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Supply Chain Risk Management

The growth and globalization of the pharmaceutical supply chain make risk assessment more important than ever for pharmaceutical manufacturers. The authors describe a program to identify, prioritize, mitigate, and communicate risks in manufacturer–supplier relationships.

 

The global supply chain for the pharmaceutical industry has expanded during the past decade as companies have striven to be competitive and harness emerging technology. Foreign markets have emerged to offer lower costs for various products.

 

Many companies find managing global suppliers and product-quality issues to be challenging. Recent industry events such as the contamination of batches of heparin demonstrate that a lack of control in the global supply chain can lead to patient harm and death, product recalls, loss of integrity, and significant financial liability for a company.

 

Current good manufacturing practice (CGMP) regulations states companies that design & manufacture pharmaceutical products must ensure that all components, raw materials, and product from suppliers meet predetermined specifications. Further, supplier relationship management is a crucial function to review current suppliers & their operations are in a state of control.

 

In today’s climate, companies should use a risk management program to assess their suppliers’ ability to provide material suitable for the manufacture of medicinal products. A risk-management program should help companies evaluate and control supplier quality and quality of the supply chain. The US Food and Drug Administration’s Pharmaceutical CGMPs for the 21st Century initiative is intended to enhance and modernize the regulation of pharmaceutical manufacturing and product quality. Its goal is to bring the pharmaceutical industry in line with the risk-management activities the medical-device industry uses to reduce patient and business risk.

 

FDA’s expectations are outlined in the International Conference on Harmonization guidelines (Q7, Q8, Q9, and Q10). Several key elements can help control and limit risk throughout a global supply chain. These articles discuss risk prioritization, risk assessment, risk control, risk communication, and risk review in greater detail.

 
 

About the Article:

 
regulatory compliance
 
Pharmaceutical Technology 
Volume 2008 Supplement, Issue 5
Susan J. Schniepp

Complete article published in PharmTech.

 

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Pharma Courses

When in-person training may not be feasible, there are still pharma courses that can ensure employees receive the required career development, says Susan J. Schniepp, distinguished fellow, Regulatory Compliance Associates.

 

Q. I am in charge of Quality training activities for my company. Company policy requires all employees receive annual good manufacturing practice (GMP) training. Since many employees are now working from home, I am struggling with how to deliver effective FDA training during a pandemic, and I want to rewrite the policy to eliminate this requirement. Is annual GMP training a regulatory requirement, and can I eliminate this requirement and still be compliant with the regulations?

 

A. It is important to maintain pharma courses for training employees even during highly challenging circumstances. In the United States, the regulatory expectation for training is defined in 21 Code of Federal Regulations (CFR) 211.25, which states:

 

“Each person engaged in the manufacture, processing, packing, or holding of a drug product shall have education, training, and experience, or any combination thereof, to enable that person to perform the assigned functions. Training shall be in the particular operations that the employee performs and in current good manufacturing practice [CGMP] (including the current good manufacturing practice regulations in this chapter and written procedures required by these regulations) as they relate to the employee’s functions. Training in current good manufacturing practice shall be conducted by qualified individuals on a continuing basis and with sufficient frequency to assure that employees remain familiar with CGMP requirements applicable to them”.

 

EudraLex Guidance

 

In Europe, EudraLex Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use has similar requirements specified in Volume 4, Part 1, Chapter 2, which states:

 

“The manufacturer should provide training for all the personnel whose duties take them into production and storage areas or into control laboratories (including the technical, maintenance, and cleaning personnel), and for other personnel whose activities could affect the quality of the product.”

 

The guideline also states:

 

“Besides the basic training on the theory and practice of the quality management system and Good Manufacturing Practice, newly recruited personnel should receive training appropriate to the duties assigned to them. Continuing training should also be given, and its practical effectiveness should be periodically assessed”.

 

The regulatory expectation is that companies continue to provide “a high level of assurance that manufacturers comply with CGMP and that products meet specifications,” even during exceptional times.

 

FDA Training

 

To ensure that FDA training requirements are adhered to and your compliance posture is not jeopardized, I recommend you start by triaging your employees. Those employees in critical roles should be your first priority to receive the necessary pharma courses in a timely manner. Employees in less critical roles could receive the training at a later time or maybe receive a truncated version of the training. Remember to document your decision in a well thought out and justified rationale.

 

The next hurdle to overcome is to determine the most effective way to deliver the training without wasting critical resources. This can be accomplished in a variety of ways. On-line training programs have been used to train remote employees for years. These programs have the capability of allowing the instructor to use virtual technology and embed questions into the presentation that must be answered before that trainee can continue. This is a great way to train people and measure the effectiveness of that training. It also allows the employee to complete the training as their schedule allows.

 

FDA GMP Training

 

If you decide to utilize this approach, you need to be sure to set a date for completion of the pharma courses and monitor the results of responses. Follow up with employees who may need additional GMP training or understanding of the concepts included in the FDA training.

 

Another approach would be to deliver the training as a webinar using a multiple person meeting app. You can prepare and distribute the information you will cover in the training, schedule a meeting time, deliver the training, and take questions from the employees during the webinar. If you have multiple manufacturing shifts, you can schedule a training session during each shift to make it easier for second- and third-shift employees to receive the training.

 

FDA Regulatory Training Courses

 

Another approach is to research virtual training and conference options offered by external organizations. Many trade organizations have converted their conferences and FDA training topics to virtual offerings covering a wide variety of topics. Many of these organizations offer the option of listening in real time or to taped recordings. Some of these venues are free, and some require a registration fee.

 

The sessions are usually 90 minutes in length, and many offer an opportunity to ask the speakers questions through a chatroom feature. If you are unable to listen to the webinar live, you may have the option to purchase a recording of it and listen to it at your convenience. The recorded option offered with these webinars can be valuable for training employees who work on the second and third shifts.

 

FDA Compliance Certification

 

The companies offering FDA compliance certification webinars advertise them well in advance of the event and often send out multiple reminders. The pre-event agenda for FDA compliance course usually highlights who will be speaking and their professional qualifications. The agenda can help you understand what content is involved in the certification, topics to be covered in the training, and what you will learn as a certified participant upon completion.

 

In addition, they will also make recommendations on who should attend so you can determine if this is appropriate training for your employees. In some cases, the webinar may offer continuing education credits for attending. This information should be printed out and used to demonstrate the appropriateness of the training.

 

FDA Website

 

Finally, you might consider using some employees who are not working remotely to lead some small-group internal training during their shift. Much of the content on the FDA website can be purposed in a train-the-trainer small group concept.

 

This satellite training can be led by a qualified, trusted, and trained employee representative that has the knowledge and expertise determined by their job experience and performance as determined by you. As with all other training, these discussions should be documented in your training system as well as the rationale for the selection of the designated trainer.

 

The bottom line is even though people are working remotely, and in-person training may not be feasible, there are still opportunities to ensure employees receive the required train-ng to meet your company’s training expectations. You should sign up to receive emails from companies and organizations that offer online training, review them to determine if they are applicable to your operations, determine who should attend from your company, and make sure you document their attendance for their training record.

 

regulatory compliance

 

Susan J. Schniepp
Pharmaceutical Technology 
Volume 44, Issue 8
 

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FDA Consensus Standards

Medical device regulatory laws continue to evolve not only with European Union changes to the Medical Device Regulation, but also with global harmonization efforts across the U.S. Food and Drug Administration (FDA). One of the more critical facets of global regulatory compliance involves FDA consensus standards and the conformity assessment procedure.

 

In general, the conformity assessment procedure is widely considered the validation of patient safety and medical device performance requirements. A primary goal of FDA new device approvals is to help ensure patients have access to reliable, high-quality products that increase efficacy.

 

What is FDA S-CAP?

 

According to the FDA’s webpage, the Standards and Conformity Assessment Program (S-CAP), promotes efficiencies and quality during the medical device regulatory review process by:

 

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  • Producing and implementing clear policies to promote the appropriate use of standards in regulatory processes
  • Anticipating the need for and leading the development of national and international consensus standards
  • Advancing initiatives to enhance confidence in conformity assessment activities
  • Fostering innovation and standardization in technologies that facilitate patient access to novel medical devices
  • Providing leadership in standards quality and utilization through outreach and global harmonization

 

Further, to fully understand the positive impact of S-CAP on the life sciences industry, this article will begin by reviewing four critical facets involved in the FDA certified process: understanding FDA standards, the criteria for regulatory submission, defining a consensus standard, and medical device lab testing.

 

Understanding FDA Standards

 

The FDA Standards Recognition Program assesses the applicability of a standard’s safety and performance during a medical device’s regulatory review. Determining applicability often includes input provided from both technical and clinical experts within the FDA’s Center for Devices and Radiological Health (CDRH).

 

Standards Recognition Plan

 

A primary goal of the Standards Recognition Program is for FDA experts to collaborate as a team while evaluating existing standards. This helps S-CAP leaders make judgements to either formally or partially recognize a standard that can potentially become a widely accepted consensus standard. Further, this could play a role in FDA labeling as well. 

 

Conformity Declaration

 

Additionally, medical device manufacturers may also submit their own conformity declarations based on FDA-recognized consensus standards. For a premarket submission, using existing consensus standards already approved by the FDA can potentially help medtech manufacturers reduce the amount of supporting clinical data required for FDA marketing approval & fda approval process.

 

Criteria for Regulatory Submissions

 

The FDA’s Standards and Conformity Assessment Program also leverages pre-identified criteria designed to identify both vendors and manufacturers that voluntarily use FDA-recognized consensus principles. These standards, developed by FDA’s CDRH, can be a potential competitive advantage for FDA medical device manufacturers.

 

Clinical Testing

 

Companies that use approved S-CAP vendors during new product development can potentially have their clinical testing burden reduced. Currently, this program is still gaining traction across the life science industry. The FDA approved list number of FDA clinical trials approved vendors is slowly increasing.

 

Defining a Consensus Standard

 

The process of defining a consensus standard is not easy. They are often established (or accepted) by Standards Development Organizations (SDOs) that help distinguish what actual adherence means. Global adherence and acceptance are often based on the various attributes and reputation principles of the FDA consensus standards development organization, including:

 

  • Transparency
  • Openness to participation
  • Industry stakeholders
  • Balance of representation
  • Due process

 

Domestically, consensus standards also help promote awareness across the life science industry to the FDA’s opinion about regulatory quality.

 

Medical Device Lab Testing

 

The majority of medical devices must go through a series of laboratory testing before being submitted for FDA approval. Some devices are evaluated for biological and chemical safety, while others may be assessed for mechanical properties, functionality, and durability. Other more complex, high-risk devices and combination devices are often submitted for multiple types of lab testing during premarket approval submissions.

 

Regulatory Submission

 

This clinical submission data from lab testing is included in the regulatory submission package proposed for FDA marketing approval. Many times, a medical device’s testing strategy depends on the medical device consultant with which a company is working, and the regulatory pathway recommended based on a pre-existing predicate device.

 

Lab Testing Facilities

 

Additionally, the program benefit is also realized by FDA employees when regulatory submission data comes from a pre-approved, ASCA-accredited testing lab. This often lessens the burden of streamlining the conformity assessment elements of medical device review. For example, instead of sifting through hundreds of pages of testing data from a non-approved ASCA vendor, FDA employees can leverage specific checklists that streamline data based on internationally approved standards from trusted ASCA approved lab testing facilities.

 

Accelerating the Submission Process

 

By completing clinical lab testing with a vendor that has been certified based on the FDA Accreditation Scheme for Conformity Assessment (ASCA), medical device manufacturers can often reduce the review time needed for regulatory submission approval. This can be an asset to manufacturers when it comes to shortening commercialization plans and bringing devices to market faster.

 

Understanding the ASCA Pilot

 

This voluntary ASCA Pilot from FDA is an accreditation system that benefits from the role that global standards already play in using regulatory science designed for submitting new products for approval. As listed on FDA’s website, the ASCA Pilot goals are to:

 

  • Streamline conformity assessment in medical device submissions
  • Enhance the FDA’s confidence in test methods and results
  • Decrease the need for additional information related to conformance with a standard
  • Promote consistency, predictability, and efficiency in medical device review
  • Serve as a least burdensome approach to conformity assessment

 

Conclusion

 

The FDA is continuously searching for new and innovative ways to bring safe, effective medical devices to market. FDA consensus standards, S-CAP, and the Conformity Assessment Pilot are just three examples of the ways in which manufacturers can partner with the FDA to provide necessary data via clear, concise mediums using the agency’s pre-approved clinical vendors. More information about lab testing vendors that are currently approved can be found on the FDA’s website or by contacting us directly through the blue form below.

 

Rod Mell is executive head, Medical Device Consulting, at Regulatory Compliance Associates (RCA). RCA provides regulatory compliance consulting services for resolution of life science challenges. The company understands the complexities of running a life sciences business and possesses areas of expertise that include every facet of R&D, operations, regulatory affairs, quality, and manufacturing. More information is available at www.rcainc.com.

 

 

About the Publisher

 

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CAPA & Corrective Action

Susan Schniepp and Andrew Harrison discuss the requirements for a successful corrective action and preventive action (CAPA) system.

 

Q. I work for a contract manufacturing organization (CMO) and am responsible for hosting audits and preparing the responses to an FDA observation. I have received multiple comments on my CAPA system from many groups, many with different perspectives. What are the real requirements for a successful CAPA system?

 

A. You can take comfort in the fact that you are not alone in this predicament. We consider investigations to be the cornerstone of any CAPA system and based on the data in the FDA database. FDA 483 citations are commonly issued for inadequate, incomplete, and undocumented investigations.

 

For some reason or another, the industry tends to focus on the immediate correction to the non-conformance. Consequently, this failure to investigate often leads to a lack of executing the corrective and preventive actions in an effective and timely manner.

 

Corrective Action

 

capa corrective actionBasically, we need to view CAPAs as improvements we make to our processes and procedures to eliminate non-conformances in our products. These improvements are based on the results of the investigations into the non-conformance for root cause. Once the root cause is determined, then a corrective action is identified and implemented into the process.

 

The change is then monitored during a period of time to determine if the proper root cause was identified and if the corrective action was effective (i.e., effectiveness check). In some cases, the root cause analysis may reveal a potential for an objectionable situation to occur resulting in compromised product. The solutions chosen to avert predicted non conformance are preventive actions.

 

Corrective Action Plan

 

The key to any CAPA system is the initial investigation into the non-conformance to determine the root cause. However, not all investigations are the result of a non-conformance and not all investigations will result in a CAPA. It is important that the investigation be thorough and complete before the CAPA is initiated and implemented.

 

The investigation process should make use of root cause analysis tools designed to examine the impact of various process inputs and their effect on the non-conformance. These tools examine the impact of the equipment, process, people, materials, environment, and management on the identified non-conformance.

 

Corrective Controls

 

In some cases, depending on the nature of the non-conformance, some areas can be eliminated as having no impact. The rationale for elimination, however, should be documented. As the elimination process progresses, the investigation will naturally and logically hone in on the root cause(s) of the non-conformance. Once this is completed, the actual CAPA can begin.

 

If we look at the CAPA system as an expressway, the immediate correction and the investigation are the on ramps, the corrective and preventive actions are the lanes, and the effectiveness checks are the off ramps. The immediate correction and investigation into that occurrence should determine if the non-conformance is a one-time occurrence or if it has happened before.

 

Root Cause Analysis

 

If the non-conformance has happened before, the investigation needs to be conducted to determine the underlying root cause. Once the root cause has been determined, the corrective action and the preventive actions can be implemented and monitored. Additionally, if the non-conformance does not recur in a specified time frame, the CAPA can be closed.

 

Background Investigation

 

The bottom line is there are many perspectives on what constitutes a good CAPA system, but the reality is the quality and thoroughness of the investigations ultimately drive the effectiveness of the CAPA. When conducting the investigation, it is important not to jump to conclusions on what caused the non-conformance.

 

The investigation should use root cause analysis tools and should address why potential areas are either eliminated as the root cause or are a potential cause of the non-conformance. Finally, if you can conduct a complete investigation, you will ultimately have a robust CAPA program.

 

Article Details

 

 

Pharmaceutical Technology
Vol. 39, No. 8
Page: 78

 

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SaMD FDA: AI & Emerging Technologies

Lisa Michels, General Counsel and regulatory affairs expert at Regulatory Compliance Associates® Inc., discusses regulatory strategies for software as a medical device (SaMD), artificial intelligence and other emerging technologies. She presents insights on working with regulatory bodies on novel devices such as artificial intelligence, machine learning and algorithms.

 

Artificial Intelligence

 

When powerful new technologies emerge, unbridled excitement often reigns. The possibilities are endless and markets are undoubtedly huge. Artificial intelligence and machine learning in medicine are at an early stage and the potential to improve medical care is solidifying. Many opportunities are being pursued including enhancing and supporting the decision-making process of physicians, individualizing patient care with precision medicine and using near real-time information to improve care.

 

AI in Healthcare

 

Early ideas such as wearables that monitor activity levels or heart rate have been on the market for some time and have mixed results as tools for patient health management. Technology platforms such as Watson from IBM have shown amazing capabilities. AI- related applications have progressed to a point where formal medical device development is occurring, but challenges remain.

 

Innovators are often fearless and can be blind to the real risks and business difficulties to commercialize emerging technology. On the other hand, the mainstream medical device community can perceive that innovation exposes threat of the long-timelines, high-costs and painful failures. The reality is probably in between both extremes and risk can be mitigated with a deliberate approach to regulatory strategy.

 

Regulatory Challenges

 

Regulatory requirements require transparency and regulators need to understand how and why a result came about. Many AI applications are a black box with little transparency and daunting complexities. AI applications can produce valid conclusions that are counter intuitive to those which individuals or even teams of experts derive. Traditionally to gain marketing clearance for a medical device, substantial equivalence to a predicate device needs to be demonstrated.

 

Artificial Intelligence in Healthcare

 

Regulators review and clear a device as a system that will not change without considerable deliberation; in fact, manufacturers go to great lengths to ensure that a device manufactured years after initial clearances demonstrates the same performance as the original device. However, one of the more powerful aspects of some AI applications is that the accuracy of output information can continually improve with continued use. This will produce a perpetually dynamic system by design. There are solutions to this dynamic situation.

 

Making applications as seamless as possible is where the challenges and opportunities are. Independent demonstration of the safety and effectiveness of the dynamic system through the Pre-Market Approval (PMA) process could be necessitated, albeit this regulatory path is much more costly, complex and difficult.

 

SaMD FDA

 

The FDA and industry has since finalized a new medical device user fee agreement that lays out the application process and expectations regarding medical devices being submitted for regulatory approval. The agreement calls for:

 

  • A new digital health unit overseeing Software as a Medical Device (SaMD) and software inside of medical devices (SiMD)
  • Opportunities to support 510(k), premarket approval and clearance pathways tailored to SaMD, SiMD, and take into account real world evidence
  • Participation in international harmonization efforts for digital health initiatives

 

Regulatory

 

1. Strategy begins with build your case, if regulators cannot or do not yet understand a technology, they will struggle to establish ways to assess the safety and effectiveness of your product.

 

  • Find clinical and regulatory information throughout the world that is supportive of what you are trying to achieve. If negative information is uncovered, do not ignore it; instead, address it.
  • Do not plan on submitting a “black box.” Spend the time to develop ways to communicate how and why a particular result comes about.
  • Seek related credible sources, publications, guidance documents and experts, reference them, and utilize them.

 

2. Plan on early and frequent meetings with regulatory authorities. Gaining regulatory clearances for emerging technologies benefits from building solid working relationships with regulatory bodies. These relationships are built over a series of meetings that begin early in the development process, aiding both parties as they learn together.

 

Regulatory Communication

 

These early collaboration meetings provide a venue for industry to explore new ideas through regulatory communication. Based on working with many novel products, we recommend the following considerations, particularly in working with the FDA.

 

  • Start with a solid pre-submission package. Make certain to follow established guidelines for pre-submissions, setting the tone that your organization has done its homework. Additionally, a complete pre-submission package enables regulators to prepare for the meeting and identify the appropriate experts needed.
  • Be ready for questions surrounding mechanism of action. In traditional medical devices, a key component of the submission surrounds the mechanism of action, or how the device is perceived to work. Be prepared to explain what your novel technology does and how it does it.
  • Prepare for the meeting. Before the meeting or teleconference, identify your question areas and structure your questions to get the specific information needed without using open-ended formats. Avoid introducing new information that the FDA is not prepared to discuss.
  • Set an open tone during the meeting. Be transparent about the information you have and the areas that are lacking. In early development cycles, gaps exist and it is important to be candid so you get accurate early feedback. Set aside any fears that your organization is setting precedent by not having complete information and instead, work to close those gaps as you progress through the product development process.
  • Set specific but realistic expectations for meetings. Your device is novel and that means regulators have not seen anything like it before. Expect regulators will have questions that will be challenging to answer. Remember, agencies can only provide feedback on what you have presented–what your device is currently– and not what you hope it will be in the future.
  • At all times, be professional and seek to understand their questions. Early collaboration around emerging technologies is a two-way street. When you provide information the FDA needs, they will provide direction to guide your product development. And remember, the agency is a resource. Be open to the answers you receive, so your processes can evolve and improve.

 

Regulatory Assets

 

There are cultural differences that exist between the Silicon Valley visionaries that are pushing novel technologies forward versus the deliberately cautious, stepwise approach taken by traditional medical device development teams. In advance of nearly any new, disruptive technology being adopted by broader medical establishments and nearly always in advance of solid profitability.

 

These teams of brilliant visionaries must still possess the regulatory assets needed to receive FDA approval. Data science has been embraced by many regulatory agencies and included in traditional medical device development organizations.

 

Application Developer

 

  • Build effective multidisciplinary teams by addressing cultural divides. When building regulated medical products based on AI, organizations will benefit from vertical structures. Software engineers must connect with key leaders from the company early in the development cycle.
  • Building SaMD medical device products requires deep subject matter expertise. Combining subject matter with technical expertise and embracing the multidisciplinary approach drives innovation, making it possible to accurately model the vision, answer the key questions and realistically hold leaders accountable for results. Team evolution needs to be intentional and designed.
  • If you are unable to set the joint domain early, one side dominates, and it becomes a challenge to bring in world-class experts from the other side. Top people recognize such unbalance and the byproduct that they will not achieve the parity in authority and respect.

 

Regulatory Compliance Software

 

Creating solid regulatory affairs teams with prior experience in addressing uncertainty surrounding quality systems and regulatory approval, specifically:

 

  • Members who understand quality management system compliance for ISO 13485 & 21 CFR 820.  
  • Members with a focused subject matter expertise in the AI/machine learning space and the mindset/ability required to work in a highly complex multidisciplinary environment.
  • Regulatory expertise introducing and gaining FDA clearance or approval for new technologies and with the intention and ability to communicate with the developers.
  • Direct expertise developing software for medical devices and developing and managing quality systems for software development.
  • Where clinical trial work is required, the CRO and strategic regulatory experts need to work closely together to generate the type of clinical data that supports the safety and effectiveness of the underlying product. Also the regulatory team needs to develop and conduct the studies in ways that bring transparency and simplify the “black box” aspects of the product.

 

Executive Summary

 

  • Embrace and enforce the multidisciplinary approach.
  • Break down the problem and bring subject matter experts to the table to solve each.
  • Beware of thinking you can do all. Inventors and software developers are uniquely brilliant but not necessarily the best at navigating regulatory challenges.
  • Don’t assume the person with the most RA experience should lead the FDA strategy. The RA and especially QA mindset can limit creativity and curiosity that propels novel technologies forward. QA is a support mechanism to the RA strategy.
  • Leverage working with RA SMEs experienced in emerging technologies and with prior nontraditional submissions.

 

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MDR Regulatory Compliance Update

The MDR Delay’s Impact on Regulatory and Testing—An Orthopedic Innovators Q&A

 

While the recent MDR delay gives companies some breathing room, it should not stall their effort in ensuring their products remain compliant for the EU.

 

regulatory compliance

 

By Sean Fenske, Editor-in-Chief at Orthopedic Design & Technology

 

Companies were beginning to get nervous in terms of keeping their products on the market in the EU. With the impending deadline for transition of MDD to MDR for legacy products already in hospitals and doctor’s offices, there would have been a significant shortage of medical devices available, potentially impacting quality of care. As a result, the EU Parliament voted to extend the deadline.
 
To find out the details of the new deadlines for transition and its impact on testing for medical device manufacturers, Jordan Elder, director of regulatory affairs at Regulatory Compliance Associates, and Thor Rollins B.S. RM(NRCM), VP, global market segment leader—Medical Device at Nelson Labs LLC, took time to address a number of questions around this important issue. They provided a comprehensive overview of what considerations medtech firms should keep in mind when looking at the new deadlines and their products they’d like to keep on the EU market.

 

Sean Fenske: The EU MDR went into effect in May 2021 so can you please explain what was postponed with regard to the latest action involving the MDR?
 
Thor Rollins: One of the latest actions involving the EU MDR that was postponed was the application of the Unique Device Identification (UDI) system for certain low-risk medical devices. The EU has delayed the UDI system’s full implementation for low-risk devices until 2027. Also due to the limited capacity of Notified Bodies, the general need for registration was also pushed back.
 
Jordan Elder: To expand on that second portion, this update does not change any of the current safety and performance requirements under the MDR, nor does it change any of the newly introduced regulations. This extension only amends the transitional provisions to give more time for manufacturers to transition from the previously applicable rules to the new requirements of the Regulation.

This extended transition period applies only to “legacy devices” or those covered by a certificate or declaration of conformity issued under the MDD before May 26, 2021. For medical devices covered by a certificate or a declaration of conformity issued before May 26, 2021, the transition period to the new rules is extended from May 26, 2024 to December 31, 2027 for higher risk devices (Class IIb and Class III), December 31, 2028 for medium and lower risk devices (Class I and Class IIa), and May 26, 2026 for Class III implantable custom-made devices.
 
However, the extension of validity for these devices only applies if one of the following conditions is met:
 

  1. The manufacturer has signed a contract with a Notified Body for the conformity assessment of the device in question at the moment of expiry.
  2. A national competent authority has granted a derogation in accordance with Article 59 of the MDR.
  3. A national competent authority has required the manufacturer to carry out the conformity assessment procedure within a specific time period in accordance with Article 97 of the MDR.

 
The “sell-off” date—the end date after which devices that have already been placed on the market and remain available for purchase—has been withdrawn. Under the original requirements, any previously approved devices that had yet to be recertified but were still available for purchase would have been required to be completely removed from the market by May 26, 2025.

 

Fenske: What’s the situation in the EU that brought about the reason for this delay?
 
Rollins: There were many factors that went into the reason for the delay, two of the biggest reasons was the COVID-19 pandemic, which has put significant strain on medical device manufacturers, notified bodies, and regulatory authorities, and also the number of notified bodies and their resources. These two factors made it evident that keeping the original date would risk having approved medical devices for the market.
 
Elder: Regarding the number of notified bodies, currently, 36 have been designated under Regulation (EU) 2017/745. As of October 2022, an additional 26 notified body applications were being processed, with three of them at an advanced stage in the application process. At the time, notified bodies reported they had received a total of 8,120 applications from manufacturers for MDR certification.

It was also reported only 1,990 MDR certificates had been issued to manufacturers. According to an estimation presented by the notified bodies, the number of MDR certificates issued to manufacturers by the original deadline (May 2024) would likely only reach around 7,000 with the current issuance rate. In 2022, due to the reduced number of notified bodies and a significantly slower rate of MDR certificate issuance than initially expected, many regulators and government officials began to voice concerns that the current compliance deadline would create a shortage of legally marketed medical devices, putting patient safety at risk.
 
The MDR certificate bottleneck was further exacerbated by COVID-19, as Thor mentioned, and its impact on the global supply chain and clinical investigations. In order to prevent a medical device shortage and reduce the strain on the notified bodies and manufacturers, the European Parliament agreed to adopt the transition delay.

 

Fenske: What changes come with the MDR with regard to testing?
 
Rollins: The MDR introduces new requirements for testing medical devices, including new rules on clinical data requirements, post-market surveillance, and clinical investigations. The MDR also requires testing to the most current ISO standard; this includes tests like extractable and leachable testing and toxicological risk assessments. These tests were not required when most of these devices were originally approved and, therefore, have gaps when looking to renew their approval under MDR.
 
Elder: Exactly. The MDR requires manufacturers to submit significantly more documentation covering the total product lifecycle than previously under the MDD. A critical change with MDR is the clinical evidence necessary to demonstrate the safety and efficacy of the device. The rules on equivalence have been revised, making it more difficult for manufacturers to use this route in their clinical evaluation.

Under the new regulation, device product classification is expanded with new and revised terms and classification rules. Manufacturers must be aware of how their product is now regulated to fully understand the level of clinical information required for their device and whether clinical testing is required.
 
In addition to the updated clinical requirements, biological evaluations are under more scrutiny by the notified bodies under the MDR. Manufacturers should be careful to ensure all stages of preclinical safety testing, including chemical characterization and evaluation, biocompatibility, and a toxicological risk evaluation, have been completed, as Thor mentioned.
 
In order to facilitate some of the new testing requirements, the MDR officially recognizes harmonized standards as a method for manufacturers to demonstrate conformity to the General Safety and Performance Requirements (GSPR). Demonstrating compliance with applicable harmonized standards allows manufacturers and notified bodies to streamline the conformity assessment process.

 

Fenske: Might this delay cause some companies to reassess their regulatory strategy in either keeping a medical device on the EU market or getting a new device to replace it certified?
 
Rollins: Yes, it certainly could. Ultimately, the delay provides more time for companies to prepare for compliance, but it also means they may have to continue selling their devices under the older Medical Device Directive (MDD) until the new regulations are fully implemented.
 
Elder: In addition, companies that have struggled to make the transition might want to reassess their strategy if they had considered discontinuing their MDR certification due to the rapidly approaching deadline. However, since the expectation is companies have already demonstrated their intent with their notified body to transition to MDR, most companies would not need to reassess their regulatory strategy beyond accounting for updated timelines.

 

Fenske: Given the delay for the recertification of MDD devices under the MDR, what timeline should device manufacturers be working under to keep a product on the market?
 
Rollins: Device manufacturers should work under the timeline of the EU MDR’s transitional provisions, which was extended as Jordan explained earlier. High-risk devices are subject to the shorter transition period ending in 2027, while low- and medium-risk devices have until the end of 2028 to complete a conformity assessment.
 
Elder: The MDR delay and subsequent MDD certificate validity extension require that manufacturers have already taken steps with their notified body to transition to MDR. Although the delay provides manufacturers more time to transition to MDR, manufacturers transitioning from MDD to MDR should work with their notified body to ensure an appropriate submission/review timeline and a smooth transition.
 
Manufacturers should avoid delaying their MDR transition more than necessary to ensure the notified body has sufficient time to review and issue the MDR certificates. Currently, notified bodies are scheduling technical file reviews more than 24 months out. Under today’s notified body timelines and bandwidth, a company that chooses to delay its transition for 20 months would be pushing its MDR certificate issuance into 2027, assuming there are no major issues (technical file deficiencies) or unforeseen delays from the notified body.

 

Fenske: From the testing standpoint, what changes with the MDR are creating the greatest challenges and why? What should device makers be doing in preparation?
 
Elder: The greatest challenge manufacturers face from a testing standpoint is the increased clinical evidence data requirements. Manufacturers should review the updated classification rules to determine whether their product’s device classification has changed under the MDR. A clinical evaluation plan (CEP) must be established. Manufacturers should review the new requirements for claiming equivalence to understand if their device may continue to utilize this pathway as a part of the clinical evaluation (where applicable). Manufacturers must demonstrate their device is “state of the art” as part of their clinical testing/evidence. Manufacturers should be aware that the need to include post-market clinical follow-up (PMCF) data as a part of the technical documentation conformity assessment will depend on the device’s risk classification and available clinical data.
 
Rollins: In addition to the clinical data and evidence challenges, I’d also point to the new rules on post-market surveillance and vigilance, and the stricter requirements for clinical investigations. Device makers should prepare by conducting comprehensive risk assessments and by conducting more extensive clinical studies and collecting more data on their devices’ safety and performance.
 
Elder: One last item to remember is a periodic safety update report (PSUR) is required for Class IIa, IIb, and III devices.
 
Rollins: Keep in mind, the changes are putting more emphasis on the chemical characterization requirements for high-risk devices and, because the industry is limited in capacity of these tests, manufacturers should not wait to start evaluating the biocompatibility requirements under MDR.
 
Elder: Manufacturers should not assume their clinical evaluation under the MDD will provide sufficient clinical evidence under the MDR. Manufacturers should review their existing clinical data and conduct a gap assessment to determine whether the device “conforms with relevant general safety and performance requirements under the normal conditions of the intended use of the device, and the evaluation of the undesirable side-effects and of the acceptability of the benefit-risk-ratio is based on clinical data providing sufficient clinical evidence,” as is stated in Article 61 of the MDR.

 

Fenske: Do you have any additional comments you’d like to share based on any of the topics we discussed or something you’d like to tell orthopedic device manufacturers?
 
Elder: Don’t delay your MDR transition due to the deadline extension. Notified bodies are already at capacity and are scheduling more than 24 months out for MDR Technical File reviews. Use this extra time to ensure your company can seamlessly transition from the MDD to MDR.
 
Rollins: Well said. Medical device manufacturers should prioritize compliance with the EU MDR and work closely with notified bodies and regulatory authorities to ensure their devices meet the new regulation requirements. They should also stay informed about any new developments or changes to the regulations and be prepared to adapt their strategies accordingly.

 

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