Expedient antibiotics production

213 Pages·2008·6.2 MB·English

uI~TINM ARIETTA ENERGY SYSTEMS LIBRARIES
3 4456 02773b3 3
ORNL-6355
Expedient Antibiotics Production
Final Report
interagency Agreement DOE 1457-14 57-A 1
and FEMA EMW-84-E-1 737, Work Unit 241 1K
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endorsement, recommendation, or favoring by the United StatesGovernment or
any agency thereof. The views and opinions of authors expressed herein do not
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la. REPORT SECURITY CLASSIFICATION 1 b RESTRICTIVE MARKINGS
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2a. SECURITY CLASSIFICATION AUTHORITY 3 DISTRIBUTION 1 AVAILABILITY OF REPORT
2b. DECLASSIFICATION I DOWNGRADING SCHEDULE
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4 PERFORMING ORGANIZATION REPORT NUMBER(S) S MONITORING ORGANIZATION REPORT NUMBER(S)
-
ORNL 6345 N /A
6a NAME OF PERFORMING ORGANIZATION 6b OFFICE SYMBOL 7a. NAME OF MONITORING ORGANIZATION
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8a. NAME OF FUNDING / SPONSORING 8b OFFICE SYMBOL 9 PROCUREMENTI NSTRUMENT~ OENTIFICATION NUMBER
ORGANIZATION Federal Emergency (If dppkdbk) Interagency Ag. EMW-84-E-1737 (FEMA)
Management Agency 1457-1457-A1 (DOE)
10 SOURCE OF FUNDING NUMBERS
PROGRAM TASK WORK UNIT
No. ACCESSION NO
I I I
2411K 9 19
I I
EXPEDIENT ANTIBIOTICS PRODUCTION
12 PERSONAL AUTHOR(S)
Paul R. Bienkowski, Charles H. Byers, and Douglas D. Lee
13a. TYPE OF REPORT 13b TIME COVERED 14 DATE OF REPORT (Year, Month, Day)
Final FROM 1985 TO 1988 April 1988
16 SUPPLEMENTARY NOTATION
17 COSATI CODES 18 SUBJECT TERMS (Continue on reverse if necessary and rdentl+ by block number)
FIELD I GROUP 1 SUB-GROUP Sulfa, Penicillins, Tetracyclines, Bacitracin,
I
I Cephalosporins, Antibiotics, Antibiotic Manufacturing,
' Antimicrobials, Emergency Production of Antibiotics (cont'd
19 ABSTRACT (Continue on reverse if necessary and Identify by block number)
~UNCLASSIF~ED~UNLIMITED0 SAME AS RPT 0 OTIC USERS Unclassified
22a NAME OF RESPONSIBLE INDIVIDUAL 22b TELEPHONE (Induck Area Code) 22c. OFFICE SYMBOL
I I 1
00 FORM 1473,84 MAR 83 APR edition may be used until exhausted. SECURITY ClASSlFlCATlON OF THIS PAGE
All other editions are obsolete.
Antibiotic Manufacturers, Antibiotic Purification and Separation,
Alternate Antibiotic Production Sites, Fermentation Equipment,
Disease Control, Pharmaceutical Industry
19. ABSTRACT (continued)
I
particular antibiotic product. The fermentation section requires specialized equipment
for operation in a sterile environment which is not usually available in other industries.
I of
The emergency production antibiotics under austere conditions will be feasible only if
a substantial reduction in the complexity and degree of separation and purity normally
required can be realized. Detailed instructions were developed to assist State and
Federal officials who would be directing the resumption of antibiotic production after a
nuclear attack. Initially, all plant managers should be contacted (using the lists
provided in this report) to determine if their facility has been destroyed or damaged.
If a plant has been damaged, the manager should determine the feasibility of making
repairs, the potential capacity of the repaired plant, and the type of antibiotic that
can be produced. If enough production cannot be realized from undamaged and slightly
damaged plants, the plants from the list of alternate emergency production sites must be
contacted, determination of the plant status made, and the managers informed of impending
of
conversion to antibiotic production. If alternate sites must be used, a team skilled
personnel must be assembled to convert the plant to antibiotic production in the austere
environment.
SECURITY CLASSIfICATION OF THIS PACE
ORNL-6355
Dist. Category UC-41
Chemical Technology Division
EXPEDIENT ANTIBIOTICS PRODUCTION
P. R. Bienkowski
C. H. Byers
D. D. Lee
-
Date Published ?lay 1988
Approved for public release: Distribution unlimited
Prepared for the
FEDERAL EMERGENCY MANAGEMENT AGENCY
Washington, DC 20472
Interagency Agreement; FEMA EMW-84-E-1737,
DOE 1457-1457-A1 formerly 40-1457-84
2411K
Work Unit No.
"This report has been reviewed in the Federal Emergency
for Approval
Management Agency and approved publication.
does not signify that the contents necessarily reflect
the views and policies of the Federal Emergency Management
Agency.' I
Prepared by the
OAK
RIDGE NATIONAL LABORATORY
Oak Ridge, Tennessee 37831
operated by
MARTIN MARIETTA ENERGY SYSTEMS, Inc.
for
the
U.S. DEPARTMENT OF ENERGY
under Contract No. DE-AC05-840R21400

iii
CONTENTS
. . . . . . . . . . . . . . . . . . . . . . . . V
LISTOFTABLES
LISTOFFIGURES . . . . . . . . . . . . . . . . . . . . . . . . vii
. . . . . . . . . . . . . . . . . . . . . . . .
EXECUTIVE SUMMARY xi
. . . . . . . . . . . . . . . . . . . . . . . . .
Objective xi
. . . . . . . . . . . . . . . . . . . . . . . .
Background . x i
. . . . . . . . . . . . . . . . . . . . . . . . .
Procedure xi
. . . . . . . . . . . . . . . . . . . . . . .
Conclusions xii
. . . . . . . . . . . . . . . . . . . . . . . . . .
ABSTRACT xvii
. . . . . . . . . . . . . . . . . . . . . . . .
1 INTRODUCTION 1
. . . . . . . . . . . . . . . . . 3
2 DEFINITION OF AN ANTIBIOTIC
3 . . . . . . . . 5
ANTIBIOTICS SELECTED FOR EXPEDIENT PRODUCTION
3.1 . . . . . . . . . . . . . . . . . . . . . 9
Penicillins
. . . . . . . . . . . . . . . . . . .
3.2 Cephalosporins 13
3.3 . . . . . . . . . . . . . . . . . . . . 14
Tetracyclines
. . . . . . . . . . . . . . . . . . . . . 14
3.4 Bacitracin
3.5 . . . . . . . . . . . . . . . . . . . . 16
Sulfonamides
4 . . . . . . . . . . . . . . . . . . 19
ANTIBIOTIC MANUFACTURERS
. . . 23
5 ANTIBIOTIC PRODUCTION TECHNOLOGIES GENERAL DESCRIPTION
. . . . . . . . . . . . .
5.1 Raw materials and utilities 25
. . . . . . . . . . . . . . . . . . . .
5.2 Fermentation 27
. . . . . . . . . . . . .
5.3 Separation and purification 28
5.4 . . . . . . . .
Analytic Procedures/ Quality Control 30
5.5 . . . . . . . . . . . . . . . .
Advanced Technologies 30
. . . . . . . . . . . . . 33
6 EXPEDIENT PRODUCTION OF ANTIBIOTICS
. . . . . . . . . . . . . 33
6.1 Alternate production sites
6.2 . . . . . . . . . 33
Conversion to antibiotic production
6.3 . . . . . . . . . . . . . . . . 44
Single Cell Proteins
. . . . . . . . . . . . . .
7 ALTERNATE SOURCES OF ANTIBIOTICS 47
. . . . . . . . . . . . . . . . . . . . . . . . . . 49
8 REFERENCES
. . . . . . . . . . . . . . . . . . 49
8.1 Cited References
. . . . . . . . . . . . . . . . . 52
8.2 General References
8.3 Penicillins . . . . . . . . . . . . . . . . . . . . . 55
8.4 . . . . . . . . . . . . . . . . . . . . 57
Cephalosporin
iv
. . . . . . . . . . . . . . . . . . . .
8.5 Tetracyclines 58
. . . . . . . . . . . . . . . . . . . . .
8.6 Bacitracin 59
. . . . . . . . . . . . . . . . . . . .
8.7 60
Sulfonamides
. . . . . . . . . . . . .
8.8 Separation and Purification 60
. . . . . . . . . . . . . . . . . . . .
8.9 Preservation 63
. . . . . . . . . . . . . . . . . . . .
8.10 Sterilization 63
. . . . . . . . . . . . . . . . . 64
8.11 Analytical Methods
. . . . . . .
APPENDIX A Production of Penicillin Antibiotics 65
. . . . . . .
APPENDIX B Production of Cephalosporin Antibiotics 87
APPENDIX C Production of Tetracycline Antibiotics . . . . . . 103
. . . . . . . . . . . . . . . . . . .
APPENDIX D Sulfonamides 111
. . . . . . . . . . . . . . .
APPENDIX E Bacitracin Production 117
. . . . . . . . . . .
APPENDIX F Organic Product Fermentations 125
APPENDIX G Enzyme Production Technology . . . . . . . . . . . 133
. . . . . . . . . .
APPENDIX H Single Cell Protein Production 139
. . . . . . . . . . . . . . .
APPENDIX I Inoculum Preservation 145
. . . . . . . . . . . . . . . . . . .
APPENDIX J Sterilization 151
. . . . . . . . . . . . . . . . . . . . .
APPENDIX K Equipment 161
. . . . . . . . . . . .
APPENDIX L Separation and Purification 171
High Performance Liquid Chromatography . . . . . . . . . . 173
. . . . . . . . . . . . . .
Supercritical Fluid Extraction 180
V
LIST TABLES
OF
Number Page
1. . . . . . . . . . . . . . . . . 6
U.S. antibiotic production
2. . . . 11
Antibiotics produced in the U.S. (by classification)
3.
Dosage forms and dosage recommendations for
. . . . . . . . . . . . . . . . . .
expedient antibiotics 12
4. Risk assessment for antibiotic producers in the U.S.
. . . . . . . . 20
assuming three different attack scenarios
5. - . . 26
Growth media for penicillin shake flask and factory
6. Risk assessment for enzyme producers in the U.S.
. . . . . . . . 34
assuming three different attack scenarios
7.
Risk assessment for fermentation ethanol producers
. . 36
in the U.S. assuming three different attack scenarios
8. Other candidates for conversion to antibiotic production . 40
9.
Alternate antibiotic production sites outside of
. . . . . . . . . . . . . . . . . . 48
the continental U.S. ,
. . . . . . 68
A-1. Raw materials needed for penicillin production
A-2. Alternate materials for defined medium for
. . . . . . . . . . . . . . . . . .
penicillin production 68
A-3. Specific uptake rates for nutrients during a penicillin
. . . . . . . . . . . . . . . . . . . . . . 71
fermentation.
A-4.
Carbon distribution into penicillin, mycelium, and
. . . . . . . . . . . . . . . . . . . 73
maintenance energy
A-5. . . . . 73
Maximum and real yields of penicillin from glucose
. . . . . . . . . . . 78
A-6. Traditional penicillin purification
B-1. . . . . . . . . . . . . . 90
Cephalosporin production media.
B-2. . . . . . 91
Carbon utilization for cephalosporin production
B-3.
Clinical characteristics of common cephalosporin
. . . . . . . . . . . . . . . . . . . . . . . 94
antibiotics
B-4. of of . . 95
Characteristics cephalosporins clinical interest
B-5. . . . 97
Microorganisms which produce various cephalosporins
vi
Number Page
E.1 . Solubility of bacitracins in various solvents . . . . . . 122
E.2 . . . . . . . . . . . . 122
Precipitating agents for bacitracin
. . . . . . .
K.1 Suppliers of oxygen probes used in fermenters 170
L.1 . Chromatographic parameters for tetracyclines . . . . . . . 177
L.2 . HPLC assays of antibiotics . . . . . . . . . . . . . . . . 178
. SCF .
L.3 related physical properties of selected antibiotics 183