Regulatory: Prepare to meet thy regulator

Prepare to meet thy regulator

MANUFACTURERS STAND TO GAIN TIME AND COST BENEFITS IF THEY CAN FACILITATE A SUCCESSFUL PRE-SUBMISSION MEETING WITH THE FDA PRIOR TO MAKING THEIR FINAL MEDICAL DEVICE APPLICATION SUBMISSION. SANDI SCHAIBLE, SENIOR DIRECTOR OF ANALYTICAL CHEMISTRY AND REGULATORY TOXICOLOGY, WUXI APPTEC, AND MICHELLE LOTT, FOUNDER AND PRINCIPAL OF LEAN RAQA, ADVISE HOW TO SQUEEZE THE MOST OUT OF THESE ONE-TIME-ONLY MEETINGS.

The more a manufacturer can collaborate with regulators, the better the manufacturer can identify submission expectations and potential challenges. An effective way to do so is through a successful pre-submission meeting with the US Food and Drug Administration (FDA). These meetings allow manufacturers to work with the FDA to review their medical device testing plans and address concerns before final submission.

Facilitating a pre-submission meeting with a regulatory reviewer is a critical resource for a manufacturer trying to get a device cleared with the FDA. Currently, there is no similar pre-submission pathway available in the European Union (EU) as notified bodies (NBs) are not available for consultive purposes. Competent Authorities are inconsistently interpreting and applying the EU Medical Device Regulation (MDR), creating a wide difference in what each NB will accept.

An effective pre-submission meeting can reduce time and money spent preparing the submission and increases the chance of gaining approval. There are three forms of feedback manufacturers can request from the FDA: written responses only; a 60-minute teleconference; or an in-person meeting. In light of the pandemic, meetings are held in a digital format via video or teleconferencing. No matter what they choose, manufacturers must come prepared to make the most of their time. Understanding how to best leverage a pre-submission meeting can set companies and their device up for successful regulatory submission.

GETTING STARTED

Manufacturers must have a detailed understanding of their device before initiating a pre-submission meeting. This includes knowing the intended use, features, functions, testing strategy, along with how it compares to a predicate.

In addition, it is critical to develop clarifying questions on FDA’s initial response to send to the FDA before the meeting. These questions should be sorted by priority and consider regulatory updates and other highrisk topics that need addressing before final submission. Once the FDA responds to the questions, this feedback will guide the specific talking points for the meeting.

WHAT TO EXPECT

The reviewers will only come prepared to discuss their responses to the questions submitted by the manufacturer ahead of the meeting. Anything outside the preliminary topics should not be addressed during the pre-submission meeting.

The pre-submission process allows manufacturers to work with the FDA directly to gain their insight. Based on the responses provided before the meeting, manufacturers can follow up and pinpoint specific areas of their plan where they would like greater detail about the reviewers’ feedback. Prioritize potential talking points to improve the testing plan and minimize additional information requests.

Keep in mind that this meeting is not the time to negotiate or barter. Even if the feedback is unexpected or not ideal, essential factors such as patient safety and submission approval may be at stake if manufacturers don’t take

the feedback seriously. Manufacturers should work with the team offline to provide potential follow-up questions for the final call.

MAKING THE MOST OF THE PRE-SUBMISSION MEETING

Prior to attending the pre-submission meeting, manufacturers should understand that the FDA will not be leading the conversation. In this meeting, they can discuss their clarifying questions in detail and provide rationale. Reviewers will voice if they agree, disagree or have further questions.

With only an hour, manufacturers should not repeat the same content addressed in the pre-submission document that the FDA has already reviewed in detail. Instead, come with a high-level outline of thoughts on the responses, prioritized by most significant concerns. For example, if a manufacturer’s device uses a novel material or manufacturing method, the biocompatibility test strategy may be particularly complex. The manufacturer may want to focus on more complex topics rather than a line-by-line review of the FDA’s feedback. In short, prioritize topics and prepare direct follow-up questions.

And finally, practice. With an established team, prepare what each attendee is going to address and when. A point person should lead the call and direct questions to the appropriate team members. As for any important presentation, it’s essential to rehearse and ensure roles are understood. Remember, there’s only one opportunity for this meeting.

Those who attend are crucial to the meeting’s success.

Considering team expertise can help determine who should attend the meeting. Everyone in attendance should have defined areas of expertise relevant to questions already posed to the FDA. Attendees should be designated to speak one at a time to those topics and should otherwise remain silent.

AFTER A PRE-SUBMISSION MEETING

If a manufacturer involves a laboratory testing partner or consultant in their submission process, the partner(s) may attend the pre-submission meeting. If they do attend, they cannot be the sole expert guiding the discussion. The manufacturer will need to drive the conversation. The FDA will bring their in-house expert counsel. Manufacturers should consider inviting testing partners and consultants to provide any additional support to the team and interpret any feedback as needed.

If the testing partner does not attend, it is critical to relay the exact feedback from the meeting to them. Do not interpret or paraphrase when communicating the results received from the FDA. Any misinformation can affect testing decisions and potentially put the entire submission at risk. Since preparation may change after the pre-submission meeting, manufacturers need to re-evaluate their testing and submission timelines to be realistic.

REAP THE BENEFITS

Facilitating a pre-submission meeting before moving forward with medical device testing will provide the solid foundation manufacturers need for a successful submission. The more input from regulators a manufacturer can receive early on, the smoother their submission experience will be.

Testing and submitting a medical device for regulatory approval is not the time for trial and error. When approaching the pre-submission meeting, manufacturers must focus on detail, be open to feedback and allocate enough time to incorporate any changes to their plan. Doing this work upfront not only saves money and time later on, is also sets manufacturers up to get their submission right the first time.

The pre-submission process allows manufacturers to work with the FDA directly to gain their insight

THE TINY REVOLUTION

AS THE CURRENT GLOBAL IMMUNIZATION AGAINST COVID-19 ROLLOUT HAS SHOWN ADMINISTERING CONVENTIONAL NEEDLE VACCINES AT SCALE HAS ITS LIMITATIONS. JOHN KAWOLA, CEO — GLOBAL, BOSTON MICRO FABRICATION, EXPLAINS HOW MICRO 3D PRINTING MICRONEEDLES COULD RADICALLY CHANGE HOW THE WORLD RESPONDS TO VACCINE DISTRIBUTION.

More than 1.5 billion doses of the COVID-19 vaccine have been administered around the world, according to the latest figures from Bloomberg.1 Those numbers are certainly impressive considering the short timeline from vaccine development to deployment, but the last several months have exposed some major logistical challenges of conventional needle vaccines — most notably, their difficulty in administering at scale.

Imagine how much easier distribution could be if a vaccine could be mailed directly to your door and administered via a tiny, painless patch that sticks to your arm. What if vaccines in this form could be sent out to impoverished or remote locations that don’t have access to healthcare? Advanced immunization technologies, namely microneedles, are bringing these ideas closer to reality.

The concept of microneedles for vaccinations or other drug delivery has been around for a while, but COVID accelerated demand and research to make it happen. But once the delivery method for microneedles is finalized, the industry faces another hurdle:

figuring out how to manufacture these tiny, functional devices at scale, and as cost-effectively as traditional inoculation methods. The answer lies in micro-precision 3D printing.

BRINGING US CLOSER TO THE FUTURE

A team of collaborators, led by Carnegie Mellon University with participation from Boston Micro Fabrication (BMF), recently revealed that they are developing a novel approach to vaccinations with a low dose, inexpensive and hybrid microneedle array technology.² The microneedle arrays consist of hundreds of tiny needles on a small patch that, when applied to the skin, can quickly dissolve and deliver the vaccination.

This delivery method requires a small dosage amount (as little as 1/100th of the dose of a traditional vaccine) without the same level of cold chain storage requirements, meaning it has the potential to simplify the transport and storage of vaccines, reduce vaccine shortages, and more easily distribute vaccines to people around the world. These are all concerns that have been exposed in recent months with traditional methods of vaccine deployment.

The research, so far, has been promising — it found that the smaller the microneedles, the easier it is to puncture the skin and deliver the vaccine effectively. This finding introduces a whole new set of challenges for putting the microneedle arrays into use, and it’s where micro 3D printing comes into play.

WHEN SMALLER IS BETTER, BIGGER CHALLENGES ARISE

As with any type of manufacturing and product engineering, the smaller the part, the harder it is to design, the more expensive it is to make, and the more complicated it is to put into production at scale. This notion is especially true in traditional manufacturing methods, such as micro injection molding and computer numerical control (CNC) machining, where the smaller and more detailed the part, the higher the cost and the longer the wait to get it (and, if this pandemic taught us anything about manufacturing, it’s that time is of the essence).

Additive manufacturing has long been considered a more cost-effective and time-efficient approach, but even 3D printing has traditionally lost its appeal as parts become smaller. Challenges with precision and accuracy have caused innovation roadblocks for years; quite simply, there has been a lack of viable additive manufacturing technologies available that can print with the right resolution and at scale.

The high costs associated with traditional manufacturing methods, combined with the lack of capable 3D printing alternatives, would have crushed the promise of microneedle vaccinations before the research was even complete if it weren’t for recent developments in micro 3D printing. Newer technologies, such as stereolithography (SLA), digital light processing (DLP), and a combination of the two called projection micro stereolithography (PµSL), can finally produce ultra high precision, micro sized parts that are suitable both for rapid prototyping and production.

MICRO 3D PRINTING FOR MICRONEEDLES

Carnegie Mellon invited BMF to participate in the research because of the company’s PµSL technology, which can print small parts down to a 2 µm resolution. The technology makes it possible to print at the right resolution, size, and accuracy with precision and efficiency … but how exactly the micro 3D printing will be used to produce the final microneedle vaccine is up for debate.

In a perfect world, PµSL would be used to print the microneedles for end use using a dissolvable, biocompatible material. This would be the most efficient way of going about bringing the arrays to production and distribution, and would cut out other processes such as molding, but this method is reliant on developing the proper dissolvable material. With time of the essence, there are a number of alternatives to consider as well.

One of these options would be using PµSL to print mold patterns that have enough strength to be used to create molds, which would then be used for production. This would allow for many microneedles to be printed off the same 3D printed mold, and would still be more cost effective, accurate and precise compared with traditional manufacturing methods.

Although microneedle vaccines are still in the early stages of research and development, there’s no doubt that micro 3D printing will play an integral role in making their mass manufacturing and distribution a reality. These tiny devices have the potential to completely revolutionize the way the world responds to health crises and immunizes millions of people, rapidly, at scale, and although COVID-19 was hopefully a once in a lifetime event, the innovative vaccine manufacturing and delivery techniques being developed today will ensure a smoother fight against any future threats.

References 1. https://www.bloomberg.com/ graphics/covid-vaccine-tracker-globaldistribution/ 2. https://www.meche.engineering. cmu.edu/news/2021/03/scalablemanufacturing-for-painless-vaccines. html