By Herman Bozenhardt, Bozenhardt Consulting Services, and Erich Bozenhardt, IPS-Integrated Project Services
This article is the second in a six-part series on how single-use systems are changing the modern biotechnology facility and process design paradigm.
Expansions and renovations to existing biological facilities, and construction of new facilities, provide a unique opportunity to rethink basic design strategies and use new technologies to build a better facility that will improve compliance. As described in our previous article, 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. Now, we will discuss how to build a facility around the SUS process technology discussed last month. This article will explore modern facility design principles that make use of the most flexible new technologies and provide a platform to rein in costs, reduce schedules, and deliver products compliantly and within business risk tolerance. The next installment will cover design implementations and options.
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. This must be achieved while protecting the product within suites, utilizing architectural features (e.g., airlocks, etc.), and controlling 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/spill removal, cleaning, and equipment flow.
The focus is typically on the primary process However, for effective facility layout, the process takes a broader view and includes 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. Understanding what an operator does is the most critical concept to grasp when designing a layout.
Although a narrow range of equipment types will be used to produce the product, 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 viral and non-viral processes and viral clearance
- Cytotoxic / toxins / potent compounds – containment and isolation of toxic process segments to protect the operators until final dosage containment
- Liposomes – use of and containment of solvents into an OSHA (Occupational Safety and Health Administration) Class I, Division 2 environment
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, occupational exposure limits (aka potency) is an important factor 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 room as secondary containment. 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. 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 all its processing, handling, and risk remediation during transport.
Open vs. Closed?
In our previous article, 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)
- Waste handling, including how you handle discarded SUS bags
- Bulk blending, mixing, and filling
In each case, we need to decide if we can contain the operation (make it “closed”) or have to dedicate a room/suite area 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 and the activity was “closed,” we can reduce the number and size of these spaces and allow a higher turnover of use without cleaning.
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, 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 single room/suite 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. 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. 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 R&D, preclinical batches, and phase I programs can often be run in a large generic service area such as a “ballroom” with appropriate controls (e.g., closed systems or spatial segregation).
- 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. Of course, this will also increase the facility size.
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
- 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.
While not all the regulations are relevant for every facility, the designer needs to understand what is critical, especially when dealing with EMA Annex II, NIH, CDC, OSHA, and handling and disposal of genetically altered materials or toxins.
The next article in this series explores how single-use systems can reduce footprints and enact closed systems to drive changes in architectural layout. Future installments will cover HVAC, utilities, and construction aspects of biopharmaceutical facility design.
About The Authors
Herman Bozenhardt has 40 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.
Erich Bozenhardt is the lead for IPS-Integrated Project Services’ process group in Raleigh, NC. He has 10 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.