The QA Pharm

A Tale of Two Deviations

2012-04-21T11:01:00.001-04:00

It stands to reason that pharmaceutical companies in compliance trouble also have problems with their Deviation Management and Corrective and Preventive Action (CAPA) System(s). After all, to maintain a good compliance profile, as well as an efficient operation, requires the ability to detect problems, determine the root cause and permanently eliminate the problems.

Good companies rejoice that a problem was detected and reward the one who detected it. It's another opportunity to improve---one more problem that they never have to deal with again. They rise to the challenge to find technical solutions and engineer-out the problem. They are thinkers who mindfully apply their education and experience. They celebrate finding and permanently expunging recurring problems. Management is aware of and measures recurring problems. They have no tolerance for it and hold department managers accountable for measurable results.

For poor companies, deviations are a way of life. Deviations are anticipated and the rewards go to those who heroically work the long hours to jump through the usual hoops to close the deviations so the lot can get out the door. They know that they will have to go through the same effort the next time. It is an exercise in onerous paperwork and checking procedural boxes. They celebrate getting the lot out the door---finally. Management measures delayed investigations and backlogs. Everyone knows what the routine problems are, and management asks no more than they be handled in the routine way---just more quickly.

Like in A Tale of Two Cities, they are worlds apart in organization culture. One cannot change culture by policies or procedures. It's a force that emanates from the top. It's a force that cannot help but to become infused into every breathing soul. Culture invigorates and identifies who we are in our very essence.

It's leadership. And leaders that build a positive culture would ask, "Why would we not permanently irradiate problems at their festering roots---even if it's one of us?"

The QA Pharm

Seven Success Criteria for Hiring (and working with) a Good GMP Consultant

2012-04-13T14:51:00.001-04:00

The high layoff numbers in the pharmaceutical industry and poor job prospects in a weak economy have flooded the market with would-be consultants to pharma companies that need extra help. Here are my suggestions for hiring and working with a good GMP consultant.

1. Define the scope of work before you start scouting for a consultant.

There is nothing worse than throwing a bunch of consultants at a problem without knowing the boundaries of the project or defining the expected results. Unfortunately, it happens all the time. It ends in frustration for all parties involved, and the tragedy is--nothing gets better.

A formal Scope of Work (SOW) helps both the client and the consultant to set expectations of each other and agree on basic assumptions that are critical to success. A draft SOW is the basis of a discussion with the perspective consultant, and the final version becomes a formal understanding that both parties can agree to. Sometimes it is beneficial to have an initial scope of work that is limited to a survey of the present situation with recommendations for an approach to the problem and a breakdown into phases or discrete chunks of work.

2. Determine the hard and soft skills required.

Consultants have been everywhere and done everything. If you don't believe so--just ask them. Resumes are inflated and each universally saved their previous client from the jaws of destruction. Many arrive like a one-person wrecking crew. Their know-it-all and negative behaviors will overshadow any remnant of dignity that your work group has left.

Explore the range of skills necessary to do the job and ask pointed questions about how the candidate's skills were applied to previous situations. Some skills may be hard technical skills, while others may be the soft skills needed to engender trust and collaboration with your team. In the back of your head you should be thinking: "Will the skills of my people be better as a result of having worked with this consultant?"

3. They really must have worked in the industry.

With due respect to my FDA friends, especially those who are now consulting, it really is better to hire someone who has actually made medicine, not just conducted inspections. The reason that FDA experience is highly valued is because the client thinks that they will get some insider perspective on what the right answer is--or what the FDA is looking for at the next inspection. There are plenty of people who can tell you what's wrong, but fewer people who offer a range of solutions or who had been responsible in their careers for results.

Inspection results have never been and never will be the true measure of future performance. Look for someone who understands the complexity of operational, technical, social, cultural issues that must be considered when resolving fundamental GMP problems. Nothing replaces specific operational knowledge.

4. Avoid career quality assurance consultants.

QA experience is important, particularly when it comes to designing the interrelating elements of a quality management system. But I am skeptical when I see a resume that is all QA experience. There is nothing like having operational experience to fully understand the practical environment in which GMP systems reside. If a quality system is not practical and useable, then users will find a workaround just to survive.

Explore the operational experience of the consultant candidate and ask how that experience has made them a better QA professional and consultant. Also, there in nothing worse that a consultant that has 25+ years experience only in QA---and all at the same company.

5. Don't write off failure.

There are some consultants who have had failures in their career. Or it may seem like a failure to you, and feel like a failure to the consultant. Experience has taught me that good people have been terminated for wrong reasons. There are those who were fired for standing up to the company against doing the wrong thing. Also, many older folks who have valuable experience were the victims of layoffs just because they were high in the salary band.

I know it goes against conventional wisdom, but be open to the person who you sense has a "history" that he or she is reluctant to talk about, or gaps in a work history. It's just not unusual these days, particularly in QA. I would take someone like that in a heartbeat over someone who had been in QA his entire career at the same company. (Talk about someone who has learned to keep his head low!) It's more about the lesson learned, what they did next and whether it built character.

6. Keep engaged with consultants and own the problem.

Unfortunately, some companies in trouble with the FDA hire consultants in the same way they would engage a contract manufacturer. You cannot sub-contract your problem. Just like a CMO, you are still ultimately accountable for results and managing the relationship. There will be no sympathy at the FDA District Office if you whine about your consultants.

The consultant and the client need each other to succeed, so keep the lines of communication open. Rarely can management solve a problem without some consultant help, and for sure a consultant cannot do it alone. Quite often, the underlying problem touches upon the bigger issues of company culture and leadership. The consultant needs the forum to openly discuss these issues.

7. Don't overcomplicate the oversight.

Consultants are typically involved in project teams that are comprised of client system owners and subject-matter-experts. While there must be management oversight, these project teams need to keep focused on getting the work done. The last thing you need is to have them distracted by preparing tedious PowerPoint updates and administrative activities to multiple layers of oversight and stakeholders.

I have always said that in the absence of real work, administrative activities will creep in and fill the void. Be sure that the consultant and your people who comprise the team are allowed to focus on what you chartered them to do.

I would be pleased to hear advice from you, my readers, from your experience working with GMP consultants.

The QA Pharm

J&J: Out from the Ashes---Not.

2012-02-26T09:33:00.000-05:00

Johnson and Johnson gutted and retooled their Fort Washington facility to come back with a bang with the launch of a new bottle designed for its grape flavored infant liquid Tylenol to guard against accidental overdosing. But instead of accolades, complaints poured in about the protective cover pushing loose when the dosing syringe was inserted. The first new product out of the new facility was added to the long list of recalls that has knocked the once respected Tylenol brand off its pedestal.

One does not need to be a rocket scientist to understand the failure mode of a problem of the plastic protective cover pushing loose when the dosing syringe in inserted. But it does take technical knowledge of different types of plastics used in pharmaceutical packaging and how variation is controlled for plastic molded parts. People actually go to school and learn about this stuff and how to apply this science to real-world pharmaceutical applications.

So what happened at J&J?

I don't have insider information, but one can only assume that there were no real packaging or quality engineers to be found. Or if they were, they were incompetent. If they were not incompetent, then they kissed their science good-bye---probably under pressure to meet the almighty new product launch date.

Who knows? I'm just reading the tea leaves. All I really know is that J&J blew a huge opportunity to come back with a great packaging concept that veterinary product manufacturers perfected a long time ago.

I am very sad for J&J.

The QA Pharm

Drug Shortage: A Story of Self-Inflicted Management Tragedies

2012-02-11T11:16:00.001-05:00

My blood boils when I read an article such as the one that appeared in the New York Times yesterday entitled Supply of a Cancer Drug May Run Out Within Weeks, by Gardiner Harris. This is one of many articles that has appeared lately about the mounting crisis of drug shortages across the country. This time it is the drug to treat acute lymphoblasic leukemia, which most often strikes children ages 2 to 5.

The article quotes the president of the American Society of Clinical Oncology saying that he hopes that the FDA's hard work can help avert a crisis. The FDA is always brought into the middle of the political quagmire of pharma companies, medical professionals and patients. But the FDA is not the "bad guy."

If you were to map the drugs that are in short supply to the FDA's Inspection Observations, Warning Letters and Consent Decrees, you will find a long history of problems that would have given any reasonable management plenty of time to permanently solve the problems.

The truth is that the problems are self-inflicted. There is not one problem that cannot be solved with the right management and the right technical and scientific expertise to establish a capable manufacturing process and facility.

Quality Assurance is not totally off the hook. Often QA cannot see the forest for the trees. They strain the gnat and swallow the camel. Often they are busy policing the proper use of indelible blue ink that they do not see the cumbersome, non-value-added administrative activities that are choking the quality management system.

I read Mr. Harris' article and though of my healthy grandchildren. Thank God.

My heart goes out to those patients who are dependent on life-saving drugs.

C'mon people get your act together!

The QA Pharm

New Years Resolutions for Pharma Quality Assurance

2011-12-30T10:52:00.001-05:00

Like anyone else, coming to the end of the year brings a time of reflection and anticipation. I look back and ask the question, "Have I made a difference in anyone's life?" I look forward and ask, "What do I want to change that I either have control or can influence?"

For the pharmaceutical professional, these questions are not only personal--but professional.

The Quality Assurance professional should always have the sense of a high calling. That calling needs to go beyond being the "checker" who culls out the defects to being the applied scientist or engineer who helps to design quality into the product.

This reminds me of the dear soul who proudly showed me the bucket of discarded product that she plucked off the conveyor belt. The occasion was a plant tour to understand how this company saw the role of the quality function. The next stop on the tour was the QC lab that was backed-up with samples. The analysts were randomly selecting their favorite tests to squeeze in before their next coffee break. It didn't take long to determine that the view of the quality function at this client was anchored in---approximately the 1950s.

On the other hand, there are companies on the cutting edge science and technology with breakthrough products that fulfill the dire need of desperately sick people. Yet, in their evolution, these very bright people did not pay sufficient attention to FDA compliance.

Looking back...

As I look back, I see pharma companies ranging in their quality assurance evolution from knuckles still dragging the ground to walking upright, but tripping over their own feet. So there is still plenty of work to do, and the enlightened--and bold--quality professional is not short of ground material to make a difference.

I say "bold" for a reason. In my opinion, the single factor holding back the quality professional, and consequently the company is the lack of courage.

The economy is not to blame for everything, but working on the inside of just about any company is an environment that is fraught with fear. Timidity is rampant. It is rare to find someone who has the balance of panache and guts to tell the Emperor that he is butt naked. It is a game of not making waves, keeping your head low--and for Pete's sake never pointing out a problem to your manager that makes him have to speak to his director. (Like that's going to happen.)

Looking forward...

My prediction is that the winnowing process will continue in our industry and those with neutered quality assurance departments will either be acquired and rehabbed--or fail. In true Darwinian fashion, the fittest will survive to reproduce.

Regardless of the situation, I would suggest these resolutions for the quality assurance professional:

1. I will make myself more valuable through continuing education that will make me a more enlightened quality professional. These will include real courses from recognized institutions, not trendy certifications.

2. I will find my voice and speak up when I see unacceptable quality and regulatory compliance risks. I may need personal coaching on how to deliver negative messages, but I will not stop going up the chain of command until I am satisfied that reasonable action has been taken.

3. I will learn how to make the business case when I see an opportunity for improvement. As a professional who has been conditioned not to be influenced by cost, I need to learn to how to develop and deliver proposals that speak in the universal language of business---money.

4. I will get out of my cubicle to see what others are doing to broaden my industry perspective. I will resist the notion that my daily working experience is necessarily typical of the industry.

5. I will understand how my role fits into the business process cycle and will hold myself accountable for results, even if the results are bad news. This may mean developing standard cycle times and finding efficiencies to complete my part on time.

6. (And my personal favorite) I will no longer prepare a useless slide deck for a management presentation on "what went wrong and recommendations" until management has supported the recommendations from the previous presentation for the same problems that went wrong. I give myself permission to expect more out of management, especially when it comes to doing my job right.

Happy New Year!
The QA Pharm

Top Ten Ways to Make GMP Training Relevant

2011-10-15T20:11:00.000-04:00

Most GMP training that I encounter is not necessarily bad--just irrelevant. In fact the same could be said for the Training Department. They jealously guard their turf and deliver mediocre, perfunctory training. Names get checked off the list, and the Training Department goes about their business being irrelevant. (Ouch!)

There is nothing that could be more exciting and fulfilling than being part of a dynamic training group that equips its organization to be a finely tuned work force of scholars that embrace GMPs as a business enabler.

Unfortunately, rather than a graduate education in the pharmaceutics of regulations, our best and brightest are subjected to a mind-dulling deck of tired old PowerPoint slides.

Frankly, the problem is endemic and here's why:

1. The concepts are not applied to the real world. We herd the mignons into the cafeteria and deliver the obligatory annual GMP training with total disrespect for what each employee does as part of his/her job everyday.

2. Training topics are not strategic. The lack of the broader view of the state of the industry and regulatory enforcement trends keeps GMP training from being proactive or responsive to the changing regulatory environment.

3. Training is not data-driven. The topics selected are often disconnected from the problems at the site as revealed at quality metric review forums such as Quality Management Review.

4. Training is the ubiquitous excuse (punishment) for corrective and preventive action. The easy out is to say that a failure can be addressed by training without truly determining the root cause.

5. The training method is not effective. When everything from a step change to a total system re-design is handled by "Read and Understand," it is difficult to distinguish between minor and really significant training topics.

6. The trainers are dreadfully boring. It's amazing how much we devalue the importance of training as evidenced by the little emphasis we place on the design and delivery skills we place on the people we put in those positions.

7. Lack of attendance is tolerated. When there is a conflict in one's schedule, the training class is always the loser. Nothing ever happens if you don't attend, because usually know one knows. No one really cares.

8. Leaders don't go to training either. It's comes down to not really expecting leadership to be trained, as though there is some special dispensation with the privileged class. They certainly aren't examples to follow.

9. The priority of the production manager is getting product out the door, not the skills and capability of his/her workers. In fact, he/she may be totally unaware of whether the workforce is getting the right training, or current with meeting individual training requirements.

10. Measurable improvement in skills and knowledge is not rewarded. We reward what we value, and training isn't it.

So, class, here's your assignment:

Turn each of these negative statements into a positive one. Then perform a self assessment of your organization against these statements.

Don't be defeated if the results are pathetic. You are in good company. It's all about what you do with the information starting right now.

Turn these into vision statements. Discuss the practical, measurable steps you can take to improve the relevance of your GMP training.

Keep it going, and watch amazing things happen!

The QA Pharm

Where were you on September 11? Let us never forget.

2011-09-10T20:34:00.020-04:00

I remember exactly where I was and exactly what I was doing on September 11, 2001. The time and place have been indelibly etched in my brain.

It was Washington, DC where I heard the announcement. I heard the sirens and saw the army helicopters fly overhead and patrols of army vehicles in the street. It was am image of a city under siege. The burning, crumbling Twin Towers and the caved-in Pentagon were replayed on the news channels. Eventually the reality of it all sank in--our homeland was attacked.

Then the news came out about Flight 93 downed in Shanksville, PA. "Let's Roll" became the rally cry of my personal heroes onboard the plane that fateful day. I was within spitting distance of the Capitol Building at the time, the likely intended target.

I passed many makeshift memorials on my walk to the train station for my failed attempt to find transportation to just about anywhere. The Capitol flag was at half-mast. People milled about. Strangers talking to strangers. I felt anger and pain for our country.

The memorial service at the National Cathedral was going on in the Admirals Club the day I was able to fly out of Dulles. Travelers turned their chairs to face the television. Little-by-little the club turned into a sanctuary. There were tears. There were prayers.

Nothing would be the same, other than our resolve to not to let our enemies take away our lifestyle. I felt a surge of patriotism and a sense of duty, and I knew that I would never be the same.

So in honor of September 11th and all those who gave their lives--and my heroes buried among the ashes in Shanksville--I am getting on an airplane.

God bless America
The QA Pharm

Decisions and Indecision—The Organizational Vortex

2011-08-21T11:34:00.001-04:00

The cover of Fortune magazine popped off the newsstand shelf last week: What Happened at Pfizer: The Inside Story of Revenge, Betrayal, and Power at the Top of the World’s Largest Drug Company.” (August 15, 2011)

Amidst the story that recounted epic boardroom intrigue, one section described the impact that these political shenanigans had on day-to-day decision-making.

“A second anonymous letter, claiming to be from ‘responsible, long and loyal Legal Division employees,’ arrived on the very day of the board meeting. It complained of ‘micromanagement,’ ‘constant’ internal reorganization, and a ‘chaotic’ decision-making process. ‘A decision is made, then reconsidered and changed. Decisions, even minor…are picked apart and often directed to be undone. Then re-studied. Then the decision-making group expands. Paranoia results. Autonomy is sapped.”

When it comes to fuzzy authority and recycled decisions, Pfizer is not alone. Wherever it occurs, at whatever level, the organization is seriously impacted. It matters how decisions are made. Nothing is more revealing about the leadership and the future of an organization than how decisions are made.

One of the most fundamental responsibilities of top management is to align the organization—to get all the oars of the scullers in the water pulling in the same direction. When company leaders compete for the megaphone it becomes, “Stroke, no don’t stroke. Pull left; I mean right—now, anyway.” The course is convoluted, not straight; energy is wasted, not conserved.

When there is leadership dysfunction, there is organization dysfunction and ultimately the patient suffers. Yes—the patient.

Whether it is getting the organization aligned to resolve its regulatory compliance problems, or on time order fulfillment, it is clear lines of authority and crisp decisions that lead us across the finish line.

So, if you feel sometimes you are in an organizational vortex of ineffective decision-making, my recommendations are these:

1. When you accept an assignment, be clear about who are the reviewers and approvers. A good Responsible, Accountable, Consulted, Informed (RACI) model applies here.

2. Establish a charter with a clear scope, lines of communication and decision-making authority. Have your oversight committee approve.

3. Before you are asked to present to your oversight committee, be sure to clarify whether your authority extends beyond recommendations to decisions. If you are the decision maker, walk the committee through your logic.

4. Clarify what decision was made. After the presentation to your oversight committee, sum up the decisions. Don’t leave until every decision is crystal clear.

5. If you were charted with decision-making authority, but your oversight committee takes it out of your hands in a meeting, ask for an explanation. Otherwise, you have no basis of moving forward.

6. Capture minutes of decisions. Whenever you sense that you are having a “Groundhog Day” meeting, remind the participants that the issue had been discussed and decision had been made as recorded in the minutes.

7. If anyone on the oversight committee starts to lobby outside of the committee to change the decision, stop it dead in its tracks. Indicate to that person that the decision was made.

8. When you detect dissention among those of equal authority and it impacts your ability to make progress, meet with them collectively with the stated objective to achieve unified direction.

9. Document a decision timeline. Nothing points to the effect of poor decision-making than a timeline of direction, redirection, and reverse direction. You may need it when you are asked why your project is behind schedule.

10. Protect your team from the effects of poor leadership decision-making. Make forward progress where you can; assume you make the decision. Resist all temptation to promulgate the organizational vortex.

Don’t be the victim of a dysfunctional environment. You may not be able to take complete control, but you can take steps to minimize its effects.

The QA Pharm

The Top Ten Warning Letter Observations about the Pharmaceutical Quality Unit

2011-08-14T08:54:00.000-04:00

The responsibilities of the Pharmaceutical Quality Unit are defined in the CGMPs and practices clarified in guidance documents. (See The QA Pharm, August 7, 2011.)

Just as it is with any legal matter, case histories help us understand how the law is applied in specific situations. That’s the reason it is a good practice to regularly review Warning Letters on the FDA website.

Here’s my condensed list of issues the FDA has had with the Quality Unit as seen in Warning letter observations.

This is the list you don’t want to be on.

1. QU failed to establish a system to ensure that…[fill in the blank for anything that went wrong]

2. QU failed to document the responsibilities applicable to the quality control unit in procedures, and fully perform these responsibilities.

3. The personnel performing laboratory tests… were not trained.

4. QU failed to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products.

5. QU failed to fully perform and/or document the review of batch production records to determine compliance with all established, approved written procedures before a batch is released or distributed.

6. QU failed to ensure that all tests are in conformance with the established specifications and that these are met prior to the release of drug products for distribution.

7. QU did not review production records to assure that no errors had occurred or, if errors had occurred, that they had been fully investigated, conclusions made and followed-up.

8. QU failed to investigate complaints involving the possible failure of a drug product to meet any of its specifications.

9. Failure to submit NDA-Field Alert Reports (FARs) within three (3) working days of receipt of information concerning any bacteriological contamination, or any significant chemical, physical, or other change or deterioration in the distributed drug products

10. And my personal favorite…a designated QU has not been established.

The QA Pharm

TheTop Ten Responsibilities of the Pharmaceutical Quality Unit

2011-08-06T08:57:00.000-04:00

The pharmaceutical Quality Unit has been the target of many FDA Warning Letters as the underlying cause of product quality and CGMP compliance problems. We have seen instances where the ultimate “no confidence” vote is cast when third-party experts are either recommended by FDA, or court ordered to take over their duties. (See The QA Pharm 9/25/10.)

Therefore, it’s very important to have a clear understanding of the regulatory responsibilities of the Quality Unit and to ensure that those responsibilities are effectively executed.

Remember—the Quality Unit is the only job description that appears in the Code of Federal Regulations!

Here’s my compiled list from FDA regulations and guidance documents that defines the job of the Quality Unit.

(It’s like being given the answers in the back of the book—and not just the odd-numbered problems.)

1. To establish the quality system

a. Establish the quality management system to describe how the firm follows CGMPs and operates to maintain a state of control

b. Keep the quality management system current with good industry practices

2. To audit compliance to the quality system

a. Audit for compliance to policies and procedures: on paper vs. practice.

b. Report quality system performance metrics, including trends, that help decision-making and taking proactive targeted actions

3. To establish procedures and specifications

a. Ensure that procedures and specifications are appropriate and followed

b. Ensure that the procedures and specifications of firms under contract are also appropriate and followed, i.e., maintain control and take responsibility for third-party services providers (contract manufacturers, contract laboratories, etc.)

4. To establish manufacturing controls

a. Ensure that appropriate manufacturing in-process controls are implemented

b. Ensure in-process controls are performed during manufacturing operations and results are satisfactory

5. To perform laboratory tests or examinations

a. Perform laboratory testing of components, containers, in-process materials, packaging materials and drug product using validated methods against scientifically-derived, fit-for-purpose specifications

b. Approve or reject drug products manufactured, processed, packed, or held under contract by another company, i.e., final product release is not delegated to a contractor.

c. Perform retests or reexamine approved components, drug product containers and closures after long storage or exposure to adverse conditions

6. To review and approve or reject all things CGMP

a. Review and approve/reject any document that gives work instructions and set requirements such as procedures, protocols, test methods, and specifications—including changes to these documents

b. Review and approve/reject reprocessing and rework procedures

c. Review and approve/reject production batch records and make the final decision to release a product lot into commerce.

7. To ensure investigation of nonconformance

a. Ensure investigation is conducted and root cause is eliminated for production and control record errors, discrepancies, and failure to meet specification, including quality attributes

b. Review complaints to determine if it relates to a failure to meet specification, if so investigate and report to FDA if it is serious and unexpected

8. To keep management informed

a. Report on product, process and system risks—and keep management informed

b. Report on outcome of regulatory inspections and ensure responses are complete and managed to verifiable closure—and keep management informed.

c. Keep management informed—get it?

9. To describe responsibilities in writing

a. Have a complete and compliant procedure that describes responsibilities

b. Follow the procedure

10. To remain independent

a. Ensure there is no conflict of interest between regulatory responsibilities and actual daily activities

b. Be independent reviewer and approver with respect to manufacturing and process/ product development units

c. Don’t drink the “Kool-Aid”

Your assignment:

Conduct a facilitated off-site meeting comprised of members of your Quality Unit Staff and other operating areas. Walk through this list and ask: “How does our Quality Unit stand up to these requirement?” Develop an action plan.

The QA Pharm

References

Federal Register Vol. 43, No 190 – Friday, September 29, 1978, “Preamble to the Drug CGMPs”
The Code of Federal Regulations Part 210 and 211
Guidance for Industry, Quality Systems Approach to Pharmaceutical Current Good Manufacturing Practice Regulations (September 2006)

Quality, Cost and Speed—can there be a balanced decision?

2011-07-31T14:43:00.000-04:00

“Quality, Cost and Speed—pick two.” This was a truism often quoted throughout my career.

Sacrifice Quality with low Cost and high Speed.

Sacrifice Cost with high Quality and high Speed.

Sacrifice Speed with high Quality and low Cost.

But does there always have to be a loser? Unfortunately, it seems to work out that way in practice.

A report dated July 27, 2011, came out from a special committee of J&J board members in response to investor lawsuits. It reported “an adversarial relationship” between quality and production; and “an emphasis on production volume” over compliance.

The committee concluded that the consumer division at J&J “should have paid more attention” to quality issues and “exercised more management oversight.”

But, here’s the real kick-in-the-pants.

This J&J blue-ribbon committee of their board was quick to take themselves off the hook by saying (I am paraphrasing):

· Nobody on the J&J Board told McNeil that quality should be sacrificed.

Nobody in his or her right mind ever gives a direct order to ignore quality. Pressure comes in much more subtle form in our industry today under the guise of “restructuring”, “Lean”, and “quick business acquisition integration” programs that are directed totally at cost reduction. These are company programs that line management is rewarded to deliver.

Someone needs to ask the J&J board of directors, “Which consulting firm gave that advice, and who at J&J approved the 35% corporate quality and compliance staff cuts in 2007?”

· Nobody told the J&J Board there was a problem.

Rarely is the person appreciated who tells the “emperor he’s naked.” They are characterized as troublemakers and non-team players. They are the ones who are obstacles to getting “drugs to our patients.” Fear of unemployment fosters a “don’t make waves” cultural environment that is endemic.

Here’s where the quality assurance function must rise to the occasion to make objective data become the indisputable target, not the messenger. That is—unless they also have drunk the Kool-Aid.

· The J&J board acted aggressively when they found out about the problem.

Isn’t this always the case? The Sarbanes-Oxley Act of 2002 was to have ushered in an era of corporate responsibility where company boards were to proactively and independently keep an eye on the legal and regulatory matters that affect the stockholders. Somewhere along the line the practice became limited to financial reporting—not compliance to CGMP.

However, all FDA Consent Decrees of Permanent injunction are accompanied by stockholder lawsuits. So you would think CGMP compliance would be on their fiduciary radar also.

So, what about Quality, Cost and Speed?

No doubt about it. These dimensions are truly interdependent.

However, great companies should be able to have honest and frank discussions about daily decisions along these three dimensions. There should be an advocate for each—quality, cost, speed—with an equal voice that is encouraged, respected, and rewarded. This is where balance is found.

Troubles begin when—for whatever reason—any one of these voices is stifled, or when any one of these voices becomes more powerful than the others.

The QA Pharm

Cartoon: The QA Quarantine Cage

2011-07-22T19:06:00.002-04:00

Are Commitments Made to FDA to be taken Seriously?

2011-07-16T11:57:00.000-04:00

Responses to FD483’s and Warning Letters are usually fully of commitments. They involve “what” will be done to correct compliance problems, and “when” it will be done. FDA has even started to ask “how” they will be done, meaning—Do you have the resources to do the work?

If these questions are not fully addressed in the FD483, then FDA asks again in the subsequent Warning Letter in the part where they acknowledge receipt of the firm’s FD483 response—and the inadequacy of it.

It is very formulaic and very predictable.

So, my first point is that there is no excuse for an inadequate response to an FD483 or a Warning Letter.

There are plenty of Warning Letters on the FDA website that provide examples of poor responses and what the FDA thinks about them. There’s no excuse for not knowing how to respond. (Also see The QA Pharm, October 10, 2010.)

Reasons for poor responses are:

· Arrogance (What problem? Let me explain why we have no problem.)

· Bad advice from house counsel (Dance around the edges, but never admit having a problem.)

· Minimalism (Commit as little as possible and don’t look for other problems.)

· Being far removed from the problem (Responses are so bad that it makes your technical insiders embarrassed.)

· No root cause (Doing lots of stuff, but very little directed toward the real problem.)

· Poor writing skills. (Difficult to follow the story line, because you have no idea what you want to say.)

My second point is never, ever miss a commitment date.

If anyone were to ask the leadership of any company under FDA enforcement action whether FDA commitments should be taken seriously, the response would be a resounding “Of course.”

Yet actions say differently.

It continues to amaze me how many companies miss commitment dates. And even more amazing—the senior management had no clue they had missed them. This is totally unconscionable and an indicator why the company has compliance trouble in the first place.

Reasons for missing commitment dates are:

· No system to track responses and commitments

· Responses and commitments are buried with hundreds of other TrackWise records, most of which are also overdue

· Overly project managed until there is more planning than action

· Lack of visibility as a standing agenda item in the management boardroom

· No accountability at any level for results

· Agency responses are kept a secret, or not sufficiently distributed to employees

· Those responsible for doing the work had no idea that a commitment was made

The best way to think about the seriousness of a commitment to the FDA is to remember that the FDA already suspects a noncompliant firm to be untrustworthy—or at best they are neutral about their credibility. To not deliver on a commitment date just confirms their suspicion and puts the relationship between the firm and FDA on shaky ground.

Not providing an adequate response simply indicates being out of the mainstream of pharmaceutical industry know-how. And missing commitment

dates is nothing less that breaking a promise.

How would you feel if you were not taken seriously?

The QA Pharm

Is flu vaccine supply in jeopardy from Australia’s CSL Biotherapies?

2011-07-03T14:19:00.002-04:00

The answer depends on who you listen to: the FDA or the EVP at CSL Biotherapies.

According to the FDA Warning Letter issued on June 15, 2011, the issues are among the most significant as any we have seen in recent years following the company withdrawal of the vaccine after reports of seizures with use in children.

Any observer and student of FDA enforcement recognizes the serious combination of observations:

No documentation of adverse events
Lack of production and process controls
Inadequate investigations into batch or component failures
Failure to reject components that did not meet specifications
Inappropriate laboratory methods

The list is lengthy. The list is significant. The list is serious.

And the Warning Letter is topped off with the universal conclusion that we have seen with McNeil, BMS, Ningbo Smart and others reported in this blog—“Your Quality Unit is not fulfilling its responsibilities.”

When the FDA doubts the Quality Unit—it doubts everything.

So what about the flu supply from one of the world’s largest flu vaccine manufacturers? Are they too big to fail? Will they be permitted to supply the U.S.?

Don’t count on it.

Remember the 2003 production problems at Chiron’s Liverpool flu vaccine manufacturing plant? Remember the shortage? Remember the politics and congressional hearings?

So what’s different this time? Let’s hope a lot.

For starters, the Warning Letter was issued within a record two and a half months of the inspection. Also, the FDA requested a meeting with the CEO and other senior management, which is the equivalent of saying, “We’re in this mess together.”

So, how does the EVP at CSL view their issues?

Mr. Jeff Davies, CSL’s EVP was interviewed on “PM with Mark Colvin” on June 22, 2011.

Mark Colvin asked Mr. Davies why he thought that CSL failed to satisfy the FDA. Mr. Davies replied, “I think they’re just concerned how we documented that process.”

It’s going to be a very interesting meeting with the FDA if CSL’s going in position is that it’s all a matter of paperwork.

Let’s hope for the global flu vaccine supply that it isn’t.

The QA Pharm

FDA Calls for Corporate Commitment and Leadership at PolyCarbon Industries

2011-06-11T23:38:00.000-04:00

Just when you think that the FDA has to stick to the script by quoting chapter and verse of CGMPs, they get very progressive and offer straight talk about corporate commitment and leadership.

We have reported before that the FDA expects corporate oversight of the Quality Management System. (The QA Pharm 4/17/11.) The Johnson & Johnson debacle is just one recent example where the FDA cited the corporate folks for taking their eye off McNeil where Tylenol is manufactured.

But the Warning Letter to PolyCarbon Industries recently posted on the FDA website has an added dimension—a call for commitment and leadership. The Warning Letter dated December 2, 2010, reads as follows:

“It is essential that your firm establish and maintain a corporate commitment to an effective pharmaceutical quality system. Your firm’s management should demonstrate leadership and ultimate responsibility by participating in the design, implementation, and monitoring for quality throughout the company. Management should establish policies that describes your firm’s overall approach to ensuring drug quality and communicates your expectation of compliance with all requirements of applicable federal law and FDA regulations.”

There’s a lot of insight packed into this paragraph. The most important aspect is what commitment and leadership behaviors look like from an FDA perspective.

So, let’s do a little behavior analysis:

1. Does your corporate group participate in the design, implementation and monitoring of quality at your company?

The best example of this that I have seen was a corporate group that facilitated a focused discussion of internal and external experts that led to the creation and deployment of company compliance policies.

The worst example was a company that hired a consultant to write the corporate policies. The policies appeared one day on the company intranet with the edict that they be deployed within six months. The old “right click on properties” revealed that the consultant had used the same policies for another client. The only thing different was the logo.

2. Does your corporate group establish and communicate policies regarding regulations and compliance requirements?

The best example of this that I have seen was a company that deployed the policies with the business message that compliance was important to patients and the ability to compete. Compliance was to be valued and the operating norm.

The worst example was a company that couched the compliance message in terms of FDA inspections getting tougher, and that—right or wrong—the bar was being raised. “We just have to face reality.”

Regulatory compliance is no different than any other area of the company that requires commitment and leadership. Frankly speaking, when there is little leadership in this area, I find little leadership in other areas too.

So to our friends at the FDA, I say: “Spot on.”

Sometime what needs to be said can’t be referenced to the Code of Federal Regulations, but is truly at the heart of the problem.

The QA Pharm

What Does it Mean to Operate in a State of Control?

2011-05-29T21:06:00.002-04:00

Once upon a time, I asked this question of a senior management group at an off-site “strategy” meeting. You know—one of those meetings where a working breakfast was followed by a day of golf, and I was the one doing the working.

The question was particularly germane to the purpose of my invitation, because these executives did not want to follow the path of other major industry giants into ruin by taking their eye off the proverbial CGMP compliance ball.

After a bit of awkward silence, someone offered a stab at the answer: Zero Defects. Another rebuked his colleague: That’s so passé. It should be Right First Time. The next ten minutes was Battle of the Buzzwords and I was the game show host. Conversation erupted in a murmur across the room.

I responded by saying that perfection was a worthy goal, but statistically impossible. I am highly suspicious of perfection, and firms that reward the strict definition of perfection drive bad behavior. In fact, when things are too perfect—I suspect fraud.

That quieted the room.

To operate in a state of control does not mean perfection. It does mean; however, the capability of a firm to detect and self-correct trends before it becomes a problem. And whenever a problem does emerge, the firm is capable of taking action to understand the reasons behind the problem, and make decisions that favorable effect the trend, or that prevent recurrence of the problem.

To make this more relevant, I drew an analogy with their Sales and Marking Department.

Their markets are broken down into regions and further into territories. Each territory manager has sales targets that they track and report up to the regional director. The regions report to countries. Eventually, all the performance metrics reach the company boardroom. Unfavorable trends and problems are investigated, decisions made and actions are taken. An eye is kept on the metrics to see if their decisions and actions were effective in increasing sales.

There is nothing here about perfection.

In this analogy, the market represents the Quality Management System and the regions and territories are its various parts organized by discipline. The territory managers, regional directors and the boardroom are the system owners and responsible management that exercise governance. Sales performance metrics are quality system performance metrics.

It was one of those beautiful “ah ha” moments.

I was intentionally being provocative with my question because I wanted this group that was responsible for a multi-billion dollar business to seriously consider how they were exercising stewardship of their pharmaceutical portfolio—for patients and investors.

What they expected to hear were Strategies for Avoiding a 483, but what I gave them was a refresher in Management 101 followed by one heck of a round of golf.

The QA Pharm

FDA: For Corrective Action Plans, Where are the Resources?

2011-05-14T21:37:00.002-04:00

Can you imagine the stream of firms that venture in to their respective FDA district offices to give presentations on their Warning Letter response and to offer their assurance that they truly “get it”?

You can be sure that theses firms had several dry runs and dress rehearsals to hone their material before stepping into what they perceive to be hostile territory. Their presentations were carefully crafted by the VP, SVP, EVP and vetted by the lawyers. Consultants who claimed to have "been there and done that" were invited guests to the prep meetings to give their insight into what “sells” at the FDA.

When the meetings at the FDA are over, the firm’s representatives heave a sigh of relief and offer each other congratulations that it went well, because it “felt good.” It “felt good” because no one on the FDA side of the table objected or got upset. So they go back to their colleagues and claim victory. The story gets exaggerated and turns into something like, “They really liked our presentation.”

In my experience, the only thing that “sells” at the Agency is results. The FDA “response” is a practiced, neutral expression that never is meant to signal agreement or acceptance. It’s all part of their “We’ll see it for ourselves when we come back to re-inspect,” modus operandi.

However, we are starting to see a very interesting twist at FDA that suggests they have finally figured out that there is more they can do to ensure effective action than sit through fancy presentations acting nonplussed while having smoke blown up their proverbial tailpipe.

The new twist is embedded in the Teva Warning Letter dated January 31, 2011, but only recently posted on the FDA website. (The delay of which I always find curious.)

The theme of Teva’s Warning Letter is a problem of cross-contamination. Teva dutifully responded with their corrective action plan, which baited the usual response from the FDA--with a bit of a twist.

We recognize that your October 7, 2010 response states that you are in the process of developing a risk management program for control of cross-contamination of the products produced at the Jerusalem Oral Solid Dosage (OSD) plant. However, you did not submit that plan, or data to support the effectiveness of the plan, with your response. We also recognize your commitment to finish the risk assessment within four months. Please provide us with any update on your timeline, and the identification of resources allocated to address this issue.

It is not uncommon for the FDA to expect a plan and timeline in a response. In fact, it is a frequent failing of companies to not provide a plan or timeline for completing corrective actions. However, in the case of Teva, FDA also requested the allocated resources to be identified.

That's the twist, and that's huge.

Frankly, this makes a lot of sense. The most successful corrective action plans have been those where the direct responsible individuals are named and appear in detailed project plans. There is a clear picture of what success looks like and how to get there. But most of all, the resources are identified to execute the work.

The regulation has always required sufficient numbers of qualified individuals to perform operations; so specifically asking about resource allocation to do the work is fair game.
Unusual—but fair.

In the past, the sincere delivery of a good presentation might have passed with the usual skepticism. Now be prepared to tell about the resources to pull it off.

Without the resources, it's just another pretty presentation.

The QA Pharm

Current Pharmaceutical Industry CGMP Compliance Trends

2011-04-17T09:00:00.000-04:00

It must be that time of year again when conference planners rack their brains on how to bolster dwindling attendance, because several have contacted me through this blog to ask my opinion on major trends in the pharmaceutical industry.

So with this edition I offer my opinion not only to those conference planners, but also to my readers. After all, why should you—my loyal readers—have to attend a pricey conference to hear what I told them?

But first, a note about—well, these pricey pharmaceutical conferences.

There are worthwhile conferences in our industry, but you really have to consider whether they are worth the price of admission. I have always thought that the best conferences were those with a strong FDA presence on the speaker roster. However, FDA speaker materials eventually become accessible to the general public. So, shortly thereafter, you can Google the name of the FDA speaker you saw in the pre-conference e-brochure and bingo. If it’s content you’re after, why not use your favorite search engine?

The worst conferences are those that recycle the same industry consultants—free advertisement. I'll save that subject for another time.

So—now to the subject at hand: current pharmaceutical industry CGMP compliance trends. Here are the top three, in my opinion:

1. There is an emboldened FDA intent on measuring up under a keenly interested Congress.

· There are sixteen (16) major pharma consent decrees dating from 1989 to 2010. What do they all have in common? No, it’s not bodies in the street. It’s GMP violations. Of these, only six (6) consent decrees have been vacated.

· Eric Blumberg, FDA Chief Deputy Counsel for Litigation, has been saying for the last ten (10) years that the FDA cannot expect progress until individuals are criminally charged. We’re starting to see that now. (Enter stage left: KV’s Marc Herelin, InterMune’s W. Scott Harkonen, Forrest’s Solomon, Glaxo’s Lauren Stevens.)

· Margaret Hamburg, FDA Commissioner, said that the FDA will no longer issue multiple Warning Letters. Criteria have been developed for selecting cases for criminal prosecution of individuals.

2. When there are repeated observations, the FDA questions the willingness and ability of the Quality Unit to exercise its responsibility.

· Repeated FDA483 observations are considered a failure of the Quality Unit, as stated in numerous Warning Letters.

· Warning Letter language recognizes that Quality Unit failure may be attributed to either an unwillingness to exercise its responsibility, or an inability due to lack of independence.

· Recent high-profile cases have ineffective quality units in common.

3. FDA expects the global deployment of the Quality Management System and oversight by corporate management.

· Corporations are expected to have oversight of the quality and regulatory compliance of their operating units.

· Some companies have “flattened” their organizations into non-compliance and lack of oversight upon the questionable advice of efficiency and cost-reduction experts.

· The Parke Doctrine holds management responsible although they may not have been directly involved or aware of violative conditions. Some of these individuals have appeared before Congress.

Now, here’s the funny thing. One conference planner asked if this anonymous blogger would agree to be a speaker. What part of “anonymous” didn’t they understand?

Perhaps I could make it work? Perhaps a backlit screen projecting my trademark silhouette?

The QA Pharm

Data Integrity Questioned at Ningbo Smart

2011-04-08T16:07:00.003-04:00

The Warning Letter to Ningbo Smart Pharmaceutical Company (March 30, 2011) revealed that they had reported conformance to specifications on Certificates of Analysis when in fact—no testing was done. (Among other issues.)

FDA rather understatedly informed Ningbo Smart, “It is essential that your firm only report results to customers when you have actually performed the analysis.”

However, FDA was quick to advise the Chinese API manufacturer of the full implication of their testing and reporting practices. “This serious CGMP violation raises concerns regarding the reliability and integrity of other data generated by your firm.”

This was the same language used by FDA in the Warning Letter (January 28, 2010) to Xian Libang Pharmaceutical Company in Shaanxi, China for using the infrared spectra for one lot of incoming material to support the release of subsequent material.

The term “data integrity” is not just casual language. It is a direct reference to the FDA Application Integrity Policy (AIP) that FDA invokes when there is evidence of fraud, bribery or other acts that impact the validity of data used to support marketing applications.

The FDA Application Integrity List is the list you don’t want to be on. Here’s the list:

http://www.fda.gov/ICECI/EnforcementActions/ApplicationIntegrityPolicy/ucm134453.htm

When FDA uses the term “data integrity” as it did with Ningbo Smart, it is another way of saying, “Why should I trust any data out of your firm?” As a result, FDA halts its review of pending new drug applications and proceeds to withdraw approved applications.

Remember, Ranbaxy was put on that list in 2009 for claims of falsifying data on product shelf life. Ranbaxy reported that it had tested compounds at room temperature when products were actually stored in a refrigerator. In addition, it tested data at different time points than claimed in drug applications.

But notice that FDA places the blame for the failure at Ningbo Smart squarely on the Quality Unit.

· “Failure of your quality unit to ensure that materials are appropriately tested and the results are reported.”

· “Failure of your QCU to exercise its responsibility to ensure the APIs manufactured at your facility are in compliance with CGMP, and must meet established specifications for quality and purity.”

· “Your QCU released API lots to the U.S. without assuring that all the required tests are performed.”

· “Your QCU also failed to detect that your COAs stated that…conformed to specifications, although the test was not performed.”

In fact, the ultimate slight was FDA’s recommendation that they hire a third party auditor, with experience in detecting data integrity problems, to assist them in evaluating their overall compliance with CGMPs. I’ve reported previously (The QA Pharm 9/25/10) that such recommendations are a vote of no confidence in the QCU.

So what can a QCU do to prevent data integrity problems?

1. Encourage your company to establish a data integrity policy to show that you are serious about falsification of data and that it is a cause for termination. Train on this policy.

2. Establish a general standard for Good Documentation Practices so that even the most innocent recording issues cannot be perceived as fraudulent. Train on this standard.

3. Establish a specific procedure on sampling/testing requirements and laboratory data recording to be clear about incoming, in process, and final testing requirements. Train on these procedures.

4. Provide specific training for secondary reviewers/approvers to ensure Good Documentation Practices are followed and suspicious results and trends are investigated.

It is impossible to prevent someone who is intent on falsifying data. However, even well meaning (but uninformed) people can give the impression of fraudulent data by erasures, unexplained cross-outs, incomplete blanks on forms, varying significant figures, signing documents after the fact, omitting/inserting data without explanation, etc. Such sloppiness at the least gives an impression of a questionable lot history, at the most—fraud.

The FDA correctly criticizes the QCU at Ningbo Smart. The QCU (a.k.a. Quality Assurance) is responsible for establishing a compliant Quality Management System (QMS) that is capable of detecting and self-correcting in order to maintain a state of control.

The QCU must be able to demonstrate that it has established and trained on policies and procedures that are designed to take data integrity seriously.

Let this be a reminder to take a second looks at your data integrity program. Go forth.

The QA Pharm

Leadership in Consent Decree Crisis

2011-03-25T17:13:00.001-04:00

It’s a most unfortunate ailment of epidemic proportions that the approach taken by many when addressing underlying CGMP compliance issues is effectively based on a checklist mentality—a “To Do List.” For sure, solving fundamental regulatory compliance problems involves tactical work that is broken down into discrete executable steps. However, I become more convinced every day that the most significant challenges in life—regulatory, or otherwise—are more about “being” than “doing.”

“Being” requires an examination of personal character and motives. It takes a deep dive into ones willingness and ability to put self-serving interests aside and share a common vision—and for Pete’s sake—work together.

Working together is hard work in the best of circumstances, but when faced with transforming an organization from non-compliance complicity to embracing standards and discipline, there is no room for silos and bunkers. What is needed; however, is a central figure—a standard bearer—that rallies the troops and encourages them to great achievements in the face of insurmountable odds.

So when the implication of a consent decree finally sets in, and when you realize more than ever that the all troops need to march in the same direction—what do you do?

1. Be the visible leader.

Face it. Most company management couldn’t find packaging line number 3, not to mention know how to converse with a second-shift hourly worker they have never met. But leadership soon recognizes the need to reach out to everyone, and becomes a quick study on how to do it. A leader is personal and accessible in times of trouble. Everyone needs to know and see who is in command of the situation. Lack of visibility builds distrust, and folks start thinking about their employment options.

2. Accept responsibility.

Blaming the FDA for a tough inspection is not the way to be credible. The workers know better, and chances are, they have been trying to tell you for years about what hasn’t been working. Leaders accept full responsibility no matter what. It becomes readily apparent to the rank-and-file whether or not there will be any significant improvement by sizing up management acceptance of responsibility. Without it, there is no reason to expect any lasting change. That’s when folks dust off their resume.

3. Rectify the situation.

Fix the problems. Fix it with your regulators, your customers and your employees. Chances are that production has stopped, workers’ hours reduced, and inventory is depleted. When it’s all over, make it right with everyone. Make them whole. Regain their trust. Your ability to compete and survive depends upon it. Your customer base and eventually your stock price are a vote of confidence. Efforts must be aligned and focused on the real problems, even if the real problem is management. When employees don’t see the real issues being addressed, they see the clock ticking and start floating their resume.

4. Solicit help.

Admit when you need help. You may have been rewarded in the past for your lean machine. But if you look around and find that your most experienced technical people took the early retirement program as part of your reduction in workforce program, swallow your pride and hire them back as consultants and contractors to help out. They will be happy for the work, and the going hourly rate will be far more than they were paid when they worked for you. But it will be worth it to them. Consulting groups are often necessary—even mandated by the court—but remember: you run your company. You have to sustain the operation when they leave. In the end, the support must be coordinated to avoid chaos. Don’t just turn them loose. When things get chaotic, people start interviewing.

5. Be open, honest and fair to employees.

Don’t make false promises. They would rather hear the truth—from you, not the locker room. However, most of the solutions to the real problems lie with the people doing the work. Invite them into the process of fixing the problems. Your credibility will be based on their prior experiences. If you need key people to hang in there with you, make it worth their while with retention incentives. If you need them, give them a good reason not to jump at the next good offer.

6. Communicate.

Communicate the problem, the plan and the progress. Make the communication personal. Employees know the difference between when a PR firm has written your sound bites and a message from the heart. Single sites are easier than corporate networks to communicate, but figure it out. It still needs to be direct and personal. Forget about keeping secrets thinking that this regulatory-legal type work is super sensitive. Everything is available on the web or Freedom of Information. Secrets are sometimes so well kept that people doing the work don’t know what commitments have been made to the FDA, or what they’re supposed to do. That’s when you’ll look around and find nobody there to communicate to. They’ve gone to the competitor.

So, while you’re occupied with “doing,” don’t forget the “being.”

The QA Pharm

Consent Decrees—It’s about Sustaining Compliance

2011-03-12T09:06:00.000-05:00

By the time a consent decree comes along, it’s no longer a discussion about responses to observations replete with well-turned phrases—it’s about a DIY Network renovation—a complete makeover. It’s a “gut-it” approach, as never before, which exposes the cracked foundation and termite-eaten beams weakened over time.

This is because the common element of a consent decree is demonstrating—sustainability. As in “over time.” That takes more than a fresh coat of paint.

Regardless of the huge effort and expense to redesign and implement a more robust Quality Management System (QMS), the real test comes afterwards—sustainability.

Long after the consultants have pulled up their tent stakes, the project plans flawlessly executed, the senior management dashboards faded away, the real mettle is yet to be tested—sustainability.

“Sustainability” is an attribute that is difficult to achieve under normal circumstances, not to mention under the supervision of the Department of Justice.

Geesch…can’t a person make an honest mistake anymore?

Is “sustainability” the same thing as “perfection”?

I sure hope not. If it is, we’re all screwed.

I prefer to think about “sustainability” in a more realistic way. Sustainability is the capability of an organization to know when it is veering off course and the ability to make the right decisions and take the right actions to re-center itself (without external intervention) to maintain a state of control.

Like in the human body, it’s an inherent homeostatic mechanism that monitors the manufacturing and quality process signals and responds accordingly to maintain healthy control of product quality.

“Sustainability” touches—nay, embraces—subjects such as values, culture, expected behaviors, empowerment and accountability. These don’t sound much like terms in the CFR. But the demands of sustainability require nothing less than organization transformation: from something, to something else that it wasn’t before—a makeover.

One thing for sure it is not. It’s not the FDA telling one over-and-over again about the same problems. In fact, consent decrees mandate a series of annual inspections performed by a third-party to determine sustainability, so FDA doesn’t have to.

In other words, FDA has already determined the recidivism of the defendant, and now they look for the third-party to spend their time and the defendant’s money to inspect and certify compliance—often for many years—measuring sustainability. Not FDA.

To achieve the attribute of “sustainability” is not easy, but worth pursuing under usual circumstances. Why wait for an injunction? The often-surprising benefit of the makeover is operating in the “sweet spot” of economic control of quality and providing a continuous supply of quality product.

Consent decrees require an entirely different kind of response than usual, because a different kind of result than usual is expected—sustainability.

Sustainability—and the organizational capability to achieve it—that’s the goal.

The QA Pharm

Consent Decrees—Just the Cost of Doing Business?

2011-02-26T08:35:00.002-05:00

The strategic reasons behind the acquisition in the works for Sanofi to purchase Genzyme are clear. It was a matter of fixing a sale price that reflected the true current and future value of Genzyme.

For those of us in the quality assurance and regulatory compliance professions, there has been the curiosity of how the history of manufacturing and compliance woes at Genzyme would factor into the sale price. I guess we’ll never know. But it is interesting that a financial analyst would minimize this kind of problem leading to a consent decree as “the cost of doing business.”

Jim Prutow, a partner in the health care practice at the PRTM consulting firm, says of the Sanofi-Genzyme deal: “… regulatory actions including consent decrees are increasingly part of the cost of business, and it is not the ‘death knell’ to a company’s growth and acquisition options that it was in the past.”¹

This points to the frustration at FDA on finding the right lever to pry some companies into compliance with the laws and regulations directed toward drug safety and efficacy and patient protection. Fines alone are ineffective, because they are just considered to be the “cost of doing business.” (And to whom are these costs passed on?)

Eric Blumberg, the FDA’s deputy chief counsel for litigation, prophetically said in May 2002 when he sign the Schering-Plough consent decree, “It's clear we're not getting the job done with large, monetary settlements. Unless the government shows more resolve to criminally charge individuals at all levels in the company, we cannot expect to make progress.” ²(See The QA Pharm 11/6/10.)

What might we expect for the future of Genzyme’s compliance profile as a result of the acquisition by Sanofi?

Christopher Viehbacher, Sanofi-Aventis CEO, says Sanofi can help Genzyme deal with its FDA consent decree and create "a culture of quality." ³

But Richard L. Friedman, Director of the FDA Division of Manufacturing and Product Quality and Diana Amador-Toro, Director of FDA New Jersey District have recently weighed in on the subject of quality at Sanofi:

· A Warning Letter was issued on January 28, 2011, at the Sanofi location in New Jersey ⁴ cited serious violations of failing to report serious and unexpected adverse advents in a timely manner. Examples given were as much as 896 days late.

· A Warning Letter was issued on February 9, 2011, at the Sanofi location in Germany ⁵ cited serious violations relating to sterility assurance and contamination control. Examples given included the repeat observation (from 2008) of failing to identify microorganisms recovered from sterility tests.

We can only hope for the sake of Genzyme’s patients who have rare, devastating lysosomal diseases that the connection is soon made between regulatory compliance and continuous supply of quality products at the most economical cost—with or without the help of Sanofi’s “culture of quality.”

The QA Pharm

¹Silverman, Ed, Sanofi Gobbles up Genzyme: What the Wags Say, Pharmalot 2/16/11.

²Miller, George, Schering-Plough Pharma Consent Decrees, FiercePharma, 10/19/10.

³Staton, Tracy, Sanofi caps Genzyme persuit with $20 Billion Deal, FiercePharma, 2/17/11.

⁴Warning Letter 11-NWJ-06, 1/28/11, Sanofi-Aventis US.

⁵Warning Letter 320-11-09, 2/09/11, Sanofi-Aventis Deutchland.

“Out of Abundance of Caution”—and Triad Group’s “One Concerned Customer”

2011-02-19T08:29:00.002-05:00

“Out of abundance of caution” the Triad Group initiated a recall of all lots of Alcohol Prep Pads, Alcohol Swabs and Alcohol Swabsticks on January 3, 2011, due to “concerns from a customer about potential contamination of products with an objectionable organism, namely Bacillus cereus.”

Triad’s Press Release on January 5, 2011, continued to state that it had received “one report of a non-life-threatening skin infection.” The date of this one report was not given. (I suspect we won’t know that date until a Warning Letter comes out.)

Triad published a fact sheet about the recall on its website. They stated, “There has been ONE report of a potential contaminant out of hundreds of millions of products sold.” (Their emphasis, not mine.)

The contaminated product was recalled, but tragically, not before the product was used with the surgery of a 2-year-old Houston boy who allegedly died from acute meningitis due to Bacillus cereus on December 1, 2010. Use of the product has been confirmed. The parents have filed a wrongful death suit. “We’ve been devastated. We’ve been absolutely crushed.”^a

Without going into a bacteriology lecture, suffice it to say, all the experts have weighed in on what every rank-in-file microbiologist in the medical products laboratory should know: Bacillus cereus is a very bad bug. This spore former is resistant to heat and tough to kill. That’s why it’s called an “objectionable organism”—it doesn’t belong in the product at any level.

“Concerns from a customer.”—one, just one customer—out of hundred of millions sold—one, just one customer. In the case of Bacillus cereus, it shouldn’t have to take more than one to crawl all over the problem.

My message to the Quality Department and those responsible for responsible for designing or operating the Complaint Handling System required by 21CFR211.198 and 21CRF820.198—sometimes it only takes one. Some complaints are so serious and potentially life threatening, that it just takes one. Don’t look for a trend.

With Triad’s one concerned customer, it’s not whether it was non-life-threatening to that one customer. Rather, it is all about Bacillus cereus.

I would have expected the “abundance of caution” at the Triad Group to be: (1) stop production, (2) recall all product, and (3) initiate a revalidation of all production lines—upon the first report of Bacillus cereus.

We don’t know yet the date of when Triad became aware of the first report. But I don’t get the feeling that the “abundance of caution” was very abundant.

UPDATED, February 25, 2011

On February 22, 2011, the FDA posted the FD483 related to this blog for the Triad Group’s parent organization, H&P Industries. Please go to this link:

http://www.fda.gov/AboutFDA/CentersOffices/ORA/ORAElectronicReadingRoom/default.htm

This is just beyond words.

It describes a fatal combination of inadequately developed processes; unvalidated sterilization processes; uncontrolled manufacturing environments; unqualified employees; failing sterility tests; and an irresponsible Quality Unit knowing releasing contaminated product into the market.

The 46 observations covering 30-page tell a story of nothing less than a foreseeable disaster. A ticking time bomb that is claimed to have caused the death of a two-year old Harrison Kothari of Houston and potential infections of more than 100 others according to the lawyers representing the Kotharis. ²

This surely will be a test case to see just how bad it has to be before the FDA takes action against individuals. (See The QA Pharm 9/11/10.)

UPDATED April 7, 2011

FDA Seizes $6 million in Products from Triad
http://www.jsonline.com/business/119352799.html

The QA Pharm

¹ Aleccia, JoNel, Parents blame toddler’s death on tainted alcohol wipes, msnbc.com, 2/15/11.

² Aleccia, JoNel, FDA defends actions at plant that made tainted wipes, msnbc.com, 2/25/11.

The Zero-Defect Aspiration at Colorific Baxter

2011-02-06T12:09:00.000-05:00

If the aspiration of Baxter CEO Robert Parkinson is “zero defects,” then the recent Warning Letter at their plant in Puerto Rico suggests that they have to get back to the basics.

The Warning Letter dated January 20, 2011, is very diagnostic of endemic issues where all the signs were there, but the symptoms were apparently ignored until it became another in the long line of regulatory enforcement events.

The symptoms were the “fabulous four” of pending failure: (1) not thoroughly investigating failures; (2) not listening to customer complaints about their failures; (3) not reporting these failures to the FDA; and (4) not resolving these failures, which were previously cited by FDA.

But to exacerbate the malady, Baxter chose to mask, rather than treat the underlying sickness.

The Warning Letter revealed an equipment failure that affected the color of the otherwise colorless liquid product. What was the Baxter approach to fixing this problem and work toward achieving zero defects?

· Baxter concluded in their investigation that healthcare professionals would detect the discolored product and not use it.

· Baxter developed and distributed a color chart to provide instructions to end-users when to use or not to use their product.

It was no surprise that the FDA editorialized, “It is unacceptable to rely upon the health care professional to fulfill your Quality Control Unit responsibilities…The end user should not be expected to make a determination of product safety and effectiveness…”

Mr. Parkinson said to analysts after the citation was issued, “Clearly, I’m not happy to have to communicate that we got a Warning Letter. Our aspiration is zero defects here. We are better than we were, be we have to get better.”

So—what’s the strategy, Mr. Parkinson? What system do you need to put in place that would have alerted you to the “fabulous four” in time to intervene? What was the role of QA in all this? And, for Pete’s sake—whose idea was the color chart?

Mr. Parkinson also knows (certainly now via the Warning Letter) that Baxter also has had an insect problem in their saline solution. So if I were Mr. Parkinson, I would be asking around whether someone in his organization was preparing an insect chart.

Class Assignment: Go to the following link and research all the Warning Letters across all the Baxter operating units. (1) How many do you count over what time period? (2) What are the common themes and underlying messages? (3) Outline a high-level corporate strategy for Mr. Parkinson to become an anticipating organization with respect to taking responsibility for the product quality/regulatory compliance.

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/default.htm#browse.

The QA Pharm

The Crack in the Wall: Unintended Consequences of Authority

2011-01-29T09:15:00.001-05:00

I remember when I was a freshly minted executive taking a window tour of the manufacturing facility. While listening to a staff member talk about the operation, I idly traced my fingertip on an ever-so-slight mar on the finish of the corridor wall, as I was lost in thought. Little did I know the chain of events that this little action would set off. By the time of my next walk into the manufacturing facility, the entire corridor was freshly refinished.

It often is with executives: a simple word, glance or unconscious pause—in my case the mindless wandering of my fingertip—has surprising effects.

Once there was a pharma exec that stated flatly that certain software was the company standard. Little did he understand that an alternative software that was justified and better suited to a unique situation had been in play for months. But his comment set off a fury of activity by dozens of employees that worked tirelessly over months to convert the data and retrofit it into the awkward “company standard” at great expense and loss of precious time and effort to deliver on commitments to the FDA.

In another example, a pharma exec questioned the timing of a purchase order request for a controlled temperature chamber for the stability program. The simple question of timing sent the requisitioner back to try again next quarter. Little did the exec know that this equipment was needed to fulfill a commitment to the FDA, and that there was a six-month lead-time to acquire it.

With authority comes unintended consequences: the rank-in-file hesitates to question it or push back on it.

Rather than creating a situation where the humble creatures fear to approach the mighty Oz, it would be helpful if the executive would take time to invite conversation about the request.

However, shame on the person who fails to make the business case, and the person who walks away fully knowing the unintended consequences of the denied request.

I have never met a company executive—whether a blustery curmudgeon, or a charismatic leader—who does not speak the language of money; who does not abhor squandering resources; or who is not willing to pay now to avoid a problem with the FDA tomorrow—when the proper business case is made. (Well—almost never.)

And—where was QA during the countdown to the day of reckoning with the FDA?

Fear is alive a well in corporations. But fear is really the result of the lack of confidence; not being prepared; absence of skills to defend a point-of-view; and often haunting memories of boogey men of the past. In short, it’s lack of conviction and courage.

Debate is productive. Contrarians sharpen the decision process. We would all do well to encourage it.

The QA Pharm