e-beam is a quicker, more cost-effective and eco-friendly option.

When choosing a sterilization method, understanding the modality’s impact on tissue is critical. Researchers must be keenly aware of all factors that elevate the bioburden load of a donor’s microflora when they conduct validation. These factors include:

  • Raw materials used to package or clean the product
  • The location in which the product was processed or collected
  • Seasonal variations present where the tissue was collected

Bioburden Knowledge is Non-Negotiable

Fully understanding bioburden is critical when conducting tissue sterilization validation. Scientists must establish bioburden before they can substantiate a sterilization dose. It requires microbial identification and characterization for aerobes, anaerobes, fungi, spore formers and other organisms. The presence of these elements helps establish bioburden, and a history of successful dose audits will determine the frequency with which they are conducted. Dose audits are small validations required quarterly at first, but the cadence and frequency can vary over time.

It is easy to run amok when measuring bioburden levels simply because dilution or correction factors reduce detection tests’ accuracy. These factors can increase bioburden and result in validation failures. Failures create additional steps which squeeze timelines, so it is essential to establish a clear sterilization protocol from the beginning. This removes uncertainty and makes sterilization methods easier to monitor and ensure the lowest possible SAL.

The dose substantiation study is pivotal in tissue sterilization validation because it determines the minimum level of radiation necessary to achieve the required SAL. Lot testing begins only after the study and SAL are complete. The entire tissue sterilization validation process includes writing a customized protocol for each product, working with a testing laboratory and finding an irradiator. A dose substantiation study can take up to three months, so expect the unexpected when planning deadlines. The timeline could stretch even thinner if there are new tissue products in the process for which bioburden has not been previously established.  

Avoid Timeline Pitfalls

When a sterilization method for tissue-based products is validated, many are then monitored through quarterly dose audits. Success is essential because failing two audits can require revalidation. This adds costly delays that can compromise a product’s release date.

Efficient time management is crucial for tissue sterilization validation. Conservative timelines provide the necessary flexibility when the unexpected occurs. Simply put, the biggest obstacle a manufacturer faces is a tight or poorly planned deadline. Three more obstacles manufacturers must consider include:

  • Sample availability: Tissue samples can be very limited. The time it will take to replace a tissue-based product is completely unknown. These products need to be handled with extreme care.
  • The product: Different tissue types all carry different bioburden levels. Some microorganisms can be resistant to radiation. Tissue types have varying expiration dates after processing. It is essential to know these factors before validation begins.
  • Travel timelines: Recovered tissue products have a shelf life—some are longer than others, but they all expire. Tissue must arrive at its destinations on time and intact. Transportation must be timely, and your laboratory partner should be prepared to receive and begin processing the tissue immediately upon receipt.

Tissue sterilization validation has unforgiving timelines, so manufacturers must anticipate and plan for unforeseen delays. Leave as much time as possible to assure optimal success. Before beginning the tissue sterilization validation process, always work with an experienced and accredited lab testing partner who shares the same goals, values and mindset.

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 5,600 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.”

Packaging Pitfalls Medical Device Manufacturers Cannot Ignore

Packaging Pitfalls Medical Device Manufacturers Cannot Ignore

As stated in the international packaging standard, ISO 11607, designing and developing a packaging system for terminally sterilized medical devices is a complicated and critical endeavor. Even if manufacturers opt for a proven packaging configuration, it needs to ensure physical protection, maintain sterility up to the point of use, provide proper documentation and allow hygienic presentation. The device components and the packaging system must provide a sterile medical device that performs efficiently, safely and effectively in the hands of the user.

Finding a compatible packaging configuration for your device plays a significant role in final delivery and performance. If you can stay ahead of potential packaging pitfalls, you may be able to support the delivery of an intact, sterile final product.

“Manufacturers need to build the packaging around the device rather than just put the device in a package that exists and hope it works,” says Britt Jones, chemistry and package testing manager at WuXi AppTec. “If end-users examine the package and see that it’s wrinkled, torn and is just messy, they may not favor that supplier as much.”

The packaging system design and choice of materials are influenced by the specific nature of the medical device, the planned sterilization methods, the intended use, expiration date, transport and storage, according to ISO 11607. Avoiding these 3 packaging pitfalls can help ensure your end-user receives a device that is fully functional and presentable.

Compromised Sterile Barriers

Above all else, a product’s sterile barrier must remain intact from the moment of initial packaging until the device’s first use. If a device’s sterile barrier is compromised, there is no way to prove the contents are sterile which, at worst, puts end-users at risk and, at best, leads to discarding perfectly usable devices.

There are myriad ways packaging choices might contribute to compromised sterile barriers. For example, packaging pouches that use foil or Tyvek poly on one side and paper on the other are popular but may not be compatible with all devices. Heavy or irregularly shaped devices can easily compromise the seal or poke through the pouch, leading to issues with packaging integrity.

Heat-sealed poly pouches can also face sterility problems, such as the folds or channels in a poly packaging pouch creating pathways for bacteria. Similarly, heat-sealed pouches with large openings can be fully sealed in one area but compromised in another. A medical device testing partner will detect packaging vulnerability with bubble emission testing or a dye penetration test, so it is good idea to have them validate your heat sealer.

Transportation and storage methods can also impact packaging choices and cost, but those decisions are usually made case by case.

“All the packages are going to require drop testing, compression testing and vibration testing,” Jones says. “But, depending on its destination, non-porous packages may go through aircraft simulation because they can swell and burst in low pressure, high altitude environments. That could cause an issue with the sterile barrier.”

Unusable or Illegible Packaging

Choosing the right configuration and ensuring sterility are paramount to medical device packaging success, but the product’s usability upon arrival to the end-user is equally important.

The US FDA says labels must be designed and applied to devices and containers well enough that they will remain in place and legible during the “customary conditions of distribution, storage and use.” User instructions and other labeling needs to remain legible during routine storage and use. The US FDA guidelines are clear that the onus for ensuring label printing is legible, and will remain so until the device is used, falls squarely on the manufacturers.

A package testing partner can conduct simulated distribution testing, which will expose labels to conditions that will help predict if they will rub off or become illegible. They can also conduct seal testing to ensure the seal holds up under normal conditions and that end-users won’t struggle to open the packaging once the product arrives.

While usability of the packaging is critical, some of the most common questions Jones receives from manufacturers focus on aesthetics. He says they are often concerned about what the packaging is going to look like after distribution or after a significant duration on the shelf.

“If it’s a wrinkled, damaged pouch or an illegible label that’s coming off, then that’s an issue,” Jones says. “The clinicians want it to look aesthetically pleasing and they often give feedback around that.”

Common supermarket behavior illustrates how quickly the average person makes a snap judgment about a product based on its appearance on the shelf. With health care professionals and eventually consumers, it is no different.

Too Much or Too Little Packaging

How much packaging a device needs is essential to consider even before a packaging partner gets involved. Some manufacturers will use single-package configurations across multiple products because they are readily available. Aggressive go-to-market timelines may also entice a company to opt for these materials.

While it may be more efficient at the time, this approach can lead to increased risk. Overly conservative estimates on the amount of bubble wrap, layers of cardboard or number of barriers needed can put the device in jeopardy. Likewise, opening an overly packaged device is not cost-effective. It could also require a sharp object, which creates room for user error that could leave the device broken or sterility compromised.

To ensure you are providing a sterile, safe, user-friendly product to end users, it is crucial to work with a package testing partner you trust. Obtaining test data will help device manufacturers predict outcomes that will save time and money, and ensure their product is sterile and usable when it gets to market. 

“You’ve got to do the testing so you’re not spending too much money on packaging on the front end, but you are using enough packaging to ensure sterility on the back end,” Jones says.

Protecting Patient Safety

Choosing the right packaging configuration for your medical device may be complex, but it is critical. Materials, enclosures, usability and presentation all contribute to device integrity and overall patient safety and, as such, cannot be ignored. Enlisting the help of a medical device packaging partner can save you from selecting a less than ideal configuration, and their partnership can help ensure a safe, usable device is delivered to your customers.

For more on the evaluations used to gauge the efficacy of product packaging, please see our services page.

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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 4,400 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.”

In the News: Readying Reprocessed Devices

In the News: Readying Reprocessed Devices

Writing cleaning instructions for reprocessed medical devices can pose unique challenges during IFU development, but it is critical to get it right the first time. In a recent article for MedTech Intelligence, WuXi AppTec Principal Scientist Dan Fowler dives into developing IFU cleaning instructions for the worst-case scenario. Fowler walks through how to determine the master product for validating product families, identify proper test soils and stay ahead of risks. 

While the cleaning validation testing stage is sometimes seen as a box to check on the path to final submission, validating against the worst-case scenario can reveal more value than a manufacturer initially anticipated. Check out “Designing the Worst-Case Test to Get the Best-Case Results” in MedTech Intelligence for advice on understanding the worst-case scenario when writing your next IFU and ensuring a smoother evaluation of your device’s reprocessing method.

Still hungry for more on this topic? Learn more in our blog on developing cleaning instructions with validation and feasibility in mind.

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

For early access and exclusive content sent straight to your inbox, subscribe today to our premium content.

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 4,100 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/

Preparing for a Pre-Submission Meeting En Route to Regulatory Approval

Preparing for a Pre-Submission Meeting En Route to Regulatory Approval

The current regulatory environment has created opportunities and setbacks for medical device companies as they work toward obtaining regulatory approval on their products. On the one hand, the delayed EU Medical Device Regulation (MDR) deadline means manufacturers have more time to prepare their applications for the European market. On the other, the industry at large is still responding to a global pandemic, which has strained capacity and led to supply chain disruptions that can affect development timelines.

To streamline the submission and approval processes for devices bound for the U.S. market, regulators from the U.S. Food and Drug Administration (FDA) encourage manufacturers to take a more active and collaborative approach to their submissions. Part of this effort includes scheduling a pre-submission meeting with regulators to discuss the device, review testing strategies and connect with the experts on your team. Doing so can help save time and money long-term by garnering regulator’s invaluable insight on the road to a successful submission—at least in the U.S.

Currently, there is no pre-submission pathway available for medical devices meant for the European market. Notified bodies (NBs) review and progress potentially new devices, but they’re unavailable prior to submission because they cannot act as consultative. In addition, while European researchers await updates to MDR, authorities are applying outdated standards inconsistently. Unfortunately, a successful strategy with one product submission may not work with another.

You can make the most out of pre-submission meetings with the U.S. FDA by preparing a clear strategy and recognizing gaps in your product, the planned evaluation and the team you plan to bring to the meeting. Regulators have a keen sense for similar products in the market and will be investigating what makes your product unique.

Basic Preparation

Scheduling a pre-submission meeting is relatively straightforward. The U.S FDA will usually assign you a timeslot within a month of your request. However, you are only allowed one meeting per device application and it only lasts an hour, so you want to make sure you and your team are ready to make the most of it.

As you prepare for your meeting with the U.S. FDA, it is important to consider a few key points. The American regulatory body generally emphasizes an experience-based methodology when categorizing risk and device classification. If a predicate device does not exist, the U.S. FDA might decide it has a higher risk classification. A higher risk classification could mean special labeling requirements, performance standards and post-market surveillance. A device deemed a significant risk (SR) or one for which no predicate device exists may require additional steps, including procuring an Investigational Device Exemption (IDE) before beginning your study. At the end of the day, the U.S. FDA will expect you to be prepared for how your device may be classified.

Ahead of your meeting, familiarize yourself with every aspect of your device, or make sure someone with the proper background knowledge is a part of the meeting. Fully understand its constituent materials and their testing history, along with your development process, and the category and classification of your device. Part of your preparation should be to anticipate the questions you think the investigators will ask. They will review your testing plans, so make sure they are up to date and as comprehensive as possible. The better prepared you are, the more successful the meeting will be.

Partnering Up

Including your testing partner during the preparation phase can be invaluable. They can be especially helpful when outlining your formal testing strategy: identifying the risk associated with the device, how to meet the identified risks, and specific tests that will be performed i.e., chemical characterization, cytotoxicity and more. The regulatory bodies will want as much detail as possible and a testing partner can provide this essential documentation.

A testing partner can also be useful as your team’s go-to expert in the meetings themselves. Testing partners might even be better able to address specific questions or concerns during the meeting. Investigators place a high value on qualified personnel developing strategies–they often want to see the CVs of those who’ve written your strategy–and it is helpful to defer to testing partners and their expertise. Some regulators prefer that manufacturers bring their testing partners with them to these meetings. You should rely on your team and your testing partner to know their roles before the pre-submission meeting begins.

The Last Word

Planning ahead and including the essential members of your team can ensure you’re ready for a successful pre-submission meeting. Doing so will assist in the approval process and prepare you and your devices for successful outcomes.

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

For early access and exclusive content sent straight to your inbox, subscribe today to our premium content.

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 4,400 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.”