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The Fermentation Process

Download Fermentation Solution Note

Fermentation Process Overview

Fermentation is widely used within the pharmaceutical, biotechnology, and food & beverage industries. It requires the cultivation in submerged culture of an identified microorganism (mainly bacterial) as a monoculture under defined environmental conditions. The incubation regime imposed, is designed to maximize the productivity of the organism of interest by providing optimal conditions for population growth (biomass). The product of interest might be a bioactive metabolite, an enzyme, a vitamin, or recombinant protein. During an incubation cycle, a nutrient energy source (e.g. glucose) is added and the biomass and end product will increase as this is depleted.

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Fermenter Design and Control

Incubation control necessitates the precise control of a number of parameters.

Of primary importance are:

Temperature, pH, DO2 or Redox, agitation, pressure, foam control, auxiliary feed or a combination of these controllers.

The control of these and any other parameters is most usually carried out in fermenter vessels specifically designed for the purpose and accommodating various working volumes depending on the yield and production requirements. Laboratory scale vessels could have a capacity of just 10 litres or less whereas production vessels may be as large as several thousand liters.

The smallest units may incorporate an electrical heater and feed stocks (e.g. Nutrient and pH control agents) may be fed from flasks via peristaltic pumps. Larger vessels have an integral jacket for controlling temperature via hot or cold water and allowing indirect sterilisation using injected steam. Where larger quantities of feedstock are required they may be held in separate pressurized tanks and fed in via valves arranged to work as a ‘thrust pump’.

The actual fermentation process is known as the Incubation Phase and is just part of the batch cycle. A complete fermentation cycle can typically include the following steps (depending on vessel design):

Sterilization of empty vessel and pipework using direct steam injection
Charging with base medium
Indirect sterilization via steam injected into the vessel jacket
Cooling of vessel and draining of jacket
Pre-inoculation – vessel environment under control
Inoculation – injection of a small sample of the monoculture
Incubation – the fermentation process itself
Harvesting – product removed ready for extraction processes

R&D clinical trial and biotechnology environments (in which many small-scale fermenters operate) are such that it is not always possible to predict the nature of a fermentation process; either in terms of culture or incubation conditions. Production facilities must also cater to a variety of products, each having precisely defined incubation profiles.

Therefore, a control system needs to provide flexibility in the way that accurate and repeatable control of the fermentation environment is achieved, and should include the following features:

Precise loop control with setpoint profile programming
Recipe Management System for easy parameterization
Sequential control for vessel sterilization and more complex control strategies
Secure collection of on-line data for analysis, archiving and reporting e.g. to support batch release
Local operator display with clear graphics and controlled access to parameters

Eurotherm Solution

Small/medium Distributed Control System
Precision control strategies
Batch/recipe management
Digital data management
Power control for electric heaters
HMIs from local panels to full SCADA solutions
High availability architecture (Redundant solutions and ‘Store and Forward’ feature)
Data analysis
AVEVA™ Historian
Reporting

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FDA 21 CFR Part 11 and EU EudraLex Annex 11 Regulations Compliancy

Fermentation plants are used in industries likely to require compliance with regulations and guidelines from the FDA, EMA or other applicable regulatory organizations (CDSCO, NMPA, etc.). With a long history in precision process control and high integrity data management, Eurotherm has a broad range of knowledge and expertise in life sciences, helping customers to comply with their Data Integrity related standards.

Data Integrity ALCOA (+) Guidelines

Key regulatory bodies (FDA, EMA, WHO) and some advisory bodies (PIC/S, ISPE) have agreed on the Data Integrity related ALCOA (+) concept. ALCOA defines that data should be Attributable, Legible, Contemporaneous, Original and Accurate. In addition to ALCOA, guidance has gone further with ALCOA (+) to help ensure data is Complete, Consistent, Enduring, and Available. As an experienced automation supplier, well established in life science processes, Eurotherm was an early adopter of that vision and contributed to the definition and the revision of some of these guidelines.

ISPE GAMP® 5 Guide: A Risk-Based Approach to Compliant GxP Computerized Systems

To help secure your investment and ease future audits of your plant, Eurotherm has developed a proprietary set of Qualification/Validation documents according to the V-model from the ISPE GAMP® 5 guidelines. These proven documents, used in hundreds of audits, help to reduce risks associated with Qualification/Validation operations: helping to minimize your qualification effort and reduce your capex and opex throughout the lifetime of your installation.

Pharma 4.0 Ready Technology

Eurotherm data recording solutions are EcoStruxure-ready, providing a Data Integrity layer within the Schneider Electric EcoStruxureTM platform. EcoStruxure is Schneider’s open IoT-enabled system architecture aiding the digital transformation to Pharma 4.0 technology.