Your Fifteen Years of Fame. Part 1

What happens when your company gets a Warning Letter from FDA?  Let’s hope it never happens to you.  But we’re going to explore that possibility in this post.  Then we’ll discuss how you should respond to FDA by reviewing a recent Warning Letter that you can see at https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/allay-pharmaceuticals-llc-609023-01272021

The Business Implications

Let’s start by mentioning all the great publicity you’re going to get from a Warning Letter.  What’s the most coveted real estate on the internet?  1^st page ranking on your favorite search engine, right? 

A Warning Letter is a quick and easy way to get a 1^st page ranking.  To see for yourself, just go the fda.gov, scroll down to the bottom, and click on ‘Warning Letters’.  Pick a recent one and paste the name of the company into your search engine.  Viola!  1^st page ranking.  The link takes you right to the WL on FDA’s website.  You can’t buy that kind of publicity, and that company wasn’t even trying.

Now think about your potential customer who is figuring out who to buy from next…

You have just lost an unmeasurable amount of future business.  Maybe you lost existing customers, as well.  Some of those customers will drop you immediately.  Some will keep you while they begin the arduous search for other suppliers.

It’s not just your customers.  You could also lose insurance coverage for your product.  Your customers may not be able to be reimbursed when they buy your product.

How long does FDA keep your Warning Letter on their site?  A lo-o-ng time.  If you correct all the citations in the warning letter and get a clean bill of health in a follow up inspection, FDA may issue a close-out letter and pull your warning letter off their website.  Otherwise, expect it to remain there forever collecting clicks like a porn site.

These are the business implications.  We haven’t mentioned the regulatory mess you’ve gotten yourself into.  At the bottom of the WL, it says that you have 15 working days to respond to FDA and detail how you will correct the observations in the WL.

How to Respond

We’re going to look through this WL and pick some specific items to illustrate how to respond to FDA.  But first, a few words about the overall format of the WL.

If you scan a WL, you will note that there is a pattern to the observations.  Each observation makes a statement like, “Your procedure for _____ is inadequate.”  It will cite a portion of the regulation.  Then it will give examples of specific gaps that the inspectors found.

WLs have this format for two reasons.  One, FDA has a software that the inspectors use to write WL.  The boilerplate in the application helps to make the inspections more consistent from inspector to inspector and across the globe. 

Two, this format has been shown to be valid in a court of law.  FDA does not want to take you to court.  But if they have to, keep in mind, that from the moment they walk into your facility they are collecting evidence that will stand up in court.

Let’s look at the WL in question.  Note who it’s addressed to, the CEO.  This is normal.  Why not the quality manager?  Because FDA does not consider the quality manager to have ultimate responsibility for the quality of the product.  Top management can delegate the execution of the quality system to others in the company.  But it cannot delegate responsibility for quality.

So, top management has to take ownership to fix the problems.  Top management has to gather resources from within and outside the company as necessary, or get out of the business.

One general comment.  You’ll see that this WL has been redacted frequently:  [(b)(4)].  Before a warning letter is published you have the ability to redact proprietary information.

The initial paragraphs simply inform the company what they already know, that their products are governed by the FD&C Act and that they are drugs.  We also see that the company was inspected six months previously and got a Form 483.  Apparently the company’s response was insufficient, because now FDA is back again with a lengthy WL.  The company needs to take this very seriously.

Let’s look at observation #1:

“Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).  Your firm failed to adequately validate the manufacturing processes for your (b)(4) tablets.”

If you look up 21 CFR 211.100a, you will see that there is no mention of “validation”.  No matter.  You have to do it anyway.  So if you don’t know what validation is, you need to get educated because it’s a much bigger topic than we can tackle here.  Start with https://www.vcillc.com/about-vci/what-validation

The WL states that the company did not prove the capability of their blender to make a homogeneous blend.  “During your process performance qualification (PPQ), blend samples were (b)(4) before analysis. When samples are (b)(4), it potentially masks the variability of your blend.” 

I’m going to guess that in this case (b)(4) means ‘composited’, meaning that instead of testing multiple samples from their blender independently, the company blended the samples together and THEN ran the content assay.  Therefore, the company has no idea whether their blender actually works.

The WL goes on to state that the company got an out-of-specification (OOS) result on one of its validation batches.  The company had shipped those validation batches despite the fact that they had an OOS, a clear violation!

The company’s proposed solution to the problem was to perform a concurrent validation.  FDA (predictably) shot that idea right out of the sky.  Validations must be prospective, not concurrent.  There were no parachutes.

FDA gives the company more details on how to respond than usual in this WL.  But there is a lot more hidden in the code of FDA-speak than is immediately obvious.

We’ll be back next week with more on this WL.  As the Air Force says, it’s a target rich environment.

How about you?  Do you have a similar story?  What has worked best for you?  Comment below.