In recent years we have seen a switch from traditional bio-pharma manufacturing toward a novel approach using Isolation Technology (IT) as both a means and method for the delivery of sterile and non-sterile drugs. We have observed this across both large and small pharmaceuticals and in certain science and technology universities campuses across the US.
Have you heard these statements in our industry? “Give me an isolator and I can run cGMP products in a parking lot.”
Or this? “Facility is secondary — cover up my process train with a tent — that is all I need to run this bio-pharma product.”
And most recently, due to an unprecedented increase in construction cost: “The building cost came in too high. We cannot afford the building but we need the process. Can we get one without the building?”
All of the statements above, and others like them, are primarily made by process engineering and/or project engineering groups; whether they are realistic or impossible requests at the moment, they create frustration in facility engineering groups that, traditionally, tend to see everything in terms of fixed assets such as “buildings and equipment.”
Tradition has its role, and we learn from past experiences; however, progress cannot be stopped and one needs to constantly apply timeless concepts in the context of new technologies, current needs, and new cultures emerging around us. For example, concepts such as “functionally driven design” or “building is disappearing” that allow the intended function/process inside to take top priority are not new. They are well over 100 years old and we now see these concepts making their way into bio-pharma engineering as well.
Figure 1 shows a high-tech lab setting under a temporary inflated roof. It could even be set on a parking lot. Some utopian ideas can indeed become reality. This lab symbolizes the notion of “temporary operation” or “reduced time to market” or “trial production” or “emergency setting” — all are good answers to the realities in today’s life.
All of the facilities mentioned above use a particular type of IT for their clean and/or hazardous processes. Facilities using IT as their primary means of running cGMP batches remind us of the “ballroom” concept already well established among research labs — they allow researchers (bio-pharma operators in this case) to design and use their own workplace creatively — yet they meet all the stringent requirements and procedures of a cGMP facility.
The essence of the ballroom (multi-purpose room) concept is flexibility and creativity in operation and its ability to adapt to changes overtime. A secondary benefit is that the ballroom by design becomes a more agreeable and friendlier place to work, showcasing the technology and methodology in order to recruit/retain science talent for both business growth and client development.
One recently built cGMP facility in the U.S. chose to follow this route, and the end results are still to be proven. The following are illustrations that highlight this project:
Figure 2 shows an artist’s rendering of the proposed cGMP multi-use room intended for sterile fill/finish operations. In this process/facility-design approach, the ballroom is much larger, somewhat taller, and less stringently classified as far as air quality and environmental variations tolerance; as a result, the showroom effect is a real possibility. With a small incremental cost increase compared with the facility as a whole, one can use the expensive process technology inside for business development, regulatory visual inspections, training, etc. Still, the confidentiality of the formulations and methods developmenttaking place in the ballroom will not be compromised.
How does this multi- purpose room design differ from the traditional, more established approach of “cleanroom to airlock to cleaner and cleanerrooms” in terms of space, flows, compliance, maintenance, and cost?
Figures 3 and 4 show what is expected in a ballroom design: a larger, clean process room with multiple types/sizes of isolators on casters, either holding the process equipment inside or facilitating the material handling from point A to point B all under strictly controlled mini-environments inside these boxes. Obviously, the room itself needs to be engineered to support the proper function of these isolators. However, the ballroom is less environmentally restrictive than the isolator itself, which should be viewed as a mini-cleanroom in itsown right.
Along the room’s perimeter we usually place suites to handle processes that are difficult, either due to their equipment size and arrangement or their hazardous nature. We also place the process support and utility support rooms here. In addition, one can also place here conference/training rooms that look deep into the process hall, unobstructed by air locks or supply/return corridors. Think how valuable such a view could be for your business’sgrowth and for employees’ morale.
All of the above can be customized many ways by design in, as opposed to the traditional cleanroom/air locks approach where segregation of operations in their designated rooms is the rule, creating in most cases a labyrinthine floor plan.
Using the blocks (bubbles)-diagram design method on the cGMP floor plan, this puzzle type of plan is better understood and developed by process architects working together with bio-pharma engineers (Figure 5). These multiple process and process support rooms are clean-rooms by definition, with various clean air classes under strict air pressurization; therefore, there will be large return air walls between these blocks. Sliding doors, visual panels, pass throughs, and bumper rails are just a few of the components of this highly technical space making it more expensive and slower to build and operate than the multi-purposeroom with isolators for an equal throughput (Figure 6).
Also shown in Figure 5, valuable real estate is dedicated to circulation/segregation of rooms, which alone rightly makes most manufacturers’ managers nervous; whereas Figure 6 provides more space to the process room, thereby making everyonehappy.
Let’s not forget another aspect; in Figure 5, the space is used for running only one clinical batch at a time, with time-consuming cleaning validation between campaigns, while multiple-type products are waiting in line. Both the time and cost to build and to operate are increased using the design in Figure 5 compared with the multi-purpose/isolator design in Figure 6 — yetnot everybody in this industry is ready to switch from the old paradigm to newmethods for reasons we know or think we know.
ANALYSIS AND DISCUSSION OF THE PROS AND CONS OF THE TWO SYSTEMS PRESENTED
What is the driving force behind this trend?
Is the “Cleanroom as a Box” concept a good concept? How about a larger room with high ceilings and glass panels that allow eye contact with surrounding areas and when possible, with the outdoors? Which is more suitable for discoveries in high-tech industry? Both are possible; the question is which one to choose.
The trend towards designing quality spaces are viewed by many as more suitable to attract and retain talented scientists — it gives them a stimulating place to be creative and to work efficiently and effectively.
Also, bio-pharma process needs are not always the same; rather, we see constant changes in the formulation, active materials properties, and finishing requirements that span both qualitative and quantitative needs.
This challenge of constant manufacturing changes requires facility engineering to maintain equipment, facility, and utilities upgrades — which in turn increases the cost and the time to market of the final product. Under the pressure of lowering the cost of manufacturing drugs, capital improvement spending needs to be reduced. Multi-purpose rooms with isolators may be the answer because the equipment is now your process room at a reduced yet appropriate scale for the desired output.
How do the operating and design engineers approach this different and unique design?
We are past the time when bio-pharma engineers used to say: “I’m glad I will retire soon, before the isolation technology will be the systemof choice for my clients.”
We have today a wealth of knowledge both from the engineering and from the equipment manufacturing sides. Gradually, the regulatory field got to know the system and — when presented with well-documented data, statistical results, and perhaps computer graphics with simulations — the reaction from most is surprisingly positive. The main concern we hear is about the cleaning validation of isolators and it is no surprise that so many goodarticles have addressed this issue in recent years.
How do the clients operate the facility once it is certified for the intended use?
Many find it challenging to accept the change in mind-set from working in an “open system” with process equipment in dedicated cleanrooms to a “closed system” where the isolator is the cleanroom holding the equipment inside. Others are excited by the challenge of creatively setting up different processes in differently sized and arranged isolators, and creating a general arrangement specific to each client’s project in an effort to be most efficient andcost effective.
What impact does this trend create on the bio-phar-ma industry?
Whether in the manufacturing, engineering, equipment, or regulatory fields, we live in a time when cutting costs and simplifying processes and procedures are regarded as “value added” to projects. We can see this merely by looking at the way that the use of “disposables” in bioprocess as a cost-cutting method was introduced and then accepted by the industry. Not only is this new method (using disposables) attractive to big pharma, but it is practically the only choice available for start-up companies whoseaccess to large capital is limited.
One other very significant step towards simplification and cost cutting is the recent introductions of “closed vial systems” for fill/finish operations. This novelty system may even challenge the need of isolators aswe know them today.
Reducing the cost of fixed assets, such as buildings and multiple pieces of expensive cGMP equipment, is a benefit across the board. In my experience, facilities using isolators cost less to build than the traditional dedicatedsuites for separate unit operations as the safeguard against cross contamination.
Reduced cost is what gives start-up companies the opportunity to play a role in this industry — helping themselves and others particularly by outsourcingdifficult to handle processes, such as potent formulations.
The need to outsource projects that involve potent compounding, by default, created the need for contract manufacturing to fill that gap. Isolators gave them both a means and method they could afford, and one that is safe for both the operators and the products.
Let me conclude by saying that having isolators in place is not the “end all and be all” in cGMP operations; facility and equipment up-keep, personnel training, and good record keeping, etc. are all equally important pieces inthe puzzle.
The author acknowledges the helpful editing of Irene Perciali, Ph.D.
Michael Perciali AIA, NCARB is the Senior Architect at Middough Consulting Inc.,2000 Crawford Place,MT Laurel,NJ,08540. He can be reached at 856-866-6581;Cell:609-851-8525; perciam@middough.com.
