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PAT Searches for its Identity
By Bikash Chatterjee, President and Warford Reaney, Head of International Operations
Pharmatech Associates
Two years ago, the Food and Drug Administration issued its landmark guidance document
on Process Analytical Technology (PAT), articulating an alternative vision to
the inspection-based quality control systems that have governed pharmaceutical
manufacturing over the decades.
What the FDA has provided is a bold chance for our industry—long mired in historical
inefficiencies and product failure—to reinvent and improve existing processes
for superior cycle-time, consistency and yield.
The PAT guidance document proposes to replace the existing test-and-release model
with an on-line surrogate testing process that judiciously employs multivariate
analysis and in-line analytical technology. This is to enable companies to release
product based on real-time data demonstrating that the product was manufactured
within the ranges of control for its critical process parameters.
Given this incredible opportunity, why haven’t we seen a glut of new PAT applications
flooding the FDA? Where are the fresh approaches to process for existing and new
product programs? The agency has approved several PAT applications spanning API
manufacturing to drug product manufacturing, but the numbers are far less than
would be expected with the promise of such a large potential upside for securing
quality control at levels never before achieved.
Now is that critical moment when pharmaceutical and biotech companies must ask:
Are we on board with this new PAT vision or not? Do we “get” the program and its
intended benefits, or do we stick with the current process status quo?
Vision without a Roadmap
The FDA has made an unprecedented effort to reinvent its perspective on quality
and catalyze the pharmaceutical and biotech industry around this new quality paradigm.
Now comes the challenge of actually implementing this vision. In an effort to
articulate clearly the vision of PAT control, the document places a much greater
emphasis on the technology solution and comparability argument than on the criticality
of thorough process and product characterization.
Although the FDA’s articulation of the PAT ideal seems straightforward at first,
the devil is in the details. The ability to fully leverage real-time measurement
technology requires a thorough understanding of both the key parameters that control
the process and the measurement devices that assess those parameters during production.
The selection of measurement tools that will be used to control the process is
a critical aspect of the PAT strategy. More importantly, the application of these
measurement tools that control the key elements of the process must be considered
carefully. These devices within the context of the process are no longer recording
devices but are now making GMP decisions about the process. If you evaluate this
requirement against the classic drug development paradigm it is easy to see the
“disconnect.” Historically very few firms have had a thorough understanding of
the error allocation between their raw materials, process and measurement techniques.
Without this knowledge, it is difficult to implement new technologies that can
credibly achieve the level of assurance described in the PAT guidance document.
This lack of a roadmap has shifted the emphasis within the industry to evaluating
the technology solution as prescribed within the guidance document and meanwhile
neglects critical process and quality considerations.
As a science-intensive industry we have joined together to work toward best practices
regarding PAT. The advent of user communities such as the International Forum
on Process Analysis and Control (IFPAC), which is dedicated to the application
of PAT, underscore the industry’s interest in deciphering the equation. However
as we sit here today, too many programs have been derailed by an unbalanced emphasis
on the technology as opposed to the process leading up to the technological solution.
The good news is we are not the first industry to consider PAT. Although our constraints
may be somewhat different, the recipe for successfully managing complex multi-disciplinary
programs is not and we can look to these models as a framework for moving PAT
forward.
Creating a PAT Roadmap
PAT has enjoyed tremendous success in other industry sectors. The chemical, automotive
and semiconductor industries have been leveraging the benefits of PAT for years.
Our industry, of course, is different in one fundamental way: We are subject to
regulatory oversight, which forces us, at least for commercial manufacturing,
to validate our process at every step. Because of this, we must acknowledge our
tendency to focus on compliance with specifications rather than process understanding.
This is due largely to the legacy structure of pharmaceutical organizations—which
are divided into specialty silos that promote individual expertise within specific
disciplines—as opposed to an organization with cross-functional knowledge. One
lesson that can be learned from other industries is to harness the power of the
entire organization when attempting to affect a quantum leap in process and product
understanding.
Multiple pharma and biotech companies have launched into PAT with the hopes of
realizing the benefits of reduced testing and improved productivity, only to stumble
and fall because of the lack of fundamental science backing up the improvement
initiative. Add to this mix the manufacturers of Near Infrared (NIR), Effusivity
and Thermal Conductivity, struggling to understand how their technologies will
fit into the continuum of product quality and process control and you have the
potential for a very complex equation. These specialty solution providers’ market
viability is predicated on the pharma industry’s ability to unravel the puzzle
of PAT implementation. To date, the industry’s obsession with the end game - that
of focusing upon analytical comparability and technology solutions - has jeopardized
many PAT initiatives.
We must assess and in some ways reinvent our industry modus operandi. A
fresh approach could shift our emphasis away from the traditional product and
compliance orientation toward an understanding of critical processes to achieve
the significant PAT benefits that have worked so well in other sectors. The implementation
of the best of PAT could drive our industry beyond current regulatory and market
liabilities to processes that are smoother, more consistent and more efficient
than ever before. It’s a matter of taking this new, groundbreaking document and
adapting it to our industry’s very specific needs and demands.
The Road Ahead
Despite its relatively short history PAT is approaching a crossroads. PAT can’t
be successful, nor can the industry realize the benefits of enhanced process control,
without clear understanding of the basic principles articulated in ICH Q8 and
Q9. Without establishing a grounded scientific basis and approach to process understanding,
PAT will continue to struggle and may never achieve the industry-wide transformation
envisioned by the FDA.
The pharmaceutical and biotech industries must develop a clear, end-to-end system
for process characterization and product development life cycle and we must cultivate
the appropriate tools to underpin our efforts. The reality is that the FDA’s available
resource pool is limited when it comes to supporting initiatives such as PAT.
This lack of resources will drive the agency to a more integrated reliance upon
field office personnel to act as their liaison on a regular basis throughout the
PAT implementation process. Also due to a lack of resources, there will continue
to be a reliance on knowledgeable external consultants and solution providers
to complement internal product and process understanding. Effectively integrating
these multiple elements requires a structured framework, which embraces communication
and data-driven decision making.
One approach to managing this project complexity would be to adopt an operational
excellence project management framework. The most widely implemented operational
initiative in our industry today is Six Sigma. Six Sigma requires that success
can only be achieved if all elements of the process equation are addressed. When
Bill Smith first contemplated Six Sigma at Motorola in 1986 he was attempting
to put a toolkit together that would result in a 100-fold increase in quality—an
audacious objective for any stage in an industry’s development. Now, twenty years
later, the semiconductor industry no longer utilizes Six Sigma because the sophistication
of their processes demand 8-9 sigma! Compare that to the 2-3 sigma processes employed
by pharma today. This scale of improvement can only be achieved by employing an
objective, data-driven cross-functional assessment of each step within the process
and product development lifecycle. PAT should consider the cross-functional operational
excellence model if it is to be successful within the industry.
The FDA has made an unprecedented effort to reinvent its perspective on quality and catalyze the pharmaceutical and biotech industries around this new quality paradigm. It is now our turn to address the challenge of implementing their vision.
Six Sigma is a registered trademark of the Motorola Corporation
Pharmaceutical Processing
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