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