By Erich H. Bozenhardt and Herman F. Bozenhardt
The life sciences industry is faced with a quickly changing market. In the drive to provide a spectrum of life-saving cell and gene therapy products, also known as advanced therapy medicinal products, we are faced with many manufacturing issues. The first is where we place production. Since one of the major demands in the pharmaceutical business is for cell therapy capacity, and real estate and property are generally available at companies' sites around the world, the natural tendency is to place the cell therapy production in an existing site, near the product development center. Since most commercial operations have learned how to optimize their production and sites, existing plants typically can find idle or underutilized space in their buildings.
In many cases, the space selected is whatever is available, and we have little choice but to convert it into a compliant, flexible, and operable space. The challenge is to make the renovated space a successful GMP facility by engineering and building it correctly within the confines of the space and utilities. This article will briefly cover the planning, implementation, and recommended approach for undertaking such a renovation. In Part 1 of this two-part series, we will look at key preparatory steps to take before beginning a renovation. In Part 2, we will cover the basic facility requirements to produce cell and gene therapies.
What Is Wrong With The Facility As Is?
Typically, legacy facilities are severely outdated and could, in some cases, be 50 years old, while both GMPs and building codes have profoundly changed over the years. The following are some questions and issues that need to be addressed immediately:
- What was the facility producing prior to its current state? There needs to be a disclosure as to raw materials, intermediates, and products. If there were potent compounds, steroids, blood-based products, or cephalosporins, major decontamination will be needed prior to and after demolition.
- Environmental contamination factors are also critical, as a legacy facility could have mold and fungus in the walls, ceilings, and interstitial spaces. Decontamination is often difficult due to the adhesion of the spores to non-polymer and non-steel surfaces, especially mortar and concrete. This is often done with chemical washdowns and a fumigant gas (e.g., chlorine dioxide).
- Asbestos is common in buildings built in the 1970s and before. Regardless of the company, we still find asbestos in buildings today. An inspection of roofing systems is needed if the building was built before 1980.
- Water damage, deteriorating roofing systems, exterior shell damage, and building infiltration problems are common with older structures. These need to be inspected prior to any construction, along with the removal of legacy ballasted systems and the installation of more appropriate membrane systems like thermoset (EPDM) membranes.
Strategic And Tactical Demolition
Once we have identified the building or floors of a building that we are to renovate and we understand the exterior building shell, we have to decide on the demolition plan and execute it. From a strategic standpoint, we want to clear the entire area of the vestiges of the past operations to provide a clear area that can be built out. This demolition should take the facility interior to the support columns, roof joists, and the wall slab. If the renovation is only for a selected floor or floors, an examination of the floor deck for penetrations and ceiling slab for penetrations (conduit, duct work, etc.) is needed. In some of the older buildings, conduit for power is embedded within them!
From a tactical standpoint, even a legacy facility has infrastructure benefits that should be re-used and that can be key points in the rebuilding effort:
- Electrical power supply on the building exterior with conduit locations into the interior panels can be reused in many cases as long as they were maintained and documented.
- Backup power from a generator is a key consideration. The location, capability (KW or MW), and the distribution needs of the plant need to be evaluated. Any new facility will need access to a backup generator to maintain the HVAC system, the process control system, and the process systems until they can be shut down in a controlled manner. BL-2 uninterruptible power supply (UPS) systems need to be coupled with the backup generator to supply power to the HVAC during a transition from normal to the backup.
- Chillers and the plant-chilled water grid can be reused if they are maintained and blocked in at the battery limits of the renovation project.
- Gas systems such as nitrogen and clean compressed air are generally central plant services that are available and need to be blocked off at the building being renovated. However, if the plant has a utility area with a maintained air compressor and/or nitrogen tank, these can be preserved for the new facility. The key is the level of maintenance and condition of the unit.
- Typically, USP, WFI, and clean steam systems are dedicated to a building and often are discarded when not in use for several years.
Prep For Engineering
One of the core fallacies in executing a renovation is doing the conceptual design or basis of design engineering before the facility is completely mapped and understood. We in the industry often spend hundreds of hours designing the perfect biotech without sufficient roof height, drains in the wrong places, and conduit penetrating the facility in the wrong places. We are often victim to a weak and undersized roof that cannot support air handling units (AHUs) and the supporting fans. This forces the user to build an external platform on the roof (expensive steel structures), take up valuable expansive floor space, or build an AHU building and run hundreds of feet of additional piping from building to building. The following is a list of "must do" tasks when renovating and demolishing, and before serious engineering expenditures:
- Ground penetrating radar of all internal slabs to uncover all drains, pipes, and conduit buried in the slab
- Borescoping the existing drains with video and precision scale measurement to identify the drain system and its branches
- Laser scanning the entire interior to identify the interior dimensions. This can be imported directly into a CADD system to provide a basis for design.
- Reviewing the transformer load and secondary slots remaining to identify the extent of the power reserve the building has to offer before a new transformer is required.
In conclusion, older legacy facilities have many hidden problems and lack documentation. We must take every precaution and consider all aspects of the original facility to establish a strong engineering baseline before any detailed design is considered. We have the tools and technology to recreate the "as-built" status of a legacy facility, and "discovery" of this space early on will prevent delays and future cost overruns.
In the second part of this article we examine the basic design aspects to consider when renovating a facility to meet the unique demands of cell and gene therapies.
About The Authors:
Erich Bozenhardt, PE, is the process manager for IPS-Integrated Project Services' process group in Raleigh, NC. He has 14 years of experience in the biotechnology and aseptic processing business and has led several biological manufacturing projects, including cell therapies, mammalian cell culture, and novel delivery systems. He has a B.S. in chemical engineering and an MBA, both from the University of Delaware.
Herman Bozenhardt has 44 years of experience in pharmaceutical, biotechnology, and medical device manufacturing, engineering, and compliance. He is a recognized expert in the area of aseptic filling facilities and systems and has extensive experience in the manufacture of therapeutic biologicals and vaccines. His current consulting work focuses on the areas of aseptic systems, biological manufacturing, and automation/computer systems. He has a B.S. in chemical engineering and an M.S. in system engineering, both from the Polytechnic Institute of Brooklyn.
Image courtesy of IPS