Your Fifteen Years of Fame. Part 2

We are continuing our reviewing a recent FDA Warning Letter.  This WL is such a rich tutorial on what not to do, we are devoting two blog posts to it.  https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/allay-pharmaceuticals-llc-609023-01272021

Last time we looked at the WL’s observation #1.  This time we will delve into just a few of FDA’s observations simply to illustrate how you should respond to a Warning Letter or a Form 483.

Observation #2:

“Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).”

The company had apparently been inspected previously and FDA had taken samples of their product to be tested.  The results of that testing were Out Of Specification (OOS) and FDA is now telling the company that their investigation of that OOS was inadequate.

Note:  The inadequacies that FDA states in this WL do not stem from the fact that FDA performed the analysis.  The investigation that FDA requires is applicable no matter how the OOS is discovered.

The observation starts by saying that the specification itself is wrong.  The ingredient specification conflicts with the specification given in the United States Pharmacopeia.  Since the USP is, by definition, correct, the company’s specification is wrong!

This WL then informs the company that FDA has warned the customer as well.  How’s that for building customer relations?  You screw up and your customer gets hammered, too.

This WL is unusual because it gives much more detailed expectations than most WLs.

The company is told that their original response to the OOS is inadequate and that they must

• review ALL the products they manufacture to ensure that ALL their specifications are appropriate.
• Update their procedures for setting product specification.
• Assess their procedures for OOSs, complaints, deviations, CAPAs, and failures.  More on this in a minute.
• Test all their produced lots that are still within expiration dates for all quality attributes.

Corrective And Preventive Action (CAPA)

Much of this WL centers around CAPA.  The requirements for CAPA are similar to the way that companies should respond to WLs, as well.  So, we’re going to spend some time on it.  You first need to find the root cause for any OOS, complaint, deviation, or failure.  We’re not going to spend time on that here, other than to re-emphasize its criticality.

It’s amazing how many smart people settle for symptomatic solutions.  Why they are willing to hose the company’s money out the door by sweeping problems under the rug baffles us.  Suffice it to say that FDA will not be satisfied with this kind of subterfuge. 

Once you’ve identified the root cause(s), develop Corrective Actions to make sure that the root cause and any contributing causes are eliminated.  Oh BTW, “Employee needs to be retrained” is rarely an acceptable corrective action.  Blaming the employee rather than the process creates fear and inhibits open investigations of problems.

When implementing your Corrective Actions, you should define effectiveness criteria so that you can verify that you truly found the root causes.

The WL again does the company a favor by spelling out that they must completely overhaul their CAPA process.  “Address how your firm will ensure all phases of investigations are appropriately conducted.”

You should then step back and review your operation for other similar situations where the same problem might occur.  Implement Preventive Actions so that they don’t occur.  This is the pay-off step because it’s cheap and it’s money in the bank.

The company’s relationship with FDA

Although compliance with the technical requirements of GMPs is essential, developing a relationship of professional trust with your FDA inspectors is critical.  This company has clearly annihilated any trust they might have had with FDA. 

Anyone dealing with FDA should look at the mission statement on fda.gov:  “…protecting the public health…”  This is the goal of every inspector that enters your facility.  They know that they cannot stand over your shoulder every day.  At some point the inspector has to leave.  The decision whether to allow you to continue operating depends on the level of trust that the company has established with FDA. 

No company is perfect.  The inspectors can always find problems.  FDA’s decisions about:

• whether to allow you to continue to operate,
• how long to stay and inspect,
• how soon to return

will depend on how much credibility you have established when you tell them that you will correct their observations. 

Keep in mind that the inspectors have careers just like you.  If they walk away leaving you in operation and then you ship product that sickens consumers, that fact will attack FDA’s bureaucracy.  The next question will be, “Who inspected these people last and why did they allow them to stay in business?”

Ok, the rest of the WL is self-explanatory.  I’ll just make one more comment on the text of the WL.  FDA told the company to get a consultant.  Let’s decode that statement.  On the surface FDA is telling the company that they don’t have the internal expertise to fix the problems.  

But the company could hire that expertise as full-time employees, right?  Yes, and they should.  But practically, no, not in the numbers that will deliver the speed that FDA wants. 

The real elephant lurking in the room is that FDA doesn’t trust management to supervise newly hired quality personnel in a way that will allow them to do their job properly.  What FDA really wants is a culture transfusion.

There is at least a chance that an independent consultant, whose reputation depends on guiding their customers through to compliance, might successfully install a permanently embedded quality system in the company.

Your response to the WL

 The WL will tell you that you have 15 working days to respond.  Take this seriously!  Here’s what to do:

1. Start with the first observation.  Copy it verbatim into your response.  Remember what we said in the previous post:  “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.”  Detail how you have addressed the specific gaps that the inspectors found.  Include documentation.
2. Dig deep into those gaps to find the root cause that allowed them to happen.  Include documentation of that investigation.
3. Document your corrective Actions.  Remember that if SOPs are revised that training will be required.  Include your documentation of that training.
4. Each Corrective Action needs a plan for verifying effectiveness.
5. Include your documentation of all of the above as attachments and move on to the next observation.

What if you can’t get all that done in 15 days??

Of course, there’s no chance that this WL could ever be remediated in 15 days, most WLs for that matter.  So, here’s what to do:

1. Follow the steps above and finish everything that you can.  Write up your work so far including documentation.
2. Write a detailed project plan for the remaining work.  Follow typical good project management practices:
   • Break down the compliance project into discrete, manageable parts.
   • Include timelines, resource identification, and responsibilities.
   • Don’t forget personnel or organization changes.
   • Be conservative with your time targets.
3. Detail how your plan will prevent risks to consumers while you are executing the compliance project, for instance:
   •  Outsourcing to qualified suppliers until you have adequate equipment and SOPs in place.
   • Suspending production of risky products.
4. Send your response to FDA within the 15-day limit including all the records to back up your progress to-date.
5. Follow up with FDA at appropriate intervals to update your progress.

This response is your starting point

Top management in the company needs to support the remediation project.  The company has put itself into a trust hole with FDA.  The task now is to get out of that hole.  As usual, step one is to quit digging.  Then it becomes a tough slog of building trust one brick at a time. 

Best advice?  Don’t get yourself into this hole.

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