By Maik W. Jornitz and Sidney Backstrom
In the lifecycle of pharmaceutical and biopharmaceutical commercial manufacturing, the one constant has been change. With the advent of modern therapeutics, large scale commercial manufacturing became common place. And typically such manufacturing produced large scale purpose built facilities designed to satisfy “blockbuster” global demand. Inside those facilities, it was not uncommon to find re-usable stainless steel process equipment up to the 20,000L scale. Improvements in expression levels in mammalian cell culture processes and the continued and growing implementation of single-use process technologies, however, have dramatically changed the complexion of commercial manufacturing. 20,000L capacities are now in far less demand which has allowed the biopharmaceutical industry to evaluate smaller footprint cleanroom infrastructures in facility design projects. Demand for smaller, more flexible, manufacturing facility designs has been further accelerated by the need to produce in-country/for country and by advances in biosimilar technology, which requires multi-product processing capabilities. Furthermore, smaller environments can provide the containment required in the production of highly potent components and purely aseptic processes in cell therapy production. Smaller volume filling created the opportunity of new aseptic processing technologies, for example pre-sterilized container systems and robotic filling in isolators. These systems are so compact that one can think about drop-shipping needed filling capacity within a prefabricated environment in a flexible placement mode. Some of these smaller infrastructures have the further benefit of being able to be rapidly deployed thus reducing the time to first production runs and the resultant monetary benefits.
Once thought of as a “moonshot” future technology, these modular facilities are now replacing traditional methodologies the industry is also beginning to see architecture and engineering firms embrace this new technology in favor of or in addition to the traditional design build paradigm. Moreover, modular companies are starting to collaborate thereby enhancing their offerings, which could be the beginning of mergers and acquisitions in this arena similar to what has occurred in the process equipment space.
The Process and the Facility Switch Places
Biopharmaceutical processes have evolved from large volume, rigid stainless steel designs to small and medium volume, flexible, single-use unit operations capable of producing the same or more high quality product with greater efficiency. Hence, in regard to processing equipment, re-usable has given way to single-use. Advancements leading to this outcome have had a profound effect on facility design. Past facilities were product dedicated and designed to accommodate only one product until its lifecycle ended. Afterwards, the facility was mothballed or had to be significantly redesigned and rebuilt. This method of operation was expensive, time-consuming and resource-consuming (man hours, management, business interruption, etc.). Modern facility designs, which can be used for multiple product lifecycles or even multi-product applications, can be built in a shorter timeframe, for less money and without requiring company resources throughout the process. In other words, in facilities, single use has given way to re-usable, from product dedication to multi-product lifecycles. A cross-road between facilities and processes emerge; whereby process shifted from multi-use to single-use and facilities now move from single-use (product dedicated) to multi-use (multi-product).
Because facilities and processes are distinctly different, they have to be designed and constructed in different ways. A facility is not necessarily flexible just because the process is single-use. The opposite is often true. Traditional facility layouts void the flexibility of single-use processes, since these process are often mobile. If the layout of the facility does not allow easy access or movement, the benefits of flexible process equipment is squandered. For example, if a cleanroom space is built to house one fermenter and one tank with no allowance for other equipment or additional personnel, and the required ductwork is interconnected into the cleanroom from the larger facility, a change as small as the addition of a second fermenter or tank could result in having to rebuild the entire room. If, however, the cleanroom was built with its own air handler and the process required the addition of another fermenter and tank, a second cleanroom could be easily added without interrupting the existing process. In the former example, the arrangement was dedicated to the product produced at only one scale and if more product or a change in process is implemented, the layout ceased to function. In the latter example, the facility was built with flexibility in mind, so a change in the process did not require an alteration to the existing cleanroom. Rather, only a small addition was required. Such an approach represents the next generation of cleanroom systems, that are not interconnected, but are designed to be autonomous units.
Is what has been described a coming reality or a lofty goal that no one expects to achieve? Only time will tell. But what is known now is that the kind of progress described has already been articulated as one of the agency’s primary goals. In its 21st Century Initiative the FDA stated their vision for cleanrooms of the future. The vision declares the need for “A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight.” This vision is satisfied with new innovative modular or podular cleanroom systems described.
Flexible facilities – Past, Present and Future
For years’ facilities were complex, lengthy and costly construction projects. The question of when to invest in such facilities often product-dedicated s required years of planning and seven to eight figure capital budgets. To address/avoid these issues, modular container based facilities emerged as a potential solution. This type of modularity achieved some market acceptance. That experience revealed that while it was proved that an entire building could be constructed in a modular or “lego block” like fashion, doing so was expensive, logistically difficult and ultimately resulted in no flexibility of space once built. The end result was a facility no more flexible than the traditional brick and mortar designs sought to be replaced. Moreover, the pre-assembling, dis-assembling and re-assembling of the entire facility did not significantly reduce the overall project schedule or lead to a more streamlined validation schedule. As a result, the initial and primary supplier of this platform did not survive.
Currently, the most prevalent modular infrastructures are designed with modular panels. These systems have a greater flexibility than the container based approach and can be erected in a shorter period of time. If expansion is required, wall panels can be removed and added to expand the overall layout. In most instances though, this means that the existing cleanroom areas and processes are interrupted, and the entire cleanroom space will need to be rebalanced and perhaps additional HVAC added or modified after the renovation. Even so, the modular panel structures have multiple advantages over the traditional brick and mortar facilities, one of them being higher quality than the traditional epoxy coated gypsum walls. In addition, wall panel structures can be introduced into high span shell buildings, instead of the typical concrete or glass structure. This again reduces the capital cost burden and lowers the time to completion, as such shell buildings can be erected in weeks or months, depending on the size. Logistical issues of the predecessor are avoided as well.
Such systems do have their shortcomings though. As mentioned, scalability can be a challenge. Such systems require construction on site leading to business interruption, and management and engineering costs. And validation will be a unique, and ergo, time intensive, process for every project.
The next generation of cleanroom infrastructures provides even more benefits without the shortcomings of the other options. Prefabricated cleanroom units are now offered in a number of different sizes and for a number of different purposes, from controlled non-classified lab enclosures to BSL-2 labs. Instead of having the cleanroom structure built on-site over months with all that comes with it: manpower, on-site management, permits, interruption, etc, these systems are built entirely off-site and factory acceptance tested there and then shipped to ultimate host facility. Once there, simple connections to water and power are made and internal cleanroom process piping is connected. The off-site prefabrication avoids all of the cost and inconvenience of the former method as the units can be installed in days, instead of months. An example led to on-site labor reduction of 8,000 hours (16 workers for 12 weeks) for a cleanroom area. And the project resulted in better worker safety, since the work was performed at ground level within an environment with plenty of space and supervision.
In addition to these benefits, off-site built modular cleanrooms do not require laydown or dedicated work areas as is common for onsite built rooms. When stick built or modular cleanroom space is erected, laydown areas for the materials is required and oftentimes this area is twice the size of the ultimate cleanroom.
One may incorrectly assume that these systems are akin to the old container based designs, but there are multiple significant differences. First, the new modular cleanrooms are not assembled in lego-like fashion to produce an entire facility. With outer facilities being fairly easy and inexpensive to build, paying for building such areas, dis-assembling them and then re-building them as well as building them to support global transportation, is simply not cost effective in the modern era. As an example, many websites note that an average commercial steel building costs between $16 and $20 per square foot, including building package (I-Beams, purlins, girts etc.), delivery, foundation and the cost of construction. Retail and commercial buildings that require additional finishing like insulation or façade customization, the cost may rise to $30 or $40 per square foot (SF). With that being the case, building non-classified space should not require off-site construction. Moreover, the time to build, test, disassemble, ship, reassemble and test does not significantly advance the timeline in a facility project.
Current cleanroom units are equipped with their own HVAC system, which not only makes them autonomous from the host facility but also means the ductwork is extremely compact and therefore avoids leakages and pressure losses experienced in external piping for stick built systems. These prefabricated cleanroom units also provide time savings relative to other options by being built in parallel to the shell/host facility and process equipment. As such total construction time can be cut in half in comparison to other options.
One of the first prefabricated manufacturing units, utilized for an oral solid dosage application, received the 2016 Facility of the Year (FOYA) award for Equipment Innovation (Figure 1). This facility, which can be used for small lot production all the way up to 500M tablets per year, was designed and built in 18 months, a time savings of as much as 2 or more years. The total cost for the facility and major process equipment was approximately $15M instead of the expected $40 - 60M. In addition, the overall footprint was reduced by 60 to 70% in comparison to traditional settings. And, perhaps above all, if demand for the product intended to be manufactured does not grow or continue, the whole facility can be re-purposed and/or moved to another location.
Figure 1: Oral solid dosage form prefabricated cleanroom POD
The facility can also be standardized and cloned as platform approach for in country/for country purposes. On the production side, the facility enables the manufacturer to produce on demand instead of based on forecasting, which will lower product inventory and reduce the risk of product expiration. And additional unit operations such as coating and encapsulation can be added without interrupting the existing structure.
These modular facilities can be placed into very modest shell buildings around the globe. These shell facilities can then hold additional modular facilities for one or several companies. In the latter example, companies can share administrative resources such as using the same quality control, purchasing, operations support, etc. In either case, cleanrooms are deployed faster for new product production or product scale up. Resources are more efficiently used. Both will lower the typical operating cost burden, since the clean space is built around the process.
While the advances in modular technology are apparent, what is also clear is that these modules will become the building blocks to standardized platform approaches for well-defined processes. A good example of this is the downstream process for a typical monoclonal antibody (mAb). Each mAb typically undergoes multiple chromatography step, viral inactivation and filtration to finally being formulated and filled. The process itself is very well defined and well known, which has been taken advantage of by single-use process equipment suppliers. These suppliers have created single-use process unit operations, which can be interconnected to a larger process stream. These unit operation can nowadays be placed into cleanroom containment systems and once again interconnected to an entire facility layout. In the past it would be left up to the customer and the A&E firm of its choosing to design the environment around that process step. The result would be significant man hours (engineering and construction) and expense and a custom built enclosure. The obvious questions this presents are; If the step, the scale and the equipment is the same, can’t the enclosure be the same? And if the enclosure is the same every time both in terms or size, equipment and materials of construction, wouldn’t that lead to a shorter time to validation? The answer to both seems to be a resounding “yes.” In fact, many A&E firms have asked these same questions themselves and come to the same answer. They have now embraced the technology instead of attempting to preserve the mountains of billable hours that projects of old generated.
With pre-fabricated modules having been designed with specific process steps in mind, it is not entirely unlikely that in the very near future process equipment companies will include in their product catalogues enclosure options for each process step that can be selected or selected and modified to fit the customer need. Thus, in addition to providing the turnkey solution for a particular process step, process equipment manufacturers will also provide the enclosure around the process equipment and thus provide a true integrated turnkey solution. Such will greatly abbreviate the current lengthy design phases and lower the cost of facilities. Facilities, like the process equipment inside, will become re-usable commodities. Conceptual design costs, which currently are not minimal, would also decrease substantially.
When will such platform designs emerge? Sooner than you think! Multiple bioproduction platform facilities, drug substance and product, have been designed and delivered, whether as modular wall panel, container based or prefabricated POD based systems. These platforms will extend into other areas as well. For example, one modular supplier has partnered with an A&E firm to generate a standardized 50,000 egg per day vaccine facility. The same modular provider has united with another A&E firm to design a standardized 2,000L monoclonal antibody site as well. Bioprocesses of multiple types and volumes can potentially become a catalogue item, instead of being reinvented over again. Standardization of processes is already a discussion point, similar such discussion can shift to cleanroom infrastructures and facility layouts.
Smaller volumes within the bioprocesses, robust containment need and new therapies have motivated new, compact designs of fill lines. These systems utilize automation, robotic fill arms and pre-sterilized container systems, which avoid human interventions. Since these systems are compactly designed within an isolator, these systems can be prequalified within the supplier site and gain the final qualification at the end-user site. The next progress in the aseptic processing filling area, is the partnering of the filling line manufacturers with modular companies to provide turnkey filling and enclosure options that can be delivered together easing the integration burden as well as shortening the timeframe for delivery and operation of filling equipment (Figure 2).
Figure 2: VanRX filling system within G-CON cleanroom POD
With the first barrier, the isolator, around the fill line and the prefabricated cleanroom as the second barrier, as well as the compactness of both and the possibility of sanitization with vaporized hydrogen peroxide, filling is easing away of being the weak link. This process step required focus and received it. It is now a firmly robust process step with an remarkably high assurance level.
Another frontier that is starting to be explored are collaborations between modular companies. In the past modular companies proclaimed to have the best “mouse trap” and would not consider working with other modular providers. Providers sought to establish themselves as the sole provider of quality modular systems. Today however, with the market acceptance of modular technologies expanding, and with modular companies beginning to carve their own niches, modular built offsite versus on-site built panels, modular companies have become more receptive to working together and bidding alongside erstwhile competitors. At least one major supplier of offsite built cleanrooms has included modular panels in some of its latest designs. Modular providers have jointly pursued projects in the recent past. Developments like these will continue. And those developments may drive further innovation and cost competitiveness in this space.
Modular Challenges - The Cost per Square Foot Question and Why It Is Not the Right Question to be Asking
Costs have always been a consideration in the industry. Now, costs are even more of a focal point with mounting competitive pressure by generics and biosimilars, as well as the call for affordable medicines by Congress and even Presidential hopefuls. Such concerns lead many to the knee-jerk reaction of asking “What is the cost per square foot?” when considering a modular option. Such however, is only the tip of the iceberg when making a capital decision. Just as it happened with the first cost comparisons between stainless steel and single-use processes, the total cost ownership must be considered Not surprisingly, low cost providers can produce an enticing quote the prospective owner must dig into the quote to see what is really being provided. The prospective owner needs to consider whether the option before him will be a turnkey solution, that will operate efficiently over the lifetime of the product being produced as well as what the value of that enclosure is after the product lifecycle has come to an end.
The following table reviews some of the parameters that should be considered in capital projects:
While there are many other considerations in the facility arena, the above list makes it fairly clear that the cost per square foot of the cleanroom space is not the only factor and may even be a secondary consideration.
Facility design requirements are evolving just as bioprocess technologies did in the transformation from stainless steel to flexible and agile single-use process technologies. These innovative technologies have created new facilities opportunities and modular solutions are clearly part of that analysis. Flexible processes lose their flexibility if they are forced into uncompromising, inflexible facility and cleanroom infrastructures. Total flexibility is achieved however, when flexible processes is fused with flexible facilities. The cleanroom enclosures can be smaller, produced in assembly-line fashion, in a shorter timeframe, and with greater ability to be repurposed or scaled. Some major pharmaceutical companies and A&E firms have started to embrace the revolution recognizing that the familiar “brick and mortar” and “stick built” approaches have succumbed to advances in technology. It is expected that more adopters will follow leading to additional growth and collaboration in the modular space. Such will also lead to more data, empirical evidence of acquisition and operating costs, regulatory acceptance, project completion timelines, etc. Such data will only further the evolution.
William Pollard, an American physicist once said “The arrogance of success is to think that what you did yesterday will be sufficient for tomorrow.” The statement was recently cited during a presentation on the new Amgen facility in Singapore, a facility, which shows significant benefits in regard to cost savings and higher efficiencies, including an 80% size reduction with the same throughput as a traditional site and a five-fold reduction of energy consumption. Additional examples of such greater efficiencies, capital and operational cost savings of new and innovative facility design are certain to be forthcoming as the revolution matures.
Moreover, aseptic processing steps, whether purification, viral clearance or filling, gained a higher containment robustness, enhancing processing safety. The different unit operations created can be standardized and interconnected to a, potentially, entire process. The formerly weak link and critical step of filling has been overhauled to extremely compact and enclosed units, which can be prequalified and placed in prefabricated cleanroom system to be drop-shipped. These new fill systems, do not just enhance safety, but also speed of deployment and efficiencies.
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