As the bioprocessing industry has shifted away from traditional stainless steel bioreactors and vessels toward single-use technology, a new breed of manufacturing facilities has arisen. Flexible facilities take full advantage of traditional multiuse technologies and combine them with increasingly popular single-use technologies, offering an ability to mitigate risk and decrease manufacturing timelines. Although some companies have made the choice to remain strictly traditional (multiple use) and others have moved fully into single use, the flexible hybrid format gives manufacturers the “best of both worlds.” That paves the way for a new and more effective approach to bioprocessing.

Here, we discuss the definition of a flexible facility and why Catalent Pharma Solutions chose to go with such a format. It partnered with ATMI LifeSciences throughout the process of moving from a 43,000-ft² facility in Middleton, WI, to a 100,000-ft² site in nearby Madison, WI. The Wisconsin production facility houses Catalent’s proprietary GPEx technology (for mammalian cell line engineering) for rapid engineering of stable mammalian cell lines that express biopharmaceutical proteins. Typical fed-batch processes give a high production concentration of 2–5 g/L. The facility also offers process development, analytical development, and current good manufacturing practice (CGMP) manufacturing with GPEx and other mammalian cell lines. The current facility allows recombinant proteins to be manufactured in small vessels (up to a 200-L scale) for the CGMP production of phase 1–2 clinical trial supplies using traditional stainless steel bioreactors.

Background

The original expansion of the Middleton facility was in planning about five years ago, when necessary conventional stainless steel bioreactors (up to a 2,000-L scale) were purchased. However, that project was put on hold during the economic down-turn, and it was revisited only a couple years ago once demand began to reach available capacity. Rather than simply implement the original expansion design, however, Catalent took time to return to the drawing board and decided to create a fully flexible facility in a nearby available building. That structure had a large open area that would be ideal for build-out of CGMP suites, but it lacked the infrastructure required for stainless steel bioreactors (e.g., for delivery of clean steam). During the initial evaluation, purchases that had been made already were kept in mind along with considering the advantages of single-use technologies on the market. Catalent already had extensive experience with disposables, having used Wave bioreactors from GE Healthcare as part of its CGMP seed train as well as bioprocessing bags for buffer preparation and storage of process intermediates.

To implement the original plan in stainless steel with a fixed plant would have involved the cost of additional piping for steam-in-place (SIP) systems as well as expensive support equipment for clean-in-place (CIP) systems. Catalent determined that building a facility that would rely on single-use vessels would require other infrastructure upgrades, but that elimination of fixed pipework would lower those costs and leverage established advantages of disposables to the facility. Factors such as a decreased risk of cross-contamination, faster suite turn-over between production runs, and shortened construction time helped to solidify the final decision. Catalent chose to sell its unused stainless steel reactors — they had not even been unpacked — and purchase single-use reactors to carry out production runs.

That decision to embrace the single-use format marks a major milestone. After Catalent’s careful research, it signifies great confidence in the biotech market and in single-use technology as well. The facility’s footprint will increase from 43,000 ft² to 100,000 ft², and the largest reactor on site will increase from 200 L to 1,000 L capacity. Once the decision to go with single-use bioreactors was made, the obvious next step was to extend the disposables implementation into mixing vessels, quick connects, and tangential-flow filtration (TFF) skids with disposable flow paths.

With Catalent’s fully flexible approach, certain areas of the plant remain fixed. For example, downstream purification skids do not have disposable flow paths, and the small-scale (≤10 L) bioreactors are multiuse. However, the vast majority of the protein production train is built out with single-use technology. Site construction is nearly finished as of this writing, and after validation is complete the first GMP production run should take place in April 2013.

Advantages of a Flexible Approach

Fundamentally, a single-use system involves use of disposables (typically plastic) for every surface that comes into contact with the product stream. Whether they are bags, impellers, piping, or even connectors, single-use components are changed out between batch runs and discarded. A single-use bioreactor generally consists of a metal shell with a disposable bag protected by that shell and often an impeller blade inside attached to a motor that spins it in a controlled, closed environment to ensure sterility. Such bioreactors also contain all necessary controls for monitoring parameters such as temperature, pH, and gas levels. New supplies of the disposable components are needed for every batch run, and the used ones may be recycled or incinerated. Single-use systems tend to be much more mobile (literally on wheels) than multiuse equipment, facilitating suite reconfiguration, whereas traditional stainless steel reactors are hard-piped into production suites.

The up-front capital required for a plant using stainless steel reactors is greater than that of one based on single-use bioreactors. In addition, CIP and SIP support equipment require additional capital, and stainless steel bioreactors and their facilities typically require more maintenance. However, those costs are balanced by the cost of consumables with single-use systems. Often, unseen costs come with disposable systems — e.g., the need to carry an inventory of expensive bags and in some cases a need for more expensive fire protection (because disposables are flammable).

Line clearance of stainless steel reactors is typically slow and tedious, requiring operator attention to ensure that it is properly performed and that corrosive chemicals and steam are used safely. It is also a very water-intensive process. Steam systems are costly to install and maintain, but they are absolutely essential to removing residual product from previous batches and to sterilizing vessels between runs for preventing cross-contamination. The time that a bioreactor is in use is largely defined by the process development team and is thus unlikely to vary greatly for single-use and stainless steel vessels. Single-use technologies, however, greatly reduces time between runs — in some instances, by days. Such technologies will allow Catalent to carry out more CGMP runs per year in its new facility while decreasing risks associated with line clearance.

Compatibility: An important factor in a company’s ability to be completely flexible and change quickly f
rom one project to the next is compatibility. This is something ATMI works to achieve by using open-architecture components that can be easily integrated with others in an almost plug-and-play way. Similarly, the vessels are all made of the same high-level film, so there is no requirement for prequalification of either film or connectors, and the design is comparable.

Another important advantage of disposable bags over fixed stainless steel is the ability to reconfigure them for customization. For example, the multiuse reactors at Catalent’s Middleton site offered just one location where certain types of probes could be placed. That did not allow for easy addition of redundant probes after a failure causing an aborted batch. Although it is possible to modify a stainless steel reactor to add additional probes, it is much easier to reconfigure bags.

Production lines based on stainless steel reactors are impractical to reconfigure because the reactor locations are fixed in their suites (piped into the walls) and thus difficult to move. Single-use vessels are wheeled, so the reactors are movable and allow different combinations of equipment for different processes. That enables a manufacturer using a well–thought-out validation strategy to reconfigure production suites without needing to “shoe-horn” a production run into available equipment. Equipment can be upgraded easily as new models become available.

A Flexible Partner

Biomanufacturers must be able to operate efficiently — and more important, compliantly. From their perspective, it is becoming clear that a flexible facility operating single-use technology is the ideal way to configure a biomanufacturing facility. A site that produces phase 1–2 clinical trials materials for multiple clients involves frequent product change-overs, and no cross-contamination from one batch to the next is ever acceptable. For all users, whether innovators or contractors or suppliers, disposables simplify validation of a new site by reducing the potential for cross-contamination potential and the need for cleaning validation.

Those benefits trickle through to suppliers of single-use technology, who in return must respond to changes in single-use configurations at a manufacturing facility. Disposable vessels might be designed for specific customers, who then reorder the same bag types for years to come. The relationship between supplier and manufacturer thus moves into and beyond supply chain mode, with a contract manufacturing organization (CMO) always one late order away from being unable to produce product.

ATMI worked with a Catalent team to identify expectations, design process flow, and implement appropriate vessels and reactor technologies for the new facility output. To carry out the flexible format, Catalent developed a close strategic relationship with ATMI, which will become increasingly more important when the facility is up and running. Reliability and quality are essential to a solutions provider such as Catalent. A CMO’s clients (biotech companies) have their own milestones to meet in terms of funding and clinical trials. ATMI has the same need to be reliable and provide high quality to its customers.

Flexibility for Antibody–Drug Conjugate Manufacturing
by Mary Robinette

Incorporating flexibility into the design of a pharmaceutical manufacturing facility is an effective way to increase the potential for contract manufacturing organizations (CMOs) to readily make a number of different products. This is especially true for manufacturing antibody–drug conjugates (ADCs), which combine different linker constructs and a variety of cytotoxic drugs and antibodies, each of which has its own handling requirements. The flexible-facility approach makes a lot of sense for commercial manufacturing of ADCs, but it proves useful for other pharmaceutical products as well. Overall, implementing disposable technology into the design of a CMO facility should enable a company to respond quickly to customer needs with process flexibility and reduced change-over times.

For ADCs specifically, it is particularly important to prevent cross-contamination because of the potency of certain ingredients. As drugs with ever-higher potencies are developed, it becomes more difficult to quantify residual amounts in equipment and vessels after a manufacturing run. Using sterile, disposable equipment eliminates pre- and postcleaning steps that present a concern in operating multiuse equipment. It also helps to address operator safety by removing some potential for exposure. However, companies must ensure that no contamination is introduced into an ADC process from plastics in single-use components (extractables and leachables).

For maximum flexibility, a commercial facility design incorporates traditional stainless steel technology with cleaning/sanitization equipment and single-use systems. As the flexible model has gained industry popularity, a number of advances have supported such installations, enabling flexibility in process set-up and reducing equipment storage requirements. Several suppliers offer agitation motor and control components for use with different sizes of disposable mixing vessels. Pump skids can be configured for a range of purification applications. Custom purification designs allow such systems to be used in tight spaces (in an exhaust hood, for example). Many standard hardware skids for disposable equipment have evolved modularly with plug-and-play aseptic connectors. That allows customers to propose new process configurations with reduced lead times.

Key items must be made available from inventory for flexibility to prevent downtime while operators wait for restocking. For custom manufacturing, single-use assemblies must be configured to meet a number of process-specific requirements, including filter media type. Custom manifolds can be designed in conjunction with single-use suppliers, or off-the-shelf units can be brought in if they are deemed suitable. For custom designs, manifold cost and availability are based on projected demand and specific client requirements.

It is also important to remember that single-use technologies are not a viable option for certain applications. For instance, some equipment (such as for ultrafiltration or chromatography), may be larger than is practical for a disposable system. And some solvents are not compatible with disposable components.

A flexible-facility approach maximizes the advantages of each component involved. Its widespread implementation is enabled by the increasing scale of disposable equipment in recent years, which further expands the capability of such equipment for relatively large batch sizes. At SAFC, our experience has been very positive with good manufacturing practice (GMP) production of active pharmaceutical ingredients using a 1,000-L jacketed mixed-bag system. Features include load cells and measurement capabilities for pH and conductivity. The system footprint is smaller than that of a 1,000-L stainless-steel tank, and changeover time is minimal. The portable nature of disposable equipment — along with its compact footprint — can eliminate the need for fixed, stainless steel tanks. That opens up a new approach to facility design and helps SAFC remain focused on providing high levels of production quality and flexibility.

Mary Robinette is lead process engineer for SAFC, 3050 Spruce Street, Saint Louis, MO 63103-2530; mary.robinette@sial.com; www.safcglobal.com.

Routine meetings are scheduled between the two company’s project teams, so they are in the habit of talking to each other. Such get-togethers sometimes may be short with little to talk about, but they provide an opportunity to “dial in” to what is coming in the future, which can ultimately save development time. Catalent and ATMI engineers work closely to ensure thei
r ability to move from project to project with customizable iterations. And ATMI experts can make engineering drawings and design processes in rapid response to modify single-use vessels that meet a customer’s specific requirements.

The Bottom Line

The flexible-facility format shows great promise for bioprocess facilities of the future. By taking advantage of the strengths of each technology — single- and multiuse — companies can create more efficient batch runs with less waste and down time. When a company is bringing a flexible facility online, it must have complete confidence in its project team — down to the simplest detail of trusting the supplier to deliver bags when needed and knowing necessary lead times for replacing existing stock. It is vital to be able to get your hands on a critical consumable quickly enough to keep from holding up your whole manufacturing process.

Beyond all that, the flexible format is about product quality. Disposable bags can be just a pinhole away from causing the loss of a million-dollar batch or a key timeline delay. Redundant supply facilities that are logistically close to one another can offer the support needed to bring such facilities online. Ultimately, a flexible factory and the supplier of key consumables for it are linked in a way that must go well beyond a vendor–consumer model to become a strategic relationship.

Author Details
Jeffery Lee Craig is global director of business development and marketing for ATMI LifeSciences, 1-636-346-2747; jcraig@atmi.com; www.atmi-lifesciences.com. Michael Jenkins is general manager of Catalent Pharma Solutions in Middleton, WI, 1-608-821-6223; michael.jenkins@catalent.com; www.catalent.com.