Bioprocesses as a Periodic Table

Bioprocesses are complex. Add in the details of the applications, equipment and organisms and it becomes overwhelming. The use of a template based on the periodic table of the elements has been used in many contexts (even for types of sandwiches). A similar chart for bioprocesses groups and organizes this information in an understandable way.      

Key

 

Applications 

BioM = Biomass
The aim is to produce as many cells as possible.  This may be further processed to use for e.g. animal feed.   

Rec = Recombinant
Production of a protein derived from addition of modification of genes. The protein could be released into the supernatant or retained within the cell.  

BioF = Biofuels
This covers a range of individual applications from ethanol production from
agricultural -waste to growth of micro-algae in photobioreactors for biofuel.   

Nut = Nutraceuticals
Can be whole cell or naturally- occurring products produced by cells.  

Vac = Vaccines
Mostly biomass but can be processed to become sub-unit and/or blended vaccines 

Che = Chemicals
Examples include the enzymes from thermophiles used in biological washing powders and production of citric acid.    

The = Therapeutic
Agents compounds with biological activity produced by microbes. This includes antibiotics,  viruses with a genetic “payload” and Stem cells.    

not included

Bre = Brewing and beverages, the obvious examples being beer and wine  

Fod = Foodstuff  solids or liquids, molecular cuisine    

Aro = Aromas and flavourings produced by fermentation  

Abi = Antibiotic manufacture, typically from fungi

 

Cultivation 

Bat  = Batch culture
of  defined time, no additional feeds. 
 

FBat = Fed-Batch culture
where nutrient feed(s) are added during cultivation in increase the productive time and/or allow specific products to be formed e.g. regulation of recombinant protein expression.  

Con = Continuous culture
with feed and harvest rates balanced to keep a fixed concentration of nutrients or cells in the vessel. 
 

Per  = Perfusion culture
is similar to
continuous but the cells may be immobilized and/or media replaced at regular intervals e.g. daily. This is commonly used with mammalian cells culture.  

Ane  = Anaerobic
No oxygen but this can vary according to how strict  the anaerobiosis must be. Truly
anaerobic cultivation requires a redox value of <-200mV (micro-aerophilic is  -180mV.

Haz  = Biohazard
This can be defined by the Bio-Safely Level. Anything above BSL1 needs special handling and some special options for a bioreactor.  Pathogens and recombinant organisms fall into this group.     

 

Optimization

DoE = Design of Experiment
This allows experiments to be planned, grouped and analysed according to specific statistical processes to allow rapid screening for key parameters and their optimization.  

PAT = Process Analytic Technology
This is a set of guidelines from the Food and Dr
ug Administration (FDA) in the United States which allow rapid process investigation and validation by combining laboratory scale experimental results with submissions for a production license.  

QbD = Quality by Design
Provides analysis of processes in terms of how it is designed and implemented. The aim is continuous improvement.   

Spc = Statistical Process Control
Looks at data from multiple batches to determine potentially hidden factors influencing productivity or quality e.g. a small change in pH producing large increases in yield.  

Com = Compare
The simplest way to optimize by looking at two different aspects and making a direct A versus B comparing performance based on specific criteria. 

SoS = Soft sensor
This allows calculation of factors such as dilution rates, exponential feeds and metabolic activity. A simple scripting language can convert equations into values and actions.    

Mod = Model
This is more complex than a soft sensor and may use several key metabolic criteria to  provide a way to influence a bioprocess in real time for e.g. optimize substrate utilization. 
 

DTw = Digital Twin
This takes real process data and crates a digital “copy” of a bioprocess which
can be used for comparison and direct control of a running batch.  

Analysis

Glu = Glucose
The sensor can be part of an at-line analyzer, or a sterile probe added to a shake flask or bioreactor. Measurement would typically be in grams per litre.        

Lac = Lactate
Usually an option for at-line analysers and estimates the increase in lactate during a bioprocess. Measurement would typically be in grams per litre.  
 

Gmt = Glutamine
Measured at-line for cell culture processes. Measurement would typically be in grams per litre.    

Amm = Ammonia
Measured at line for cell cultures. Measurement would typically be in grams per litre.    

MS = Mass Spectrometer
For bioprocesses, they are used for analysis of entry and exit gasses to provide quantitative data, usually as a percentage of total gas volume.  

NIR = Near InfraRed
This is used for analysis of culture supernatant in real time to provide estimates of key biochemicals.   

Ram = Raman Spectroscopy
Usually linked to an optical probe in the bioreactor and can provide a spectrograph of constituents in close to real-time.   

Spe = Spectroscopy
This typically uses light (from infra-ed, through visible to ultraviolet) to detect various components of a culture according to the wavelength used e.g. proteins, D.N.A and biomass.  

 

Bioreactors 

Min = Mini bioreactors
These normally have the form of a Stirred Tank Reactor (STR) but with a < 1 L working volume. They tend to be elements in a multiple, parallel system.   

Ben = Bench-scale bioreactors
Covers a range of 1 to 10 L working volume and are either single use or autoclavable. It is possible to get versions which are in-situ sterilizable but these are less common.   

ISS = In Situ Sterilizable bioreactors
They have stainless steel vessel over 10L working volume and include technical and pilot scales. Steam is supplied to the unit for sterilization and heating in most cases.  

Pro = Production Volume
These are large bioreactors, typically mounted on a skid framework. Working volumes of 1,000 litres are common for microbial products. 

Proc = Process Level Control
This is top-level control and can involve multiple bioreactors and peripheral equipment working in a co-ordinated way.  

Sca = Supervisory Control And Data Acquisition (SCADA)
This is control at the level of one or more bioreactors and relates to aspects such as  different phases of a bioprocess.
  

HMI = Human Machine Interface
Local measurement and control for one or more bioreactors form a local operating panel. This includes control loops, cascades, parameter configuration and sterilization.   

PLC = Programmable Logic Controller
This can be a rack system or an SoC (system on a chip). This is control at the level of individual actuators such as valves, pumps motor and heater.  

Mic = Microbial
Covers bacteria, yeast, fungi, archaea and relevant sub-groups. The bioreactors are typically STRs with an emphasis on good mixing and oxygen transfer.    

Cel = Cell
Includes mammalian, Insect Hybridoma cell lines. Design is for low-shear, foam-free operation.   

Sub = Single Use Bioreactor
Commonly used for cell culture and provide pre-sterilization qualification and no cleaning/preparation.    

SSF = Sold State Fermenter
Can be an STR or special design. Mixing and heat tranfer in solids leads to special modifications.  Some systems allow single-vessel treatment of solid substrates and fermentation in the same vessel.  

Pho = Photobioreactor
Adding lights to an STR is possible but not ideal due to penetration when cell densities increase. A flat-panel design, especially when coupled with a sensor, can provide optimum control of lighting. Lights are LEDs and specific spectra can be created, with warm white being a good default.  

MuP = Multiple, Parallel
These can be 1 to 6 units for bench-scale units  with 24 or more vessels of mini-bioreactor systems e.g. 15 – 500 mL.  Centralized control and shared heating / stirring are common.  

ISF = Instrumented Shake Flask
It is possible to add a number of sensors and even feed options to make a shake flask behave more like a bioreactor vessel in terms of parameter values and control.  

MW  = MicroWell plates
Sensor spits can provide information regarding pH, pO2 and OD. Micro-valve technology allows feeding of individual wells and gassing solutions give some control.  Scale-up from wells to bioreactors is possible.  

 

Downstream  

Har = Harvest
This is the first stage of the process for batch and fed-batch cultures, with transfer of the vessel contents to a downstream processing unit or storage tank.  

Ctg = Centrifugation
A low speed  centrifugation separate whole cells from the culture supernatant. This can be a continuous process with a direct feed from the vessel or may require manually transferring aliquots of culture into centrifuge bottles.

UCf = Ultra-centrifugation
This step can separate cell debris and macro-molecules. It can be used for precise separation with methods such as the use of  a sucrose density gradient.     

Col = Column Chromatography
This is one of the most common ways of separating macromolecules., based on rates if retention on a substrate in a column or disc as a solution is eluted.   

AfC = Affinity Chromatography
This type of column uses antibo
dies, antigens, enzymes, ligands of nucleic acid to specifically bind to the required macromolecule and hold it within the column until a change of conditions allows to be released.  

ATF = Alternating Tangential Flow Filtration
This is a separation system using a separation across a fibre or membrane based on molecular weight/size.  The alternating part involves repeatedly pumping  e.g. whole culture of microbes or cells across a membrane. The required molecules can pass through the membrane and larger compounds, such as cells, are returned to the bioreactor.  

Any = Analysis
Any separation system must be able to detect when the correct component or fraction is released.
At its simplest, this could be a simple spectrophotometer tuned to detect proteins.  

BiA = Biological Activity.
When the product has been detected and isolated, a concentration step and subsequent bioassays can determine quality based on degree of specific activity e.g.
an immune response.   

 

Organisms 

Bac = Bacteria
Eukaryotic cells with no defined nucleus. Some interior separation of functions but not to the same extent as Prokaryotes.  

Yst = Yeast 
P
rokaryotic cells with a nucleus and complex interior separation of functions.

Fun = Fungi
Prokaryotic and can be filamentous with multicellular organisation and the ability to produce specific fruiting bodies (e.g. mushrooms) and spores.  

Arc = Archaea
Primitive ancestors of both eukaryotes and prokaryotes.  

Ma = Mammalian cells
From a range of tissues such as Hamster kidney (HEK) cancer cells (HeLa) and ovary (CHO). Large (compared to bacteria or yeast, shear-sensitive and able to
generate complex folding of folding  i.e. glycosylation.   

Ins = Insect Cells
From insect organs such as ovaries. They have the advantage of containing no virus material capable of harming humans. Often used as a host for
baculovirus for recombinant work.   

Bar = Barophiles
P
ressure loving organisms, usually bacterial  

Hal = Halophiles
Grow in high salt concentrations  

Psy = Psychriphiles
Grow in cold conditions   

Me = Mesophiles
Grow  in temperate environments   

TPh = Thermophiles
Thrive in high temperatures 

Ext = Extremophiles
A generic term including those microbes which can grow in harsh conditions 

Vir = Virus
Small organisms which can only reproduce inside a host using their metabolic processes  

Phg = Bacteriophage
Viruses which infect bacteria

Pri = Prion particles
Mis-folded proteins capable of causing diseases such as Bovine Spongiform encephalitis (BSE) by triggering a re-arrangement of normal  protein structures in the brain. Unlike all other infectious agents, they contain no nucleic acid  

Plnt = Plant 
Prokaryotic cells with a rigid cell wall capable of photosynthesis in specific organelles

Alg = Algae
Single cells capable of photosynthesis  

CnB = CyanoBacteria
Bacteria capable of photosynthesis 

 

Options  

SIP = Sterilize In Place
Standard for larger, steel vessels. Can be chemical for smaller systems. The process is controlled automatically, based on temperature, pressure and time.   

CIP = Clean in Place
Allows cleaning by use of spray balls inside the vessel. Cycles of washing with de-ionised water, base solution and acid solution are followed by a final  rinsing. Results can be tested  to ensure no residual organic material remains.   

AirL = Air Lift
A vessel design which does not require a motor for liquid circulation and mixing. Introduction of gas at the base and a large hydrostatic head allow make this possible. A tall 10:1 aspect ratio is typically used.
 

Pek = PEEK
This highly corrosion-resistant material can be used to make interior bioreactor  vessel components such as drive shafts and the vessel top plate. Used with glass components, this creates an inert environment for growth of extremophiles which can cause pitting and leeching of metals 

Imm = Immobilization
Some cell lines will not grow in suspension and require immobilization on beads or fibres  

HSG = Head Space Gassing
This is often used with mammalian cell culture and helps prevent foaming at the gas/liquid interface. A squat aspect ratio e.g. 1:1 assists in allowing good transfer.  

StC = Sterile Cross
This option provides a means for adding liquid feeds and inoculum to a ISS vessel from an external bottle or tank  while maintaining sterility.   

Mpt = More ports
ISS vessels will have a default number of top and base ports for sensors etc. The ability to add more during specification can allow for extra parameter measurement or circulation loops.  

Gas = Gasses
Additional gas flow control can be used for e.g. production of biodegradable plastics from biogas by allowing each component of the biogas mix to be controlled separately.  

MC = Magnetic Coupling
This separate the drive shaft of a bioreactor from the outside environment without the need for a mechanical seal. This is popular for mammalian cell culture, which can last several weeks.  For microbial vessels, it removes an element which has to be checked and replaced regularly.  

Cont = Containment
The degree of modification to a standard vessel depends on  its size, design and level of risk. Items may include a double mechanical seal, kill tanks below a bioreactor or double O rings with live steam between them.   

StG = Steam Generator
This is an option for smaller ISS vessels where a steam generator of appropriate size can be mounted on the same support frame as the bioreactor vessel for space-saving and portability.   

 

Scale-up 

Mas = Maser Seed
The first step in the seed train. Typically taken from a frozen or freeze-dried ampoule and plated or added to liquid medium.  

SFC = Shake Flask Culture
Normally up to 1L working volume. Multiple flask cultures may be combined to create an inoculum equivalent to 5 % of the working volume of the bioreactor used for the next stage.  

STR = Stirred Tank Reactor
This will be a bench scale unit used to create a culture at higher density and large volume than is possible in shake flasks.

Tec = Technical Scale Bioreactor
This can be in the laboratory or plant hall and amplifies the culture volume and density by at least a factor of ten. This produces an inoculum for a pilot-scale vessel. 

Plt = Pilot Scale Bioreactor
This can produce enough culture for testing of a production process or create a seed inoculum for a vessel of several thousand litres capacit.

LSc = Large Scale Bioreactor
This is for production volumes and can encompass vessels which  can be major engineering projects in their own right.    

ScD = Scale-Down
This is the idea of taking a sample from a large vessel, dividing into aliquots and then using multiple,  low-volume bioreactors for optimization experiments in real time.   

 

Parameters  

Tem = Temperature
Typical range 10 – 70o °C, usually 20  -40o °C 

Str = Stirrer speed
 Typical range 20 – 300 min-1 (cells) 100 – 1500 min -1 for microbial 

pH  = pH
Typical range 2 – 12, usually 4.5 – 7.5   

pO2 = dissolved oxygen
Typical range 0 – 100 %, usual 20 – 90 %  

AF  = Antifoam
Sensitivity suitable to detect most foams  

AFl = AirFlow (litres/minute)
Range depends on vessel  and type e.g. 0.05-2 VVM  

Fed = Feed (grams/hour)
Range 0-100 %, calibrated to specific feed in mL min-1 or gm -1 

GM = Gas Mix (based on % O2 in mix)
range 0 – 100 % (2 gas) or -100 ±100 % (3 gas)   

OD = Optical Density
Range typically 0 – 4 Au.   

xO2= Exit oxygen
(% in exit gas stream) Range typically o – 25 %, usually 16 – 21 %

xCO2 = Exit carbon dioxide
(% in gas stream)
Range typically 0 – 20 %, usually 0.04 – 10 % 

Prs = Pressure
(bar- in vessel)
Typically 0-2 Bar  

N2F = Nitrogen flow
(litres/minute) 
Range depends on vessel  and type e.g. 0.05-2 VVM  

O2F = Oxygen flow
(litres/minute)
Range depends on vessel  and type e.g. 0.05-2 VVM  

Red = Redox potential
(mV) Range -1000 to +1000. Typically -200 to 0.  

CO2F = Carbon Dioxide Flow
(in litres/minute)
Range depends on vessel  and type 0.05-0.5 VVM  

Cdy = Conductivity
(in
Siemens/metre) Range 0 – 5000 can be expressed as mS cm

 

Actuators 

Htr = Heater (Pulse Width Modulation)  

CoV = Cooling valve (Pulse Width Modulation)  

Mtr = Motor (analogue or PWM)  

MFc = Mass Flow Control valve (analogue, or Modbus) 

PcV = Pressure Control Valve (analogue, or Modbus) 

AfP = Antifoam Pump (Pulse Width Modulation)  

AcP = Acid Pump (Pulse Width Modulation)  

BaP = Base Pump (Pulse Width Modulation) 

FeP = Feed Pump (analogue)  

F2P = Second Feed Pump (analogue)  

F3P = third Feed Pump (analogue) 

EGC = Exit GAs Cooler water flow valve (digital) 

Fre = Free Input/Output channel (digital)

OTc = Over Temperature  Cut out (digital)  

Ster = Sterilization Run of Phases (multivalve) 

 

Control 

SP = Set point
set
manually or auto or remote

Rng = Range
of
possible controller output (-100<0>+100)

Out = Output 
Value, which can be 
0 to 100 %, -100 to 0 % or 100 to +100 %  

PID = Proportional Integral Derivative
Factors in the controller output equation 

Cas = Cascade
A master parameter in
fluences the set point of other parameters in a parallel or serial way  e.g. pO2 (see also stirrer spee and air flow).

Cal = Calculated
Usually needs bioprocess software to create the necessary calculations

Pha = Phases
Controls different parts of a process in a linear sequence (or loop) to provide changes in parameter set points based on time or events 

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Mic Chaudoir
12.05.2020
Mic Chaudoir

Fun, informative way to organize the information - nice.

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