Erythromycin Microbial Bioprocessing Peter Leung, Akhila Nair & Roberto Rodriguez ALS 420,Keck Graduate Institute, Claremont

,CA
History Erythromycin was first produced by isolating it from the metabolic products of strain of Streptomyces erytheus (Saccharopolyspora erythraea) by Eli lilys research team led by J .M . McGuire in 1949. Lilly filed for patent protection of the compound and U.S. patent 2,653,899 was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone. Erythromycin was formerly also called Ilotycin. Today this drug is manufactured 66 companies and is a component of almost 1200 drugs 4 Uses Erythromycin is a broad spectrum antibiotic used to treat infections caused by bacteria5 Conditions like bronchitis; diphtheria; Legionnaires' disease; pertussis (whooping cough); pneumonia; rheumatic fever; venereal disease (VD); Renal impairment, Hepatic impairment and ear, intestine, lung, urinary tract, and skin infections It is also used before surgery or dental work to prevent hospital acquired infections6 Market
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Microbial Sources Microbial Source: Erythromycin is produced from Saccharopolyspora erythraea (formerly known as Streptomyces erythreus), which is a species of actinomycete bacteria1. Block Flow

Fermation Processing Details

Through out the scaling up process, the temperature is maintained constant, as it is the optimal temperature for growth. On the other hand the rotation of the impeller decreased with every passage. The reason for the decrease is the increase in bacterial density. With every increase in density the bacterial is under greater pressure therefore original speed of the impeller is more likely to shear and lyse the bacterial. Another parameter that varies is the aeration rate. The aeration carries oxygen and is CO2, where by erythromycin production enhanced
Fermentation Specifications 2.5 m3 Fermenter (FJ2102, HEC, China)
220 rpm 33C 1.0 vvm

25 m3 Fermenter (FJ2203, HEC,China)

180 rpm 33C 1.2 vvm

132m 3 Fermenter (FJ2303, HEC, China)

60-126 rpm 33 C 0.8-1.2 vvm Axial impellar 1270mm

dissolved CO2 and oxygen allows for aerobic fermentation to occur.

Challenges and Drivers

The antibiotics market generated sales of US$42 billion in 2009 globally, representing 46% of sales of anti-infective agents (which also include antiviral drugs and vaccines) and 5% of the global pharmaceutical market.7 Erythromycin belongs to Macrolides group which made a sale of $4.8 million In USA, New York has the maximum market size of $15.25 million, covering 22.7% of the country sales and 4.2% of the world market. Globally, Paris has the largest market size of $7 million which is 2.7% of the world wide sale.(2009)8 Regulatory Requirements

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Antibitoics market in USA8

References According to Federal regulation 16 CFR 1700.14(a) (10), erythromycin as a prescription drug can only be administered orally and dispensed only upon written or oral prescription of a licensed practitioner by law.2 Erythromycin ethylsuccinate granules for oral suspension and oral suspensions in packages containing not more than 8 grams of the equivalent of erythromycin2 Erythromycin ethylsuccinate granules for oral suspension and oral suspensions in packages containing not more than 8 grams of the equivalent of erythromycin2 Erythromycin is also subject to special packaging regulations outline under the Poison Prevention Packaging Act (PPPA). Such regulations includes a requirement for drugs like erythromycin to have special packaging which is designed to be significantly difficult for children under five years of age to open3.
1. [Webpage] ErythromycinNCBI2014. Retrieved on: February 13, 2014. Available from: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=12560 2. 16 Cfr 1700.14. (2014) 1-1-12 Edition ed., US Government Printing Office, 3. Poison Prevention Packaging Act. (1970) October 14, 2008 Version ed., Consumer Product Safety Comission, 4. [Article] Cortes, J., Haydock, S. F., Roberts, G. A., Bevitt, D. J., and Leadlay, P. F. (1990) An Unusually Large Multifunctional Polypeptide in the Erythromycin-Producing Polyketide Synthase of Saccharopolyspora Erythraea. 5. [Article] Garcia-Rey, C., Aguilar, L., Baquero, F., Casal, J., and Dal-Re, R. (2002) Importance of Local Variations in Antibiotic Consumption and Geographical Differences of Erythromycin and Penicillin Resistance in Streptococcus Pneumoniae. J. Clin. Microbiol. 40, 159-164 6. [Article] Ginsburg, C. M., and Eichenwald, H. F. (1976) Erythromycin: A Review of its Uses in Pediatric Practice. J. Pediatr. 89, 872-884 7. [Article] Gonzales, R., Steiner, J. F., and Sande, M. A. (1997) Antibiotic Prescribing for Adults with Colds, Upper Respiratory Tract Infections, and Bronchitis by Ambulatory Care Physicians. JAMA. 278, 901-904 8. [Article] Hamad, B. (2010) The Antibiotics Market. Nature Reviews Drug Discovery. 9, 675-676 9. [Article] Minas, W., Brnker, P., Kallio, P. T., and Bailey, J. E. (1998) Improved Erythromycin Production in a Genetically Engineered Industrial Strain of Saccharopolyspora Erythraea. Biotechnol. Prog. 14, 561-566 10. [Article] Zou, X., Hang, H., Chu, J., Zhuang, Y., and Zhang, S. (2009) Oxygen Uptake Rate Optimization with Nitrogen Regulation for Erythromycin Production and Scale-Up from 50L to 372m< Sup> 3</sup> Scale. Bioresour. Technol. 100, 14061412

Legend Yellow Boxes: Flow of the erythromycin compound through the various chambers Green Boxes: Details the starting micro-organism and the final erythromycin product Blue Boxes: Describes facilitating processes and transitional steps Figure adapted from Zou et al. study10.