By Wayne Koberstein, contributing editor
Most of the questions posed in this article might well be addressed to an expert. But the actual function of the article is to arbitrate already well-known expert opinions rather than add to them. The two best-known bodies of opinion on this month’s topic represent the perennial dichotomy between industry and FDA supporters.
If you subscribe to the view that the FDA is an ever-more opaque miasma of bureaucratic obstruction, you may be in the industry camp that believes process changes in drug manufacturing should be left to the plant engineers. From the agency’s perspective, however, the current procedures for validation of process changes simplify regulation and make it more transparent — precisely by giving you and your suppliers responsibility for deciding when a particular change in process is sufficiently significant to trigger FDA involvement. If any cooperation among all three parties is going to take place, its success will hang on that decision.
I will get to the matter of cooperation with your supplier in a moment. But first, let’s consider how the processchange procedure might look from the FDA perspective.
Is It More Or less regulatory oversight?
One of the industry’s chief complaints about the massive agency is its lack of personal continuity. As with the help department for your computer vendor, every time you call the FDA about a pending matter, you get a different person, often with a much different disposition, and varying from helpful to disdainful. But what you are seeing may be an artifact not of more but less regulatory oversight.
Since the early 2000s, the agency has operated on the principle of “risk-based regulation,” meaning it would leverage its meager resources by putting companies on their honor to monitor and report many quality-related data points in lieu of previously customary inspections. Despite changes in administration, budgetary pressures alone have been enough to keep the risk-based approach in motion. The fact that the FDA now waits for a producer to report a significant process change determines the structure of the agency organization charged with responding. It is unlikely to be linear and continuous; it is quite likely to be the opposite.
Nevertheless, I can see that the agency is making a serious effort to map the way — to elucidate the right steps to take with process changes. Last May, the FDA’s Susan Kirshner gave a presentation at the AAPS National Biotechnology Conference. Perhaps ironically, my attempts to contact Kirshner for this column went unanswered — but maybe that’s because I’m the press. In any case, she was authorized at AAPS to elaborate on FDA guidances, add her own insights, and answer audience questions. (I can’t give you a simple url link to Kirshner’s slides, but if you search for “Ask the Regulator AAPS Susan Kirshner,” you should see a PDF download close to the top of the results.)
The session began with a focus on process changes and paid particular attention to federal regulation 21 CFR 601.12, which provides risk-based reporting categories for changes to an approved biologics application. A Kirshner slide quoted the Guidance for Industry Changes to an Approved Application: Biological Products 1997: “Applicants are required to demonstrate … the lack of adverse effect of the change on the identity, strength, quality, purity, or potency as they may relate to the safety or effectiveness of the product.” Moreover, §601.12 presents the three main categories of changes that require reporting, in order of how much a change could potentially have adverse effects. If the potential is minimum, you must merely describe it in your annual report; if moderate or substantial, supplements are required.
Unless I’m reading it wrong, what that seems to say is that you — the big collective that includes your entire company and your supplier — must decide when to report a change based on your assessment of its adverse potential. Because you — this time the company you — ultimately hold the bag if you don’t happen to report something that later turns out to be harmful, or maybe an inspector happens to stumble upon it some day and thinks it might be harmful. That’s where the “how you can work with your supplier” comes into play regarding cooperation with the FDA.
PAT Is Scarce
If you’re not sure about a change, there are some objective ways of settling the matter. Regulation section §601.12(e) describes a “comparability protocol” of tests and “acceptable limits” sufficient to prove a change lacks adverse effects on safety and efficacy. The protocol is meant for changes already reported, but if you or your supplier is contemplating any change in process, there are ways nowadays of modeling the process on a small or virtual scale before spending the money to implement. It’s called PAT (process analytical technology), but you won’t see much of it around this industry, yet. Used in all kinds of other industries, yes, even those where process changes can be a lifeor- death concern, PAT is a rational and flexible technology that can be applied broadly or incrementally on the plant floor.
Perhaps the small-molecule crowd is feeling a bit overlooked at the moment. It’s true much of the material cited above is directed at biologics, but I have a sense that much of it still applies to everything from API to finished product in the traditional pharmaceutical lines. Like the regulatory requirements, the solutions largely apply to both sides, biologics and pharma. My closest look at a PAT application in this industry has been a changeover to real-time automated monitoring and control of moisture in a fluid bed dryer. (By the way, if you want to know more about PAT, search for it on the FDA website.)
Often lost in the perennial debate about the recalcitrant regulators at the poor old FDA, the other two main elements in the equation of cooperation are you and your supplier. If you haven’t already, make it your business to bring those two elements together. Start with the easy stuff — fund some pilot projects — but work steadily and persistently toward the level of cooperation that allows you to make smart choices about process changes.