INTRODUCTION TO SCALE-DOWN AND SCALE UP IN FERMENTATION TECHNOLOGY

Two of the most common phrases one often met in fermentation technology research is 'Scaling up' and 'Scaling down' studies. However, the phrase 'scaling up' is more commonly understood and practiced during the designing of industrial scale fermentors. Where as 'scaling down' studies are rarely heard that frequent. In reality many fermentation technologists are not aware that during most times of their work they are doing 'scale down studies' Maybe the phrase 'scale up' has more impact factor than 'scale down' studies.

Let us simplify the similarities and differences between these two phrases in fermentation technology. A good example is when we intend to start with a fermentation process with the ultimate objective of producing the fermentation products on the level of industrial scale. Products need to be produced at large volume so that the process is economically viable. This requires scaling up. We do scaling up studies to ensure that the fermentation process is technically and economically viable to be produced in the end at a large scale


SCALE UP STUDIES
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Scale up studies are studies carried out at the laboratory or even pilot plant scal fermentors to yield data that could be used to to extrapolate and bui;ld the large scale industrial fermentors with sufficient confidence it will function properly with all its behaviours anticipated. More important during scale up exercises you are trying to build industrial size fermentor capable or close of producing the fermentation products as efficient as those produced in small scale fermentors

INITIAL SCALE UP STUDIES
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Most scale up studies are usually carried at different phases involving different scales of fermentors.Preliminary work are carried out at the level of petri dishes and small scale laboratory fermentors to establish whether the process is:

1 Technically viable, meaning it is possible to produce such fermentation process and the products on the small scale. Additional parameters not provided by petri dishes studies and for more confidence are obtained by carrying further studies using submerged liquid fermentation using various sizes laboratory scale fermentors and even a pilot plant fermentor.

There are a few rules of the thumb followed when doing scale up studies such as:

1 Similarity in the geometry and configuration of fermentors used in scaling up
2 A minimum of three or four stages of increment in the scaling up of the volume of fermentation studies. Each jump in scale should be by a magnitude or power increase and not an increase of a few litres capacity. Slight increase in the working volume would not yield significant data for scale up operation

It must be appreciated as the size of fermentation increases during scale up various parameters measured might not show a predictable linear co relationships. Certain parameters changes. Some remained constant. Some parameters need to be modified and adjusted during scale up studies. The objective is to try to get the same fermentation efficiency as obtained in small scale fermentors at the most economical values

IF SCALE UP STUDIES FAILED?
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Should at this stage the fermentation process is technically not possible and is a failure than we have two options:
1 Either find the cause of the failure or back to the drawing board!
2 Abort the whole project with minimum economic loss to the investors

The investors and engineers need more confidence in predicting how the behaviour of the fermentation will occur at the level of industrial scale. If it fails it might mean millions of dollars lost in the exercise where failure was not seen. So scaling up will give the investors more confidence on the chances of success and against economic disasters

The exercise in scaling up involved a number of programmed research or steps that has to be established so as to predict the final behaviour of the final large scale production fermentor. Studies carried out during scale up include:

1 Inoculum development
2 Sterilization establishing the correct sterilization cycle at larger loads
3 Environmental parameters such as nutrient availability,ph, temperature,dissolved
oxygen,dissolved carbon dioxide,
4 Shear conditions, foam production


SCALE DOWN STUDIES
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In scale down studies the main objective is to carry out studies on smaller bioreactors in order to gain data and confidence and predict the behaviour how things actually will behave in large production fermentor. Scale down studies are also used while during the operation of large industrial scale fermentors in trouble shooting or trying to optimize the industrial scale fermentation. This method is called the fermentation monitoring experiment.

The goal when scaling down is to create a small-scale or lab-scale system that mimics the performance of its large-scale (pilot or manufacturing) counterpart, when both the process parameters are varied within their operating ranges and also when a process parameter deviates outside its operating range.

The main type of studies in scale down such as:
1 Medium design
2 Medium sterilization
3 Inoculation procedures
4 Number of generations
5 Mixing
6 Oxygen transfer rate

RULES OF SCALE DOWN
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In scale down a few rules that should be followed:

SIMILAR FERMENTOR GEOMETRY
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1 Similar model geometries and ratios of system. The impeller and sparger designs, and placements within the vessel must be identical or similar. Wrong models used in scale down studies might invalidate the data obtained. Since a typical fermentation process might involved different fermentor capacities,scaling down will therefore be very challenging and proper strategies need to be developed during scale down studies.

SIMILAR METHODS OF MEASURING ANALYZING SAMPLES

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Similar methods of analyses and monitoring be applied at scale down studies such as:

1 sample-dilution schemes and measurement times for calculating culture optical densities,

2 wet and dry cell-weights,

3 media metabolite levels.

SAMPLING VOLUME

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Due to the involvement of small scale fermentors which contained less working volume, the sampling volumes should be minimized to prevent depletion of culture broth beyond acceptable levels. If the sample size cannot be reduced, then adjust the frequency of sampling.

OXYGEN TRANSFERS
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Mass transfer of oxygen between big and small fermentors is a critical issue in scale down studies. The efficiency of oxygen transfer on production scale fermentor is much lower compared to the lab scale fermentor. The strategy in doing scale down studies in oxygen transfer is to maintain similarity in sparger design, calibration and placement within the small fermentor and the large fermentor. If the sparger design is different between scales, then agitation, aeration and oxygen enrichment may need to be adjusted to provide equivalent oxygen transfer in the small fermentor

INOCULA
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It is very important in doing inoculum development during scale down exercise to maintain the vessel geometries, incubation conditions, and working volumes whenever possible during the scale down exercise. If in the process it is not possible to obtain fermentors of similar geometries
the operational control parameters may need to be adjusted to account for different vessel geometries.

STERILIZATIONS

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During sterilization studies in scale down studies, the sterilization temperatures, procedures for probe calibration, and post-use cleaning protocols should be the similar as the large-scale fermentor.

FERMENTATION FEED

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The raw materials used in scale down studies should be identical to those used for the full-scale process.

FERMENTATION CONTROL PARAMETERS

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Similar operating regimes and controls should be applied to the small scale fermentor such as

1 process temperature

2 pH

3 inoculation percentages (v/v) for each step

4 schedule of feed-media additions.

A linear adjustment method should be used for all the volume-dependent operational control-parameter set points except agitation. The scale factor should be equivalent to the ratio of overall process volumes. Examples of linear adjustments in:

1 Pre-and post-sterilization volumes of growth media.

2 Feed media delivery rates.

3 Total airflow.

4 Oxygen flow rate.

AGITATION RATE

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Set agitation in scale down studies to provide either representative :

1 oxygen transfer rate

2 tip speed,

3Reynolds Number, or

4power-input per unit volume,

Under conditions of similar fermentor geometry it is recommended that the oxygen transfer rate studies be carried out.

CULTURE GROWTH

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Culture growth is a critical performance parameter for qualifying the scale-down studies.

Oxygen utilization is a very important performance parameter for scale-down exercise. Similar patterns in dissolved oxygen profiles, and oxygen and airflow rates represent comparability in oxygen usage by the cultures at each scale.

PRODUCT YIELD

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A biochemical finger print should be established for both large scale and scale down fermentation for comparison for similarity in efficacy

PROCESS SENSITIVITY

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Process-control sensitivity for dissolved oxygen, pH, temperature, agitation and feed delivery must be verified at the small-scale.

DO SCALE DOWN STUDIES A FEW TIMES

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In general, for greater confidence it is good toperform at least three small-scale runs to confirm reproducibility and to determine the inherent variability in the process.