single-use vs stainless steel-2016

December 2015 13(11)si BioProcess International A

GE Healthcare

Comparing single-use and stainless steel strategies for microbial fermentationKen Clapp, Eva Lindskog, Kjell Eriksson, and Sandeep Kristiansson

Process economy and production capacity

B BioProcess International 13(11)si December 2015

Figure 1: Production schedules for a single-product facility using either (a) stainless steel or (b) single-use equipment; in the former, one complete culture (including equipment preparation) takes four working days to complete. With single-use equipment, the culture can be harvested after only three days, saving a full working day.

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December 2015 13(11)si BioProcess International 1

S ingle-use technology spans a vast array of applications and associated products. Single-use components have been incorporated into subsystems and overall

systems alike. Disposable filters, fittings, connectors, and tubing (among other things) have been a mainstay of bioprocess operations for decades. Proper application, selection, and implementation of disposables have been essential to improving biopharmaceutical end-product quality, reducing cost, and simplifying operations.

In recent years, single-use technology has been migrating into many unit operations. Of interest for this discussion are fermentors for microbial culture. Like some components mentioned above, single-use bioreactors have been implemented for over a decade. Practical implementation, commercial availability, and lack of scalability were early limitations to adoption and use of such systems. That was until the WAVE Bioreactor system burst onto the market, sowing the seed for growth of single-use bioreactors and fermentors across the market.

With the commercial availability of such systems, end users had a new option for process development and production that would not rely on operational complexities and utility requirements of conventional sterilize-in-place (SIP) or autoclavable systems. The resulting freedom allowed for revisiting old ways of working and the opportunity to consider new ways to think about bioprocessing, including a focus on cost structures prevalent in the industry.

At first, the idea of a “plastic bag” bioreactor was met with some skepticism. However, benefits came with appropriate application and proper implementation of the technology. Success with the rocking platform made way for single-use stirred-tank bioreactors to emerge. They could rely on decades of design and performance experience established by their stainless steel counterparts. Despite all that experience, here too the technology was adopted cautiously. But single-use bioreactors have found their place and become a foundation of bioproduction based on animal (particularly mammalian) cell culture.

Success with single-use systems in large-scale cell culture — along with advances in material science, improvements in design understanding, and a resurgence of microbe-based biologics production — are converging to create exceptional opportunities. Whereas for animal cell culture, little was known initially about single-use bioreactor scalability and long-term viability, the same is not true for single-

use fermentors and microbial culture. Cell culture in single-use bioreactors has created a body of knowledge related to process equipment, single-use bag assemblies, and their integrated operability. That body of knowledge can serve as a springboard for microbial applications and should lower their threshold for adoption.

It is important to note, however, that just as for cell culture processes, single-use technology may not apply to each and every microbial process. It is the responsibility of practitioners to properly assess their own applications, select appropriate technology, and manage its implementation. Adopting a technology just for the sake of doing so can prevent consideration of important variables and may not lead to successful outcomes. The motivation to incorporate a single-use fermentor into a development or production environment must be based on an understanding of the value it brings to a given company and product. Implementing single-use technology also means accepting change, challenging conventional thinking, and reconsidering established ways of working. With all this in mind, GE Healthcare presents the following process-economic model as a contribution to discussions about implementing single-use fermentors.

Process-economic comParison

GE Healthcare has compared production capacity and process economy between stainless steel and single-use equipment in microbial processes. Economic simulations are based on an Escherichia coli domain antibody (DAb) process, with production scenarios considered for both single- and multiproduct facilities.

This study shows that annual production capacity can be increased up to 100% over stainless steel with a single-use strategy, primarily because of faster batch change-over procedures. With that increased production capacity, a defined number of batches can be produced in a shorter time using disposables (e.g., in a manufacturing campaign or during process development). Increased batch throughput presents a greater profit opportunity, a benefit that can outweigh the higher production cost per batch associated with the single-use alternative. With the decreased financial risk, the business case for single-use equipment becomes more agile than for stainless steel equipment that incurs higher fixed costs.

special report

2 BioProcess International 13(11)si December 2015

Background: Microbial fermentation is used for manufacturing a broad range of products in the biopharmaceutical industry, including small nonglycosylated proteins such as human growth hormone, peptides such as insulin, organic molecules such as antibiotics, and vaccines against pneumonia and cholera. Recently, biosimilars, biobetters, and antibody fragments have been added to the list of products produced by fermentation processes.

The primary advantages of microbial fermentation include straightforward cloning procedures, simple culture conditions, and rapid culture growth. By comparison with eukaryotic cells, microorganisms are less complex and limited in, for example, their ability to perform posttranslational modifications. Extensive research has been conducted to enhance microbial expression systems, including glycoengineering to enable correct protein glycosylation capability. The dominant organisms in today’s biomanufacturing are E. coli and Pseudomonas fluorescens bacteria, Saccharomyces cerevisiae and Pichia pastoris yeasts, and Aspergillus filamentous fungi.

Historically, bioreactors and fermentors have been constructed of stainless steel or glass. At the end of the 1990s, however, plastics entered the scene, providing for the possibility of using disposables and single-use equipment in culture processes. Adoption of early single-use rocking WAVE Bioreactor systems showed that users could save both time and money through this novel disposable approach. Soon, Xcellerex bioreactors (with their bottom magnetic drive) pioneered the single-use stirred tank field, enabling use of disposables from small-scale process development to 2,000-L manufacturing scale. Although both rocking and stirred-tank systems were designed for mammalian cell culture, they also have found use in some microbial processes with lower optical density (OD) requirements.

Microbial biomanufacturers are also interested in the benefits of single-use bioreactors: increased process flexibility, reduced cross-contamination risk, and higher batch throughput. However, the associated engineering requirements are more challenging for fermentors used in microbial processes than for bioreactors used in animal cell culture. Sufficient mass transfer of oxygen and removal of excess metabolic heat are some specific requirements of a microbial process. The Xcellerex XDR-50 MO system was the first single-use stirred-tank fermentor purpose-designed for microbial cultivation. A 50-L fermentor system was introduced in 2007 and is currently used in both process development and good manufacturing practice (GMP)–compliant production of recombinant proteins and vaccines. The XDR-50 MO fermentor exhibits performance comparable with stainless steel systems, accommodating an OD as high as 375 in a P. fluorescens culture producing a monoclonal antibody (1). Success with the 50-L fermentor led to the announcement of a larger 500-L XDR-500 MO fermentor in 2015.

What remains to be understood are the process-economic implications of using disposables for microbial biomanufacturing: to identify scenarios in which single-use solutions can be more favorable than traditional stainless steel equipment. Here, such questions are discussed

Table 1: Capital investment costs

Stainless Steel System Single-Use SystemBiostat D-DCU 50-L single O2 enrichment bioreactor with control unit

Xcellerex XDR-50 MO fermentor system

Bioreactor vessel load cells Exhaust condenser for XDR-50 MO

System clean-in-place (CIP) and steam-in-place (SIP) operations

Temperature control unit (TCU) for XDR-50 MO

Extended documentation Xcellerex XDM Quad single-use mixing system

Substrate pumpPressure hold test

Table 2: Unit operations for qualification and cleaning validation (NA = not applicable)

Unit OperationStainless

SteelSingle-

UseIQ/OQ of fermentor and control unit (establishing of protocols)

Included Included

IQ/OQ of fermentor and control unit: factory acceptance test (FAT) and site acceptance test (SAT)

Included Included

IQ/OQ of fermentor and control unit (reporting)

Included Included

OQ temperature mapping of SIP procedure

Included NA

PQ of fermentor (using bioindicators for stainless steel system) and control unit

Included Included

Cleaning validation Included NASterile medium hold test Included NAIQ/OQ of mixing unit (establishing of protocols)

NA Included

IQ/OQ of mixing unit (FAT and SAT)

NA Included

IQ/OQ of mixing unit (reporting) NA IncludedAnalytics for cleaning validation and sterile medium hold test

Included NA


based on a model setup for an E. coli DAb production process run at 50-L scale (2). Data and assumptions were validated; that is, prices and costs were verified to generate a nonbiased and realistic outcome that should facilitate decisions related to microbial production scenarios.

Process-Economic Model: A model E. coli DAb process was used to assess process economy in four hypothetical production scenarios involving both single-use and stainless steel equipment in single-product and multiproduct facilities: single-product facilities with stainless steel and single-use equipment, and multiproduct facilities with stainless steel and single-use equipment.

The scope of this process-economic simulation is limited to the upstream fermentation process

and DAb production phase. Other unit operations (e.g., downstream processing) have been omitted for simplicity. The single-use fermentor unit selected for this investigation was the Xcellerex XDR-50 MO system, and a Biostat D-DCU 50-L stainless steel fermentor (Sartorius Stedim Biotech) was used as a reference. Specific objectives for this investigation include the following:

• Investigation of equipment-choice effects on production capacity

• Estimation of batch-production costs for processes in which either stainless steel or single-use equipment was used

special report

Figure 2: Production schedules for a multiproduct facility using either (a) stainless steel or (b) single-use equipment; the time dedicated to maintenance (red) is equal in both scenarios, whereas the time dedicated to cleaning and associated analyses (yellow) is shortened with single-use equipment. The time needed for carry-over calculations, reporting, and quality assurance (QA) approval (blue), included in the stainless steel scenario is omitted from the single-use scenario. If five batches are harvested (green) in each campaign, then 67 batches can be harvested annually with stainless steel and 135 annual batches with single-use equipment.

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• Understanding of how equipment strategy affects total annual cost at different batch throughputs

• Assessment of profit opportunity for different equipment strategies.

General Assumptions: Several general assumptions were made. Availability for fermentation was set at 300 days/year; the remaining time would be dedicated to annual maintenance. Capital investments (including 10% interest) and qualification costs are spread over the number of batches that can be produced during the equipment’s depreciation period (10 years). Labor costs are set at US$100/hour. Fermentation is assumed to run overnight, with two operators present to monitor the process (same for all scenarios). Labor is divided into two shifts: 6:00 am to 2:00 pm and 2:00–10:00 pm. And no batch failure rate was considered.

The aim of this study was to make an objective comparison between single-use and stainless steel fermentors to provide a representative assessment of the two alternatives and aid in understanding their respective strengths and weaknesses. Hence, all assumptions and costs were verified with data or information from existing processes whenever possible. The following specific assumptions were made:

• For single-product facilities (scenarios 1 and 2, single-use and multise, respectively), only one product would be produced and the 300-day production capacity used to 100%.

• For multiproduct facilities (scenarios 3 and 4, single-use and multiuse, respectively), the facility would produce different products and use its 300-day production capacity to 100%. Products were assumed to be produced in five-batch campaigns each.

Cost Categories: The model includes five cost categories: capital investments (Table 1); installation and operation qualifications (IQ/OQ ),

performance qualification (PQ ), and cleaning validation (Table 2); annual requalification and maintenance (Table 3); process-related costs (Table 4); and disposables, chemicals, water for injection (WFI), steam, and similar necessities (Table 5). The process-related costs listed in Table 4 includes system preparations before fermentation and the fermentation process itself. Costs of qualifications, cleaning validation, annual requalification, and maintenance (as well as production-related costs) were estimated by evaluating the labor in hours required for each respective unit operation.

Some elements were omitted from the model because certain needs and procedures are identical for all scenarios or have minimal differential cost effects. Those with identical needs include a seed-culture generation procedure using shaker f lasks; the type and amount of culture medium components and supplements; minor hardware such as scales and tube welders; minor disposables (e.g., C-Flex tubing, pump tubing, syringe filters, vials, and so on); the number of autoclave cycles for tubing sterilization (cost for steam and electricity); nitrogen for calibration of dissolved oxygen (DO) sensors; and general facility requirements. Elements with minimal impact on overall cost include energy consumption per batch and air and oxygen demands (which are slightly higher for single-use equipment because of its lower maximum stirring speed). The model excludes a cost of goods sold (CoGS) calculation for given amounts of final product because of the small production volumes assumed.

results

Production Capacity: Production schedules were developed for stainless steel and single-use fermentation scenarios in a single-product facility. Stainless steel fermentation batches can be harvested every third day, allowing for a maximum of 100 batches per year at 100% capacity use with the assumption of 300 available days. Under the same conditions, single-use

Figure 3: Production capacity for the four scenarios included in this study

0Single-Product

Facility

Num

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Ann

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MultiproductFacility

Stainless steelSingle-use

20

40

60

80

100

120

140

160

Table 3: Unit operations for annual requalification and maintenance (NA = not applicable)

Unit Operation Stainless Steel Single-UseOQ temperature mapping of SIP procedure (annual retesting)

Included NA

Cleaning validation (annual recovery study)

Included NA

Annual maintenance of fermentor system

Included Included


fermentation batches could be harvested every second day, allowing for a maximum of 150 batches per year.

For the production scenario in Figure 1, a batch produced in single-use fermentation equipment will take 33% less time to complete than one made in stainless steel. Figure 2 outlines production schedules for both scenarios in a multiproduct facility. The stainless steel equipment supports production of 67 batches/year, about 13 full production campaigns annually. The corresponding numbers for single-use equipment is 135 batches/year in 27 full campaigns. For this multiproduct facility, production capacity can be doubled with single-use equipment over stainless steel.

Figure 3 summarizes production capacities for all four scenarios. Throughput is higher in the single-product facility than in the multiproduct facility. And in both, single-use equipment enables a higher throughput than does stainless steel. However, the difference between single-use and stainless steel equipment is most prominent in the multiproduct-facility scenario.

cost analyses and Profit oPPortunities

Cost/Batch: The total cost per batch was calculated for all four scenarios, and detailed analysis was based on assessing costs for six main categories: capital investments, qualification, annual maintenance and requalification, production preparations, production (fermentation), and consumables (disposables, facility media, and chemicals). The costs for a batch production in stainless steel scenarios served as a reference when normalized and set to 1.00 for all categories. Figure 4 summarizes the results.

Total cost and individual cost profiles are very similar for both facility scenarios. Relative to stainless steel processes, the total cost per batch is higher for single-use processes: 29% higher in a single-product facility and 25% higher in a multiproduct facility. The higher batch cost with single-use equipment comes from an increased consumables cost. For stainless steel, however, capital investments, qualification costs, and annual maintenance costs are all higher. That can be expected because a facility based on stainless steel reusable equipment requires more fixed infrastructure. Production-related costs are comparable for all scenarios.

Costs for Varying Facility Use Rates: Batch cost analysis was based on the assumption that each facility’s production capacity is fully used. In

reality, however, many facilities run at lower use rates, which changes the dynamics of this cost-calculation model. In certain cases (e.g., during a manufacturing start-up scenario), use rate might be very low. If only four batches are required for toxicology studies during the first year and an additional 15 batches for phase 1 studies during the second year, for example, a company would still need to invest in the equipment early on. So equipment qualification

special report

Table 4: Unit operations for production activities (NA = not applicable)


SteelSingle-

UseHandling of disposables and chemicals

Included Included

Weighing of medium components and additives

Included Included

Mixing of medium and additives Included IncludedAutoclave/filter additives Included IncludedAssemble fermentor tubing Included IncludedAutoclave fermentor tubing Included IncludedConnect tubing to fermentor Included IncludedConnect medium and additives to fermentor tubing

Included Included

Preparations in fermentation room

Included Included

Calibration of fermentor sensors Included IncludedSterilization of sensors NA IncludedInstallation of single-use fermentor bag and sensors

NA Included

CIP of fermentor Included NAPressure hold test of fermentor Included NATransfer medium concentrate (including autoclavable additives) and WFI to stainless steel system

Included NA

SIP of fermentor including sensors

Included NA

Filtration of additives (non-autoclavable) into stainless steel system

Included NA

Transfer medium to single-use fermentor bag via filtration

NA Included

Transfer additives to single-use fermentor bag

NA Included

Inoculation of bacterial cell culture

Included Included

Fermentation Included IncludedHeat treatment before harvest Included IncludedCIP of fermentor Included NASIP of fermentor Included NAWaste disposal Included Included


and costs for annual maintenance and requalification also would need to be considered.

To investigate this further, analysts used four, 15, 30, 50, 100, and 150 annual batches as input data for the model and calculated the annual costs for stainless steel and single-use scenarios, respectively (Figure 5a). At low use rates, data show that a single-use strategy is more beneficial from an annual cost perspective. For 4 and 15 batches annually, that strategy is associated with ~27% and ~10% lower costs, respectively, than with a stainless steel strategy.

The main reason for the lower cost with single-use equipment is less time spent on equipment qualification. For stainless steel equipment, over three times as much time is spent on qualification activities. When that time is translated to cost, the resulting annual cost for maintenance of stainless steel equipment is 21 times higher than that for single-use equipment. Maintenance cost remains constant regardless of equipment use rate. As use rate increases, however, the difference between stainless steel and single-use strategies levels out. At 30 batches annually, their annual costs are more or less equal.

As the number of batches increases, the stainless steel strategy is a feasible alternative up to 100 batches annually, when the production capacity becomes limiting for that scenario. For

capacity needs over 100 annual batches, the single-use strategy would be the preferred alternative. For an extreme case in which a facility is not used at all during a whole year, our model shows that the annual costs for capital investment (assuming a 10-year depreciation cycle and interest rate of 10%) and for qualification, annual maintenance, and requalification are 122% higher for a facility based on stainless steel equipment. So single-use equipment offers f lexibility and benefits at both low and high capacity needs.

Profit: This study is based on fermentors at a 50-L scale, but few (if any) manufacturing processes run at this scale. More appropriate 50-L applications include process development, pilot-scale production of clinical material, and seed preparations for larger-sized fermentors. However, GE Healthcare’s analysts were interested in profit dynamics of single-use and stainless steel strategies, so they performed a profit calculation.

Revenue of one million US dollars was assumed for each batch, and the production cost was subtracted from that to obtain a gross profit figure. This calculation was performed for both the stainless steel and single-use scenarios in a single-product facility, and the result was plotted against total capacity use for both scenarios (Figure 5b). Clearly, the profit opportunity is higher for the single-use alternative. Increased batch throughput is the main reason for that outcome, in which benefits essentially outnumber the slightly higher production cost per batch for the single-use scenario.

discussion

GE Healthcare analysists set up a model to understand the cost and capacity implications of single-use equipment in microbial fermentation processes compared with reference scenarios based on stainless steel equipment. The main conclusion from this study is that a substantial amount of time can be saved with single-use equipment. For a single-product facility based on single-use equipment, batches can be harvested every second day; with stainless steel equipment, harvest takes place every third day. Thus, disposables enable a relatively higher facility throughput. For a single-product facility, 50% more batches (150 batches) can be produced annually using single-use equipment than with stainless steel equipment (100 batches).

For a multiproduct facility, the capacity difference is even more pronounced, with a doubled annual throughput with single-use

Table 5: Disposables, facilities, and chemicals included in this study (NA = not applicable)


SteelSingle-

UseXDA single-use fermentor bag NA IncludedPlus Quad MBA single-use mixing bag for medium preparation

NA Included

Probe sheath NA IncludedTap water for CIP (NaOH/acid solutions)

Included NA

WFI for CIP (final rinse) Included NANaOH solution for CIP Included NAAcid solution for CIP Included NABlack steam for heating of CIP solutions

Included NA

Steam for SIP Included NAPlant steam for system heating during fermentation

Included NA

Air vent filter inlet (Sartofluor Junior, Sartorius Stedim Biotech GmbH)

Included NA

Air vent filter outlet (Sartofluor mini, Sartorius Stedim Biotech GmbH)

Included NA

GE ULTA HC, 6-inch filter for medium transfer to system

NA Included


equipment (135 batches) relative to stainless steel (67 batches). The higher productivity of a single-use facility is related to omitting the need for equipment cleaning and cleaning validation procedures after a campaign.

In a facility based on stainless steel, the final equipment clean-in-place (CIP) procedure at the end of each campaign is followed by cleaning validation. Equipment swab samples commonly are analyzed for total organic carbon (TOC), and final rinse water typically is analyzed for both TOC and endotoxins. Analytical results are usually available five days after sampling. The time for carry-over calculations, reporting, and quality assurance (QA) approval of the resulting report is estimated to take an additional two days. So this seven-day cleaning validation procedure is significantly reduced or eliminated by a single-use fermentor, in which all materials that come into contact with process f luids are disposed of after use. During the downtime of that stainless steel

fermentor, a single-use fermentor can be up and running to produce additional batches.

In a multiproduct facility, not only the equipment, but also the production suite needs to be cleaned before starting a new campaign for a different product. Facility cleaning procedures include emptying production suites followed by cleaning of walls, ceilings, and f loors. Cleaning verification is conducted through environmental monitoring performed by quality control (QC) personnel. However, the environmental risk from a production suite can be assessed from previous analytical results. The final QC results and QA approval of the environmental monitoring report therefore are not required typically before starting a new campaign. Instead, the critical activity is equipment cleaning and associated validation, which become the limiting factors for facilities

special report

Figure 4: Relative cost per batch in (a) single-product and (b) multiproduct facilities using either stainless steel (SS) or single-use (SU) equipment; the cost for batch production using SS equipment is used as reference and set to 1.00 for all categories.

1.001.00

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fermentatio

nConsumables (disposables,

facility media, chemicals, etc.)


using stainless steel equipment due to the risk of product carry-over. With single-use equipment, however, that specific risk is nonexistent. A risk-based strategy may be used for valuable time savings, and a new campaign can be started the day after sampling for environmental monitoring.

The improved productivity achievable with single-use equipment also can have implications beyond increasing the total capacity of a production facility. During product development, for example, shorter process times can contribute to significant time savings and a decrease in overall development time. That in turn can make positive financial impact and speed access to market. With single-use equipment, more batches can be produced in a

set product development period, allowing more experiments to be conducted. That can generate additional regulatory support data to aid in development of a strong chemistry, manufacturing, and control (CMC) documentation package. It also can help to eliminate poor therapeutic candidates earlier in development, ultimately saving money that would otherwise be wasted on them.

When studying batch costs, GE Healthcare analysts found that the total cost per batch at a 100% equipment use rate is 25–29% higher for a single-use scenario than for a stainless steel scenario. Consumables are the category that drives most costs for single-use scenarios. That includes disposable fermentor bags, mixing apparatus, tubing, and sterile filtration consumables. However, the fixed-cost burden — including capital investment, annual maintenance, and qualification costs — is higher for stainless steel equipment. Those fixed costs remain whether or not a facility is in use, whereas variable consumable costs incur only when a facility is actually in use for production of profit-generating biologics.

The implications of having a larger portion of fixed costs rather than a variable operational costs become apparent with production scenarios running at a low facility use rate (e.g., in a start-up company). At low facility use rates (<30 batches/year), the annual costs are lower for facilities based on single-use equipment. As the number of batches increases, stainless steel equipment becomes the less expensive alternative until the point at which production capacity becomes a limiting factor. In this process-economic model, that point comes at 100 batches/year. If a higher production capacity is required, single-use equipment again becomes the preferred option.

The vast majority of microbial-based GMP manufacturing processes are performed at scales much larger than 50 L. However, an initial assessment of profit dynamics shows that profit opportunity is higher for a single-use strategy than for stainless steel because of larger batch throughputs. To examine process economics at larger production scales, the model used herein would be adjusted to each specific scenario. However, the general principles applied in this study should be valid for microbial fermentation processes at all scales.

choosing single use

Several conclusions can be drawn from these results. A single-use equipment strategy is

Figure 5: Annual total production cost by (a) number of batches produced and (b) annual accumulated profit against total capacity use are analyzed for single-use and stainless steel equipment. (a) Total production cost by number of batches produced annually in single-use and stainless steel scenarios; after 100 batches, the maximum annual production capacity is reached using stainless steel equipment. With single-use equipment, 150 batches can be produced annually. (b) Total accumulated profit is plotted against total annual capacity use; for the stainless steel scenario, 100% capacity represents 100 batches; for the single-use scenario, 100% capacity represents 150 batches.

0 100 200

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(B)


advantageous in microbial fermentation under the following conditions:

• When a certain number of batches must be produced in the shortest possible time (single-use equipment offers an agile solution, for example, in early product development, production of clinical-trial or toxicity study materials, or in vaccine surge capacity scenarios)

• When high production capacities are needed (here, a single-use strategy enabled a 50% higher batch capacity over stainless steel in a single-product scenario and a 100% higher capacity in a multiproduct scenario)

• At full facility use (profit opportunity was higher for the single-use alternative, with 150 annual batches, than for the stainless steel alternative, with 100 batches annually)

• If facility-use rates are low (lower up-front capital investment and low costs for annual maintenance and qualification lessens fixed costs associated with single-use equipment compared with stainless steel).

For Further Consideration: This modeling exercise was instructive, and the scenario results are informative. Both are thought-provoking. Perhaps this discussion has prompted more questions than it provided answers. Although the model was created to be practical and unbiased, it is still dominated by GE Healthcare’s preexisting knowledge of current processes and workflows. For practical reasons, it was also restricted to the fermentation process only. Expanding the application and implementation of single-use technology to specific unit operation systems (e.g., bioreactors, purification, and so on) would provide either a requirement or an opportunity to rethink existing ways of working, depending on your perspective.

Consider having a blank slate on which to establish an ideal fermentation process based on single-use technology. Is that ideal process founded on a scaled-out set of disposable fermentors, or does it rely on one assuming the role of an N – 1 or N – 2 fermentor for seeding larger stainless steel equipment? In either case, what is the most beneficial working volume? Would the host organism stay the same? Could an organism be engineered to maximize the potential of a single-use–based fermentation strategy? What would the facility be like? Could it be fully optimized for single-use technology implementation both up- and downstream, from the ground up? Do microbial fermentation processes demand a hybrid equipment

facility? How does the building footprint of a scaled-out process compare with that of a scaled-up process? Would a corresponding reduction in utility requirements convert to even greater cost savings and higher net profits? How much faster could a drug be brought to market?

Regardless of the form that the ideal fermentation process and facility might take, single-use bioreactors have forever altered the buyer–seller relationship. Shared information about materials and process constituents, especially as they relate to adverse interactions, has become essential to end-product quality. Security of supply is critical to both process development and production. Supply agreements are important to codifying physical supply and achieving appropriate buyer cost targets. Single-use–based fermentation stands to benefit from all this experience.

disclaimerResults and conclusions presented herein are valid for this specific study only. Other study conditions and assumptions could significantly affect the outcome. The overall finding of this study is that despite the higher batch cost, single-use fermentation equipment can generate more batches annually. So if all batches lead to sold product, the single-use alternative would contribute to a higher gross profit.

references1 Application Note 29-0564-39 AB. Microbial

Fermentation in Single-Use Xcellerex XDR-50 MO Fermentor System. GE Healthcare Bio-Sciences AB: Uppsala, Sweden, September 2013; www.gelifesciences.com/gehcls_images/GELS/Related%20Content/Files/1392320581787/litdoc29056439_20140213234550.pdf.

2 Application Note 29-1341-11 AA. Comparable E. coli Growth and Domain Antibody (DAb) Expression in Single-Use and Stainless Steel Fermentor Formats. GE Healthcare Bio-Sciences AB: Uppsala, Sweden, May 2015; www.gelifesciences.com/gehcls_images/GELS/Related%20Content/Files/1432051180778/litdoc29134111_20150519175927.pdf. •

Corresponding author Ken Clapp is senior global product manager, Eva Lindskog is upstream marketing leader, Kjell Eriksson is a senior scientist, and Sandeep Kristiansson is a senior research engineer, all in life sciences at GE Healthcare Bio-Sciences Corporation, 100 Results Way, Marlborough, MA 01752; 1-484-695-5844; [email protected]; www.gelifesciences.com. WAVE Bioreactor and Xcellerex are trademarks of GE Healthcare. Biostat is a trademark of Sartorius Stedim Biotech. C-Flex is a registered trademark of Saint-Gobain Performance Plastics.

special report


www.gelifesciences.com/BioProcessGE, GE monogram, and Xcellerex are trademarks of General Electric Company. © 2014–2015 General Electric Company. First published Apr. 2014. GE Healthcare Bio-Sciences AB, Björkgatan 30, 751 84 Uppsala, Sweden.

29120140 AC 09/2015

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