GENengnews.com|NOVEMBER 1, 2018

Single-Use Modules
Expedite Total Solutions

Draw on End-to-End Expertise, Says Sartorius,
to Facilitate the Shift to Flexible Biomanufacturing
Ganesh Kumar, Michael Koch,and Gerben Zijlstra, Ph.D.
As the biopharmaceutical industry continues to grow at a rapid pace, companies arerealizing that they may need to transformtheir biomanufacturing networks to respond to changing market dynamics andanticipate customer requirements. A major factor behind the growth of the biopharmaceutical industry has been the hugeand continued success of the monoclonalantibodies segment. Within the industry,
however, companies have started to diversify their pipelines, developing products
such as antibody-drug conjugates, nonantibody recombinant proteins, genetherapies, and autologous and allogenic
cell therapies.
With continued growth of the existing portfolio combined with the diversification of available therapeutics, biopharmaceutical companies are envisioning growth in existing as well as in various emerging markets. As a result, thesecompanies are planning to increase theirglobal reach by manufacturing products
within the target market regions. Besides managing growth, product diversification, and footprint issues, the industry
also needs to address four key imperatives:

reduce costs, improve flexibility, shorten
time to market, and increase quality/process robustness.
Biopharmaceutical companies realize that it will be impossible, in thenear term, to have one facility that will
fulfill all these market and process demands. Rather, the companies may selectfrom a range of biomanufacturing scenarios. According to the Biomanufacturing Technology Roadmap, which
was issued by the BioPhorum Operations Group (BPOG) in 2017, there areat least five such scenarios:• Large-scale stainless-steel
fed-batch operations• Intermediate-scale single-use
perfusion plants• Intermediate-scale multiproductsingle-use fed-batch facilities• Small-scale portable facilities• Small-scale factories for
personalized medicines
Single-use and distributed scenarios
are more likely if smaller product quanti-Figure 1. Typical room layout concepts

ties are required. Stainless-steel and centralized scenarios are more likely if larger
quantities are required.
It is the authors’ opinion, however,that by switching to intensified fed-batch/perfusion processes, it is also possible tocommercially produce high quantities
of multiple biological drugs in state-ofthe-art single-use/hybrid flexible andmodular facilities at an acceptable cost ofgoods sold (COGS). And this would represent a very attractive model for the biomanufacturing facility of the future. Thisapproach would present the best option
for companies to initially design andbuild the facility at a lower cost, realizing
a high-throughput, low-cost-per-gramprocess platform that can bring productto market faster and, eventually, “scaleout” in a flexible and modular way as themarket diversifies and demand increases
over time.

Conceptual Design
For biopharmaceutical companies,
advantageous manufacturing strategies
may be determined during conceptual
design (CD) if a process-centric approachis adopted. Such an approach is supported by the Sartorius P4S® (Process 4 Success®) platform, a detailed CD offeringthat helps companies optimize variables
such as throughputs, process strategies(fed-batch, intensified), and technologies(single-use, hybrid).

By using a process-centric approach,companies may build facilities that incorporate suitable technologies, follow
effective manufacturing and automation strategies, and manifest riskbased classifications (closed, functionally closed, etc.). The companies may arriveat the best layouts (Figure 1) for meeting
their throughput goals.
In addition, a company could carry out
process modeling using the BioPharm Services BioSolve® tool, for example. Doing sowould allow the company to estimate theoperational expenditures and COGS forthe entire facility.
Executing a CD project prior to making an investment decision would be extremely beneficial to a biopharmaceuticalcompany. It would reduce uncertainties
related to process, manufacturing, andautomation strategies, as well as thoserelated to market demand. It would alsoheighten a company’s confidence in its
business case, including its product pricing strategy.
At the start of a CD project, the Sartorius P4S tool may be used to define massbalance for a specific process or even a generic process. In a multiproduct scenario,
mass balance helps companies select technologies and size equipment. It includes
the relevant processing parameters for allprocess steps and defines the required volumes and processing times.
During this exercise, the individual

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process steps are defined within all related unit operations and can be drawn
directly into a process flow diagram. For
the GMP room layout, the process andrelated requirements such as scheduling,media/buffer preparation, and distribution strategy are of central importance.
The manufacturing suites will be designed
around the process and not vice versa.

Insights from a Case Study
An instructive case study concerns a
6 × 2 kL plant that employed different
manufacturing scenarios, namely fedbatch (3 g/L), N-1 perfusion (6 g/L), andconcentrated fed-batch (10 g/L). It was
found that the maximum capacity was
between 500 and 1800 kg/year depending on the scenario used. The related
capital investment cost needed for thefacility was in the region of €100 million ($115 million), and the annual costs
were a fraction of those of a traditional
stainless-steel facility, which were dominated by depreciation.
The detailed design and realization ofthis kind of intensified facility requires
adoption of certain processing units andtechnologies as there are existing limitations in single-use products and technologies in the market. These limitations,however, are minor and will no doubt
be overcome by near-term advances thatwill enable full-scale intensified processing with single-use technologies.

The design of such a facility can behighly flexible, enabling multiple products to be produced with short changeover times. In such a facility, it would bepossible to implement 1) closed singleuse technologies in upstream processes,and 2) single-use/hybrid technologies indownstream processes that are closed or
can be made functionally closed. It could
also prevent contamination of processes
in cleanroom surroundings and processes
further downstream, and even allow forballroom/dance-floor operation for entire
processes up to formulation. Designing
unit operations in a modular way in theselayouts further enhances process flexibility and minimizes changeover times byenabling easy exchange of unit operationequipment or sequence.
Project execution needs to be rethought based on process needs, singleuse materials, and automation. Soon,
there will be a need for companies tohave consumables (bags, filters, andtransfer sets) supplied in per-batch packages based on predefined solutions plus
contingency packages that include themost critical consumables for the batch.
To satisfy this need, companies will start
simplifying supply chains, improving logistics, and minimizing warehouse footprints to accommodate the single-useprocesses. Today, the opposite is often
the case.

Process Automation
Besides rethinking project execution,
the industry needs rethink process automation, a task that must be based on
digitalization, usability, scalability, andsystem access. The emphasis should beon bringing digitalization down to thefield level by focusing on modular solutions with decentralized intelligence.
This enables flexibility through the integration of intelligent package units
and their respective process skids into a
distributed control system (such as theFigure 2. ISA S95 structure: four-level automation concept. Abbreviations: BMS/EMS:
building monitoring system/environmental monitoring system; DCS: distributedcontrol system; ERP: enterprise resource planning; OEE: overall equipment
effectiveness; PAT: process analytical technology; PI: process intelligence; PLC:
programmable logic controller; SCADA: supervisory control and data acquisition.

Siemens Simatic PCS7®) and the overall
automation landscape of the biomanufacturing facility.
The process automation system isthe focal point of the plant and mustsatisfy ISA S88 and GMP requirements
for reporting, data management, user
handling, auditing, and visualization.
This approach will open the door for
smart single-use bioproduction facilities
that use electronic batch records, reviewby-exception methodology, and multivariate data analytics tools (such asthe Sartorius Umetrics® Suite, a dataanalytics platform) for real-time process monitoring, control, reporting, andrelease. The use of process analyticaltechnology enables developers to build
quality into the product and allows operators to track how the current processcompares to an optimized process—thisis known as golden batch analysis.
The process automation concept canalso be aligned with the facility automation concept using an ISA S95 architecture for the environmental monitoring
system as well as the building monitoring
system and some integration to commer-

cial enterprise resource planning systems.
Refer to Figure 2 for the ISA S95 structurethat would be followed in these facilities.

Partnering with a Total
Solution Provider
A customer that intends to carry out
an overall conceptual design for a GMP
facility should work with an end-to-end
solution provider. Such a provider can ensure that the process part of the facility
will respond to the customer’s needs. Besides benefiting from a total solution, onethat is process-centric and encompasses
technology and equipment, the customer
may obtain an optimized single-use integration concept, a process layout, anoverall automation strategy, a media/buffer distribution concept, and an overall
process schedule for a high-throughput
facility. Once these needs around the process are fulfilled, it is then recommended
to transfer these results to an engineering company, which would then focus
on developing the overall facility design,
incorporating elements such as quality
control labs, warehouse facilities, offices, HVAC (heating, ventilation, and air

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Figure 3. Advantagesof working with end-toend solution providers.
Abbreviations: CAPEX: capital
expenditure; COGS: cost ofgoods sold; PAT: process
analytical technology.

conditioning) systems, clean utilities, andblack utilities.
With this approach, companies
would be able to get an overall solution(including equipment, consumables, andautomation) at an optimized cost withtotal support and ownership of the project during the execution and follow-up

phases. Also, an advantage would be toget tested and prequalified solutions thatcan be easily integrated into the facility
and decrease the time required fromconcept to performance qualificationconsiderably. Refer to Figure 3 for advantages of working with an end-to-end
solution provider.

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Ganesh Kumar is a process consultant,Michael Koch is a sales director, andGerben Zijlstra, Ph.D., is a platform
marketing manager on the IntegratedSolutions team at Sartorius Stedim
Biotech. Website: www.sartorius.com.