How much a 510k costs is the most common question I receive from customers, and there are three parts to the cost of a 510k.
There are three parts to the 510k cost of submission:
Testing
Submission Preparation
FDA User Fees
The highest cost is testing
The testing cost is the most significant cost, but I think the average is around $100K for our clients. For devices that only consist of a software (i.e., software as a medical device or SaMD), the testing costs are less, but the cost of documenting your software validation and cybersecurity will be more extensive than the cost of preparing your 510k and the FDA user fee. The more you can do in-house, the lower the testing costs will be. Biocompatibility testing for a non-invasive device might be only $13,000, but a long-term implant can cost as much as $100,000 for implantation studies. Sterilization validation testing depends upon the method of sterilization and whether you are doing a single-lot method or a full validation. Typical costs for EO sterilization validation are around $15,000, and then you should add several thousand more for the shelf-life testing.
For devices that are powered and/or have software, you will need to perform software validation in accordance with IEC 62304 ed 1.1 (2015). There are also five FDA guidance documents that apply:
You can do all of the software validation in-house, but some firms outsource the software validation. In the long term, you need to learn this, and it pays to hire an expert in IEC 62304 to help your team learn how to document software validation if you have not done this before. Typically, software validation documentation will be between 300 and 1,000 pages long.
Electrical safety and EMC testing are often the most expensive part of the testing process for our customers. EMC testing should always be done first to ensure you can pass the immunity and emissions testing. If you must modify the device to pass the EMC testing, you must repeat any electrical safety testing. The total cost of this testing is typically $50-60K.
Performance testing is the last part of the testing process. Performance testing should be performed on sterile and aged products if your product requires sterility and claims a shelf-life. Most of the testing is benchtop testing only to demonstrate performance. This includes simulated use testing (e.g., summative usability testing), cadaver testing, and computer modeling. Benchtop performance testing typically takes tens of thousands of dollars to complete, but you might be able to do the testing in-house. If animal testing is required, this typically costs around $100K. Finally, if a human clinical study is required (i.e., ~10% of 510k submissions), you should expect to spend between $250K and $2.5 million. Some simple clinical studies (e.g., IR thermometers) cost less than $100K, but these resemble benchtop performance testing in many ways.
The second highest cost is the cost of submission preparation
Medical Device Academy has two different options for preparation consulting fees. Your first option is hourly consulting fees. The second option is a flat fee. As of July 2023, we are charging $3,500 for pre-submission preparation and $17,500 for 510k submission preparation.
The first option is to avoid the FDA altogether and submit to a third-party reviewer. We only recommend one third-party reviewer (i.e., Regulatory Technology Services), because the other companies do not have sufficient experience to have predictable review times and positive outcomes. The typical RTS third-party review cost is 6% more than the FDA Standard fee.
The second option is to submit directly to the FDA. The standard user fee for FDA review of a 510k is $21,760 for FY 2024.
The third option is to apply for small business status. For companies that have annual revenues of less than $100 million USD, the FDA will grant you small business status. For companies with small business qualifications, the FDA user fee is reduced to $5,440.
Reduce 510k cost by applying for small business status
Any medical device company with revenues of less than $100 million annually can apply, but you must apply each year. There is no application fee, but you must complete FDA Form 3602 if you are a US firm. The form must be completed for each subsidiary too. FDA Form 3602A must be completed for foreign firms, and the national tax authority must verify the accuracy of your income statement on the form to submit it to the FDA. If your national tax authority refuses to sign the form, you can justify it, but I don’t know anyone who has done this yet. The qualification review by the FDA requires 60 days. Therefore, you should apply every year in August for the next fiscal year (October 1, 2023 – September 30, 2024, is FY 2024). The form will request that you include your Organization ID #. A Dun & Bradstreet Number (DUNS #) is also required if your firm is located outside the USA. Finally, you need to attach a copy of your tax return. Therefore, you must file your tax return–even if your firm had a loss or had no revenues. You can also use R&D tax credits in the USA or Canada if you are a start-up device company developing a new device.
About the Author
Rob Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certifications. From 2009 to 2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone at 802.258.1881 or by email. You can also follow him on Google+, LinkedIn,YouTube, or Twitter.
Maybe you need an FDA inspection plan. Does everyone in your company know what they need to do when FDA inspectors arrive at your facility?
Be proactive and don’t just let FDA inspections happen. You need to have an FDA inspection plan, and that plan needs to cover the roles and responsbilities for everyone. Below we have a list of 15 items that are in our FDA inspection work instruction (WI-009). If you already have a plan, try using the following checklist to assess your readiness for the next next inspection:
What will you ask and do when your FDA inspector calls the Friday before the inspection?
Who should be contacted by the FDA inspector if you are on vacation?
How will you communicate to the rest of your company that an FDA inspection is planned for Monday morning?
Who will greet the FDA inspector upon arrival, and what should they do?
Which conference room will the FDA inspector spend most of their time in?
Who will be in the conference room with you and the FDA inspector?
How will you track document and records requests, and how will you communicate that information to others?
How will you retrieve documents and records requested by the FDA inspector?
Who will conduct a tour of the facility with the FDA inspector and how will the tour be managed?
When quality issues are identified, how will you respond?
What will you do for lunches during the inspection?
Who will attend the closing meeting with the FDA inspector?
Should you “promise to correct” 483 inspection observations identified by the FDA?
How and when will you repsond to the inspector with corrective action plans?
If your company is outside of the USA, what should you do differently to prepare?
What will you ask and do when your FDA inspector calls the Friday before the inspection?
Most people begin their FDA inspection plan with the arrival of the inspector. However, you should consider including earlier events in your plan. Such as closure of previous 483 inspection observations, scheduling of mock-FDA inspections in your annual audit schedule, and details of how to interact with the inspector when they contact you just before an inspection. Most inspections will be conducted by a single inspector, but occasionally inspectors will be training another inspector. In this situation you can count on them following the QSIT manual more carefully, and you are more likely to receive an FDA 483 inspection observation. In the worst-case scenario, the lead inspector will split up from the trainee, and they will “tag-team” your company. This is not proper FDA procedure, but you should be prepared for that possibility. Therefore, make sure you ask the inspector if they are going to be alone or with another inspector when you speak with them on the phone. You should also get their name and phone number. You may even want to consider reviewing FDAZilla Store for details about your FDA inspector’s past inspection 483s and warning letters. Immediately after the call with the inspector, you should reserve a conference room(s) for the inspection and cancel your other meetings for the week. You should also verify that the person that contacted you is really from the FDA. You can do this by looking up their contact information on the Health and Human Services Directory. Your inspector should have a phone number and email you can verify on that directory.
Who should be contacted by the FDA inspector if you are on vacation?
You should always have a back-up designated for speaking with FDA inspectors, handling MDR reporting, and initiating recalls when you are on vacation. These are critical tasks that require timely actions. You can’t expect inspectors, MDRs, or recalls to wait you to get back in the office. It doesn’t matter what the reason is. Weddings, funerals, and ski trips should not be rescheduled. You need a back-up, and often that person is the CEO or President of your company. Make sure you have a strong systems in place (i.e. an FDA inspection plan, an MDR procedure, and a recall procedure). Whomever is your back-up needs to be trained and ready for action. This is also the purpose of conducting a mock-FDA inspection, including examples of MDRs in your medical device reporting procedure, and conducting mock recalls. This ensures you and your back-up are trained effectively.
How will you communicate to the rest of your company that an FDA inspection is planned for Monday morning?
Most companies have an emergeny call list as part of their business continuity planning, and after the past 18 months of living with a Covid-19 pandemic your firm should certainly have a business continuity plan. Your FDA inspection plan should leverage that process. Contact the same people and notify them of when the FDA inspector is coming. If you are unable to find a conference room available for the inspection (i.e. see below), then ask the manager(s) that reserved the designated room for FDA inspections to relocate to another conference room for the week. Make sure you tell them who the inspector will be, and you might even be able to provide a photo of the inspector (try seraching LinkedIn). Make sure that you remind everyone to smile, and to listen carefully to the question asked. Everyone should be trained to answer only the questions asked, and nobody should run and hide. There should also be no need to stop your operations just because an inspector is visiting. You might even include the name of the inspector on a “Welcome Board” if your company has one at the entryway or in public areas. The more an FDA inspection appears as “routine” the better your outcome will be.
Who will greet the FDA inspector upon arrival, and what should they do?
By the time an FDA inspector(s) actually arrives at your company, all of the managers in your company should already been notified of the inspection and a conference room should be reserved for the inspection. Therefore, when the person that is greeting people in the lobby comes to work on Monday morning, you (or their supervisor) need to communicate with them and make sure that they are prepared for arrival. There are four things that should be communicated:
the name of the inspector(s) that are arriving
the list of managers that should be notified when the inspector(s) arrives (possibly identical to the buisness continuity call list)
the conference room that is reserved for the inspection
If the person greeting the inspector(s) is also going to escort them to the conference room and help them get set-up, then they will need additional instructions. If that escorting inspectors to the conference room and helping them get set-up is delegated to a different person, then the following considerations should be included in that person’s instructions:
the location of bathrooms and emergency exit instructions in case of a fire
the information for wireless connectivity
recommendations for seating in the conference room based upon the expected participants (see below)
It is important that an escort for the inspectors is able to bring the inspector(s) to the conference room as quickly as possible. They should not be expected to wait more than a few minutes for an escort.
Does your FDA inspection plan identify a specific room for the inspector? Is there a back-up?
Some companies have a specific room that is designated for inspections and 3rd party certification audits. If your comapny can do that, it will be very helpful because it reduces the decision making that is required immediatley prior to the inspection. Having a specific room for the inspection also eliminates the need to tell everyone else in the company where the inspector will be. Instead the location of the inspection can be in the work instruction or written FDA inspection plan. You shouldn’t need a back-up plan if there is a specific room designated for an FDA inspection, but our firm has a client that will be hosting three notified body auditors simultaneouly for three days. In that situation, you might need more than one room.
Does your FDA inspection plan have assigned seating?
You might think that it really doesn’t matter where people sit in a conference room, but you will probably want consider the layout of charging cords and the flow of interviewees requested by the inspector. In your conference room, you will need room for at least the following people:
the inspector(s)
the management representative (i.e. you)
a scribe
an interviewee
If there is an inspector and a trainee, you will probably want to seat them together to facilitate them working together. You as the Management Representative also need to be in the room, and it may help for you to sit next to the scribe to facilitate communication between you and to make it easier for them to hand you documents after the scribe logs the documents into their notes. The scribe should probably sit closest to the door, because they will be receiving documents, logs, and records that are brought to the room. You will also need one more seat next to you, and probaby accross from the inspector(s), for interviewees. This person will rotate as different processes are reviewed. I also recommend having a location in the middle of the table for an “in box” where documents, logs, and records for the inspector are placed after being logged in. A second location in the middle of the table can be used for a “discard pile” as you finish using your copy of each document, log, and record. You may refer back to these copies later. The “discard pile” should be 100% copies rather than originals. Originals should never be brought into the room with the inspector.
Who is the scribe in your FDA inspection plan?
The perfect scribe would know the quality system well and they would have the typing skills of a professional stenographer. You might have someone that is an executive assistant in your company or a paralegal that could do this job, but you might also have a document control specialist that fits this requirement. Some companies will even hire a temp for the duration of the inspection that has this type of skill, but a temp is unlikely to know the jargon and quality system requirements well. I have taken on the role of scribe many times for my clients, because I type fast and know their quality system. I also don’t want to interferre with the inspection process. As scribe I can answer questions and offer suggestions when appropriate, but most of my time is spent taking notes and communicating by instant messenger with company members that are outside of the inspection room.
You should seriously consider using an application such as Slack as a tool for communication during the inspection. Then anyone in your company that needs to know the status of the inspection can be provided access to the Slack channel for the inspection. This can also act as your record of requests from the inspector. It’s even possible for people on the Slack channel to share pictures of documents to confirm that they have identified the document being requested. You could even invite someone to speak remotely with the inspector via Slack with Zoom integration. All the scribe needs to do is share the Zoom app with a larger display in the same conference room so the inspector can see it too.
Does your FDA inspection plan include provisions for document and record retrieval?
The most important part of document and record retrieval during an FDA inspection is to remember that inspectors should never receive the original document. Ideally, a copier would be located immediately outside of the conference room and three copies would be made of every document before it enters the inspection room. The originals can be stored next to the copier until someone has time to return them to the proper storage location. The three copies should all be stamped “uncontrolled documents” to differentiate them from the originals. When the three copies are brought into the room, they should be handed to the scribe. The scribe should log the time the copies were delivered in the Slack channel. Then the copies should be handed to you, the Management Representative. You should skim the document to make sure that the correct document was received. Then one copy would be given to the inspector and another copy would be made available to the interviewee. If only two copies are needed, the extra copy can be placed in the “discard pile.” Even if your system is 100% electronic, I recommend printing copies for the inspection. The paper copies are easier for inspectors to review, and it eliminates the ability for the inspector to hunt around your electronic document system. In this situation, the scribe may do all of the printing.
Does your FDA inspection plan indicate who will conduct a tour of the facility with the FDA inspector and how will the tour be managed?
I’m surprised by the number of companies that don’t seem to have a map of their facility. Medical device manufacturing facilities should have two kinds of facility maps. One should identify where pest control monitoring stations are located, and the second should indicate your evacuation route to exit the building. All guests should be shown the evacuation route map, probably within the first 30 minutes of arrival. The second map will be requested by the inspector eventually if you conduct manufacturing at your facility. Therefore, it would be helpful to use one or both of these facility maps as a starting point for creating a map of the route that inspectors should be taken on during a tour. I prefer to start with where raw materials enter the facility, and then I follow the process flow of material until we reach finished goods storage and shipping. If you can do this without back-tracking multiple times, then that will probalby be the preferred route. The purpose of planning the route out in advance is to help estimate how long the tour will take, and to make sure there is consistency. If someone starts the tour, and then another person takes over the tour, the new person should be aware of what the next location is and what areas have not been observed yet. There may also be safety reasons for avoiding certain areas during a tour and asking the inspector to observe those areas from a distance. Welding processes, for example, often fall into this safety category.
When quality issues (i.e. FDA 483 inspection observations) are identified, is this covered by your FDA inspection plan?
Third party certificaton body auditors will typically make you aware of nonconformities as they are identified, but FDA inspectors often will hold off on identifying 483 inspection observations until the end of the inspection in a closing meeting. However, you can typically identify several areas that may result in a 483 inspection observation during the inspection. You and the manager of that area may want to consider initiating a draft CAPA plan for each of these quality issues before the closing meeting. This would give you an opportunity to demonstrate making immediate corrections and you might be able to get feedback from the inspector on your root cause analysis and corrective action plan before the closing meeting. Sometimes this will result in an inspector identifying low-risk quality issues verbally instead of writing them out on FDA Form 483. I find the best way to make sure CAPA plans are initiated early is to have a debrief each day after the inspector leaves. All of the managers involved in the inspection should participate, and the debrief can be done virtually or in person. Virtually may be necessary, because often managers need to leave work before the inspector ends for the day. You should consider including this in your FDA inspection plan as well.
Does your FDA inspection plan include plans for daily lunches?
If your facility is located outside the USA, skip this paragraph and go to the section below about companies located outside the USA. If your company is locagted inside the USA, you can be certain that the FDA inspector will not eat lunch at your facility. They will leave for lunch on their own, and then they will return after lunch. Therefore, you may not have control of the timing of a lunch break but you will have time to take one. Most managers use the lunch break as a time to catch-up on emails. However, I think it makes more sense to change your email settings to “out of office.” You can indicate that you are hosting an audit and you will answer questions as a batch that evening or then next morning. You might use the lunch break to take a walk and relax, you might have short debrief meeting with other managers, and you might spend some time preparing documents, logs, and records that the inspector may have requested before they left. Most inspectors use this strategy of asking for a list of documents and records in advance. This is also a good strategy to learn as an internal auditor or supplier auditor. If you have a back-room team that is supporting you, don’t make them wait for a break. Have someone in your company take their lunch orders or arrange for a catered buffet lunch. This will keep your support team happy, and you should definitely remember to include lunch for the team and changing your email settings to “out of office” in your FDA inspection plan.
Does your FDA inspection plan state who will attend the closing meeting?
Most companies have every manager that was in the opening meeting attend the closing meeting. This is ok, but it is important for anyone that might need to initiate a CAPA to be present in the meeting so that they can ask the inspector for clarification if needed. Scheduling a closing meeting should be part of your FDA inpsection plan. However, the past 18 months of the Covid-19 pandemic has taught us that we can attend this type of meeting remotely via Zoom. Therefore, we recommend letting the managers go home early if they are no longer needed as auditees. Instead, ask them to call in for a Zoom meeting at the time the FDA inspector estimates for review of the 483 inspection observations with the company.
Should you “promise to correct” 483 inspection observations identified by the FDA?
During the closing meeting the FDA inspector will review 483 inspection observations with you and any of the other managers present at the closing meeting. The inspector will ask if you promise to correct the 483 inspection observations that were identified. You should confirm that you will, and the FDA inspector will add this to the Annotations in the Observations section of FDA Form 483 that you will recive at the closing meeting. By stating this, you are agreeing to create a corrective action plan for each of the 483 inspection observations. You could change you mind later, but the better approach is to perform a thorough investigation of the 483 inspection observation first. If you determine that corrective action is not required, you can explain this in your CAPA plan and provide data to support it. The only likely reason for not correcting an observation is that you determined the incorrect information was provided to the inspector. In that case, you may need to do some retraining or organize your records better as a corrective action to prevent recurrence in a future inspection. You might even make modifications to your work instruction for “Conducting an FDA Inspection” (i.e. FDA inspection plan).
How and when will you repsond to the inspector with corrective action plans?
Your FDA inspection plan should include details on how respond to FDA 483 inspection observations and when the response must be submitted by. The FDA inspector will give you instructions for submission of your corrective action plans by email to the applicable email address for your region of the country. This email address and contact information should be added to your work instruction as an update after the first inspection if you are not sure in advance. You should respond with a copy of your CAPAs with 15 business days. Regardless of what the inspector told you, there is always a possibility that the outcome of your inspection could be “Official Action Indicated.” This is because the inspector’s supervisor makes the final decision on whether a Warning Letter will be issued and regarding the approval of the final inspection report. You should also confirm what the 15-day deadline is, because your state’s holidays may be different from the US Federal holidays.
If your company is outside of the USA, what should you do differently to prepare?
The US FDA only has jurisdiction over companies that are located in the USA. Therefore, if your company is registered with the FDA, you can only be inspected if you agree to host the FDA inspector when they contact you. FDA inspectors will contact foreign firms 6-8 weeks in advance, and they will typically give you a couple of weeks to choose from. After you confirm the dates for the inspection, then they will make their travel plans. Therefore, you will know exactly when the FDA inspection is schedulea and you will have more than month to prepare. Therefore, you should do four things differently:
You should send the FDA inspector directions from the airport to your facility and provide recommendations for potential hotels to stay at. Ideally the hotels you recommend will provide transportation from the airport and managers that are speak passable English). The hotels should be appropriate for business travel–not royalty. If it is convenient, you may even offer to pick-up the inspector at the hotel each day to ensure they have no problems with local transportation.
You should offer to provide lunches for the inspector during the inspection. This should not be considered entertainment. The purpose is make sure the inspector has lunch (i.e. a light meal or snacks) and drinks (i.e. water and coffee) during the inspection so that they do not have to negotiate local traffic, struggle with ordering food in a language they don’t know, and to eliminate delays associate with having lunch off-site. Make sure you remember to ask about food allergies and dietary restrictions. You might even follow-up with a draft menu to obtain confirmation that your proposed menu is appropriate.
You should schedule a mock-FDA inspection immediately to verify that everyone is prepared and to identify any CAPAs that need to initiated before the FDA inspector finds the problems.
During the first day of the inspection, you may consider asking the inspector if they would like to go out for dinner one of the evenings with a couple of people from your company or if they would like any recommendations for restaurants to eat at. If you are not familiar with US customs and international travel, ask the hotel concierge for advice. When you are out to dinner, the conversation should remain professional and if you normally drink alcohol at dinner you may want to consider the “BOB” compaign in the Netherlands as a role model.
How are you going to train everyone in your company?
You need an easy way to train everyone in your company. Why not give them a video to watch? Next Monday, July 26, 2021 @ Noon EDT, we are hosting a webinar on how to prepare for an FDA inspection. It is a live webinar where you will be able to ask questions, and we are bundling the webinar with our new work instruction for “Conducting an FDA Inspection” (WI-009). If you register for the webinar, you will receive access to the live webinar, you will receive the native slide deck, and you will receive a copy of the work instruction. You can use the work instruction as an FDA inspection plan template for your company. The webinar will be recorded for anyone that is unable to attend the live session. You will be sent a link to download the recording to watch it as many times as you wish, and we recommend that you use the webinar as training for the rest of your company.
Did you know you can download competitor inspectional observations to learn which quality issues are likely to result in warning letters?
Not long ago the FDA published their Inspectional Observation Data Sets. They are Excel spreadsheets of the dreaded 483 inspection observations and warning letters that the FDA issues after performing inspection of manufacturers. There is a spreadsheet for each of the following topic areas, and we will take a look at the ‘Devices’ observations. A post-mortem data analysis or speculative data autopsy if you will… What can we learn when examining an FDA inspection observation?
Biologics
Drugs
Devices
Human Tissue for Transplantation
Radiological Health
Parts 1240 and 1250
Foods (includes Dietary Supplements)
Veterinary Medicine
Bioresearch Monitoring
Special Requirements
Total number of inspections and 483s
These are nonconformities written by the FDA to the Code of Federal Regulations, so there won’t be any statistics for ISO 13485:2016 or Regulation (EU) 2017/745. There will be lots of findings under the ‘QSR’ or 21 CFR 820. The good news, unlike an ISO Standard, is that the Code of Federal Regulations is publicly available online for free. It isn’t a pay-to-play game and we can share the full text of the requirement without violating any copyright licensing agreements.
The top 10 areas for inspection observations and warning letters are:
CAPA procedures
Complaint procedures
Medical Device Reporting
Purchasing Controls
Nonconforming Product
Process Validation
Quality Audits
Documentation of CAPA actions and results
Training
Device Master Record
Corrective and preventive action is the most common reason for warning letters
The winning quality system requirement that resulted in the most 483 inspection observations and warning letters was for Corrective and Preventive Actions under 21 CFR 820.100(a). This finding is listed when a manufacturer fails to establish a CAPA procedure or the procedure is inadequate. This finding was cited 165 times. In addition, CAPA activities or their results were not documented or were not documented adequately a total of 32 times under 21 CFR 820.100(b). This gives us a grand total of 197 observations for the CAPA process.
Corrective and preventive actions are either fixing an identified problem and making sure it doesn’t happen again, or stopping a potential problem from happening in the first place. It is both the reactive and proactive response for quality issues and product non-conformance. The text of the requirement is:
Ҥ820.100 Corrective and preventive action.
(a) Each manufacturer shall establish and maintain procedures for implementing corrective and preventive action. The procedures shall include requirements for:
(1) Analyzing processes, work operations, concessions, quality audit reports, quality records, service records, complaints, returned product, and other sources of quality data to identify existing and potential causes of nonconforming product, or other quality problems. Appropriate statistical methodology shall be employed where necessary to detect recurring quality problems;
(2) Investigating the cause of nonconformities relating to product, processes, and the quality system;
(3) Identifying the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems;
(4) Verifying or validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished device;
(5) Implementing and recording changes in methods and procedures needed to correct and prevent identified quality problems;
(6) Ensuring that information related to quality problems or nonconforming product is disseminated to those directly responsible for assuring the quality of such product or the prevention of such problems; and
(7) Submitting relevant information on identified quality problems, as well as corrective and preventive actions, for management review.
(b) All activities required under this section, and their results, shall be documented.“
We can see that under section (a) the requirement is that there is an established and maintained process control with a numerical list of required inputs and outputs of that process. The process control is easy, use a procedure. You have to establish a procedure and you have to maintain it. That is one part of the first 165 observations.
The second part is that the procedure needs to be ‘adequate’. That means that bullets (1)-(7) need to be addressed within that procedure. For example number (2) is “Investigating the cause of nonconformities relating to product, processes, and the quality system;”. This means that the procedure should be explaining not only that your quality system will be doing that investigation, but who will be doing it and how they will be doing it.
“The cause of nonconformities shall be investigated”, may not be an adequate process control. Yes, it addressed the need for a root cause evaluation, but does it do that adequately?
“The RA/QA Manager will complete or assign a staff member to complete the root cause evaluation of Corrective Actions utilizing methods such as a ‘5-Why Analysis’ by filling in section 2. Of the CAPA report form.” This wording is much closer to what is needed in a procedure. It explains who is doing what, roughly how they might do it, where that activity gets documented and identifies the record that the activity produces.
Which brings us to the extra 32 findings where the activities and their results either weren’t documented or were done so poorly. This is why identifying the input (Root Cause Analysis) and the output (Section 2. of the CAPA report) are important. It allows you, the inspector or an auditor to trace from the procedure to the record that part of the process produces to demonstrate conformity.
As the age old saying goes, “if it isn’t documented, it didn’t happen”. That record should show that yes you did a root cause analysis (the activity) and what the conclusion of that analysis was (the results of that activity). These types of records are so vital to your quality system that there is an entire process dedicated to the control of records. I’ll give you a hint, it is Subpart-M of the QSR.
This is also a great segway to show how the processes go hand in hand and CAPA is interrelated to Document Control, Record Control, and your Quality System Record. Your system processes will continually wrap back around to each other in this manner. For example, CAPAs are a required input into your Management Review process so if you don’t have a CAPA procedure you aren’t performing adequate management reviews.
A note on other systems
If your quality system is also ISO 13485:2016 compliant, Corrective Actions and Preventive Actions are separate items under separate sub-clauses. Corrective Actions are in 8.5.2., and Preventive Actions are in 8.5.3. Meaning if you have a mature quality system that has never had a preventive action, then your CA might be fine, but the PA of that process may be inadequate.
An industry standard for CAPAs is applying a risk based approach, and we have an entire webinar dedicated to the subject! How to create a risk-based CAPA process
Complaints are the second most common reason for warning letters
The silver medal goes to complaints. Much like CAPA the biggest issue is no, or inadequate complaint handling procedures. This specific finding was cited 139 times (overall complaint handling has more but this specific issue was the most cited). Not to sound like a broken record but again, complaint handling is a specific process that requires an ‘established and maintained procedure”.
As a procedure it has to exist, it has to be maintained, and each process has requirements for inputs and outputs that must be outlined. Complaint handling is a little bit different in the QSR in that there isn’t a ‘complaint’ sub-part. Complaints are under Sub-Part M- Records, specifically 21 CFR 820.198 Complaint Files.
To compare, Complaints in accordance with ISO 13485:2016 are under Measurement Analysis and Improvement, specifically Sub-clause 8.2.2. Complaint Handling. It is sandwiched in between Feedback and Reporting to Regulatory Authorities. That had to have been done on purpose because those processes are inherently intertwined and their inputs and outputs directly feed into each other:
Ҥ820.198 Complaint files.
(a) Each manufacturer shall maintain complaint files. Each manufacturer shall establish and maintain procedures for receiving, reviewing, and evaluating complaints by a formally designated unit. Such procedures shall ensure that:
(1) All complaints are processed in a uniform and timely manner;
(2) Oral complaints are documented upon receipt; and
(3) Complaints are evaluated to determine whether the complaint represents an event which is required to be reported to FDA under part 803 of this chapter, Medical Device Reporting.”
This sub-section of ‘Records’ may be less intuitive than what we saw under CA/PA. We can see that we have to maintain complaint files. We also need a procedure that covers receipt, review, and evaluation of complaints. Then we have to name a formally designated complaint handling unit to do all of that.
Further we need to make sure that complaints are handled uniformly and efficiently. It should be a cookie cutter process with a known timeline. Every complaint goes through the same review and evaluation within a specific time period. If it takes six months to review a complaint, that definitely is not a ‘timely manner’.
Not every complaint will be sent to you via certified mail with ‘Complaint’ written across the top in big BOLD letters. Sometimes people will simply tell you about a complaint they have verbally and your process needs to define how it is addressing these verbal communications. Otherwise your FDA inspection observation will be written, and you run the risk of receiving warning letters.
This of course begs the question, what is a complaint? How will I know if I received one? Fortunately 21 CFR 820.3 provides us with definitions, one of them being what exactly a complaint is “(b) Complaint means any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, safety, effectiveness, or performance of a device after it is released for distribution.”.
There is no quiz at the end of this but I would caution you that this will probably be on the test. Anytime you ask a question like that and the regulation provides a definition for it, then it’s a good idea to include that definition within your procedure. This is a way to make sure that there is uniformity in the understanding of a procedure. If you miss a complaint because you didn’t realize that it was a complaint then your process is not effective. Eventually an auditor will pick up on the deficiencies in the process, document a finding and you will be doing a CAPA to fix it.
Every complaint needs to be reviewed, but not every complaint needs to be investigated. This was a much less cited issue (5). You are allowed to decide that an investigation isn’t needed. However, if you do then you must keep a record of why you decided that and name the person responsible for that decision.
That isn’t carte’ blanche to just write off investigations whenever you want. There are some things that require an investigation and there is no accepted rationale for not performing one. An example is when there is a possible failure of a device, it’s labeling or packaging to meet any of their specifications. Those need to be investigated without exception. What your system is allowed to do though is if you have already done an investigation and you received related similar complaints, there is no need to repeat the same investigation for every complaint.
An important concept of complaint handling is that you should be triaging your complaints as you receive them. There are certain types of complaints that must be reported to the FDA. More information is actually found under 21 CFR 803, not the 820 that we have been examining. These special complaints need to be identifiably separate from your normal run of the mill complaints. These complaints specifically need a determination of;
Whether the device failed to meet specifications;
Whether the device was being used for treatment or diagnosis; and
The relationship, if any, of the device to the reported incident or adverse event.
Outside of those special reportable complaints, all investigations have certain required outputs. By addressing every complaint in a uniform repeatable manner, this can be boiled down to a form. In fact creating a specific complaint form makes sure that all of the required information has been documented. Each record of an investigation by your formally designated complaint handling unit has to be include;
The name of the device;
The date the complaint was received;
Any unique device identifier (UDI) or universal product code (UPC), and any other device identification(s) and control number(s) used;
The name, address, and phone number of the complainant;
The nature and details of the complaint;
The dates and results of the investigation;
Any corrective action taken; and
Any reply to the complainant.
Some companies and corporations sprawl across the globe and have many sites all over the place. Not every manufacturer is limited to containing all of their operations within a single building. There are times where the formally designated complaint handling unit may be somewhere other than where the manufacturing is taking place. That is acceptable as long as communication between the two is reasonably acceptable. The manufacturer needs access to the records of the complaint investigations performed. Just as everything must be documented, all of that documentation must be producible as well. If not, your inspector will produce FDA 483 inpsection observations and warning letters.
If the complaint handling unit is outside of the United States the records have to be accessible in the United states from either the place where the manufacturers records are normally kept or at the initial distributor.
Complaint Handling and vigilance reporting are topics that we often find stuck together like velcro. We find them so interelated that we have a combined Complaint Handling and Vigilance Reporting Webinar.
Medical Device Reporting is the third most common reason for warning letters
The bronze medal recipient shows a drop in sheer numbers of FDA inspection observations. A total of 68 were written for the fiscal year of 2020, and these findings have a high likelihood of resulting in warning letters because these incidents may involve serious injuries and death. We are slowing down, but this is still a topic that gets an FDA inspection observation almost every week.
But again part of the issue is no, or bad procedures to control this process. Not to be confused with the (EU) MDR since as an industry we love acronyms so much, Medical Device Reporting is referenced within the Quality System Requirements of 21 CFR 820. We took a peek above in Complaint Handling. What makes this unique is that MDR actually lives in 21 CFR 803 Medical Device Reporting. What makes it even more special is that Part 803 is further broken down into sub-parts.
We will take a look at Sub-part E which is the reporting requirements for manufacturers. Medical Device Reporting is a process and as such needs a procedure to control it and that procedure must be maintained.
Some key points to capture is that there are reporting timelines that are measured in calendar days from when you become aware of information that reasonably suggests that one of your devices;
“(1) May have caused or contributed to a death or serious injury or (2) Has malfunctioned and this device or a similar device that you market would be likely to cause or contribute to a death or serious injury, if the malfunction were to recur.”
There are some crucial takeaways. First, the clock starts ticking down calendar days, not work days, and holidays count. You can’t hold off reporting that your device killed someone because it’s around the holidays and over a few weekends.
Second, is that reporting timelines vary, generally between 5 and 30 calendar days. That means it is important to know the specific timeline for the type of report you are making and what the authority having jurisdiction requires for a timeline. The FDA may differ from Health Canada which in turn may differ from the EU, etc.
Third is that the bar to meet is what would be ‘reasonably known’, and that is somewhat of an ambiguous requirement open to interpretation.
They help clarify this with,
“(i) Any information that you can obtain by contacting a user facility, importer, or other initial reporter; (ii) Any information in your possession; or (iii) Any information that you can obtain by analysis, testing, or other evaluation of the device.”
The first two are usually not an issue, but the one that tends to get less attention is deeper analysis, testing or evaluation of the device. Due diligence is required here to make sure that you actually do know the information that should be ‘reasonably known’ to you.
The burden of investigation and root cause determination is placed squarely on the shoulders of the manufacturers and that is a process that can take some time. What happens when the reporting timely is fast approaching but your investigation won’t be finished before the clock runs out? The short answer is to report it anyway.
The longer answer is to report what information you do have with an explanation of why the report doesn’t have all of the required information. Then explain what you did to try to get all of the information, and file a supplemental or follow-up report later to fill in the gaps. Only having a partial report ready is not an excuse to miss the reporting deadline. It is however, the perfect excuse to get an FDA inpsection observation or warning letters.
If you have a surprise FDA inspector visit, you should never be scared because there is no difference between the best and worst-case outcome.
Why are you scared of an FDA inspector?
There are a number of reasons why you might be scared of an FDA inspector, but if you keep reading you will learn why 95% of your fear is self-induced. A small percentage of device manufacturers evaluate the performance of quality managers based on the outcome of FDA inspections, but you have no control over whom the FDA Office of Regulatory Affairs (ORA) assigns to perform your inspection. If your company belongs to this 5% minority, you need to change top management’s approach to regulators or you need to find a new employer. For the majority of us, we are scared of embarrassment, failure, or being “shut down.”
There are rare examples of where the FDA has taken action to stop the distribution of medical devices, but this is only done as a last resort. Usually, companies cooperate with the FDA with the hope of being able to resolve quality issues and resume distribution after corrective actions are implemented. Not only is this type of action rare, but there will be a prior visit to your facility and prior written communication from ORA before you receive a warning letter–let alone removal of your company’s device(s) from the market. You can’t pass or fail an FDA inspection. The FDA inspector is verifying compliance with the FDA Quality System Regulation (i.e. 21 CFR 820) as well as the requirements for medical device reporting (i.e. 21 CFR 803), reports of corrections and removals (i.e. 21 CFR 806), investigational device exemptions (i.e. 21 CFR 812), and unique device identification (UDI). FDA inspectors only have time to sample your records, and with any sampling plan, there is always uncertainty. When you do receive an FDA 483 inspection observation you should not consider it to be a condemnation of your company. Likewise, an absence of 483 observations is not a reason to celebrate.
Why you should not be embarrassed when you receive a 483 from an FDA inspector
The most irrational response to an FDA 483 inspection observation is embarrassment. Our firm specializes in helping start-up medical device companies get their first product to market. This includes providing training and helping them to implement a quality system. When our clients have their first FDA inspection, it is not uncommon to receive an FDA Form 483 inspection observation. Start-ups have limited resources and limited experience, and most of the employees have never participated in an FDA inspection before. Experience matters and immature quality systems have only a limited number of records to sample. Any mistakes are easy for an inspector to find.
Instead of feeling embarrassed, acknowledge and embrace your inexperience. For example, during the opening meeting with an FDA inspector, you might say, “We are a new company, and this is our first FDA inspection. I am also a first-time quality manager. If you find anything that we are doing incorrectly, please let us know and we will make immediate corrections and start working on our CAPA plan.” You can say this with a smile :), and you can genuinely mean what you said because it’s true.
Anticipation is always worse than reality
Another reason you are scared of an FDA inspection is that you don’t know exactly when the inspection will be. Only Class III PMA devices, and a few Class II De Novo devices with novel manufacturing processes, require a pre-approval inspection. For the rest of the Class II devices, ORA prioritizes inspections based on risk. There are a few companies prioritized for inspection within the first six months of your initial FDA registration, such as reprocessors of single-use devices and contract sterilizers. For the rest of the Class II device manufacturers, your first inspection should be approximately two years after your company registers with the FDA. If you are located outside the USA (OUS), your first inspection might take three years to schedule. Finally, Class I device manufacturers and contract manufacturers, are unlikely to ever be inspected by the FDA. If you didn’t know what the typical timeline was for ORA to schedule your first inspection, you probably just breathed a HUGE sigh of relief when you read this paragraph.
Even if you already know the approximate timeline and priorities for FDA inspections, it’s normal to feel a little anxiety when the date of your first visit is unknown. Your boss and the rest of the top management are probably feeling just as much anxiety as you are, or even more if they have no idea what the timeline and priorities are. You should make sure that everyone in your company understands what they are supposed to do during an FDA inspection, and if you forget to tell them you might cause a lot of unneeded drama when they find out an FDA inspector is in the front lobby. Preparing for an FDA inspection is no different from conducting a fire drill. Everyone should know the procedure, and you should practice (i.e. conduct a mock FDA inspection). Practice ensures that everyone knows what to do during the first 30 minutes of an FDA inspection, and nobody in your company will panic when an FDA inspector actually arrives.
Let’s define “surprise” visits by an FDA inspector
A surprise visit from an FDA inspector is extremely rare, but in the USA inspectors will call on Friday to confirm that your company will be open the following Monday for an inspection. The FDA has jurisdiction over medical device manufacturers located in the USA, and they are not required to give advanced notice. However, inspectors need time to prepare in advance for their inspection–just like an ISO 13485 auditor. Therefore, before an inspector arrives on-site for a routine (Level 2) inspection, the inspector will first make a courtesy call to the official correspondent identified in your establishment registration.
What happens when an FDA inspector travels outside the USA
In the case of OUS medical device manufacturers, the FDA inspector does not have jurisdiction. Therefore, they will contact the official correspondent 6-8 weeks in advance to schedule an inspection. Inspectors will typically make contact via email, and you may be given a couple of weeks to choose from for the FDA inspection. The duration of your inspection should be 4.5 days. The inspector will arrive on Sunday, and the inspection will begin on Monday morning. The inspector has four major process areas to cover, and Friday morning will be focused on generating a preliminary report of 483 inspection observations. The reason why you can predict this OUS routine with a degree of certainty is two-fold: 1) these are government workers following a procedure, and 2) the FDA inspector needs time to get to the airport for their flight home.
What is the outcome of an FDA inspection?
FDA inspections have three possible outcomes:
No action indicated – there were no FDA 483 inspection observations identified by the FDA inspector
Voluntary action indicated – there was at least one FDA 483 inspection observation identified by the FDA inspector, and the FDA inspector requests submission of a CAPA plan to prevent recurrence
Official action indicated – there was at least one FDA 483 inspection observation identified by the FDA inspector, and the FDA inspector requires submission of a CAPA plan to prevent recurrence; if a plan is not received in 15 business days, a warning letter will automatically be generated on the 16 day
Even in the rare instances with there is “no action indicated” (i.e. best case scenario), I have always noticed one or more things during an FDA inspection that were overlooked and we needed to initiate a new corrective action plan(s). In the other two possible scenarios, the FDA inspector identified the need for one or more corrective action plans. Therefore, regardless of whether your FDA inspection results in the best-case scenario or the worst-case, you will always need to initiate a new corrective action plan(s).
If the outcome is always a CAPA, what should you do?
Give your FDA inspector a big smile and say, “We are a new company, and this is our first FDA inspection. I am also a first-time quality manager. If you find anything that we are doing incorrectly, please let us know and we will make immediate corrections and start working on our CAPA plan.” Making sure that you have a genuine smile is just as important as what you say. Smiling will relax you and the anxiety and stress you are feeling will gradually melt away. Smiling will encourage the FDA inspector to trust you. Maybe your smile will even be contagious.
If you need help responding to an FDA 483 inspection observation, or you want to conduct a mock-FDA inspection, please use our calendly app to schedule a call with a member of our team. We are also hosting a live webinar on FDA inspections on July 26, 2021 @ Noon EDT.
About the Author
Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.
This article helps you understand how to pass the FDA Refusal to Accept (RTA) screening process 510k submissions – updated April 2022.
What is an RTA Checklist?
The “RTA” in RTA Checklist stands for Refuse to Accept. The FDA uses this tool to determine if your 510(k) submissions will be accepted or not for a substantive review. Accepted, not approved because this is simply a verification that the required information is included in your submission. As stated in the 2022 FDA guidance document for the FDA’s Refuse to Accept Policy for 510(k)s “a minimum threshold of acceptability and should be accepted for substantive review.”(Ref.1). That does a nice job summarizing the RTA checklist. It is a tool used to help assess whether or not your submission contains the required information to continue with a more thorough review of the contents of the submission itself.
What does the Refusal to Accept (RTA) policy apply to?
The Refusal to Accept (RTA) policy applies to all 510k submissions. The RTA checklist or more checklists apply specifically to each 510(k) submission type:
Traditional 510k
Abbreviated 510k
Special 510k
There is a different RTA checklist for each submission type. The checklists are in the Refuse to Accept Policy for 510(k)s guidance document. Specifically, in the PDF document that the FDA reissued in April 2022, the checklists can be found in the following areas:
Traditional 510k – Appendix A.
Abbreviated 510k – Appendix B.
Special 510k – Appendix C.
Note that the title of the checklist refers to an ‘acceptance checklist.’ It is not called the RTA checklist until you get to the footer of the page. It is also listed as an acceptance checklist on the FDA website. The best way to think of the process is as preliminary screening by the FDA.
What does the FDA look at during the Refusal to Accept (RTA) screening process?
During the screening process, the assigned RTA screener will review the 510k submission and try to identify all of the requirements listed in the applicable RTA checklist. The person screening your submission is required to answer “yes,” “no,” or “n/a” to the questions in the checklist. This person must also enter the document and the page where the information can be found in the submission. Finally, if an element required by the refusal to accept (RTA) checklist cannot be found, then the screener adds a comment at the end of that section in the checklist. The comment will state what your deficiency is and it may even identify a guidance document that can help you address the issue. If you are missing requirements, you will receive an email from the RTA screener with the completed RTA checklist attached. We call this an “RTA Hold” letter. If your submission is not rejected, then your 510k is administratively complete, and you will receive an automated email indicating that your submission was accepted and the substantive review will begin.
Refusal to Accept (RTA) Time Frame
As stated in the guidance document, the Refusal to Accept policy includes “an early review against specific acceptance criteria and to inform the submitter within the first 15 calendar days after receipt of the submission if the submission is administratively complete, or if not, to identify the missing element(s).” (Ref. 1). If the assigned screening person is unable to complete the process within 15 calendar days, then you will receive an automated email stating that they were unable to complete the RTA checklist within 15 calendar days, and your submission is automatically moved to the substantive review stage of the 510k review process.
Taking the time to perform your gap analysis before submitting could avoid a simple error. For example, if you forget to include the signed Truthful and Accuracy Statement in your submission, it could take 15 days to be notified of that missing element. The person screening your submission could email you to provide this missing element in an interactive review to avoid placing your submission on hold. Still, they are not required to give you a chance to provide this interactively by email. If you do receive an RTA Hold letter, you might be able to correct missing elements on the same day, but the 510k review clock is automatically reset when your 510k is placed on RTA Hold. When you respond to an RTA Hold letter, there will be another 15-day refusal to accept (RTA) screening of your submission.
What do you do with the information in the comments of the RTA checklist?
The RTA checklist is the criteria that your submission is being evaluated against. Suppose your submission has deficiencies during the initial review against the RTA Checklist. In that case, the FDA will refuse to accept it, and the substantive review will not begin until those deficiencies have been corrected. Since the FDA does not hide what they are looking for or how they will evaluate your submission, use that to your advantage. Assuming that you have correctly determined the type of 510k submission you have, perform a gap analysis of your submission against the RTA checklist. Either perform these actions in-house or hire an outside consultant to do them for you, but make sure you don’t try to check your own work because you will miss something.
Scope of the FDA Refusal to Accept Guidance Document
The scope of the FDA guidance document is provided for the benefit of the FDA personnel reviewing your submission and not specifically for the 510k submitter. It also provides a loose framework for systematically and consistently reviewing submissions. This ensures all submissions receive equal, nonbiased treatment. There are some things that this guidance document does not address or alter by its own admission. One is the “substantial equivalence decision-making process once the submission has been accepted for review.” Refusing to accept (RTA) guidance also does not address FDA user fees. Other guidance documents address those issues.
What are the most common reasons for FDA refusal of your 510k submission?
Although there are dozens of reasons (43 to be exact) why the FDA could reject your submission in the 35-page RTA checklist, most of the refusals (~80%) result from a small percentage (~20%) of reasons. The most common is that your submission is poorly organized. Either you did not provide a table of contents, your submission is not organized in accordance with the sections outlined in the guidance, or the pages of your submission are not properly numbered. When trying to review a 1,200-page submission, poor organization is extremely irritating and wastes the reviewer’s time. If it were my decision, I would refuse to complete the entire checklist until you gave me a properly organized submission.
The second most common reason for refusal is submitting a device description that is inadequate. The FDA needs more detail than most companies provide for the device description because they need to understand the differences between your device and the predicate device. This includes much more than just the indications for use. Who are the intended patients and users? What is the intended environment of use? What are the materials for patient-contacting components? What is the source of power for your device? Which design features does your device include when compared to the predicate? What is the user interface for your device? Which accessory devices are needed with your device? You can even make the mistake of being inconsistent in your submission by not repeating the content in the device description in other sections of the 510k submission. It is important to duplicate certain content verbatim in other documents, such as the 510k summary, the executive summary, the substantial equivalence comparison, and the instructions for use. Paraphrasing and summarizing certain information will not work.
The third most common reason for refusal of your submission is likely related to software validation documentation. In addition to complying with the recognized IEC 62304 standard, you must also comply with the five software guidance documents published by the FDA. The FDA and 3rd-party reviewers use an 11-item checklist based on the 2005 FDA guidance document on software validation documentation. In addition, if your device has any of the following five elements, your submission must also comply with the two FDA guidance documents on cybersecurity:
Cloud communication
Network connection (active or not)
Wireless communication in any form
USB/serial ports/removable media
Software upgrades (this includes patches)
Finally, biocompatibility is the one testing section of your 510k submission that is most likely to result in refusal to accept by the FDA out of the seven sections requiring testing reports. There are several reasons why biocompatibility results in more refusals than the other six testing sections. First, the FDA requirements go above and beyond the ISO 10993-1 standard requirements. Second, the FDA requires that you submit full testing reports for biocompatibility, while you can submit summaries for other sections (e.g., sterilization validation). Third, many submitters try to provide a rationale for why testing is not required for their device. Still, the FDA has very stringent requirements for the use of a biological risk assessment or a biocompatibility certification statement in lieu of testing.
Do you have to follow the RTA checklist exactly?
You can, but you are also not bound by it. Like all guidance documents, they “contain nonbinding recommendations”. The checklist is released as part of a guidance document, so it is a guidance and not a regulatory requirement. That being said, if your submission is missing an element in the checklist, your 510k submission will be considered administratively incomplete unless you provide a clear explanation as to why the checklist element does not apply to your submission or you explain how you meet the 510k submission requirement in another way.
Medical devices vary wildly, and there is no one size fits all approach. The FDA recognizes that and includes some wiggle room that gives them some discretion in reviewing submissions. However, 100% of the 3,500+ submissions received each year are screened using the refusal to accept (RTA) checklist, and the screening person’s job is to verify that your submission meets the criteria. As it says in the guidance document:
“The purpose of the 510(k) acceptance review is to assess whether a submission is administratively complete, in that it includes all of the information necessary for FDA to conduct a substantive review. Therefore, the submission should not be accepted and should receive an RTA designation if one or more of the items noted as RTA items in the checklist are not present and no explanation is provided for the omission(s). However, during the RTA review, FDA staff has the discretion to determine whether missing checklist items are needed to ensure that the submission is administratively complete to allow the submission to be accepted. FDA staff also has the discretion to request missing checklist items interactively from submitters during the RTA review. Interaction during the RTA review is dependent on the FDA staff’s determination that outstanding issues are appropriate for interactive review and that adequate time is available for the submitter to provide supporting information and for FDA staff to assess responses. If one or more items noted as RTA items on the Acceptance Checklist are not present, FDA staff conducting the acceptance review should obtain management concurrence and notify the designated 510(k), contact person, electronically that the submission has not been accepted. “ (Ref. 1).
The portion above notes that explanations may be provided for omitted portions of the submission. So, the answer to the question is that no, you do not have to follow the RTA checklist exactly. However, if you should purposefully omit a section you should provide an explanation and your rationale justifying why the omission is appropriate for your individual device and 510(k) submission. Again, just because you have included an alternative approach or justification does not automatically mean it will be accepted. The FDA personnel who are conducting the acceptance review will judge whether or not your deviation is acceptable.
What if your 510k submission is refused?
If your submission is refused, you will be provided with a copy of the completed RTA checklist, and each of the deficiencies you must address will be highlighted. Sometimes, there will be an attachment to the checklist that has additional issues that are not in the RTA checklist, but the reviewer thinks you may need to address them later. You might also see comments that are not highlighted. These are suggestions from the reviewer that you may or may not choose to address.
There is a 180-day timeline for response to an RTA Hold letter. The response must be submitted to the CDRH Document Control Center (DCC) as an eCopy, and the response must be received within 180 days. If the response is not received within 180 days, your submission will be automatically withdrawn on the 181st day. Your response may not be piecemeal. You must address all of the issues in the RTA checklist or your submission will be placed on RTA Hold again (i.e., RTA2). If you are not sure how to organize your response, a previous blog posting and YouTube video address this topic directly.
About the Author
Matthew Walker – QMS, Risk Management, Usability Testing, Cybersecurity
Matthew came to us with a regulatory background focused on OSHA and NFPA regulations when he was a Firefighter/EMT. Since we kidnapped him from his other career, he has worked in medical device quality systems and technical/medical writing and is a Lead Auditor. Matthew has updated all of our procedures and is currently a student in Champlain College’s Cybersecurity and Digital Forensics program. We are proud to say he is also a Golden Keys and Phi Theta Kappa Honor Society member! Matthew participates in our audit team and is passionate about risk management and human factors engineering. Always the mad scientist, Matthew pairs his professional life in regulatory affairs with hobbies in the culinary arts, as he also holds a Butchers/Meat Cutters certificate from Vermont Technical College.
A poor RTA response will cause a two-week delay, but an additional information request only gets one chance to avoid the dreaded NSE letter.
An Additional Information Request (i.e. AI Request) is typically received just before the 60th day in a 90-day 510k review, while a Refusal to Accept (RTA) Hold is typically received on the 15th day. If your response to your first RTA Hold (i.e. RTA1) is inadequate, the reviewer will issue another RTA Hold letter (i.e. RTA2) and your 510(k) review clock will be reset to 0 days. You will have another 180-days to respond to RTA2, and issues identified in an RTA Hold are usually easy to address. Most RTA Hold issues also have one or more guidance documents that are available to help you to obtain an RTA Accept letter. You can always request a submission-in-review (SIR) meeting to clarify what information the reviewer needs to address the RTA deficiencies too. If you want to learn more about responding to an RTA Hold, please read last week’s blog. The rest of this article is specific to responding to requests for additional information.
What happens after 60 days during a 510k review?
On the 60th day of the 510k review clock, or a few days prior to the 60th day, the lead reviewer must determine if they need to issue an Additional Information (AI) Request. The alternative to an AI Request is for the lead reviewer to issue a letter indicating that you have entered the Interactive Review Phase. This only happens if the reviewer believes they can make a decision regarding substantial equivalence in the next 30 days. If the decision is to issue an Interactive Review Letter, then the lead reviewer believes that only minor issues remain and there is only the need for interactive email responses between the lead reviewer and the submitter. An interactive review is the ideal outcome of the substantive review process but it rarely happens.
If you receive an Additional Information Request, what are your options?
The AI letter will indicate that you have 10 days to request a clarification meeting with the reviewer. The wording of this section of the AI letter is provided below:
“FDA is offering a teleconference within 10 calendar days from the date on this letter to address any clarification questions you may have to pertain to the deficiencies. If you are interested in a teleconference, please provide (1) proposed dates and (2) a list of your clarification questions via email at least 48 hours before the teleconference to the lead reviewer assigned to your submission. We would like to emphasize that the purpose of the meeting is to address specific clarification questions. The teleconference is not intended for the review of new information, test methods, or data; these types of questions could be better addressed via a Submission Issue Q-Submission (Q-Sub). For additional information regarding Q-Subs, please refer to the Guidance for Industry and FDA Staff on Medical Devices: Requests for Feedback and Meetings for Medical Device Submissions at https://www.fda.gov/media/114034/download.”
If you wait too long to request the teleconference, then FDA will require you to submit a formal pre-sub request or “Submission in Review” (SIR) meeting request. If you request a SIR meeting within 60 days of receiving an AI Request, the FDA will schedule a SIR meeting with you within three weeks of receiving the request–assuming resources are available. If you wait longer than 60 days to request the SIR meeting, then the FDA will default to their normal target of 60-75 days for scheduling a pre-sub meeting. For example, if you submit your SIR meeting request on day 75, and the FDA takes 75 days to schedule the meeting, you will be granted your SIR meeting at 150 days and you will only have 30 days remaining to respond to the AI Request before your submission is automatically withdrawn.
Therefore, it is important to request a clarification meeting immediately after you receive the AI Request. While you are waiting for your clarification meeting, you should immediately begin preparing any draft testing protocols that you want the FDA to provide feedback on during a SIR meeting. Then after you have the clarification meeting, you should submit your SIR meeting request and include any draft testing protocols you have prepared. This may include a statistical sampling rationale, a proposed statistical analysis method, a summative usability testing protocol, or a draft protocol for some additional benchtop performance testing. The FDA can review examples of preliminary data, a protocol, or a proposed method of analysis. The FDA cannot, however, provide a determination of substantial equivalence.
The Most Common Mistakes in Responding to an Additional Information Request
Most companies make the mistake of asking the lead review if they provide specific additional information, “Will this be sufficient to obtain 510(k) clearance?” Unfortunately, the FDA is not able to provide that answer until the company has submitted the additional information and the FDA review team has had time to review it thoroughly. This is done only when the submitter delivers an FDA eCopy to the Document Control Center at CDRH, and the review team is able to review the information. This new information is assigned a supplement number (e.g. S001), and it will typically require three weeks to review the information. Then the lead reviewer may request minor modifications to the labeling, instructions for use, or the 510k summary. This request is an interactive request, and the submitter must respond within a very short period (e.g. 48 hours), and the wording of the request may be “Please provide the above information by no later than COB tomorrow.”
FYI: “COB” means “close of business.” Wow. The FDA loves acronyms.
Best Practices in Responding to an Additional Information Request
If you receive an AI request on a Friday afternoon, 58 days after your initial submission, you should immediately request a clarification teleconference with the FDA reviewer for the following week. The only exception is if you only have minor deficiencies that you feel are completely understood. During the days leading up to the clarification teleconference, your team should send a list of clarification questions to the lead reviewer and begin drafting a response memo with a planned response to each deficiency. After the clarification meeting, you will have approximately 6-7 weeks to submit a SIR meeting request. However, you should not wait that long. Your team should make every effort to submit your SIR meeting request within 2-3 weeks. If the FDA takes 3 weeks to schedule your meeting, then you will have used approximately 6 weeks of your 26 weeks to respond to the AI Request.
In your SIR meeting request, you should always try to provide examples or sample calculations to make sure the FDA review team understands what you are proposing to submit in your supplement. For example, the FDA reviewers do not have enough time to review your entire use-related risk analysis (URRA) in a SIR meeting request. However, you can provide an example of how you plan to document a couple of use-related risks. Then you can show how these risks would translate into critical tasks. Finally, you could provide a draft summative usability testing protocol for FDA feedback. The FDA review team doesn’t have enough time available to review much more. You will only have one hour for your SIR meeting.
How to Prepare Your Response
In section “V” of the FDA guidance on deficiency responses, the FDA recommends that you restate the issue identified by the reviewer in your response. Next, your response should include one of the following:
the information or data requested, or
an explanation of why the issue is not relevant, or
alternate information with an explanation of why the information you are providing addresses the issue.
Before you respond to an AI Request, you should look up any FDA guidance documents referenced in the AI Hold letter to make sure that you address each requirement in the applicable FDA guidance document(s).
The most important technique to learn when you are responding to regulators is to organize your response in a tabular format that is numbered in exactly the same order that the request was made. Typically there will also be sub-parts to certain issues. In that case, you should duplicate the numbers and/or letters of each sub-part and segregate each sub-part in a different row of the table. Personally, I like to alternate the color of the font I use in the table to make it even more obvious which information is a restatement of the reviewer’s comment and which information is the company’s response to the AI Request.
Why you don’t get a second chance to respond to an AI Request
Once you respond to an AI Request, and the DCC receives your FDA eCopy, the FDA review clock will then resume the countdown to 90 days. In our example above, you received the AIR Request on the 58th day. The FDA must review everything you submitted and make a final substantial equivalence decision before the 83rd day because they still need to submit their recommendations to senior management in their branch. If any changes to the labeling, instructions for use, or the 510k are required, you should receive those requests several days before (i.e. 76-83 days). You can respond to interactive requests via email, and then the final SE decision will be made. If you do not respond to all of the deficiencies in the AI Request, the FDA reviewer will not have enough time to request that you address the remaining gaps and finish their review. Therefore, an incomplete AI Response will certainly result in a non-substantial equivalence (NSE) letter.
If you need to respond to an additional information request from the FDA reviewer, we can review your planned response to identify potential gaps. If you need help please use our calendly app to schedule a call with a member of our team.
About the Author
Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.
When an FDA reviewer places your 510k on RTA Hold, there are secrets you can learn to improve your chances of a successful response.
Test your knowledge about the FDA RTA Hold process
Did you know that approximately 50% of 510(k) submissions are placed on RTA Hold? Did you know that you can be placed on RTA Hold multiple times for the same submission? Did you know that the 90-day review clock is reset to “0” when you submit your response? Do you know how to respond to the FDA when the reviewer is incorrect? Did you know that you can avoid the RTA screening process for any 510(k) submission if you use the correct template? Every year there are more than 1,000 submissions placed on RTA Hold, but did you know there is an FDA guidance specifically telling you how to respond to deficiencies? You can learn the secrets to responding to an FDA RTA Hold just by reading this article.
What is an FDA RTA Hold?
When the FDA receives a Traditional 510k submission FDA eCopy, the eCopy is uploaded to the FDA system within hours of the submission being received. If the eCopy does not meet the eCopy format requirements, then the submission will be placed upon eCopy Hold. The official correspondent will receive an automated email indicating that the submission is on eCopy Hold, and the submitter will be asked to correct the submission format to meet the eCopy submission requirements and provide a replacement eCopy. If the FDA user fee has not cleared, then the submission will be placed on User Fee Hold. It is possible to be placed on eCopy Hold and User Fee Hold at the same time.
If your eCopy is accepted, then a reviewer is assigned to screen your submission for compliance with the FDA Refusal to Accept (RTA) policy. The reviewer has 14 days to complete this review, and on the 15th day the reviewer must do one of three things: 1) issue a RTA Hold letter to the submitter, 2) issue an RTA Acceptance letter to the submitter, or 3) issue a letter that states the RTA screening was not completed on-time and the submission was automatically accepted. If your receive an RTA Hold letter, it will be via email from the reviewer and the RTA Checklist will be attached. In the checklist, there will some items highlighted in yellow and deficiencies will be noted in those sections. The reviewer may add additional comments to the checklist, but you are only required to respond to the highlighted sections. The process that the reviewer follows for RTA screening is defined in the FDA guidance for the Refusal to Accept process, and the guidance includes a checklist for traditional, abbreviated, and special 510k submissions. Some companies will fill in these checklists themselves and submit a copy of the checklist with the 510k submission. This is intended to help the reviewer identify where all of the requirements in the RTA checklist can be found. Third-party reviewers require that the company complete the RTA checklist and provide it to them with the eCopy.
How many times can you be placed on hold for the same submission?
Technically there is no limit to the number of times a submission can be placed on RTA Hold, and our firm has seen a few submissions placed on RTA Hold twice in a row. The first RTA Hold is referred to as RTA1, and the response to that RTA Hold is referred to as the first supplement (i.e. K123456/S001). If a second RTA Hold is issued, that hold is RTA2, and the response to that RTA Hold is referred to as the second supplement (i.e. K123456/S002). A response to an eCopy Hold is referred to as an amendment (i.e. K123456/A001).
What happens to the 90-day review clock when you are placed on RTA Hold?
When the FDA reviewer places your submission on RTA Hold, the 90-day review clock is automatically reset. Therefore, even if you respond to an RTA Hold on the same day you receive the RTA Hold, and your submission is received the next day, the “real” review timeline is now 106 days instead of 90. If your submission is placed on RTA Hold twice, then the “real” review timeline is now 122 days instead of 90. If the lead reviewer of your 510k requests additional information, this is referred to as an “AI Request.” We will address this in a future blog, but an AI Request does not reset the review timeline. The AI Request, however, will increase the review timeline. Although we rarely have an RTA Hold, we almost always have an AI Request. This is why our average submission is approximately 125 days (i.e. ~30 days are required to respond to the AI Request.
How should you respond if the FDA reviewer is incorrect?
The average 510(k) submission has grown over time from 300 pages to more than 1,200 pages, but the FDA review “clock” is still 90 days and the RTA screening is limited to 15 days. Therefore, it is not reasonable for you to expect the reviewer to understand and absorb every detail of your submission. If the reviewer can’t find the information they are looking for quickly, the reviewer may state that they could not find the information in the submission or that you did not provide it. If the information is found in the submission, you should provide a reference to the section of the submission, including the document and page number, in your RTA response. You may even choose to quote the information in your response memo if it is brief.
Other times the reviewer may not understand why certain information is not relevant to your submission. In this case, you should restate why the information requested is not relevant. You may want to review relevant FDA guidance documents that explain how to justify why information is not required. For example, if you did not provide biocompatibility testing reports for some of the endpoints that are identified in ISO 10993-1:2018, then you should either provide a detailed biological risk assessment in accordance with the FDA guidance on the use of ISO 10993-1, or you should provide a biocompatibility certification statement.
If you are not sure why the FDA reviewer stated the information you provided is not acceptable, you might try calling or emailing the reviewer to ask for clarification. If you do this, be respectful of their time and be brief. You should identify who you are (you must be the official submission correspondent to speak with the reviewer), you should identify which submission you are contacting the reviewer about (they are working on many simultaneously), you should restate the issue identified by the reviewer (it may have been an issue of another member of the review team), and then you should indicate where the information can be found in the submission. If they believe this addresses the issue, then they will instruct you to provide that information in an RTA response. If the information does not address the issue, usually they will explain why. Your chances of receiving an email response are also better than speaking to the person on the phone–especially during the Covid-19 pandemic.
FDA eSTAR submissions are not subjected to the RTA screening process
When you use the FDA eSTAR submission instead of creating an eCopy, your submission should already meet all of the RTA screening requirements. The eSTAR includes automation to validate that the submission is administratively complete and therefore the reviewer does not need to do an RTA screening of an eSTAR submission. Therefore, most companies should realize a shorter overall 510k clearance timelines, because they will only have an AI Request and the review clock will not be reset.
Does the FDA offer any guidance on how to respond to deficiencies?
When the FDA writes deficiencies, the reviewer is supposed to follow the FDA guidance for deficiency content and format. However, the RTA checklist deficiencies typically are shorter and may not be as clear as a deficiency in additional information (AI) requests or non-substantial equivalence (NSE) letters. The first part of the deficiency is a reference to the information that was provided by the submitter (i.e. section, page number, or table). In an RTA checklist, each deficiency is provided in the comments section at the end of the section of the checklist. Therefore, if you have a deficiency related to your device description, the deficiency will be written at the end of the device description section of the RTA checklist. The comment will be highlighted in yellow, and there will be a checkbox next to the specific checklist item indicating that the requirement was not met. In the far-right column of the checklist, there will be a reference to the page of the submission where the deficiency can be found.
In the comment there reviewer should explain why the current information does not meet the requirement of the RTA checklist. The reviewer should also clarify the relevance of the deficiency with regard to the substantial equivalence determination. For the example of a deficiency related to your device description, usually, the issue is that your submission has inconsistencies between the various submissions or there is insufficient detail about your device. At the end of the comment, the reviewer should provide an explicit request for the information needed to address the RTA Hold.
In section “V” of the FDA guidance on deficiency responses, the FDA recommends that you restate the issue identified by the reviewer in your response. Next, your response should include one of the following:
the information or data requested, or
an explanation of why the issue is not relevant, or
alternate information with an explanation of why the information you are providing addresses the issue.
Before you respond to an RTA Hold, you should look up any FDA guidance documents referenced in the RTA Checklist to make sure that you address each requirement in the applicable FDA guidance document(s).
The most important technique to learn when you are responding to regulators is to organize your response in a tabular format that is numbered in exactly the same order that the request was made. Typically there will also be sub-parts to certain issues. In that case, you should duplicate the numbers and/or letters of each sub-part and segregate each sub-part in a different row of the table. Personally, I like to alternate the color of the font I use in the table to make it even more obvious which information is a restatement of the reviewer’s comment and which information is the company’s response to the RTA Hold.
Regardless of how well your response is organized, you must respond within 180 days. On the 181st day, your submission will be automatically withdrawn. The agency has granted extensions of an additional 180 days during the Covid-19 pandemic, but that will end and you should verify if you can obtain an extension from the reviewer rather than assume that this will happen. If the 180th day is on a weekend or US holiday, the Document Control Center (DCC) at the FDA will not receive your submission until the next business day. Therefore, you will need to ship your submission earlier to ensure the delivery is received on time. Since most companies are shipping their RTA response via FedEx or UPS to the FDA, you also will want to make sure you take into account customs clearance for international shipments and local holidays where you are. If you are shipping from the UK, for example, you can’t expect FedEx to ship on a British holiday. If you need help with printing and shipping your RTA response, Medical Device Academy offers an eCopy print and ship service for $99/eCopy (including the overnight FedEx fee).
If your 510k submission was placed on RTA Hold by the FDA, we can help you respond to the deficiencies identified by the FDA reviewer. We can also review your planned response to identify potential gaps. If you need help please use our calendly app to schedule a call with a member of our team.
About the Author
Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+, LinkedIn or Twitter.
Did you forget any of the MDR labeling procedure requirements when you were updating your device labeling for CE Marking?
MDR Labeling Procedure
Don’t forget to subscribe to our YouTube channel for more medical device quality and regulatory training. The topic of this article is how to create an MDR labeling procedure for compliance with Regulation (EU) 2017/745 (MDR) for CE Marking of medical devices. The MDR does not actually include a requirement for a labeling procedure. In fact, the MDR doesn’t even specifically require that you have ISO 13485:2016 certification. ISO 13485:2016, clause 7.5.1 states that you shall implement “defined operations for labeling and packaging,” but the standard doesn’t specifically say that “the organization shall document procedures” for labeling. In 21 CFR 820.120, the FDA states that “each manufacturer shall establish and maintain procedures to control labeling activities.” But there is no similar requirement in the MDR.
MDR Quality System Requirements
Article 10 is the section of the MDR that defines the obligations for device manufacturers to create quality system procedures, but a labeling procedure is not specifically mentioned. Article 10(9)(a) states that your quality system shall include “a strategy for regulatory compliance, including…procedures for management of modifications to the devices covered by the system,” and this would include label changes and other control of other design changes. The next paragraph states that your quality system shall include, “identification of applicable general safety and performance requirements.” The general safety and performance requirements (GSPRs) are found in Annex I of the MDR, and the very last GSPR (i.e. GSPR 23) is for your label and instructions for use.
Then, which changes do you need to make for the MDR labeling procedure?
The GSPRs in Annex I of the MDR are longer than the Essential Requirements that were in the MDD. In addition to the new requirements for UDI compliance (which you should address in a UDI Requirements Procedure), GSPR 23 has new general requirements (i.e. 23.1) and new requirements for information on the sterile packaging (i.e. 23.3). There is also a more detailed specification for the information on the label (i.e. 23.2) and the information in the instructions for use (i.e. 23.4). The approach for demonstrating compliance with the GSPRs suggested in the MDR is to provide a checklist. Therefore, most manufacturers of CE Marked devices have replaced their Essential Requirements Checklist (ERC) with a GSPR checklist. However, if you are reviewing a draft label for approval, you don’t want to review and update your entire 22-page, GSPR checklist for every label.
The more efficient approach is to create one or more labeling checklists that are specific to the requirements in GSPR 23. If you create a separate checklist for the label, the information on the sterile packaging, and for the information in the instructions for use, then you would have three shorter checklists to complete. The label checklist and the checklist of the information on the sterile packaging would be only one page each, while the checklist for the instructions for use would be approximately four pages. There may be additional labeling requirements for specific countries and types of devices. Electrical medical equipment also has specific labeling requirements in IEC 60601-1 and IEC 60601-1-2. You will also need to create a user needs specification that can be used as criteria for summative usability testing (i.e. validation that the design and risk controls implemented meet the user needs specification). You should also document a use-related risk analysis (URRA), and perform formative testing, in order to identify critical tasks which need to be in the instructions for use to prevent use errors.
Are there any other MDR requirements that you should address in a labeling procedure?
There are two other requirements that should be addressed in your labeling procedure. The first is the general labeling requirements in GSPR 23.1. Withing GSPR 23.1, there are actually nine “sub-requirements.” The first “sub-requirement” in GSPR 23.1 is to provide the identity of the device, your company, and any safety and performance information needed by the user on the packaging or the instructions for use, and on your website. Many manufacturers do not want to make this information available on their website, because it makes it easier for competitors to copy the instructions for use, but this is not optional. This requirement and the other eight requirements in GSPR 23.1 could be included in your procedure or as part of a fourth labeling checklist associated with your MDR labeling procedure.
The second requirement is the requirement to translate your instructions for use into an official Union language(s) determined by the member state where your device will be made available to the intended user or patient. Creating these translations, and verifying the accuracy of the translations, can be expensive and burdensome–especially if your device is sold in most of the member states.
You might also consider implant cards as labeling requirements and try to add them to your MDR labeling procedure. However, if the requirement for implant cards (see Article 18 of the MDR) is applicable to your company you should create an implant card procedure instead because this is a detailed and critical requirement that will not apply to most of the other labels in your company. You should make sure that the implant card procedure is compliant with MDCG 2021-11 released in May 2021 and MDCG 20201-8 v2 release in March 2020. These guidance documents also have great examples of how to design your implant cards.
Other changes in labeling requirements
The ISO 15223-1:2016 standard has been revised and was expected for release at the end of 2020. However, only draft versions are currently available (i.e. ISO/DIS 15223-1:2020). This new version of the standard for symbols to be used with labeling will also need to be updated shortly in your MDR labeling procedure. This new version is already referenced in the medical device standard for information provided by the manufacturer (i.e. EN ISO 20417:2021)–which supersedes EN 1041:2008. Consultants and chat rooms have argued over whether the requirement for identifying the importer must be on the label or if it could be presented in other documents. EN ISO 20417:2021 resolves this dispute in section 7.1: “Where necessary, the label of a medical device or accessory shall include the name or trade name and full address of the importer to which the responsible organization can refer.” In the note following that clause, it clarifies that “This can be required by the authority having jurisdiction.” There is even a new symbol referenced for importers (i.e. Symbol 5.1.8 in ISO 15223-1).
If you have specific questions about device labeling or MDR compliance, please use our calendly app to schedule a call with a member of our team. You can also purchase our labeling and translation procedure (SYS-030) to save yourself the time and effort of making your own versions of the labeling checklist described above.
About the Author
Robert Packard is a regulatory consultant with 25+ years of experience in the medical device, pharmaceutical, and biotechnology industries. He is a graduate of UConn in Chemical Engineering. Robert was a senior manager at several medical device companies—including the President/CEO of a laparoscopic imaging company. His Quality Management System expertise covers all aspects of developing, training, implementing, and maintaining ISO 13485 and ISO 14971 certification. From 2009-2012, he was a lead auditor and instructor for one of the largest Notified Bodies. Robert’s specialty is regulatory submissions for high-risk medical devices, such as implants and drug/device combination products for CE marking applications, Canadian medical device applications, and 510(k) submissions. The most favorite part of his job is training others. He can be reached via phone 802.258.1881 or email. You can also follow him on Google+,LinkedIn or Twitter.
The US FDA does not require that 100% of your quality system be implemented before 510k clearance, but these 10 activities need to be done.
The form above allows you to register for a live webinar we are hosting on Friday, May 21, 2021 @ 1 pm EDT. The webinar will share the 510k project management lessons learned by our team since 2016. In addition to 510k project management, MedTech companies also need to implement their quality system in parallel with their regulatory submissions. Some people say that you need to implement your quality system before you submit your 510k. That is not an FDA requirement, but you do have quality system activities that need to be done before you will have all of the technical documentation you need to submit a 510k. This article describes 10 quality tasks you need to prevent unexpected delays.
Design & Risk Management Planning
Design & Risk Management Planning is your 1st priority because you want to identify all of the major activities that need to be completed in your design and risk management processes and which activities are critical path items. Otherwise, you will have unexpected delays. You can and should add details to the plan as you go, but items 2-9 listed below should be included in that initial plan–along with your design and risk management activities.
Risk Management Activities are Needed Before 510k Clearance
Formative Usability Testing is your 3rd priority because this helps you evaluate your device design while it’s still evolving. Formative testing helps you identify opportunities for improvement, provides confirmation that your design is moving in the right direction, and identifies potential use errors while there is still time to implement effective risk controls such as alarms and other safety features. References:
Software Validation is Needed Before 510k Clearance
Software Validation is your 4th priority because it must precede electrical safety testing for electromedical devices and most companies underestimate the time required to document software validation in accordance with IEC 62304:2006 / AMD 1:2015 and the FDA’s five guidance documents:
Supplier Qualification is Needed Before 510k Clearance
Supplier qualification is your 5th priority because you do not want to order all of your prototype parts for the initial testing parts and then find out that the supplier is not capable of supporting you commercially. If you have to switch suppliers you might be forced to repeat biocompatibility testing and other design verification testing due to changes in the manufacturing process. Implementation of a supplier qualification process before 510k clearance is needed.
Label & IFU Requirements Specifications
Label requirements and instructions for use requirements specifications is your 6th priority because you cannot perform electrical safety testing or design validation (including summative usability testing) of your device without labeling and instructions. These requirements are the design inputs for information provided to the user and these must be controlled under design controls rather than document control.
Packaging Specifications
Packaging specifications is the 7th priority you should implement before 510k clearance because the packaging is needed to maintain sterility, to ensure product stability, and to protect the product from shipping. Companies are also frequently surprised by the long lead times associated with ordering custom packaging and you may not have the budget to validate sub-optimal “stock” packaging for your 510(k) submission and then repeat the validation for the optimized packaging later.
Quality System Implementation
Quality system implementation is the 8th priority for implementation before 510k clearance because you will need a fully functional quality system by the time your 510(k) is cleared. Quality system implementation typically takes 6+ months while the 510(k) review should take 4 months or less. Quality system implementation includes writing 25+ procedures, reviewing and approving those procedures, training your employees, and actually using those procedures to begin generating quality system records. For companies that are pursuing Canadian Licensing or CE Marking, the quality system must be fully implemented and certified before the regulatory submission is possible. (Quality System Requirements for the U.S. FDA are outlined within 21 CFR 820-Quality System Regulation)
Apply for Small Business Status Before 510k Clearance
Application for small business status should be the 10th priority for implementation before 510k clearance because this can save your company $16,000+ but it requires that you submit your application at least 60 days before you need to pay the 510(k) user fee.
About the Author
Matthew Walker – QMS, Risk Management, Usability Testing, Cybersecurity
Matthew came to us with a regulatory background that focused on OSHA and NFPA regulations when he was a Firefighter/EMT. Since we kidnapped him from his other career, he now works in Medical Device Quality Management Systems, Technical/Medical Writing and is a Lead Auditor. He is currently a student in the Champlain College’s Cybersecurity and Digital Forensics program, and we are proud to say that he is also a member of both the Golden Keys and Phi Theta Kappa Honor Societies! Matthew participates as a member of our audit team and has a passion for risk management and human factors engineering. Always the mad scientist, Matthew pairs his professional life in regulatory affairs with hobbies in the culinary arts as he also holds a Butchers/Meat Cutters certificate from Vermont Technical College.
This blog discusses why contract manufacturers need to have a strong risk management process, and your company needs to help your contract manufacturers. This article was updated on April 28, 2022, and the original publication was January 05, 2011. Please ignore the date of publication at the top of the post for articles that are more than a year old.
Can contract manufacturers exclude risk management from the scope of their quality system?
Most contract manufacturers in the medical device industry exclude design from their Quality Management Systems. Unfortunately, most of the contract manufacturers also associate risk management with only the design process. Risk Management cannot be “not applicable” in anISO 13485Quality Management System. The requirement of section 7.1 is: “The organization shall establish documented requirements for risk management throughout product realization. Records arising from risk management shall be maintained.” The Standard also referencesISO 14971as a source of guidance on Risk Management.
Have you experienced an audit dialogue at a contract manufacturer similar to this?
The auditor asks, “How do you manage risk throughout the production process?” Then the auditee responds, “That is the responsibility of our customers. We will prepare a risk analysis if customers pay for it, but usually, customers do the risk analysis.”
For a contract manufacturer, compliance with ISO 14971 is not my primary concern as an auditor. My primary concern is to verify that contract manufacturers analyze risks associated with the processes that they perform and do their best to minimize those risks. What I don’t understand is why more companies don’t want to have strong risk management processes. Risk management is how we prevent bad things from happening. Bad stuff like scrap, complaints, and recalls. Should we expect our suppliers to have a strong risk management process?
Duh.
Why your company needs to be involved in the risk management process?
Contract manufacturers should be doing everything they can to get better at risk management. During pre-production planning, they should be asking, “What happens if…” The contract manufacturer knows best HOW things will fail in production, while the customer knows best WHAT happens when things fail in production. To be safe and effective, both companies need to collaborate on risk analysis.
In any risk analysis, you need to estimate the severity of potential harm and the probability of occurrence of that harm. For production defects, the contract manufacturer can estimate the probability of occurrence of defects (i.e., P1 in Annex E of ISO 14971:2007), but the likelihood of occurrence of harm is less. The probability of occurrence of harm is the product of multiplying P1 and P2. The probability that occurrence will result in harm is P2, and P2 is a number that is less than 100% or 1. Your company can gather pre-market clinical data and post-market clinical data to estimate P2, but before launching your product, you can only guess at the value of P2. Your contract manufacturer, however, is not able to estimate P2 at all. It’s ok to estimate risk without P2 during the design phase because this will overestimate risks and result in more conservative decisions.
In addition to P2, your contract manufacturer is also not capable of estimating the severity of potential harm. As the designer of the medical device, you will know best how your device is used and what the likely clinical outcomes are when a device malfunctions. There may even be multiple possible clinical outcomes. The contract manufacturer knows what can go wrong during manufacturing, but you will need to define the clinical outcomes due to malfunctions.
Why do contract manufacturers avoid doing risk analysis?
The reason contract manufacturers avoid doing risk analysis is because it’s time-consuming and tedious.
Too bad, so sad.
Balancing my checkbook is time-consuming and tedious too, but I balance my checkbook to prevent an overdraft charge. Not doing a risk analysis can be much more painful. Scrapping out a part can cost tens or hundreds of dollars. Complaints can cost thousands of dollars. Recalls can cost millions of dollars.
If I owned a contract manufacturing company, I would ensure that everyone in the company is involved in risk management. We don’t want scrap, we can’t afford mistakes that lead to complaints, and a recall could put us out of business.
How Medical Device Academy Can Help?
Medical device academy can help both the contract manufacturer and the specification developer utilizing a contract manufacturer as a supplier! We offer training on 14971:2019 as well as procedures on risk management and supplier quality management.
Two-part Risk Management Training Webinar for ISO 14971:2019 – Part 1 of this webinar will be presented live on Tuesday, March 29 @ 9-10:30 am EDT. Part 2 of this webinar series will be presented live on Tuesday, April 5 at 9-10:30 am EDT. Purchase of this webinar series will grant the customer access to both live webinars. They will also receive the native slide decks and recording for the two webinars.
