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 the best at getting the job done in a sustainable way 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 creating 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 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 keeps the project moving toward the solution. The best consultants are good listeners who can help you design the right solution that works for you. But, if the only team members that show up to meetings are the consultants, something is terribly wrong. Do not outsource your responsibility to consultants. Let them help you, but it's your company and you own the results.

• Determine the deliverables. Many teams go off the rails because they 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? Consider whether this is yet another attempt at solving the same old problem. Remember that recurring observations lead to increased levels of enforcement. Be sure you know the problem is truly solved.

• Avoid Information Technology (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 if at all possible.

• Use Project Management Principles and Tools. Quality System development work is not like a capital project where 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 the patient. You may discover that multiple linking systems are affected after you start looking at the problem 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 a foregone conclusion. When you see that the timeline is slipping, ask for help and consider first what it will take to get back on track. Don't just keep moving the target date back as the default solution.

• 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. Recurring compliance problems are frequently a culture problem that discounts the value of an effective Quality Management System and regulatory compliance to the business. 

• 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. Sponsors are the champions who are willing to delve into the level of the working team to provide visible support, rather than sit on the management team and undermine their own folks at project update meetings. Being sponsors of quality system remediation projects 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 always include the risk of meeting a commitment date made to the FDA. Take commitment dates seriously. 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 that actually does the work and governance. Learn how to escalate and resolve potential problems quickly. Nothing consumes the timeline as much as reluctant escalation and indecision.

• 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. Be a healthy skeptic and ask, "How do we know for sure the problem is permanently solved?"

• 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?

The QA Pharm

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 multi-billion dollar profit to establish or ensure that an effective and sustainable Quality Management System (QMS) is in place--along with suitable facilities for intended use 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 regulatory enforcement action, disgorgement and penalty fines, consumer stakeholder lawsuits, loss of goodwill from patient advocate groups, and a 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 than 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 you 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

The Quality Management Triad: a Model for Performance Sustainability

Establishing a sustainable Quality Management System that helps a company to become an anticipating, rather than a reactive organization requires intentional effort to bring three essential element together. I call these elements the Quality Management Triad.

The first part is Quality Governance, this is the body that provides:

• Vision—the aspirational view of the future, and how Quality Management is integral to the business strategy for operational performance and continuous product availability to patients;

• Leadership—the top business unit and functional heads who motivate, align, plan, and engage the organization toward its quality goals;

• Standards—endorse the policies and norms, which establish the quality requirements—the interpretation of laws and regulations to your operation—the “what” is required;

• Oversight—the communication channels and forums that give Leadership visibility to product quality and compliance risks and trends—in order to make effective data-driven decisions—and provide Leadership the means to exercise management responsibility.

The second part is the Pharmaceutical Quality System (which is the ICH Q10 term for the Quality Management System). The Pharmaceutical Quality System—or PQS:

•  Management System—the totality of policies, standards, processes that directs and controls activities with regard to quality;

• Processes—to ensure consistency and intentional ways of working when applying the standards to your operation—and to control variables, including the human variable;    

• State of Control—quality is about controlling variation, and the Pharmaceutical Quality System provide the capability of self-detecting and self-correcting problems and give us a clear picture of our current state of control.

• Continuous Improvement—knowing the top regulatory compliance risks at any give time and having project teams directed toward resolving them with verifiably effective solutions.

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 managing the constituent parts of the Pharmaceutical Quality System:  Ownership responsibility includes:

• Execution—they manage the daily operation of the quality processes described in procedures and ensure procedures are effective;

• Maintenance—they ensure that the quality process remains current with regulatory requirements and industry practices; and remain applicable to your changing business;

• Performance—they measure how well the process is working and identify problems with the process, and problems that the process detects—and always seeking ways to meet the requirements in the most efficient way.

• Escalation—they identify unacceptable conditions or events that puts the patient and the business at risk—and take the immediate actions necessary to mitigate the risk, and make 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. Much like Safety is everyone’s responsibility, it is the Quality function’s responsibility to establish the ways and means for the Quality Management Triad; and ensure effectiveness.

Why is The Quality Management Triad important?

The pharmaceutical industry is a dynamic business environment.  Acquisitions, operational realignment, portfolio changes, manufacturing relocation, facility re-purposing, 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: 

A 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 underlying theme of the series of FDA483s and the eventual warning letter when the site was fraught with recurring manufacturing deviations, missed target dates, and ineffective solutions promised to the Agency.

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 in the business environment. 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.

The Quality Management Triad is a key element of a business strategy to sustain performance and ensure a continuous supply of quality product to patients.

The QA Pharm

Quality System Design Attributes: Criteria for an Operational and Sustainable Pharma Quality System

There are many instances when a pharmaceutical quality management system (QMS) must be improved in part or as a whole. In some cases improvements are made in response to regulatory inspection observations. In other cases improvements are made when new company standards are deployed in order to remain current with changing regulatory requirements and current industry practices. Still other improvements are made to support the changing mission and product portfolio of the business.

Whatever the driver may be, a mindful approach must be taken when designing the quality system to ensure that the organization is capable of operating and sustaining the system. Unfortunately, improvements are often viewed as an SOP-writing exercise without considering the factors that help to ensure that implementation is successful.

The following is a discussion of ten Quality System Design Attributes (QSDA) that must be considered as part of the quality system improvement process to ensure that the organization is ready and capable of operating and sustaining the system. These attributes can be considered essential design criteria, because these attributes are the most common root causes for the failure of the quality management system and consequent regulatory enforcement actions.

These attributes are worthy of serious consideration by those who are engaged in quality system development, as well as change management coaches that support adoption of new systems.

1. Standards and Site Procedures

These are part of a document hierarchy that collectively comprise the Quality Management System (QMS) and declares how a company intends to operate in compliance with laws, regulations and company requirements. While standards establish the requirements, procedures provide the detail for how they are applied to a specific operation. This architecture provides the structure for the library of interlinking requirements and instructions. Without standards and procedures, there is no control over the way work is performed and how decisions are made.

2. Process

An orderly process flow facilitates a common understanding of how work is performed. Process flow diagrams commonly appear in procedures, and process mapping is often the first order of business when designing a new system, or improving an established one. Process flows also support value stream analysis and employee training by showing the big picture, key interactions and decision points. Incomplete, inefficient and disjointed processes open the door to informal practices to develop over time due to the lack of a fluid, practical or understandable way of working. Designing the process to be Fit-for-Purpose and useable is essential for compliance.

3. Decision Processes

Most processes have decision points. While some decisions may be very straightforward, others may require critical thinking skills to weigh available information, assess the risks and implications in order to make the best-informed decision. Some decisions require the participation by other stakeholders, or escalation to higher levels of management, especially when events or conditions arise that create an unacceptable risk. Ensuring that decision processes, decision makers and escalation criteria are clearly described in procedures helps to establish appropriate responsibilities, governance and risk management.

4. Role of Quality Assurance

Quality Assurance (QA) has a unique, independent decision-making role codified by the Code of Federal Regulations. It involves review and approval of all cGMP matters, as well as the release of product into interstate commerce. QA also has a role within each quality system that must be procedurally established. This will include QA reviews and approvals, as well as a description of the type of events and conditions where QA must be notified. QA must not be put into a role where there would be a conflict of interest such as expediting production or approving its own work. Establishing the role of QA ensures the independent oversight and support required by our industry.

5. Records and Documentation

Equally important to procedures are the records created when procedures are followed. Examples of records include batch records, forms, logbooks, drawings, recording charts, and printouts. Instructions are given in procedures on how to complete associated records. These records are signed and dated by the one performing the work at the time the work is performed. Some records are considered so important that the work and the entries must be witnessed. It is common to have standards and training on good documentation practices to promote clear and consistent written entry conventions, as well as to prevent the perception of fraud. The design and content requirements, as well as storage and archiving of records are very significant. Complete, accurate, and timely records provide the batch history and facilitate data mining and support investigations.

6. Performance Metrics

Performance metrics are at the core of managing the quality management system. Performance metrics are designed into system procedures and are intended to help the system owner manage the performance of the system, and to detect problems. Metrics also help to identify improvement targets and measure the effectiveness of decisions and actions. The review of quality system performance metrics is the main content of the Quality Management Review (QMR) process. The QMR is at the core of Quality Governance, since it brings together cross-functional management, system owners, and performance metrics for the purpose of ensuring that risk are identified, effective decisions are made, and that the quality management system is continually effective. Performance metrics are essential for becoming an anticipating organization.

7. Infrastructure

Infrastructure is an attribute that encompasses a wide variety of tangibles that support the effectiveness and efficiency of the system. These could include facilities, equipment, software, and co-location of system users. Supporting infrastructure may be mentioned in procedures if they are part of the process (e.g., TrackWise software). Sometimes infrastructure is assumed (e.g., space and computers). Since infrastructure support takes significant lead-time to implement, be sure to allow sufficient time in the implementation plan in order to meet commitment dates.

8. Organization, Skills and Resources

To effectively execute the process and make appropriate decisions requires skilled system users and a supportive organization structure. Changes to each quality system require that the organization structure, skills and resources be evaluated to ensure that the organization is capable and ready to operate the new system.  Each role specified in a procedure must have identifiable personnel that have the education, experience and skills to perform the assigned activities. Implementation of the new system requires role-based training and a learning assessment in advance of start-up to ensure organization readiness. The bigger the change, the more effort will be required to be ready for effective implementation.

9. Dependent Linkages

The QMS is a network of interrelated systems. When designing a quality system, it is important to consider not only the inputs and outputs within a system, but also between systems. Inadequate linkages between systems create “short circuits” and can cause the quality management system to fail. Ensuring effective linkages can be a challenge when undertaking a comprehensive quality system remediation effort, since the state of the relevant linked systems can be a moving target, or the sequence of remediation targets may not be optimized. Nonetheless, the identification and continual assessment of dependent linkages is essential for an integrated and well functioning quality management system.

10. System Ownership

Each quality system must have a defined owner who takes responsibility for the design, procedures, operation, performance, reporting, and improvement of the system. The system owner also ensures that the system continually evolves as regulatory and industry expectations change, and when there are changes to the business portfolio, organization structure and function. Clear system ownership and ownership behavioral expectations are essential to fundamental quality system management. Establishing systems owners sets apart key personnel who can work together within and across sites for internal benchmarking and continuous improvement. These system owners also become a sub-set of company experts where investment of continuous education and development is well placed.

A Word About Working with OpEx Change Management Coaches

Quality system development efforts definitely require the organization to be ready and capable of adopting and adapting to changes required for sustainable implementation. The value of the effort in terms of time and cost can only be realized if the improved quality systems that are the result can be sustained. So this area of the business is definitely worthy of Change Management attention (not to be confused with the Change Control quality system). The challenge is to align and leverage quality system development and change management activities and targets. Here is where the ten Quality System Design Attributes come in.

These ten Quality System Design Attributes represent the areas where the most significant changes will occur and where support may be needed. Teams must identify the anticipated changes for each of these ten attributes. Each change must be clearly described (from what to what?) and expressed as a tangible quality system design deliverable. These changes must be assessed to determine whether the change is incremental or transformational. Change Management coaches can facilitate the conversation and organization preparation to receive and operate the new or improved system, particularly where the most significant changes will occur.

The QA Pharm

Ownership Responsibility for the Pharmaceutical Quality Management System: Setting New Expectations

In Texas we have an expression: If it's left to two people to water the horse, the horse will go thirsty.

Our quarter horses are well-watered because of established roles and responsibilities around the ranch. But I am no longer surprised that in the pharma industry it's not that easy to point to who is responsible for what when it comes to the details of the quality management system.

I typically get one of two responses to the question, "Who owns the [fill in the blank] system?" Whether it is Training and Qualification, Deviation and CAPA, Document Management, Complaint Handling--or whatever-- it's the same:

• Ultimately it is the Head of Quality, or
• What do you mean "own" (or responsible) exactly?

Sure, the Head of Quality has the ultimate functional responsibility, and in the sense of the Park Doctrine, the CEO has the penultimate responsibility. But that is a neither practical or effective.

I published an article that discusses the importance of identifying clear ownership at the operational level for each element of the quality management system and the benefits to the business when new expectations are set.

Follow this link to read the article on IVT Network-->  Ownership Responsibility

I hope you find this article beneficial. Write to me, or post a comment to this blog and tell me what you think.

The QA Pharm

Company Culture and CGMP Compliance

I’ve come to the conclusion that compliance with the FDA Current Good Manufacturing Practices (CGMP) is just as much about company culture as it is about anything else. A corollary to this is that resolution of regulatory compliance problems is just as much about organization transformation than anything else.

I have divided companies with significant regulatory issues into two categories: those who seriously strive to intellectually make the connection between the purpose and intent of the regulations and weave it into their business values; and those—well, those who see the FDA regulations as bureaucracy that encumbers its business with onerous rules.

The former eventually arrives to a point of mental assent that CGMPs are a business enabler, since they support the mutual goal of safe and effective drugs that meet important public needs. The latter is frustrated that CGMPs seem to get in the way with its legalistic—almost forensic—investigation and documentation when things do not go as expected.

The former eventually sees company policies and procedures as the declared intent of the company to control the human variable by doing work the best possible way to achieve a predictable outcome. The latter sees policies and procedures as restrictive to their ability to ad lib when situations call for flexible ways of working when faced with the unexpected.

The former sees the quality management system as the means to assure product down to the unit dose level when sampling and testing could never be of sufficient size to provide that level of assurance. The latter considers it a success when all the final product test results are met—or rationalized—and that there are no bodies lying in the street.

The former sees CGMPs as a supporting consistent, reliable manufacturing and continuous product supply to its patients. The latter scoffs at CGMPs saying, “Don’t you understand? We have medically necessary products. We have to find a way to release this lot.”

Culture starts at the top. The behavior of company senior leadership sets the tone for whether the culture embraces or is antagonistic toward the U.S. Food and Drug Cosmetic Act and the Current Good Manufacturing Practices—the price of admission into this business.

The company that applies these regulations in the spirit and intent, as well as efficiently and effectively as possible—will have the most economical control of quality, and will have a competitive advantage.

So in the end, how will you know when the culture has favorably changed? It will be when everyone—top to bottom—becomes self-correcting. When one sees another doing something out of compliance, he/she says: “We don’t do it that way here.”

The QA Pharm