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 integr