ENBioProcessingSolutions

ESSENTIAL GUIDE TO CELL CULTIVATION
IN BIOREACTORSBioreactor Bioprocess Control
Cell Cultivation in Bioreactors
Cell cultivation is fundamental to studying viruses, determining the role of genes in diseases, and thedevelopment of vaccines and other biopharmaceuticals.
Bioreactors provide precise control over cultivation processes. Equipped with new-generation sensors
and software, these sophisticated vessels continuously monitor critical operating parameters such astemperature, pH, and oxygen levels in order to maintain optimal cell growth conditions.

Effective bioprocess control within bioreactors is

Precisely adjusting variables requires a deep

crucial for ensuring the vitality and productivity ofunderstanding of the cells' biological requirements

cell cultures. Key parameters—including nutrientand metabolic responses. As the culture develops,

balance, waste management, and environmental

these parameters require continuous recalibration

conditions—must be meticulously managed toto prevent nutrient depletion or toxic byproductpromote optimal cell growth and maintain culture

accumulation. A responsive control system of thelongevity.

bioreactor adapts to real-time feedback from thebioprocessing environment.

For example, adjusting nutrient concentrations

Bioreactors such as the IKA HABITAT also facilitate the transition of optimized conditions from thelaboratory to industrial scale, enabling commercial-scale production of cells and cell-derived products.
These sophisticated support systems nurture cell cultures, enabling the scalable production oftherapeutics, biofuels, and more. With their ability to maintain optimal growth conditions and enablescalability, bioreactors have become indispensable equipment in biomedical research and biotechnology.

and effectively managing waste products within aThis nuanced control directly influences productculture environment can significantly influence cellconsistency, downstream processing efficacy,

health and the duration of the bioprocess. Theseand the economic viability of the production

adjustments also have downstream effects on theprocess. Adeptness of these elements ensures

final product's concentration and efficacy.

both maximal yield and high-quality production inbiomanufacturing.

PILOT UNIT

INDUSTRIAL
BIOREACTOR
Production

Pilot StudyLAB SCALE
BIOREACTORLAB SCALE

Screening &Cell optimization

Simulation processOptimization

FROM R&DValidation of technicalfeasibility

TO INDUSTRY
Process optimization
Validation of industrialperformance

Full production capacity

Figure legend: Upscaling process

Essential Guide to Cell Cultivation in Bioreactors | 2

Essential Guide to Cell Cultivation in Bioreactors | 3

/// Cell Growth Phases in Bioreactor Cultures

12

34Lag
phase

Exponential
phase

Stationaryphase

Deathphase

12Exponential phasehreticalAfter cells have adapted to the reactor, the rate of cell division reaches its
maximum (exponential or log) phase. Cell numbers increase exponentially andbiomass increases. Nutrients and O2 are metabolized at the maximum rate
and production of CO2 increases. Many waste products (e.g. organic acids)
are produced, affecting pH levels. At this phase, it is important to maintainconditions that best support cellular growth. During the log phase, somecells decompose (lyse), introducing free cellular proteins into the medium andincreasing the risk of foam formation.

wteoThLag Phase
When cells are first introduced into a reactor (inoculation), they must adjust
to their new environment and respond with a slowed growth (lag phase).
Shortening the lag phase is achieved by starting a preculture in a small vessel
within the bioreactor under the same conditions (medium, temperature)and, then, rapidly transferring the cells to the next sized vessel during their
exponential growth phase.

gro

Number of cells

Mastering the complexities of cellular development is a fundamental aspect of advanced bioprocessing.
The following is a detailed examination of the cell growth phases within bioreactor cultures.

3

Stationary phase
During this phase of nutrient depletion, cell growth starts to slow. Cell divisionand the death of microorganisms or cell cultures still are balanced.

Time4Death phase
In this phase, nutrients become depleted and conditions in the bioreactor
become increasingly unfavorable for cells resulting in cell death.

Essential Guide to Cell Cultivation in Bioreactors | 4

Essential Guide to Cell Cultivation in Bioreactors | 5

/// IKA HABITAT’s Cell Cultivation
Advantages

Precise environmental control for cell cultivation
Mass flow controllers precisely regulate the input of air, nitrogen, and oxygen,optimizing cell growth. Dissolved oxygen (DO) levels are a critical parameter in thisprocess.
A dedicated carbon dioxide supply system maintains optimal pH levels, whileheadspace gassing options facilitate efficient oxygen transfer with minimal cellularperturbation. This precise control over the cell culture environment promotes
consistent and reproducible experimental results.

Advanced monitoring with next generation sensors
Advanced sensors for comprehensive bioprocess monitoring, including newgeneration sensors for biomass, cell viability, and off-gas analysis, offer highselectivity, sensitivity, and long-term stability. These sensors enable contaminationfree bioprocessing and improved operator efficiency by monitoring dissolved
carbon dioxide, conductivity, turbidity, Redox, cell viability, off-gas, temperatures,and non-intrusive foam.
Soft-sensors can be used to calculate and display specific batch data, such asparameter setpoints, organism-specific rates (μ, qs, RQ, etc.), and extended batchvalues (culture broth weight, biomass).

Reducing shear stress
IKA HABITAT Bioreactors have a reactor geometry with a pitched blade andimpeller design that ensures a gentle yet efficient mixing without the risk ofdamage from excessive shear forces. This approach optimizes the growth andmaintenance of suspension and sensitive adherent cells. A new chaotic mixing
mode that follows mathematical principles of chaotic-dynamic systems also
provides for a more homogeneous mixture.

Essential Guide to Cell Cultivation in Bioreactors | 62023/// IKA HABITAT’s Operational Benefits
IKA Bioreactors are more than mere cultivation tools; they are integrated solutions designed to enhance operations with smoother,more efficient workflows tailored to the dynamic needs of our customers.

Award-Winning DesignSolutions that Scale

Recognized by the iF DESIGN AWARD 2023, the IKA
HABITAT Bioreactor integrates the capabilities of a bioreactor,
photobioreactor, and fermenter, reducing the need for multiple
setups and switching. Its ergonomic handling, intuitive
operation, and user-friendly features, such as an open skid,
unique lid stand, and lightweight components, reduce operator
fatigue and improve portability. The compact design maximizes
bench space. The bioreactor's intelligent support systems andcontrols make it accessible to both beginners and experts.

HABITAT Bioreactors excel from micro-scale research to industrial
production. They feature a chaotic mixing option for fastermixing, an advantage especially beneficial at the beginningof an experiment. The bioreactor’s design includes a range ofvessel volumes from 0.5L to 10L, available in both single anddouble-wall configurations. Properly-sized motors for eachvolume—small for up to 2L, and larger for 5L to 10L—ensure
efficient operation and customization in contrast to the standard
one-size-fits-all motor approach. Advanced, integrated control
systems guarantee consistent scale-up processes, enabling
seamless capacity growth.

Consistent Quality
The IKA HABITAT Bioreactor sets the benchmark for consistentquality in bioprocessing by ensuring that each production
cycle meets the high standards expected in the industry.
Its sophisticated control systems and precision engineering
provide a dependable foundation for operations, guaranteeing
uniform outputs that streamline the entire downstream process.
Variable-speed, bi-directional peristaltic pumps and an optional
fifth pump provide for diverse fluid management. This fidelity
in performance facilitates the scalability of production andsignificantly reduces the occurrence of batch failures, mitigating
downtime and waste.

Cross-Platform Integration
OPC UA integration and extensive interface options includingUSB, Ethernet, and RS-232 to provide comprehensive dataconnectivity. The lid's additional ports enable customized
modifications to accommodate a range of bioprocessing
applications.

Worldwide Presence, Local Support
IKA's global presence provides comprehensive support,including technical service, spare parts, calibration, qualification,and commissioning, empowering customers to achieve theirbioprocessing goals.
Essential Guide to Cell Cultivation in Bioreactors | 7United Kingdom

GermanyPolandUSAThailandTurkey

China

Spain

UgandaJapanIndia

Kenya
Korea

MalaysiaBrazilVietnamGlobal Partner for BioProcessing Solutions
GERMANY
IKA-Werke GmbH & Co. KG
StaufenPhone: +49 7633 831-0
sales@ika.de

MALAYSIA
IKA Works (Asia) Sdn Bhd
Kuala Lumpur (Rawang)
Phone: +60 3 6099-5666
sales.lab@ika.my

INDIA
IKA India Private Limited
Bangalore
Phone: +91 80 26253 900
info@ika.inUSA
IKA Works, Inc.
Willmington
Phone: +1 910 452-7059
sales@ika.net

CHINA
IKA Works Guangzhou
Guangzhou
Phone: +86 20 8222 6771info@ika.cn

BRASILIKA Brasil
Campinas/Rio de Janero
Phone: +55 19 3772-9600
sales@ika.net.br

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