FDA

New FDA Guidance documents for combination drug/device products, medical devices, and FDA inspection trends.

Device Supply Chain Disruptions

What can you do to stay ahead of medical device supply chain disruptions and comply with reporting requirements of possible device shortages?

Device Supply Chain Disruptions Device Supply Chain Disruptions

Supply chain issues can be somewhat cyclical. As we approach the holiday season, we also approach the shipping season. Public shipping services such as FedEx and UPS see an increase in freight as the holiday seasons approach. Manufacturers need raw materials and components to stock the shelves with all of those holiday gifts. Since we are still living under pandemic conditions, I would be willing to bet there will be more care packages and mailed gifts in place of traditional gatherings. On top of the approaching increase in demand, staffing shortages can very quickly exacerbate supply chain bottlenecks. All the while importers are still expected to… well, import! If transportation affects all general industry you can bet it can also cause medical device supply chain disruptions.

So what does an overburdened mail service have to do with medical devices and quality systems?

Consider, how are your customers getting your product in their hands? How are you receiving raw materials and components? How about your contract manufacturer? Do they have supply chain redundancies? Does your supplier quality agreement address notifications for shipping disruptions? 

Do you have a regulatory obligation to report a shortage/supply chain disruption or interruption of manufacturing to the FDA, or Health Canada? The FDA monitors for discontinuance and meaningful disruption of manufacturing certain devices and similarly Health Canada monitors their own list of devices for market shortages. Supply chain disruptions either through difficulty sourcing of raw materials and components, or through transportation breakdown of finished devices to market are just one way you could experience a reportable disruption or shortage.

Matthew did not choose the topic of medical device supply chain disruptions randomly. His signature brand of pessimistic cynicism is the reason we have him tasked with keeping his fingers on the pulse of global concerns and potential threats and risks. Potential supply chain disruptions will involve your quality staff in developing preventive actions and contingency plans in case there is an issue. Then, your regulatory team will be in charge of reporting and AHJ notification if you are an affected manufacturer (or importer in Canada!). Understaffed and overloaded shipping and transportation suppliers are about to be bombarded with seasonal freight. This makes them an attractive target for ransomware because, just like healthcare facilities, they will not be in a situation where they can afford any downtime. 

fda logo Device Supply Chain Disruptions
U.S. FDA

The FDA requires reporting shortages and supply chain disruptions to CDHR of permanent discontinuance or interruption in manufacturing of a medical device in Section 506J of the FD&C Act. Especially so in response to the COVID-19 public health emergency. In part, the general public’s need for healthcare during the pandemic guides what devices the FDA needs notification about.

Currently, the FDA is concerned about specific device types by product code or any devices that are critical to public health during a public health emergency. For the most up to date list, the URL to the FDA website will show the specific product codes of the monitored device types;

health canada logo sante canada 1024x224 1 Device Supply Chain Disruptions
Health Canada

As an Authority Having Jurisdiction, Health Canada also has reporting requirements for supply chain disruptions of specific types of medical devices. Health Canada is also an independent authority that uses a different device classification system than the U.S. FDA.

The table below shows the device types by their classification level that HC requires supply chain disruption notifications for. This information is current as of September 5th, 2021, and the following link will take you to the HC webpage for the most up-to-date list.

Class I Medical Devices
Masks (surgical, procedure or medical masks) – Level 1, 2, 3 (ATSM)
N95 respirators for medical use
KN95 respirators for medical use
Face shields
Gowns (isolation or surgical gowns) – Level 2, 3 and 4
Gowns (chemotherapy gowns)
Class II Medical Devices
Ventilators (including bi-level positive airway pressure or BiPAP machines, and continuous positive airway pressure or CPAP machines)
Infrared thermometers
Digital thermometers
Oxygen Concentrators
Pulse Oximeters (single measurement)
Aspirators/suction pumps (portable and stationary)
Laryngoscopes
Endotracheal tubes
Manual resuscitation bags (individually or part of a kit)
Medical Gloves – Examination and Surgical (Nitrile, Vinyl)
Oxygen Delivery Devices
Class III Medical Devices
Ventilators (including bi-level positive airway pressure or BiPAP machines)
Pulse Oximeters (continuous monitoring)
Vital Signs Monitors
Dialyzers
Infusion Pumps
Anesthesia Delivery Devices
Class IV Medical Devices
Extracorporeal Membrane Oxygenation (ECMO) Devices

How to prevent device supply chain disruptions

Harden your supply chain with redundancies. Now is the time to qualify a second supplier as a contingency plan before it is too late…. Maybe even consider opening a Preventive Action? (HINT HINT for those ISO 13485 manufacturers that need to beef up their Clause 8.5.3. operations!)

Supply chains have both up and downstream functions. First, you likely need to source raw materials and components for production. Then you also need to ship those finished devices to distribution centers and your customers. Disrupt either of those and your ability to sell your devices is compromised or even completely halted.

Ask yourself, “Do I have a backup option for shipping?”, and “Do I have a backup option for raw materials and components?”.

Why?

Why go through all of that effort? Well, if you lose UPS and have to use FedEx instead, are their shipping procedures identical? Likely you will need a WI level document for each shipper to explain the process. It is easier to pre-qualify a contingency supplier and establish a WI now rather than in December when holiday shipping is at its peak. Consider if you also need to open accounts, etc. Scheduling pickup online may not be intuitive.

Just identifying a backup is important, but you can take that a step further and pre-qualify them. If they are a shipping and transportation supplier then give them a shipment or two in order to evaluate them. Hold them to the same standards you would for your primary supplier.

Did your shipment arrive on time? Was it damaged during transit? This is provisional, or pre-qualification. Did they perform adequately enough to use as a tentative supplier in the event the primary supplier is unable to perform? This is designed to make a full qualification of this supplier simple and easy… If you need to utilize them that is. Maintaining this pre-qualification should also be simple and easy as well. Once a year or so have them deliver a shipment for you.

That is just for importing or shipping finished devices. Do you have backup raw material or components suppliers identified? If not identifying or even pre-qualifying secondary suppliers might not be a bad idea either. You are probably tied down to a specific geographic area for shipping and transportation. You may not be for raw materials. If you need barrels of silicone consider a backup supplier from a different area than your primary supplier. Natural disasters create havoc for shipping. If your silicone comes from Company A, and they are closed down because of a hurricane then Company B ten miles away is likely affected as well.

For example, if you are in the U.S. and your primary supplier is in the Northeast then a backup supplier in the Southeast may be strategically important. Whereas a backup supplier from the Southwest may be cost-prohibitive.

What about your suppliers? Is your device high-risk enough that if your supply chain is disrupted, you have an obligation to report it to the FDA? In that scenario, if you use a contract manufacturer, it may be worth requiring supply chain contingencies and clearly identifying who owns what reporting responsibilities within your quality agreement with them.

There is an element of proactive responsibility in reporting these shortages, or projected shortages. In order to be able to predict medical device supply chain disruptions, there should be metrics that your quality system is monitoring. What is your monthly production capacity? How much raw material or components does your warehousing have on hand? How many units could you manufacture if the transport industry stopped right this second?

Determine what you need to track in order to identify a disruption before it occurs.

Prepare for notification now. This article looked at the problem from the point of view that transportation issues were the root cause of the supply chain disruption. However, many other things could be disruptive, such as natural disasters and supply availability. Therefore, develop a WI level document for conducting these types of regulatory reporting activities and train personnel before a disruption happens. It is easier to tackle these kinds of problems if you already have process controls in place and trained competent staff than if you wait until the reporting timeline clock is already ticking.

In the near future, we will be posting a new blog about 506J and Shortage Reporting. We will also have a work instruction and training webinar available soon.

Future blogs about device supply chain disruptions…Shortage Reporting

About the Author

20190531 005146 150x150 Device Supply Chain DisruptionsMatthew 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. Matthew has updated all of our procedures for  He is currently a student in 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.

Email: Matthew@FDAeCopy.com

Connect on Linkedin: http://www.linkedin.com/in/matthew-walker-214718101/

Device Supply Chain Disruptions Read More »

Does your FDA inspection plan include the answers to these 15 questions?

Does your FDA inspection plan need to be proactive first?

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:

  1. What will you ask and do when your FDA inspector calls the Friday before the inspection?
  2. Who should be contacted by the FDA inspector if you are on vacation?
  3. How will you communicate to the rest of your company that an FDA inspection is planned for Monday morning?
  4. Who will greet the FDA inspector upon arrival, and what should they do?
  5. Which conference room will the FDA inspector spend most of their time in?
  6. Who will be in the conference room with you and the FDA inspector?
  7. How will you track document and records requests, and how will you communicate that information to others?
  8. How will you retrieve documents and records requested by the FDA inspector?
  9. Who will conduct a tour of the facility with the FDA inspector and how will the tour be managed?
  10. When quality issues are identified, how will you respond?
  11. What will you do for lunches during the inspection?
  12. Who will attend the closing meeting with the FDA inspector?
  13. Should you “promise to correct” 483 inspection observations identified by the FDA?
  14. How and when will you repsond to the inspector with corrective action plans?
  15. 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:

  1. the name of the inspector(s) that are arriving
  2. the list of managers that should be notified when the inspector(s) arrives (possibly identical to the buisness continuity call list)
  3. 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:

  1. the location of bathrooms and emergency exit instructions in case of a fire
  2. the information for wireless connectivity
  3. 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:

  1. the inspector(s)
  2. the management representative (i.e. you)
  3. a scribe
  4. 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:

  1. 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.
  2. 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.
  3. 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.
  4. 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.

Does your FDA inspection plan need to be proactive first? Read More »

Are you a little curious, or fascinated by competitive warning letters?

Did you know you can download competitor inspectional observations to learn which quality issues are likely to result in warning letters?

Wheel of misfortune cropped 1 Are you a little curious, or fascinated by competitive 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: 

  1. CAPA procedures
  2. Complaint procedures
  3. Medical Device Reporting
  4. Purchasing Controls
  5. Nonconforming Product
  6. Process Validation
  7. Quality Audits
  8. Documentation of CAPA actions and results
  9. Training
  10. 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:

§820.100 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

%name Are you a little curious, or fascinated by competitive 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:

§820.198 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.

Are you a little curious, or fascinated by competitive warning letters? Read More »

Smile, because you should never be scared of a surprise FDA inspector

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:

  1. No action indicated – there were no FDA 483 inspection observations identified by the FDA inspector
  2. 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
  3. 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

Rob Packard 150x150 Smile, because you should never be scared of a surprise FDA inspector

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.

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How to pass the FDA Refusal to Accept (RTA) Screening Process

This article helps you understand how to pass the FDA Refusal to Accept (RTA) screening process 510k submissions – updated April 2022.

Refusal to Accept How to pass the FDA Refusal to Accept (RTA) Screening Process

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:

  1. Cloud communication
  2. Network connection (active or not)
  3. Wireless communication in any form
  4. USB/serial ports/removable media
  5. 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

20190531 005146 150x150 How to pass the FDA Refusal to Accept (RTA) Screening ProcessMatthew 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.

Email: Matthew@FDAeCopy.com

Connect on Linkedin: http://www.linkedin.com/in/matthew-walker-214718101/

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Private Labeled Devices with FDA Approval

This article explains the FDA regulations related to private labeled devices that are already 510k cleared and distributors want to import.

Untitled presentation 1 e1650334733162 Private Labeled Devices with FDA Approval

This article was initially inspired by a question asked on the Medical Devices Group website hosted by Joe Hage. Companies often ask about how to private labeled devices in the USA, because they are unable to find anywhere in the FDA regulations where private labeling of the device is described. The reason for this is because the FDA regulations for devices allow for the labeling to identify the distributor only—without any mention of the OEM manufacturer on the label. In contrast, most other countries have “own-brand labeling” regulations or regulations for private labeling devices. It is also important to remember that the FDA only approves devices through the pre-market approval (PMA) pathway. All other devices fall into one of three categories: 1) 510k exempt, 2) 510k cleared, or 3) De Novo classification request approved. Devices that fall into the third category will subsequently fall into category 1 or 2 after the FDA approves the classification request.

Questions about the private labeled devices process for FDA

Our distribution company is interested in getting a private labeled devices agreement with an OEM to sell a Class II medical device in the USA. The OEM has 510(k) clearance, and the only product change will be the company’s name and address on the label. There will be no change to the indications for use. Please answer the following questions:

  1. Is it legal to eliminate all mention of the OEM from the device labeling?
  2. Who is responsible for complaint handling and medical device reporting? OEM or private-labeled distributor?
  3. What is the process to get this private label for the Class II device?
  4. How can our distribution company avoid paying the FDA user fee?

Answer to the first question about private labeled devices

The FDA is unique in that they allow either the distributor or the manufacturer to be identified on the label, but both are not required. Therefore, if Joe Hage were the distributor, and you were the manufacturer, there are two legal options for the private labeled device: 1) “Distributed by Joe Hage”, or 2) “Manufactured for Joe Hage.”

The manufacturer is not required to be identified on the label. However, the OEM must be registered and listed with the FDA. If the OEM is outside the USA, then the distributor must register and list with the FDA as the initial importer and reference the K number when they complete the FDA listing. There is no approval required by the FDA. You will need a quality agreement defining the roles and responsibilities of each party, but that is all.

Answer to the second question about private labeled devices

The quality agreement must specify which company is responsible for complaint handling (21 CFR 820.198) and medical device reporting (21 CFR 803). In this situation, the OEM is the specification developer, as defined by the FDA. Therefore, the OEM will be responsible for reporting and execution of recalls. Therefore, even if the distributor with a private label agreement is identified as the “complaint file establishment,” the OEM will still need to obtain copies of the complaint information from the distributor, and determine if medical device reporting and/or corrections and removals are required (i.e., recalls).

Answer to the third question about private labeled devices

There is no formal process for “getting a private label.” The entire private label process is negotiated between the distributor and the OEM with no involvement of the FDA. However, in the listing of devices within the FDA FURLS database, all brand names of the device must be identified. Therefore, the OEM will need to add the new brand name used by the distributor to their listing for the 510(k) cleared product. However, the FDA does have the option to keep this information confidential by merely checking a box in the device listing form.

Answer to the fourth question about private labeled devices

If the distribution company is the initial importer of a device into the USA, then the distributor must be registered with the US FDA as the initial importer, and the distributor will need to pay the FDA user fee for the establishment registration. That user fee is $5,236 for FY 2020, and there is no small business discount for this fee. The only way to avoid paying the user fee is to have another company import the device, who is already registered with the FDA, and to distribute the product for that company. I imagine some logistics brokers might be acting as an initial importer for multiple distributors to help them avoid paying the annual FDA user fee for establishments. That company might also be providing US Agent services for multiple OEMs. However, I have not found a company doing this.

Is private labeling of device legal in the USA?

The FDA is unique in that they allow either the distributor or the manufacturer to be identified on the label, but both are not required. Therefore, if Joe Hage were the distributor, and you were the manufacturer, there are two legal options for the private label: 1) “Distributed by Joe Hage”, or 2) “Manufactured for Joe Hage.”

Who must register, list, and pay user fees for medical devices?

This question is frequently asked, and the table with the information was not visible on my mobile browser. Therefore, I copied the table from the FDA website and posted the information in the image below. The information is copied directly from the FDA website:

Registration and Listing Requirements for Domestic Establishments

Who must register list and pay fig 1 1024x697 Private Labeled Devices with FDA ApprovalWho must register list and pay fig 2 1024x710 Private Labeled Devices with FDA Approval

Registration and Listing Requirements for Foreign Establishments

Who must register list and pay fig 3 1024x947 Private Labeled Devices with FDA Approval

For products that are manufactured outside the USA, and imported into the USA, the initial importer is often the company identified on the label. There are two typical private labeling situations, but other possibilities exist:

  1. If the initial importer owns the 510(k), then the manufacturer outside the USA is identified as the “contract manufacturer,” and the initial importer is identified as the “specifications developer.” Both companies must register their establishments with the FDA, and there needs to be a quality agreement between the two companies defining roles and responsibilities. The contract manufacturer outside the USA is not automatically exempt from reporting requirements and complaint handling. The contract manufacturer outside the USA may decide to label the product as a) “Manufactured by”, b) “Manufactured for”, or c) “Distributed by.” Options “a”, “b” and “c” would list the importer’s name because they own the 510(k), and they are the distributor. This situation often occurs when companies outside the USA want to sell a product in the USA, but they do not want to take on the responsibility of obtaining 510(k) clearance. These firms often believe this will exempt them from FDA inspections, but the FDA is increasingly conducting FDA inspections of contract manufacturers due to this private label situation.
  2. If the manufacturer owns the 510(k), then the manufacturer outside the USA is identified as the “specifications developer” and the “manufacturer,” while the initial importer will be identified as the “initial importer.” The importer may also be specified as the complaint file establishment and/or repackager/relabeler in the FDA registration database. The manufacturer outside the USA will not be able to import the device into the USA without identifying an initial importer in the USA in the FDA FURLS database. The manufacturer outside the USA may decide to label the product as a) “Manufactured by”, b) “Manufactured for”, or c) “Distributed by.” Options “b” and “c” would list the importer’s name, while option “a” would list the manufacturer’s name. This situation often occurs when US companies want to be the distributor for a product made outside the USA, and the company wants a private labeled product. This also happens when the OEM wants the option to have multiple US distributors.

In both of the above private-label situations, the non-US firm must have a US Agent identified because the company is located outside the USA. The US Agent may be the initial importer, but this is not required. It could also be a consulting service that acts as your US Agent. The US Agent will be responsible for receiving communications from the FDA and confirming their role as US agents each year when the registration is renewed. Medical Device Academy offers this service to non-US clients we help obtain 510(k) clearance.

Follow-up questions

A Korean company, with a US distribution subsidiary, would like to private label a medical device with an existing 510(k) owned by another company in their name. Does the Korean company need a contract in place before private labeling? Does the US subsidiary and/or the Korean parent company need to be registered in the USA prior distribution of the private-labeled version of the device in the USA?

Rob’s response: Initially, it was unclear from the wording of the question as to whom is the 510(k) owner, which company will be on the label, who is doing the labeling, and who is doing the importing to the USA. The person asking Joe Hage this question tried clarifying their question via email, but we quickly switched to scheduling a phone call using my calendly link. I have reworded the question above, but here are some of the important details I learned during our phone call:

  1. The person asking was already acting as the relabeler, repackager, and they were distributing the product in the USA. This person’s company is also registered with the FDA.
  2. The device is 510(k) cleared by another US company, and there is no need to worry about the complications of an initial importer being identified for a product manufactured in the USA.

In this situation, the relabeler/repackager can relabel the product for the Korean company’s US subsidiary as long as there is a quality agreement in place for all three parties (i.e., relabeler, distributor, and manufacturer). There is no need for the Korean parent company to register with the FDA. There is no need for a new 510(k) submission, and the US subsidiary does not need to register with the FDA—as long as the quality agreement specifies that the US subsidiary will maintain records of distribution, facilitate recalls if required, and notify the manufacturer of any potential complaints and/or adverse events immediately. The manufacturer with 510(k) clearance will be responsible for complaint handling, medical device reporting, and execution of recalls according to the agreement. The relabeler will be responsible for maintaining records of each lot of product that is relabeled for the US subsidiary, and the relabeler must maintain distribution records that link the original manufacturer’s lot to the lot marked on the relabeled product.

If you have questions about the private labeling of your device, please contact us.

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FDA Guidance Documents Released Recently

The article reviews FDA guidance documents released in the past few months, including the new Final FDA guidance on biocompatibility, published June 16.

ODE Final Guidance Documents FDA Guidance Documents Released Recently

For anyone responsible for monitoring new and revised regulatory requirements, the FDA guidance documents are something you probably check at least once every month. If you are not familiar with these FDA resources, here are the links for two of the medical device FDA guidance documents webpages:

New Final FDA Guidance Documents

The last time I reviewed an FDA guidance document was in February for the new guidance document from the FDA related to usability engineering and human factors engineering. There was a new final FDA guidance document released by the office of device evaluation on June 16: “Use of ISO 10993-1.This biocompatibility guidance was expected for release in December, but the release was delayed.

Use of ISO 10993-1

The new biocompatibility guidance that was published last month provides specific guidance about the application of certain tests required for demonstrating biocompatibility. For example, test article preparation and risk assessments for the applicability of specific tests is addressed. A revised test matrix is included in the guidance document. Special considerations are provided for each of the following biocompatiblity tests:

  • cytotoxicity,
  • sensitization,
  • hemocompatibility,
  • pyrogenicity,
  • implantation,
  • genotoxicity,
  • carcinogenicity,
  • reproductive and developmental toxicity, and
  • degradation assessments

New Final Rule for Symbology

In addition to FDA guidance documents, the FDA also released a final rule on symbology that will modify 21 CFR Parts 600, 801, and 809. The FDA is finally changing its position on the acceptance of harmonized symbols in place of English text. The FDA is accepting ISO 15223-1 as a recognized standard and allowing manufacturers to use the symbols instead of English text to facilitate global harmonization of labeling. The FDA is only allowing the use of Rx-Only as to indicate that a product is a prescription only. The guidance even defines the acceptable process for creating new product-specific pictograms. The effective date of the new final rule will be September 13, 2016. 

New Draft FDA Guidance Documents

In addition to final FDA guidance documents, there have been several new draft guidance documents that were released recently:

  1. List of Highest Priority Devices for Human Factors Review
  2. Public Notification of Emerging Postmarket Medical Device Signals (“Emerging Signals”)
  3. Characterization of UHMWPE for Orthopedic Devices
  4. Technical Considerations for Devices for Additive Manufacturing

The second two FDA guidance documents focus on materials that are important for orthopedic manufacturers because UHMWPE is used as a wear surface for join implants, and many of the implants and instruments are now being manufactured using additive manufacturing instead of forging, casting or milling bar stock.

How to keep up on FDA Regulation Changes

If you are interested in keeping up on new and revised regulations from the FDA, I wrote a blog explaining four ways to identify new and updated FDA regulations. The blog identifies FDA webpages for the following four types of updates:

  1. Guidance Documents
  2. Recognized Consensus Standards
  3. Device Classifications
  4. Total Product Lifecycle (TPLC) Database

The ISO 15223-1 standard for medical device symbols has been released for several years, but the FDA did not recognize it until June 14, 2016. The recognition of the Standard is part of the implementation process for the new final rule regarding the use of symbology for medical device labeling. The timing of this new final rule coincides with the implementation of UDI labeling requirements for Class II devices. Also, the new European Medical Device Regulations now specify labeling requirements for the primary sterile packaging as part of the Essential Requirement (ER) 19.2:

  • (a) an indication permitting the sterile packaging to be recognized as such,
  • (b) a declaration that the device is in a sterile condition,
  • (c) the method of sterilization,
  • (d) the name and address  of the manufacturer,
  • (e) a description of the device,
  • (f) if the device is intended for clinical investigations, the words: ‘exclusively for clinical investigations’,
  • (g) if the device is custom-made, the words’ custom-made device’,
  • (h) the month and year of manufacture,
  • (i) an indication of the time limit for using or implanting the device safely,
  • (j) an instruction to check the Instructions For Use for what to do if the sterile packaging is damaged etc.

These new requirements will require many manufacturers to redesign labeling for sterile packaging, and the ability to use symbology will assist in creating globally harmonized labeling.

FDA Guidance Documents Released Recently Read More »

FDA 483 Inspection Observations Pareto Chart for FY 2015 Data

This article presents a Pareto Analysis of FDA 483 inspection observations from FY 2015. It compares the trends observed with a similar Pareto analysis that was performed a couple of years ago on FY 2013 data.

FY 2015 Pareto Analysis of FDA 483s FDA 483 Inspection Observations Pareto Chart for FY 2015 Data

Method of Data Analysis for FDA 483 Inspection Observations

The FDA posts Excel spreadsheets on the website to download data for FDA 483 Inspection Observations. These spreadsheets include inspection results for all the divisions of the FDA. To perform data analysis for FY 2015 results, I deleted the sheets that were not specific to medical device manufacturer inspections (i.e., only used data from CDRH). I sorted the data by the regulation that was referenced. For example, all the sub-clauses for 21 CFR 803 were combined into one category for the Pareto analysis. The combined categories were then sorted from the most frequent 483 inspection observations to the least frequent 483 inspection observations. The data was then added to the graph that I produced in February 2014 using FY 2013 results as a second data set. The resulting graph is shown above.

Comparison of FDA 483 Inspection Observations between FY 2013 and FY 2015

For MDR Compliance (i.e., 21 CFR 803), there was a slight increase in the number of 483 observations issued from FY 2013 to FY 2015. However, the difference was only a 1% increase from 6.2% to 7.2% of the total number of 483s issued. There was an even smaller increase in the number of findings related to purchasing controls (i.e., 5.6% increased to 6.1%). I noticed a slight drop in the number of findings related to design controls, CAPA, and complaint handling. However, the overall trend for FY 2013 and FY 2015 is essentially the same.

There are two other categories where an increase was observed: 1) process validation increased by 0.7% from 4.8% to 5.5%, and 2) control of nonconforming product increased 0.8% from 4.3% to 5.1%. These areas are important. Control of nonconforming product is one of the major sources of CAPAs and often results in design changes. Therefore, FDA inspectors are reviewing your data for a nonconforming product during inspections to help them identify potential CAPAs and design changes that may have been made. The typical sequence is 1) nonconformity, 2) investigate nonconformity as part of a CAPA, and 3) initiate a design change as a corrective action.

Process validation is a completely different area that is separate from CAPA, complaint handling, and MDRs. However, inadequate process validation is a common root cause of nonconformities. Therefore, inspectors often follow an audit trail from a nonconforming product record back to a process change that was implemented but inadequately validated. Thus, an increased focus on nonconformities may be the reason for an increase in FDA 483 inspection observations related to process validation.

So what’s the big deal?

This proves that the FDA inspectors continue to be predictable. The “playbook” for FDA inspections is the QSIT Manual. It hasn’t changed since 1996. Yet, companies continue to be shocked and amazed by FDA inspectors.

Additional Resources

If you want to learn how to prepare for FDA inspections, I recorded a webinar you can download (FREE). I recorded the webinar in May of 2014, but it’s been a couple of years, and I’ve learned a few new tricks. Therefore, I’m going to re-record the webinar and update it for lessons learned. I’ll even share a few tools and approaches to avoid findings and reduce the risk of warning letters. I’m also evaluating a new application that is designed for teams to have private chats and file sharing during an inspection. Stay tuned to my webinars page, and I’ll post that webinar soon. Maybe I’ll record something from Germany next month.

Until then, I am working on a webinar specific to medical device reporting. Many companies have still not updated their MDR procedures to reflect the eMDR process using electronic submissions gateways. Therefore, I’m releasing an updated procedure for MDRs, and I am offering a webinar bundle to train people on how to comply with 21 CFR 803 and the procedure. You might also be interested in my previous webinar specific to control of the nonconforming product.

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483 Response: Which corrective action plan should you write first?

Article explains how to determine which FDA Form 483 response you should write a corrective action plan for first and why.

chicken and egg 483 Response: Which corrective action plan should you write first?

In a perfect world, you would not receive any inspection observations from your next FDA inspection. However, most companies get at least one observation resulting from an FDA inspection and often there are multiple observations on an FDA Form 483. If you

Most Common FDA 483 inspection observation

Companies that have not experienced an FDA inspection before worry too much and prepare too little. Inspections are predictable and certain inspection observations are much more common than others. A couple of years ago I wrote an article analyzing the most common FDA inspection observations. The most common observations are specific to design controls (i.e., 21 CFR 820.30). However, this fact is distorted because many companies receive multiple observations during the same inspection related to design controls. For example, a client of mine recently received three from one inspector: 1) lack of design reviews, 2) lack of design validation, and 3) lack of risk analysis. All three were found during the review of the same design history file and the one corrective action addresses all three observations.

how to determine which FDA Form 483 response you should write a corrective action plan for first

2nd Most Common FDA 483 inspection observation

The second most common observation is specific to corrective and preventive actions (i.e., 21 CFR 820.100). Typically the company has inadequate procedures for verifying and validating effectiveness of corrective actions taken. If this is one of your FDA 483 observations, then you may have a problem with CAPA training or with the design of your CAPA form. If there is no place on the CAPA form to document your effectiveness check, then you might easily forget to perform the verification and validation of effectiveness. Another possibility is that personnel are confused between verification of implementation and the verification of effectiveness.

What if you have multiple FDA 483 observations?

Other common FDA 483 observations include medical device reporting, complaint handling and rework of nonconforming product. If you receive more than one FDA 483 inspection observation, you need to assume there is a chance that the inspection outcome will be “Official Action Indicated” (OAI). In this case, you need to provide a 483 response to your FDA district office within 15 business days. With such a short time to prepare your 483 response, you need to be efficient. Which 483 response should you initiate first and why?

If one of the inspection observations is related to the CAPA process, that 483 response should be your top priority. The reason for this is that the FDA will want to see objective evidence of implementing corrective actions whenever possible. If you use your CAPA procedure and form to document the 483 response, then you can show the FDA how the revised procedure or form will be used in your 483 response. If you write your 483 response for other inspection observations first, then the other 483 responses are using the existing procedure or form that the identified as inadequate.

Your first step should always be to implement corrective actions to address an inadequate CAPA process by revising the procedure or the form. Once the procedure or form is updated, then you can use the new process to document the rest of your 483 responses.

Training Webinar for an FDA 483 response

If you need help preparing an FDA 483 response, click here for our webinar explaining the 7 steps for responding to an FDA Form 483 inspection observation. You can also download a CAPA procedure and CAPA form from our SOP page.

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FDA Human Factors Guidance

In 2016, the FDA released a final FDA Human Factors Guidance that explains the requirements for human factors testing of medical devices.

Screenshot 2016 02 04 at 1.24.04 PM FDA Human Factors Guidance

FDA Human Factors Guidance

The FDA released a final guidance document on the subject of “Applying Human Factors and Usability Engineering to Medical Devices.” This is a final guidance document that replaces the previous version that was released in 2000 and the draft that was released in 2011. The diagram below is Figure 3 from this new FDA guidance, and it includes references to sections 5 through 9 of the guidance document.

What’s in the new FDA human factors guidance?

The organization of the guidance is similar to an ISO standard. Section 1 is the introduction. Section 2 is the scope of the guidance. Section 3 includes definitions, and Section 4 provides an overview of the human factors process and usability engineering as these concepts apply to medical devices. Sections 5 through 9 of the guidance explain the details of the process for applying these concepts to medical devices and risk management. The guidance document includes six references to national and international standards that include human factors engineering or usability engineering, and there are 19 references to articles about human factors engineering and usability engineering at the end of the guidance document.

Adding human factors to your risk management procedure

The steps in the process for human factors engineering and usability engineering mirror the risk management process as defined in ISO 14971 except this guidance does not specify developing a risk management plan or the need to create a risk management file. Identification of hazards related to use errors is the first step. Risk controls are implemented in order to reduce the risk of harm due to use errors. The risk controls are verified and validated, typically through simulated use studies or clinical studies. Therefore, you should be able to integrate usability engineering into your risk management process by specifying that hazards should include use errors, the environment of use, and the device/user interface. The risk controls section does not need to be revised, but the verification and validation of risk controls need to include simulated use and/or clinical studies in order to verify that risk controls specifically reduce the risk of use errors. It might also be useful to specify that the environment for use should be included in simulated use studies.

Creating a Usability Engineering Report Template

Clients often ask me what they need to do with regard to human factors engineering and usability engineering for documentation in their technical file and design history file. I recommend that they create a usability engineering report based on ANSI/AAMI/IEC 62366. However, companies often do not want to purchase the standard, and they seldom have time to read and understand what the standard is recommending. Now we have a free guidance document that is available from the FDA. Therefore, I recommend that you create a template for your usability engineering report based on this new guidance. If your company makes many types of products with multiple hazard types, then you will need a somewhat generic report template. However, companies with only one or two device families should be able to pre-populate a report template with sections for specific categories of hazards that are applicable to their device family. Once you have a template, this can be used to create a usability engineering report during the design process for any new medical device you are developing.

Updating Your Risk Management File to Include Usability

For products that are already on the market, you should already have human factors engineering and usability engineering incorporated into your risk management file. If you don’t, I recommend updating your risk management file in the following ways:

  1. update your post-market surveillance plan/risk management plan to specifically gather information about use errors related to the use environment, the user, and the device/user interface

  2. update your hazard identification report to include hazards related to use errors

  3. update your risk analysis to include risk controls that you have implemented to reduce the risk of harm related to use errors

  4. perform and document verification and validation of any new risk controls that you may implement related to use errors

  5. update your instructions for use to include warnings and precautions about use errors

  6. develop training tools, such as videos, to demonstrate possible use errors and how to avoid them

The bulk of human factors engineering and usability engineering are documented in the risk management file. Risk management documentation is only required for FDA submissions that include: 1) software of moderate level of concern or higher, 2) De Novo Classification Requests, and 3) PMA submissions. If you have a non-software device for which you are submitting a 510(k), then you do not include a risk analysis with your submission. Therefore, the only way that the usability factors are addressed is by reviewing the simulated use validation of the device and the instructions for use. It is still critical that design teams address usability engineering, however, because identifying use errors and implementing risk controls to eliminate use errors will prevent product complaints and adverse events. If these issues are not addressed during the design of a new product, corrective actions and possibly recalls will be needed after the product launch. FDA inspectors will also identify weaknesses in your risk management activities when they identify complaints that are not addressed in your risk analysis.

Additional Training Resources for Usability Engineering

Our human factors testing webinar was recently updated by Research Collective–a consulting firm specializing in usability engineering. SYS-048, Medical Device Academy’s Usability Procedure, is compliant with IEC/ISO 62366-1 (2015). The procedure includes a template for conducting summative (validation) usability testing. We have also updated our design plan template to include usability testing elements.

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