Facilities of the Future

“These are the little considerations that can cause you to stumble on your pre-approval inspection (PAI), says Chatterjee. Putting together a risk management framework up front that talks about the compliance, operational, design, business component, is really important.” The Chinese biosimilars plant currently has more than 40 different risk management plans for compliance alone, he says. 

When a new plant will use any different or innovative technologies, it is a good idea to get FDA’s input and prequalify that equipment from the earliest stages, says Fluor’s McNeill. At Grifols blood fractionation plant in North Carolina, due on-stream by the end of next year, a staged process was used with a novel centrifugation system. FDA inspectors were invited to allow the company to prequalify the system from the start.

Modular Technologies
Modular plant construction platforms have become a requirement for more pharma plant projects. “Roughly 30% of our pharma and biopharm clients ask for modular solutions,” says Susan Stipa, Business Development Director with Foster Wheeler Biokinetics.

Vendors offer a range of technologies, from GCon’s enclosed PODS, to the more traditional stick-built systems of Modular Partners and Pharmadule. Engineering and construction (E&C) companies are partnering with all these vendors, and offering pharma clients a wider range of options, but targeting solutions closely to fit specific process needs. They also offer an “agnostic” or objective point of view, Stipa says, and can help end-users compare the pros and cons of each technology.

For all its strengths, modular construction can be expensive. Shipping costs and taxes can be very high in some parts of the world. In addition, there can be some complications in shipping. For instance, GCon just introduced new module sizes to facilitate shipping on flat-bed trucks in Europe, says Maik Jornitz, business development director.

The trick to reducing overall project costs is only to the processing and GMP-critical areas, says Fluor’s McNeill. “You want to reduce cleanroom space,” he says. “You move HVAC and controls into a central spine that is easily modularized and shippable. It’s a simple solution that lets you gain a high degree of control.”

People are looking to turnkey solutions with a central processing space, McNeill says. “That’s slightly different than fully modularized. Only 25% of the facility is actually processing space.

Using both modular technology and single-use process equipment requires thinking through process and facility needs from the start of any project. “Single-use systems force one to think of the manufacturing space in new ways,” says Foster-Wheeler’s Miles. Unit operations are typically portable, he says, and multiple configurations for different products must be considered before committing to construction.

The design and layout of single-use tubing is extremely important, and often overlooked, E&C experts say. This is true in cleanrooms, which require a large amount of hygienic piping, says McNeill. “Connecting sterile connectors is not as easy as it seems.”

“Understanding the process and equipment interactions is the key to success,” says Miles. “Having detailed conversations with the operators and equipment suppliers upfront will prove to be a valuable investment.”

In general, says McNeill, designs must be simpler and, by definition, more mobile than traditional layouts. For fluid transfer, three-fourths of the process fluid will be in tubing, driven by peristaltic pumps. These pumps are slow and can have operating issues. “Without proper planning you can end up with piping spaghetti,” he says.

Single-use systems also pose challenges in plants that are being built in developing markets, Chatterjee says. “As you move through the process chain, and to sterile environments, you have this juxtaposition of equipment capability and operator performance. Single use puts much more pressure on the operator.”

In China, he says, in regions around major urban centers, there is a large, skilled workforce familiar with bioprocessing needs. But when you move out to the more rural areas, that skilled labor pool is limited.

In addition, Chatterjee says, the larger size of some of the single-use bags poses technical and operational challenges.

“If you’re doing cell culture in a CMO-based facility, you may have two different products going through from cell packing to inoculant in parallel, with separate process streams,” he explains. “One can be in process, one can be staged. More often than not, if you’re using a single-use design at the end of the cell culture harvest function, that product can be bulked and staged for the purification process in the room, but what happens if those bags leak?” It becomes more of a question of supplier capability and risk management, he says.

In general, operator and overall workforce skills should be considered closely during initial design stages, Chatterjee says. “Do a mistake-proofing exercise when you get to the process design and marry that with risk management tool assessment. The goal is: How can we design it so we can’t fail.”

Pharmatech designed one single-use facility with different connectors, and used color coding and secondary reinforcement. Within the facility, zones were in different colors so operators had reinforcement, and it was easy for them to do the right thing.

“In any facility, you’ll always have the issue of process sequence, and that’s more difficult to engineer into the process,” Chatterjee says. “That’s what you give up when you move to single use. You can’t automate everything.” 

This article was published in the January 2013 issue of Pharmaceutical Manufacturing.