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By Scott E. Mackler, Clestra Cleanroom, Inc.

Often the most challenging issue in facility design and construction is the lack of firm process knowledge. Often the procedures are new, and will only be truly tested after the facility is in use. Therefore, all layouts are predictions—and most predictions are inaccurate. In 1986 Louis Sullivan, the Chicago high-rise designer wrote, "Form ever follows function." I think that Winston Churchill really hit the nail on the head (no pun intended) with his quote "We shape our buildings, and afterwards our buildings shape us."

Pharmaceutical facilities must be designed around the process, and the superordinate goal is a facility that "meets or exceeds the specification." It is in the conceptual stage of the project where the greatest impact on cost can be made. As cleanroom designers and builders, it is in the conceptual stage where we normally begin working with an owner, and/or the owner's representative, to develop an optimized facility. In this preliminary planning stage, modular construction offers an advantage in the preparation of accurate budget estimates. Input for the owners cost model will not vary significantly from programming through commissioning, given relatively consistent scope.

The recently released for review ISPE Baseline Guide for Sterile Manufacturing Facilities asks these questions in its Appendix 3, Section 4:

At what point does the product become sterile? How does it enter the aseptic manufacturing area? At what point is the product exposed to the environment? How is the product placed into its final enclosure? Does the product have to be transferred in its final enclosure before it is sealed? How is the product protected until it is sealed? At what point is the product considered sealed into its final enclosure? How does the product leave the aseptic manufacturing area?

Do the components need washing? Do the components need sterilization? How do the components enter the aseptic manufacturing area? Do the components need cooling in the aseptic area? How are the components fed into the filling machine? How is the sterile stopper bowl protected, where is it located? How are the components handled after filling and sealing?

At what points in the process do the operators intervene with the product? At what points in the process do the operators intervene with the product's contact components? How are the components and product transferred and handled within the aseptic manufacturing area? How many operators are required in the preparation area? How many operators are required in the aseptic manufacturing area? Where will operators stand in the aseptic area under normal operation?

What type of washing equipment is used before sterilization of components? What type of sterilization equipment is used to transfer components into the aseptic area? Is any accumulation of sterilized product final enclosure required? Do any parts of the equipment produce large amounts of particulate loads (will this be considered "background", what are the particulates, are there any OSHA regulations that must be considered}? Do the equipment items which have exposed sterilized components or product need regular operator intervention? How is equipment maintained, is it from within the aseptic area or from outside the area?

What other items need to enter the aseptic manufacturing area? How do other items enter the aseptic area? Is there any storage requirements of product contact parts (machine parts, filters, etc.) within the aseptic area? Cleaning sterilization regimen? Required hours of operation of the facility?

It is amazing how many times we are asked to quote, or even design and build a facility, before the questions above have been answered. In some cases, it is not even known that these questions need to be asked!

The good news is that with the ability to re-arrange, expand, provide external to the envelope maintenance access and even relocate, the owner of a modular facility will have the versatility to adapt to changing process and product requirements quickly, systematically and cost effectively.

Nonprogressive, demountable wall panels provide for flexibility in moving equipment in and out of rooms, particularly where such equipment may be too large to pass through standard size doors. With no vertical or horizontal members or studs anywhere in the controlled area envelope, maximum flexibility is clearly ensured and bulkhead mounting of any shape or size of process equipment is feasible.

If the following listed minimum Facility Conceptual Design Elements are not extant at the time we are first inquired, then we must first establish a Basis of Design Document (BOD) consisting of:

Process Description and Process Flow Diagrams cGMP Floor plan and General Equipment Arrangement Sized Major Process equipment List with Utilities Requirements/Consumption Sized Process Support Services Utilities List (e.g. WFI, etc.) Functionality Flow Diagrams (process, people, product, material, components, waste, directionality of air flows) HVAC zoning and room classifications including microbial limits Budget-quality (±20%) cost screening estimate w/preliminary "Scope of Work" Matrix

After completion of a BOD, and assuming that we do not have to go back and do significant "value-engineering" (although at least now we have a rational, analytical basis for value -engineering) then we can proceed into generation of the elements of modular systems detail design:

Pre-Engineering: This terminology is often misunderstood. In the pre-engineered facility we focus on customization and optimization to meet process requirements (e.g. equipment placement & integration) and building and site constraints, as the individual components and details required to meet performance specifications and cGMPs already exist as proven, reproducible, matched solutions. Pre-engineering for these complex facilities provides the owner maximum control over content, cost and schedule.

In pre-engineering, cleanroom classification, pressure level, temperature, relative humidity, room layout and selection of components are finalized, and certification prints are generated for approval by the owner and for regulatory authority comment (typically the pre-construction design review) prior to initiation of fabrication. Layouts for regulatory review must designate, as a minimum, airflow direction in critical and controlled areas, pressure differentials for each adjacency and again, the functionality flows.

Plans for the qualification of facilities, equipment, HVAC, computer controls, process support services and the validation of the actual processes should be an integral part of the preliminary design specifications and all constructability reviews as well.

Modulation, a design development activity, ensures that the minimum number of different size panels are selected and that the largest feasible panel size is utilized. The objectives of the modulation exercise are to get economy of scale in manufacturing and to minimize the number of joints. Also, panels are typically specified in integral multiple sizes, to achieve maximum re-arrangement utility.

When modulated optimally, ceiling tracks for the wall panels mate with the post caps between the ceiling panels, and expansion or re-arrangement of walls is completely independent of the ceiling.

Pre-Fabrication:As stated earlier, unlike conventional construction which must follow, by its nature, a much more sequential time line, much of the pre-engineered facility can be fabricated offsite concurrent with site and building preparation, thus shortening schedule time.

Pre-Testing:In process quality control and factory run-in of all prefabricated systems and components under load helps to eliminate the long debugging process associated with field erected custom or built-up HVAC equipment. The use of proven, matched components means that the field is not necessarily the first time that the HVAC system is brought together in the project specific configuration.

Packaged HVAC units can be ETL (Engineering Testing Lab) or CE marked, assuring the owner that third party independent quality and safety checks have been performed.

The need for flexibility, prevention of cross contamination and the requirement for individual room pressure, temperature and humidity control often results in a more costly HVAC system for biotechnology facilities versus the classic large volume systems commonly applied in the typical chemical-based pharmaceutical facility. Most biotechnology facilities consist of several suites, each made up of multiple small rooms.

Generally, the closer that the HVAC equipment can be located to the processing areas, and the smaller the volume of 100% once-through air, the lower the installed cost. Pre-engineered, pre-fabricated, pre-tested packaged double-wall HVAC equipment—having a relatively small footprint—often provides an advantage in this application. Most packaged HVAC units today utilize direct drive variable frequency control plug fans, lending flexibility to the initial placement orientation and making post-installation balancing easier and faster.

Also, 100% once-through outside air containment facility applications require more extensive MUA pretreatment than that needed for recirculating type systems. Outside air intakes should be located on the side of the building exposed to prevailing winds and all ductwork should be leak-tested in-situ. Individual room pressure control is typically provided by variable frequency direct drive-controlled exhaust fans, with all of the room exhaust receiving HEPA filtration before discharge into the atmosphere.

When multiple small HVAC units are used, a central station PC-based operator interface for control and monitoring must be provided. This interface should support full graphics, system start/stop and status, and access to individual zone devices and environmental conditions. The computer must also provide PID settings for all control loops and mechanical devices including the ability to change setpoints, view actual outputs, force outputs for OQ protocol challenge tests and provide alarm management, data trending, report generation, remote monitoring, networking and data transfer.

In the design of controlled environments, the use of rounded corners and smooth surfaces to prevent dust shelving and facilitate cleaning, as well as the integrity of the atmospheric seal, are major concerns. Transitions from the walls to the floor, walls to ceiling, glazings and corner junctions must be rounded, completely airtight and smooth. All surfaces must be impervious to moisture, bacterially inert, chemically resistant and non-particle shedding. These are the pivotal criteria for the elimination of areas that may harbor microbes.

Prefabricated cGMP steel wall panels are far more appropriate for cGMP facilities than conventional gypsum board style construction. Gypsum board on stud walls are not impermeable to moisture, and over time the gyp board inevitably shifts on the stud and cracking occurs. With daily cleaning, solutions will permeate the gypboard and create a non-validatable condition. And unlike concrete masonry unit construction, technical access for process support services is provided within the modular wall system postcap junction, permitting the chasing of small diameter piping and process and convenience electrical, computer cabling, etc., throughout the entire cleanroom envelope—both walls and ceilings—at each and every juncture.

Clestra CP-3 Cleanroom Wall provides maximum flexibility for redesign.

No exposed piping or conduit is permitted in a GMP facility and this built-in chase system will save the owner time & money during installation and in the future, when it will inevitably be necessary to add additional process support services. Pre-fabricated steel, or stainless steel panels—with integral utility chases—eliminate the mystery of trying to find services that have been "buried" in gypboard or CMU construction by the contractor during initial facility construction.

Details such as fully cleanable double wall return chases and technical access panels for areas with high densities of process support services are standard details that do not have to be redesigned from scratch each time. When utilized in a design/build facility delivery package, this pre-fabricated envelope system eliminates the finger pointing that so often occurs on so-called "plan and spec" projects between the architect /engineering firm that prepared the design, and the general contractor responsible for execution.

Prefabricated steel panels have been subjected to rigorous strength and durability testing including smoke and fire testing, immersion in various hydrocarbon solvents, bodily fluids and typical cleaning, disinfecting and sterilizing solutions including cationic surfactants, hydrogen peroxide, peroxyacetic acid, sodium hypochlorite, dilute Clorox solutions and sporocidin, all without noticeable effect.

We have seen recently some manufacturers in the US offering plastic coated panels. We do not recommend these as per Factory Mutual Engineering & Construction Loss Prevention Data Specification 1-56, "Fire retardant plastic panels should not be used in construction of clean rooms. Plastic increases the fuel available to fire within the room".

25 years ago in the Silicon Valley we began putting up so-called tilt-up metal buildings and populating them with modular vertical tunnel-type laminar flow cleanrooms. Today the same techniques can be applied worldwide to build cost effective pharmaceutical facilities. You don't need to wait 3-4 years and raise hundreds of millions of dollars to build a monument to God and mankind to get a product safely to market. Today, we can say: "Form follows Funding".

Consider a 4,000 square foot CGMP facility in $50 per square foot metal building. Contingent space is available for mirror image expansion. A project such as this can be ready for occupancy in as little as 20 weeks from design initiation (given an adequate BOD).

As I stated in the first article in this series, the successful design andrealization of a cleanroom or containment project will not happen by chance. The time spent in the preparation of as complete a "Basis of Design" as is practicable will be saved many times over during the actual implementation.

Modular systems technology encourages the use of rational optimization (benefit cost analysis) in facilities design. The manufacturing process should be designed first, independent of the facility, then development of the process flow and facility layout can proceed.

Modular systems construction is the favored route for fast track projects with tight deadlines and will be cost comparable with conventional construction, if early in the project the designer takes advantage of the features and benefits provided. Panelized construction will meet "build-clean" protocols with little extra effort.

Facilities are always asked to provide greater throughput and are utilized longer than originally anticipated. It is increasingly difficult to predict whether or not today's plant will meet tomorrow's facility requirements. The design goal today should be to provide the owner with future planned-engineered contingency. There is a universal rule - "All Buildings Grow" - and today, probably more money is being spent on changing existing facilities than on building new ones.

Modular systems provide the assurance that a consistent, worldwide reproducible standard is applied to facilities design and construction. The finished installation will meet the requirements of FDA validation and international cGMPs.

For more information: Scott E. Mackler, General Sales and Marketing Manager, Clestra Cleanroom, Inc., 7000 Performance Dr., North Syracuse, NY 13212-3448. Tel: 315-452-5200.

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