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CONTINUOUS BIOPROCESSING PROMISES AND CHALLENGES BioProcess

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CONTINUOUS BIOPROCESSING PROMISES AND CHALLENGES Babu Halan and Wolfgang Minas

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BioProcess International eBooks

February 2020

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Enabling Technologies and Unit Operations

The Role of Single-Use Technologies

Process Configuration Possibilities

Status Quo in Biopharmaceuticals

The Future of Continuous Bioprocessing

From BPI Archives

References

About the Authors

Continuous Bioprocessing Promises and Challenges

by Babu Halan and Wolfgang Minas

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B iomanufacturing commonly is executed in batch processes, especially for downstream processing (DSP) operations. Increased fermentation titers, reduced operating scales, and efforts toward improved product quality have driven interest in developing continuous bioprocessing. Within the next 10 years, about half of all drugs under development will be biopharmaceuticals (1), making it worthwhile to develop more efficient processes.

A continuous process is defined as one consisting of integrated (physically connected), continuous unit operations with zero or minimal hold volume between operations (2). Changing to continuous processes reduces the size of traditional unit operations, thus allowing low investment costs for the same “space–time” yield. About 90% of biological products now are produced using batch and fed-batch cultivations (e.g., for upstream processing, USP) and batch-wise DSP operations. The development of platforms for continuous processing is one indication that this technology is reaching maturity (3). Industrial and academic researchers are investigating the potential of continuous systems for manufacturing biopharmaceuticals.

In the past 10 years, space–time yields in USP have provided up to 100-fold improvement. This has been driven by a number of advances such as improved expression systems, genetically engineered cell lines, optimized media, and better bioprocess controls (4). By contrast, only a few advances have been made in DSP. So the focus now has shifted toward improving this stage of biomanufacturing (5). Unlike USP, the cost of DSP increases linearly with feed-stream volume, currently accounting for nearly 80% of total production costs. Biomanufacturers are under pressure to reduce production costs without compromising product quality. So disruptive and game-changing technologies are in high demand in traditionally conservative biopharmaceutical environments (6).

Between 2011 and 2016, the US Food and Drug Administration (FDA) approved several protein therapeutics. Nearly 50% of those were monoclonal antibodies (MAbs), and coagulation factors, and enzymes accounted for 19% and 11%, respectively. Plasma proteins, fusion proteins, growth factors and hormones accounted for the remaining 22% (7). Herein we focus on bioprocesses for different drug products, including MAbs, enzymes, coagulation factors, adeno and lentiviruses, and RNA/DNA-modified products. We highlight current trends, technologies, challenges, and perspectives for continuous bioprocessing and focus on the influence of single-use technologies (SUTs) on continuous bioprocessing.

Enabling Technologies and Unit Operations Fully integrated continuous bioprocessing offers several advantages over traditional batch and fed-batch processing. They include low residence and cycle times; sustained operation with consistent product quality; reduced equipment size; high-volume productivity; streamlined process flow; and minimized waste, energy consumption, and raw material use (2, 8). Such benefits would

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reduce capital expenditure and operating costs. However, continuous bioprocessing requires deep process knowledge and implementation of process analytical technologies (PATs). Biomanufacturers also would need to address batch definition, handling of out-of- specification (OoS) materials, and related regulatory issues. In this section, we describe available unit operations that can be operated in continuous mode.

Cell Culture: Perfusion systems are well established and understood by major biomanufacturers such as Genzyme, Bayer, Janssen, BioMarin, Shire, Merck Serono, Novartis, and Pfizer. Perfusion bioreactors enable harvesting of unstable proteins with minimal degradation. The US Food and Drug Administration (FDA) has approved about 20 biologics produced in perfusion systems (9). Such systems are used up to 4,000-L scales (10) and can be operated continuously for over 60 days. The overall longevity of a process mainly is driven by a molecule’s genetic stability, which requires significant research.

Harvest/Primary Recovery: Although continuous filtration devices (e.g., belt and drum filters) commonly are used in industrial- scale microbial fermentations, they have never been adapted for use in cell cultures. Alternating tangential-flow filtration (e.g., ATF system from Refine Technology, now Repligen Corp.) can be used for cell retention and is currently the most preferred unit operation for initial clarification of cells, especially in perfusion systems. An ATF system can be operated continuously with up to 2,000-L culture volume (11). Other unit operations have been studied and are applied in process industries (e.g., continuous centrifugation, acoustic separation, aqueous two-phase separation, and membrane adsorbers). Adaptation of such technologies might be difficult for a given biological product but could be attractive for future bioprocess developers designing truly continuous operations. Table 1 lists commonly used unit operations in DSP with their availability in single-use units.

A continuous aqueous two-phase extraction (ATPE) process has been adapted for antibody purification from cell-culture supernatant based on polyethylene glycol (PEG)/phosphate extraction and subsequent washing (12). This approach is as an alternative to typical chromatographic processes supporting continuous operation, scalability, and economic feasibility (12). An ATPE unit operation can be integrated as a continuous product capture step in DSP. Although the technology has been well adapted, it is still at an early development stage for biological products. Overcoming some problems (e.g., understanding the partition mechanism) could further this technology toward upscaling (13).

Membrane Adsorbers: Dynamic capacities of chromatographic resins often create a bottleneck in protein purification. To match high bioreactor productivities, chromatographic columns are oversized. Membrane adsorbers can be alternatives to traditional chromatography processes during capture and polishing steps. Surface-functionalized membranes offer high purification

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productivity (14). Examples include Sartorius’s Sartobind Q, Pall’s Mustang Q, EMD Millipore/Natrix Technology’s Natrix HD-A, and Natrix HD-Sb membranes. Such adsorbers are validated for contaminant removal in a flow-through mode (negative chromatography) to bind DNA, residual proteins, host-cell proteins (HCPs), endotoxins, viruses, and aggregates. The adsorbers are disposable and come in SUT modules (14, 15).

Continuous Viral Inactivation: Bioprocesses based on mammalian-cell expressions require at least two independent steps for removal of adventitious viruses. These steps can include low-pH treatment, solvent/detergent treatment, and nanofiltration or UV treatment. The selected methods and their sequence depend on drug-product characteristics. All steps must be validated, and treatment parameters such as time, temperature, pressure, flow, and so on need to be controlled.

Traditionally, low-pH viral inactivation has been a batch process. Researchers now have developed a continuous viral inactivation system in a coiled flow inverter (CFI) module. The reactor module enables nearly plug-flow behavior at laminar-flow regimes. This continuous low-pH (pH <4) virus inactivation technique is built as a single-use unit (16).

Development of alternative viral-inactivation techniques will be important for future bioprocesses, especially because some currently used solvents (e.g., Triton brande from Union Carbide Co.) are likely to be banned in the near future. Bayer Technology Services has developed a compact tubular reactor module that spirals around a UV irradiation source (254 nm). The system provides efficient mixing and maximizes virus exposure to UV light (17). Its implementation into continuous processing at pilot and commercial

Figure 1: Unit operations used for antibody purification include cation-exchange (CEX), anion-exchange (AEX), and mixed-mode chromatographies (MMC) as well as ultrafiltration/diafiltration (UF/DF).

Inoculum

Upstream Downstream

Cryoculture

Shake flask culture

Seed fermentor

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Continuous Upstream

Bioreactor with perfusion system

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CEX Chromatog.

AEX Chromatog.

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Depth filtration

Viral inactivation

Microfiltration Virus filtration UF/DF

Formu- lation and

filling

Harvest tank

MMC Virus inactivation

MMC Virus filtration

Formulation and filling

Continuous Downstream

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scales has not been explored yet, particularly with respect to potential protein damage. Virus filtration remains a delicate process requiring tight controls on constant flow and controlled pressure and temperature, making its integration into continuous processes difficult.

Chromatography: Simulated moving-bed (SMB) chromatography is an established continuous purification system that has been used for separating small molecules (e.g., fructose and glucose). SMB chromatography also could be applied for continuous purification. Some recent developments enable its use in bioprocessing, including integration with upstream operations (Table 2). But considerable information technology knowledge will be needed in such processes to check compatibility of individual unit operations for integration with other systems.

Centrifugation: Centrifugation technologies have played a crucial role in initial clarification. Recent developments have offered promising results in reducing cell damage and product loss. For example, kSep (Sartorius Stedim Biotech) and UniFuge (Pneumatic Scale Angelus) systems are clean/steam-in-place (CIP/SIP) independent SUTs and are paving the way toward continuous processing (11).

Separators or decanters (e.g., GEA, Alfa Laval, Flottweg, and others) provide options to discharge collected biomass during a run and are scalable over a wide range.

Table 1: Unit operations used for antibody purification

Process and Unit Operation Equipment

Availability in SUT

Continuous Mode Possibility Comments Reference

Filtration Depth filters Yes Yes, with automated switching

Free of particles, protects chromatographic columns; nearly unlimited culture volume; usually coupled with centrifugation

11

Filtration Tangential-flow filtration (TFF)

Yes Yes Culture volume up to 2,000 L (e.g., Allegro CS, Pall; Pellicon single-pass TFF (SPTFF); XCell AFT, Repligen for perfusion systems)

11 and Footnote 1

Filtration Viral removal filters Yes No e.g., Planova or Pegasus prime virus removal filters; virus retention

Footnote 2

Filtration Bioburden reduction filters

Yes Yes, with automated switching

Prolongs life of capsules; reduces bioburden; is widely available

Footnote 3

Clarification Centrifuge Yes Yes Removal of submicron particles still challenging (e.g., CARR Centritech Unifuge, kSep)

11 and Footnote 4

Purification Chromatography Yes Yes See Table 2 Table 2

Purification Membrane adsorbers Yes To be investigated Attractive alternative to conventional resins; more research needed

6 and Footnote 5

Virus inactivation Plug-flow reactor To be investigated

Yes Low pH viral inactivation technology; promising technology 16, 17, and Footnote 7

Virus inactivation Stirred-tank reactors/ bags

Yes Partly Cadence with 50-L single-use mixers (e.g., Pall); low-pH technique

16, 17, and Footnote 7

Concentration, buffer exchange, perfusion

Ultrafiltration/ diafiltration

Yes Yes (with SPTFF) SPTFF allows continuous UF/DF (Cadence SPTFF, Pall) Footnote 8

Concentration, buffer exchange, perfusion

TFF Yes Yes Culture volume up to 2,000 L (e.g., Allegro CS, Pall; Pellicon single-pass TFF; XCell ATF, Repligen for perfusion systems

11 and Footnote 9

Bulk filling Bag filling Yes Partly RoSS system www. susupport.com

1 www.pall.com; www.merckmillipore.com/CH/de/20181016_170845; www.repligen.com 2 www.pall.com; planova.ak-bio.com/products_services 3 www.gelifesciences.com; www.sartorius.com; www.pall.com 4 www.sartorius.com; www.psangelus.com 5 www.gelifesciences.com; www.sartorius.com; www.natrixseparations.com 7 www.gelifesciences.com; www.pall.com 8 www.pall.com; www.merckmillipore.com 9 www.pall.com; www.merckmillipore.com/CH/de/20181016_170845; www.repligen.com

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Ultrafiltration (UF) and Diafiltration (DF) Tangential-Flow Filtration (TFF): UF and DF operations are part of almost all biopharmaceutical DSP. In shaping UF/DF technology toward continuous operation, single-pass TFF (SPTFF) is an emerging concept for continuous concentration of proteins (18). Customization (different types and areas of membranes), PAT needs, and user requirements on process control make implementation difficult and slow.

Precipitation: Continuous precipitation technology is a simple, robust, and economically feasible method to remove process-related impurities from clarified cell-culture supernatant. Although precipitation technology is applied in blood plasma fractioning (noncontinuous mode), it is not commonly practiced in the biopharmaceutical industry. This technique is emerging, however, and studies already have shown that by implementing novel reactor modules such as coiled flow inverter reactors (CFIRs), precipitation can be integrated into a continuous bioprocess (19).

The Role of Single-Use Technologies Increasing use of SUTs has been a driver for continuous bioprocessing. But the limited scalability of most SUTs (2,000-L limit for single-use bioreactors from most suppliers) requires an alternative to improving space–time yields and reducing operating expenses (OpEx).

SUTs are available for most unit operations — from cell preculture systems through drug-substance freeze–thaw (20–22). SUT probes and sensors have been developed and are proven to be suitable for continuous bioprocessing to reduce CIP requirements. Continuous manufacturing processes using exclusively SUTs are possible using plug-and-play systems. Table 1 lists SUTs implemented in most unit operations, and the “Expert Perspectives” box includes different viewpoints on SUTs and continuous processing.

SUT systems generally lower capital expenditures (CapEx), but OpEx increase. SUT auxiliaries are available for most upstream components to facilitate continuous operations. Not all DSP components are available in single-use form yet (Table 1).

Single-use sensors are gaining widespread acceptance in good manufacturing practice (GMP) environments. Such devices can be integrated easily into continuous bioprocessing. However, single-use probes have limitations. The durability and functional integrity of

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Table 2: Overview of continuous chromatography processes

Product Name Developer Platform Technological Competence BioSC continuous chromatography

Novasep Sequential chromatography platform (SMC)

Up to six columns (sixfold increase in productivity); reduced resin and buffer capacity by 75%* (www.novasep.com)

Cadence BioSMB continuous chromatography

Pall Corporation Simulated moving-bed (SMB) technology

Available as single use; up to 16 columns; reduces sorbent and buffer requirement by up to 80%* (www.pall.com)

SMBC continuous chromatography

Semba Biosciences

SMB Up to eight columns; continuous unattended purification from milligram to gram scale

3C- or 4C-PCC continuous chromatography

GE Healthcare Periodic counter-current (PCC) technology

Up to four columns; straight-through processing; greater use of chromatography resins

CaptureSMB continuous chromatography

ChromaCon PCC Two-column PCC

* Reduced compared with batch process

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such sensors over extended periods of time have to be well characterized. However, values are mostly monitored as only trends, and values for batch records are determined using in-process control (IPC) samples measured in quality control (QC) laboratories.

Process Configuration Possibilities Figure 1 shows different process configurations and possibilities for implementing continuous bioprocessing. A process consisting of both batch and continuous operations is referred to as a semicontinuous or hybrid approach. Case studies have demonstrated

Figure 2: Holistic perspective on continuous bioprocessing; experts’ views from regulatory, industry, equipment manufacturing, research, and project planning aspects are in the box below.

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Substrate Product

Industry Perspective: “Continuous processing in the biopharmaceutical industry is still at the development stage. However, it’s on the right track toward commercialization. Some issues need to be discussed among industry stakeholders and especially by the regulatory agencies (e.g., challenges in batch definition, process validation, and consistent product quality). In general, lower manufacturing costs and local instead of global manufacturing could be realized with continuous processes.” — Suyamburam Sathasivam (Sun Pharma)

Regulatory Perspective: “Regulatory agencies, especially the FDA and European Medicines Agency (EMA), are quite open to innovations that would improve drug-product quality and help prevent drug shortages. Accordingly, several guidelines and programs have been set up for continuous manufacturing regulations that also can be applied to biotechnology processes. For small molecules, such approvals already exist. Taking into account process analytical technology (PAT), real-time release testing (RTRT) aspects, quality by design (QbD), and enhanced process validation strategies with deep process knowledge — delivering the right critical quality attributes (CQAs), and critical process parameters (CPPs) as part of a sound control strategy — the regulatory requirements are set and only await individual application.” — Dr. George Sinclair (formerly at Chemgineering Business Design GmbH)

Project Engineering Perspective: “Continuous processing requires highly reliable equipment and robust process controls. Ideally, there is no need for intermediate storage, but a risk-based approach is needed to identify and define possible hold-up scenarios. For out-of-specification results, clear parameters should be defined as to when material can be released again.” — Dr. Wolfgang Minas (Chemgineering Technology AG)

Equipment Manufacturing Perspective: “Single-use technologies have enabled facilities to be built and commissioned in a fraction of the time and for a fraction of the investments of conventinal facilties. So far, they have been of limited use for commercial manufacturing because of their limited output. The process intensification trend within the industry is helping companies mitigate that limitation and substantially improve productivity of single-use manufacturing facilities, combining the best of both worlds in terms of speed, cost of goods, and flexibility.” — Dr. Gerben Zijlstra (Sartorius Stedim Biotech SA)

Research Academic Perspective: “New process and equipment supporting continuous operations in biomanufacturing are appearing. It is our expectation that advanced data handling, process modeling, and machine learning will enable even more robust and contiguous implementation and that the bioreactor digital twin will become a powerful tool in this regard.” — Dr. WIlliam G. Whitford (GE Healthcare)

Expert Perspectives for Figure 2

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that it is possible to link continuous upstream and downstream systems, resulting in an end-to-end integrated process. That is possible with cell-culture processes for antibodies or other biopharmaceuticals that are expressed constitutively. Induced productions or production of secondary metabolites are less suitable for continuous processing. Their fermentation is a batch or fed-batch operation that, at the end, requires a rapid workup of the entire volume.

Continuous USP with Batch DSP: Figure 1 shows a continuous USP coupled to a batch DSP. Such hybrid systems have been used to produce complex/labile proteins such as enzymes, blood factors, and MAbs (10).

Batch USP with Continuous DSP: For this process, a traditional fed-batch mode is combined with a continuously operated DSP. A strong motivation for using such an approach is the significant increase in expression levels and product concentrations (5–10 g/L) obtained in upstream operations over the past decade. To address such improvements, biomanufacturers continue to evaluate continuous DSP options. Moreover, operational costs could be reduced by up to 70% when a batch operation is switched to continuous downstream mode (23).

Continuous chromatography plays a central role in product capture and polishing. Many continuous chromatography MAb processes have been developed and are commercially available for laboratory and pilot-scale applications (Table 2) (24). Continuous protein purification is limited (e.g., by an inability to operate over a prolonged period under strict bioburden environments) (2). And significant challenges remain before that approach is realized for commercial-scale operations (23). Such a hybrid system would be difficult to implement when multiple bioreactors feed into one DSP system and when extended downstream processing times are not favorable for protein purification.

Continuous USP and DSP: To realize its full potential, a complete system should be operated end-to-end continuously. That is a goal for many biopharmaceutical companies. Tables 1 and 2 show that most unit operations used in a standard MAb DSP process now can be handled continuously. But not all unit operations currently are available at commercial scale. At development scale, few fully integrated continuous bioprocesses have been reported (25–27). The critical challenge is to integrate USP with DSP because operating DSP continuously can be difficult (11). However, a partly continuous option still would be possible with high risks, depending on facility design. Such a system might be fine for a single-product facility, but a multiproduct facility with several and possibly different-sized single-use bioreactors feeding into a continuous DSP would limit flexibility and/or require installation of multiple DSP lines.

Status Quo in Biopharmaceuticals Thus far, the FDA has approved continuous manufacturing processes for three products: Vertex’s cystic fibrosis drug Orkambi (lumacaftor

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and ivacaftor combination) (28), Prezista (darunavir) from Janssen (29), and Verzenio (abemaciclib) from Eli Lilly. The agency encourages efforts of the biopharmaceutical industry to move in the direction of continuous bioprocessing.

Current reports refer to pilot- and laboratory-scale continuous operations but not to implemented industrial-scale biopharmaceutical production. Sanofi-Genzyme, Merck, and Bayer all have demonstrated advanced process examples at laboratory and pilot scales. Sanofi- Genzyme reported an end-to-end continuous production method for recombinant MAbs (25, 27). The process architecture includes a perfusion bioreactor (12 L) with ATF (Refine Technology LLC) at the upstream and periodic countercurrent chromatography (PCC) at the downstream. The system reached a productivity of 8 g/day, with an overall yield of 80% and a consistent product quality over 30 days (27, 30).

Another example is Merck’s demonstration of an integrated bioprocessing concept known as a “protein refinery operation laboratory” (PRO lab) using single-use systems. The facility had 10-L perfusion bioreactors upstream. Single-use TFF and SMB chromatography (BioSMB, from Pall) were integrated as core unit downstream operations. The entire process was controlled with integrated analytics. This advanced concept obtained a productivity of 10 g/day (31, 32).

Bayer Technology Services has developed a “biofacility of the future” platform that is continuous and disposable. Perfusion bioreactors (two 10-L Bayshake) were used in USP. SUT inclined gravity settlers were used for retaining cells within the perfusion system. For polishing the product during DSP, mixed-mode and anion-exchange chromatography were coupled in a BioSMB platform. The manufacturer achieved a productivity of 22.7 g/day using this system. SUTs were used for most DSP unit operations, and a Siemens control system was used for process automation (26). This DSP operated for only 2.5 days, compared with 28 days for USP operations.

Efforts will be needed to extend the operational duration of DSP. Despite the above success stories, biomanufacturers have been slow to adopt continuous manufacturing at commercial scales. However, progress is growing steadily.

The Future of Continuous Bioprocessing The biopharmaceutical industry generally is viewed as conservative partly because it operates in one of the most regulated markets worldwide. It costs billions to develop and market a new drug. Changing a registered production process (e.g., change of production technology) is difficult and expensive because new clinical trials and approvals are required. However, introducing a new product opens up the possibility of implementing new technologies such as continuous processes. Slowly but steadily such advances are progressing and being implemented in the biopharmaceutical industry. Continuous bioprocessing requires extensive process knowledge at the technology, R&D, and regulatory levels.

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Technology: Implementation of new process technologies should be considered during early process and drug development. Technology, drug product, and regulatory should go hand in hand.

Many R&D issues also should be addressed before new technology implementation. For example, genetic stability of a cell line in a long-run continuous process remains a limitation. The concept of PAT is not new, but its adaptation in a continuous bioprocess is challenging and needs significant additional R&D efforts. Close collaboration with regulatory authorities and equipment vendors can accelerate technology development and implementation. A holistic approach and a close collaboration among stakeholders is helpful in realizing continuous bioprocessing at commercial scale (see “Expert Perspectives” box).

Regulatory: The FDA’s perspective on continuous bioprocessing looks encouraging, as evidenced by its approval of Symdeko (tezacaftor/ivacaftor and ivacaftor) from Vertex, which is manufactured using a continuous process. The FDA strongly recommends that biomanufacturers have early and frequent discussions with the agency at all stages of continuous process development (33).

Linking USP and DSP would change the design of a facility. Often several bioreactors feed into a single DSP train, particularly in

Back to ContentsFrom the BPI Archives at https://bioprocessintl.com Goby JD, et al. Control of Protein A Column Loading During Continuous Antibody Production: A Technology Overview of Real-Time Titer Measurement Methods. September 2019.

Brower M, et al. Continuous Biomanufacturing: A New Approach to Process Scale. June 2019.

Montgomery SA, et al. Making Downstream Processing Continuous and Robust: A Virtual Roundtable. June 2019.

Cooney B, Jones SD, Levine HL. Quality By Design for Monoclonal Antibodies: Establishing the Foundations for Process Development, Design Space, and Process Control Strategies. June 2018.

Rajamanickam V, Herwig C, Spadiut O. Data Science, Modeling, and Advanced PAT Tools Enable Continuous Culture. April 2018.

Whitford W, et al. The 2017 World Biological Forum: Successes and Future Trends in Continuous Biomanufacturing. October 2017.

Holzer M. Is Continuous Downstream Processing Becoming a Reality? May 2017.

Scott C. Continuous Processes: Disposables Enable the Integration of Upstream and Downstream Processing. May 2017.

Munk M. The Industry’s Hesitation to Adopt Continuous Bioprocessing: Recommendations for Deciding What, Where, and When to Implement. April 2017.

Schmidt SR. Drivers, Opportunities, and Limits of Continuous Processing. March 2017.

Sherman M. Continuous Cell Culture Operation at 2,000-L Scale. November 2016.

Monge M. Deciding on an Integrated Continuous Processing Approach: A Conference Report. June 2016.

DePalma A. Special Report on Continuous Bioprocessing: Upstream, Downstream, Ready for Prime Time? May 2016.

Mothes B, et al. Accelerated, Seamless Antibody Purification: Process Intensification with Continuous Disposable Technology. May 2016.

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multiproduct plants. In such cases, linking USP and DSP would require additional DSP trains, one for each bioreactor. Linking USP and DSP makes sense mostly for monoproduct production lines if the USP can be operated in perfusion mode for extended periods.

References 1 Jozala AF, et al. Biopharmaceuticals from Microorganisms: From

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3 Thiess H, et al. Engineering Challenges of Continuous Biomanufacturing Processes (CBP). Continuous Biomanufacturing. Subramanian G, Ed. Wiley- VCH: Weinheim, Germany, 2018, 69–106.

4 Rader RA, Langer E S. 30 Years of Upstream Productivity Improvements. Bioprocess Int. 13(2) 2015: 10–14.

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6 Gottschalk U. The Future of Downstream Processing. BioPharm Int. 24(9) 2011.

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8 Status Paper: Facility of the Future. DECHEMA: Frankfurt, Germany, 2017. 9 Schmidt S. Drivers, Opportunities, and Limits of Continuous Processing.

BioProcess Int. 15(3) 2017: 30–37.

10 Pollock J, Ho SV, Farid SS. Fed-Batch and Perfusion Culture Processes: Economic, Environmental, and Operational Feasibility Under Uncertainty. Biotech. Bioeng. 110(1) 2013: 206–219.

11 Schmidt S, Wieschalka S, Wagner R. Single-Use Depth Filters. BioProcess Int. 15(1) 2017: i7–i11.

12 Rosa PA, et al. Continuous Purification of Antibodies from Cell Culture Supernatant with Aqueous Two-Phase Systems: From Concept to Process. Biotechnol. J. 8(3) 2013: 352–362.

13 Iqbal M, et al. Aqueous Two-Phase System (ATPS): An Overview and Advances in Its Applications. Biol. Proced. 28 October 2016; doi:10.1186/s12575- 016-0048-8.

14 Jacquemart R, Stout J. Membrane Adsorbers, Columns: Single-Use Alternatives to Resin Chromatography. BioProcess Int. 15(1) 2017: i16–i17.

15 Jacquemart R, et al. A Single-Use Strategy to Enable Manufacturing of Affordable Biologics. Comput. Struct. Biotechnol. J. 14, 2016: 309–318. doi:10.1016/j.csbj.2016.06.00.

16 Klutz S, et al. Continuous Viral Inactivation at Low pH Value in Antibody Manufacturing. Chem. Eng. Process. 102, 2016: 88–101; doi:10.1016/j. cep.2016.01.002.

17 Zydney AL. Continuous Downstream Processing for High Value Biological Products: A Review. Biotechnol. Bioeng. 113(3), 2016: 465–475; doi:10.1002/bit.25695.

18 Challener C. Evolving UF/DF Capabilities. BioPharm Int. 31(1) 2018.

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19 Kateja N, et al. Continuous Precipitation of Process Related Impurities from Clarified Cell Culture Supernatant Using a Novel Coiled Flow Inversion Reactor (CFIR). Biotechnol. J. 11(10) 2016: 1320–1331; doi:10.1002/biot.201600271.

20 Shukla AA, Gottschalk U. Single-Use Disposable Technologies for Biopharmaceutical Manufacturing. Trends Biotechnol. 31(3) 2013: 147–154; doi:10.1016/j.tibtech.2012.

21 Whitford WG. Single-Use Technology Supporting the Comeback of Continuous Bioprocessing. Pharm. Bioprocess. 1(3) 2013: 249–253.

22 Whitford WG. Single-Use Perfusion Bioreactors Support Continuous Biomanufacturing. Pharm. Bioprocess. 3(1) 2015: 75–93.

23 Holzer M. Is Continuous Downstream Processing Becoming a Reality? BioProcess Int. 15(5) 2017: i20–i27.

24 Jungbauer A. Continuous Downstream Processing of Biopharmaceuticals. Trends Biotechnol. 31(8) 2013: 479–492.

25 Warikoo V, et al. Integrated Continuous Production of Recombinant Therapeutic Proteins. Biotechnol. Bioeng. 109(12) 2012: 3018–3029; doi:10.1002/ bit.24584.

26 Klutz S, et al. Developing the Biofacility of the Future Based on Continuous Processing and Single-Use Technology. J. Biotechnology. 10(213) 2015: 120–130; doi:10.1016/j.jbiotec.2015.06.388.

27 Godawat, et al. End-to-End Integrated Fully Continuous Production of Recombinant Monoclonal Antibodies. J. Biotechnol. 10(213) 2015: 13–19; doi:10.1016/j.jbiotec.2015. 06.393.

28 Elder D, Savla R, Tindal S. Modernising the Supply Chain Using Continuous Manufacturing. Eur. Pharm. Rev. 22(5) 2017: 51–54.

29 Marriott N. EMA Approves Janssen’s Prezista Continuous Manufacturing Line. Eur. Pharm. Rev. 27 June 2017; https://www.europeanpharmaceuticalreview. com.

30 Konstantinov K, et al. Integrated Continuous Manufacturing of Therapeutic Protein Drug Substances. US Patent US20140255994A1, 2014.

31 Bisschops M, Schofield M, Grace J. Two Mutually Enabling Trends: Continuous Bioprocessing and Single Use Technologies. Continuous Biomanufacturing. Subramanian G, Ed. Wiley-VCH: Weinheim, Germany, 2018; 149–169.

32 Brower M, Pollard D, Hung F. Protein Refinery Operations Lab (PRO Lab): A Sandbox for Continuous Protein Production and Advanced Process Control. Integrated Continuous Bioprocessing (ICB2) Conference, Berkeley, CA, 1–5 November 2015.

33 Lee S. FDA CDER Perspective. Third FDA/PQRI Conference on Advancing Product Quality, Washington, DC, 22–24 March 2017. cc

About the Authors Corresponding author Dr. Babu Haland ([email protected]) is a project engineer, and Dr. Wolfgang Minas (wolfgang.minas@ chemgineering.com) is global lead of the Competence Center for Biotechnology, both at Chemgineering Technology AG, Binningerstrasse 2, 4142 Münchenstein, Switzerland; www.chemgineering.com.

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