May 1, 2017 (Vol. 37, No. 9)

Angelo DePalma Ph.D. Writer GEN

Fixed-Tank Gives Way to Single-Use Operations, Changes Facility Design and Development

The term “modular” has come to mean many things in bioprocessing. Modularity can refer to unit operations, processes, facilities, and even how business is conducted. GE Healthcare describes certain of its process chromatography systems as “modular,” but as we will see the company also takes a big-picture view of modularity. Finesse Systems describes “modular bioprocess measurement and control,” presumably to provide flexibility in diverse process environments. And Bend Research touts a modular, automated sampling technology that promises flexibility for implementing process analytic technology “in the real world.”

Regardless of the process, equipment, operation, or facility, every modular bioprocess system should retain some aspect of turnkey or plug-and-play operation. At the facility level, we now have processes that are dropped into clean spaces, or entire cleanrooms placed into nonclassified buildings as the need arises. 

Coining a Phrase

Maik Jornitz, CEO of G-CON, defines modularity as “flexibility of prefabricated infrastructure units, similar to Lego® blocks, where components representing individual operations are interconnected or free-standing within a shell building.”

Jornitz, whose company has pioneered the PODS® flexible, scalable, and eminently modular cleanroom units, sums up the current modular dynamic. “Bioprocessing is at a crossroads where market forces are transforming processes from reusable to single-use, and facilities from single-use to reusable or repurpose-able.”

Under this model, a principal benefit of modular facility design is time-to-production—where every delay translates to millions of dollars in lost revenue.

“Biotech companies are seeking to standardize manufacturing site designs that can be cloned and rapidly deployed in any geographic location to create capacity to meet any level of demand.” More-rapid time-to-production allows companies to delay investment decisions, which is critical when a drug’s success is still unknown.

“Since some of these systems employ segregated air handling and ducting, ‘Lego’ cleanroom units are ideal for critical processes where containment is a major priority.” Suitable applications include the manufacture of highly potent or toxic products, vaccines, or cell therapies requiring high biosafety levels.

Classical modular facilities may have the potential for relocation as well. This occurs infrequently, but may be appropriate where either the end product or production location has not yet been determined. “Traditional structures by definition must stay put and become lost assets,” Jornitz says.

Since modular facilities appear to be here to stay, the question becomes: what is the next phase in their evolution?

Jornitz has some interesting predictions. “The real innovation comes in the creation of modular facility platforms that can be standardized, cloned, or chosen from a catalog. As an industry, we all too often cling to legacy processes and avoid adopting technologies with the potential to create significant economic advantages in terms of total cost ownership.”

The PODS concept is comforting in its technologic neutrality. Process equipment and utilities may be identical to those in static facilities—or not. Fixed-tank and single-use operations are equally applicable. “The exception is the prefabricated modules themselves, each with a separate air handler instead of having centralized, interconnected HVAC systems. The separation of the air handling and distribution adds to the flexibility of the cleanroom units, as scaling can happen without interrupting existing processes.”

Single-use equipment will play prominently in modular biomanufacturing, but as Jornitz notes the flexibility of single-use processes is only as good as the environment around the processes. “Traditional cleanroom infrastructures often do not allow the free movement of single-use equipment, like pallet tanks, therefore the flexibility is voided. New cleanroom infrastructure designs, either ballroom or linear positioned unit operations, allow movement and enable full use of single-use flexibility”

PODS modular cleanrooms from G-Con connect like Lego® blocks, forming flexibly configurable composite structures.

Facilities to Processes

For Ralph Melfi, vice president of marketing at AES Clean Technology, the advantages of modular facilities include clean, rapid construction and the ability to accommodate modular processes. “That means not just modular materials of construction but taking a modular approach to utilities, which allows you to bring modular platforms into and out of the facility, with finishes that meet today’s decontamination requirements. In that regard, modularity becomes much easier to commission than a stick-built facility, where finishes are applied at substantial cost and time investment.”

The architectural aspects of modular facilities—rapid expansion and removal of process components—are well established. Equally recognized are the financial aspects that provide the tax benefits for capital equipment acquisition vs. capital improvements. Depreciation for the latter occurs over five to seven years, compared with 30 years for capital improvements.

This point has been made by G-CON’s  Jornitz as well as, recently, by Eric Langer of Bioplan Associates, who sees modular bioprocessing as part of a strategy for avoiding “being stuck with legacy technologies.” Langer’s vision of a bioprocessing landscape where new technologies are under constant evaluation seems overly optimistic and, given the industry’s risk aversion, less compelling than the economic benefits cited by Jornitz and Melfi.

Modular facilities provide the ability to implement bioprocess platforms that are more flexible and easier to design and implement. A significant component is single-use processing, which itself has changed how facilities are designed. “Modular and single-use go together, particularly for cell therapy and biologics,” Melfi adds.

Modular facilities also provide greater access to innovative technologies, when applicable. For example, companies may investigate (and later adopt) novel cell culture or purification technologies without the need to invest directly in related equipment.

This is already the case with isolator technologies, which companies adopt to reduce deployment of expensive classified space: modular facilities become the macro-environments for incorporating advanced cleanroom and/or isolator technologies.

AES works closely with G-CON. “We view their PODS as over-sized isolators that prefabricate specific processes or unit operations that can be dropped directly into an AES macro environment,” says Melfi. “Think of our facility as a large, open ballroom into which G-CON can introduce PODS. Processes can be built very quickly in their facility, in parallel to the owner waiting for their process equipment, and everything arrives just in time. When our macro-environment is ready, we leave a large opening in our walls, they drop the PODS in place, we close up walls, and the result is a 2D and 3D integrated facility.” The process is remotely visualized in design software and assembled once, on site.

In this nomenclature, 2D refers to the footprint or floor space, 3D to the facility populated with process equipment.

Another aspect of modular processes is the strategic placement of process utilities that allow for plug-and-play of both stainless-steel fixed processing or disposable technology, which have significantly different utility requirements.

While modularity and single-use go hand in hand, true modular designs must accommodate fixed-tank processing because some processes, whether because of scale, mechanical, or other issues, do not work well in single-use. In those instances, we design modular stainless-steel skids but retain the potential to use single-use whenever possible,” Melfi says.

Flexible modular bioprocessing suite [AES Clean Technology / Chris DeWitt Photography]

Real-World Example

In 2006, JHL Biotech (JHL) opened the world’s first KUBio™ bioprocessing plant in Wuhan, China. According to the GE Healthcare website, KUBio is a prefabricated cGMP biomanufacturing site that comes online in 18 months at a fraction of the cost of conventional facilities. The Wuhan plant will manufacture biosimilars and clinical-stage monoclonal antibodies. Bioreactor capacity is 4 x 2,000 L, 2 x 500 L, and 3 x 50 L bioreactors.

The Wuhan plant was designed around single-use technologies. “There are ways to integrate multi-use systems into modular buildings, but JHL chose to utilize single-use systems because this approach significantly reduces facility design, construction, and validation cost and time,” JHL Biotech’s associate director of business development Greg Manker says.

A similarly configured fixed-tank plant takes between four and six years from concept to cGMP operation. Manker attributes commissioning speed to KUBio’s single-use manufacturing technologies. “Because KUBio is modular, the building could be constructed in Germany while JHL prepared the site in Wuhan. Parallel construction allowed us to save a lot of time.”

Conventional pharmaceutical plants have long lives. KUBio/Wuhan was built to such exacting standards that JHL expects it to last as long as or longer than a conventional plant.

Jury Is Out

Pall also supplies equipment for modular facilities, but has not yet formally entered that business. The company’s entry points, says Helene Pora, Ph.D., vice president of single-use technologies, are single-use and continuous processing.

“Single-use equipment enables rapid deployment and streamlining of facility layout, which facilitates parallel facility construction and commissioning,” she says, “but this general strategy does not preclude using fixed-tank bioreactors.”

Dr. Pora accepts, based on news reports, that modularity can accelerate facility-building by about one year, but this occurs at the price of added complexity. “Bioprocessors tend to view modular facilities as black boxes, but how regulators see them is unclear.” On the basis of recent regulatory quality initiatives, “black boxes” are frowned upon except for processes where a high degree of platforming is appropriate.

She recognizes the significance of modularity in constructing facilities in relatively undeveloped countries that lack the engineering and construction know-how for building biomanufacturing plants. Such projects take on much of the character of technology transfers, where the technology is the plant itself.

But time- and cost-savings are not free. “Time savings are the only side of the equation that people see,” Dr. Pora notes, suggesting that in an industry where something-for-nothing does not exist users may in fact be paying for flexibility and modularity in excess of time-to-market benefits.

In any case, the number of truly modular facilities in operation is small, and their potential economic advantages remain, at least for now, shrouded in those numbers.

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