Not long ago, when a company sought to buy a closed-loop automation solution, only a handful of vendors could deliver that level of automation. But in the past two years, their numbers have greatly increased. Some users are already saying to the vendors, ‘If you want our order, then you'd better offer this.’ “It's gone from being technology for its own sake,” says Larry West, “to technology for improving bioprocess management.” Vendors have begun investing in automation technology as not simply another feature to add to their systems, but rather, a strategic advantage to offer their customers.

West mentioned Nova Biomedical as one company that's particularly active in this area. “They put a significant amount of money into automating their nutrient monitors to give them OPC capability. This capability, coupled with similar efforts from firms such as Groton Biosystems in the realm of automated sampling, have in effect permitted the building of bridges between normally stand-alone processes.” (See the OPC box on the next page for more information.) “This inherently makes these devices more capable of communicating with associated next-generation controllers that are fast becoming increasingly dominant in the market.” Other active companies he mentioned include New Brunswick Scientific, SciLog, and Sartorius. Others have highlighted Aber Instruments and BioSpectra. On the controller side, West highlighted DASGIP as a company that's made interacting with other equipment part of its mandate.

“When I say who we're working with,” Hentschel pointed out, “that doesn't mean there's no one else. But we worked together with Werum Software to develop the MES we have in place. And we have different suppliers for the process equipment automation: e.g., DCSs from Honeywell or Siemens. MESs offer great advantages. For example, they can detect out-of-range events and automatically alarm you, which is a big benefit during your batch record review — so you don't have to go through everything by hand. The very high traceability of processes also allows you to use process automation and data collection as a tool for process optimization.”

Procyshyn points out that vendor advancement depends somewhat on communication with end users. “But I think it's got less to do with the vendors themselves,” he said, “than with the projects being done. People aren't willing to work on developing new sensor technology and new installations in the middle of a project. So when there isn't a solution that's been developed ahead of time and proven and used, people will choose the path of least resistance. During the past few years, it's really the vendors with more process knowledge that can propose those solutions with some process understanding to back them up. And that allows people to take the leap.”

WHAT IS OPC?
Object linking and embedding (OLE) for process control (OPC) was the original name for a standards specification developed in 1996 by an industrial automation industry task force. It's how real-time data is communicated among control devices from different manufacturers. The OPC Foundation maintains this standard, saying that officially OPC is no longer an acronym, so the technology is simply known as OPC. Although it has been heavily used in process industries, it is also widely used in discrete manufacturing, thus the deemphasis of the phrase process control.

Electronic Records, Electronic Signatures: For those of us who have been covering the bioprocess industry over the past decade or more, the first thing we think of when we hear someone talk about process control data is 21 CFR Part 11. We all remember the trauma that came along with its 1997 introduction — and guidance documents published in 1999 and 2003 didn't help much. Although they narrowed the scope of the regulation, they also managed to contradict it in some areas. A final guidance appeared in May 2007, but the original regulation had since been withdrawn for consideration. A new version of Part 11 was expected in 2006, but it has yet to appear. At least one member of the FDA's Part 11 working group has publicly stated that the timetable for that release is “flexible.” (To say the least!)

West told us that 21 CFR 11 “put us all through the drill of self-analysis. We did a lot of things to accommodate it, but we also went kind of silly on some things (chart recorders, for example). Everything got hit so hard with that broad-stroke brush that it really ended up intimidating some people.” Now such memories may be translating into a fear of automation.

“The pendulum has swung back a bit,” West said, “to where we appreciate 21 CFR 11, but we also have clearly defined where it does and doesn't go. Now we're able to use the equipment and associated technologies to take us to the next level.” Interestingly, he pointed out, “now the drivers aren't as much regulatory requirements as business necessity. ‘We're running out of money. How are we going to run this plant with 30% fewer people?’”

Companies such as Emerson Process Management make automated plant management systems, another concept that's finally making headway in the bioprocess industry. Procyshyn said, “In my experience, that's becoming a forefront if not the standard for most systems, particularly in North America. We're seeing its migration into aseptic and fill-finish facilities. We built ours without electronic batch records, but with 100% supervisory control and data acquisition (SCADA) control and MES planning for data historians and process operations. Almost every process in a modern pharmaceutical system is now electronically controlled in some form. In fact, some of the earlier work that Emerson and others did were in the early days of biotech with upstream production. So it definitely always has been and always will be part of it.”

West is the named inventor on the patent for the DeltaV-based BioNet bioprocessing control system from Broadley-James. “So my answer will be a bit biased,” he admitted. “If you take a step back, Emerson is really just DeltaV when it comes to bioprocess control and management. Are DCSs the future of bioprocessing? Are we going to see hybrids of DCSs for plant networking and benchtop PCs for research? Four years ago, we were all using programmable logic controllers (PLCs). Three years ago, there was a renaissance with DCSs that just ran its course due to cost factors. Today, emerging controllers from companies such as Applikon, New Brunswick, and Finesse have moved away from DCSs to platforms such as the Intel Atom processor much like that found in a high-end personal computer. So we've almost come full circle. Ten years ago, you couldn't give a PC to a bioprocess person because the ‘blue screen of death’ scared them out of their scientific socks! Today, with the evolution of the Microsoft Windows operating system and several years of comfort, PCs are reemerging as a viable platform on which to do bioprocess work. Not to mention, they're about one-tenth the price.”

Upstream, Downstream, Fill and Finish: One thing we wondered, having seen some discussion of perfusion cell culture in recent meetings and articles (4), was whether the nature of this cell culture mode makes it more amenable to automated control. Larry West, too, has noticed this resurgence of interest. “I was at a meeting not too long ago,” he told Lorna, “where people were asked if they had an opportunity to use perfusion and just walk away from the batch, whether they would switch to perfusion culture. The vast majority of people in the room raised their hands.” When the same room was asked who was actually using it, however, only two people answered in the affirmative.

“From an automation standpoint,” West continued, “perfusion has its own challenges. Some of its associated failures, automation can't fix (for example, central failure due to drift over time). In some instances, very highly informed process management people are addressing some of these shortcomings with technology, and the case in point would be pH probe drift due to their exposure to the process stream. In perfusion, that's significant because that exposure timeline can be so long. Five years ago, you bought a $2,000 retraction assembly, and you pulled out your pH probe and changed it, then put it back and hoped you didn't get contamination. All this associated infrastructure, it wasn't very practical. Today, you've got the same probe in line, but now you've also got a nutrient monitor and associated in situ sensors providing improved insight into the bioprocess. However, nutrient monitors and associated automated sampling functionality have really redefined the process. Today, an in situ pH sensor can indicate a reading of 6.2, but a quick check of the nutrient monitor can determine that to be 6.5, indicating drift on the part of the pH sensor. This allows for the controller to adjust its control strategy for the correct pH while initiating a standardization of the pH sensor to correct for the drift. That's using the technology as a resource, and it makes perfusion more practical.”

Procyshyn doesn't think perfusion is any more amenable to automation than other culture modes. He said they all have “some level of continuous process monitoring adjustment.” And Hentschel agreed. “We've automated a lot of different processes in cell culture, batch fermentation processes, chromatography columns, filtration systems, and so on. For example, our weighing processes for raw materials are highly automated. We also have perfusion culture established, and I wouldn't say that it is necessarily a prominent example for automation.”

“Personally,” Rhiel put in, “I do like perfusion a lot. But only a few companies are using perfusion culture. If it runs well, and its well automated and under control, it can have the highest productivity you can get. But it's not so commonly used.” Maybe that will change if the process can truly offer the walk-away solution West mentioned. Clearly, many upstream process engineers would be interested in learning more.

Another topic many people are talking about these days, particularly in relation to monoclonal antibody production, is platform purification technologies. And it's another advancement that we thought might help automation find a place in biomanufacturing. “Absolutely,” Larry West agreed. “That's where the money's at. The downstream guys know they'll have to break up some bottlenecks and invest in the necessary technical infrastructure to do so. If you look at nutrient monitors five years ago, they would give you pH and dissolved oxygen (DO) readings. Three years ago, they would give you pH, DO, amino acids, and gas analysis. Then in 2009, they started measuring IgG. So they're moving downstream as well, and that can correlate directly to automation and tying in real-time measurement feedback to optimize chromatography.”

“I believe platform technologies make automation in downstream processing easier,” said Hentschel. “Copying an existing automation program for downstream operations requires less adaptation if you can apply most of the same subroutines. Processes are also automated without platform technologies; it just takes more effort.”

Aseptic processing is an area where automation seems to be really taking hold. Is this as true for biopharmaceuticals as for classical drugs? Yes, Hentschel told Lorna. In fact, “aseptic processing, in some aspects, was very highly automated from the beginning. For biotech products, you typically cannot sterilize your aseptically filled product, so you want to prevent any human intervention whenever possible. So a high degree of automation is desireable. There was a very interesting talk by Martin Van Trieste (vice president of quality at Amgen) during the annual PDA meeting, where he showed a very highly automated aseptic processing operation in his talk on the future of aseptic processing (5).”

West countered that “automation is making a strong move in inspections, especially. Traditionally, it was associated mostly with low-risk APIs. But what Genentech proved with their Oregon facility, when they went all DeltaV, they embraced the idea that classic automation solutions could be applied to biotherapeutics. They kind of validated the concept of fill-finish running on DCS. Bosch and other contract packagers have used PLCs, which have been considered faster than DCS for on-off applications such as fill and finish. But over the past several years we have seen companies such as GE and Emerson partner to create a chromatography skid that allows discrete (on/off) functions to be handled by the GE Unicorn platform while analog functionality is managed by Emerson's DeltaV system. This model is rapidly evolving: In 2009, we saw a SciLog TFF skid controlled by the Emerson DeltaV platform, which manages associated discrete I/O. Such application progressions ensure the continued evolution of automation throughout a product's life-cycle, begining in research and ending in fill-finish.”

Procyshyn pointed out that the pick-and-placement and visual analysis functions in fill and finish are ideal for automation. “One thing we're focusing on is developing tools and techniques for use in areas where isolator technology and peroxide sterilization is possible. In that case, once you've achieved that level of operation in a clean and sterile environment, then there is a lot that can be automated. I would suggest that nothing can't be automated. The problem I've seen with traditional approaches to aseptic automation is that typically it's an add-on, an added complication or level to a process, whereas in other industries it is integrated from the bottom level. If you add additional levels of complexity and failure points, this has been some of the challenge.”

He explained that his company's focus is “actually looking at processes from a design standpoint, how automation and microprocessors can give us new tools and opportunities in redesigning processes. I think very much the turn of the future is toward fully aseptic operations. It's very clear that humans and human-born contamination are the largest problem. And we're seeing that those facilities that embrace automation are having excellent success. We're also seeing regulators in the field getting a lot more stringent in their expectations for contamination control, so I think the general trend is for this to come about a lot sooner than what some people might have thought in the past.”