Transcript A j - Portal UniMAP

Simulation Of Bioprocess
ERT 315/4
5
TYPES OF BIOPROCESS
AND
BIOPRODUCTS
Criteria to select appropriate
biocatalyst
 What yield, product concentration, and productivity can be reached?
 What substrate can be utilized, what additional media components
are required, and how does it all effect downstream processing?
 What by-products are formed and how do they affect yield and
downstream processing?
 What are the challenges in biocatalyst preparation, storage,
propagation, security, and safety?
 What are the optimal reaction conditions, e.g. temperature, oxygen
supply, shear sensitivity, foam formation, etc?
 How well do we understand the reaction mechanisms, are they
robust and genetically stable?
 If the product is expressed intracellularly, how is it extracted?
 How do we purify the desired product form the many impurities in
the process?
Characteristics of biocatalyst
Biocatalyst
Production
device
Raw
material
Timescale
Purification
Complex protein
structure
Viral/prion
risk
Process
examples
Enzymes
Bioreactor
Pure substrates
Short
Simple
No
No
Simple media
Short
Medium
No
Small
Bioreactor
Bioreactor
Simple media
Complex media
Medium
Medium
Medium
Medium
No
Yes
Small
Medium
Plant cells
Bioreactor
Simple media
Medium
Medium
Possible
Small
Transgenic
plants
Bioreactor
Fertilizer, CO2,
various others
Long
Complex
Possible
Small
Transgenic
animals
Whole plant
Various plant &
animal materials
Certain parts of
plants, animals
and humans
Long
Complex
Yes
High
Long
Complex
Possible
High
Cyclodextrin,
Acrlyamide, L-dopa
Lysine,Vitamin B2,
Insulin
Citric acid, antibiotics
Monoclonal
Antibodies,
Interferons
Taxol, shikonin,
Methyldigoxin
Antibodies, antibody
Fragments, HAS,
PHB
Α1-antirypsin, HAS,
Lactoferrin
Plasma,components,t
axol
Bacteria and
yeast
Fungi
Mammalian
cells
Bioreactor
Extractive
technology
Whole animal
Biocatalyst
Enzyme Biotransformation
-enzymes: protein with a unique three-dimensional structure able to bind a substrate,
usually but not always a small molecule, and catalyze a specific reaction, similar to
chemical catalysis but under mild conditions of temperature and pressure
-classified in six groups according to the chemical reaction: oxido-reductase,
transferases, hydrolases, lyases, isomerases, ligases
-highly selective and specific in the reaction: regio-, stereo- and enantioselective
-can be in solution or immobilized
-widely used in the production of fine chemicals and pharmaceuticals, e.g. vitamin C,
amino acids, antibiotics, and steroids
-five major of reactions where enzymes are used industrially: hydrolysis of proteins,
palysaccharides,esters,amides, nitriles, epoxides; synthesis of esters, amides,
glycosides; carbon-carbon bond formation; reduction reaction; oxidation reactions
Metabolic Bioconversion using cell cultivation
- Classified into five groups: Bacteria, Fungi, Mammalian cells, insect cells, plant cells
(i) Bacteria
-unicellar prokaryotes with a rigid cell wall
-key determinants for their growth: media composition, temperature,
gaseous environment, pH
-show a range responses to oxygen: aerobic bacteria- require oxygen for their
growth; anaerobic bacteria- grow only at the absence of oxygen; facultativelyanaerobic bacteria- able to grow under both conditions
-temperature optimal for growth: psychrophiles (20-30 °C), mesophiles
(30-40 °C), thermophiles (45-60 °C), extreme thermophiles (extremophiles) (80-105 °C)
-optimum pH: 6.5-7.5
(ii) Fungi
-divide into two subgroups: yeasts, molds
-yeast: small, single cells that can grow as individual cells or clumps
-used to produce alcohol in anaerobic fermentation, baker’s yeast, yeast extract as
food additive
-molds: multicellular, vegetative structure call mycelium, as usually
highly-branched systems of tubules
-mostly grown under aerobic conditions and the formation of a dense
filamentous mycelium in the form of cell aggregates and pellets often cause
oxygen-transfer problems
-used for citric acid production, antibiotics, and riboflavin
(iii) Mammalian cells
-produce correctly folded proteins and secrete them to the culture environment
-carrying out required post-translational modifications of proteins, e.g. glycosylations
-generally produce high-value proteins where are correct (native) three-dimensional
structure is crucial
-have complex nutritional requirements requiring serum, e.g. fetal calf serrum
-grow quite slowly, with typical doubling times of 12-20 h
-temperature : 37 °C, pH: 7.3
-mammalian cell product: monoclonal antibodies, interferons, vaccines, erythropoietin
(iv) Insect cells
-produce recombinant proteins less expensively and more quickly than mammalian
cells and at high expression levels
-typically grow at around 28 °C, and pH 6.2
-used fir veterinary vaccines for the swine fever virus
(v) Plant cells
-10 to 100 times larger than microbial cells and more sensitive to shear
-slow metabolism, with doubling times of 20-100h resulting in low volumetric
productivities even though high cells densities can be reached
-cultivate as a callus or a lump of undifferentiated plant tissue growing on a solid
nutrient medium or as aggregated plant cells in suspension
-used to produce secondary metabolites, anticancer drug paclitexel (taxol), recombinant
proteins of high value
Transgenic Plants
-genetically modified plants to produce a wide variety of products
-the expression can take place in the whole plant or only in a certain part as in the seeds
-commonly used plants: tobacco, potato, rice, wheat
-inexpensive, easy to scale-up, free of human pathogens
Transgenic Animals
-reduce the dependency on the seasonal and geographical conditions, post-translational
modifications are more likely to mimic the native structure
-usually done by injecting exogenous DNA into egg cells to produce a vital embryo that is
later able to express the desired product
Extractive Technologies
-comprise all processes where a product is extracted from natural material
- Used in the extraction of pharmaceuticals from human or animal blood and from plant
material
-the products usually chemically complex non-protein materials
Bioproducts
Product Classifications/Characteristics
-according to size, bioproducts can be divided into:
a. Small molecules
b. Large molecules
c. Solid particles
-Small molecules
i. sugars, amino acids, organic acids, vitamins
ii. Molecular weight of 30-600 Da and a radius smaller than 1 nm
Iii divided into primary and secondary metabolites:
a. Primary metabolites: sugar, organic alcohols, acids-produced in the primary growth
face of the organism
b. Secondary metabolites: formed at or near the beginning of the stationary phase, e.g.
antibiotics and steroids
-large molecules
i. proteins, nucleic acids, polysaccharides
ii. Molecular weight of 103-106 Da and a radius typically larger than 1 nm
-solid particle
i. Whole cell like yeast, animal cell, ribosomes, viruses
ii. A radius of up to several µm
-by the scale of production, bioproducts can be classified into:
a. Bulk or commodity chemicals made at large scale
b. Fine chemicals
c. Pharmaceuticals made a smaller scale
-bulk chemicals
i. Produced in very large amounts (e,g, more than 1 000 000 tons per year)
ii. Simple downstream processing
iii. Sold at a relatively low price
iv. Medium purity
v. Biocatalyst that grows in inexpensive media and reaches at a high productivity are
necessary
-pharmaceuticals
i. produced in a small amounts (as low as few kg per year)
ii. high price
iii. used expensive media and complex equipment with low productivities
iv. complex product separation and purification is acceptable for economic commercial
production
-fine chemicals
i. Used as intermediates and have application in a variety of industries
ii. Annual production, price, and required purity lie between bucl chemicals and
pharmaceuticals
Product classes
-describe by its function (proteins, organic acids, lipid) or application (food and feed
additives, pharmaceuticals, detergents, chemical intermediates, agriculturally used
products)
-organic alcohol and ketones
- produced in anaerobic fermentations, from inexpensive
carbon-energy sources such as glucose, starchy materials, molasses, sucrose containing
materials
-organic acids:
-used as intermediates or as food additives
-major organic acids produced are citric, lactic, gluconic acid.
-amino acids:
-the building blocks of protein and are connected via peptide bonds
-used as food additives, feed additives, and in pharmaceuticals
-most important amino acid are L-glutamic acid and L-lysine that are produced from
molasses and starch hydrolysates
-nucleic acids:
-used as therapeutics, e.g. DNA vaccines, gene therapy
-produced as short interference RNA molecules (sRNAi), aptamers (small DNA, RNA, or
peptide molecules that bind with high specifity and affinity to DNA, RNA, or proteins
-antibiotics:
-frequent use in human and animal health
-produced on fungal fermentation
-vitamins:
-produced in bioprocesses, e.g. vitamin A, C, E, and the B vitamins
-biodegradable biopolymers:
-plastics derived from renewable material
-common biopolymer are polyhydroxyalkanoates (PHA) and polyhydroxybutyrate (PHB)
-dextran and xanthan:
-industrially produced microbial polysaccharides
-used as thickening, gelatinizing, suspending agents in food and pharmaceuticals
-carotenoids:
-natural pigments (yellow or red color)
-produced by microorganisms
-pesticides
-lipids:
-including fats, oils, waxes, phospholipids, steroids
-commercially produced lipid: prostaglandins, leukotrienes, thromboxane
-proteins:
-characterized by four level of structure: primary structure (linear amino acid sequence),
secondary, hydrogen-bonded structure (alpha helix and beta sheet), tertiary (folding
pattern of hydrogen-bonded and disulfide-bonded structures), quaternary structure
(formation of homo- and hetero- multimeric complexes by individual protein molecules)
-two major applications: as industrial enzymes, as therapeutic and diagnostic proteins
Raw materials
-Water:
-dominant raw material
-other component of the reaction medium: macronutrients and micronutrients
-macronutrient:
-needed in concentrations larger than 10-4 M
-including carbon –energy source, oxygen, nitrogen, phosphate, sulfur, and some minerals
such as magnesium and potassium ions
-carbon-energy source:
-dominant requirement as it provides the carbon for biosynthesis as well as energy derived
by its oxidation
-Typically used carbons sources: glucose, starch, corn syrup, molasses. soybean oil, palm
oil, ethanol, methanol
-50% is incorporated in the biomass, and remaining 50% is used to derived energy for
biosynthesis
-nitrogen:
-accounts for 10-14% of the dry cell mass
-most widely used are ammonia and ammonia salts, proteins, amino acid, urea,
complex materials
-oxygen and hydrogen:-20% of the cell mass (oxygen), 8% (hydrogen)
-phosphorus: 3% of cell dry weight and is provided by phosphate salts
-sulfate: 0.5% of cell mass is added as sulfate salts or with amino acids contained in
complex media
-magnesium and potassium ions: provided as inorganic potassium and magnesium sulfate
-micronutrients:
-required in low concentrations:
-including iron, zinc, manganese ( almost always needed), copper, sodium, calcium, boron
(needed only under specific growth conditions)
-added as inorganic salts
-also can be classified into defined or synthetic media and complex or natural media
-defined media:
-contain specific amounts of pure chemicals with a known composition
-complex media:
-include one or more natural materials whose chemical composition is not exactly known
and which may vary with source of time
-natural media:
-cheaper
-cause less reproducible fermentation and more complex downstram processing
-bacteria and fungi: need only a relative simple media and very low cost
-mammalian cells: more complex medium is necessary, need serum as required ingredient
(complex media) or not (synthetic media)
-plant cell: require a carbohydrate cell source, inorganic macronutrients and micronutrients.
1. Avoid waste formation
2. Reduce waste formation
Economic savings
3. Extend material use
4. Recycle material
Ecological costs
Waste treatment, Reduction and
Recycling
5. Downcycle material
6. Treat waste/energetic recovery
7. Safe water disposal
Steps of waste avoidance and treatment
1. Avoid waste formation
-to avoid the formation of waste
-if feasible and cost-effective, subsequent treatment is unnecessary
-if cannot be prevented completely, try to reduce it as much as useful
2. Reduce waste formation
-reuse of material, e.g. a chromatography resin can be used for multiple cycles, the annual
amount of waste is significantly reduced
3. Recycle material use
-recycling of an organic solvent used in an extraction step: good of cost-effective recycling
-Compared the amount recycle and the amount of material and energy necessary for the
recycling to decide it is economically and environmentally favorable
-if cannot be recycled because the purification becomes too expensive, used another
purpose that requires less purity (downcycling)
4. Treat waste/energetic recovery
-have to be treated or disposed safely
-some energy is produced during the treatment (e.g. incineration)
Types of waste
-gaseous stream:
-cause from the exhaust air from a bioreactor (contains air, CO2, and water), distillation
and evaporation steps (e.g. associated with crystallization)
-solid waste:
-categorized as hazardous and non-hazardous waste
-hazardous waste:
-containing heavy metals or highly toxic substances
-need special treatment or disposal with high-safety manners- cause higher costs
-non-hazardous waste:
-wet biomass
-if a recombinant organism is used, sterilization of the material is necessary, usually by
heat
-can be used as animal feed or organic fertilizer or treatment plant
-liquid waste:
-treated in a biological sewage treatment plant at the production site of the
bioprocesses
-also can be released to the municipal sewer system
-pretreatment is necessary – at a high low or low pH, the liquid has to be neutralized by
adding base or acid
Overall development process
Literature/patent review
Biocatalyst screening
Development steps
Biocatalyst optimization
Medium and reaction condition optimization
Selection of downstream steps
Identification of PFD
Optimization of unit operations
Plant size
Scale-up : Lab – technical - industrial
Approval, clinical trials
Process modeling and uncertainty analysis
Economic and environmental assessment
Development process
Product idea
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Goal of every process development: product
Product- should have a market, potential market, sufficient size that economically
justifies the required environment
Required literature and patent review – to clarify if there are similar products already
on the market or in the development
Find a biocatalyst (organism or an enzyme that catalyses the formation of the desired
product)- to reach an economically feasible product yield and concentration
The medium and reaction conditions are adjusted enable the best performance of the
catalyst- medium should be as simple and inexpensive as possible and the reaction
conditions should provide the best environment for the biocatalyst
The process flow diagram (PFD) put together all the operation
All unit operations have to be chosen and connected in an efficient and robust
manner- to maximize the overall yield
Determined the size plant- validate the market share of the product estimated at the
beginning
Scale up the process
Plan and implement the clinical trials for pharmaceuticals
Build a process models to estimate the material balance, energy consumption, labor
requirement and equipment needed
Process
Raw
material
Upstream
processing
Consumables
Utilities
Labor
Bioreaction
Donwstream
processing
Waste
Treatment/
disposal
Final
product
6
Sustainability
Assessment
Sustainability Assessment
What is “sustainability”?
-the development that meets the needs of the present without compromising the ability of
the future generations to meet their own needs (Brundtland, 1980s)
-the optimal growth path that maintains economic development while protecting the
environment and optimizing the social conditions with the boundary of relying on limited,
exhaustible natural resources
-a business approach that creates a long-term shareholder value by embracing
opportunities and managing risks deriving from economic, environmental, and
social development
Sustainability
Economic Ecological
Social
Economic Assessment
Bioengineering
Conversion, yield
Raw materials
Process flow diagram
Volume/mass
of product
Equipment
prices
Utilities/waste
Purchase equipment
cost
Labor
Consumables
Operating cost
Multipliers
Capital investment
1.Estimate the capital investment
2.Operating costs can be derived from the different cost items
Capital cost estimation
-total amount of money that has to be spent to supply the necessary plant (the fixed
capital investment) plus the working capital that is needed for the operation of the facility
-how to estimate:
i. Equipment purchase cost
ii. Estimation of total capital investment:
a. Direct cost- the purchased equipment that need to be installed
b. Indirect cost- a number of planning costs, like the preparation of design books that
document the process, the design of equipment, etc
iii. Multiplier values –for a realistic estimation of the capital investment, derived from the
empirical data and are different for different process types
iv. Prices indices- changes of equipment price over time due to inflation/deflation or
market conditions
Present prices = Price at t0 x index value today/ index value at t0
v. Scale-up Factors- the cost of a single piece of equipment or a complete plant changes
when its capacity is changed
C2= C1 x (q2/q1)0.6, where C1: coast of a plant with a certain capacity q1
Operating-cost simulation
-the total of all costs operating the plant and recovering the capital investment, i.e. the
annual amount of money necessary to produce the product and pay back investment cost
-Divided into variable, fixed, plant overhead cost
-Variable cost:
1. Raw materials – the list of raw materials and the amounts consumed
2. Consumables- all material and equipment parts that have to be replaced from time to time
3. Labor- determined by the operator hours and the hourly wage
4. Operating supplies- including clothing, tools, and protective devices for the workers and also
everyday items needed to run the plant
5. Laboratory, quality control, and quality assurance
6. Utilities- energy consumption for heating, cooling, evaporation/distillation, aeration, etc
7. Waste treatment and disposal
8. Royalty expenses- single unit operations or even the whole process that has to be covered by a
patent owned by others
-Fixed Cost (Facility-dependent cost)
1. depreciation- a capital investment that was need to built a plant and this investment has to be paid
by charging an annual amount of money
2. Maintenance and repair
3. Insurance and local taxes-derived from the direct fixed capital (DFC)
4. Rent and interests
-Plant overhead cost –factory expenses, or plant overhead costs caused by the operation of facilities
that are not directly related to the process, e.g. medical service, safe and protection
-general expenses- the general expenses that has to cover to manage the company, to sell product
and computer support. Including administration, distribution and marketing, research and developmen
-Unit production cost (UPC)- the total product cost allocated to the annual amount of product
Profitability Assessment
-revenues: sum of all sales of the main and side product of a process within a certain time period
usually a year. For a single-product facility, the revenue r for year j is :
rj= mjxpj ,
where mj is the amount of product sold in year j and pj the (average) price realized in this year
-measurement of profitability- a number of indices that are used to evaluate the profitability of a
process
i. The gross profit in year j (Gj) is the annual revenue rj minus the annual total product cost including
depreciation:
Gj=rj-cj
ii. The net profit in year j (Nj) is the gross profit minus the income tax. The income tax is determined
by the tax rate Ф
Nj = (rj-cj)x(1- Ф) = Gjx(1- Ф)
iii. The net cash flow in year j (Aj) is the sum of net profit and the depreciation dj of the year
Aj=Nj+dj
iv. The return on investment (ROI) is the ratio of profit to investment and measures how effectively
the company uses its invented capital to generate profit. Usually calculated using the net profit
and the total investment (TCI) and is shown in percentage value:
ROI=Nj/TCI x 100
v. The payback period (PBP) is the length of time necessary to pay out the capital investment by
using the annual cash flow that return to the company’s capital reservoir. In most cases, the
direct fixed capital (DFC) is used for this index
PBP=DFC/Aj
The PBP also can be calculated using the TCI and the net profit
PBP=TCI/Nj=100/ROI
Time value of money: time-value of the earned money
NPV=ΣAj/(1+i)j
n
j+1
Environmental Assessment
-to identify the environmental ‘hot spots’ of the process
Process characteristics
Modeling and simulation
Component properties
Impact categories
Material balance
ABC classification
Mass indices (MI)
Environmental factors
(EF)
Environmental indices
(EI)
Impact categories
Process
Components
Assessment structure of the method
Structure of the method
-two starting point:
a. Process and characteristics by Superpro Designer model
-the result is the material balance of the process
-from the material balance, Mass Index (MI) can be calculated for all input (states how
much of component is consumed to produce a unit amount of the final product) and output
components (how much of a component is formed per unit final product)
b. From the component properties
-classified into A, B and C classes that represent environmental relevance (high, medium,
low relevance) from the 15 impact categories (IC) that may have a negative effect on
human health and the environment
-the IC are allocated to six impact groups, representing an important field concerning
environmental, health or safety aspects
-numerical values for the classes A, B and C, and a weighting factor (=environmental
factor) is derived from its classifications in the impact groups
-next step:
-Link the amount of the components in the mass balance with Environmental Factors
-The resulting Environmental Index (EI) helps to identify those components that are
environmentally most relevant in the process
Weighting factors/indices
Calculation
Mass Index component i, MIi (kg/kg P)
mi= amount of component i (kg);
mp= amount of final product (kg P)
MI=mi/mp
Mass Index process, MIprocess (kg/kg P)
MIprocess,In =Σmi/mp
MIprocess,Out=1+Σmi/mp
EFMv,i=(IG1,i+IG2,i+IG3,i+IG4,i)/j
Environmental Factor component i,
EFi (index points/kg)
Via arithmetic average; as EFMv,i,In/EFMV,i,Out
IGj,i= value of component i in Impact Group j;
j= Number of impact Groups
Environmental Factor component i,
EFi (index points/kg)
Via multiplicatiom; as EFMult,i,In and EFMult,i,Out
EFMult,i=πIGj,i
Environmental Index component i,
EIi (index points/kg P) (as EIi,In or EIi,out)
EIi=EFi,x mi/mp=EFi x MIi
Enviromental Index process
EIprocess (index points/kg P) (as EIIn or EIOut)
EIprocess=ΣEIi
Generak Effect Index Process
GEI (nondimensional)
GEI=EIprocess/MIprocess
Impact categories
Impact groups
Environmental Factors
Raw Material Availability
Land Use
Resources
Complexity of Synthesis
Grey Input
Thermal Risks
Component Risk
Environmental Factor
Input component
Acute Toxicity
Chronic Toxicity
Organism
Ecotoxicity
Global Warming Potential
Ozone Depletion Potential
Acidification Potential
Air
Photochemical Ozone Creation Potential
Environmental Factor
Output component
Odor
Eutrohication Potential
Water/Soil
Organic Carbon Pollution Potential
Impact category
I/O
Class A
Raw Material
Availability
I
Only fossil,
Only fossil, predicted
Predicted exhaustion exhaustion in 30-100
years
within 30 years
Land use
Critical material
used
I
I
Complexity of the
Synthesis
Thermal risk
I
I/O
>100m2/kg
Critical materials like
heavy metals, AOX,
PCB used or
produced in
stoichiometric
amounts
>10stages
R 1-4, 9, 12, 15-17,
44; EU; F+, E; NFPA
F+R: 3,4
EU:T+; R 26-28,32;
CH-poison class:
1,2; NFPA H:4; WGK
3;
ERPG:<100mg/m3;
IDLH: <100mg/m3
Acute toxicity
I/O
Class B
>10m2/kg and<100m2/kg
Critilcal materials involved
in sub-stochimetric
amounts
Class C
Exclusively
renewable, or
guaranteed long term
supply (>100 years)
<10m2/kg
No critical
compounds involved
3-10stages
<3 stages
R 5-8, 10, 11,14,18,19, 30; NFPA F+R: 0,1
EU: F, O; NFPA F+R:2
EU: T, Xn,Xi,C; R 20-25,
29, 31,34-39,4143,65,66,67; NFPA H: 2,3;
WGK 2; ERPG: 1001000mg/m3; IDLH: 1001000 mg/m3
CH-poison class: 5;
NFPA H: 0,1; WGK 1,
ERPG: >1000mg/m3;
IDLH:>1000mg/m3
Impact category
I/O
Class A
Class B
Class C
Chronic Toxicity
I/O
MAK:1mg/m3;
IARC;1,2A;R 4549,60,61
MAK:>10mg/m#;IAR
C: 4: CH-poison
class: 3,4,5
Ecotoxicity
I/O
EU:N;R 50 WGK 3;
MAK:110mg/m3;IARC;2B,3; R
33,40,62,63; EU: T,T+,Xn;
CH-poison class: 1,2
R 51-58; WGK 2
Global Warning
Potential
Ozone depletion
potential
Acidification
potential
Photochemical
ozone creation
potential
Odor
O
GWP>20
GWP<20
O
ODP>0.5
ODP<0.5
O
AP>0.5
AP<0.5
O
POCP>30 or NOx
30>POCP>2
Euthrophication
potential
Organic carbon
pollution potential
O
O
O
Odor threshold
<300mg/m3
N-content>0.2 or Pcontent>0.05
N-content<0.2 and Pcontent<0.05
ThOD>0.2 g O2/g
substrate
WGK ! Or no water
hazard
No global warming
potential
No ozone depletion
potential
No acidification
potential
POCP<@ or no
effect known
Odor threshold
>300mg/m3 or no
odor compound
without N and P
Compound without N
and P
ThOD<0.2g O2/g
substrate or no
organic compound
Social Assessment
Aspect
Health and safety
Quality of working conditions
Employment
Education and training
Social Indicators
Technology development
Technology application
-risk group of biological
substances
-risk factors for health and safety
-voluntary health measures
-quality of health and safety
management
-working time arrangement
-degree of psychological strain
-Percentage of women in leading
positions
-measures taken to improve
working conditions
-safeguarding of jobs
-continuity of job creation effects
-regions of job creation
-extent of job creation
-focus on employee training
-quality of human resource
management
-identification of training needs
-incorporation of employee
expectations
-job security levels
-amount of hazardous substances
-voluntary health measures during
application
-voluntary health measures during
usage
-working time arrangements
-degree of psychological strain
-percentage of women in leading
positions
-measures taken to improve working
conditions
-safeguarding of jobs
-continuity of job creation effects
-regions of job creation
-extent of job creation
-apprenticeship
-voluntary training offerings
-identification of training needs
-incorporation of employee expectations
Aspect
Knowledge management
Innovation potential
Product acceptance and social
benefit
Societal dialogue
Social Indicators
Technology development
Technology application
-Degree of knowledge exchange
-Used information system
-Control of knowledge exchange
-Employee involvement in
decision-making
-commercial exploitation potential
-contribution to scientific debate
-management of patents and
licenses
-number and types of patents
-stakeholder involvement
-usage of genetic engineering
methods
-social standards in supply chain
-societal benefits
-voluntary provision of information
-reporting of core activities to
neighborhood
-stakeholder involvement in
strategic decision making
-communication channels to
political debates
-aspects of knowledge exchange
-Used information system
-Control of knowledge exchange
-Employee involvement in decisionmaking
-degree of innovation
-product readiness and marketability
-estimated market penetration
-number and types of patents
-product acceptance
-usage of genetic engineering methods
-social standards in supply chain
-societal benefits
-used communication channels
-reporting of core activities to neighbors
-targeted dialogue partners
-measures taken to promote dialogue