A Proposal for Six Sigma Integration for Large-Scale Production of Penicillin G and Subsequent Conversion to 6-APA

Six Sigma methodology has been successfully applied to daily operations by several leading global private firms including GE and Motorola, to leverage their net profits. Comparatively, limited studies have been conducted to find out whether this highly successful methodology can be applied to research and development (R&D). In the current study, we have reviewed and proposed a process for a probable integration of Six Sigma methodology to large-scale production of Penicillin G and its subsequent conversion to 6-aminopenicillanic acid (6-APA). It is anticipated that the important aspects of quality control and quality assurance will highly benefit from the integration of Six Sigma methodology in mass production of Penicillin G and/or its conversion to 6-APA.

[1]  P. Gunasekaran,et al.  Production of Penicillin G acylase from Bacillus sp.: Effect of medium components , 2003 .

[2]  F. Kargı,et al.  Bioprocess Engineering: Basic Concepts , 1991 .

[3]  Eyal Dassau,et al.  Combining Six-Sigma with Integrated Design and Control for Yield Enhancement in Bioprocessing , 2006 .

[4]  M. Rito‐Palomares,et al.  Direct comparison between ion-exchange chromatography and aqueous two-phase processes for the partial purification of penicillin acylase produced by E. coli. , 2006, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[5]  J. Skłenar,et al.  Heterologous expression of leader-less pga gene in Pichia pastoris: intracellular production of prokaryotic enzyme , 2010, BMC biotechnology.

[6]  J. Cabral,et al.  Production of 6-aminopenicillanic acid in aqueous two-phase systems by recombinant Escherichia coli with intracellular penicillin acylase , 2004, Biotechnology Letters.

[7]  V. Meevootisom,et al.  Localization and characterization of inclusion bodies in recombinant Escherichia coli cells overproducing penicillin G acylase , 1997, Applied Microbiology and Biotechnology.

[8]  Gülnur Birol,et al.  A modular simulation package for fed-batch fermentation: penicillin production , 2002 .

[9]  Ye-Wang Zhang,et al.  ENHANCED PRODUCTION OF 6-AMINOPENICILLANIC ACID IN AQUEOUS METHYL ISOBUTYL KETONE SYSTEM WITH IMMOBILIZED PENICILLIN G ACYLASE , 2009, Preparative biochemistry & biotechnology.

[10]  Norman E. Davey,et al.  Structure of the immature retroviral capsid at 8 Å resolution by cryo-electron microscopy , 2012, Nature.

[11]  R. Quintero,et al.  Penicillin acylase extraction by osmotic shock , 1992 .

[12]  C. Perry Chou,et al.  Engineering cell physiology to enhance recombinant protein production in Escherichia coli , 2007, Applied Microbiology and Biotechnology.

[13]  Q. Ye,et al.  Production of Alcaligenes faecalis penicillin G acylase in Bacillus subtilis WB600 (pMA5) fed with partially hydrolyzed starch , 2006 .

[14]  J. Cheesbrough,et al.  A rationalised virological electron microscope specimen testing policy. PHLS North West Viral Gastroenteritis and Electron Microscopy Subcommittee. , 1999, Journal of clinical pathology.

[15]  M. Moo-young,et al.  Simultaneous clarification of Escherichia coli culture and purification of extracellularly produced penicillin G acylase using tangential flow filtration and anion-exchange membrane chromatography (TFF-AEMC). , 2012, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[16]  W. Deckwer,et al.  High yield recombinant penicillin G amidase production and export into the growth medium using Bacillus megaterium , 2006, Microbial cell factories.

[17]  B. Nunnally,et al.  Comprar Six Sigma in the Pharmaceutical Industry: Understanding, Reducing, and Controlling Variation in Pharmaceuticals and Biologics | John S. McConnell | 9781420054392 | Informa Healthcare , 2007 .

[18]  A. B. Rosa,et al.  Periplasmic penicillin G acylase activity in recombinant Escherichia coli cells permeabilized with organic solvents , 2003 .

[19]  N. Moazami,et al.  Immobilization of whole cell penicillin G acylase in open pore gelatin matrix , 2002 .

[20]  Yung-Chuan Liu,et al.  Direct penicillin G acylase immobilization by using the self-prepared immobilized metal affinity mem , 2011 .

[21]  M. Arroyo,et al.  Biotechnological applications of penicillin acylases: state-of-the-art , 2002, Applied Microbiology and Biotechnology.

[22]  Ignacio E. Grossmann,et al.  Computers and Chemical Engineering , 2014 .

[23]  Warren D. Seider,et al.  Product and Process Design Principles: Synthesis, Analysis, and Evaluation , 1998 .

[24]  Alle Bruggink,et al.  Penicillin Acylase in the Industrial Production of β-Lactam Antibiotics , 1998 .

[25]  A. Kheirolomoom,et al.  The combined effects of pH and temperature on penicillin G decomposition and its stability modeling , 1999 .

[26]  Roger A Sheldon,et al.  Immobilised enzymes: carrier-bound or carrier-free? , 2003, Current opinion in biotechnology.

[27]  P ? ? ? ? ? ? ? % ? ? ? ? , 1991 .

[28]  J. Shewale,et al.  Hydrophobic interaction chromatography of penicillin amidase , 1987, Biotechnology Letters.

[29]  R. Ocampo-Pérez,et al.  Adsorption of Fluoride from Water Solution on Bone Char , 2007 .

[30]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[31]  Shi-yun Li,et al.  Expression and purification of extracellular penicillin G acylase in Bacillus subtilis. , 2001, Protein expression and purification.

[32]  K. Bush.  The Evolution of β‐Lactamases , 2007 .

[33]  J. Choi,et al.  Secretory and extracellular production of recombinant proteins using Escherichia coli , 2004, Applied Microbiology and Biotechnology.

[34]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[35]  A. Shepherd,et al.  Comparison of electron microscopic techniques for enumeration of endogenous retrovirus in mouse and Chinese hamster cell lines used for production of biologics. , 2003, Journal of virological methods.

[36]  S. Suen,et al.  Purification of penicillin G acylase using immobilized metal affinity membranes. , 2003, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[37]  M. Danquah,et al.  A proposal for a quality system for herbal products. , 2013, Journal of pharmaceutical sciences.

[38]  Lidia Westers,et al.  Bacillus subtilis as cell factory for pharmaceutical proteins: a biotechnological approach to optimize the host organism. , 2004, Biochimica et biophysica acta.

[39]  M. Moo-young,et al.  Biotechnological advances on penicillin G acylase: pharmaceutical implications, unique expression mechanism and production strategies. , 2013, Biotechnology advances.

[40]  Nina F. Thornhill,et al.  A process systems engineering view of biochemical process operations , 1996 .

[41]  E. Vroom,et al.  Innovations in cephalosporin and penicillin production : Painting the antibiotics industry green , 2000 .

[42]  W. Marsden.  I and J , 2012 .

[43]  Mandal Asit Baran,et al.  Biocalorimetric and respirometric studies on production of Penicillin G acylase from Bacillus badius pac in E. coli DH5α , 2011 .

[44]  S. Gordon.  Antibiotic prophylaxis against postoperative wound infections. , 2006, Cleveland Clinic journal of medicine.

[45]  Neil Genzlinger.  A. and Q , 2006 .

[46]  Sung H. Park,et al.  Six Sigma for quality and productivity promotion , 2003 .

[47]  X. Soberón,et al.  Production of a fully functional, permuted single‐chain penicillin G acylase , 2004, Protein Science.

[48]  J. Cabral,et al.  An integrated downstream processing strategy for the recovery and partial purification of penicillin acylase from crude media , 2002 .

[49]  P. Roingeard.  Viral detection by electron microscopy: past, present and future , 2008, Biology of the cell.

[50]  M. Reuss,et al.  A mechanistic model for penicillin production , 2007 .

[51]  J. Shewale,et al.  Molecular aspects of penicillin and cephalosporin acylases , 1992 .

[52]  Warren D. Seider,et al.  Product and Process Design Principles: Synthesis, Analysis and Design , 1998 .

[53]  Kevin Barraclough,et al.  I and i , 2001, BMJ : British Medical Journal.

[54]  Jiju Antony,et al.  Some pros and cons of six sigma: an academic perspective , 2004 .

[55]  J. Kennedy,et al.  Advances in enzymatic transformation of penicillins to 6-aminopenicillanic acid (6-APA). , 2000, Biotechnology advances.

[56]  Joseph Moses Juran,et al.  Juran Institute's Six Sigma Breakthrough and Beyond , 2004 .

[57]  Michael Sauer,et al.  Recombinant protein production in yeasts , 2005, Molecular biotechnology.

[58]  C. Madeley.  Rationalised virological electron microscope specimen testing policy , 2000 .

[59]  G. Branlant,et al.  Periplasmic aggregation limits the proteolytic maturation of the Escherichia coli Penicillin G amidase precursor polypeptide , 1994, Applied Microbiology and Biotechnology.

[60]  J. Cregg,et al.  Recombinant protein expression in Pichia pastoris , 2000, Molecular biotechnology.

[61]  Jason A Roberts,et al.  Electron microscope detection of an endogenous infection of retrovirus-like particles in L20B cells. , 2013, Microscopy.

[62]  Roy Jefferis,et al.  Antibody therapeutics: , 2007, Expert opinion on biological therapy.

[63]  C. Hoischen,et al.  Synthesis and secretion of recombinant penicillin G acylase in bacterial L‐forms , 1996, Journal of basic microbiology.

[64]  O. Abián,et al.  Improving the Industrial Production of 6‐APA: Enzymatic Hydrolysis of Penicillin G in the Presence of Organic Solvents , 2003, Biotechnology progress.

[65]  P. Gunasekaran,et al.  Application of cross‐linked enzyme aggregates of Bacillus badius penicillin G acylase for the production of 6‐aminopenicillanic acid , 2007, Letters in applied microbiology.

[66]  G. Turner,et al.  The optimization of penicillin biosynthesis in fungi. , 1998, Trends in biotechnology.

[67]  N. Woodford.  Antibiotic resistance: Origins, evolution, selection and spread , 1998 .

[68]  John McConnell,et al.  Six Sigma in the Pharmaceutical Industry: Understanding, Reducing, and Controlling Variation in Pharmaceuticals and Biologics , 2007 .

[69]  O. Singh,et al.  The realm of penicillin G acylase in β-lactam antibiotics , 2008 .