Single-Use Perfusion Bioreactors Support Continuous Biomanufacturing
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Pharmaceutical Review 3 Review Single-use perfusion bioreactors support continuous biomanufacturing Pharm. Bioprocess. The field of biomanufacturing employs many single-use (SU) systems for features such William (Bill) G Whitford as lower initial investment and reduced time-to-market. Continuous manufacturing GE Healthcare, Cell Culture, 925 West methods can provide increased product quality and process control, and reduced 1800 South, Logan, UT 84321, USA [email protected] operating costs. Continuous biomanufacturing (CB) additionally promises reduced classified area extent, personnel requirements and operating steps. The benefits of SU CB include heightened processing parameter consistency and increased process flexibility. Perfusion culture (PC) is supported by many specialized SU and hybrid bioreactors. These and many accessory perfusion-enabling technologies are the main way of implementing upstream CB. Valuable features provided by PC include reduced product reactor-residency and increased reactor-volumetric productivity. SU PC supports the dream of enterprise managed, modular, end-to-end integrated and closed CB providing higher environmental sustainability. Single-use systems bioreactor harvest [11] . While existing systems The biopharmaceutical industry now incor- for disposable processing have been accepted porates significant levels of single-use (SU) in bioproduction for many operations, new technology and systems in the majority of developments in the technology and scale of animal cell culture-based production pro- application continue to be presented. This cesses [1,2]. Implementation of these technolo- includes SU applications in vaccine manufac- gies has resulted in prepackaged and steril- turing [12,13] and cell-based therapies [14–16] . ized systems, complete and ready for use with Exciting advancements continue in the areas preinstalled impellers and monitoring probes of fluid connectivity and reactor component (Box 1) [3]. SU bioreactors (SUBs) are now sampling and monitoring [17] . While SU- available from multiple suppliers, with sev- based bioproduction has traditionally been 1 eral offerings of up to a 2000 l working vol- applied to animal cell-based production, an ume [4–6]. A variety of sparging/mass-trans- increasing number of system suppliers are fer and cell suspension/segregation designs supporting manufacturing-scale microbial are available − from innovative packed bed to fermentation. While such applications are just 2015 rocker-style, top or bottom-mounted mixing beginning, it is anticipated that in the near devices, orbitially shaken or even ‘air-wheel’ future, SU fermentation of yeast, bacteria and impelled reactors [7]. fungi will become commonplace. From upstream process material prepara- Off the shelf, SU systems are now in regu- tion through final product formulation, bio- lar use to some extent in nearly every segment pharm sponsors are increasingly presented of the production train by contract manufac- with numerous SU solutions supporting all turing organizations (CMOs) and sponsors major production platforms [8–10]. SU flow- in regulated production applications [18–20] . path centrifuges, depth and diafiltration The field has progressed to the point that (including tangential flow filtration [TFF]) there now exist pre-engineered, modular, and heat exchangers allow disposable down- modular microenvironment and turn-key part of stream processing to begin directly from the facilities [21] . Such futuristic facilities can 10.4155/PBP.14.58 © 2015 Future Science Ltd Pharm. Bioprocess. (2015) 3(1), 75–93 ISSN 2048-9145 75 Review Whitford Box 1. Commercially available upstream single-use bioprocessing components. • Preparation and storage of media/buffers in single-use (SU) mixers • SU liquid and gas filtration of many types, including tangential flow filtration (TFF) • SU valving and SU peristaltic or diaphragm(s) pumps • SU process fluid heat exchange/manifold distribution • Storage of media and buffers for continuous processing feeding in SU bioprocess container (BPC) • SU storage and metered distribution of dry powders • SU or hybrid bioreactor cell culture in seed generation • Production in SU or hybrid-SU perfusion bioreactors • Continual appearance of new SU probes and sensors • SU real-time automated online multianalysis interface • SU flow-path online real-time controlled feed porting • Clarification by SU centrifugation or filtration into BPC employ areas of discrete and limited classified space ufacture. Another distinction is that batch produc- (controlled environmental modules, modular micro- tion is frequently segmented into many individual environments, isolation chambers or dedicated isola- steps, often performed at separate facilities (suitees, tor cabinets) or even within prefabricated trailers or buildings or cities) with significant effort involved in pods [22,23]. As this trend toward flexible bioprocess- intermediate hold and transport, whereas continu- ing modules and plug-and-play factories continues, ous processing (CP) occurs uninterrupted at a single we anticipate such facilities to become available with location. higher-level integrated system management [24,25]. For It should be considered that terminology in this a number of reasons, including component availabil- dynamic field can sometimes get fuzzy – for example, ity, process unit operations or even individual instru- continuous processing is also referred to as continuous mentation composed of both single-use and reusable production, continuous flow processing or continu- product contact components (hybrid systems) remain ous manufacturing. Furthermore, minor (to nonspe- quite common. cialists) distinctions are often made between differ- ent implementations and styles. In fact, few processes Continuous processing are absolutely and exquisitely ‘continuous’ in a strict Continuous manufacturing processes proceed for sense, and contemporary definitions often allow for variable lengths of time – from days to months to some degree of continual, multiple discretation of the years – and are only interrupted for such reasons as process or output. Depending on the periodicity and cleaning of equipment or the incremental deteriora- duration of entire production episodes, or the specific tion of enzymes, catalysts or cultures. This is in con- nature of more discrete individual component opera- trast to the discontinuous ‘batch’ production, where tions, some apply such terms as semi-, pseudo- and a specific quantity of product is manufactured in a quasicontinuous, hybrid or even microbatch based single, discrete volume during the same cycle of man- processes. Nevertheless, the characteristics and values described here do apply to many such incompletely Key terms continuous processes. Single-use systems: Processing equipment or material used in one manufacturing cycle and then retired from Continuous biomanufacturing use. Often composed of disposable materials in reusable Interest in the use of CP techniques in large-scale bio- housings. Hybrid systems: Here, either the use of both reusable and manufacturing has increased dramatically in the past single-use components in a process (or operation) or the few years, to the extent that many are now predicting use of both continuous and batch operations in a process. its eventual dominance in the industry [26,27]. This is Continuous processing: A manufacturing approach in due to the many benefits either CP itself, or the pro- which materials continuously flow through and between equipment as they are continually processed into an cess intensification operations contributing to it (see intermediate or final product. Table 1) [28]. Continuous biomanufacturing (CB) is Continuous biomanufacturing: Manufacturing of encouraged by pharmaceutical regulatory agencies and biological products employing continuous end-to-end provides many specific benefits in bioprocessing[29] . A processes and an integrated control strategy – beginning with starting materials and yielding final dosage units. growing number of biopharmaceutical manufacturers also commonly refers to continuous flow unit operations currently employ continuous processes in unit opera- demonstrating the potential to be a component of the full tions, and recent developments promise to stimulate process. even more interest in them [30]. 76 Pharm. Bioprocess. (2015) 3(1) future science group Single-use perfusion bioreactors support continuous biomanufacturing Review Quite a number of culture mode and process options CB is further enabled by ongoing technological that can accommodate a CP approach have existed developments in mixing and mass-flow systems and for decades. Recently, a number of manufacturing- (even more importantly) by the many recent advances scale perfusion or perfusion-capable bioreactors have in process monitoring and feedback/feed forward man- been launched (Table 2), and this includes the cur- ufacturing process control [31] . It should be noted that rently most popular stirred tank single-use bioreactors CB efficiently promotes both the tools and goals of (SUBs). Successful CB implementations have now operational excellence, thereby enabling such initiatives been achieved in a number of good manufacturing as PAT and QbD [32,33]. It readily accepts many new practice (GMP) installations of premiere biopharma- in/on-line monitoring approaches, real-time quality ceutical sponsors, including for approved products. For assurance as well as developments and advances in pro- example, Genzyme’s continued