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General bioprocess flow
Various types of Penicillin
A Penicillin-Producing Company
Make your own penicillin now!!!
How is it Made into a Drug?
General bioprocess flow
Like other industrial plant products, all of them have a process flow which begins from the basic raw materials to the downstream processes resulting in the final product. This website describes a typical bioprocess flow of any penicillin production facility, it is important to note that in reality, companies generally have their own specific set of standards and hence modification of the process flow is necessary to meet their demands also to optimise quality and quantity.
Below here is the actual General Process flow diagram use in the production of penicillin,
The actual process flow of penicillin
Not to worry, the process flow can be summarise into the flowchart that I have drawn,
As you can see, in any bioprocess facility, there has to be an upstream and downstream process,
the upstream processes in this case are refering to processes before input to the fermenter, while the downstream processes refers to the processes that are done to purify the output of the fermenter until it reaches to the desired product.
Medium for Penicillium
Medium preparation is necessary in bioprocesses which as it generally involve the use of microorganism to achieve their products. In the case of the Penicillium fungus, the medium usually contain its carbon source which is found in corn steep liquor and glucose. Medium also consist of salts such as Magnesium sulphate, Potassium phosphate and Sodium nitrates. They provide the essential ions required for the fungus metabolic activity.
Corn steep syrup
Medium is sterilse at high heat and high pressure usually through a holding tube or sterilse together with the fermenter. The pressurized steam is use usually and the medium is heated to 121
at 30psi or twice of atmospheric pressure. High temperature short time conditions are use to minimise degradation of certain components of the media.
Fermentation for penicillin is usually done in the fed-batch mode as glucose must not be added in high amounts at the beginning of growth which will result in low yield of penicillin production as excessive glucose inhibit penicillin production. In addition to that, penicillin is a secondary metabolite of the fungus, therefore, the fed-batch mode is ideal for such products as it allows the high production of penicillin. The typical fermentation conditions for the
mold, usually requires temperatures at 20-24
while pH conditions are kept in between 6.0 to 6.5. The pressure in the bioreactor is usually much higher than the atmospheric pressure(1.02atm) this is to prevent contamination from occurring as it prevents external contaminants from entering. Sparging of air bubbles is necessary to provide sufficient oxygen the viability of the fungus. Depending on the volume of medium, for 2 cubic metres of culture, the sparging rate should be about 2.5 cubic metres per minute. The impeller is necessary to mix the culture evenly throughout the culture medium, fungal cells are much hardy and they are able to handle rotation speed of around 200rpm.
Like any other scale up process, usually the seed culture is developed first in the lab by the addition of
spores into a liquid medium. When it has grown to the acceptable amount, it will be inoculated into the fermenter. In some cases,the spores are directly inoculated into the fermenter.
The Penicillium fungus
Removal of biomass
Filtration is necessary at this point of the bioprocess flow, as bioseparation is required to remove the biomass from the culture such as the fungus and other impurities away from the medium which contains the penicillin product. There are many types of filtration methods available today, however, the Rotary vacuum filter is commonly employed as it able to run in continuous mode in any large scale operations. Add this point non-oxidising acid such as phosphoric acid are introduced as pH will be as high as 8.5. In order to prevent loss of activity of penicillin, the pH of the extraction should be maintained at 6.0-6.5.
Rotary Vacuum Filter
Adding of solvent
In order to dissolve the penicillin present in the filtrate, organic solvents such as amyl acetate or butyl acetate are use as they dissolve penicillin much better than water at physiological pH. At this point, penicillin is present in the solution and any other solids will be considered as waste.
Amyl Acetate as Solvent
Centrifugation is done to separate the solid waste from the liquid component which contains the penicillin. Usually a tubular bowl or chamber bowl centrifuge is use at this point.The supernatant will then be transferred further in the downstream process to continue with extraction.
Disk centrifuge- One of the most common type of centrifuge for large scale production
Penicillin dissolve in the solvent will now undergo a series of extraction process to obtain better purity of the penicillin product. The acetate solution is first mixed with a phosphate buffer, followed by a chloroform solution, and mixed again with a phosphate buffer and finally in an ether solution. Penicillin is present in high concentration in the ether solution and it will be mixed with a solution of sodium bicarbonate to obtain the penicillin-sodium salt, which allow penicillin to be stored in a stable powder form at room temperature. The penicillin-sodium salt is obtained from the liquid material by basket centrifugation, in which solids are easily removed.
Batch extraction unit
Basket Centrifuge- Extremely using in the removal of solids in this case Penicillin salt
Fluid bed drying
Drying is necessary to remove any remaining moisture present in the powdered penicillin salt. In fluid bed drying, hot gas is pump in from the base of the chamber containing the powdered salt inside a vacuum chamber. Moisture is then remove in this manner and this result in a much drier form of penicillin.
Fluid bed drying tube
Powdered penicillin being blowned by hot air
Penicillin salt is stored in containers and kept in a dried environment. It will then be polished and package into various types of products such as liquid penicillin or penicillin in pills. Dosage of the particular penicillin is determined by clinical trials that are done on this drug.
The White Penicillin-Sodium salt
Chemical Structure of the Penicillin Sodium Salt
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