Thinking Inside the Box

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.

(OPENING ART: STOCKBYTE, GETTY IMAGES.)

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.

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.

A manufacturer can purchase a room-sized module and assemble it at its site.PHOTO: COURTESY OF PHARMADULE

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.

The machine that makes the module

Stainless-steel equipment. Biopharmaceutical production processes can be the same, whether a CMO uses a traditional or modular approach. Likewise, the equipment inside the modules can be much the same as it is in a traditional facility. A modular facility can incorporate familiar stainless-steel equipment. Likewise, a process skid of stainless-steel equipment can serve as a module. This equipment must be easily movable, and CIP and SIP operations should be set up as part of the modular manufacturing process. "It would actually be more efficient for stainless-steel equipment manufacturers to use modular designs so that their equipment allows for capacity increases simply by adding modules," says Ron Trudeau, vice-president of facilities-engineering services at Baxter Healthcare (Deerfield, IL).

Xcellerex's FlexFactory platform includes enclosed unit operations that can be housed in an unclassified clean space.PHOTO: COURTESY OF XCELLEREX

One complication is that improved yields from high-producing cell lines may result in downstream product-pool volumes that are larger than upstream volumes, thus creating the need for an array of large tanks for process pools and buffers. "The solution is to apply a modular engineering approach and assemble these tanks as process modules that are still constructed and tested off-site as entire modules, but are disassembled for transport and installation in the facility on location," says Niels Guldager, senior consultant for bioprocess and technology of NNE PharmaPlan (Copenhagen).

Stainless-steel equipment alone is not the ideal approach to modular manufacturing, partly because it requires cleaning and related downtime. Also, to attain flexibility, a CMO must buy a lot of stainless-steel machines up front. "You may get the scale wrong—a lot of 10,000-L cell-culture vessels are standing idle today," says Eric Grund, senior director of biopharmaceutical applications at GE Healthcare (Waukesha, WI). Some stains-steel components will always be required, he adds, but they can be designed better to enable flexibility and ensure safety.

Single-use equipment. "It is the arrival of plug-and-play and ready-to-use components that is enabling most of the modular-manufacturing revolution," says Grund. Cleaning operations for reusable equipment entail the risk of cross contamination and, therefore, require development effort. Procedures must be tested and validated and require extra utilities. Disposable, presterilized equipment solves these problems by eliminating the need for cleaning and cleaning validation. In addition, disposable components enable rapid changeover between batches or products and make it easier to establish multiproduct facilities.

Disposable equipment is increasingly available in a unit-operation format. Companies often can install these units within six to eight weeks, which is much faster than they can install stainless-steel equipment, says Thomas Paust, global director of marketing integrated solutions at Sartorius (Göttingen, Germany). The caveat is that disposable components that contact the product must be tested for extractables and leachables, qualified, and validated.

Single-use components facilitate modular manufacturing more than traditional equipment because they enable modules to be small by reducing the amount of complex piping and resulting automation dramatically, says Xcellerex's Galliher. A module with less complexity often is simpler, more reliable, and requires less operator training and maintenance.

Disposable media-preparation devices, cell-culture vessels, and harvesting equipment already are available, making it possible for a CMO to establish a completely single-use upstream module. Downstream applications such as membrane chromatography for protein purification are being accepted and validated for commercial processes, too. Sartorius soon will introduce a single-use crossflow-filtration device that incorporates a disposable fluid path, pressure sensor, pressure valve, and flow sensor, says Paust.

What's in it for CMOs?

CMOs are likely to benefit most from modular manufacturing, particularly when they use disposable components, says Mani Krishnan, director for Mobius single-use processing systems at Millipore (Billerica, MA). CMOs always must be ready to produce various molecules that require distinct processes, and they must be able to produce materials at various scales. A modular manufacturing facility can be reconfigured ra-pidly to meet the needs of the molecule. CMOs that use this approach thus can apply Lean strategies to respond quickly to particular customers' changing needs and change over between different customers' projects easily. This flexibility can help CMOs increase their output and reduce their costs.

Disposable downstream equipment such as chromatography columns is being accepted and validated for commercial processes. PHOTO: COURTESY OF GE HEALTHCARE

Even before production begins, a modular approach can be beneficial because it simplifies validation. The CMO's burden is less to begin with because the equipment vendor has already started the validation work. Furthermore, a CMO can perform process validation more easily and with less work if it involves one unit operation at a time instead of two, three, or four connected together. The chances of demonstrating consistency by completing three perfect batches are greater for one operation than for many, says Galliher.

Modular manufacturing enhances a CMO's speed and flexibility in the production of modern vaccines, monoclonal antibodies, and novel biomolecules entering the clinic. A company can design a modular facility that accommodates various kinds of bioreactors (e.g. for mammalian cells or for bacteria) and manufactures at several scales. Disposable components make it possible to dedicate a modular facility to a single product (e.g., recombinant proteins, monoclonal antibodies, or vaccines) or to allow it to produce multiple products as required, says Grund.

If properly designed, a modular process could help a CMO to increase the number of contracts it can execute in one plant simultaneously. Ordinarily, a plant might have five or six unit operations in a row that are all dedicated to one client or to one cleanroom. But a CMO can install enclosed, modular unit operations to enable it to serve five clients in the same room, each in its own module. This arrangement would give a CMO five times the revenue with the same manufacturing group that it had before. "That gives us a huge multiplier on profits, margins, and revenue capability," says Galliher.

This approach works because the enclosed module becomes the cleanroom, and the module often can conserve valuable plant space. For example, the FlexFactory from Xcellerex has a footprint that is 35–40% smaller than a traditional cleanroom facility that includes gowning areas and access hallways, according to Galliher. The cost of a gray space with cleanroom modules is also lower than that of a conventional cleanroom.

On the other hand, the initial development costs for modular equipment often are higher than those for traditional machines, and this factor might prevent some companies from taking a modular approach, says Trudeau. Yet CMOs ultimately have a strong incentive for embracing the technique because it increases their speed to market, he adds.

The future of modular manufacturing

Despite the advantages that they stand to gain, CMOs have not yet rushed to embrace modular manufacturing for several reasons. For one, single-use technology, a critical element of modular manufacturing, is still evolving. CMOs are not yet comfortable with these components because they don't believe that they are as robust as they should be. Most contract manufacturers are using disposable technologies for noncritical applications such as preparing buffers and media, but not for running critical unit operations, says Millipore's Krishnan. CMOs don't see these technologies as tried and tested, and many of them have not evaluated all the new disposable components.

In addition, modular manufacturing still is a relatively new strategy for the biopharmaceutical industry, and CMOs need to become familiar and comfortable with the technique. The modular approach is a change in mindset. CMOs already have invested in stainless-steel manufacturing equipment, and attitudes about what is possible and what is impossible with single-use technologies must change, says Krishnan.

SAFC (St. Louis) considered building a modular, multiproduct viral facility at its site in Carlsbad, California. Despite the technique's promise of flexibility and easy scale-up, SAFC finally decided to establish a stick-built facility. The company was uncertain about the long-term applicability of modular walls to a containment facility that needed complete segregation of products and air, said Dave Backer, SAFC's director of business development and marketing. Instead, SAFC incorporated modular sections in some of the facility's walls to enable the movement of large equipment. New systems probably have alleviated the company's original concerns, Backer acknowledges.

For the moment, limitations on available single-use technology force CMOs to decide whether to maximize flexibility at the expense of scale or vice versa, says Backer. But the landscape is changing. "Modular manufacturing will become more commonplace, particularly for early-phase clinical trials," says Backer. "The increased use of disposable bioreactors will most likely accelerate this process."

"We are seeing more and more CMOs talking to us with an intent to set up single-use manufacturing facilities," says Krishnan. "Certainly we are seeing the movement there, but I don't know if anybody has fully set up a facility like that yet."

The adoption of modular manufacturing is on the rise, and CMOs are starting to use modular approaches for new facilities and processes, says Pharmadule's Almhem. Preconceptions that modular manufacturing is expensive and inflexible are changing as more modular projects are completed and more companies embrace the concept.

Baxter recently began using modular processes at its Bloomington, Indiana, facility, says Trudeau.

CMOs that are pursuing modular manufacturing are now in the minority, but acceptance of the technique is growing. Some believe that the industry is on the brink of a paradigm shift. "In the not-too-distant future, most manufacturing processes and facilities will be built using modular concepts and technologies," says Almhem.

The slow adoption of modular manufacturing is not unusual because the industry traditionally has been reluctant to accept innovations and unfamiliar technologies. But observers believe that change is on the way. "Three years down the road, if CMOs are still building traditional facilities, that would certainly be a surprise to me," says Krishnan.