Thursday, October 23, 2014

Part 2: Responding to FDA483 Observations and Fulfilling Commitments

Part 2: Organizing to Get the Work Done

Responding to FDA483 observations was my focus in Part 1 of this series. Responses lead to commitments, and commitments lead to changes that are intended to prevent recurrence of the underlying problem that led to the observation.

In Part 2, I share my views on getting the work done to fulfill the FDA commitments. The following have become benchmarks from those who are best at getting the job done and getting the problems behind them:
  • Form teams. This might seem obvious, but forming cross functional teams representing stakeholders is often overlooked. The solution will very likely involve different ways of working that cross functional lines. It is a rookie mistake to think that the fix is something for the Quality Department to do on its own, or just an editorial change to a procedure. Depending on the problem, the team may need to be dedicated to allow focus, particularly if accelerated timelines are involved. Include on teams subject-matter-experts that have the scientific, technical, and cGMP backgrounds to provide appropriate guidance.
  • Use consultants judiciously. Consultants can provide valuable additional support. They should bring relevant industry experience that can help scope the project and give practical advice that keep the project moving. The best consultants are good listeners who can help you design the right solution that works for you. If the only team members that show up to meetings are the consultants, something is terribly wrong. Do not outsource your responsibly to consultants. Let them help you because you own the results.
  • Determine the deliverables. Many teams go off the rails because that fail to determine the tangible deliverables that address the problem. You cannot grasps the degree of effort, determine the resource needs, or estimate the timeline until there is a clear vision of what "done" looks like. If you cannot describe "done," then you do not know the problem well enough.
  •  Solve the problem, not just the Commitment. Make a careful assessment of what it will take to prevent recurrence of the observation, not just satisfy the specific commitment. The FDA always states in the FDA483 that the observations are just examples and are not all-inclusive. Companies are expected to determine all that is necessary to permanently resolve the problem that underlies the observation wherever it applies. Perform a root cause analysis and ensure that the solutions are operational and sustainable. That invariably involves more work that the narrow view of a specific example cited in an observation or the response given.
  • Determine how you will know the problem is solved. In true fashion of a CAPA, determine how you will measure effectiveness. What will tell you that the solution worked? What will be your first sign that it did not work?
  • Avoid IT Solutions. This may sound a bit strange, but in my personal experience, nearly every commitment made in a FDA483 response that involved an IT solution missed the commitment date by light-years. I know that it should not have to be that way. I'm just saying that in my 20 years of consulting experience, that has always been the case. Consider applying an IT solution as a later improvement, not within the commitment time line.
  • Use Project Management Principles and Tools. Quality System development work is not like a capital project where the much of what is needed to estimate the time and cost is known upfront. Quality system and compliance projects are more often like exploratory surgery where a lot is learned once you open it up. You may discover that multiple systems are affected after you start looking more deeply.  Recognize that plans will need to be adjusted along the way. Do not confuse progressive revelation with scope creep. Be adaptable. Establish plans and reports based on the work and target dates, not subjective feel-good dashboards with perpetual dates that slip. Anticipate problems with hitting the date and mitigate them before failure is foregone conclusion.
  • Provide Infrastructure Support. Remediating compliance problems often require new ways of thinking, not just new ways of working. Compliance problems frequently go hand-in-hand with company culture problems. Progressive companies that recognize the business value of an effective Quality Management System also recognize the opportunity that regulatory inspections provide to examine its culture and values. Change management coaches can help a company adapt to the changes required to support a quality and regulatory compliance culture.
  • Provide Management Support. Ensure that each project team has a sponsor who is the best fit based on the functional owner of the process being remediated. Clearly identify the role of the sponsor and ensure that it includes removing obstacles such as lack of organization alignment, stalled decisions, team dysfunction, and inadequate budget. Sponsor are the champions who are willing to delve into the team level to provide visible support, rather than sit on the management team and undermine their own folks at project update meetings. Quality system remediation provides a unique opportunity for function heads to understand dependent processes across functional lines.
  • Establish Governance Oversight. The work associated with fulfilling commitments is tightly connected to managing risk. Thus it is important to keep site governance councils frequently updated with progress and informed about unacceptable risks. These risks would also include the risk of meeting a commitment date made to the FDA. Other unacceptable conditions uncovered along the way should also be communicated to the governance body. Establish clear lines of communication and escalation between the team actually doing the work and governance. Learn how to escalate and resolve potential problems quickly.
  • Verify that Deliverables Solve the Problem. Take an independent look to ensure the work is completed and that the tangible deliverables are in-place and in-use. This is a good role for an independent consultant. It is far better to find out for yourself that the mark was missed than for the FDA to call it to your attention as a repeated observation in a Warning Letter.
  • Revisit Commitments. Although you may have verified that the solution is in-place and in-use, revisit the problem at an appropriate time interval to ensure that the organization has not reverted to the old ways of working.
How have you managed regulatory commitments? What are your success stories? What have been epic failures, and why?

In Part 3 we will examine how to get out of the old stimulus-response cycle of receiving inspection observations and fixing the problems.

John Snyder
The QA Pharm

Friday, October 17, 2014

Part 1: Responding to FDA483 Observations and Fulfilling Commitments

Part 1: The FDA483 Response

This three-part series will discuss responding to the FDA483, getting the work done to fulfill the commitments in a sustainable way, and a methodology to guide the remediation work.

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 by saying exactly how problems will be addressed.

There is plenty advice available, even from the FDA, on what constitutes a good response. For certain, the difference between a good and a poor response may calibrate how you are viewed by the FDA.

From my experience, the following are points to consider that have worked well when forming a response:
  • 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