By Herman & Erich Bozenhardt
Expansions and renovations to existing biological facilities, conversions to cell and gene facilities, and tissue therapy facilities, and construction of new greenfield facilities, provide a unique opportunity to rethink basic design strategies and use new technologies to build a better facility that will improve compliance. As we have discussed in the past, the implementation of single use systems (SUS) is enabling an evolutionary step in the nature of bioprocessing, allowing for a smaller plant footprint and elimination of several common operations. The newer cell and gene SUS technologies are the next generation in process equipment to work in this quickly growing space. Now, we will discuss how to build a facility around the SUS process technology. This article will explore modern facility design principles that make use of the most flexible new technologies, recognizing they have evolved, and provide a platform to first process our therapies and then rein in costs, reduce schedules, and deliver products compliantly and within business risk tolerance.
Where to Start
The key to layout of a biopharmaceutical facility is solving the mixed-integer programming problem of multiple goals, constraints, and adjacencies — and all for the lowest cost (typically, the lowest square footage). The goal is to evaluate the process requirements and risks involved with the product and process and build a facility that will facilitate the operation (often making the operator's work path and activities less complex and enabling compliance). This must be achieved while protecting the product within suites, utilizing architectural features to provide operational segregation (e.g., airlocks, etc.), using local HVAC to keep the product areas GMP-clean with appropriate containment, and controlling material pathways. We will begin this discussion by defining a few key concepts that will focus design direction.
The driving force behind any facility is the product it will produce. The facility must be built to promote ease of production by the operators, taking into account the workflow path, safety enablement, minimization of bioburden, and compliance enforcement. The production process includes all aspects of the operation, including personnel flow, product flow, raw material flow, waste/trash flow, spill removal, facility cleaning, and equipment flow and maintenance.
These facility aspects have become more visible after reading the recent 483 received by Emergent Biosolutions in April 2021. Our business is dealing with more BL-2 (and in some cases, BL-3) organisms and viruses. In the design/development/construction of a BL-2 facility and cell/gene-based facility, we need to recognize that materials coming in (donor cells, blood plasma, viruses) and exiting can and will be contaminated, and as such must be contained as well as their pathways.
The concept of pre-viral and post-viral separation and isolation must always be in consideration.
The focus is typically on the upstream and downstream process. However, for effective facility layout, the process today, particularly for viral vectors, must take a broader view and includes the final aseptic dosage, as well as operations like how you make up the media; where the media travels; how you contain and clean a spill; and how drums, bags, funnels, and transfer tools are removed cleanly. Understanding what an operator does is the most critical concept to grasp when designing a layout, and providing operators with the tools to prevent contamination, media spills, and media dust can make the difference in production yields and in wrestling with deviations due to a contaminated batch. We will need to include the aseptic fill in this as we have seen the increased need for small batches, personalized medicine, and orphan drugs, as well as clinical batches.
There is a wide range of equipment types used to produce the different products. The equipment will have different implications depending on the product and its needs. For example:
- Simple protein / monoclonal antibody (mAb) – minimize bioburden by minimizing handling and transfer
- Viral inoculated / plasma derived – segregation of pre-viral and post-viral processes and careful plan of the viral clearance process and its transition
- Cytotoxic / toxins / potent compounds – containment and isolation of toxic process segments to protect the operators during processing and decontamination until final dosage containment is achieved
- Liposomes – use of and containment of solvents into an OSHA (Occupational Safety and Health Administration) Class I, Division 2 environment
- Viral vector – handling in an isolator environment and material transfer in a mode to protect the operator and protect the cells
- New cell and gene equipment – accommodate the transition from manual manipulation to evolving robotic handling
Each one of these product classes might (or might not) require containment from human exposure or isolation from upstream or downstream processes. Minimizing bioburden will be a given in any layout, and isolation and containment will become recurring themes as we continue to discuss the layout puzzle.
When dealing with conjugated mAbs and potent compounds (cytotoxins, steroids, etc.), occupational exposure limits (aka potency) are important factors in how you deal with the production steps and execute the process. The International Society for Pharmaceutical Engineers (ISPE) provides general guidelines on handling potent compounds by occupational exposure bands (OEBs), which range from band A (harmless) to band F (Immediate, life threatening). Handling of these materials varies from normal GMP gowning at band A, through dust masks and respirators to full isolation/remote manipulation at band F.
Each process design requires appropriate level(s) of containment, which typically includes a SUS or stainless steel vessel and the primary containment, the processing room as secondary containment. That addresses the process, but what about the operators? The operators must have gowning/airlock that allows them to put on the appropriate level of barrier between them and the processing because they are in the room! This also requires the layout to accommodate a degowning and disposal of a contaminated gown in such a way that the operator can separate themselves from the gown and have the discarded gown and components wrapped in a container for decontamination or disposal. The containment design requires additional care in planning access and flow patterns. The lower potency materials can be contained in the SUS and, with careful handling, can be economically clustered in a multiple-use suite/exit airlock. The higher potency materials must be physically isolated during the process and contained in use and transport. This will require a separate suite for the potent compound and extreme care in all its processing, handling, and risk remediation during transport.
Open vs. Closed?
In the past, we discussed SUS and the biopharmaceutical industry’s drive to employ this technology. However, before implementing SUS, it is important to completely understand what steps will utilize a “closed” process versus an “open” process. While the bioreactor itself might use an SUS and be considered a closed process, we also must understand all the other processing steps, including connections, cleaning, and transport.
In any process design exercise, it is a useful to create a flow chart of the process and identify the steps, including which (if any) have open processing, such that the product or its components are exposed to the room or human handling. These can include:
- Media preparation (must always have its own contained space)
- Buffer prep, dispensing, make up, disposal, and cleaning
- Cleaning vessels, skids, parts, mixers, and handling equipment (always a concern for moisture and cross-contamination)
- Bulk blending, mixing, and filling
- Inoculation of a seed vessel or in a scale-up train
- Any open transfer of cells or inoculation
For viral vectors and autologous cells, the closure should consider the risk of contaminating the environment after the product has been removed from the system. For example:
- Removal of filters from racks or housings
- Disconnection/breakdown of SUS
- Handling of reusable portions of SUS (e.g. chromatography column)
- Waste handling, including how you handle discarded SUS bags
In each case, we need to decide if we can contain the operation (make it “closed”) or have to dedicate a room/suite area or an isolator to that operation or related series of sequential procedures. Once we designate “open,” then we immediately need dedicated floor space for the activity and a cleaning routine to remove potential for cross-contamination (which adds time and cost). That floor space then becomes a growing cost factor. Alternatively, if we used an SUS or a closed stainless steel transfer system and the activity was “closed,” we can reduce the number and size of these spaces and allow a higher turnover of use with minimum cleanup or disruption.
The last major aspect of beginning a facility layout has more to do with the business aspects of our industry and their relationship with the quality organizations. Risk assessment focuses on the potential for product cross-contamination, product loss, product quality, and financial loss. The assessment typically breaks down into the following classes:
- If the facility is a single-product facility, then the risk profile is low and the main concerns are worker safety, bioburden, and post viral exposure / viral clearance. In this case, the design can consolidate any number of steps into a minimum number of rooms/suites as practical.
- In the case of a multiple-product facility, the concerns are increased by potential cross-contamination via microbial or viral means and by inadvertent mistakes (see April FDA 483 discussed above). Multiple products are at lower risk during R&D and clinical phase I trials. In multiple-product phase II through commercial manufacturing, individual products must have a closed or secure manufacturing sequence and path to protect the consumer. Best practices layout as well as careful campaigning and sanitization/decontamination can help reduce the risks and the multiple suites and flow paths.
- In the case of a contract manufacturing organization (CMO), where numerous clients, products, and processes must coexist in the same facility, multiple-product risk is accentuated. When engaging a CMO facility, most clients want to know what products have been manufactured there, past and present. This almost always becomes a point of contention and drives some CMOs to a compartmentalized suite approach for phase II through commercial. The contract development & manufacturing organization (CDMO) R&D, preclinical batches, and phase I programs often run in a large generic service area such as a “ballroom” with appropriate controls (e.g., closed systems or spatial segregation). This is now moving toward smaller "mini-suites" to provide better containment as the sensitivity to the materials and processes increase.
- Risk is also measured in the value of the batch of material. As titers and batch sizes are increased, and yearly productions are consolidated into a few or single batches, the financial implications of a batch failure from bioburden or cross contamination are extreme. In these cases, as financial exposure increases, so too does the need to increase the levels of isolation, reduce batch size, increase production time, and protect the process steps within the facility.
Regulatory Compliance – More Than You Think
At this point in the process — after determining the process steps and required suites — most engineers and architects will begin drawing layout concepts. However, a series of regulatory laws must be adhered to in order to design, build, and construct any biopharm facility. Below are some of the key regulations that constrain facility design and provide insight into the regulatory expectations:
- 21 CFR 211:42-58
- 21 CFR 600.3(t)
- 21 CFR 601.22
- 21 CFR 600.12e
- Contract manufacturing
- 21 CFR 210, 211, 600-680, 820
- Basics for inspection
- EMA Annex I, II
- EMA Annex 14 (blood-based therapies)
- Waste handling and flow
- 40 CFR Part 261
- 40 CFR Part 264
- Safety in processing
- 21 CFR part 600.11, subchapter F
- Plant cell cultures
- National Environmental Policy Act (NEPA) guidelines on plant cell cultures
- Toxins / cytotoxins
- Refer to agent classes via Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and OSHA
- Spore formers
- Biosafety levels (BSL 1-4)
- NIH guidelines for containment and architectural requirements
- Federal, state, and local building codes
- National Electric Code (NEC), OSHA, National Institute for Occupational Safety and Health (NIOSH), National Fire Protection Association (NFPA), Americans with Disabilities Act (ADA), etc.
As we have seen in recent 483s and the industry’s drive to build and operate facilities for COVID-19, the CDC’s guidelines on organisms and viruses, along with the NIH design guidelines, have taken on a profound input to our new facilities and retrofits.
While not all the regulations are relevant for every facility, the designer needs to understand what is critical, especially when dealing with EU Annex II, NIH, CDC, OSHA, and handling and disposal of genetically altered materials, viruses, or toxins.
Today, although we may be building in the US, the EU Annex 1 and 2 have taken on an increased importance and are the design drivers. That more conservative and prescriptive approach provides good guidance for the FDA and EU.
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. 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. He can be reached via email at email@example.com and on LinkedIn.
Erich Bozenhardt, PE, is a lead process engineer for regenerative medicine operations. He has 15 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. He can be reached via email at firstname.lastname@example.org and on LinkedIn.