Kevin L. Healy, TAC Precision Environments Group
I’m willing to bet that I can identify one characteristic that every reader of this article has in common. And, no, it’s not that you all read Cleanrooms magazine. It’s that every one of you has benefited from pharmaceuticals at least once in your life.
As consumers, we typically don’t perform extensive research studies on each drug we take. Instead we trust our doctor, who in turn puts his or her trust in the pharmaceutical company that manufactured the substance. This article will explore how these companies accomplish the safe, consistent and high-quality production of pharmaceutical products by reviewing some of the key points in the design and delivery of aseptic cleanroom projects, where some of the most critical quality-control measures are implemented in drug manufacturing processes.
Without thinking too much about it, we should all know that the greatest potential source of contamination in a cleanroom is ourselves. When we enter a cleanroom, we not only bring in contaminants on our clothing, but every time we breathe, sneeze, sweat, walk or simply stand still, we contribute to the contamination levels in the room. Take a look at Table 1 to get a better understanding of the potential impact humans have on contamination levels in a cleanroom.
And this is just the viable particle generation of airborne particles. This is what drives the HVAC design criteria relating to the number of air changes required to maintain the proper particle counts in the cleanroom. Table 2 shows the microbial contamination that humans can contribute. This is another reason for the HVAC system to address airborne particulate. It is also one of the biggest drivers of architectural finishes to aid in the cleanability of the room respective to microbial growth.
In an ISO Class 5 area (a typical setting for aseptic processing), guidelines state that the air quality must contain no more than 100 particles of 0.5 μm and larger per cubic foot and must contain less than 0.1 CFU per cubic foot. This is further detailed in Table 3, which demonstrates a comparison between the old Federal Standard 209E and current ISO 14644 standards, with additional reference to EU guidelines.
Application of standards
As consumers, we can take some comfort knowing the standards outlined in Table 3 are in place and being enforced by quality assurance teams and independent authorities such as the FDA. As with any standard or guideline, a plan needs to be created and executed to deliver a cleanroom that will effectively meet those standards. This brings us into the meat of this topic as we explore how to properly design and construct these mission-critical aseptic cleanrooms. This effort is not performed in a vacuum: There are guidelines available such as the ISPE baseline guide to sterile manufacturing facilities. But, as with any guideline, there are many gray areas subject to customer-specific applications. Naturally, these are maintained as guidelines because each and every process and application is different and each company deserves the opportunity to design their facility to meet their unique needs most efficiently. There are, however, key success factors in all aseptic cleanrooms.
There are a host of choices that have proven successful in achieving quality aseptic detailing. Whether you choose prefabricated modular, conventional site construction (stick-built), or a combination of both, you need to incorporate the following core details to maintain cleanability and contamination control.
■ Minimal corners and crevices: This aids in the cleaning process and minimizes areas for dust collection and microbial growth. Remember, in an ISO 5 cleanroom you cannot have more than 0.1 CFU/ft3. This requirement includes all wall-to-wall, wall-to-ceiling and floor junctions. The most widely used solution to this challenge is to create a radius cove at these junctions. Wall-to-wall and wall-to-ceiling junctions can utilize an applied coving, as in stick-built configurations, or an integrated coving available with some modular systems. The key with the applied coving is to properly seal the exposed joints. Flooring can be built up and coved to match the wall and ceiling coving.
■ Flush integration of accessories and equipment: As with the above coving requirement, if the integrated equipment and accessories leave a ledge or crevice where material can collect, then proper cleaning of the space becomes more difficult.
■ Chemical resistance: It is necessary to utilize some potent chemicals in order to kill any microbial content. This value will vary from process to process depending on the customer-specific cleaning protocol. Typically, a customer will utilize some type of strong oxidizer such as the trade brand SporClenz or Deconspore. Isopropyl alcohol (IPA) is also used in the process and is often a daily wipe-down agent. Regardless of the customer process, the specific chemical cleaning process must be specified prior to selection of architectural finish. The most typical finishes are composite materials found in modular construction, such as PVC steel or high pressure laminates (HPL), or surface-applied finishes adhered to the gypsum board surface in stick-built configurations. It is also feasible to apply quality epoxy paint in situations where the chemical wash-down process is not that aggressive.
■ Minimal airborne particulate generation: This relates back to the room finish material. The goal here is to select a material that will meet your chemical resistance needs and also not off-gas or shed particulate. From a risk standpoint, the safer selection to implement would not contain materials that would become airborne when scratched or punctured. Most modular systems offered for aseptic applications utilize an aluminum honeycomb core and surface finish that will not become airborne when damaged. Surface-applied finishes, as used in stick-built constructions, also exhibit good scratch resistance, but if the wall is ever punctured by a machine, fork-truck or similar device, the gypsum board substrate can contaminate the space and require an HVAC shutdown, cleaning, recertification and revalidation.
HVAC design considerations
Like the concerns mentioned above, HVAC design must be addressed on a case-by-case basis. If the customer process is a contract manufacturing application where multiple products could be utilized, there are a number of solutions for keeping the products separated within an HVAC system. This section will focus on just one room in which one product process is performed.
■ Laminar flow: This requirement is based on the type of product being manufactured. Most often employed in parenteral applications, the current trend is moving toward barrier isolation of fill lines, eliminating the need for a laminar flow cleanroom ceiling and effectively removing the operator interface, which is, as we discussed, the biggest source of contamination in your process. If the project is of a smaller scale, it may be more economical and feasible from the standpoint of flexibility to integrate a laminar flow ceiling. These units can either be prefabricated or build-in-place. The main advantages of the prefabricated units are the ability to FAT the unit and the potential for better quality control. The component build-in-place units have the main advantage of lower cost compared with the majority of prefab units.
■ Non-laminar flow: If the process does not require laminar flow or if the design integrates barrier isolation technology, you’ll still require an ISO-grade HEPA-filtered air delivery system. The filter location will be at the ceiling and can be disposable or room-side replaceable. The main advantage of room-side replaceable filters is the ability to remove a filter without compromising the integrity of the room as it is sealed to the surrounding environment. This saves time and money when the room is brought back on-line after filter maintenance. This convenience has a cost, as these filters can be as much as triple the cost of the disposable variety. One way to properly select the appropriate filter type is to evaluate the impact of having to completely recertify and revalidate the space over the expected lifecycle of your filter maintenance program.
Table 1: Cleanroom contamination from humans
■ Low wall returns: The employment of low wall returns is encouraged in all ISO cleanroom levels implemented in aseptic manufacturing. In this application, you have a variety of options for effectively implementing a low wall return scheme. The amount of low wall space required is determined by the amount of air that you’re going to move in the space. With stick-built construction, your most feasible option is bringing ductwork down into the room and connecting it to a return grill on the room side. When utilizing modular construction, most systems are designed to allow use of the wall partitions as a means for air convenience, requiring only a duct connection at the ceiling level. Modular also lends well to the option for a raised return-air wall design. This allows for better cleanability of the floor area and potentially the return-air wall cavity. As a final note, return air can also require filtration with efficiency as high as HEPA to keep the return ductwork and overall HVAC system free of airborne product. This is very common in powder applications.
Table 2: Bioburden contamination from humans
■ Control system: The majority of new applications will tend to comply with FDA’s 21CFR Part 11 guidelines allowing for a paperless environment, although in some early-stage drug development, or very small-scale operations, a paper system may still be the most effective way of achieving regulatory compliance. Regardless of your choice, however, both methods require adherence to cGMP guidelines for installation, operation and maintenance. A paperless system nevertheless introduces a host of additional guidelines and standards, such as Good Automated Manufacturing Practices (GAMP4) and the ever-evolving 21CFR Part 11 regulation for electronic signatures. This is where teaming with a good controls partner can prove invaluable.
Table 3: Environmental requirements for sterile medicinal products
You have a number of options for getting your room built effectively. The traditional design-bid-build method, Design-CM @ Risk, and Design-Build are some of the most recognized options. Each method has its advantages and defines a certain risk profile. The basic points that need to be considered when evaluating the different options are as follows:
■ Project size: This takes into account the staff the customer has to dedicate to project delivery, the number of tasks that need to occur for successful delivery, and timeline for delivery.
■ Cost management (risk): This consideration goes hand-in-hand with the risk profile that you assign to the project. Based on the level of risk that you introduce to the project you need to look at project ownership. Design-bid-build puts risk on the design, but the main risk element is translation of the design intent from whoever is in charge of the bidding process. Design-CM @ Risk helps reduce the risk incurred during the bidding phase, but still leaves the door open for conflict between the designer and CM. Design-build puts the responsibility for design and execution on one entity, removing the potential for conflict between design and execution.
As we all know, pharmaceuticals are used for more than curing an occasional headache. They are a means to improve and save lives. As contamination-control professionals, we have an obligation to abide by the latest standards established to ensure that the quality and availability of these products remains consistent. This article has examined some of the high-level considerations when working through options for project execution. Additional contributing factors are on a project-by-project basis.
Kevin Healy is a sales engineering manager for TAC’s Precision Environments Group. He has a master’s degree in engineering from Drexel University and has been serving different facets of the life sciences industry for eleven years. TAC Precision Environments specializes in the design and construction of controlled high-precision rooms, such as cleanrooms, metrology, nanotechnology and specialty labs. Mr. Healy can be contacted by telephone at (610) 716-9941 or via e-mail at [email protected]