Complacent or Overly Compliant? Why Has Industry Been Slow to Adopt Single-Use for Bioprocess Control?

A few weeks ago, we hosted a webcast which addressed questions surrounding the relatively slow uptake of single-use technologies for biopharma measurement and control. Speakers Michael Kowolenko (formerly Sr. VP with Wyeth Biotech and Biogen Idec), Kit Erlebach (Merck) and Paul Priebe (Sartorius Stedim) offered a range of perspectives on what has been holding back single-use in biopharma. (A partial transcript is below. Also, access the full on-demand webcast here—brief registration required.)

Kowolenko offered this assessment: “A lot of times what you battle with as you bring in a new innovation, you have management who says . . . what advantage does it give me? Oftentimes you can make those cases . . . but you have to actively do that. The technology in and of itself won’t do it. You have to make the appropriate business case. The pharmaceutical industry has to become a little more aggressive on this stuff. We’re very conservative and to a certain extent complacent. To me, the steps that ICH and the FDA are taking with regards to process understanding, analytics and control should be pushing the industry in that direction. I truthfully think the industry should have done that on its own. We shouldn’t have needed that. We should want to know about our process and how to make it more efficient and to decrease waste.”

Has industry been too complacent? Has the regulatory environment been too great an inhibitor? Priebe actually puts much of the burden on the vendor community. In an interview at this year’s BIO show in Chicago, Priebe said: "We can't just provide our customers with a box of legos," he says. Single-use technologies have to be more integrated and standardized.

What’s your take? Here below is some of the discussion from the webcast:

What improvements are needed in single-use sensor and measurement technology, and what process variables need to be measured and controlled?

Priebe: In general we’re still early on in the maturation of single-use technologies. From the supplier-base perspective, we’ve seen a lot of movement . . . the supplier base understands that we don’t want to revolutionize; we want to fit into the existing paradigm. Certainly, flow and pressure are reasonable well done. Conductivity is not that well covered—there are a few solutions out there. Cell culture dissolved oxygen seems well covered at this point . . . Each supplier is scrambling to bring solutions that make sense to the marketplace.

Erlebach: As an industry generally we’re conservative, so in terms of options we like to see other people being involved with this and using it, which is always a hurdle in this industry in terms of innovation. . . . For us it’s a continued supply of information and data to allow us to get there. Alongside that, what’s always going to be there is, how do they compare in terms of accuracy to what else is already available? The big thing that would get us there is some kind of innovation that you . . . could do in-line with a single-use sensor that would enable us to say, “We’ve got to use it.” . . . That’s what I’m looking for. How do we put something in-line that we couldn’t do elsewhere?

We’ve been using single-use or disposable elements within a process for 12-plus years, so . . . it’s not as if we’re against single-use. It’s around the application of how you’re going to make it fit together and what’s the benefit . . . we’re not going to replace one that’s a multi-use one with a single-use one simply because it’s a single-use component. Either it’s got to save you something in costs or allow you to do something differently, or you’re looking at a new system whereby you’re going to changeover because there’s a real benefit as compared to something else.

Kowolenko: If you have a company that embraces PAT, then you start an operational philosophy that requires you to do much more in analytics than you would normally get . . . . you can look at stainless vs. plastic and start looking at the sensor technology and it’s not that different if we’re just going to do the classic pH, dissolved oxygen, conductivity, those sort of things . . . those things are just being developed for stainless steel, never mind for plastic. But there’s no reason this can’t be applied to plastic. I think, as Kit said, the industry has been a bit conservative here. Other industries have been doing this for 30 or 40 years, and looking at processes and how to measure reaction times and things like that. We have to get a better handle on this.

Thomas (moderator): Michael, doesn’t that give single-use the opportunity to innovate in terms of measuring new variables?

Kowolenko: Absolutely. That’s the point. If you’re going to develop this, go beyond and look to the future . . . where are we driving to? The answer to me is better understanding of my process and what’s important. I don’t think anyone is going to be able to design a reactor that has all the probes and that’s in a single type of configuration to allow you to answer all those questions. It’s going to depend on the platform you use and the cell line and what’s important to your product attributes . . . so you need flexibility. Keep that in mind as you start to develop new technologies moving forward. You’re pretty much on an equal footing here when you’re looking at stainless vs. plastic in answering those questions.

What factors are limiting the development of integrated single-use systems or unit operations? What role will hybrid systems play?

Kowolenko: . . . Where I started to see where [disposables] could have a real advantage . . . was looking at certain, in this case, microbial cultures, and understanding what I would have to do for different pathogens that we were trying to develop for vaccines, looking at types of closed systems that we’d have to have and the cleaning issues, and those sorts of things, and I saw a tremendous opportunity to blend that sort of fermentation process in with our purification trains, so it became one of what were the needs of the system, and what could I get away with with my existing infrastructure as opposed to having to tear down a facility or perhaps trying a new approach.

Erlebach:
I’d agree with that, Michael. Our perspective has been, you use single-use disposable or appropriate solutions to solve the issue you’ve got. I’ve seen people run headlong into, “We need to just rip it all out and go disposable.” Well, no, look at what you’ve got and fit it in . . . to me we’re always going to be in a hybrid situation . . . .

Kowolenko: I agree with you. Yes, it’s nice not to have to deal with the cleaning validation, you can deal with that, but it’s what else do you get with it?

Priebe: So as long as the drivers are there to go to a integrated, single-use system—whatever the factors are, speed, economics, or existing facilities or greenfied, the drivers that lead to a decision—to me the factor that is limiting the development is that we’re in the very early stages of this stated need from the end user community. Only within, say, the past two years have we even seen integrated unit ops offered . . . and whether they’ve even been integrated into processes yet remains an open questions. I think it’s a matter of time and experience and maturity that is probably the single biggest factor.

Once it’s justified to do it, some of the pieces and parts exist, but some don’t exist yet. It’s simply that technology is not quite there yet, but it’s coming.

Are efforts towards standardizing single-use sensors and platform technologies on the right track, and progressing fast enough?

Priebe: My personal feeling is that there’s a time and a place for standardization and it may not be in the early stages of innovation, because you may put yourself in a corner and limit access to technologies you don’t even know about today. If we’re smart about standardization and start talking about, say, communication protocols—not just the sensing element itself but how it talks to equipment . . . we don’t want to reinvent that wheel. Our perspective would be to embrace the standardization that already exists, and innovate where there is room to innovate.  

Erlebach: From a user’s perspective . . . we’ve got to be able to standardize the communication protocols to allow us to use them. You then have to say, if standardization doesn’t work because your sensor is too small to fit normal port sizes because you deliberately made it smaller, then as a supplier you’re going to look at adapting what you’re supplying to fit it. . . .

What role, if any, must FDA and regulators play to push the use of disposable technologies for process control?

Kowolenko: It’s cGMP. As companies embrace this and inspectors see more of this implemented in different environments, it’s going to become the expectation.

Priebe: I think “push” is maybe not the right word. It’s to be clear that the scrutiny by the regulators will be no different if it’s single-use or multi-use—that they’re open and embrace these technologies . . . If there’s an advantage to the process and the patient, then clearly the Agency should be ready to look at these processes with a knowledgeable eye, and not react because it’s a new technology and a scrutiny that many end users wouldn’t want to face—and that’s I think what the fear is right now.

Kowolenko: But don’t you think there’s an opportunity because you’re starting to see newer things implemented with this drive that disposables are just another way to address it? As long as you can answer the questions, they don’t care!

Priebe:
Exactly, that’s what I mean. I don’t think they should be pushing towards single-use, but just embracing it when it answers the questions correctly.

--Paul Thomas