We sit at the beginning of 2022 amid the industry’s frantic and hurried effort to find, build out, and enable more aseptic fill capacity. The capacity needed ranges from the 200 units per minute high-speed lines for COVID-19 vaccines to the 300 per hour for clinical batches and even slower for some cell therapies. Aseptic capacity or, we should say, excellent aseptic capacity has always been in short supply in the global market. Our challenge today is the engineering management of the acquisition, expansion, and preparation of the aseptic plant capacity and making it useable, compliant, and productive.
Part of our challenge is to understand what we are signing up for when we acquire, expand, and “improve” our facility.
To frame our discussion, we will classify the several common types of scenarios of aseptic facility expansion that we have seen repeatedly in the last three years, so we can identify the engineering tasks to consider, identify, scope, and build. Here are our common scenarios:
A CMO that has acquired an old operating facility and expects to run it and produce product ASAP. Expansion will be necessary into old buildings, some of which may be 50 years old that may or may not have seen GMP production.
An existing aseptic facility that needs to expand and “push out” into existing office, warehouse, or utility areas to install new formulation suites and filling lines.
An existing facility that has had an increasing level of environmental monitoring events and is not able to flatten the trend with routine cleaning and normal care. This trend has forced an increased number of deviations during a time when production requirements are increasing.
The key in this discussion is old or existing or non-GMP spaces. The non-GMP spaces, especially in old locations and acquisitions, typically do not have the documentation of the spaces and may not have been not maintained properly. As a consequence, these spaces have the potential to be a microbial and particulate nightmare.
Every project’s scenario may seem different, but, fundamentally, they need to establish the same objectives:
identify the building’s constraints
understand the potential sources of contamination
clean/clear the facility for success
build on a known information model platform
execute with open eyes and focus on the quality of the build.
The risk in doing anything less will place the company in grave jeopardy during the equipment installation and when the environmental monitoring (EM)/process qualifications (PQs) are executed and the daily quality control (QC) program begins.
In most capital projects, we have no choice but to use the existing space due to internal plant traffic logistics or the desire to build under one roof, thinking it will save time and money.
Let’s Start The Aseptic Expansion/Renovation Project
Scenario: We have been told to open this old idled GMP area, put in some new suites during a long shutdown, reusing as much of the walls in place as possible, and the old HVAC system should be adequate. This seems like a simple effort; let’s bring in the contractors, demo the old area, build, and get this over with.
Planning And Design
Let’s look at the space and possible pitfalls that could occur and recommendations to prevent further issues.
Where are the drawings of the building and are they up to date? This question generally has a two-sided answer, with “some” drawings available but they are usually out of date. There is always justification to update drawings on an area being retained for GMP documentation. But before demolition of an area being repurposed, we recommend having an engineering or construction firm perform a pre-demo review of the key manifold connection points to isolate the utilities prior to demolition. Once these points are isolated, documented, and locked out, the demolition should commence, and the area gutted to the structural steel. The next step is to have a 3D laser scan of the entire space done and have it uploaded into the database that the architectural/engineering firm is using for their design CADD work. These 3D laser tools and systems will provide accuracy at one-eighth of an inch. This will assure the engineering drawings of the new space will be accurate and avoid clashes and interference with structural members and any above the floor fixtures. This is particularly useful for equipment placement and spacing for safety and maintenance. Reliance on existing drawings, even for major structural elements, has caused issues when the drawings are not verified as built.
We carefully mentioned “above the floor” in the previous paragraph because the underground area below the floor has been the source of continuous interruptions in construction over many years. The plumbing and utilities under the floor are the most frequently overlooked areas in design and the most poorly documented. Underground drains, piping, and power are installed at the beginning of each project, and if that project was in the 1970s and 1980s, it most likely was “field installed” or “field engineered,” which means some contractor placed the drains, but the pipe routing is a mystery. These mysteries will resurface when the renovation project needs to cut the floor to install a new lyophilizer, put additional structural steel in for roof support, or install additional sinks or drains. What typically happens is the floor is cut and an underground line is exposed or damaged and the project is put on hold to discover what that line or conduit is and where it runs. From there, a redesign of the building’s support structure is initiated to accommodate the discovered line. This could all be avoided after demolition with a floor survey using a combination of ground penetrating radar and radio location borescope. This device and the data generated can also be used to map all the undergrounds and upload the information into a CADD system for a more accurate design. A short effort in preparation could easily save significant time in execution.
HVAC is the one clear engineering aspect of any aseptic facility design or renovation. The design team must evaluate if the existing air handling units (AHUs) and HVAC duct system will be able to provide the following:
The air change rate (ACR) of at least 20 for EU grade D and 30 for EU grade C;
Maintain 15 pascals per EU grade change of pressurization; and
A suite-by-suite airflow pattern that protects the product and equipment with a symmetrical ceiling supply and floor-level return.
We often knowingly ignore the capabilities of a legacy HVAC unit and compromise our design. The only way to prevent a poor design from becoming a marginal facility is to properly redesign the HVAC system to assure the project has the capacity to achieve our HVAC goals. This could be as simple as upgrading a fan drive or replacing cooling coils.
HVAC - Let’s use the existing AHU; it will be fine!
From a physical standpoint, using an existing HVAC system is an important decision that has to be investigated in great depth. Any HVAC system over 10 years old, unless maintained meticulously, should be subject to a predesign analysis. This analysis means opening the AHU systems and reviewing all the externals support, internal mechanicals, coils, and ductwork. The following are some actions and points to consider:
Inspect the blower drives, belts (if any), and test (via ammeter) the power consumption and any bearings for wear / replace the bearings.
Cooling coils are notorious for being fouled with mold and various fungi: these need to be externally cleaned along with the drain pan (looking for mold and corrosion).
Coils also leak and deteriorate with age, and new coils maybe needed. All the fittings and valves need to be inspected and replaced where needed.
HVAC drains after years of use become corroded and often blocked, causing the condensate to back up in the drain pain and blow downstream to the plenums. It is necessary to inspect the plenums and ducts for standing water, mold, and any corrosion.
HVAC systems also need to have the coils flushed internally and checked for flow rate, because over the years coils can be fouled from the cooling fluid.
HVAC insulation is another serious issue, because older facilities had the insulation mounted inside the plenum shells and ductwork. All HVAC ductwork needs to be verified that it is clear of insulation. Otherwise, as we have discovered over the years, the fiberglass insulation internally sheds particles. We have even found, in some facilities from the 1970s, the internal insulation is asbestos, which could be catastrophic inside a GMP facility.
Ultimately, all insulation must be external to the ducts, AHUs, and plenums, with pristinely clean interiors.
If the coils or drains are not adequate, they will need to be replaced. It is also a great idea to install UV lights at the cooling coils to inhibit the growth of mold and paint the cooling area, pans, and near downstream with an anti-microbial paint.
How does the HVAC plan to humidify in winter? Many facilities in the 1970s and ’80s humidified with plant steam injectors. Using common plant steam inside an aseptic area should not be permitted; instead, clean steam should be used. The most interesting issue discovered at the plant steam injectors/sprayers is they are commonly severely clogged and corroded with continuous leaking/dripping condensate on the plenum where it runs down the ductwork. This often leads to mold in the ducts, corrosion, and getting the downstream terminal HEPA membranes wet and corroding the HEPA cans and their fasteners.
We have also found in some poorly designed facilities AHU systems that feed the downstream air into mechanical spaces and chases without a plenum. The theory is that the mechanical space, when pressurized, pushes the air through the HEPA filters. That theory is correct for the HEPAs, but the pressure also pushes mechanical space air through every crack, crevice, wall plate, and wall penetration and could lead to a contamination source blowing through the wall via a wall switch or a ceiling-mounted fire sprinkler.
In the end, reusing any existing HVAC requires a serious investigation.
In most renovation or remediation efforts, the walls are demolished and new walls are erected; however, there can always be the drive to save time and money by reusing existing walls, which may be a miscalculation. Regardless of the approach, there are several aspects of the renovation that must be taken into consideration:
Most legacy facilities used commercial-grade gypsum board with steel studding. The demolition of these walls will release a plethora of particles into the environment. All standard commercial gyp boards contain cornstarch and wood fibers, unacceptable for a GMP area. Therefore, special care must be taken during removal.
The more serious issue is the incorporation of existing walls into a new design and layout. The most critical aspect of incorporating any wall is to examine the wall behind the GMP space. The older gyp board walls do not stand up to cleaning, and the moisture from the bottom of the floors is “wicked up” into the board, which becomes swollen and mold-ridden. This wicking effect keeps the studding moist, and, with the aggressive chemicals, the studding corrodes and is essentially eaten away. Overall, this becomes a safe harbor for mold, fungus, and a variety of bacteria that eventually will make its way into the environment.
One of the most disturbing observations on legacy facilities is the use of plywood and wood studs. In some plants, wood was used to connect wall sections and set door systems into the walls. All wood needs to be removed from the plant, and this can only be accomplished by identifying it by inspection or by wall-penetrating ultrasonic detection.
Another trademark of a legacy facility is rollup doors, which were used to save space and reduce costs. Rollup doors tend to deteriorate (consequently shedding particles), are difficult to clean, and, when rolled up, they harbor and accumulate microbials and particles in the door reel. Unless the project has them in CNC or NC spaces, legacy rollup doors need to be removed.
Modern wall systems for EU grade C and better are generally polymer (AES, Kynex, Polycore, etc.), due to their ease of assembly (self-supporting), lack of dust and construction debris, and cleanability. EU grade D facilities typically can use polymer systems or the non-permeable/fiberglass mat wall board such as GP Dens Armor Plus (with steel studs) covered with a PVC liner. The CNC and NC areas can be constructed with the Dens Armor with an epoxy coating.
The good news about floors is that in almost all cases, floors will be redone in renovations due to the demolition and material and equipment movement. However, there are a few important aspects we need to consider:
Floor quality is critical to maintaining a low microbial count; therefore, the floor needs to be smooth enough to present a monolithic surface for sanitization but must have a texture to prevent slipping. For this to be the correct quality, it has to be carefully inspected and felt with the human hand to determine the quality; a specification is meaningless unless it feels right across all the floor, especially the sides near the walls and coving. The urethane topcoat cannot correct a poorly laid floor. Today, epoxy terrazzo and various epoxy floors like Stonhard are the choice because they are hard, durable, and resist all the common cleaning chemicals available.
Before any floor is applied, the subfloor needs to be inspected to ensure it is monolithic, free from cracks and slopes, and is ground down to a common substrate. Sub-floor defects will be apparent in the finished surface!
Floor drains and drain cleanouts need to be eliminated, except for CNC and NC spaces. In today’s modern aseptic facilities with single-use systems (SUS) and isolators, there is no need for vessel washing and wash pits.
Pit scales are another legacy benchmark. Pit scales are one the most serious repositories of contamination. These need to be eliminated by filling them in and making them part of the contiguous floor. The scale functionality should be replaced by one of the low-profile electronic platform scales that are portable (for cleanability).
Similar to the pit scales are various other hydraulic lifts and systems that have below-floor openings and subfloor components that are not cleanable; these have to be removed from the floor.
During a renovation and reconstruction, legacy ceilings are typically removed; however, the temptation to replace the ceilings in kind is often a mistake. Many of the older facilities use “solid” ceilings, which consist of ceiling-mounted gypsum board, with openings cut for HEPAs and other necessary penetrations. Gypsum board for ceilings, like in walls, leaves residual dust and debris, plus the solid feature makes it difficult to access the space above the ceilings for HVAC adjustments and troubleshooting. Access panels have to be designed, which requires more engineering, cutting, and potential gravity fallout through the penetrations from the area above the ceiling space.
Today, modern ceiling systems are “grid based” modular, gasketed and sealed, but, if needed, they can be opened easily. The modular ceiling systems are polymer, snap in place, and are built to accommodate the HEPA filter “cans” and lighting fixtures.
Ceiling penetrations in legacy buildings include intercoms, radios, sensors, and fire suppression sprinklers. As a general rule, only GMP fire suppression outlets should be in a ceiling and all other fixtures are fitted into the wall. This minimizes the gravity infiltration effect of microorganisms and particles from the unclassified interstitial space above the ceiling.
Much to our surprise over the last several years, we have encountered plants with no fire suppression in manufacturing areas. It is important that the entire facility have fire protection, and if the previous area did not have coverage, the entire plant’s fire suppression/delivery system must be evaluated. This could mean new sprinkler headers and a new fire water grid. It should be noted that with the increased usage of SUS, a reevaluation against current local fire codes needs to be conducted to address the increased sprinkler density required for increased plastic usage.
In the case where ceiling sections are reused along with the reuse of HEPA filter fixtures, lighting fixtures will be challenging. This challenge begins with trying to assure the tightness of the HEPA fixture and preventing bypass or HEPA leakage with caulking and more caulking. If your installation needs extensive application of caulking and recaulking, you are better off putting in a new ceiling grid built for the HEPA installation.
Interstitial Spaces And Mechanical Spaces
The final area to discuss is probably the area most prone to cause mold, fungus, and environmental hits: the interstitial/mechanical/chase spaces. These spaces are the breeding grounds for all the environment problems the plant faces. Legacy facilities, warehouses, and office areas typically have vast sections of the plant that are non-classified areas that contain pipe runs, HVAC equipment, and spaces for maintenance of autoclaves, lyos, parts washers, and other process or utility equipment. These areas typically contain dripping/weeping lines, open drains, rusted equipment sections, wet insulation, swollen gypsum board walls, debris, spider webs, wood, and dirt from construction. During a renovation, these areas need to be either removed entirely or remediated with extreme measures. These measures include all the basic repairs, re-insulation, cleanup, which may include ozone treatment to kill all the mold and fungus, painting all the interior surfaces with an anti-microbial paint, and installing a UV light as a maintenance feature.
The other surprise we face in older facilities is finding asbestos insulation on piping or on structural steel. In this case, we have to perform asbestos remediation prior to any demolition or renovation. It is critical that on the facility reviews and walkthroughs, we identify these highly hazardous areas and schedule them for pre-construction remediation.
As you can see clearly, the time, effort, and expense in the remediation or renovation of a non-GMP area or legacy facility or expansion into an undeveloped area is very challenging. The pre-work before the design and the pre-construction work on the facility will increase the project’s duration and may impact the cost significantly. You need to ask yourself:
Is the extra time to survey, analyze, and remediate the facility worth it to the project?
Does the remediation deal with all the hazards and problem areas?
Can you deliver the therapy to the market quickly?
Can you build a fully functional and compliant facility in this space?
Will the series of remediations, renovations, and further discoveries lead to a full-scale reconstruction?
Why are we doing this and who benefits?
In a lot of the cases we have seen over the years, the conclusion is the endless levels of facility problems and the associated fixes that make a project not financially viable and/or do not provide the time savings expected. Use this discussion and the points above to make your case. Sometimes the obvious answer is not the correct answer.
In the case of some that have stumbled down the road of an “easy renovation”, and not considered most of these points, they have entered the zone of the never-ending project.
About The Authors:
Herman Bozenhardt has 45 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. He has a B.S. in chemical engineering and an M.S. in system engineering, both from the Polytechnic Institute of Brooklyn. He can be reached via email at firstname.lastname@example.org and on LinkedIn.
Erich Bozenhardt, PE, is the lead process engineer for regenerative medicine operations at United Therapeutics. He has 16 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