Friday, October 17, 2014

Part 1: Responding to FDA483 Observations and Fulfilling Commitments

The FDA483 Response

Although not legally required, it is standard industry practice to respond to FDA483 observations. Companies that want to be responsive and have a good relationship with the FDA respond to each observation. There is plenty advice available, even from the FDA, on what constitutes a good response.

This approach has worked well for me:

  • Do you agree with the response? Stating up front that you either agree or disagree, in part or on the whole, stages the rest of the response. Think twice before you say you completely disagree especially with everything-- because the FDA will always have the regulations, industry good practice, and the facts on their side. But it is quite possible that the FDA investigator got the facts wrong or drew the wrong conclusion. This is why a close-out meeting with investigators at the conclusion of the inspection is important. It is better to straighten out the record at the close-out meeting than in a FDA483 response.
  • Defend what you are doing right. The examples of violations cited in observation are just a snapshot in time. Although you may not be proud of what was found, the finding may not be representative of the current state of control. The example may pre-date significant improvements that you have made on your own initiative, although they may be in progress. Be sure to give yourself credit for such improvements. The last thing you want to do is give the impression that the FDA was the first to call an problem to your attention.
  • Take product lot numbers seriously. When the FDA mentions specific lot numbers associated with a problem, it immediately puts you in the position of having to defend why those lots are still on the market, and why you have not shut down manufacturing associated with that product, process, or facility. Put your best minds and writers to work that lays out the defense of your release decision and the state of control. Be objective and use data. If you come to the conclusion, albeit late in the game, that the product should be recalled, seriously consider the right thing to do. Also take into account causing a drug shortage, because the FDA will work with you to avoid a shortage while you resolve inspection-related problems.
  • Defend State of Control. Some types of observations paint a picture of being out of control, particularly when it is associated with sterility assurance, potency, content uniformity--you know--the SISPQ issues. Also, when the collective observations run the gamut across the quality system can indicate precarious state of control. Take your best, realistic, honest shot at how you know you are manufacturing and distributing a safe, quality product. And, for goodness sake, do not--I repeat--do not anchor your defense that there have been reported dead bodies. Meeting all end product specifications may be the best defense you have if statistically treated, but be aware that this defense and will always peg you as a quality dinosaur living in the 1970s.
  • Commit to Action. Address the specific issues that were called to your attention, but do not stop there. Carefully determine the root causes of the issues cited in the observations. There will not always be a one-to-one relationship of root cause to observation. Nonetheless, run the problem to ground and understand what is behind the problem. Determine the action required to prevent the reoccurrence of the problem cited. Undoubtedly, the solution will require changes in multiple areas at the system level. Be sure to convey that you are taking system-level action, not just addressing the superficial, specific examples. Remember, observations are just examples. Indicate the action you promise to take and target completion date. Be clear in your own mind what "done" looks like and the specific deliverables that will provide the evidence of completion.
  • Commit to Developing Appropriate Action. If you do not know exactly what all is necessary to fix the problem, it is completely acceptable to indicate that the scope of activities and target dates will be established in a plan to be provided later. But indicate the date that the plan will be completed and communicated. Major milestones of a plan are usually acceptable in a follow-up communication.
  • Recognize the Minimalism. Very likely you have taken a minimum essential approach to the commitment. By the time all the internal reviewers have edited the response, you have pared down the work to something manageable for normal business. However, the work associated with FDA inspection observations in not normal business, and the scope of the actual work required to prevent recurrence of the observation when you delve into the root cause and prevent recurrence through systemic changes. 
  • Provide Realistic Target Dates. There is always a balance between showing responsiveness with aggressive target dates and over committing to unrealistic dates. When dealing with operational and quality system problems, there may be more work involved than meets the eye. Some problems may require engineering studies or process development in order to understand the right approach to take when solving a problem. Take time to really think through all that is involved in order to provide realistic target dates. You don't want to go back to the FDA--at least too often--to revise target dates.
  • Engage Your Internal Associates. I cannot tell you how often I discover the situation where commitments and target dates were given to the FDA in very well written responses, but those who carry out the work were clueless. It's best to involve those who have to carry out the promises made in the response in the actual writing of the response. Time is of the essence when preparing a response, but cutting out those who actually do the work will always uncover significant execution  issues at the worse possible time.
  • Take FDA Suggestions. When the FDA makes a suggestion about retaining a GMP consultant to assess your overall quality system and help you to improve--take the suggestion. This recommendation usually comes in Warning Letters where the FDA has come to the conclusion from the breadth of problems that there is no confidence in your Quality Unit or Management Oversight. Consider such a recommendation as a direct hit and taking on water, not a shot across the bow. So be responsive and act accordingly.
What is your experience with preparing regulatory observation responses? What has worked well? What has not worked well?

In Part 2 I will talk about organizing to get the work done to fulfill commitments.


John Snyder
The QA Pharm



Tuesday, September 16, 2014

If You Need a Burning Platform to Justify Change, You Must Like Firefighting

Often times pharma has a split personality. One personality loathes firefighting, and the other personality needs a burning platform to justify doing anything that requires spending money.

Go figure.

This becomes evident in our industry when some companies cannot part with a pittance of their billions of dollars profit to establish or ensure that an effective and sustainable Quality Management System (QMS) is in place--along with suitable facilities and sufficient staff levels.

This is really obvious when such companies are at the heart of the devastating drug shortage problem. The burning platform appears in the form of with regulatory enforcement action, disgorgement and penalty fines, consumer stakeholder lawsuits, loss of goodwill from patient advocate groups, and drop in stock price.

A burning platform you want? A burning platform you get.

But what about the patient? 

The patient deserves better. No company can claim to put the patient first without solidly and confidently knowing that an effective QMS is in place, in use, and providing the data-driven evidence that you are operating in a state of control. 

But that is way too boring. 

It is much more exciting to emerge victorious from the daily firefights. The person who rescues the baby will always get more recognition that the schmuck who goes around changing the batteries twice a year in the smoke detectors.

So the next time you hear someone say that there is no burning platform to motivate spending the money, investing the capital, or authorizing the project, tell them it is too late when the platform is on fire. Make the business case that the QMS and other worthwhile quality / compliance projects are an investment in ensuring a reliable supply of quality products to desperately needy patients. 

You will always spend more money at the most inconvenient time and under the most impossible timelines when have to react to a crisis. Smart companies know how to anticipate a problem; not react when the damage is done.

Waiting for the platform to burn ends up scorching the patient.


The QA Pharm


Sunday, August 3, 2014

Three Essentials for Sustaining an Operational Pharmaceutical Quality System: The Quality Management Triad.

After nearly twenty years helping the biopharmaceutical industry to regulatory enforcement by implementing a operational and sustainable Quality Management System, I have come to the conclusion--at the most fundamental level--there are three quintessential elements required for success. I call it the Quality Management Triad.





The first element is Quality Governance. This is the body that provides:

    • the Vision—the aspirational view of the future, and how Quality Management is integral to the business strategy;
    • the Leadership—the top business unit and functional heads who motivate, align, plan and engage the organization toward its quality goals;
    • the Standards—the policies and standards that are endorsed by Leadership that establish the quality requirements—the “what” is required?

    • the Oversight—the communication channels and forums that provide to Leadership the direct visibility of product quality and compliance risks and trends—in order to make effective data-driven decisions.
The second part is the Pharmaceutical Quality System (which is the ICH Q10 term for the Quality Management System). The PQS:


    • establishes the Document Architecture—the hierarchy of the official, approved written instructions and executable records;
    • implements the Procedures—the processes—or the “How” to apply—the requirements of the Standards to your operation;
    • maintains Control—quality is about controlling variation, and the Pharmaceutical Quality System establishes your intentional and consistent ways of working to control variables—including the human variable—to operate in a state of control.
    • includes the Records that captures the product history and the manufacturing and environmental information that surrounds it.
The third part is Quality System Ownership , which is the specific application of the concept of Business Process Ownership that sets expectations and accountability for the constituent parts of the Pharmaceutical Quality System:  Ownership includes responsibility for:

    • Execution—the daily management of the quality processes described in procedures to ensure it works and is being followed;
    • Maintenance—to ensure that the quality process remains current with regulatory requirements and industry practices; and remains applicable to your changing business;
    • Performance—the measurement of how well the process is working and being managed, as well as the problems and opportunities the process is detecting;
    • Escalation—the identification of unacceptable conditions or events that puts the patient and the business at risk—and taking the immediate actions necessary to mitigate the risk, and making recommendations for permanently solving the problem.
At the center is the Quality function whose responsibility it is to engineer the processes for these three parts, and to ensure that they work—and work together effectively. 

To be clear—quality is everyone’s responsibility. But much like “Safety” is everyone’s responsibility, it is Quality’s responsibility to establish the ways and means of the Quality Management Triad, and to report on the effectiveness of the processes and manage risks.

Why is The Quality Management Triad important?

The pharmaceutical industry is a dynamic business environment.  Acquisitions, operational realignment, portfolio changes, manufacturing relocation, facility repurposing, and organization restructuring and integration are among the strategies to increase stockholder value. These continual changes impact the Quality Management System, and like any other aspect of the operation, it must be managed to remain effective and relevant.

Take this hypothetical example of the single-ingredient, solid-oral tablet manufacturer that constructed a dedicated facility for their new product.

Later, high-potency, multi-ingredient tablets were introduced into this facility as line extensions. The facility was then expanded to manufacture oral liquids and eventually retrofitted to produce oral suspension products.

Plans were being made to introduce parenteral drugs into the facility when the decision was made to enter into an agreement with a contract manufacturing operation—a CMO—for that technology, which was the firm’s first venture into a third-party partnership.

All the while, volumes were increasing, markets became global and the company turned to a twenty-four seven operation to keep up with demand. The increased profitability was directed toward the development of promising new drugs, while operating expenses were reduced and tightly controlled to fund new initiatives.

While this was great news for investors and employees, an unintended consequence was quietly undermining the business. The Pharmaceutical Management System had not evolved with the business, and was no longer capable of reliably detecting and managing product quality and compliance risks.

“Loss of management control” was the theme of the series of FDA483s and the eventual warning letter when the site was fraught with recurring manufacturing deviations and missed target dates to the FDA for solving the problems.

Although this is a hypothetical case, many people identify with some parts of this story when I share it.

Unfortunately, the Quality Management System is often viewed as a resilient tome of instructional content with little susceptibility to changes to the business. Nothing could be farther from reality.

Quality professionals across the industry who have looked back at their past quality problems and regulatory enforcement action, say—ironically—that their Quality Management System was a victim of their success.


Whatever the environment, the Quality Management System must be managed to ensure that it is Fit-for-Purpose and that it continually serves and protects the business.

What are your thoughts? How mature is the Quality Management Triad at your company? 

Please engage in this conversation. I would be pleased to hear from you,  and I would like to help your management team improve on these vital processes.

How healthy is your Quality Management Triad?
Please contact me to discuss how we can work with your senior staff and quality leadership to ensure these essential elements are in place at your company.

Please Contact Me:
John Snyder
John Snyder & Company, Inc.
john@john-snyder.com

Also, find me on LinkedIn for peer-reviewed articles on Quality Management System Topics.

John Snyder
The QA Pharm

Wednesday, April 16, 2014

CAPA backlogs? Five underlying causes.

You would think that the Corrective and Preventive Action (CAPA) system would be a business enabler---you know, a disciplined approach to permanently resolving problems once and for all. Unfortunately, the way most CAPA systems are designed and used, it is more of a stumbling block. The system gets so chucked full of stuff that backlogs are the norm, and a logarithmic increase in staff is required if you really want to keep current—or at least close as many CAPAs as you open for any given week.

You know the story. We have to get ready for the next inspection. EMA said they were coming in, and we are also overdue for an FDA inspection. There is a clutching of the chest because we know we're not in great shape. Our backlogs are back up again, and we cannot afford another observation about overdue CAPAs, and they are really on to us about liberally doling out extensions to the point that original target dates were meaningless to begin with. We keep kicking the preverbal can down the road.

Regardless, we form Tiger Teams of our best and brightest to focus full-time for the next several weeks to reduce the backlog--typically viewing the exercise as just paperwork. These stellar players let the work of their normal day job slip while well intentioned management asks for daily updates that chip away at time normally intended for sleep. The only metric that matters at this point is the backlog so that the very least we would be able to show a downward trend to the next inspector. 

Thus the saw-tooth cycle continues for years with the backlog steadily going up, followed by focused efforts to drive them down. And somehow we really feel good about our Can-Do attitude. It may not be fun, but we know how to pull together and deliver in times of crisis. Management rewards us once again for the firefight.

Sound familiar?

Such story only serves to show that the spirit and intent of the CAPA system has long been lost, and in reality, our CAPA system is out of control—and has been for a very long time.

The CAPA system is not making us any better and has actually become a "hidden factory" within our organizations that has found some self-serving purpose that has no relationship to making our products, processes or systems any better.

I really think we need to step back and do a reality check and admit that our CAPA system is broken and that we need to determine the underlying cause that lead us to this situation and prevent it recurrence.

That sounds like a CAPA for the CAPA system.

Whatever we call it, we need to examine just about every aspect of the way we manage CAPAs, and be willing to let go of some deep-seated beliefs. One thing I have learned about the CAPA system over my 35 years is that beliefs about the CAPA system are held very deeply with doctrinal zeal.

So, let's look at some fairly common CAPA practices that I believe are the underlying causes of the phenomenon I call “The CAPA Paradox.” In other words, with all these CAPAs, why aren't we getting better?

1. The CAPA system is has become a quality work order system

The Corrective and Preventive Action (CAPA) system, by definition, is intended to address problems and prevent them from recurring. However, CAPAs are opened for sundry reasons that range from delving deeper into a subject, to giving visibility to the team determining how frequently to change the pink ice in the urinal. In fact, a common practice is for every chartered project to also have a corresponding CAPA that contains the purpose, team member composition and roles, and major milestones. There is no problem statement, no data, no root cause analysis, no action plan, no defined deliverables that correlate to the root cause—and no mention of how effectiveness will be determined. In other words, very little content having to do with the intent of a CAPA system.

2. TrackWise has become a project management tool.

TrackWise is a valuable enterprise computer application that gives visibility to its contents through its capability of tracking, notifying, and reporting. Unfortunately, rather than seeing these TrackWise features as a tool to support the CAPA system, TrackWise has become an end to itself. Anything that we want to give such visibility automatically goes into TrackWise. Thus, the capability of the tool has defined the CAPA system. The floodgate is opened to all who have access, which inflates the number of “CAPAs," which causes the periodic panic.

3. CAPAs are opened without knowing the root cause.

When the unguarded portal of the CAPA system is open to the masses, then we should expect a wide variation in practices and applications. Although Quality Assurance may be required to review and approve CAPAs, they are doing so against the long-eroded purpose—enabling bad practices. If there were just one high-leveraged change that would start the shift back to the fundamental purpose of the CAPA system, it would be to require a root cause (or most probable root cause) as the price of admission to the CAPA system. No root cause—no CAPA. A root cause provides the target for the purpose: Correct what? Prevent what? Right behind this would be for Quality Assurance to be the gatekeeper to the CAPA system and to launch aggressive root cause analysis training and a strategy to reduce the number of employees that have access to the system.

4. CAPAs are not associated with things that matter.

One could go further to say, in addition to requiring a root cause, the root cause must be an output of the Deviation Management System for which a root cause can be assigned to a nonconformity or unacceptable trend. By considering Deviation Management and CAPA as one continuous process, the CAPA system is properly directed toward product, process and quality system events that have some probability of product impact. Adopting this view screens out the myriad of misapplications that come just short of the company suggestion box. Not only is the number of CAPAs reduced, they are CAPAs that matter—a better representation from a regulatory inspection perspective..

5. The low deviation threshold is debilitating.

Even though we associate the Deviation Management and CAPA systems, when events that are many degrees removed from product impact are treated with the same rigor, it is difficult to distinguish the significant issues from the noise. Providing alternative, risk-based pathways that permit rapid, real-time corrections and documentation is reasonable and compliant. Taking a “…for the want of a nail the shoe was lost, for the want of a shoe the horse was lost, for the want of a horse the soldier was lost….” to every event is neither noble or compliant, especially when valuable resources are equally directed toward the employee who used a “non-GMP ink” as the recovery of a microorganism in product not previously identified in the manufacturing environment. Management 101 better handles the former, and a CAPA the latter.

 Take this simple test to determine whether you need to examine how well your CAPA system is working.

1.   Do you have a saw-tooth backlog of CAPAs that result from heroic efforts?

2.   Are your CAPAs only directed toward something that you can actually correct and prevent?

3.   Do you have recurring, predictable deviations?

4.   When you compare the total deviations per year for the last five years, is there a downward trend?

5.   When you get a TrackWise report, is it readily apparent the most significant problems that require immediate attention.

6.   Does your company have intolerance for recurring deviations?


If your results are troubling, then it’s time to take a look at the design of your CAPA system and, perhaps, get back to the fundamentals.


The QA Pharm