Throughout the regulations and guidances you will find something like this: “As with other aspects of the development program, documentation may be ‘less vigorous’ in early phases, but ‘they would still need to be adequate in order to allow for traceability of the manufacturing process.'”
Agencies, like the FDA, have consistently stated that phase 1 is less vigorous but starting in phase 2 you are fully GMP. These regulations are meant to ensure basic safety and documentation standards are met in the manufacture and testing of phase 1 clinical trial material and to encourage the design of quality into the process. It is expected that enhanced process controls and GMP standards will be employed as the material transitions into later clinical stages.
With the speed of development, and the fact early phase material can support commercialization, this phased in approach is an important balancing act in advanced therapeutics like cell and gene therapy. It is crucial that manufacturers of phase 1 clinical trial material assess potential risks associated with their manufacturing process, facilities, equipment, methods, materials, etc. and the associated impact of these risks on the safety and quality of the material. All significant risks should then be mitigated, and appropriate controls implemented to reduce potential adverse impact for the patients and data generated.
Recognizing the difference between the elements of a strong quality system and what is needed for GMPs. Folks often confuse the two and have difficulties maturing quickly. The stuff in the orange? That’s system and is not GMP dependent.
Some GMP, such as clean room controls or starting materials controls should be robust from the beginning. Others, such as cleaning validation, are developed as you move through the phases.
An appropriate level of root cause analysis should be applied during the investigation of deviations, suspected product defects and other problems. This can be determined using Quality Risk Management principles. In cases where the true root cause(s) of the issue cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. Where human error is suspected or identified as the cause, this should be justified having taken care to ensure that process, procedural or system based errors or problems have not been overlooked, if present.
Appropriate corrective actions and/or preventative actions (CAPAs) should be identified and taken in response to investigations. The effectiveness of such actions should be monitored and assessed, in line with Quality Risk Management principles.
EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Chapter 1 Pharmaceutical System C1.4(xiv)
The MHRA cited 210 companies in 2019 on failure to conduct good root cause analysis and develop appropriate CAPAs. 6 of those were critical and a 100 were major.
My guess is if I asked those 210 companies in 2018 how their root cause analysis and CAPAs were doing, 85% would say “great!” We tend to overestimate our capabilities on the fundamentals (which root cause analysis and CAPA are) and not to continuously invest in improvement.
Of course, without good benchmarking, its really easy to say good enough and not be. There can be a tendency to say “Well we’ve never had a problem here, so we’re good.” Where in reality its just the problem has never been seen in an inspection or has never gone critical.
The FDA has fairly similar observations around root cause analysis. As does anyone who shares their metrics in any way. Bad root cause and bad CAPAs are pretty widespread.
This comes up a lot because the quality of CAPAs (and quantity) are considered key indicators of an organization’s health. CAPAs demonstrate that issues are acknowledged, tracked and remediated in an effective manner to eliminate or reduce the risk of a recurrence. The timeliness and robustness of these processes and records indicate whether an organization demonstrates effective planning and has sufficient resources to manage, resolve and correct past issues and prevent future issues.
A good CAPA system covers problem identification (which can be, and usually is a few different processes), root cause analysis, corrective and preventive actions, CAPA effectiveness, metrics, and governance. It is a house of cards, short one and the whole structure will fall down around you, often when you least need it to.
We can’t freeze our systems with superglue. If we are not continually improving then we are going backwards. No steady state when it comes to quality.
Program management is commonly defined as “a group of projects that contribute to a common, higher order objective.” The projects in a program are related, and the intent of achieving benefits would not be realized if the projects were managed independently.
Program management includes the practices and processes of strategic alignment, benefits management, stakeholder management, governance, and lifecycle management. Program governance creates the control framework for delivering the programs’ change objectives and making benefit delivery visible to the organization’s control.
There are different styles of program management and what I am focusing on here is what is sometimes called “heartbeat”, which aims to achieve evolutionary improvement of existing systems and processes or organizational change. This program type creates value by reconciling contradicting views and demands for change from various organization actors in order to enhance existing systems and practices while sustaining operations.
Heartbeat program management is all about awareness of the contexts of the program and requires knowledge of strategy, competition, trends in the industry, and differences in management practices between the business units of the company. A good heartbeat program manager is highly concerned about their program’s long-term effects and implications for the company’s business.
Programs exist to create value by improving the management
of projects and to create benefits through better organization of projects. The
fundamental goals of program management are:
Efficiency and effectiveness: Aspects of management that a proficient project manager should address and benefit from coordination.
Business focus goal: The external alignment of projects with the requirements, goals, drivers and culture of the wider organization. These goals are associated with defining an appropriate direction for the constituent projects within a program as well as for the program as a whole.
Efficiency and effectiveness goals
Assist in identification and definition of project inter-dependencies and thereby reduce the incidence of work backlogs, rework and delays
Improved dependency management
Reduce the amount of re-engineering required due to inadequate management of the interfaces between projects
More effective resource utilization
Improve the effectiveness and efficiency of the allocation of shared resources Assist in providing justification for specialist resources that deliver an overall improvement to program delivery and/or business operations
Provide a means to identify and improve upon transferable lessons. Facilitate organizational learning
Greater senior management ‘visibility’
Enable senior management to better monitor, direct and control the implementation process
Business focus goals
More coherent communication
Improve communication of overall goals and direction both internally and externally to the program Target management attention clearly on the realization of benefits that are defined and understood at the outset and achieved through the lifetime of the program and beyond Assist in keeping personal agendas in check
Improved project definition
Ensure that project definition is more systematic and objective, thereby reducing the prevalence of projects with a high risk of failure or obsolescence Enable the unbundling of activities in a strategic project-set into specific projects Enable the bundling of related projects together to create a greater leverage or achieve economies of scale
Better alignment with business drivers,
goals and strategy
Improves the linkage between the strategic direction of organizations and the management activities required to achieve these strategic objectives Provide an enabling framework for the realization of strategic change and the ongoing alignment of strategy and projects in response to a changing business environment (via project addition/culling, etc.)
The Attributes of a Good Heartbeat Program Manager are the
Attributes to a Good Quality Leader
As quality leaders we are often ambassadors to ensure that
the quality program is progressing despite the conflicting requirements of the
various stakeholders. We need to actively influence quality-related decisions
of all stakeholders, including people holding superior positions. Having a
well-developed personal network within the organization is particularly
It is critical to always be communicating about the quality
program in a visionary way, to be seen as passionate ambassadors. Playing this
role requires constant attention to differing expectations of the stakeholders
and various ways to influence stakeholders for the benefit of the quality
system. To always be striving to build quality, to advance quality.
As advocates for Quality, it is a core competency to be able to stand up and defend, or argue for, the quality program and team members. This ability to challenge others, including their superiors, in a productive way is a critical ability.
A key focus of the quality program should be on engagement with a conscious and sustained drive to secure buy-in from key stakeholders (including senior management) and win over the hearts and minds of those responsible for execution to make changes feel less painful and inflicted. As quality leaders our aim should always be to engender a climate of comprehension, inclusion and trust, and to draw upon expertise globally to create fit for purpose processes and systems
Effective quality leaders need to be “heavyweight”
Core Competencies of the Heartbeat Manager
A note on program life
Many standard approaches perceive programs to have a finite life. This is constraining given that the strategies themselves, especially as applied to quality, have long lifetimes. I believe that program management has as much to learn from quality management, and there is a lot of value in seeing an indefinite time horizon as beneficial.
We have these quality systems with lots of levers, with interrelated components. And yet we select one or two metrics and realize that even if we meet them, we aren’t really measuring the right stuff nor are we driving continious improvement.
One solution is to create layered metrics, which basically means drill down your process and identify the metrics at each step.
Lots of ways to do this. An easy way to start is to use the 5-why process, a tool most folks are comfortable with.
So for example, CAPA. It is pretty much agreed upon that CAPAs should be completed in a timely manner. That makes this a top level goal. Unfortunately, in this hypothetical example, we are suffering a less than 100% closure goal (or whatever level is appropriate in your organization based on maturity)
Why was CAPA closure not 100% Because CAPA tasks were not closed on time.
Success factor needed for this step: CAPA tasks to be closed by due date.
Metric for this step: CAPA closure task success rate
Why were CAPA tasks not closed on time? Because individuals did not have appropriate time to complete CAPA tasks.
Metric for this step: Planned versus Actual time commitment
Why did individuals not have appropriate time to complete CAPA tasks? Because CAPA task due dates are guessed at.
Metric for this step: CAPA task adherence to target dates based on activity (e.g. it takes 14 days to revise a document and another 14 days to train, the average document revision task should be 28 days)
Why are CAPA task due dates guessed at? Because appropriate project planning is not completed.
Metric for this step: Adherence to Process Confirmation
Why is appropriate project planning not completed? Because CAPAs are always determined on the last day the deviation is due.
Metric: Adherence to Root Cause Analysis process
I might on report on the top CAPA closure rate and 1 or 2 of these, and keep the others in my process owner toolkit. Maybe we jump right to the last one as what we report on. Depends on what needs to be influenced in my organization and it will change over time.
It helps to compare this output against the 12 system leverage points.
These metrics go from 3 “goals of the system” with completing CAPA tasks effectively and on time, to 4 “self organize” and 5 “rules of the system.” It also has nice feedback loops based on the process confirmations. I’d view them as potentially pretty successful. Of course, we would test these and tinker and basically experiment until we find the right set of metrics that improves our top-level goal.
Sonja Blignaut on More Beyond wrote a good post “All that jazz … making coherence coherent” on coherence where she states at the end “In order to remain competitive and thrive in the new world of work, we need to focus our organisation design, leadership and strategic efforts on the complex contexts and create the conditions for coherence. “
Ms. Blignaut defines coherence mainly through analogy and metaphor, so I strongly recommend reading the original post.
The system creates value for the multiple stakeholders. While the ideal is to develop a design that maximizes the value for all the key stakeholders, the designer often has to compromise and balance the needs of the various stakeholders.
The degree to which the system components are aligned and consistent with each other and the other organizational systems, culture, plans, processes, information, resource decisions, and actions.
The system is designed to be as convenient as possible for the participants to implement (a.k.a. user friendly). System includes specific processes, procedures, and controls only when necessary.
System components are interconnected and harmonized with the other (internal and external) components, systems, plans, processes, information, and resource decisions toward common action or effort. This is beyond congruence and is achieved when the individual components of a system operate as a fully interconnected unit.
Complexity vs. benefit — the system includes only enough complexity as is necessary to meet the stakeholder’s needs. In other words, keep the design as simple as possible and no more while delivering the desired benefits. It often requires looking at the system in new ways.
Participants in the system are able to find joy, purpose and meaning in their work.
Knowledge management, with opportunities for reflection and learning (learning loops), is designed into the system. Reflection and learning are built into the system at key points to encourage single- and double-loop learning from experience to improve future implementation and to systematically evaluate the design of the system itself.
The system effectively meets the near- and long-term needs of the current stakeholders without compromising the ability of future generations of stakeholders to meet their own needs.
I used the term congruence to summarize the point Ms. Blignaut is reaching with alignment and coherence. I love her putting these against the Cynefin framework, it makes a great of sense to see alignment for the obvious domain and the need for coherence driving from complexity.
So what might driving for coherence look like? Well if we start with coherence being the long range order (the jazz analogy) we are building systems that build order through their function – they learn and are sustainable.