May 7, 2015

Modular Manufacturing Platforms for Biologics


May 01, 2015
By Randi Hernandez
BioPharm International
Volume 28, Issue 5

It should come as no surprise that the good design principles governing the execution of pharmaceutical manufacturing in modules were birthed in Sweden, home of IKEA, and neighbor to Denmark, home of the Danish modern furniture movement. While the idea of modular construction has been used in other industries for decades, it has only started gaining traction for pharmaceutical applications during the past 20–30 years.

Modular systems can refer to a variety of different physical configurations, which can be a source of confusion. Whether something is called a pod or module seems to largely depend on where the unit is actually constructed (on site or off site) and where all of the cleanroom components live (inside the actual unit that is shipped or inside the existing facility infrastructure). There are modular room enclosure systems (such as from Daldrop, AES, or Plascore); modular room enclosure systems with utility systems (such as from G-CON Manufacturing or SmartFit Modular); building modules with utility systems (such as from Pharmadule/Morimatsu); or building modules with process systems (such as GE Healthcare Life Systems’ KUBio FlexFactory platform). According to Pär Almhem, president of ModWave, modular design and construction in pharmaceutical process facilities can include either breaking a facility and its manufacturing processes into functional building blocks/modules or into physical building blocks/modules. Functional blocks “create opportunities to simplify, standardize, verify, and reuse designs and modules in different implementations,” while physical modules allow for the construction of modules off site, reducing “congestion and disturbances on site,” notes Almhem.

Blocks—also called modular suites, mobile or modular cleanrooms, pods, or flexible or expendable cleanrooms—can include stand-alone modular buildings or those that can be installed into an existing building shell. They can also include configurable skids; process modules/skids based on single-use equipment; or unit operations within modules, such as suites made exclusively for aseptic filling of prefilled syringes or continuous manufacturing lines (1). Prefabricated fill line/cleanroom unit combinations via pods—or autonomous containment systems—can be introduced into an existing process easily, says Maik Jornitz, president of G-CON Manufacturing.

A common choice for modularization has been in the form of utility suites, says J. Lee Emel, executive director of CRB Consulting Engineers. “Over the past 10–15 years, the industry has been experimenting with various ways of incorporating modular design into project delivery of capital programs,” says Emel. “Modular design of process systems (superskids), utility systems, spaces (penthouses and electrical rooms), and wall-panel systems have been utilized with much success,” he adds. According to Emel, speed to market is no longer the only business driver behind using modular systems; asset flexibility, cost of goods, and investment deferment are now key significant drivers of modular construction.

A full module typically is fashioned with its own mechanical, electrical, HVAC ductwork, high-efficiency particulate air filters, and plumbing systems--and process equipment is usually already part of the module (2). There are numerous benefits related to quality control with building and qualifying units off site. If a full module is unrealistic because of budget or existing architectural constraints, a piecemeal approach to modularity could incorporate turnkey process and utility equipment, including clean-in-place skids, wall-mounting systems for piping, and air handling/temperature control units (2). For best results, modular solutions need to be planned during the early stages of a project (3).

Advantages of modular systems include shorter time to market, higher cost predictability for each module, the ability to standardize operations, reduction of manufacturing disruption to current operations, less waste, and the flexibility to set up and test complete product runs before they are commercially deployed (1, 2). In addition, closed modular systems are said to reduce required manufacturing area, HVAC requirements, chilled water and steam demands associated with cleaning, construction and start-up times, and potentially, cost of goods (4). A modular facility is said to be associated with an approximately 15% reduction in energy consumption and, after accounting for risk, is estimated to be 5% more cost effective than a traditional facility (5, 6). Not only are modular production facilities more cost effective to operate, they also take a shorter time to construct: While a traditional facility can take three to seven years to complete, its possible for a modular facility for oral solid dose, biologics bulk, or aseptic filling to be built in only 12 months from project start to operational qualification, estimates Almhem. Pods can be built in an even shorter amount time, says Jornitz. “If one utilizes a shell building/cleanroom pod scenario, the shell building can be erected in six to eight weeks; the cleanroom pods are built parallel to the shell building and require 15–18 weeks.” The 15–18-week timeline likely aligns with process equipment and utility bundles, he adds.

Standardized but customized
A key element of early project planning deals with the customization of modules to meet a client’s needs. While modularity supports standardization and repeatability, it can also support customization if done correctly, says Almhem. “Taking a fixed process and installing it in a building module does not promote customization,” he says, but “dividing a process into well-defined process steps—with defined inputs, outputs, and transformations—is the best way to allow for customization while maintaining quality and efficiency.” As Emel notes, different modular approaches will work for different manufacturers, especially if one has a large-scale high-throughput facility using large steel tanks while another has a smaller facility focused on lean manufacturing and single-use systems. Robert Dream, consultant at HDR Company says that while true modularity helps to reduce capital expenditure and operating expenses, and helps ensure better manufacturing practices, standardization is not necessarily a requirement of modularity. Though not required, standardization is likely desired, counters Jornitz: “Even when a project pod is designed, if such a pod is replicated, we would always recommend to clone the system to reduce the qualification and validation burden.”

Current modular facilities
While there are numerous examples of facilities that have been built with a modular concept in mind—such as Genentech in San Francisco, CA, and Singapore; Lilly in China, Egypt, Ireland, the United Kingdom, the United States, and Puerto Rico; and Merck in Singapore, Ireland, the United States, and Puerto Rico—Almhem points out that these units have become permanent facilities once they were constructed. There are fewer examples of modular facilities that have been moved and reconfigured, he asserts. Mike Booker, manager of business development at PortaFab, a manufacturer of cleanroom wall systems and other modular cleanroom products, says the company has a Mid-West pharmaceutical client that uses modular construction to meet its “ever-changing facility requirements.” Modular construction helps PortaFab’s clients reduce backend costs due to the reusability and flexibility of existing materials.

Contract development and manufacturing organizations (CDMOs) and contract manufacturing organizations (CMOs) have traditionally viewed modular approaches as too expensive and, as a result, have been reluctant to adopt them, notes Almhem, but this may change as it becomes more clear that modular concepts are competitive models. Because the CMO business model may put more cost pressure on delivery, adds Emel, CMOs may “be willing to try newer methods or technologies if they have the possibility to reduce their initial capital investment.” While single-use equipment lacks some flexibility in a traditional facility, Jornitz says that podular systems combined with single-use systems, in particular, could be ideal for CMOs, as CMOs typically run different products, volumes, and processes depending on individual clients. The addition of single-use systems reduces turnover and allows for more flexibility in production planning. With single-use systems, “The changeover to another product can be swift, and potential cross-contamination can be avoided, since the product contact layers are disposable,” says Jornitz. Plus, if “capacity demands flex, [the CMO] could potentially add or deduct some of the cleanroom areas.”

Pods: Portable facilities
Local diseases often require local solutions, and getting production online quickly is a major concern in emergency situations. Therapeutic treatments produced via a modular vaccine suite—a pandemic-ready modular facility—could be a good option in the future when dealing with the proliferation of tropical diseases and regional outbreaks. Smaller manufacturing subsystems are best suited for emerging markets where local resources are limited and speed of production is a crucial element (1). A surge capacity is necessary to rapidly scale up production in case of emergencies, and a traditional manufacturing facility may not be able to meet quickly escalating demands (4).

Modular bioprocessing facilities may be best suited to countries that struggle with GMPs. Pods, in particular, may be especially useful for emerging markets, points out Emel, “where local construction expertise or materials are not readily available.” In well-developed markets, where the process can be fully closed, “other delivery methods may prove to be more cost effective and flexible,” Emel determines.

A pod (also known within the industry as a POD, although the word is not an acronym in this context) is a prefabricated cleanroom box designed and built off site, explicates Jornitz. The pod hosts the air handlers, fire suppression system, and controls—which are all in the mechanical space—and the mechanical space is accessible from the gray space of the host facility. “The cleanroom space is accessible via air locks within the pod, which are connected to a classified corridor,” he says. This infrastructure is unlike stick-built cleanrooms, which are interconnected via ductwork that is often as large as the building structure itself. In essence, instead of building a shell around the process, the process is being integrated into the shell.

Jornitz says that his company could produce antivirals and containment systems via pods in approximately 12–18 weeks. Caliber Therapeutics, originally a subsidiary of G-CON, LLC until the formation of G-CON Manufacturing Inc. in 2014, was established with Defense Department funding from the Defense Advanced Research Projects Agency (DARPA) to be able to respond to biological and pandemic threats. Caliber has received inquiries from government officials about whether it could help manufacture ZMapp, a treatment to fight the Ebola virus. Caliber uses G-CON’s pods for its entire downstream processing, says Jornitz. The work with G-CON through Caliber’s
Nicotiana benthamiana plant expression system “shows that podified downstream processing structures can be deployed and redeployed rapidly without compromising required quality attributes.”

Cleanroom pods can be used for entire process streams, as in the Caliber example, or can be used as a single pod for filling purposes, such as with PaxVax, which uses a 24-foot-wide pod for this purpose. PaxVax installed the pod at its GMP vaccine production facility located in San Diego, California in 2013 for the clinical and commercial manufacturing of its single-dose oral cholera vaccine. The pod, customized specifically for PaxVax, was the first controlled non-classified (CNC) cleanroom environment to be delivered into the state of California, which the company admitted presented a few “regulatory and engineering challenges” (7). Because pods are prefabricated and must be introduced into an existing shell building, once they arrive at a facility, wall panels, doorways, and existing pillar structures can limit their movement within the facility, notes Jornitz. For this reason, a number of different sized pods can be clustered or put into place as a single unit, he adds.

While pods may be good solutions as far as individual cleanrooms or laboratory spaces go, Almhem says they are typically not good “for an integrated process suite or facility that extends over more than three to four modules.” Scalability of pods is also a concern, and pods are generally more expensive than other modular implementations. Emel concurs that compared with open, flexible manufacturing spaces using closed processing, podular systems are less flexible and adaptable. Sid Backstrom, director of business management at G-CON, disagrees with the sentiment that pods cannot be integrated in concert successfully, and says that a recent delivery by G-CON “belies that opinion.” He says, “We delivered six pods clustered together that integrated a complete OSD [oral solid dosage] line from GEA Pharma that includes continuous mixing and direct compression, wet granulation, drying, and a tablet press. The unit will be used for R&D work at first, and then commercial manufacturing, either domestically or disassembled and redeployed overseas. Another five-pod configuration is in fabrication now,” he says. “Our very first customer purchased six pods, and these are connected via a clean corridor. Caliber Biotherapeutics employs six pods for every step of its downstream purification process,” he adds. Backstrom says that the flexibility of the OSD line allows site managers to seamlessly add pods for other process operations, such as encapsulation, without affecting cleanroom operations.

Jornitz notes that there has been recent interest in the use of pods for analytical, microbial, polymerase chain reaction, and assay development, as well as interest in the use of pods for broader healthcare purposes, including transmissible disease containment. He says G-CON has been approached to design a mobile containment system to be able to segregate patients. “The transmissible disease containment systems range from patient transfer to installed patient care units,” he says.

Modularization of biologics and biosimilars
Emerging markets and the increasing demand for biosimilars may prompt pharmaceutical manufacturers to adopt a “local sourcing” attitude that has historically been reserved for other consumer goods. As a result, biosimilar approvals may influence facility design needs, and these facilities may crop up in new areas. “Biosimilar production site [managers] look for a high degree of flexibility and often try to run multiple products through the same process, especially in an in-country/for-country situation,” notes Jornitz. Biosimilar end users are keen to incorporate single-use process designs and flexible cleanroom spaces, he says. “Robust containment is a key element when one wants to use multiple products within the same process.”

Depending on certain key factors, prefabricated buildings or manufacturing pods may also be viable solutions for fast-track projects. Emel points out that schedule flexibility associated with modular manufacturing could be a significant competitive advantage, especially in crowded therapeutic markets where similar products are in a race for regulatory approval. Emel writes on CRB’s website, “Being able to compress project schedules also allows manufacturers the opportunity to delay investment, allowing them to further scrutinize market data, or conversely, seize a market opportunity before their competition” (8).

Almhem says that increasing pressures to shorten time to market, decrease operating cost, and improve efficiency will push biosimilar developers toward facilities that are smaller, more efficient, and more flexible. The answer may not only lie with modular models, but with a combination of cost-saving efforts. While the industry will continue to look for ways to reduce capital investment when bringing a drug to market, Emel says that “the holy grail may very well be continuous processing, which could make manufacturing facilities significantly smaller, faster to build, and much less costly.” Indeed, Richard Steiner, business development manager at ConsiGma at GEA Pharma Systems and a proponent of PCM&M or PCMM (portable, continuous, miniature, and modular) systems, told Pharmaceutical Technology, “continuous processing is enabling miniaturization; miniaturization is allowing processing systems to become portable and modular” (9).

PCMM systems, launched in partnership with Pfizer, GEA Pharma, and G-CON, are virtually factories within a pod. The first example of this type of unit, constructed to produce oral solid-dosage drugs, was delivered on March 17, 2015. Final site acceptance and commissioning are in process. The continuous processing skid was prefabricated in Belgium, integrated into a portable cGMP pod that had been prefabricated in College Station, TX, and then re-assembled into Pfizer’s gray warehouse space in Groton, CT. According to Michael O’Brien, vice-president of Pfizer Pharmaceutical Sciences Technology & Innovation Group, who spoke about the units at the 2015 Parenteral Drug Association Annual (PDA) Meeting on March 16–18, 2015 in Las Vegas, NV, PCMM systems help facilitate production and distribution on demand, rather than via forecast models. Using the same equipment for development and manufacturing could help minimize technical transfer costs and resources, he wrote in his PDA presentation notes, and could reduce inventory overheard while still allowing patients to gain access to crucial medications (10).

In fact, DARPA’s Battlefield Medicine program seems to take a similar approach to PCMM in that it focuses on the flexibility of a modular reaction design. According to the Battlefield Medicine website, “In developing a flexible, miniaturized synthesis and manufacturing platform, Battlefield Medicine will leverage continuous flow approaches that will, if successful, pave the path forward for enabling distributed, on-demand medicine manufacturing capabilities in battlefield and other austere environments” (11).

Another example of modular system that is available is via a Lödige continuous line. In this example, the line itself is modular, says Almhem, and can be installed into existing cleanroom or mechanical areas. Alternatively, the line can be implemented as a complete processing suite in part of an integrated facility, rather than just in a stand-alone pod. “Continuous manufacturing has great potential to significantly reduce manufacturing cost for OSD products,” he says.

By using modularization and the other aforementioned technologies such as continuous manufacturing, facilities to produce monoclonal antibodies (mAbs) can also be operational 12 months after project initiation, Almhem says, and there are several modular mAb facilities that are already in operation. In fact, modular systems are best for mAbs and are likely better than any other system design for these products, states Jornitz, as most new mAb processes are at the scale of 2000 L, which fits within the pod design. While large-scale bioreactor systems may require a traditional facility design, he says that once harvest volumes are concentrated via ultrafiltration, podular processes can resume. “Because it is compact and highly integrated, a continuous line lends itself very well to a modular implementation,” Almhem adds.

Challenges associated with modules and pods
“Building one module is easy; building an integrated modular facility takes a lot more skill and expertise,” observes Almhem. Some of the oft-mentioned challenges associated with modular models deal with technical construction and the workforce planning and training required to get a facility fully operational. On-site construction and compliance teams may need to engage in testing and qualification activities throughout the duration of each project (2).

Pods are required to have a shell building around them, as they are critical cleanroom spaces, notes Jornitz. The shell is required to ensure the humidity and temperature within the pod remain stable, he adds. In the pod example (sometimes known as “plug-and-play”), this infrastructure can be minimal and cheap, as all of the critical cleanroom components are contained within the pod. In contrast, in a module-based approach, an entire facility is often built, shipped, and reconstructed on site.

Governing regulatory agencies for modules: Building codes
Regulatory bodies will require some amount of infrastructure around every cleanroom space, notes Backstrom. Obtaining proper cleanroom protocol, regulatory objectives, and the desired International Organization for Standardization (ISO) classifications can introduce significant obstacles and have the potential to negatively affect the quality of a module, comments Booker. Closed processing is used in modules and is generally governed by a grade D environmental classification (6). Open processing areas--as required for seed preparation, final purification, and bulk aseptic filling--are designed to be grade C and are performed in biosafety cabinets with laminar air flow (6). Using CNC modules, however, can allow manufacturers to circumvent most cleanroom classification requirements, says Emel. As noted by Nelson, CNC areas (noncritical areas in GMP-manufacturing facilities) provide some operation conditions, but do not have a cleanliness class assigned to the space and are not monitored like grade-classified rooms or ISO areas (4). Although the goal of a cleanliness classification through a Federal Standard 209 is to prevent contamination, as PortaFab points out on its website, “the presence of viable particles (living organisms) within the particle count achieved by applying methods described in Federal Standard 209 may affect operations of a cleanroom” for biopharmaceutical processes. Thus, the company writes, a measure of both viable and nonviable particles is required to provide enough information about whether or not a cleanroom is suitable for a biologic (12).

The level of segregation between processing areas should be determined using a risk-based approach and should consider air handling, viral processing, live organism zones, and cell cultivation and cell purification activities (6). The module should also have areas for product formulation; fill/finish; material dispensing, washing, sterilization of parts; and lyophilization.

A manufacturer has to consider location-specific challenges related to the local code requirements for construction in that geographic region and be well-versed in the rules governing expansions or upgrades. As an alternative option, modules or pods can be constructed off-site, which is said to simplify site logistics, enhance quality control, and reduce waste (6).

Cost of building a biomanufacturing module
Although some sources say that modular facilities require a modest upfront capital investment (3), others, such as consultant Emel, attest that a full modular suite can be prohibitively expensive. Although costs of building materials for pods may exceed that of stick-built facilities, Almhem says the cost differences are small and can be “easily compensated by the efficiencies of building in a factory rather than in the field, allowing for the same or potentially lower cost for a modular execution.” Plus, modular design will save clients costs by eliminating architectural general contractor fees, says Booker.

Cost calculations associated with the incorporation of modular processes often do not take into account the total cost of ownership, says Jornitz, and are typically just accounting for cost per square foot. Traditional structures are designed for one product lifecycle, whereas pods have a lifespan of more than 20 years and can be repurposed or relocated, he attests. Other benefits of pods include compact ductwork (which lowers the operating costs); they can be sanitized robustly and therefore can run in multi-product modes; and they are easily scalable, so installation is minimally disruptive to other existing processes.

Although the most environmentally friendly approach to incorporating modules in a facility may be to salvage and convert existing assets, and this method may be “an important consideration from a cost, schedule, and investment depreciation perspective,” according to Emel, most industry experts envision gutting a building to a shell and reusing only the utilities, parking, access systems, and administration of legacy systems. The prevailing attitude appears to be that current facility architecture and design is quickly becoming obsolete. “The challenge today is that many of the legacy facilities were designed for single products or platforms, as well as lower production efficiencies, so they aren’t always at the right scale or utilize the appropriate technology to address the current business needs of many biotech manufacturers,” says Emel, who points out that most biotech companies are focusing on specialty market products requiring smaller batch production requirements. “If existing assets are able to be converted, biotechs are creating flexible open spaces leveraging closed processing to meet their needs.”

References
1. P. Almhem, Pharm. Process. 24 (4), pp. 30-32 (May 2014).
2. J. Gilroy and G. Martini, Pharmaceut. Proc. 27, pp. 22-23 (2012).
3. A. Shanley and P. Thomas, Pharm. Manufact. 11 (1), pp. 2-9 (2012).
4. K.L. Nelson, “Approaches for Flexible Manufacturing Facilities in Vaccine Production” supplement to BioPharm Internat. 24, pp. s22-28 (2011).
5. H.L. Levine et al., BioProcess Int. 11 pp. 40s-45 (April 2013).
6. P. Almhem et al., “Modularisation in Biologics Manufacturing,” Pharma Focus Asia, www.pharmafocusasia.com/manufacturing/modularisation-biologics-manufactu..., accessed March 25, 2015.
7. G-CON Manufacturing, “G-CON Manufacturing Announces Delivery and Operation of a Custom Made POD for PaxVax, Developer of Oral Vaccines for Infectious Diseases,” Press Release, Jan. 18, 2013.
8. J.L. Emel, “Building A Thoughtful Manufacturing Supply Chain,” CRB, www.crbusa.com/blog/536-building-a-thoughtful-manufacturing-supply-chain, accessed March 25, 2015.
9. J. Markarian, Pharm. Tech. 38 (11), pp. 52-54 (2014).
10. M.K. O’Brien, “Portable, Continuous, Miniature, & Modular (PCM&M) Development and Manufacturing: The Foundation for a Transformational Development, Manufacturing, and Distribution Model,” presentation at the 2015 PDA Annual Meeting (Las Vegas, NV, 2015).
11. DARPA, “Battlefield Medicine,” www.darpa.mil/Our_Work/BTO/Programs/Battlefield_Medicine.aspx accessed April 1, 2015.
12. Portafab, “Bio-Pharmaceutical Cleanroom Design Guidelines,” Portafab, www.portafab.com/bio-pharmaceutical-cleanroom-design.html, accessed March 25, 2015.


Article Details
BioPharm International
Vol. 28, No. 5
Pages: 18–25
Citation: When referring to this article, please cite it as R. Hernandez, "Modular Manufacturing Platforms for Biologics," BioPharm International 28 (5) 2015.


Tags: modular; modules; manufacturing; flexible; facilities