“The work being done in these facilities is not a routine production of pills and tablets. These labs are developing highly innovative products and processes,” says Alan Orton, a principal with NFOE Architects in Montreal and NXL Architects in Toronto.

Four recent North American lab projects—two in the design phase and two recently constructed—illustrate the drive to develop GMP-compliant labs: the Cell Therapy Centre of Excellence in Montreal; the Experimental Tissue Engineering Laboratory at L'Enfant-Jésus Hospital in Quebec City; the Veterinary and Food Biotechnology Institute in Montreal; and the Connell O’Reilly Cell Manipulation Core Facility at the Dana Farber Cancer Institute in Boston. In all four cases, the potential to participate in clinical trials, develop marketable products, or significantly advance a lab’s capabilities must be weighed against the increased costs of consulting, validation, and ongoing GMP-compliant operations.

“We are not talking about laboratories that are ‘kind of compliant’. We are talking about labs that are seeking to achieve true GMP regulatory compliance whether with Canadian, American, or European standards,” says Orton.

GMP-compliant facilities must adhere to guidelines and practices enforced by regulatory agencies in every major country. Work flow processes, products, and documentation must be repeatable and traceable and adhere to international standards for quality control.

Centre for Excellence in Cell Therapy

The 6,530-sf Centre for Excellence in Cell Therapy (CECT) currently being planned for the Maisonneuve-Rosemont Hospital in Quebec has an existing program that provides autologous (re-transplant of treated cells to same patient) and allogeneic (transplants from a different donor) treatments. Officials at the Centre want to modernize operations and expand the facility’s capacity to do innovative allogeneic cell manipulations, create cartilage cell cultures for autologous transplants, and do cell treatments for retinal and corneal transplants. Existing GMP-compliant processes and protocols would be replicated and updated in the planned facility.

“The goal is to be able to participate in clinical trials, but still maintain a not-for-profit service orientation. It is not a commercialization-driven project,” says Orton.

A GMP-compliance and technical feasibility study was conducted as part of the initial process engineering review of the planned facility. The planning team developed process flow diagrams to map out all the steps used in the intended process.

“Process-flow diagrams enabled us from a functional and technical programming point of view to make decisions about which rooms can be combined, what needs to be segregated, and what can be done to provide for some degree of operational flexibility,” says Orton.

Current plans call for three suites: one for GMP cell manipulation of non-infectious materials, another for handling potentially infectious materials in a level-two containment environment, and a third area for core facility support services. The expected fit-out costs, excluding scientific and consultancy fees, comes to $7.2 million.

“CECT officials haven’t made a decision yet whether they are going down the road to full compliance or not because they recognize there is a high level of cost and commitment involved,” says Orton.

Experimental Tissue Engineering Laboratory

The 1,860-sf Experimental Tissue Engineering Laboratory at L'Enfant-Jésus Hospital in Quebec City primarily grows autologous skin cells for re-transplant to burn patients. Lab officials want to expand the facility’s workflow capacity, broaden its product range, and increase the ability to participate in pre-clinical and clinical trials.

“The project’s preliminary design has been completed and there is a pre-existing processes in place that will need to be upgraded to move into a more compliant GMP environment,” says Orton.

Plans include creation of a new core lab for the generation of reconstructive tissue products. GMP support space would meet ISO Class 8 cleanroom requirements, and the three independent production lab suites would meet ISO Class 7 requirements. Estimated construction cost for fit-out of the laboratory is approximately $1 million, or $535 per nsf.

Facing consultancy fees for validation and compliance services on top of the usual 10 percent for architectural, mechanical, and electrical design services, as well as increased staffing demands, laboratory planning officials must decide whether they are going to move forward with pursuing full GMP compliance.

Veterinary and Food Biotechnology Laboratory

The 5,385-sf Veterinary and Food Biotechnology Laboratory is a newly opened lab designed for the development of innovative veterinary and human biotherapeutic products. The lab is part of a new research annex constructed on the Univeristy of Montreal’s Faculty of Veterinary Medicine campus in St. Hyacinthe, Quebec.

The facility was intended to comply with GMP requirements for the manufacture of biological veterinary products. Other objectives include development, scale-up, and pilot production of pioneering viral and bacterial vaccines, as well as production of clinical materials, licensing batches, and small scale commercial runs.

“It was an ambitious project because there wasn’t a pre-existing program in place and officials at the Veterinary and Food Biotechnology Lab wanted to get into full scale-up and pilot production of products. They were starting from zero and headed down the road to creating a fully GMP-compliant facility,” says Orton.

The $13.7-million project was completed in the last quarter of 2005 and validation activities were 60 percent complete in 2007. Total consultancy fees incurred were in the order of 30 percent of the $6.1 million construction cost.  In the long run, the expectations of University officials and the project’s promoters differed. Lab status and operational authority limits were not clearly defined, and funds were not immediately available to complete the GMP compliance effort. As a result, the validation process has been temporarily suspended while the facility mission is under review.

“GMP compliance requires long-term planning. The expectations of the project’s promoters and of the underlying institution are not always the same. You have to make sure that there is an alignment of purpose and that there is a shared vison and committment to supporting the facility’s operations,well beyond the initial investment ” says Orton.

Connell O’Reilly Cell Manipulation Core Facility

The successful Connell O’Reilly Cell Manipulation Core Facility (CMCF), located at the Dana Farber Cancer Institute in Boston, provides autologous and allogeneic cell therapy treatments to patients within the Harvard Medical Center and Boston-area healthcare networks. The recently completed 3,990-sf facility currently supports more than 30 clinical trials and processes approximately 800 stem cell and immunotherapy products annually.

“The goal of the CMCF was to create a fully GMP-compliant facility to improve patient outcomes, to reduce the risks, and to optimize the procedures for manufacturing novel therapeutic cells,” says Orton. “This was a key to acquiring funding support.”

The facility includes a Class 10,000 cleanroom, dedicated HVAC and BAS systems, terminal HEPA filtration, and high purity gas systems. Since QC/QA programs were already in place when construction was completed in 2004, the facility was able to achieve validation four months after opening. Consultancy fees for architecture, engineering, and validation represented 31 percent of the project’s $3.3 million construction budget. Design reviews held by the CMCF and its design team with the FDA and the NIH were also instrumental in identifying compliance expectations.

“You really need to have a global vision before you start a project like this. The feedback that the CMCF got from FDA and NIH was critical because it had previously underestimated the burden of QC/QA documentation—which is very common in these types of facilities,” says Orton.

The ongoing operation is supported by research funding and clinical activities on a fee-for-service basis with other organizations such as the Center for Human Cell Therapy, Harvard Stem Cell Institute, and the Translational Cell Therapy Laboratory.

“It is very important to develop a pipeline of organizations that want to work in a facility like this and that are willing to pay for it,” says Orton.

Learning From Experience

The four facilities provide valuable insight into the complex challenges of developing GMP-compliant labs. Among the most important lessons learned is the fact that—due to the significant increase of cost, time, and required documentation—organizations should only pursue compliance when absolutely necessary.

“GMP-compliant labs are expensive to design, build, and operate, and difficult to repurpose. It’s critical to get them right-sized which means establishing user-requirement specifications early in the process,” says Orton.

Laboratories with established processes and programs in place have a much better chance of success because there is an understanding of the QC/QA documentation that is involved.

“During those first four to six months of validation, the facility is not in operations, but the staff is being paid. If you are validating and providing a service using the same methodology that you were providing before, as long as you are not stepping up to a more ambitious program, you may be able to continue to operate during the validation process,” says Orton.

Institutional support for the long-term operation of GMP facilities is also essential to success.

“You have to make sure during the early planning that the hospital or university hosting the facility shares the same long-range vision and that resources will be there after GMP compliance is achieved to ensure that the laboratory’s operations can be successfully continued,” says Orton.

By Johnathon Allen