“Designing a GMP facility requires changing the way you think. The goal in a research facility is to make as many “errors” as quickly as possible in order to narrow the focus of the research. With manufacturing, the goal is to create an error-free, repeatable, traceable, and highly documented methodology. It also means going from a design that is flexible and adaptable to something that is much more fixed and restrictive,” says Alan Orton, a principal with NFOE Architects in Montreal and NXL Architects in Toronto.

GMP regulatory requirements are enforced by governing bodies around the world—including Canada, Europe, and the U.S.—to ensure that manufacturing labs produce products with pre-established quality and safety standards. Academic labs that are GMP compliant are used for a number of applications, including improving the safety of pharmaceutical products already being delivered to patients; supporting translational research projects; participating in clinical trials; and ramping up to product commercialization. Any lab involved in commercializing a product or doing clinical trials must be GMP compliant. In most cases, facilities used for private-sector contracts must also be compliant depending on whether they are doing pre-clinical or clinical work.

The decision to be GMP compliant can add considerable expense to a project and should be carefully considered. Process engineering is one aspect that frequently has unexpected higher costs, especially in an institutional setting. Increased requirements for specialized consulting, validation, detailed documentation, and process engineering can increase capital expenses as much as 25 to 30 percent.

“Building these facilities is not cheap. The cost of validation experts, compliance experts, and process engineers, along with the usual expenses for architects, engineers, and project managers, can be quite a significant step up,” says Orton.

In the case of the Connell O’Reilly Cell Manipulation Core Facility at the Dana Farber Cancer Institute in Boston, officials wanted to increase the facility’s compliance in support of clinical care and research. The 3,990-sf lab included a Class 10,000 cleanroom, dedicated HVAC and building automation systems, terminal HEPA filtration, and high purity gasses. The QA/QC programs were already in place when construction was completed in 2004 and the facility was validated four months after it opened. Consultancy fees for architecture, engineering, and validation constituted 31 percent of the project’s $5 million budget.

“Whatever you think your initial budget and schedule is, it is very likely going to cost more and take longer,” says Orton.

Planning and Procedures

Extensive pre-planning is critical to GMP compliance. The increased amount of time and money involved demand a clear business strategy from the outset.

“It’s important to prepare the business case in advance to justify the cost. This is not a case of just finding the financing and building the project. You have to invest in the up-front process definition and the preparation of a compliance plan, as well as plan for the ongoing burdens of maintaining a compliant operation,” says Orton.

A number of issues must be considered before starting planning and design. The manufacturing process needs to be clearly defined in order to map space allocation, work flow, procedural documentation, equipment requirements, and utility loads.

“Success depends on working with professional consultants who have done this type of work before. Regardless of who you engage, it’s critical that you have your own operations, validation, and quality control staff on board early to assist those professionals in doing their job,” says Orton.

The ability to overcome technical design challenges depends on knowing what level and type of cleanroom environment and biosafety/chemical containment are required. Designers must anticipate complex, dedicated HVAC systems and provide easy access for maintenance and calibration. Involving officials from the relevant regulatory body during the programming process can be a critical component to success.

“It really helps to get the regulatory authorities with jurisdiction over your project involved right away—be it the FDA, the Public Health Agency of Canada, or the European Agency for the Evaluation of Medical Products (EMEA)—so you have a clear understanding of  what the specific requirements are going to be,” says Orton.

It is easy to underestimate the amount of documentation required for adequate compliance. Consequently, Orton emphasizes the importance of pre-qualifying critical contract bidders.

“You typically have to push contractors very hard to get the kind of documentation needed for validation,” he says.

Documentation is Everything

Documentation of every aspect of the process, procedures, equipment, training, and operations, is a significant part of achieving compliance.

“The GMP compliance process of a facility begins as soon as the project starts. As the regulatory agencies say: ‘In God we trust. For everything else, we want documentation,’” says Julie-Léa Lipszyc, a compliance and regulatory affairs expert with SNC Lavalin Pharma in Montreal.

A key part of GMP requirements is validation: a methodology for establishing documented evidence that a specific procedure, process, equipment, material, activity, or system will consistently produce a product meeting pre-determined specifications in compliance with GMP expectations.

“It is basically the process of commissioning everything. You validate because it is not physically possible to test 100 percent of the final product,” says Lipszyc.

In order to assure purity, traceability, and quality control of products, all processes must be tightly controlled and validated. Personnel must be extensively trained to conduct the procedures, and all raw materials and packaging components must be tested and accepted as per quality control requirements. Air change rates, humidity, temperature, and pressure must all be controlled, maintained, and validated.

“Once you decide, for any reason, that a facility needs to be GMP, you can’t just pick one or two elements to implement. It is everything or nothing,” says Lipszyc.

Lessons in Execution

Orton and Lipszyc offer a number of recommendations for organizations considering GMP compliance. Laboratories that are already operating with clear programs or clinical missions have a greater chance of success, according to Orton. Identifying regulatory expectations early in the project helps avoid “over-quality” or “low-quality” designs. In this respect, working in advance with regulatory officials is crucial to understanding the burden. Moving from an innovative research orientation to routine production operations also means a paradigm shift for staff.

“Due to the significantly higher investment of time, money, and planning, compliance must be a key objective and processes should be well defined before starting design,” says Orton.

Project planning must anticipate ongoing staffing and operational costs, and secure long term institutional buy-in. Likewise, validation is a time-consuming, costly effort that can typically take four to six months from mechanical completion of construction to compliant operations.

“The expectations of the project’s promoters and of the host institution are not always the same for these facilities. You have to make sure there is a shared vision and commitment so that resources are there to support the operation well beyond the initial investment,” says Orton.

Once the facility is built, the hard part begins. In addition to maintaining the ongoing validation of all processes, the facility must maintain a full-time quality control and quality assurance staff to support that operation. There will also be a heightened need to market the facility and maximize its use in order to recover the significant added costs.

“I can’t stress enough the importance of getting out there and promoting these facilities because they don’t run on their own. It’s great to have one or two researchers with projects going but you have to find a lot more support within your university and healthcare network to feed this type of lab,” says Orton.

By Johnathon Allen