Thinking Inside the Box

A modular approach to biopharmaceutical production could bring process flexibility, and contract manufacturing organizations are beginning to take notice.
May 02, 2010
Volume 34, Issue 5

Money is tight in our weakened economy, and biopharmaceutical companies in particular, most of which are new firms that depend on investor capital, are feeling the pinch. Consequently, the contract manufacturing organizations (CMOs) that serve the large-molecule industry face increased pressure to reduce their expenses and improve the efficiency of their operations. Modular manufacturing is a strategy that potentially could help CMOs achieve these goals, and companies' interest in this relatively new solution is increasing.

Divide and conquer

The facility as module. Modular manufacturing allows plant and process designers to divide the manufacturing process into standardized, discrete units that can be assembled, moved, and disassembled easily. A module can be a room attached to or installed inside an existing building, or it can even be an entire facility constructed from prefabricated building blocks that contain process equipment, utility distribution, and ventilation.

A modular facility can be built in a factory while infrastructure and support (e.g., power and utilities) are established at the site where the facility will be installed. As an alternative, the vendor can incorporate utilities into the modular facility. After the modular facility is built and tested at the vendor's factory, it must be transported to the owner's site for assembly and startup. The site owner can add elements such as entrance portals and outside stairs to integrate the modular building into the surrounding site and infrastructure.

A manufacturer can purchase a room-sized module and assemble it at its site.PHOTO: COURTESY OF PHARMADULE
Pharmadule (Stockholm) provides modular facilities to the pharmaceutical and biopharmaceutical industries. The company's modules typically are 44 × 14.5 × 14 ft, but it provides units of various sizes. Several modules can be combined to encompass a large process and to build a facility of nearly any size. The ability to transport the module to the manufacturing site limits the module's size.

Compared with the traditional method of constructing a facility in the field, building a modular facility in a factory reduces lead time, controls costs, and results in a better-quality facility, according to Pär Almhem, president of the US arm of Pharmadule. Factory construction also enables much higher productivity than building in the field, which is "the main reason why a modular concept is typically more economical as the facility complexity increases," says Almhem.

Modular facilities are designed to be installed anywhere and, because they are built under controlled conditions by trained personnel, to have the same high quality regardless of their ultimate sites. This consistency is a major benefit when a facility is intended for a location where knowledge or labor is limited. Modular facilities also can be disassembled and moved to another site with relative ease.

The unit operation as module. Instead of a room or a building, a module also can be defined as a portable, self-contained device that incorporates one unit operation such as cell culture, filtration, or chromatography. This kind of module is a plug-and-play machine that can be set up and operated anywhere. To form the process train for a given product, personnel place process modules in bays that are general enough to accommodate various process steps. Operators can rearrange modules into various process trains to manufacture different products. This reconfigurability allows CMOs to meet customers' varied demands easily.

The latest modules are designed to reduce downtime during changeover and to enable rapid scale-up. A CMO can scale up a process by adding extra modules of the same size instead of increasing the volume of individual steps. This approach ensures a fast and successful scale-up, but requires extra equipment and facility space.

Unit-operation modules that contain stainless-steel equipment must be able to connect to clean-in-place (CIP) systems, steam-in-place (SIP) systems, and clean utilities. Modules that contain single-use devices such as bioreactors don't necessarily need this feature because operators can throw the presterilized equipment away at the end of the production run.

Most biopharmaceutical process steps must occur in a relatively clean environment, and housing these steps in an isolator or self-enclosed container is generally the approach to modular manufacturing, according to Howard L. Levine, president of BioProcess Technology Consultants. Facility designs are changing, however, and more equipment is being installed in unclassified, controlled space. Rather than sitting entirely in a Class 7 room, today a bioreactor might be in an unclassified area except for sensitive parts such as sample ports and collection valves, which would be inside a cleanroom environment.

This arrangement is similar to the idea behind Xcellerex's (Marlborough, MA) FlexFactory platform, which comprises 4 × 4 ft enclosed modules connected in an unclassified main room. An operator can walk around the room in one level of gowning and operate the machinery through disposable glove ports. This arrangement eliminates the need for the operator to degown and regown to enter various cleanrooms. The system provides efficiency and flexibility because each module could have a different drug in it at a different stage of manufacturing, says Parrish Galliher, founder and chief technology officer of Xcellerex.

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