FDA Leverages Corporate Responsibility for GMP Compliance

The response by the FDA to the GMP violations at McNeil Consumer Healthcare represents a revitalized, but often-unheeded trend. This trend has two salient earmarks: (1) remind corporate officials of their responsibility, and (2) expand inspections to other facilities in the corporate network.

In the case of McNeil Consumer Healthcare, its parent corporation Johnson and Johnson was lectured on corporate responsibility in a January 15, 2010 Warning Letter concerning Tylenol problems:

“Corporate management has the responsibility to ensure the quality, safety and integrity of its products. Neither upper management at J&J nor at McNeil Consumer Healthcare assured timely investigation and resolution of the issues.”

Then, it is no surprise that the FDA inspected the J&J Lancaster, PA facility to see if more than the McNeil brands of Tylenol, Motrin, Zertec and Benadryl had problems.

And more problems they found. This time with J&J OTC brands: Mylanta, Pepcid and Imodium.

In another recent example, the FDA issued a Warning Letter to Apotex (March 29, 2010) after concluding an inspection of their Toronto facility. Again, the Agency pointed to corporate responsibility:

“…inspection uncovered several violations that are identical to those found during a December 10 – 19, 2008 inspection of your Etobiocoke, Canada site that resulted in the issuance of a Warning Letter to the Etobiocoke site in June 2009. These identical CGMP violations demonstrated a lack of adequate process controls and raised serious questions regarding your corporation’s quality and production systems.”

I say “revitalized” response since a broader, corporate view by the Agency is not really new. Perhaps it’s just juicing up a bit more under the new administration and the consumer advocate-turned FDA bulldog Joshua Sharfstein, principal deputy commissioner.

For example, in 2007 there was the Abbott Laboratories Warning Letter (March 13, 2007) that pointed to their need to apply corrective actions globally:

“Although the Agency recognizes your firm’s commitment to improving product quality and compliance with the Quality System Regulation, the Agency is not satisfied with the pace and results of your firm’s past corrective actions as they have not been effectively, timely and globally implemented..."

And in 2006, Boston Scientific was issued a Warning Letter (January 25, 2006) covering three sites, but the FDA reiterated in that letter their awareness of issues at three additional sites from previous inspections:

“The purpose of this letter is to apprise top management of your inadequate corporate-wide corrective action plan as evidenced by the continuing serious deficiencies identified at each of these facilities and to remind you of your responsibility to ensure all facilities continuously comply with the Act and all pertinent regulations.”

The purpose of this FDA strategic direction can be summed up in one word: “leverage.”

Similar to Archimedes’ lever, the FDA recognizes that in order to move the earth it needs a lever long enough and a fulcrum on which to place it. Thus the strategy is to place the long lever of enforcement action on the fulcrum of corporate officers.

It’s not as though the industry has not had sufficient warning. In her address in 2009 to the Food and Drug Law Institute, Dr. Margaret Hamburg, M.D., Commissioner of Food and Drugs, said:

“The FDA will no longer issue multiple warning letters to noncompliant firms before taking enforcement action. If we find that we must move quickly to address significant health concerns or egregious violations, we will consider immediate action – even before we have issued a formal warning letter.”

Adopting a global and integrated perspective of quality and regulatory compliance by multisite, international corporations will require no less an effort and no less keen minds and effective leadership than any other functional area of the corporation where the global strategies are deployed to manage growth and to identify, control and mitigate business risk. GMPs are part of a business risk strategy.

And for those who do not yet make a connection between GMP compliance and the business, consider this.

CNN Money.com reported this week (July 20, 2010) that Johnson & Johnson said the successive recalls, as well as the shutdown of the Fort Washington plan, resulted in a 27.5% sales drop and about $600 million reduction in annual sales.”

Presently all eyes are on Johnson & Johnson’s end of the lever.

The QA Pharm

http://theqapharm.blogspot.com

An Intriguing Executive GMP Tutorial

I was invited by a disheartened head of a pharmaceutical QA department to provide a private tutoring session for the company COO on the topic of Current Good Manufacturing Practices. She said that he had refused to participate in the half-day annual GMP training course.

This was a rather intriguing request.

I asked a few questions of her to be sure that I understood the need to be addressed, the objective of the private session, and any other parameters to be considered.

Her answers were just as intriguing.

The perceived need: The boss “just doesn’t get it.”

The objective: To gain his support for GMP-related decisions.

There was only one working parameter: I had thirty minutes.

I still took the assignment, well—because it was intriguing.

I sat down and wrote out a simple discussion outline of the underlying principles of GMPs and made sure that it was straight-talk and free of buzzwords. Instead of “presenting” to him, we said that the thirty minutes would just be a “conversation.”

After belabored calendar coordination, this is the outline of the conversation that took place:

1.    Patients take the individual dose, not the average—sometimes everyday for their entire life.

a.     Your patients deserve the assurance that their drug will meet every quality requirement for each dose, not just on the average.

b.    That’s the objective of GMPs, and that should be no less the objective of your business.

2.    Your manufacturing process is fraught with opportunities for unwanted variation to creep in.

a.     All the way from incoming raw materials and components, to your equipment, test methods, operators, facilities, utilities, and so forth.

b.    Continually producing a product that is faithful to what your market approval was based on and all your quality requirements only happens when you do so intentionally.

3.    Your standard operating procedures declare how you intend to control variation.

a.     The operative word is “standardize,” not “randomize” the way you work.

b.    You have the liberty to standardize how you control variation and meet regulatory requirements to be as efficient as possible.

4.    When you follow your standard operating procedures, records are created that capture the results of your intent.

a.     The way you record results and when you enter these results are important.

b.    Sometimes recording of the result is so critical to the outcome that it must be witnessed.

5.    These records contain data that measure how well you achieved your intent.

a.     The data can be interpreted into information.

b.    The information can be transformed into targeted action for improvements.

6.    A regularly review of these measures by a cross-functional management group is your mechanism to provide oversight and governance.

a.     The review enables you to be an anticipating organization, rather than a reactive one.

b.    This review is your primary source of knowledge that you are operating in a state of control.

7.    When you put this all together, you will be able to maintain economical control of quality and increase your ability to compete.

a.     GMPs are an enabler of your business, not an antagonist.

b.    GMPs enable continuous quality, which is quality you trust.

8.    This pretty much summarizes the purpose of GMPs, which are embodied in your quality management system.

a.     This is fundamentally no different than how you manage sales and marketing to ensure that each of your regions is performing to expectations. If not—you adjust.

b.    The quality management system will be your best friend, and your best defense to regulatory inspectors—as well as personal injury attorneys.

The conversation was an absolutely engaging. The COO had never thought of GMPs in these terms.

He wanted to know how he could personally help to communicate the value of GMPs across the business.

The thirty minutes? As I left the room, the COO and the head of quality were still talking.

Sometimes one needs to reach out to the key players in the organization with a customized message, not drag them in to the same-old-same-old.

Mission accomplished. Intriguing.

The QA Pharm

http://theqapharm.blogspot.com

The Qualitative Message of FDA483s

One of the first questions I ask a pharmaceutical executive is how he or she gets information to know that their quality management system is effective. On one occasion and after a slight hesitation, I had to re-phrase my question. The conversation went something like this:

“What I mean is: How do you know that your product quality assurance/ GMP compliance program is working well?”

“Oh, well—quality is a priority for me. I pay a lot of personal attention to our quality program. We have a lot of quality projects at this site.” He motioned out the window to the Six Sigma flag in the courtyard. “I’d love to give you a tour. We have posters of all our projects in the cafeteria.”

That wasn’t exactly the answer to my question, so I tried another approach. “How do you decide the projects to work on?”

Proudly, he replied, “We have self-directed work teams here. They are empowered to select their own projects that make their areas more efficient.”

“That sounds really special.” I tried to sound sincere. But now I was starting to worry. After all, the reason for my visit was to help him prepare for an FDA District meeting regarding his most recent FDA483.

I tried again, “How do you think you fared through your last inspection?”

“Well, that’s why I asked you here.” He pointed for me to take a seat. “Our FDA inspections have continuously improved.” He passed a trend chart to me and continued, “Our corporate risk management group keeps a rolling average of the number of 483 observations. We only had six observations this time—greatly reduced number compared to the last time. That brought down our average.”

I pointed to a dotted line running across the chart. “What’s this?”

“Oh, that’s the norm for our entire global network. These last inspection results brought us well below the corporate norm. So we’re looking good from a corporate perspective.”

“So this is how you get a picture of how well you’re quality management system is working?” I asked trying to keep the tone of my voice flat.

“Sure,” he replied confidently. “But it’s the damndest thing.” I let the comment hang a moment as I waited for him to complete his thought. “The FDA inspector was rather hostile. So I thought we’d better go pay a visit to smooth things over. Six—just six observations! The inspection was over in two days! It wasn’t but two years ago that the FDA camped out here for three weeks and gave us nineteen observations! That’s continuous improvement, isn’t it?”

I didn’t answer his question right away. Instead, I took a few minutes to review the FDA483’s from their previous inspections. It became abundantly clear what was going on between this company and his FDA district office.

The inspector went only as far as he needed to go to document that the same issues remained—then he simply quit and went home.

Management was high-fiving each other in the corridor at the relatively few observations calling the one-pager “a light one.” Evidently the FDA inspector left with a different impression.

Although this is the year 2010, the kind of thinking depicted in this dialog dating to the Paleozoic era is still around.

Here’s what I say to such fossilized specimens:

First, numbers of observations cannot be statistically treated. You can neither average them, nor calculate a relative standard deviation because the number of observations is not derived from a single, predictable, defined process. Inspectors differ; the scope of inspections differs; the length of inspection differs. So, you cannot pool the data and statistically treat to make any kind of meaningful inference. In this case, fewer definitely was not better.

Second, the absence of a negative comment does not mean agreement. For example, just because an inspector walked through the warehouse that was not temperature and humidity controlled to get to the receiving inspection area, does not imply concurrence with operating an uncontrolled warehouse.

Third, inspection results are a seriously lagging performance indicator—if not lethargic. Much like the company stock price, by the time serious lack of compliance has had its dastardly effect—it’s too late to stop the shareholder lawsuits. Additionally, inspectors do not look favorably upon their observations being the measure of compliance—or the impetus for a quality plan. In fact, boilerplate language in Warning Letters points out that the list is not intended to be an all-inclusive list of deficiencies. The expectation is for company management to know for themselves the state of control though established internal review processes.

Fourth, efficiency “projects” may not address, but rather cause compliance issues. Efficiency and compliance are two different things. Efficiency deals with the most economical way of working. Compliance deals with a consistent way of working that meets regulatory requirements. For example, a self-conducted survey by an active ingredient supplier of its own operation is very cost effective, but inadequate for meeting the requirement for you to know their capability of consistently meeting your specifications.

More important than the number of 483 observations is the qualitative message. Taken collectively, the qualitative themes in this example were: (a) inadequate management control, (b) inability to sustain compliance, (c) failure of the quality control unit to establish an effective quality system, and—what we are seeing more of lately—(d) lack of corporate oversight and action.

An appropriate response to the qualitative message should be considerably different than the quantitative one. The qualitative response reads more like an organization overhaul—organization transformation, while the quantitative response appears more technical.

Heed the qualitative message of regulatory inspection observations; don’t average them.

The Quality Assurance Practitioner: A Metaphorical Model

There can be no higher calling than to be a quality assurance professional in the pharmaceutical industry.

And, I do mean a calling. It’s not just a job. It is an honorable profession where art and science are skillfully applied to improve and save lives.

That sounds a lot like a medical doctor, doesn’t it?

Actually, the medical practitioner provides an excellent model to think about what we do, and how to continually strive to improve our service.

Metaphorically speaking, as quality assurance practitioners we:

OBSERVE to detect the earliest symptom that could indicate a quality well-being problem.

APPLY QUALITY SCIENCE to describe and characterize the presenting problem.

DIAGNOSE the underlying cause and systems involved using problem-solving and decision-making skills.

COMMUNICATE to all affected to ensure that there is understanding of the nature, extent and consequences of the condition if left untreated.

CONSULT the literature, colleagues and specialists to ensure that current knowledge and objectivity are applied to the problem.

PRESCRIBE a remediation plan using current science, technology and Management 101 with an emphasis on prevention.

OVERSEE the implementation of the remediation plan to ensure the plan is executed and well managed.

FOLLOW-UP at appropriate intervals to review progress and to evaluate the effectiveness of the remediation plan.

RESEARCH to continually advance the field and apply new knowledge to the practice of the art and science.

DEVELOP skills that continuously enhance personal effectiveness in applying the art and science.

What is it that you like about your favorite physician? Is it your access to him when you really need help? Is it her pleasant and professional staff? Perhaps you feel he is a good listener. I also imagine that getting results is high on the list.

Did you ever stop going to a doctor for a particular reason?

Was it because he multi-tasked while you were trying to talk to her? Did he always seem to be in a rush for her next appointment? Unsympathetic? Did he talk down to you? Perhaps you felt unsettled whether the visit was really productive.

Likewise, pharmaceutical quality assurance professionals interact daily with people and problems. Metaphorical thinking helps to shine a light on where we may need to improve--both what we do, and how we interact with others.

Consider it our own version of competent "bedside manner."

The QA Pharm