Earlier this year, the FDA issued its long-awaited process validation guidance document, which had been several years in development. It is well written and effectively articulates what many progressive companies have been thinking and doing for years. But many people in the industry are asking questions: How will it affect our process development programs? How will it affect the submissions and licensure of our products? And how will it aid in our commercial operations? Or will it have no effect?

Consider what the document says. In the simplest terms, it articulates four main messages. A strong process development program is essential — preferably using quality by design (QbD) — to eventually obtain expedited product approval and benefit from a relaxed regulatory position with the agency. Process validation (PV) is linked into that activity in verifying its conclusions: a set of team-based activities requiring many disciplines to work together to be effective. PV is value added and never stops. It requires a life-cycle approach with continuous verification and adjustment. (So continuous improvement is central to the activity.) By applying these principles, you will end up with a more reliable process that yields consistent products to meet your customers’ requirements, resulting in more satisfied customers. The overall take-home message is that PV is part of the drug development life cycle, that it never stops, and that it is a value-added activity. This can be described using what I call the “four Ds”:

• Design (build each process to a set of standards or requirements focusing on what a customer wants/needs)

• Demonstrate (by conducting experiments and validation to show that process and product meet design requirements)

• Document (the cornerstone of good work is recording it for posterity)

• Determine (ensure that results remain valid, or make changes as knowledge and experience grow — for continuous improvement).

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A Little History

To determine what impact the document will have on all the industry's questions and systems will require time. The answers rest in how companies use the guidance in process development, regulatory submissions, and operations. To fully appreciate its potential, however, step back and examine the status quo on PV's role in product development — as it began and has evolved until now.

When it was first incorporated in the mid 1980s, PV was viewed as a new regulatory requirement to be performed sometime in phase 3 of the clinical development cycle. That was when processes were being locked down and companies hoped their products would be proven safe and efficacious. Whether going for a drug approval or biologics licensure, a company either submitted protocols and performed PV later (but before sale of the first lots) or submitted the completed PV reports with its submission. Once that was complete, you could put your reports on a shelf and forget about them unless you made radical changes to your product or process. This was not a value-added activity, but rather a check-the-box process.

Meanwhile, the FDA wanted all legacy products (those that had been approved before PV) to have their processes validated, too. This created a flurry of activity in the 1990s (and later) to retroactively validate those products. But again, the folders were then stored away and ignored. All that entailed a great amount of work with very little return on investment beyond keeping products on the market and keeping companies out of regulatory trouble.

That was the old paradigm. Over time, companies began to use PV activities to demonstrate ruggedness of their processes by choosing worse-case settings for critical parameters in three PV runs. This method brought value to the work involved, but it was impossible to examine all high and low conditions for all critical parameters in all combinations and permutations in just three PV exercises or runs. The work was labor intensive, yielding relatively little return on investment. However, the paradigm was changing.

Then came QbD, another FDA-driven concept. It was broadly placed into the “GMP in the 21st Century” initiative that came about because of several factors. The FDA was viewed by many detractors as very conservative and not amenable to change or to encouraging implementation of new technologies into processes and products — particularly for those that had already been approved. Further, the agency was under pressure of increasing workloads with a noncommensurate increase in resources. It was forced to do what industry has always done: more with less. Faced with that, the agency attempted to create new visions whereby industry investment into creating better interactions with regulators regarding process and product understanding might allow the FDA to relax its oversight somewhat. That would allow it to slacken the strings of control and give industry more opportunity to control its own destiny.