Published September 8, 2016 on labdesignnews.com
In this month’s column for Lab Design News, we take a look at lab design for translational medicine.
Translational medicine lab design complexity and efficiency
Translational Medicine (TM) is an interdisciplinary branch of the biomedical field focused on treating disease and often pairing research with healthcare. The combination allows, in many cases, new, personalized therapies developed in the laboratory and subsequently delivered to the patient in a “bench-to-bedside” approach. For lab designers, the challenge lies in understanding how conventional lab planning and design strategies apply in this relatively new type of lab.
While conventional lab organization (bench to support adjacencies; lab planning modules; etc.) can be applied to TM laboratories, a host of different criteria must also be considered like criteria developed on the clinical healthcare side of architectural practice. This includes attention to module size, scalability, economy of movement and the details regarding the nature of the environment. Environmental details include the larger scale movement of people, product and material; and the mechanical requirements specific to GMP work.
The “Clean Room” environment
The term GMP, which stands for Good Manufacturing Practice, is often applied to these laboratories. Depending on the scientific discipline, the term GMP and the ramifications of meeting GMP criteria may mean something different when applied to a specific research area. The GMP laboratory must be clean regardless of the range of TM conducted within. The space may accommodate creation of medication in tablet form or discovery of new patient specific therapies. To meet the needs of the GMP and the regulations associated with clean environments, the designer must be cognizant of the standards of cleanliness required – the ISO (International Standards Organization) classification. The use of ISO standards are different from bio-safety levels (BSL) that designers often consider in lab planning and design. Unlike biosafety levels, ISO classifications have been determined and are controlled in FDA guidelines. For example, those guidelines state that the work on cell-lines requires an ISO-5 (Class 100) standard of cleanliness – achievable in the bio-safety cabinet. The room where the bio-safety cabinet is located is generally designed to ISO-7 (Class 10,000). The ISO or Class refers to the number of particles of a specific size (dust or other) found in a specific volume of air. For example ISO-7 achieves 10,000 .5um particles in a cubic foot of air.
Two examples of translational work that may require these higher levels of cleanliness are GMP Gene Therapy and Stem Cell Labs. Often these laboratories are both required within the same overall GMP facility and both deal with material that comes from and, in many cases, goes back into patients. In general terms, both labs are similar to typical cell culture or tissue culture laboratories. However, they require additional precautions to insure a clean environment because of the nature of the product that is handled within their walls.
The stem cell side of a GMP handles product that may be accommodated in a series of rooms with multiple bio-safety cabinet work stations in each. Those work stations include a typical array of equipment: a class II/A2 bio-safety cabinet, incubators, refrigerators, etc. However, another level of equipment to support the work of researchers who are isolating, growing and dosing cells is required. Where cell-line work is happening, accommodation of production is the key. Like smaller cell culture labs, the working triangle of biosafety cabinet, incubator and bench must be addressed in an efficient way by analyzing the cell culture process; minimizing the distance between the bench, biosafety cabinet and incubators.
The Gene Therapy side of the GMP may take more consideration in terms of separation from its surrounding environments. Because gene therapy work often involves the use of vectors – viral vectors – that assist in the delivery of specific therapies to the specific site of cancer or tumors in the body, smaller rooms with single biosafety cabinets are more typical. Air balancing is of special concern due to the need to isolate individual products. To achieve separation, a series of airlocks is used, often one (or two) for each Gene Therapy Lab. Uni-directional flow also helps to contain the work in these typically BSL-2 labs and, subsequently, there is often clean-side and dirty-side corridors that ensure proper protocol. Air flow within the GMP gene therapy or stem cell lab is also crucial. Designing with high supply and low exhaust helps improve airflow, air quality and maintenance of the clean ISO-5 environment required within the biosafety cabinet.
Once the room types and research conducted within them are determined, the next stage of planning and design draws from the flow of people, product and materials.
People – GMP staff are required to gown into and out of the facility. In some cases double gowning may be required if higher degrees of isolation are to be achieved. Uni-directional flow may be needed and, if so, staff may be required to pass through airlocks upon entry and exit from the space. In that airlock, space should be allocated for personal protective equipment (PPE) dispensing / storage and disposal. Consideration needs to be given not only to research / clinical staff but also those who maintain, stock and clean the laboratories. Wet and dry housekeeping closets should be located on both the clean- and the dirty-side of a facility, should that be required.
Product flow analysis
Product – Due to the sensitive nature and clinical requirements of the products moving in, through and out of the facility, adequate space needs to be allocated for proper tracking of the product. Dedicated, secure space is required for logging the arrival and departure of product. Storage for packing materials associated with shipping the product long distances is required as well.
Location of the product receipt and handling is important as, in many cases, the product is often prepared to be administered to a patient. Often the product is thawed at the bedside. Whether the product is prepared in a dedicated lab space associated with the GMP or at the bedside, it is important to understand how far the product needs to travel within the institution and how that product will be handled. The adjacency and travel distances to and from the patient must be considered. Locating the space where product will be thawed near or along major institutional corridors will improve delivery times.
Long term safe product storage requires dedicated cryogenic storage that may take up a good deal of space. The amount of space depends on the size and through-put of the GMP facility. Within the GMP, product is brought down to a final low temperature with controlled rate freezers. These insure a controlled reduction in temperature of the product that minimizes damage to the cells. Controlled rate freezers are located on the bench top and do not require a large space. However, access to liquid nitrogen (often piped) is required along with backup from liquid nitrogen dewars. The dewars also help control LN2 pressure as controlled rate freezers are often sensitive to pressure fluctuations. A location between the GMP and non-classified space is desired for the controlled rate freezer room.
Longer term cryogenic storage may be remote and require access to large amounts of liquid nitrogen as well as be in a secure location. Adequate provisions for large (5’-0” diameter) cryogenic freezers and the required growth of cryo storage is required.
Material – A large amount of consumables need to move in and out of the facility. Because these materials may come in contact with product in the GMP, significant controls must be in place.
The materials receiving room must be secure, though it can be remote if adequate space for staging GMP materials is provided adjacent to the GMP. Like product, material must be logged and tracked. Space is required that will accommodate large boxes of materials with bench / desk space for computers that will allow the appropriate logging-in of materials.
Once received and logged – secure space for “quarantined” and tracked materials must be provided. Before the consumable materials are moved into the GMP they organized in “kits” specific to the particular work that will take place. This helps organize the work and keep protocols clear for the researchers and clinicians working within the GMP.
Keeping the GMP Clean
Air flow design maintains product isolation and insures a clean environment
Clean and Cleaner, the challenges – Systems that are affecting the quality of the product in the GMP need to be tested and qualified. This process is outlined in FDA guidelines. To make this efficient it is important to know to what extent these systems need to be validated. Generally speaking whatever touches the product directly or indirectly should be evaluated. Current practice is to consider a boundary – typically “drawn” at the individual rooms – and make sure everything that affects the product within that room is, in fact, properly validated.
Mechanical nuts and bolts – To preserve the cleanliness of the biosafety cabinets – typically operating at an ISO-5 level of cleanliness – efforts should be taken to control airflow within the room to reduce turbulence. Locating supply diffusers away from workstations helps. Also locating exhaust grilles low on the walls and away from workstations creates a laminar flow in the room that improves cleanliness and reduces turbulence.
Air change rates are often designed above and beyond that of the typical laboratory. Often labs may require around 4-6 air changes per hour (ACH). In GMP spaces much higher rates are considered – up to 50 ACH. However, it’s the cleanliness of the air, not necessarily the volume that affects the GMP. Effort should be taken to reduce the air change rate number. HEPA filters in the exhaust side and recirculating air can increase the efficiency by reducing the amount of once-through air typically designed into the facility.
Planning for the science of Translational Medicine is similar, in many ways, to the process of planning for more biological research laboratories. However, the designer needs to consider a broader approach that includes both planning rules for traditional biology labs and rules that apply to clinical environments as the line between research and healthcare becomes harder to define. Module size, plan organization, and proximity of support space rules of thumb all apply, but new parameters need to be integrated. These parameters include rules about flow, containment, environmental quality, which must be applied in a new and more rigorous way. Remaining sensitive to both the needs of healthcare and research ensures the overall success of the GMP design.