By Herman Bozenhardt, Bozenhardt Consulting Services, and Erich Bozenhardt, IPS-Integrated Project Services
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. One of the biggest drivers in the current evolution of biological facility design is the implementation of single-use systems (SUS).
The adoption of SUS in the biopharmaceutical world is being driven by two contemporary themes: 1) rapid modification of existing (in some cases, old) biological production facilities to accommodate new products, therapies, and cell cultures, and 2) rapid design and build of new facilities on an existing site to launch new products. And all of these projects share two important considerations — time and risk.
This six-part article series will review the key design features and philosophies that will drive compliance to a successful conclusion. It will also explore modern facility and process development methods that make use of the most flexible new technologies and provide a platform to rein in costs and reduce schedules.
The series will take an “inside-out” approach to plant design, with this article focusing on the “process core” and future installments covering facility layout, HVAC, utilities, and construction. Each article will explore the current state of industry for a given component.
SUS Application Throughout The Process Core
Manufacturing in the biopharmaceutical industry faces two major challenges: the drive to improve quality and the drive to reduce costs. These pressures have caused the industry to reexamine how its equipment and facilities interact. One prominent design philosophy that has emerged is the idea that the boundary around a process should be as close to the process as possible and should minimize interactions with the exterior environment. This thought process has led to the migration from sometimes open processes to functionally closed processes (with CIP/SIP) to further-closed disposable processing. The pinnacle of this progression is a return to the ballroom concept, where all operations occur in the same room in closed systems.
For any given unit operation in a biological facility, implementation of single-use technologies varies due to historical experiences, regulatory challenges, business drivers, maturation, and scale. The following sections will discuss the application of SUS in various biopharmaceutical processing operations.
Media preparation operations have witnessed a rise in hybrid stainless steel/single-use approaches. Media operations face contamination issues from incoming materials, microbial counts in the room itself, and the potential for migration of room contamination into the process. The latter two issues have driven organizations to find better ways to close up a process that used to involve dumping materials in a manway. Single-use bags that dock to a vessel have become the predominate method for media powder addition in new and retrofit designs. These powder bags can be prepared in a dispensing area on site or purchased prefilled with the requisite formulary weight of powder.
For facilities that have historically performed open charging, the additional cost of single-use bags has led to increased use of closed transfer bags for select high-risk components. Powder blenders have improved in operation and reliability over the years, but they are still relegated to niche applications (e.g., hard-to-dissolve powders). The addition funnel is typically cleaned out-of–place, and the desire to have a barrier to the room either discounts this equipment or requires the addition of a barrier technology (e.g., laminar flow hood, isolator, etc.). Feeding a powder blender from a bag that connects to the addition port often results in vacuum collapse of the bag, forcing operators to “massage” powder out of the bag. Most commercial-scale facilities run volumes that prohibit the use of single-use mixers for the main bioreactor feed, but they do utilize single-use mixers for smaller setups.
Concerns about contamination in the media components have driven the industry, over the years, to chemically defined media, but some processes still utilize animal-derived components. The viral contamination that shut down Genzyme’s Massachusetts and Belgium facilities in 2008 and 2009 highlighted this concern. The use of high-temperature short-time (HTST) viral clearing/processing can help reduce this risk, but most facilities/processes are not utilizing HTST technology at this time. Instead, they plan for space and utilities to support these systems during new builds and retrofits. Single-use systems are enabling additional layers of engineered contamination risk mitigation on top of the procedural risk mitigations, leading toward a more robust and repeatable method for mitigating contamination.
A wide spectrum of single-use technology has been implemented in buffer operations, from additional hold vessels for existing facilities running at higher rates, to new facilities that have no buffer preparation area. Buffer preparation has been viewed as a low-risk area where many companies have begun their exploration of single-use systems. Due to the high chloride content of some buffers, SUS holds a significant cost advantage over traditional high alloy tanks and piping systems.
Facilities are implementing multiple methods to reduce the space required for buffer holding by staging buffers at the entrance of suites (just-in-time production) and stacking/racking for longer holds. In some cases, new facilities are opting to use buffers that are prepared off-site, sterilized, and delivered in single-use bags. These facilities are reducing capital costs by using high-density warehouse space instead of classified or controlled not classified (CNC) space for storing buffer. This operational mode requires additional efforts in supplier quality assurance and shipping qualification.
Inoculation is traditionally a high-risk operation, where a single contamination can wipe out an entire production slot. Vial breakages in biosafety cabinets (BSCs) with a Grade C (ISO 8 in operation) background are typical. Both BSCs with a Grade B (ISO 7 in operation) background and isolators with a Grade C background are competing to become the new gold standard. Closed processing after vial breaks is becoming the norm for reducing the risk of contamination. Pre-sterilized flasks and roller bottles with sealed tube ends for sterile welding along with the traditional single use rocker bags enable a closed single-use path in inoculum areas.
Single-use systems have experienced broad implementation in seed trains for cell culture/fermentation. The high assurance levels for cleanliness and sterility have driven this trend, coupled with the economics of eliminating bioreactor cleaning. These systems are well-characterized (including known growth inhibition with certain film /cell lines) and in certain cases can handle microbial fermentation. A ceiling has existed at 2,000L, but new offerings have reached 3,500L.
Harvest operations at 2,000L scale and below have capitalized on encapsulated filters to eliminate the space and utilities required for centrifugation. Single-use centrifuge systems are still implemented in processes that require cell recovery, but not as often for supernatant recovery. Above 2,000L-scale, disc stack centrifugation remains a staple of harvest operations. In such cases, the use of encapsulated clarification filters can still offer advantages in utility consumption and lower room ceilings. Challenges with encapsulated filters include vendor specific designs of holders such that changes in filter vendors (e.g., between campaigned products) can require inventorying multiple holders. Also, filter disassembly requires careful attention to procedure development from ergonomics and cleanliness perspectives.
Disposable flow path chromatography systems are being implemented in smaller-scale process, typically 2,000L or less bioreactor scale. The advantage here is in cleaning and the utilities required for cleaning — the space gained from using a disposable flow path chromatography pump/controller instead of a stainless steel one is minimal. The use of prepacked/ready-to-use columns has the potential to reduce facility size, increase throughput by reducing change over time, and minimize the risk of contamination during packing operations. Supplier quality assurance and pre-use pressure drop verification are critical for the successful implementation of this technology.
Tangential flow filtration systems with a disposable fluid path are currently limited in scale and have similar footprints to stainless steel skids. Their advantage is in cleaning and a simpler changeover. In processes where single-pass tangential flow filtration can be implemented, the smaller size of the disposable fluid path systems provides a good match for larger-scale and small-scale operations. Due to their smaller size, disposable fluid path systems provide low hold-up volumes and easier implementation of single-use technology.
Viral filtration and bulk filtration have been readily adapted to single-use, since the functional part (the filter cartridge) was always single-use. Encapsulated filters can either be connected to existing stainless steel systems or sterilely connect to other single-use systems.
Some unit operations (ultra-centrifugation, sonication/cell disruption) required for certain vaccine processes are not driving towards a single-use solution. Some vaccine platforms are exploring the use of ultrafiltration/chromatography instead of ultracentrifugation, or lysates in place of cell disruptors, in an effort to create a more robust commercial process. Current technology doesn’t support direct equivalents in single-use systems for these unit operations.
The (Cleaner) Road Ahead
The examples above demonstrate how the biopharmaceutical industry is using disposal systems to simultaneously reduce cost and mitigate contamination. Several studies have compared the capital and operating cost of single-use and stainless steel equipped facilities (see References). These studies typically neglect to take into account the lost opportunity cost of a batch failure due to contamination and the regulatory impact of multiple contamination events. Closed processing and disposable flow paths provide an effective method for avoiding such costs.
Future installments in this series will explore how single-use systems can reduce footprints and enact closed systems to drive changes in facility layout (design basics and design options), HVAC, utilities, and construction.
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.