Partner at Jacobs Wyper Architects, 1232 Chancellor St., Philadelphia, PA, 19107, tel: 215.985.0400, www.jacobswyper.com.

Eric Bohn

	Not all types of construction are the same-there are significant differences between renovation and new or “greenfield” construction. Experienced construction professionals know that the design and renovation of a legacy facility is harder than starting from the clean slate of an unbuilt, green field. With new construction, because there are so few constraints, anything that is required (and within budget) can be provided. It’s a matter of having a clear definition of the user requirements, engaging in a systematic development of the design, and then executing the construction. Nearly as straightforward is stripping an existing facility down to the structural frame, sometimes referred to as “brownfield”. Again, except for the structure and its spatial constraints, everything is new. The only limits of what can be achieved are essentially practical and financial in nature.

	A renovation, however, is by definition less intrusive, leaving much of the existing facility intact. Here the story is more complex. Although the new portions of a renovation are as straightforward as any other new construction, this new work does not stand in isolation. It is necessary for the new work to respond to and be integrated into the existing facility. A practical, cost-effective approach demands that existing systems and infrastructure be leveraged to the greatest advantage. This melding of old and new also presents an opportunity to address current problems and to extend the longevity of the existing infrastructure. In addition, it can facilitate the upgrading and change-out of obsolete systems.

	The first step then is a systematic, thorough evaluation and inventory of the existing building and its utilities and services. Existing capacities must be identified, deficiencies enumerated, and strategies developed to address the infrastructure involved. But installed utilities usually are difficult to observe in their entirety and existing documentation is often inaccurate or, at times, non-existent. This limitation drives the design team to rely on experience to make judgements that will not be validated until the construction work is underway. A thoughtful strategy is needed to mediate the potential cost risks from these unknowns. A unique type of creativity, which grows out of experience and a knowledge of older systems and construction practices, is required.

	With an in-depth understanding of the existing facility, the team can move forward with design. The requirements of the new design, however, must be superimposed on the existing, operating facility and its infrastructure. An assortment of tactics must be developed that reflects the specific conditions and circumstances of the individual systems involved. Some systems may be provided for the first time, while others will require refurbishment, extension, or replacement. Plans should be developed that optimize the value of the existing capital investment while delivering an effective operational installation.

	The utilities required for the new portion of the facility is a case in point. Balancing the user needs and superimposing them on the existing limitations and opportunities of the facility is not easy. While providing as much new infrastructure as possible can simplify the design, leveraging the existing infrastructure is a powerful cost-savings tactic both in terms of first costs and ongoing operational expenses. Where to locate the new utility generation equipment is an important concern. Expanding an existing mechanical room has obvious advantages. But given the presence of existing ductwork and piping, the routing, coordination, and installation of services to support the new area is often a challenge. Careful location of the tie-in points is another related consideration. Where possible, finding appropriate tie-ins close to the area of work provides the best solution.

	Besides its impact on initial costs and operations, achieving the chosen mix of new and existing will have a significant impact on the amount of manufacturing disruption required by implementation. With renovations, maintaining the ongoing operations (which is the source of revenue) is always an issue. Not only does the design need to integrate with the existing plant, but the new work has to be planned so that its execution minimizes interruption of the ongoing production activities. Phased construction is usually vital to attaining this end. Phasing can be broad and easy or it can be complex, requiring many successive construction stages. Regardless, the design has to support and facilitate the phasing strategy adopted. Working in these smaller construction components is by necessity less efficient than doing all the work at once. It is typically the best response, however, in order to maintain a facility’s ability to continue to make product during the construction phase.

	In addition, the design has to reinforce the legacy facility and its current operations. Perhaps the most important consideration in this regard is maintaining, reinforcing, and expanding the flows for materials, equipment, personnel, and waste. Working in a GMP environment demands that compliance issues be embraced. It may be appealing to drop a new functional need into an existing open space, such as a warehouse, but this can be self-defeating. Any savings obtained by the easier execution will be wasted if overall GMP compliance is not maintained. Reinforcing and expanding the existing flows and gowning strategies is crucial to a successful facility that is sustainable for years to come.

	Related to having and maintaining a clear system of process flows is anticipating future changes. Change is a constant in the pharmaceutical and biopharmaceutical industry, and a successful manufacturing facility will be called upon repeatedly to support any number of new products and processes. Any renovation work must keep open the ability to meet future opportunities. Appropriate access needs to be preserved so that new equipment can be moved into existing production spaces. Future expansion of the flow of material, personnel, and waste must not be excluded, and a plan should be in place to provide future space for expansions, even if it includes off-site scenarios.

	Renovations are more complex and difficult to execute than new construction. There is greater complexity and creativity required to develop good solutions that do not detract from the existing or future operations. Integrating the new work into the existing infrastructure presents many challenges, but it is also an opportunity to exploit the capital already vested in the legacy facility. Facility managers should look at the constraints of existing infrastructure as resources that can be leveraged to great advantage and renovation as an opportunity to improve the entire facility.


	Eric Bohn is partner at JacobsWyper Architects, 1232 Chancellor St., Philadelphia, PA 19107,  tel: 215.985.0400, 

	Citation: When referring to this article, please cite it as E. Bohn, “How to Get the Most Out of Facility Renovations,” 

Articles

Renovating a facility requires careful design and a plan to minimize production interruption.

How to Get the Most Out of Facility Renovations

Modular construction is a loose term used to define a number of different prefabrication strategies. In general, it is a technique of assembling components in a factory that, once completed, are transported to the construction site. The term is used to distinguish it from the traditional practice of field fabrication, where basic materials are assembled on site. Modular construction, however, is a term used indiscriminately to describe many unrelated approaches ranging from process/utility skids and pre-engineered, modular cleanroom wall systems up to the prefabrication of entire buildings. Using modularity or field fabrication directly impacts the design process, the construction cost, and even operations and their attendant costs. Understanding the advantages and disadvantages of different types of modular construction can contribute to a more informed decision.

	The notion of modularity, by itself, is appealing. The idea of discrete, standardized components that can be assembled in different configurations offers benefits that are easy to imagine. Combining standard components in multiple ways symbolizes flexibility and scalability. It suggests an ability to increase capacity by merely plugging in new modules and the potential for reuse by removing and relocating existing modules. Fabrication in the controlled setting of a factory represents dependable, repeatable quality that reduces or even eliminates rework. In addition, it promises greater safety for the construction workers. The conditions within a factory also imply schedule benefits. Not being subject to the variable conditions found in the field-such as weather, difficult access, and inefficient sequencing-results in fewer delays. Finally, these attributes often combine, leaving the impression that modular design can reduce costs.

	Due to the demands of the pharmaceutical industry, however, the ability to standardize has significant limitations. Every facility has process and installation conditions that demand special and often unique considerations. As a consequence, modular packages end up being “optimized”; for all intents and purposes they are designed to order. When facility changes become necessary, plug-and-play is not the only scenario. Over time, changes to the prefabricated components themselves will be required. The reality is, due partially to the tight tolerances afforded by assembly in a factory, prefabricated components can be difficult and expensive to modify once in the field. On a direct capital comparison, modular construction usually represents greater initial costs. When there is savings, it is usually not found in the first cost, but in associated costs such as operational or validation savings.


	Probably coming closest to meeting the ideals imagined for modular design is the skid mounting of various process and utility equipment. Most tank, valve, and pump-based operations can be skid mounted. Some examples include various process components, clean-in-place/sterilize-in-place systems, valve clusters, and cleanroom utilities. To fit on a skid, all components need to be installed within a defined footprint. This type of installation requires careful coordination to ensure there is adequate access for both operations and maintenance activities. Too tight a footprint can result in a contorted configuration. Valves and components may be oddly located and difficult to access, hindering operations and maintenance activities. Provided the plan allows enough space, discrete unitized skids can be quickly and easily installed and capacity readily expanded. The efficient layout, build quality, and space efficiencies provided by skidded equipment can be well worth the additional cost.

	Similar to equipment skids, but different in level of integration, is modularized equipment. This approach uses multiple packaged units that are assembled to operate in parallel or series and can be expanded by plugging in additional units. This approach is readily applied to boilers, compressors, vacuum pumps, etc., and it can be a good choice when a facility has expectations for future expansion. While the cost for a modular system will be higher than a similar sized conventional unit, it is still less than buying a single unit that is oversized for an anticipated future capacity. Such underutilized equipment operates inefficiently. Meanwhile, the future capacity may never arrive. If and when the need does arise, a modular system is expandable to meet the demand, and a high level of operating efficiency and built-in redundancy are achieved.


	Pre-engineered, modular cleanroom wall systems are designed specifically for GMP-compliant operations. The best systems provide an integrated system of walls and ceilings with a finish that is truly seamless. The cleanability of such smooth surfaces is unsurpassed. Wall thicknesses are less than traditional, field-assembled construction, being roughly half the thickness of drywall. In a large facility, these inches add up, and reasonable increases in usable space are possible. Utilities, however, do not fit well within the thickness of modular walls. Some systems are UL listed for the installation of power cabling, but other piped utilities are not accommodated as easily. Unlike drywall partitions, where larger studs can provide for most piping conditions, modular cleanroom walls require that chases be built for piped services.

	Because these systems are designed to be demountable, there is potential for wall reconfiguration. Demounting and reinstalling prefabricated components generates little dust and is a much cleaner process than reconfiguring conventional walls, but the seamless integration of wall and ceiling makes this a more complicated undertaking. The modifications that seem to happen most relate to changes of equipment and their utilities. Cutting panels that are already installed requires a skilled and experienced technician to achieve a clean outcome. Unless one employs the panel installer, this is difficult to execute well.

	With modular cleanroom systems, the advantages need to be weighed against the initial high cost. There are, however, potential tax advantages that can be considered. As tangible personal property, modular walls can be depreciated over a much shorter period than conventional construction.


	Perhaps the pinnacle of modularity is buildings entirely composed of prefabricated modules. Such modular structures come in various forms. All of them, however, are integrated assemblies that join together to create facilities of significant size, housing multiple functions and pieces of equipment. Because they are transported over the road, their dimensions are limited. Fairly representative of the largest prefabricated unit is a typical 8-feet wide by 40-feet long intermodal container. While a temporary office might use a single unit, a pharmaceutical facility typically uses multiple units assembled side by side and often stacked one on top of another. In some cases, only the mechanical areas, such as penthouses and central utility plants, are modularized.

	Besides the greater initial capital cost, perhaps the largest limitation is the relatively small dimension of the module. Comparatively, the structure of an 8- by 40-foot unit is nearly 75% smaller than a relatively typical 30- by 40-foot site-erected structural bay. The increased number of columns in a modular building can make  the layout inefficient and may result in a larger footprint. There are many instances, however, where modular is a superior choice, such as for remote locations where the knowledge and skills to construct a sophisticated pharmaceutical facility are not readily available. Also, off-site fabrication allows overlapping activities, potentially shortening the construction schedule, particularly when commissioning and validation are considered.


	On a first-cost basis, modular construction is more expensive than field fabrication. It impacts facility design and must be integrated early. However, in the right circumstance there are many benefits. The higher level of control in a factory setting provides dependable quality, worker safety, and reliable scheduling. Modularity can allow flexibility and future expansion. Higher capital costs can be offset by operational and even tax benefits. While not a panacea, modular construction can be a great choice to meet a facility’s needs, but only after a thorough review of the costs and benefits.

	Eric Bohn is partner at JacobsWyper Architects, 1232 Chancellor St., Philadelphia, PA, 19107, tel: 215.985.0400.


	When referring to this article, please cite it as E. Bohn, " Deciding When To Use Modular Construction," 

Different types of modular systems have advantages and disadvantages.

Deciding When To Use Modular Construction

Right-sizing implies operational effectiveness and efficiency. Since the 1980s, the phrase has been used in management circles as a euphemism for layoffs, but in facility design, right-sizing can be a euphemism for minimal cost. Flexibility, on the other hand, is about having the capacity to adapt to future changes quickly and easily. Flexibility, however, typically requires an investment in infrastructure. At their most extreme, these two ideas are at opposite ends of a facility-design continuum.


	The idea of “right-sizing,” when applied to design, is to create an optimal facility. An example is found in the best practice recommendation of designing for actual equipment loads instead of the traditional method of estimated loads (1). Without the data of real loads, the practice of estimating results in oversized systems that increase energy and operational cost. But at what point is the glove’s fit tailored too tight? Experience has established that--in the pharmaceutical industry--change is inevitable, making flexibility a necessary facility consideration. When building a facility, it is wise to build in some accommodation for future modifications. Anticipating the future can be daunting, but experience proves that it is prudent to try.

	To effectively tailor a design for current needs, while at the same time planning for future potential, the different types of change that may occur must be considered. The most obvious potential change is increasing the manufacturing capacity to meet demand for the current drug portfolio. This change will require more and/or larger equipment of the same type as already exists. Another consideration is how new products will be introduced to the facility. Over the long haul, the ability of a facility to adapt to changing market and business conditions ensures its value far into the future. Inevitably, this ability will require more than just adding similar equipment, and new and different technologies will need to be accommodated.


	In all cases, at a minimum, drug manufacturing facility owners need to allow for additional space. Planning for more space can be as simple as laying out a facility so that the manufacturing area has a direction in which to expand, such as into a warehouse or to the exterior into a future building addition. Key to effective growth, however, is having a strategy for internal circulation, with a sound way for materials and personnel to access the future area. Because continuity is harder to achieve if it has not been planned, a good place to start is ensuring that the current manufacturing circulation (i.e., the flow of materials and personnel) can be extended directly into the future area. While the exact use of the future space may be unknown, the need to get personnel and materials in and out in a way that is operationally effective and compliant is certain.

	Over time, the drive for greater manufacturing efficiencies and capabilities leads to new equipment. All equipment has a limited useful lifespan. In addition, drug reformulation can demand additional or modified equipment, and new products and their processes may be added to an existing portfolio. A facility design should allow for the removal of existing equipment and the installation of new models. Dimensional clearances and movement pathways need to be integrated into the design. Without such a mindful approach, equipment may become inaccessible, and changes may require major interruption of ongoing operations.


	Planning for additional space and new equipment is relatively easy to implement. A greater challenge, with greater cost burden, is planning for future utilities and services. Again, smart strategies need to be applied. Near-term flexibility can be provided by a thoughtful approach to system distribution. For example, service mains can be installed and sized so that local distribution can be easily added in the future. If judiciously done, this oversizing of a system can, for little upfront cost, provide for relatively easy and efficient growth in the future. In some situations, however, extending the current system may not be the right approach. If not, a strategy for future utilities still needs to be developed. One strategy is to plan a pathway and space for new mains and distribution to be installed later. Another strategy is to make a decision to develop a separate system in the future. In any case, it is better to build in a strategy at the beginning than to be without options later.

	The greatest cost potential is in the generation of overall utility capacity, which is typically a longer-term consideration related to an expanded manufacturing footprint. Using modular equipment that can provide phased growth is a strategy that has found much success. Admittedly, this will not work for all systems, but it can work for many. Such an approach enables spending only what is required and delaying future capital expenditures until they are actually needed. Another option is purchasing extra capacity up-front by way of oversized equipment, thus anticipating the future need for increased capacity. You can ignore this possibility by rationalizing, “if we are that successful, we’ll deal with it then,” or you can develop a strategy that affords flexibility and a relatively quick and easy response when needed.


	Right-sizing is more than responding to the immediate, foreseeable requirements of a facility. To optimize a design, there needs to be a prudent investigation of the potential for growth. With right-sizing, as the phrase implies, one size does not fit all. An approach needs to be crafted appropriate for the situation and the potentials that exist for a facility. Right-sizing is about finding value, the sweet spot where design, management, and operational considerations are balanced and deliver a quality facility for an appropriate cost. Finding the “right size,” involves the creation of an efficient design with an appropriate amount of flexibility.


	1. US Environmental Protection Agency, 

Laboratories for the 21st Century Best Practice Guide: Right-sizing Laboratory Equipment Loads 


	Eric Bohn is partner at JacobsWyper Architects, 1232 Chancellor St., Philadelphia, PA 19107, tel: 215.985.0400, 

:
	When referring to this article, please cite it as E. Bohn, "Flexibility vs. Right-Sizing: Determining the Right Facility Size," 

Choosing the right facility size requires tailoring the design for current needs as well as anticipating the future.

Flexibility vs. Right-Sizing: Determining the Right Facility Size

Traditionally, room pressurization is considered a heating-ventilation-air conditioning (HVAC) issue. It is well known that air pressure is a matter of balancing the quantity of air supplied into a room against the air exhausted. By regulating the relationship between the two, either a negative or positive pressure can be developed and maintained. What is often overlooked, however, is the integrity of the “container” that holds the pressure. If the room is not tight enough, air leakage will result, and the desired pressure will not be maintained. As the phrase “container integrity” implies, any penetration of the interior surface of the room is a potential problem. This article addresses how to handle some of the most common causes of pressurization failures.


	To be functional, it is necessary for every room to have a door. These wall penetrations are intentional and planned. In fact, for a door to work, air leakage is a necessity. If a swinging door is airtight, then the pressure on the door will either prevent it from opening or, depending on the direction of air flow, it will never close. The amount of air passing through a door, however, can be calculated. It is standard design practice to integrate this anticipated leakage into the capacity of the ventilation system within a cleanroom. While it is always necessary to consult with an engineer, the usual practice is to provide seals on the sides and top of the door while leaving the bottom of the door (the undercut) open. This approach provides a great deal of control over air flow and the influence of doors on the air system.

	To facilitate the movement of materials in and out of GMP spaces, large openings are required. In the past, this was achieved using bi-parting, swinging doors. Today, it has become commonplace to use high-speed, fabric roll-up doors instead. Roll-up doors are complex devices with many parts, and they present difficulties in achieving predictable levels of leakage. Manufacturers have responded to this need, and today some manufacturers make fabric doors that are pressure-tested and purpose-built for GMP installations. Having a known leakage value allows an air system to be designed with adequate capacity. Only those doors that have a tested leakage value should be used.


	It is in the room enclosure itself, however, where difficulties regarding pressurization usually arise. The most common type of commercial ceiling is a 2 x 4-ft. lay-in panel. Such a ceiling can be acceptable in less critical GMP spaces, if a vinyl-faced, cleanroom tile is used and is placed in a gasketed suspension grid. Gypsum wallboard ceilings, however, are obviously more monolithic and present significantly less opportunity for leakage. In contrast, every 2 x 4-ft. ceiling panel has 12 linear feet of perimeter, and every inch is a potential location for a leak. A gasketed grid begins to address this situation, but it is still necessary to ensure that the gasket is fully engaged in all locations. A heavy, gypsum wallboard ceiling tile is a good choice, and the use of hold-down clips provides even more reassurance, especially when the room is positively pressured and the ceiling tiles are being lifted by the pressurized air. In any case, for more demanding applications, a solid gypsum wallboard ceiling should be used.

	Regardless of the type of ceiling specified, light fixtures need to be appropriately selected, including consideration for room pressurization. Fixtures that are not intended for GMP application have numerous holes, which create opportunities for air to pass through the housing and be exchanged with air in the plenum above. Even with a sealed GMP fixture installed in a gypsum ceiling, leakage can occur at the perimeter where the housing meets the gypsum board. Ideally, this joint is caulked. This detail of sealing devices directly to the gypsum wallboard should be applied to all penetrations, including process piping and equipment. Even when these are installed with an escutcheon plate, which provides protection around the joint, it is important to also caulk around the plate to create a seal tight enough to resist the passage of air.

	It is not just ceiling penetrations that can compromise a room’s containment. In a typical facility, there are probably more penetrations in the walls than in the ceiling. Besides equipment and process piping, common penetrations from devices located on the walls include electric and data outlets, fire and security devices, light switches, human-machine interfaces, and utility drops of all sorts. Power and data outlets are perhaps the greatest obstacle to achieving a tightly sealed room. There is no such thing as a GMP back-box, and conventional back-boxes are designed with perforated tabs that are removed to accommodate a multitude of wiring configurations. In addition, there are no seals where the wiring enters the box. The result is that, under pressure, a large quantity of air can pass through these boxes. Retrofitting them after they are installed and wired is a difficult task. One approach is to install a gasket under the face plate. However, one must be sure that the socket or switch that protrudes from the faceplate is, in fact, sealed. The most comprehensive strategy is to specify waterproof devices. The gaskets and seals that prevent the intrusion of water also prevent excessive air leakage.


	Room pressurization is about more than just balancing the HVAC system. The quality and integrity of the room enclosure must also be considered. Achieving a monolithic enclosure is not as easy as it might seem at first. The materials of construction need to be considered, and the various types of penetrations must be identified and understood. For each type of penetration, an appropriate strategy has to be developed. In some cases, a special product or accessory can be specified, but in many cases, the only way to maintain a tight seal is to field caulk. To do this effectively, knowing where holes are found is paramount. By taking the time to investigate and address these common conditions, room air leakage can be controlled and a room can be successfully commissioned for the production of pharmaceuticals.


	Eric Bohn is partner at Jacobs Wyper Architects, 1232 Chancellor St., Philadelphia, PA 19107, tel: 215.985.0400, 

:
	When referring to this article, please cite it as E. Bohn, "Preventing Room Pressurization Failures," 

All openings and potential apertures for air penetration must be considered when designing a cleanroom so that the HVAC system can maintain the desired negative or positive pressure.

Preventing Room Pressurization Failures

The operating expenses of a biopharmaceutical manufacturing facility are significant and contribute directly to the cost-of-goods sold, thus management is always looking for ways to reduce operating expenses. Recent efforts have focused on the savings that can be realized from closed processing, especially single-use technologies, when combined with a reduction in room air classification.  This article presents a case study for an existing, cell-based manufacturing process where isolators were added and room spaces were downgraded from Grade A or B to Grade C, as defined by the European Union’s 


	This case study assesses the compliance risks and cost benefit (i.e., return on investment) that resulted from changing the classification of a suite of rooms containing a biological process. Except for two specific, open procedures, the processes involved were all closed, aseptic operations. The facility was a 3600-ft

 processing suite composed of two, 21-ft x 16-ft Grade A processing rooms with full laminar-flow ceilings. The existing open processes within the two Grade A rooms had to be executed under aseptic, laminar air environments. These rooms were surrounded and supported by a series of Grade B spaces.

	The renovation created a single Grade B suite that supports two Grade A isolators for the open processes. This renovation allowed downgrading of the rest of the 3600-ft

 summarizes the square footage change and shows that more than 80% of the space was able to be downgraded.

			Table I. Renovations to a biopharmaceutical processing suite.			

	To make these changes, modifications to the physical plant were required. Four existing rooms were reconfigured to create a single, 330-ft

Grade B room to house the two isolators and their processes. Separate personnel entry and exit airlocks as well as a separate material airlock were built to provide access to the Grade B room. The two existing Grade A laminar flow rooms were maintained as they were, but their air change rates were reduced and requalified as Grade B space; this strategy was chosen to save construction costs and to allow the potential for the rooms to return to a Grade A air classification if required by a yet unidentified future process. All the remaining spaces were downgraded to Grade C without further modifications.

	The construction cost for this work was quantified by an experienced construction manager at $150,000. The cost of the isolators were provided by the owner at $700,000 each.


	Based on the new room configuration, the reduced air classifications, and the revised procedures supporting the changes, the team analyzed the annual savings that could be expected, as follows:

		Deletion and downgrading of gowning requirements eliminated more than 10,000 gownings during a single year, which translates to $136,000 savings from gowning supplies.

		The cleaning regime for the lesser-grade spaces provided a savings of $75,000 in supplies.

		The reduction in gowning time and transferring of materials into the higher-grade spaces provides a labor savings of almost 3200 hours or $130,000.

		Reduced environmental monitoring, both of the spaces and personnel (i.e., gowns and gloves), eliminates 2800 tests a year for a savings of $530,000.

		The projected annual savings from the reduction in utility demand was calculated at $143,000.

 shows that the total sum of the savings is just over $1 million a year. The cost of environmental monitoring, especially for gowns, is the single largest savings by nearly a factor of four.

			Table II. Savings resulting from room declassification.			

	As discussed, there are investment costs before any operational cost reductions can be realized. The capital cost to modify the facility and purchase new equipment must be taken into account. 

 shows the cost needed to create the new isolator suite, rebalance the new air classifications, and purchase two new isolators.

			Table III. Capital cost of renovating the facility.			

	This study did not identify costs required for requalification of the new room classifications. Comparing 

, however, the hard costs of equipment and construction, when considered by themselves, return their value in 18 months. In addition, there are operational savings in terms of time, which result in greater efficiency and have the potential to be converted to more production capacity and the corresponding additional revenue. 

	The company that undertook this study recognized that substantial costs were unnecessarily being spent on maintaining Grade A and Grade B spaces. By evaluating the process, doing a risk assessment, and reconfiguring the space appropriately (including right sizing of critical spaces), the majority of the cell-processing area could be successfully downgraded to Grade C. The key was defining the area where open processes occurred and moving these into closed-process isolators.

	The savings potential for other facilities begins to become apparent when you consider that in this example, a 3600-ft

 facility returned $1 million in cost avoidance annually. For a larger facility where the process allows similar improvements, it is reasonable to expect even greater returns. Unless a facility is being built new, an upfront capital investment will be needed to make the necessary modifications, but the return on investment could still be worth it. In addition, there is a potential advantage gained in operational time. The 3200 hours saved here is equal to 1.5 FTE (full-time equivalent) over the course of a year. These hours are made available for other, more productive activities and can help drive the facility towards greater efficiency and higher productivity. This case study demonstrates the multiple benefits of striving towards closed processing. By understanding the process and appropriately providing protection where needed, substantial operational savings are possible.

EudraLex Volume 4: Good Manufacturing Practice Guidelines

, “Annex 1, Manufacture of Sterile Medicinal Products” (Brussels, 2008).

, 1232 Chancellor St., Philadelphia, PA 19107,  tel: 215.985.0400. 

 When referring to this article, please cite it as E. Bohn, “Generating Savings from Room Declassification,” 

Creating closed processes and reducing room air classification in a biopharmaceutical facility can reduce operational costs.

Generating Savings from Room Declassification

	When designing a facility for pharmaceutical manufacturing, a foremost consideration is preventing product contamination. International GMP standards talk about contamination in terms of contamination of the product itself and cross contamination between   different products and batches. In production areas, especially where the product is exposed, the environment needs to be tightly controlled and clean. A significant aspect of this cleanliness is control of particulate by way of room air filtration. This technology is well known and codified in several widely used standards, primarily International Organization for Standardization (ISO) 14644-1 (1) and, for the manufacturing of sterile pharmaceuticals, 

, Volume 4, Annex 1 (2). Other factors besides air classification impact the potential for product contamination and production area cleanliness, and these are embodied within the concept of clean zones, which is defined in general terms by the International Society for Pharmaceutical Engineering (3) and ISO (4). The following factors must be considered when establishing a strategy for levels of cleanliness in a facility.

The most obvious concern when establishing zones of cleanliness is control of airborne particles. Within a space, particle sources that represent potential contamination include the process itself (materials and equipment), the people, the garments being worn, and the pace at which activities are undertaken. Particle control is obtained through filtration and air changes. Filtration (typically using high-efficiency particulate arrestance [HEPA] filters) ensures that clean air is entering the room. Besides providing the room with a constant supply of filtered air, the clean air can also be directed over specific operations within the space. Air changes eliminate particles by exhausting contaminated air and allowing clean, filtered air to fill in behind it.

 Pressurization is a method of dealing with the transfer of contaminates to adjacent spaces. It can be understood as the direction that air flows between spaces. Positive room pressure ensures an outward flow of air away from and protecting a critical production area. Negative pressure provides airflow into production rooms. If the intent is containment, then negative pressure is preferred. Negative pressure is most often used when dust is present in the operation or in multi-product oral solid-dosage facilities where containment keeps product residue from leaving one area and contaminating adjacent areas. Positive pressure is typically used to protect product, such as in aseptic processing where it keeps foreign material away from the sensitive area. Sometimes, such as with vaccine production, positive pressure is necessary to protect the crucial production area while, relative to the larger environment outside of production, the area must simultaneously be negative. In this way, the crucial process is protected while containing the biologically active agents and thereby protecting the environment outside of production.

 Gowning has several functions. First and foremost, it is about protecting the product. The human body is continually generating particles through hair loss, shedding of dead skin, exhalant, and saliva. Of the potential sources of contamination in cleanrooms, people generate the most, and greater activity increases the release rate of these contaminates. Gowning (i.e., the covering of exposed hair, skin, and, in some cases, the nose and mouth) contains contaminates and protects the production area from the operators. When working in such areas, residue can collect on the exposed surfaces of the gowning materials. If personnel enter other areas, the residue can be transferred, thus causing cross contamination. Gowning procedures can keep these contaminates from passing between adjacent spaces by requiring disposal of used gowns and re-gowning before entering another production area.

 Closely related to gowning and the prevention of cross contamination of adjacent spaces is the application of unidirectional flow of people, material, equipment, and waste, which occurs when progress through a plant proceeds in a linear manner such that there are segregated entry and exit sequences through the critical production areas. Unidirectional flow ensures that these areas are entered only once before leaving. A simple illustration is found in personnel flow. The entry is highly controlled and occurs only through a locker room or gowning sequence. Once entering a crucial production area, personnel leave through a separate exit and de-gown. The gowning, which has been exposed to contaminates, is discarded, thus ensuring that surface residue cannot be transferred to other spaces. To enter another production area, the operator must re-gown appropriately for the next space. In a unidirectional flow facility, this linear movement is applied to the various categories of flow, including material, equipment, and waste.

Transition spaces are closely related to and often confused with gowning rooms. While they are frequently the same space, their purposes are independent. Transition spaces are used to achieve proper pressurization and to maintain the integrity of zones of different classification. When these can also be used as gowning rooms, a high degree of efficiency is achieved. In a sequence with cascading pressure, passing through two interlocked doors of a transition space ensures that the production area maintains its overall pressurization. In addition, transition spaces can be positively pressured to create a pressure bubble or negatively pressured to create a pressure sink. Depending on the specific layout and needs of the facility, these are tools that can help protect the crucial production area ensuring appropriate containment.

To maintain the functionality of production spaces, routine cleaning is a crucial activity. The type of drug product, its exposure within the room, and the cleaning processes dictate the appropriate procedures. Cleaning activities can range from simple vacuuming and wipe down to robust hose-down and even fumigation. The agents used and the severity of the washing activity control the choices of room and equipment materials and finishes. To withstand these procedures, the interaction with the finish materials must be evaluated and appropriate selections made. Virtually all production spaces generate at least a few tools and equipment that require cleaning in dedicated washrooms. Where to locate these dirty processes in relation to crucial production and how to return the clean materials is a significant consideration in maintaining the cleanliness of a zone. Washrooms need to be integrated into the establishment of the cleanliness zones.

 The final consideration and perhaps the most important, because it informs all the others, is quality risk management. Evaluating the quality risks within each of the factors discussed facilitates informed and evidence-based decisions. The current standard recognized by FDA and globally is International Conference on Harmonization (ICH) Q9 

. The methodology described in this standard makes possible the disciplined identification of actual areas of risk as opposed to assumed or perceived risks. It provides a high level of assurance that potential risks are dealt with effectively. While facilities were previously developed using a number of rules of thumb and commonly held beliefs, today there is a growing demand that this disciplined approach be used.

	The prevention of product contamination is a primary concern in the design and operation of pharmaceutical manufacturing facilities. To support and protect the multiple stages of manufacturing, it is necessary to have clearly defined zones of cleanliness. Applying the factors discussed in this article can create hygiene zones that provide varying levels of product protection. The establishment of each zone needs to be appropriate for the processes, product exposure, and risk of contamination that are present. Central to instituting zones that meet these needs is the application of quality risk analysis. In today’s regulatory environment, rules of thumb are no longer adequate. By carefully evaluating the needs and risks inherent in the process being maintained, hygiene zones can be properly applied. The result is a greater assurance of product quality while simultaneously optimizing productivity and the cost of goods.

Cleanrooms and associated controlled environments-Part 1: Classification of air cleanliness

Volume 4: Good manufacturing practice Guidelines

 “Annex 1, Manufacture of Sterile Medicinal Products,” (Brussels, 2008).
	3. ISPE, "Glossary of Pharmaceutical and Biotechnology Terminology," 

Cleanrooms and associated controlled environments–Part 6: Terms and Definitions 


	Eric Bohn is partner at Jacobs Wyper Architects, 1232 Chancellor St., Philadelphia, PA 19107,  tel: 215.985.0400, 

 When referring to this article, please cite it as E. Bohn, “Designing Clean Zones,” 

Clearly defined zones of cleanliness must be designed and maintained to prevent product contamination.