What is an FDA warning letter & how should firms respond

Firms that are active in the biologics space face many possible challenges but the possibility of getting an FDA warning letter is one of the most intense.

The goal of today’s post is to explain what an FDA warning letter is all about. This analysis includes what such a letter means and what steps come next. How does this play out in the cell therapy space specifically too?

What’s in this article

What is an FDA warning letter? | Examples of Warning Letters | Untitled Letter | How should firms respond? | References

For some of the companies in the stem cell space who get such an FDA warning, they may not really know what a warning letter even means.

What does the agency expect of them? Are they in serious trouble?

FDA warning letter
FDA warning letters indicate apparent serious compliance issues.

What is an FDA warning letter?

Once a week, the FDA posts new warning letters on a hub of enforcement actions. These now-public letters tend to be newish. However, sometimes the agency will delay posting a warning letter publicly for some time. I feel like we are seeing that kind of delay less often these days, which is good.

An FDA warning letter is essentially a formal notification of one or more major violations. Here’s how the FDA defines it:

“A letter notifying a regulated industry about violations that FDA has documented during its inspections or investigations. Typically, a Warning Letter notifies a responsible individual or firm that the Agency considers one or more products, practices, processes, or other activities to be in violation of the Federal Food, Drug, and Cosmetic Act (the Act), its implementing regulations and other federal statutes.”

The agency doesn’t waste time sending a warning letter for minor things.

What is the structure of a typical letter of this kind?

It usually starts with recounting a recent inspection of the firm. The early part of the letter typically also references why the FDA has authority in this case. In the cell therapy space, we often see an initial statement in the letter that the firm is marketing an unapproved drug product. Also, it’s common to see statements that the clinic or other entity is not eligible for exemptions to specific regulations.

Then the letter may list specific violations. I’ve seen letters with nearly two dozen bullet points and sub-bullet points. Others are much shorter but highlight major problems.

For stem cell clinics, this list frequently mentions failure to comply with cGMP standards. Such a letter usually is sent by CBER.

Examples of warning letters

Here are some typical kinds of warning letters in the stem cell space.

Of course, the FDA can send warning letters outside the cell therapy space as well. Here are two examples of such letters.

  • Pfizer FDA warning letter. In 2020, the FDA sent a warning letter to Pfizer regarding its plant in India.
  • Prevagen FDA warning letter. The firm received this letter a decade ago. I haven’t seen any more recent agency action here. I recently wrote a fact-check of Prevagen and found serious reasons for concern.

What is an FDA untitled letter?

Most firms in our field contacted by the FDA don’t get a warning letter. Instead, an untitled letter arrives.

In a general sense, an untitled letter from the FDA is a step below a warning letter in terms of seriousness. However, I’ve seen FDA untitled letters to stem cell clinics that seem similar in content and tone to warning letters. It’s not always clear how the agency decides whether a letter is untitled or a warning.

One difference is clear. Most often, a warning letter follows an in-person FDA inspection and generation of a 483 inspection report, while an untitled letter does not.

I sometimes refer to untitled letters as “mini-warning letters.”

These letters could mean more action is to come in the future. The FDA has sent hundreds of untitled letters to regenerative firms just in the last few years. However, it’s unclear if they will follow up on those firms that continue to be non-compliant in a serious way.

I’ve suggested that the agency sometimes forgo requiring itself to do an inspection and issue a 483 form prior to issuing a warning letter. This change is meant for the stem cell clinic industry where hundreds of non-compliant firms are likely ignoring untitled letters. It’s not practical for the FDA to inspect all of them, but serious action is warranted.

How should firms respond to warning letters?

Typically, the FDA ends a warning letter by indicating what the firm should do next. The agency also will give the recipient a specific period of time during which a response is required. Most often this is around fifteen days. Maybe a few weeks.

There’s a sense of urgency.

If the recipient of the letter has one or more FDA compliance experts on staff, they should develop a plan to respond to the letter.

Firms in the unproven stem cell space that receive warning letters often have little-to-no FDA compliance expertise. It’s difficult for them in the short time given for a reply to bring new expertise on board, but it’s essential. There are consultants out there including law firms that can help devise a practical response to an FDA warning. You want someone with many years of expertise.

The response should be constructive. Either the firm should indicate it is going to do what the FDA wants or explain convincingly why not. Some letters do both, depending on the list of issues. It’s unusual for firms to respond aggressively but I’ve seen it a few times. I’m not sure that is an effective way to go.

While the FDA can be slow in taking the possible next steps for persistent non-compliance issues after a warning letter, the ultimate response could be serious. In rare cases, it could lead to an injunction effort.

Most often we never learn what happens after a warning letter or untitled letter. Two years ago the FDA sent out an unusually large number of letters in a short time but did that 2020 burst change anything more broadly?  Hard to say.

If all goes well in your response to the agency’s warning letter, you will receive an FDA close-out letter indicating as much.

References & notes

5 thoughts on “What is an FDA warning letter & how should firms respond”

  1. PS: I left out one other key, key area of focus of the FDA and that is “Training of all personnel” and maintaining “Personnel training files” – I can’t stress that one enough !!

    The FDA is huuuge on cGMP (Current Good Manufacturing Practices) and also concepts such as Total Quality Management and often one receives specialized off-site training in areas such as process control and statistical methods and statistical sampling/process control methods and if in QC one would be specially trained on “sterility techniques and practices”.

    If one works in a “clean room area” it’s an entire one day class with a qualified trainer on “How to gown and un-gown and dress” to enter the clean areas, including how to wash hands properly, put gloves on properly, understand “clean side” vs “dirty side” of gowning areas, use of air locks, what level clean room means what in terms of air particle counts and HEPA filtration levels, how to work inside the clean area properly, etc.

    IF you work in properly run FDA “regulated plant or environment” it’s almost a given that “Day one of employment” (actually many days in most cases) are spent in training, training, training !! From a VP down to a factory floor labor person “working the production line” – you must have proof of “being trained” on ALL company policies, procedures, all current FDA applicable regs and polices related to what you do or make at said facility, specifics to the area/product line you work on, etc.

    Before I ever set foot inside the manufacturing areas – or really did any actual “work” for the company – my entire first week was “training” (and the company must pay people while receiving their training, this can not be after-hours for people like the hourly factory floor labor, etc) and we had a formal “training department” and that’s all they did. And that includes “other training” such as “sexual harassment polices” to many other “company policies” but the bulk, was focused on “You are now in a FDA regulated environment – and here is what you need to know every single day you come to work”.

    Our entire facility had 24/7 manned guard gates to enter the parking lot and “pass keys on your badge” to “swipe” every area of the plant you entered, even just to get “on the property” from the parking lot, one went through pass-key badge operated “turn-style” gates to even get to a “door” to enter say the office areas or cafeteria even, etc.

    Day one – CURRENT GOOD MANUFACTURING PRACTICES via watching professional made videos, doing Q&A workbooks and “mini test taking” on what you viewed, having the company “training person or team” in the room giving lectures with Powerpoint slides, etc.

    You then, after each “Training” you receive – you sign a “I was trained on procedure or policy XYZ document and the trainer signs and dates it” and that goes into a key file, your “training record file” which on a FDA inspection, they often want to see those and may “pull them at random” and actually ask to speak to that person on the production floor for example and validate “were you trained as it says here in this training record” etc.

    IF a company is smaller – their are contract firms who can provide this training via expert “FDA compliance trainers” and via on-line courses, whatever is needed.

    The FDA does not accept “training” where the factory floor worker when asked “So, how did you learn what you do here at your work station” and the answer is, “Oh, they just had me stand here by Betty for a week and I watched what she did and I sort of learned or figured out what to do and now I run this station” when the FDA conducts a “surprise” on-site visit. Nope, not going to be accepted by the FDA as “having been trained properly”.

    The answer they want is, “I went through a classroom session with the company trainer on the ABC production lines and we also did a cGMP update and then they had a production lead who is a trainer, train me on my new work station. I also received written training documents and the operations manual for the workstation and spent my first week with the shift lead who is trainer certified until I could prove I could operate the machine and process in-compliance with no errors” blah blah etc.

    As stated – FDA is big, big big on “training of your personnel” and want to see proper records keeping of same. I, as a fairly high level technical person – I even maintained in my own files and “planner” I carried, all my training sessions, training “ratings” I received such as “cleared to work on product line A, B and C and all production lines and inside all clean room areas” blah blah. My badge even had stickers on it, showing all areas of the plant I was allowed to enter and was “trained” to enter and work on said equipment inside same etc. Almost like various security clearances for aerospace or similar jobs.

    That is a big one I left out – training, can’t emphasize it enough and RECORDS KEEPING !!

    All I can say is you better have proof and records and well kept files – it’s the FIRST THING the FDA asks for and examines every single time I saw them enter our plant, no matter what reason they were doing said “inspection” ; every single time began with “controlled documents inspection” and it could rapidly go down-hill fast from there if you couldn’t produce what they wanted to see !!

    1. @Rick,
      Thanks for all the info and interesting perspectives. A few quick reactions related to unproven stem cell clinics and suppliers who sell biologics to the clinics. They generally argue that they aren’t drug manufacturers at all so many of the FDA expectations about cGMP, record keeping, training, sterility, etc. don’t apply in the same way to them. We saw how that worked out in the Liveyon case where dozens of people got infections or even septic. It seems that the FDA expects more of good citizens of the field and is less strict with the clinics and suppliers. Less strict in the sense that hundreds of places selling unapproved biological drugs don’t get inspected at all and no action has been taken on them….so far.

  2. For many years I worked for a FDA regulated drug product maker – an “infusion drug product”. We were a private company (non public traded) and had been bought-out by a very large EU based medical products/drug making company, a company nearly 100 yrs old and still “family” owned.

    We operated numerous manufacturing facilities all over the globe and many in the United States. The facility where I worked as stated, we made a variety of “infusion based products” that were obviously FDA regulated.

    All I can say – is IF you’re running a legit, and seriously well managed company under the umbrella of “FDA regulated” you take ANY communication/inspection by the FDA ultra serious – from plant inspections to 483 warnings and of course the big daddy “Formal Warning Letter” or “Product field recall” – where all recalled product is segregated in your warehouse literally behind a chain link, locked fenced-off area in “quarantine”, all boxes opened via special QC folks, etc !!

    I was shocked when I’d see these stem cell pay-to-treat clinics get FDA 483 inspection warnings and then even a “Formal Warning Letter” and literally blow them off or write them back a one page, “No, we don’t break the law so leave us alone you FDA pests” etc !! I knew these firms were “tickling the tail of the dragon”, an old expression from the Manhattan Project atomic bomb days based on a highly dangerous experiment they performed.

    In my case, despite being a company with several $billion with a “b” in global sales – even WE would get FDA inspected on a regular basis and yes, we often had “screw ups” or “record keeping issues” etc that led to 483 warnings. We had ONE incident I know of that led to a FDA “Formal Warning Letter” – and here’s the response I’m familiar with in every single case I was involved in:

    INSTANTLY we’d have everyone from the plant director, to a Vice President who sat a door from the director, to all key engineering personnel, to the QC quality control folks, to the plant floor supervisors to the plant floor shift “leads” etc in a “All hands meeting” (series of meetings) and find out who, what, where, when, why etc and then a very high level FDA “regulatory expert” in the company would engage the FDA and meet regularly with them and address ALL their concerns until we were “cleared” and “in compliance again” via formal correspondence etc.

    In the “formal reply(s) to the FDA signed by our FDA regulatory expert and likely co-signed by a VP and plant director etc – we’d have laid-out in extreme detail ALL steps we planned to take aka “corrective actions” to get back into “compliance” per their 483 warnings and/or “Warning letter”, with a time-line, any issues or questions to them, a plan to meet with them regularly and give “corrective process project updates” etc. Detailed and formal !!

    We expended tremendous resources at great cost when the FDA “came a knocking” – as it can literally get an entire manufacturing plant “shut down” (hello Baby Formula news – anyone read that recently ?) and cost the company $millions to $10’s of millions or more in lost “down time” at a plant/facility the size of a major city block, employing many 100’s of people or more, etc.

    Here’s the basics on “How the FDA regulates facilities” – as there are many gross misconceptions !!

    The FDA DOES NOT tell anyone “You must make your product like this and such” or “You must do it using this process and this machine” etc. No.

    The FDA allows firms via their own engineering and development people etc great latitude to basically run their operation any way they see fit – as long as they have a “Compliant and in-control process” such that the FDA can “validate said process” – that’s the key !!

    When the FDA enters your facility – per my experience, they most often go straight to the “Product and production control and quality control document areas” (controlled documents of your process, procedures, quality control, etc. IF you don’t have said documents like that – “good luck” is all I can say !!) and they AT RANDOM begin to pull documents (the FDA has tremendous freedom after entering your facility to pretty much go anywhere they want, demand copies of and view any documents they want, etc).

    They then enter the plant area with said documents in-hand and they want to “validate” that you SAY WHAT YOU DO (in the written procedures) and then DO WHAT YOU SAY via observing the plant operations. That is how it “works”. First level FDA compliance training day, “SAY WHAT YOU DO, then DO WHAT YOU SAY” and you stay out of trouble most of the time !!

    Thus, just writing your FDA control documentation is sort of a “art-science” in and of itself. IF you say, “The product leaves machine A and then the operator turns to the left, picks it up, and then takes two steps and places it on a pallet to be moved to area B”, then by gosh that better be EXACTLY how it’s done, or they note “non compliance with procedure, operator turned to the right and took 3 steps, not two” – to use a sort of “over the top” example, but a real life kind of example.

    Thus, one learns to write their control procedures more “open” as in “The product leaves machine A and is transferred via pallet to room B, a non clean-room area via the air lock”, or whatever. Then the FDA can make “suggestions” such as, “When we saw product moved from machine A, we noted that the air lock is sometimes not closed fully, before the pallet operator is already opening the side to the unclean area. That should be corrected” and you reply, “We will correct that issue as asked, and present a plan and follow-up of the corrections we’ve made”. FDA, “Great, we accept that corrective action and will be awaiting the specifics as to your correction(s), thank you”

    Also, the FDA is obviously huge on things like sterility and cleaning procedures etc. Thus, you must have daily “cleaning schedules” (or hourly or whatever makes scientific sense for what your process entails) and be able to prove and document same. Example – we had miles of stainless medical grade piping carrying fluids that eventually end up in the veins of human patients – after X number of run hours, we’d have to run a hot steam “sterilization cycle” to ensure all piping was “sterile grade clean” at all times.

    The FDA would be big on watching, seeing and observing processes like that being executed- take swab samples, temperature samples to see you’re hot enough to kill bacteria, observe your piping instrumentation placement so that no “dead head traps” existed where bacteria can collect and form even during a sterilization, etc.

    That’s a 30,000 ft overview- it’s serious business and we held large group meetings CONSTANTLY on safety, compliance, diligence, MAKE A GOOD PRODUCT etc as “What we make here, IF we make mistakes can literally kill a family or loved one in the hospital or at the dialysis center, so YOU must do good work, and report anything you see that you feel is a risk or non compliant” blah blah.

    NEVER MESS WITH THE FEDS – always respond quickly, and take it deadly serious as their powers are broad and vast and can kill to a cold dead stop, a $200 million annual run-rate plant and turn it to a hunk of parked capital dollars sitting idle and worthless, and do it via the stroke of a pen and not much else !!

  3. Helpful explainer, and kudos to you for conveying some complicated issues in language understandable to non-lawyers!
    One additional note that may be useful* – many of FDA’s Untitled Letters, particularly in the Regenerative Medicine space, are aimed at violative marketing and promotional claims made on clinics’ websites, advertisements, and live talks. The problematic conduct raised in these letters include a broad range of actions, incl. but not limited to: (1) statements that an intervention has systemic bodily effects, which brings the cell therapy into the realm of “Drugs” (if it isn’t already!) – a classification that has many stringent requirements for evidence gathering, reporting, snd FDA approval, as well as limitations on promotional claims made prior to FDA approval and on charging patients / research participants; and (2) unsubstantiated claims of effectiveness that have not been established by valid and sufficient data.
    This latter category has had some interesting activity recently, incl FDA’s usage of patient testimonials posted on a company’s website and containing inappropriate claims as a proxy for the company itself making the same claims directly.
    Great job again, Paul!

    *Nothing in this entire post should be used or interpreted as a legal opinion, nor relied upon as legal advice.

    1. Thanks, Beth. Very useful additional info.

      As to agency activity re: the patient testimonials, can you cite a specific example or give a link?

      A helpful resource for searching for past or new untitled letters by CBER is here: https://www.fda.gov/vaccines-blood-biologics/enforcement-actions-cber/bimoteam-biologicsinternet-surveillanceother. However, my understanding was that the agency sent a few hundred cell therapy-related untitled letters in 2020-2021 and that’s clearly not reflected in the CBER resource page. Any thoughts on that? Were most of those letters not actually technically “untitled” but belong to some other nebulous class of letter?
      Also, only one untitled letter is listed for all of 2022, which is a very low number that I’m puzzling over.

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