Sweeping changes instituted by FDA in recent years are beginning to have a tangible impact on the way pharmaceutical manufacturers conduct business. This time, though, it isn’t a compliance fire drill focused on electronic signature capture or electronic application delivery formats. Instead, it goes much deeper, transforming the way life sciences companies look at their research, development and manufacturing process engineering organizations.
FDA’s “Pharmaceutical Quality for the 21st Century—A Risk- Based Approach” squarely takes aim at the issue of product quality, this time from a lifecycle perspective. The first incarnation of this initiative, originally floated in 2002 by FDA as the “Pharmaceutical CGMP Initiative for the 21st Century—A Risk-Based Approach” introduced the industry to the idea of process analytical technology (PAT).
This latest incarnation reflects a more holistic and mature perspective, recognizing the fact that implementing risk-based approaches to product quality management in manufacturing is only one piece of the puzzle: one that shares multiple interdependencies with upstream processes in research, development and early-stage commercial production.
The evolution of FDA’s Pharmaceutical Quality for the 21st Century initiative has been a journey, not only for the industry it impacts, but for FDA itself. The agency has, to its credit, openly acknowledged that previous compliance prescriptions have had unintended side effects—namely, discouraging manufacturers from embracing new technologies and process improvements even though such improvements might positively influence product quality outcomes, reduce waste, improve yields and ultimately drive costs down for consumers. The costs and risks associated with change, as a consequence of stringent validation and regulatory re-filing requirements, have simply been perceived by manufacturers as too high.
On the flip side, it’s only fair to point out that exorbitant product margins have allowed big-brand life sciences manufacturers to quietly absorb the expense of excessive inventories, waste, production inefficiency and variability that would put even the savviest consumer electronics manufacturer out of business in a heartbeat.
That said, the winds of competitive change are finally taking their toll, and FDA, in collaboration with partners from industry and academia, is encouraging the application of science and engineering to drug product manufacturing, as well as to its own internal validation and quality management processes.
This internal- and external-facing effort, labeled by the agency as “Quality by Design,” represents a sea change for the conservative life sciences industry, whose relationship with FDA has been cordial at best, and also for FDA. The latter has been actively engaged for the past three to four years in what amounts to a significant internal transformation and public relations campaign to gently persuade industry that the agency truly can—and should— become a change leader and a steward.
What began with PAT some five years ago has matured into a broader vision of change for the entire industry. PAT hasn’t gone away, mind you. If anything, the Quality by Design (QbD) vision provides a conceptual framework that helps companies position PAT as part of a greater strategic initiative, rather than relegating it to an isolated process control exercise (which was sadly the fate of many early forays into the application of PAT in manufacturing).
Positioning PAT in a QbD World
The concepts behind FDA’s Quality by Design initiative are quite straightforward. The idea is that quality should be built into a product (versus tested only after the fact) with a thorough understanding of the product and process by which it is developed and manufactured, along with a knowledge of the risks involved in manufacturing the product and how best to mitigate those risks.
Sounds simple enough, but the fact is that getting to the “thorough understanding of product and process” is a tall order. This is where PAT comes in.
If QbD defines “what to do,” then PAT is a framework for “how to do,” offering a system for designing, analyzing, and controlling manufacturing through timely measurements (during processing) of critical quality and performance attributes of raw and in-process materials and processes, with the goal of ensuring that the final product performs as specified on various measures. PAT isn’t a single product or technology.
Rather, it’s an architecture that incorporates elements of instrumentation, real-time data acquisition and storage, analytics, and—in its most sophisticated incarnation—advanced process simulation and multivariate process control. Furthermore, PAT has a dual role to play.
In a cGMP context, it promotes process control, and ultimately, the holy grail of release by exception (or perhaps more accurately, release unless there’s an exception!).
In support of QbD, it can feed empirical data about product and process interactions back to upstream development processes.
Today’s focus continues to be primarily on improving product quality and compliance while driving down the cost of high variability. However, the allure of feeding knowledge garnered from the manufacturing environment back to product R&D—potentially reducing the risks inherent in tech transfer processes—has forwardlooking manufacturers exploring new ways to model product and process data, specifically for cross-organizational knowledge sharing and reuse.
As it turns out, many of these early adopters are taking their lead not from the esoteric design world, but from the ISA S88 models already employed by the process modeling, control and execution systems in their manufacturing plants.
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