FDA Inspections: Being prepared when you know you have problems

I am often asked how best to prepare for an FDA inspection when you know that you have problems. My first response is that they have already taken the first step: acknowledging that there are problems. Believe me. That is a huge first step. Just like AA’s 12 step program, it’s not until you are willing to admit this aloud that you are on the road to recovery. But just knowing that problems exist is not enough to survive an FDA inspection.

Here are the various positions that firms find themselves when the FDA comes knocking. You can decide which of these scenarios is the best possible position.

1.    We know what our problems were, but they have been resolved.

Let’s say an FDA investigator stumbled upon a manufacturing work order system that allowed changes to production equipment without a review by QA on the impact on the state of validation. The best position to be in is to say that you were made aware of the problem; the system has been revised and employees trained; a retrospective review of maintenance work orders was conducted for product impact and appropriate action taken.

It engenders confidence when an inspector can see evidence that a problem has been resolved and a product impact analysis has been performed. It portrays the firm as being responsive to self-detected problems as a normal course of business.

2.    We know what our problems are; we have a comprehensive plan; we are executing the plan on schedule.

A common strategy for firms that anticipate a Warning Letter or a Consent Decree is to have a third party conduct a thorough systemic audit and to develop a comprehensive corrective action plan. It’s a way of saying to the FDA, “You can’t force us do anything that we aren’t already forcing ourselves do.” The plan is in writing, deliverables defined, reasonable target dates are established, responsibilities assigned, and management is tracking accomplishments versus the plan.

It can diffuse an otherwise nasty inspection when management demonstrates that it is taking the initiative to deeply understand its state of compliance and holding itself responsible for timely results. The FDA inspector may still give you observations, but the Establishment Inspection Report (EIR) will note the initiative you have taken. Also, the FDA may quibble over the scope of the plan, or the timetable for completion, but it is far better to have the plan be the center of discussion than inaction.

3.    We know what our problems are; we have a plan.

The difference between this position and the one above is the failure to execute according to the schedule provided in the comprehensive corrective action plan. In my opinion, failure to execute is one of the most significant issues that separate the wheat from the chaff. Some companies just cannot get out of their own way to accomplish meaningful change. Administration substitutes for real work; team meetings substitute for personal accountability; and production schedules take priority over executing the comprehensive compliance plan. Something else always is more important—there is no discipline, no organization alignment, and no leadership.

It becomes evident during an FDA inspection that it is all talk and no action. FDA cites repeated observations from previous inspections. With FDA on record that there will be no multiple Warning Letters, this places you in the crosshairs of increased enforcement action.

4.    We know what our problems are; we have no plan.

This is perhaps the most dangerous position to be in. Consciously not taking action when there are known problems is irresponsible. When faced with an issue during an inspection, you are either forced to say that you were not aware of the problem, or that you were aware of the problem and have not taken action. Neither response is very pretty. One is actually a falsehood.

This signals to the FDA inspector that CGMP compliance is not considered to be important to the firm, and that the dots have not been connected between regulatory compliance and patient safety. To be clear, management is personally legally liable for knowing its problems and resolving them. This is a real slippery slope.

5.    We don’t know what our problems are.

What problems? This describes companies that rely on FDA inspections to tell them what the problems are, and the firm is always aghast to learn about the problems and ready to call someone on the carpet. This describes management that thinks an FDA483 with five observations is an improvement over the previous one with ten. This also describes the company that does not have established processes to take responsibility for the effectiveness of the quality management system such as: management review of quality system performance metrics, internal compliance audits—or just generally thinking that it is someone else’s job to worry about it.

You would be surprised at the number of senior management who can’t even tell you what their top five problems are. FDA calls this “inspecting into compliance,” and they have very little patience for this unenlightened perspective. These are the bottom feeders in our industry.

So, which position would you rather be in during an FDA inspection when you know you have problems?

The QA Pharm

When All is Said and Done, there is More Said than Done

I couldn’t help but contrast the claims made by NexgenPharma on their website¹ with the responses to observations cited in the recent FDA Warning Letter about their operation.²

Website: Each pharmaceutical product undergoes rigid process validation…

Observation: Your firm has not conducted adequate cleaning validation or provided scientific justification.

Response: We’ve done it this way for the past [redacted].

Website: We test and analyze raw materials, products in production and finished goods using advanced analytical techniques…

Observation: Your firm does not have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance…including the identity and strength of each active, prior to release.

Response: …are closely related in structure and thus, do not necessitate individual testing for strength…We will test each drug product component at least once a year…

Website: Each pharmaceutical product undergoes rigid… stability…

Observation: Your firm does not have a written testing program designed to assess the stability characteristics of drug products…

Response: …stability studies are only performed if the customer pays to conduct the studies…(we) rely on stability data recorded in the years before and after to support the label expiry…

Website: Nexgen adheres to the strict standards of the current Good Manufacturing Practices (CGMPs) established by the US Food and Drug Administration…

Observation: …we remind you of your responsibility for ensuring that your firm’s drug manufacturing operations comply with applicable requirements, including the CGMP regulations. FDA expects NexgenPharma, Inc. to undertake a comprehensive and global assessment of your manufacturing operations to ensure that drug products conform to FDA requirements.

Response: None. (What can possibly be said after that?)

It’s a really impressive website. But it reminds me of the adage: “An ounce of image is worth a pound of performance.” On behalf of all the patients dependent upon their performance, good luck.

The QA Pharm

¹ http://www.nexgenpharma.com

² http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm233276.htm

Routine Problems, Routine Explanations

Here I am at a foreign airport with time on my hands due to a significantly delayed flight. Usually I roll with the punches when travel is disrupted, and I have even grown accustomed to routine, scripted explanations. Same problems; same explanations. This time it was the ubiquitous "delayed incoming plane." The gate agent started to get annoyed when I said that “delayed plane” is a symptom, not a root cause. (It’s not her fault.)

This triggered a thought about disruptions—or more to the point—manufacturing problems that become commonplace, and routine ways I recall having seen them handled—or not.

One clever approach to handling a particular recurring deviation was to have a pre-printed form. The investigation was already written with the exception of the slight nuances, which were accommodated by blanks. This "Mad Lib" approach was completed in a matter of minutes, and a QA approval was handily secured.

Another very "efficient" approach was to use a "planned change" system to work around the recurring (planned?) problem. Another variation on this theme was an "emergency change" system used to document the quickie permission to urgently deviate from the established process—as it had many times before for the same emergency.

I would be the first to acknowledge that "things" happen, and that there needs to be a mechanism to efficiently and expeditiously handle the unusual. CGMPs would not have provided for a deviation investigation system if we lived in a perfect world.

But when the "unusual" becomes standard practice, and when quickie methods routinely substitute for permanent technical solutions, then we are buying into form over substance; ad lib over defined; accommodation over discipline; rationalization over justification. Our patients, which is to say—our business—deserve better.

Warning Letters are replete with observations about recurring problems. So, why do we tolerate habitual humans errors, aging equipment, half-baked processes, retro facilities, and uncoordinated support services that cause problems that are more predictable than our processes?

You tell me.

The best practice I've seen is the "Three Strikes You're Out." When a recurring deviation and obviously ineffective CAPA happens the third time, you no longer own the deviation/ investigation/ CAPA—your boss does. Each time thereafter, it goes up the chain of command. Now that is taking solving problem seriously—or a reaction out of frustration.

Besides, isn’t “repeat CAPA” an oxymoron?

I see the premium members queuing at the gate. I just might get stateside today.

The QA Pharm

FDA Enforcement Inflation: What's Next?

I grew up in a home where just a cast of my mother's glance was enough to cause me to stop dead in my tracks. I knew "the look" quite well. There were no raised voices.

When a parent doesn't follow through on the gentlest of correction, then the parent is communicating that an appropriate response is optional. Out of frustration, parents often up the ante by resorting to yelling and making idle threats. Nothing really changes, because nothing has to. There is more yelling than consequences.

Such has been the history of FDA regulatory enforcement. The threats had to escalate. Their voice had to get louder. The stakes had to get bigger to get industry attention.

I remember the day (now I sound really old) when an FDA483 caused you to clutch your chest and wonder whether your career was over. Over time the FDA483 just became a "calling card" as we used to call it. It was just evidence that the FDA paid a site visit. “It’s just a short one,” we’d say. “No biggie.”

Then Warning Letters became more prolific because FDA483s just didn’t get sustained compliance. “Everyone takes their turn in the barrel,” we’d say. “It was just our turn.”

Then the yelling started.

Eli Lilly (1989), Warner Lambert Consent Decree (1993) and American Red Cross (1993) ushered in a new era and a new FDA enforcement lever. There are now over sixteen major Consent Decrees, not counting those from the swath cut through the medical gas industry in early 2000.

Rather than the "pay-as-you-go" investments in improving the manufacturing operations and ensuring the state of control, some apparently have chosen profits over control until one day all goes wobbly and the FDA finally blows its stack. Even so, a fine of multi-millions of dollars is a drop in the bucket to the company. (The cost, of course, is passed on to patients.) “A blip in the stock price. A one-time hit,” we’d say.

But last week things started getting personal, and the FDA is threatening to up the ante again. Now mom is throwing the china to get attention.

Although the Parke Doctrine had been at the FDA's disposal since 1975, apparently it is being dusted off because, well—it has to be.

The Parke Doctrine is all about personal accountability. Individuals—not corporations—are personally charged with a crime. Their careers are over, and a criminal record taints them for life. (See The QA Pharm 9/11/10.)

Unfortunately, this just might be what it takes for the management at some companies to take their personal role seriously in assuring that they are in compliance with FDA regulations enacted to ensure public safety.

Thankfully, not all pharmaceutical companies are recidivists. Hopefully, reading the trade news about Consent Decrees will not become passé. 

Threat of personal prosecution needs to grab industry attention—like Consent Decrees, ah…like Warning Letters, um…like FDA483s used to.

The QA Pharm