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By Agnes Shanley, Editor in Chief
“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 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.”
Redefining Modular Construction
Pharmadule AB was formed in March 2011 when Pharmadule’s assets were acquired by its close partner, the Japanese process equipment manufacturer Morimatsu. As Ulf Danielsson, marketing director, explains, the Japanese company is a large manufacturer with a strong presence in China, where it employs 3,000 people at its process equipment factory in Shanghai. “We can provide the building envelope around our partner’s equipment,” he says.
The company has developed a new biopharm concept facility based on traditional modular and pre-engineered solutions. “The idea is to try to make as much as possible pre-engineered. We want to manufacture as much as possible in the workshop, not in the field,” Danielsson says.
Entering the scene fairly recently is GCon Bio, which has extended the definition of modular, offering self-standing pods, each with its own HVAC and control equipment, that can be plugged into new, and even existing, facilities. The pods, now in Generation 3 of their original design, can drastically reduce the time required for commissioning and starting up a new facility (Table).
The company’s history is inextricably tied with that of personalized medicine and, specifically with Gradalis, a company founded by David Shanahan, grandson of Mary Crowley, who established the Mary Crowley Clinic to improve the quality and availability of cancer therapies. At the clinic, there was a need to handle a lot of small volumes of medicine on a patient-by-patient basis, explains Maik Jornitz, business development director, “but you also had to run multiproduct lines through that area, and had to be able to decontaminate, scale up and scale down easily.”
Gradalis Construction licensed the pod technologies that Shanahan and Barry Holtz had developed, to form the new company, now called GCon. Each pod is fully equipped and autonomous because it features a redundant HVAC system, and cleanroom processing system with or without gown in area, connected to a Class 8 corridor. The pods are 42-foot-long, 18-foot-wide containment systems that can float on air bearings allowing them to be disconnected and reconnected and moved around.
As Jornitz explains, the pods can maximize flexibility when equipped with single-use technology. “You can plug and play downstream and harvest processes. If you’re using one filtration system for a particular cell line, then you need to switch to a different harvest step; you can unplug the part with the filtration system and bring in a totally different part, for example, for centrifugation.
As Susan Stipa, business development director for Foster Wheeler Biokinetics, explains, the pods can be constructed while engineering is happening, cutting some project timelines from three years to 15 or even down to 12 months. Instead of building a Greenfield facility, users can install pods in moth-balled older plants or even into leased warehouses.
The technology has been installed at the NCTM at College Station and at Caliber Biotherapeutics, a GCON subsidiary that worked on the DARPA funded Blue Angel vaccine project, which received $40 million in government funding, and reduced startup time to 18 months. In addition, projects are underway in Asia, Europe and southern California, where both single-use and stainless equipment is being used as well as a large blender.
Modifications were made when the systems moved from personalized medicine to vaccine manufacturing, with the emphasis changing from straight ISO cleanroom classification to biosafety level. “The question is whether you need a pod with a positive or a negative pressure cascade,” Jornitz said. The pods are designed to prevent downstream cross-contamination, which is especially important for cytotoxic API work.
This article was published in the January 2013 issue of Pharmaceutical Manufacturing.
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