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

Eric Bohn

	Regulations addressing good manufacturing practices (GMPs) are a set of principles that are promulgated and enforced internationally by regional and national agencies. Within GMPs, the design of the physical plant is always addressed. One principal that is central to GMP design is ease of cleaning. For example, the European Union guidelines to good manufacturing practice states that in production areas, “interior surfaces (walls, floors, and ceilings) should be smooth, free from cracks and open joints, and should not shed particulate matter and should permit easy and effective cleaning and, if necessary, disinfection” (1). To illustrate and appreciate how cleaning impacts the design of a facility, this article will look at the selection and specification of a range of divergent products used in the construction of GMP manufacturing rooms. These products include high-speed roll-up doors, sprinkler heads, epoxy paints, and exposed pipe supports.
	
	


	High-speed roll-up doors have become a practical solution for openings that are required to accommodate the movement of materials and equipment. These doors are complex devices with a host of components and moving parts including motors and drivetrains. They are far from the ideal flush, smooth-surfaced mechanisms that are desired in a GMP production area. As an example, the tracks that hold the fabric, because of their configuration, are difficult to clean. For pharmaceutical-grade doors, these tracks, along with other hard-to-clean surfaces, are typically shrouded by stainless-steel covers that present an easily cleanable surface.
	
	The single largest and the most prominent component of a high-speed roll-up door is the fabric. In GMP environments, frequent and regular washing occurs with harsh, usually caustic, cleaning agents. To withstand constant washing, the fabric must be non-porous and compatible with the cleaning chemicals. Manufacturers usually provide several fabric options, and an appropriate fabric must be selected. Perhaps the most important feature of a roll-up door is the door’s ability to maintain room pressurization. In the past, these doors were not pressure tested and presented many problems when installed. Special and deliberate attention must be given to the design of high-speed roll-up doors if they are to be used in GMP production areas. Only doors with published test data can be relied upon to provide the sealing necessary to maintain room pressure.
	
	Besides proper selection of the product and its options, the details of the door’s installation is also important. Roll-up doors require an independent control box that is rather large and bulky. Where to locate this device, how to mount it, and concealing the wiring to the door within the walls cannot be overlooked. Due to this cabling, the controllers can be located remotely. One option is to place the control panel in the ceiling. Ceilings at this type of door, however, are usually high and hard to access. If a gypsum wallboard ceiling is necessary, then an airtight access door is also required and must be large enough to provide access. An alternative is to mount the controller on a wall near the door. If this option is selected, the panel should be placed on the “less clean” side of the door and installed in a manner that minimizes horizontal surfaces that require cleaning.
	
	


	Automatic fire sprinkler systems are devices that are virtually ubiquitous throughout every pharmaceutical facility; however, no sprinkler heads have been developed exclusively for GMP applications. Instead, standard models are used, and again, cleaning is an important consideration in their selection. In addressing this issue, there are two schools of thought. First, and perhaps the most common today, is the use of concealed, flush-mounted heads. The second approach is to use a common, pendent-type head installed with an extended escutcheon.
	
	Concealed heads present a visually clean appearance due to the near-flush condition they provide. These heads are actually recessed and a cover is installed that sits nearly flat against the ceiling. When the ceiling and cover are the same color, they present a near monolithic surface plane. In the event of a fire, the cover releases and falls to the floor, and the head activates. When cleaning the ceiling, only the cover is touched, leaving the sensitive head undisturbed. The criticism of this approach is that the recess and the head is not cleaned, and cleaning residue can build up between the cover and the ceiling.

	The alternative is to use conventional pendent heads but with an extended escutcheon. This was standard practice before concealed heads became commonplace. The reasoning behind the selection of an extended escutcheon is that it is easy to clean. The conical shape of an extended escutcheon results in the head being well below the plane of the ceiling. This configuration provides excellent access and visibility. The prominence of the head means it is easy to see and avoid. In addition, the visibility and range of movement about the head results in excellent access. It is this access to all sides that makes cleaning easy. The argument against this installation is Murphy’s Law; anything that can go wrong, will go wrong. In other words, if the heads are exposed, eventually they will be hit and the resulting water discharge is not worth the risk.
	
	


	The concern with paints in a GMP facility is that coatings that are usually used for interior construction will deteriorate if exposed to cleaning chemicals. Flaking and peeling paint is an obvious source of particulate, but an even worse scenario occurs when moisture gets behind the paint and promotes mold growth. Therefore the painting of walls, doors, and ceilings in GMP facilities needs deliberate consideration. Cleaning with harsh cleaning agents is a frequent activity, and conventional paints are not acceptable. In the construction industry, epoxy paints are specialty products commonly found in heavy industrial settings. If properly specified, however, they are a practical, relatively inexpensive solution for GMP production areas.
	
	Traditionally, epoxies have been solvent based. These products are extremely durable, but shortcomings include difficulty in working with them and the release of large quantities of volatile organic compounds (VOCs). Although acceptable when constructing a new facility, VOC release is not acceptable when the facility is already occupied. The fumes from solvent-based epoxies are substantial and hard to contain to the construction area. Complaints from plant personnel and increased sick leave are to be expected. Therefore, when working in an existing facility, a water-based product is the coating of choice. These paints are generally easy to work with and have substantially lower VOC content. Not all water-based epoxies are durable enough for a pharmaceutical application. One-component epoxies should be avoided. They are easy and fast to work with, but have the least chemical resistivity and likely will fail after a period of time exposed to a regular cleaning routine. A two-part, waterborne epoxy system should be sought out. Two-component epoxies cure by both solvent evaporation and chemical reaction. When the two components are combined, a cross-linking chemical reaction occurs, and the coating obtains a greater resistant to chemical exposure.
	
	


	Products for the support of piping and conduit have been available in the mechanical and electrical trades for many decades. However, the cleaning criteria integral to a GMP space renders conventional supports unacceptable. Personnel engaged in the design, maintenance, and operation of process systems understand this and rely on sanitary supports to provide easily cleanable conditions. Although these specialty products are readily available, they are not widely known and specified outside the process community. In addition, these supports are expensive relative to conventional alternatives.
	
	Many of the utilities that serve process equipment are provided by the base building systems. When base building systems enter a process room and the materials and fittings become exposed, their specifications need to change to allow for cleanability. Hangers and supports get little attention as part of base building systems, and they can easily be overlooked once they enter the process space. It is important to ensure that sanitary supports are used universally in GMP areas.
	
	These special products are available from several manufactures. They are specifically designed to minimize the accumulation of contaminants and are easily cleaned. Besides the housing that secures the piping, a rod is required to support and fasten the assembly to the ceiling, wall, or floor. In base building systems, this is typically achieved with a fully threaded rod. In a GMP environment, however, the threads are problematic because they collect contaminates. To address this issue, sanitary-hanger manufacturers provide rods and stanchions that eliminate the exposed threads.
	
	


	The previous examples illustrate how, when designing and constructing a facility, the simple statements used to describe GMP requirements must be carefully considered. GMP principles, such as “easy and effective cleaning,” are expressed in minimal terms, but the implications are significant. The specification of materials and products for pharmaceutical production areas require specialized knowledge and experience that goes beyond conventional construction. Even when using materials found in typical construction, GMPs often require special applications  to achieve appropriate GMP room design.
	
	

Volume 4: Good manufacturing practice (GMP) Guidelines

,  “Part 1, Chapter 3: Premises and Equipment,” 

ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/cap3_en.pdf


	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, “Considering GMPs In Room Design,” 

Articles

Cleanability is crucial when choosing components for GMP manufacturing areas.

Designing GMP Manufacturing Areas

Considering GMPs In Room Design

The foundation of any successful quality-assurance system is strict adherence to good manufacturing practices (GMPs). Quality must be built into the design of a facility to ensure that drugs are manufactured under conditions and practices required by the GMP regulations. This concept is broadly embraced across the globe and promulgated by drug regulatory agencies, such as FDA in the United States, the European Medicines Agency in the European Union, and the World Health Organization, whose drug regulations are often used by developing countries and individual countries (e.g., China, India, and Brazil). 

This principle is further enhanced by the practice of being current. FDA explains the idea of “current” as follows:

…the “c” in cGMP stands for “current,” requiring companies to use technologies and systems that are up-to-date in order to comply with the regulations. Systems and equipment that may have been “top-of-the-line” to prevent contamination, mix-ups, and errors 10 or 20 years ago may be less than adequate by today’s standards (1).

In a new facility, the expectation is that the design successfully embodies cGMPs. In existing legacy facilities and as buildings age, however, ensuring compliance with cGMPs is more complicated. A review of a facility’s gowning operations can bring significant insight into the current state of cGMP compliance. 

Gowning embodies many of the major elements of cGMPs and as such is a window into a facility’s cGMPs. A highly compliant facility will have gowning operations that are clearly defined and readily understood (see 

). Such operations are easy to diagram, easy to describe, and easy to apply consistently. Conversely, confusing, complicated, or highly individualized gowning operations are indicative of a facility with compliance issues. When gowning procedures are not simple or when there is a lack of consistency and gowning exceptions are allowed, a red flag should be raised and a detailed review of the facility undertaken.

Because gowning is integral to a facility’s operation and reflects many of the fundamental aspects of cGMPs, an initial evaluation of a facility can be conducted by analyzing where and how gowning occurs. The following are three major gowning characteristics to look for.


  Is gowning centralized or decentralized? Centralized gowning, occurring as part of the entry to a specific production area, although not a guarantee, is indicative of organized and orderly production zones. For centralization, functions of the same cleanliness grade must be grouped together and not dispersed into individualized or isolated islands of production. Centralized gowning is also indicative of organized material and personnel flows. If activities of one hygiene type are aggregated together, materials and personnel only need enter the zone once to have access to all the functions within. This can be contrasted with decentralized zones that require material and personnel to enter and exit production areas multiple times in the course of processing a single batch. Operational time is wasted on excessive material handling and multiple gowning/de-gowning sequences.


  Is the protective clothing appropriate for the cleanliness level of the area? In production areas designed to be classified as controlled environments (i.e., designed using ISO 14644-1 or Annex 1 of the EU GMPs [Manufacture of Sterile Medicinal Products]), the greatest source of contamination is the people working in the space. The clothing requirements must provide the amount of protection commensurate to the type of product processed, the operation being undertaken, and the cleanliness class or grade of the space. 

We’ve seen facilities, for example, where primary and secondary packaging are combined and have only a single gowning access. As a consequence, secondary packaging must be maintained at the same high level of cleanliness that is required for primary packaging. In these facilities, the flow of materials for both primary and secondary share the same routing and result in intermixing of raw and in-process materials as well as primary and secondary packaging components. In this example, the easily identified misapplication of gowning reveals a larger GMP issue of confused and disorganized material handling. In addition, always gowning to the higher level increases operating costs in terms of gowning materials used and operational time.


  Do you see gowned personnel walking outside their production areas? There are older facilities where the delineation between production and controlled non-classified areas is not strictly drawn. If gowned and un-gowned personnel are walking past each other in the same hallway, this is a significant problem. Problems that can be surmised about such a facility include:

Gowning is not centralized and time is wasted entering and exiting production suites.

Functional areas and hygiene zones are not organized for greatest operational effectiveness.

Flows are not unidirectional, resulting in raw and in-process materials routinely crossing paths.

The risk of mix-up and cross contamination is heightened.

There is an excessive amount of standard operating procedures. 

Air-handling units are not efficiently designed or operated.

Although efficient air-handling units are not strictly a GMP issue, like all the other issues enumerated, these operational inefficiencies are reflected in a higher than necessary cost of goods. In air handling, for example, an economy of scale, duct layout, and energy usage is realized when functions of a single cleanliness zone are clustered together.


  To evaluate a facility, consider asking the following questions about the facility’s gowning operations: 

Is the gowning operation easy to diagram? 

Is the hierarchy of gowning simple and clear? 

Is the hierarchy of gowning sequential relative to air classifications or grades? 

Is there clear and complete segregation of types of gowning? 

Are there exceptions to gowning protocols? 

What do gowned personnel do when they go to the restrooms? 

What do gowned personnel do when they go to the cafeteria? 
  

Do you need to gown and de-gown just to get to a desired destination?
  

Regulatory guidelines for GMPs include straightforward statements, but the application of cGMPs to a facility is not so simple nor is it obvious. Because gowning is deeply integrated into a facility’s operation, many cGMP fundamentals are reflected in gowning implementation. These questions can be used to help conduct a simple, initial evaluation and to gain a better understanding of compliance issues in a facility. The result will reveal where a facility is compliant and where there is room for improvement.  Either finding will enable proceeding from a basis of knowledge and moving forward with confidence and a clear goal for maintaining compliance.

Facts About Current Good Manufacturing Practices (cGMPs)


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

In legacy facilities and as buildings age, ensuring cGMP compliance can become complex. A review of a facility's gowning operations can bring insight into the current state of cGMP compliance. The author presents characteristics to look for and questions to ask.