Is a new FDA guidance imminent?
by Tom Spurgeon
What are the regulatory pressures facing aseptic process validation today and what will they be like over the next few years? An inquiry into existing literature and with current industry personnel reveals a corner of the pharmaceuticals industry driven by a lattice of suggested improvements, a constant hum of activity and improvements that fight to keep pace with general industry trends and emerging technology. Those working in aseptic processing validation must consistently look five years ahead and five years behind, at rules and informative processes and market realities, all of which play off one another like so many strings on a musical instrument. With an important FDA guidance revision just now beginning its long fade into routine and a brand new one described as imminent, aseptic processing and its regulatory outlook is at the forefront of pharma and biopharma business plans.
It's worth noting that the core guidance revisions for aseptic processing validation are still new. "The reason it's a hot area is that we had the aseptic processing guidance that was revised in 2004," said Hal Baseman, chief operating officer and a principal partner at Valsource.
Maurice Phelan, director of Pharmaceutical Technology, BioProcess Division at Millipore Corp., noted that newer statements are driving much of the attention: "The one thing that's gotten everybody interested, and sort of sparked a lot of interest in this subject over the last say year and a half, is the major statements by particularly the FDA about the need to change the way we manufacture sterile products."
Mr. Baseman added, "In September of 2004, there was a revision of the aseptic processing guidance. That resulted in a lot of discussion around validation of aseptic processing and things like that. It's always been a hot issue, an important issue, if you look at it from a risk management perspective. It's certainly a process that gathers a lot of attention."
Mr. Phelan sees the 2004 guidance as even more important in context. "I think it's the 2004 guidance, which was long awaited, but is also the strategic plan that the FDA has laid out, all of the concepts that are embodied in their GMPs for the 21st century initiative. All of the high-level sorts of concepts and aspirations that they have that are laid out in things like the Critical Path Initiative. And then there's the 2004 aseptic process guidance, when it's considered in the context of quality by design, design space concepts, all of the buzz in the industry around efficiency and manufacture, things like process analytical technologies -- when you consider all of those as contributors, then I think the buzz that's around aseptic processing and next generation manufacturing is a result of all of those together, and the context they have for whatever kind of manufacturing you do, whether it's biotech, or classical pharma-type manufacturing. It all depends on your interpretation on what it means to you."
The 2004 revision was the first major one since 1987, and therefore drew attention not just for the new standards it suggested, but for how the revision reflected modern industry practices. The result was a wave of attention to such issues that continues unabated. There are at least two major conferences this autumn that promise discussion of the subject, and specific classes on techniques involving aseptic processing and its validation that are filled weeks in advance. Mr. Phelan noted that there is genuine change reflected in the approach to process validation, within the hierarchy of validation.
He said, "Historically much of the body of work that would be called process validation wouldn't necessarily differentiate between that which was super-critical and that which was a required component but had variability that the process could tolerate. Intuitively the FDA is saying it's not just practical. Intuitively, if you've thought through a rationale that allows you to rank the criticality of unit operations in your process, then there should be a corresponding validation in your unit operations that's increasing in focus and scientific content as you go up the criticality scale. "I've heard an FDA inspector say, ‘Say what you're going to do. Prove that you can do it. And then when you get into manufacturing, do what you say you do.' That's a fairly straightforward statement for these guys to make."
In making its guidance revisions, the FDA gathers information from industry sources and then, once compiled, releases it back, causing a re-affirmation of the industry's best practices distinct, in its way, from standards the FDA might apply to drive companies into certain practices. At one meeting in 2002, the FDA's Advisory Committee For Pharmaceutical Science heard from several industry leaders and its own speakers on a variety of subjects related to aseptic process validation, including container-closure and sterile isolators. As Mr. Baseman put it, "Because we had an opportunity to comment extensively as the FDA allowed us to do [for the 2004 guidance], it became a reflection of what the industry was doing."
That give-and-take continues into the field. Said Mr. Phelan, "I heard this from the FDA as recently as last week: If you want to interact with them, and you're prepared to think about applying some of these next generation concepts, than they want to engage you." This is a change from times past, he noted. "Historically the FDA would have said, ‘Our door is open, and nobody's coming to talk to us. It's a one-way affair for us, and we have no option but assume a worst-case scenario. The only opportunity we have to share information is in the limited capacity of inspections or audits or reviews.' Now they're saying, ‘We have to change the way we do business. It's our view that you, the manufacturing community, need to look at how you manufacture and look at these types of areas.' Quality by design is the classic example of what they'd like to see.
"They've put programs into place," he added. "They have a pilot program that's gone on for the last 12 months for the review of new drug applications, where they've invited people to participate in basically a risk-based construct for the CMC sections in their new drug application."
The Guidance revision not only provides a platform for understanding the FDA's expectation and current industry practices, it also serves as a spur to science by offering up its own set of ways to approach certain problems while fostering from related organizations more up-to-the-minute, specific technical solutions.
With the FDA's more general efforts starting in 2001 to implement GMPs "for the 21st Century" -- itself two decades since the last similar effort -- came an emphasis on risk analysis. Risk analysis became the tool through which managers began to approach the validation of their aseptic processing techniques.
Mr. Baseman explained the general process as it has an impact on a facility's approach to their processing procedures: "Most biological contamination comes from people. So anything involving human intervention is going to be a riskier step. If we're doing an aseptic process test, let's say there's a step in there where somebody has to add a component manually, like a stopper. That becomes a riskier step. If we can eliminate that step by having some automated system to do that, then we eliminated and improve the process. That pushes us towards using isolators rather than conventional filling lines." The prioritization that comes with risk-management engenders a step-by-step vetting of the process validation. It puts emphasis on key points such as filtration, and then works its way backward to elements with less of a risk. As risk-management works its way to and then through those industry agents that have yet to fully embrace that approach, their use should become more and more routine.
This is just the way the FDA wants it, said Mr. Phelan. "Classically, validation exercises have been very, very document-heavy exercises. The FDA are now saying that we think there's a very practical approach to be taken in addressing all of the validation that needs to be done in a manufacturing process, assessing what the risks and/or overarching benefits are to putting so much effort into that enormous body of work, and then maybe thinking about a different way of justifying the amount of focus you put on in respect to validation, exercises based on their risk to your program."
Despite the fact that ideal sterilization technique is terminal, or heat-based, the market should drive more and more companies into aseptic processing. As most are quick to point out, terminal sterilization is a poor technique to apply to unstable products such as those represented by protein-based drugs. Aseptic processing places a specific emphasis on filtration as the last process performed to destroy organisms or contamination within a product. "Filtration would be where you would take the product, put it through a .2 micron filter and then fill it under very controlled conditions, in a clean room, perhaps in an isolator or perhaps in a conventional clean room but one with a lot of controls to keep the contamination out of the product," said Mr. Baseman. "Because there will be no subsequent step to destroy those organisms. That's why filtration is of interest related to aseptic processing."
With technology, market concerns and the introduction of new techniques and practices all driving interest in aseptic processing and its validation, one might think of the regulatory backbone as one of pressure and punishment. Actually, the opposite seems closer to the truth. Mr. Baseman praised the FDA for its ability to solicit commentary when preparing its guidances, both from individual players and major industry organizations like the Parenteral Drug Association (PDA). Not only does this give them a wider array of knowledge to use, the process settles industry players for whatever changes are to come. "I believe it's rare for the FDA to come out with something that's a big surprise," said Mr. Baseman. "For the most part what happens is that guidance gets issued that reflects what the FDA has been talking about and what the industry has been doing.
"I think there's an anticipation, but I don't think people are sitting there saying, ‘Maybe we shouldn't do any process validation this year because everything is going to change.' I don't think that's the case. The FDA has done a good job indicating where it's heading with this. They certainly put out some pretty good information in their initiative documents. There was a CPG that came out I think last year, but that CPG -- and that's their internal guidance document -- talked about what the agency would internally be looking for when it reviewed submissions. So if you read that, you kind of understood what the Agency is looking to do."
Groups like the PDA provide further support by issuing technical reports following guidances and standards, reports that provide a very specific way of meeting required standards, to be accepted, used or even refused, and make more clear the science of what's being done, away from purely regulatory motivations. For instance, PDA Technical Report #42 deals specifically and in what is described as a "practical" fashion with Process Validation in terms of protein manufacturing.
This system of multiple supports and reinforcements sets the stage for a revised guidance from the FDA for processing validation. Mr. Phelan characterized such revisions as "imminent." As to what that revision will entail, Mr. Baseman opined, "I think it may have something to do with new techniques. There's so much new technology that's coming out now, and I think it's important that the PDA weigh in on new technology, things down the road: new technologies for monitoring and so forth."
Mr. Phelan thinks the emphasis will be on the principles driving multiple solutions. "What I would expect is that it will contain all the intellectual components that one would classically associate with process validation and then it will have loaded on top of those good validation practices the concepts of design space, critical process parameters, risk-based decision-making and then practical validation approaches -- a rationale that says I understand what drives my process and I understand the critical parameters I need you to control and I need to validate.'"
As more companies are driven to work with drug forms that resist terminal sterilization, those that embrace GMPs and a risk-based outlook should find strong support in terms of aseptic process validation techniques, applied to steps ranging from filtration to use of isolators to air flow, that match the criticality of each phase to their overall function. Look for future guidance and technical papers to build on rather than replace the general outlook, at least until it becomes routine, as all former hot topics must sooner or later.