Volume 6 : Excipients of Sterile Products _1.pdf

Handbook of Pharmaceutical
Manufacturing Formulations
Volume Six, Sterile Products

Handbook of Pharmaceutical
Manufacturing Formulations,
Third Edition
Volume Six, Sterile Products
Sarfaraz K. Niazi

CRC Press
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To Dean Shamsuz Zoha
Dean Shamsuz Zoha passed away in 2010; he was the dean of pharmacy school in Pakistan
where I began my career and I had the privilege of receiving his blessings throughout my life.

vii
Contents
Preface to the Series—Third Edition.........................................................................................................................................xxv
Preface to the Series—Second Edition....................................................................................................................................xxvii
Preface to the Series—First Edition.........................................................................................................................................xxxi
Preface to the Volume—First Edition................................................................................................................................... xxxiii
About the Author.....................................................................................................................................................................xxxv
PART I Regulatory and Manufacturing
Chapter 1 Sterile Manufacturing Formulations Template........................................................................................................3
I. Autoclaves...................................................................................................................................................6
II. Aseptic Contract Manufacturers.................................................................................................................6
A. Manufacturing Formulations Template............................................................................................... 6
III. Clean-Room Design and Construction....................................................................................................... 6
IV. Clean-in-Place/Steam-in-Place (CIPISIP)..................................................................................................6
V. Closure Washing and Sterilization.............................................................................................................6
VI. Consultants.................................................................................................................................................6
VII. Disinfectants and Preservatives.................................................................................................................. 7
VIII. Distillation Equipment................................................................................................................................7
IX. Engineering and Construction....................................................................................................................7
X. Filling Machines.........................................................................................................................................7
XI. Filter Aids................................................................................................................................................... 7
XII. Flowmeters (Sanitary)................................................................................................................................7
XII. Freeze-Dryers (Sterilizable)........................................................................................................................7
XIII. Microfiltration Equipment and Filters........................................................................................................7
A. Manufacturing Formulations Template............................................................................................... 8
XIV. Pumps (Sanitary)........................................................................................................................................ 8
XV. Sterile Tanks and Related Stainless Equipment......................................................................................... 8
XVI. Sterility Test Equipment............................................................................................................................. 8
XVII. Sterilizing and Drying Tunnels (Hot Air)..................................................................................................8
XVIII. Stoppering Machines..................................................................................................................................8
Chapter 2 Inspection of Sterile Product Manufacturing Facilities......................................................................................... 11
I. Introduction.............................................................................................................................................. 11
II. cGMP Compliance Basics........................................................................................................................ 11
A. Personnel........................................................................................................................................... 11
B. Buildings........................................................................................................................................... 11
C. Air�� 11
D. Environmental Controls.................................................................................................................... 11
E. Equipment.......................................................................................................................................... 12
F.
Water for Injection.............................................................................................................................. 12
G.
Containers and Closures.................................................................................................................... 12
H. Sterilization....................................................................................................................................... 12
1. Methods...................................................................................................................................... 12
2. Indicators.................................................................................................................................... 12
3. Filled Containers........................................................................................................................ 13
I. Personnel Practices............................................................................................................................. 13
J. Laboratory Controls............................................................................................................................ 13
1.
Retesting for Sterility................................................................................................................. 13
2.
Retesting for Pyrogens............................................................................................................... 13
3. Particulate Matter Testing........................................................................................................... 13
4. Production Records.................................................................................................................... 13

viii Contents
III. Aseptic Processing...................................................................................................................................... 13
A. Introduction......................................................................................................................................... 13
B.
Buildings and Facilities....................................................................................................................... 14
1.
Critical Area (Class 100)............................................................................................................... 14
2. Supporting Clean Areas................................................................................................................ 15
3. Clean Area Separation................................................................................................................... 15
4. Air Filtration................................................................................................................................. 15
5. Design��16
C.
Personnel Training, Qualification, and Monitoring............................................................................. 17
1. Manufacturing Personnel.............................................................................................................. 18
2. Laboratory Personnel.................................................................................................................... 19
3. Monitoring Program...................................................................................................................... 19
D.
Components and Containers/Closures................................................................................................. 19
1. Components.................................................................................................................................. 19
2. Containers/Closures...................................................................................................................... 19
E. Endotoxin Control................................................................................................................................20
F. Time Limitations................................................................................................................................... 21
G.
Process Validation and Equipment Qualification................................................................................. 21
1. Process Simulations...................................................................................................................... 21
2. Filtration Efficacy.........................................................................................................................24
3.
Sterilization of Equipment and Containers/Closures....................................................................24
H. Laboratory Controls.............................................................................................................................25
1. Environmental Monitoring............................................................................................................26
2.
Microbiological Media and Identification.................................................................................... 27
I. Sterility Testing.....................................................................................................................................28
1.
Choice of Methods........................................................................................................................28
2. Media��28
3. Personnel.......................................................................................................................................28
4.
Sampling and Incubation..............................................................................................................28
5.
Investigation of Sterility Positives................................................................................................28
J.
Batch Record Review: Process Control Documentation...................................................................... 30
IV. Processing Prior to Filling and Sealing Operations.................................................................................... 30
A.
Aseptic Processing from Early Manufacturing Steps.......................................................................... 30
B.
Aseptic Processing of Cell-Based Therapy Products (or of Products Intended for Use as
Cell-Based Therapies)�� 31
V. Aseptic Processing Isolators........................................................................................................................ 31
A. Maintenance......................................................................................................................................... 31
1. General��31
2. Glove Integrity.............................................................................................................................. 31
B. Design.................................................................................................................................................. 31
1. Airflow��31
2.
Materials of Construction............................................................................................................. 31
3. Pressure Differential..................................................................................................................... 31
4. Clean-Area Classifications............................................................................................................ 32
C.
Transfer of Materials and Supplies...................................................................................................... 32
1. Introduction................................................................................................................................... 32
2. Discharge...................................................................................................................................... 32
D. Decontamination.................................................................................................................................. 32
1. Surface Exposure.......................................................................................................................... 32
2. Efficacy �� 32
3. Frequency...................................................................................................................................... 32
E.
Filling Line Sterilization...................................................................................................................... 32
F. Environmental Monitoring................................................................................................................... 32
G. Personnel............................................................................................................................................. 32
VI. Blow-Fill-Seal Technology.......................................................................................................................... 33
A.
Equipment Design and Air Quality..................................................................................................... 33
B.
Validation and Qualification................................................................................................................. 33
C.
Batch Monitoring and Control............................................................................................................. 33

ix
Contents
VII. Lyophilization of Parenterals......................................................................................................................34
A. Introduction.........................................................................................................................................34
B.
Product Type and Formulation.............................................................................................................34
C. Filling...................................................................................................................................................34
D.
Lyophilization Cycle and Controls...................................................................................................... 36
E. Cycle Validation................................................................................................................................... 36
F.
Lyophilizer Sterilization and Design.................................................................................................... 37
G. Finished Product Testing..................................................................................................................... 38
1. Dose Uniformity........................................................................................................................... 38
2. Stability Testing............................................................................................................................ 38
3. Sterility Testing............................................................................................................................. 39
H.
Finished Product Inspection—Meltback............................................................................................. 39
VIII. High-Purity Water Systems......................................................................................................................... 39
A. System Design..................................................................................................................................... 39
B. System Validation................................................................................................................................ 39
C. Microbial Limits..................................................................................................................................40
1. WFI Systems.................................................................................................................................40
2. Purified Water Systems.................................................................................................................40
D. WFI Systems........................................................................................................................................ 41
E. Still...................................................................................................................................................... 41
F.
Heat Exchangers.................................................................................................................................. 41
G. Holding Tank....................................................................................................................................... 42
H. Pumps.................................................................................................................................................. 42
I. Piping................................................................................................................................................... 42
J.
Reverse Osmosis.................................................................................................................................. 42
K. Purified Water Systems........................................................................................................................ 42
L. Process Water....................................................................................................................................... 43
M.
Evaluation Strategy.............................................................................................................................. 43
Relevant Guidance Documents (FDA)................................................................................................................... 43
Glossary..................................................................................................................................................................44
Bibliography........................................................................................................................................................... 47
Chapter 3 New Drug Application for Sterilized Products...................................................................................................... 49
I. Introduction................................................................................................................................................. 49
II. Terminal Heat Sterilization......................................................................................................................... 49
A.
Description of the Process and Product............................................................................................... 49
B.
Thermal Qualification of the Cycle...................................................................................................... 49
C.
Microbiological Efficacy of the Cycle................................................................................................. 50
D.
Microbiological Monitoring of the Environment................................................................................ 50
E.
Container/Closure and Package Integrity............................................................................................ 50
F.
Bacterial Endotoxins Test and Method................................................................................................ 51
G.
Sterility Testing Methods and Release Criteria................................................................................... 51
H.
Evidence of Formal Written Procedures.............................................................................................. 51
III. Other Terminal Sterilization Processes....................................................................................................... 51
A. Ethylene Oxide.................................................................................................................................... 51
B. Radiation.............................................................................................................................................. 51
IV. Aseptic Fill Manufacturing Processes........................................................................................................ 51
A.
Buildings and Facilities....................................................................................................................... 52
B.
Overall Manufacturing Operation........................................................................................................ 52
C.
Containers and Closures...................................................................................................................... 52
D.
Procedures and Specifications for Media Fills.................................................................................... 52
E.
Actions Concerning Product When Media Fills Fail........................................................................... 53
F.
Microbiological Monitoring of the Environment................................................................................ 53
G.
Container/Closure and Package Integrity............................................................................................ 53
H.
Sterility Testing Methods and Release Criteria................................................................................... 53
I.
Bacterial Endotoxins Test and Method................................................................................................ 53
J.
Evidence of Formal Written Procedures............................................................................................. 53

x Contents
V. Maintenance of Microbiological Control and Quality: Stability Considerations....................................... 53
A. Container/Closure Integrity................................................................................................................. 53
B. Preservative Effectiveness.................................................................................................................... 54
C.
Pyrogen or Endotoxin Testing............................................................................................................. 54
Chapter 4 Validation of Cleaning Process.............................................................................................................................. 55
I. Introduction................................................................................................................................................. 55
II. Background.................................................................................................................................................. 55
III. General Requirements................................................................................................................................. 55
IV. Evaluation of Cleaning Validation.............................................................................................................. 56
A. Equipment Design............................................................................................................................... 56
B.
Cleaning Process, Written Procedure, and Documentation................................................................. 56
C. Analytical Methods.............................................................................................................................. 57
D. Sampling.............................................................................................................................................. 57
1.
Direct Surface Sampling............................................................................................................... 57
2. Rinse Samples............................................................................................................................... 57
3.
Routine Production In-Process Control Monitoring..................................................................... 57
V. Establishment of Limits.............................................................................................................................. 57
VI. Other Issues................................................................................................................................................. 57
A. Placebo Product................................................................................................................................... 57
B. Detergent.............................................................................................................................................. 58
C.
Test Until Clean................................................................................................................................... 58
Chapter 5 Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin........ 59
I. Introduction................................................................................................................................................. 59
II. Potential Sources of Virus Contamination.................................................................................................. 59
A.
Viruses That Could Occur in the Master Cell Bank............................................................................60
B.
Adventitious Viruses That Could Be Introduced during Production...................................................60
III. Cell Line Qualification: Testing for Viruses...............................................................................................60
A.
Suggested Virus Tests for MCB, Working Cell Bank, and Cells at the Limit of In Vitro Cell
Age Used for Production��60
1.
Master Cell Bank..........................................................................................................................60
2.
Working Cell Bank........................................................................................................................60
3.
Cells at the Limit of In Vitro Cell Age Used for Production........................................................60
B.
Recommended Viral Detection and Identification Assays...................................................................60
1.
Tests for Retroviruses.................................................................................................................... 61
2. In Vitro Assays.............................................................................................................................. 61
3. In Vivo Assays............................................................................................................................... 61
4. Antibody Production Tests............................................................................................................ 61
C.
Acceptability of Cell Lines.................................................................................................................. 61
IV. Testing for Viruses in Unprocessed Bulk.................................................................................................... 61
V. Rationale and Action Plan for Viral Clearance Studies and Virus Tests on Purified Bulk........................ 62
VI. Evaluation and Characterization of Viral Clearance..................................................................................64
A.
The Choice of Viruses for the Evaluation and Characterization of Viral Clearance............................ 65
1. “Relevant” Viruses and “Model” Viruses...................................................................................... 65
2. Other Considerations.................................................................................................................... 65
B.
Design and Implications of Viral Clearance Evaluation and Characterization Studies....................... 65
1.
Facility and Staff........................................................................................................................... 65
2.
Scaled-Down Production System.................................................................................................66
3.
Analysis of Step-Wise Elimination of Virus.................................................................................66
4.
Determining Physical Removal vs. Inactivation...........................................................................66
5. Inactivation Assessment................................................................................................................66
6.
Function and Regeneration of Columns....................................................................................... 67
7. Specific Precautions...................................................................................................................... 67
C.
Interpretation of Viral Clearance Studies............................................................................................. 67
1. Acceptability................................................................................................................................. 67

xi
Contents
D.
Limitations of Viral Clearance Studies................................................................................................ 68
E. Statistics............................................................................................................................................... 68
F.
Reevaluation of Viral Clearance........................................................................................................... 68
VII. Summary..................................................................................................................................................... 68
Glossary.................................................................................................................................................................. 69
Appendix 1: Products Derived from Characterized Cell Banks which Were Subsequently Grown In Vivo......... 69
Appendix 2: The Choice of Viruses for Viral Clearance Studies........................................................................... 70
Appendix 3: Statistical Considerations for Assessing Virus Assays...................................................................... 70
Probability of Detection of Viruses at Low Concentrations........................................................................ 71
Appendix 4: Calculation of Reduction Factors in Studies to Determine Viral Clearance..................................... 71
Appendix 5: Calculation of Estimated Particles per Dose..................................................................................... 71
Chapter 6 Analysis of the Expression Construct in Cells Used for Production of rDNA-Derived Protein Products............. 73
I. Introduction................................................................................................................................................. 73
II. Rationale for Analysis of the Expression Construct.................................................................................... 73
III. Characterization of the Expression System................................................................................................. 73
A.
Expression Construct and Cell Clone Used to Develop the Master Cell Bank................................... 73
B.
Cell Bank System................................................................................................................................. 74
C.
Limit for In Vitro Cell Age for Production.......................................................................................... 74
IV. Conclusion................................................................................................................................................... 74
Glossary.................................................................................................................................................................. 74
Chapter 7 Stability Testing of Biotechnological/Biological Products.................................................................................... 77
I. Preamble...................................................................................................................................................... 77
II. Scope of the Annex..................................................................................................................................... 77
III. Terminology................................................................................................................................................ 77
IV. Selection of Batches.................................................................................................................................... 77
A.
Drug Substance (Bulk Material).......................................................................................................... 77
B. Intermediates........................................................................................................................................ 78
C.
Drug Product (Final Container Product).............................................................................................. 78
D. Sample Selection................................................................................................................................. 78
V. Stability-Indicating Profile.......................................................................................................................... 78
A. Protocol................................................................................................................................................ 78
B. Potency................................................................................................................................................. 79
C.
Purity and Molecular Characterization................................................................................................ 79
D.
Other Product Characteristics.............................................................................................................. 79
VI. Storage Conditions...................................................................................................................................... 79
A. Temperature......................................................................................................................................... 79
B. Humidity..............................................................................................................................................80
C.
Accelerated and Stress Conditions.......................................................................................................80
D. Light.....................................................................................................................................................80
E. Container/Closure................................................................................................................................80
F.
Stability after Reconstitution of Freeze-Dried Product.......................................................................80
VII. Testing Frequency........................................................................................................................................80
VIII. Specifications...............................................................................................................................................80
IX. Labeling....................................................................................................................................................... 81
Glossary.................................................................................................................................................................. 81
Chapter 8 Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/
Biological Products................................................................................................................................................ 83
I. Introduction................................................................................................................................................. 83
A. Objective.............................................................................................................................................. 83
B. Rationale.............................................................................................................................................. 83
C. Scope.................................................................................................................................................... 83

xii Contents
II. Guidelines.................................................................................................................................................... 83
A.
Source, History, and Generation of the Cell Substrate........................................................................ 83
1. Introduction................................................................................................................................... 83
2.
Origin, Source, and History of Cells............................................................................................. 83
3.
Generation of the Cell Substrate...................................................................................................84
B. Cell Banking........................................................................................................................................84
1.
Cell Banking System....................................................................................................................84
2.
Cell Banking Procedures............................................................................................................... 85
C.
General Principles of Characterization and Testing of Cell Banks...................................................... 85
1.
Tests of Identity............................................................................................................................. 86
2.
Tests of Purity............................................................................................................................... 86
3.
Cell Substrate Stability................................................................................................................. 87
4.
Tests for Karyology and Tumorigenicity...................................................................................... 87
Glossary.................................................................................................................................................................. 88
Bibliography........................................................................................................................................................... 88
Appendix 1: Primary Cell Substrates..................................................................................................................... 88
Introduction................................................................................................................................................. 88
Source Tissue and Other Raw Materials..................................................................................................... 89
Preparation of Primary Cell Substrates....................................................................................................... 89
Testing of Primary Cell Substrates.............................................................................................................. 89
Chapter 9 Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process......... 91
I. Introduction................................................................................................................................................. 91
A.
Objectives of the Guideline................................................................................................................. 91
B. Background.......................................................................................................................................... 91
C. Scope.................................................................................................................................................... 91
D. General Principles................................................................................................................................ 91
II. Guidelines....................................................................................................................................................92
A.
Considerations for the Comparability Exercise...................................................................................92
B. Quality Considerations........................................................................................................................ 93
1. Analytical Techniques................................................................................................................... 93
2. Characterization............................................................................................................................ 93
3. Specifications................................................................................................................................94
4. Stability��94
C.
Manufacturing Process Considerations............................................................................................... 95
D.
Demonstration of Comparability during Development....................................................................... 95
E.
Nonclinical and Clinical Considerations..............................................................................................96
1.
Factors to be Considered in Planning Nonclinical and Clinical Studies......................................96
2.
Type of Studies..............................................................................................................................96
Glossary..................................................................................................................................................................97
Bibliography...........................................................................................................................................................97
Chapter 10 Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products...................99
I. Introduction.................................................................................................................................................99
A. Objective..............................................................................................................................................99
B. Background..........................................................................................................................................99
C. Scope....................................................................................................................................................99
II. Principles for Consideration in Setting Specifications................................................................................99
A. Characterization...................................................................................................................................99
1. Physicochemical Properties..........................................................................................................99
2. Biological Activity...................................................................................................................... 100
3. Immunochemical Properties....................................................................................................... 100
4.
Purity, Impurities, and Contaminants...........................................................................................101
5. Quantity��101
B. Analytical Considerations...................................................................................................................101
1.
Reference Standards and Reference Materials............................................................................101
2.
Validation of Analytical Procedures............................................................................................ 102

xiii
Contents
C. Process Controls................................................................................................................................ 102
1. Process-Related Considerations.................................................................................................. 102
2.
In-Process Acceptance Criteria and Action Limits..................................................................... 102
3.
Raw Materials and Excipient Specifications............................................................................... 102
D. Pharmacopoeial Specifications.......................................................................................................... 102
E.
Release Limits vs. Shelf Life Limits.................................................................................................. 102
F. Statistical Concepts............................................................................................................................. 102
III. Justification of Specification...................................................................................................................... 103
IV. Specifications............................................................................................................................................. 103
A.
Drug Substance Specification............................................................................................................ 103
1.
Appearance and Description....................................................................................................... 103
2. Identity��103
3.
Purity and Impurities................................................................................................................... 103
4. Potency��104
B.
Drug Product Specification................................................................................................................ 104
1.
Appearance and Description....................................................................................................... 104
2. Identity��104
3.
Purity and Impurities................................................................................................................... 104
4. Potency��104
6. General Tests............................................................................................................................... 104
7.
Additional Testing for Unique Dosage Forms............................................................................ 104
Glossary................................................................................................................................................................ 105
References............................................................................................................................................................ 105
Appendices........................................................................................................................................................... 106
6.1
Appendix for Physicochemical Characterization............................................................................. 106
6.1.1
Structural Characterization and Confirmation...................................................................... 106
6.1.2 Physicochemical Properties.................................................................................................. 106
6.2
Appendix for Impurities................................................................................................................... 107
6.2.1
Process-Related Impurities and Contaminants..................................................................... 107
6.2.2
Product-Related Impurities Including Degradation Products............................................... 107
Chapter 11 Essential Clean-Room Design Elements.............................................................................................................. 109
I. Optimized Designs.....................................................................................................................................111
II. Turbulent Type Clean Rooms.....................................................................................................................115
III. Vertical Flow Clean Rooms.......................................................................................................................115
IV. Laminar Flow Clean Rooms......................................................................................................................116
V. Horizontal Laminar Flow Clean Rooms....................................................................................................116
A.
Design of Class 500,000 Rooms.........................................................................................................117
B.
Design of Class 100,000 Rooms.........................................................................................................119
C.
Design of Class 10,000 Clean Rooms............................................................................................... 123
VI. The USP 797 Guidelines...................................................................................................................... 126
A. Issues................................................................................................................................................. 126
B. Definitions.......................................................................................................................................... 127
C. Recommendations.............................................................................................................................. 127
Appendix: Air-Handling Unit............................................................................................................................... 129
AHU Data Sheet........................................................................................................................................ 129
Nonhazardous Clean Room—Room Data Sheet....................................................................................... 129
PEC and Buffer Room (Nonhazardous Clean Room)—Room Data Sheet............................................... 129
Anteroom (Nonhazardous Clean Room)—Room Data Sheet................................................................... 129
Hazardous Clean Room—Room Data Sheet............................................................................................. 130
PEC and Buffer Room (Hazardous Clean Room)—Room Data Sheet..................................................... 130
Controlled Substance Vault and Secured Dispensing Receiving Area—Room Data Sheet...................... 130
Dispensing, Prepacking and EXTEMP—Room Data Sheet..................................................................... 130

xiv Contents
Appendix A............................................................................................................................................................................... 133
Appendix B............................................................................................................................................................................... 153
PART II Manufacturing Formulations
Sterile Product Formulations................................................................................................................................................. 193
Abciximab Injection............................................................................................................................................. 193
Acetazolamide Injection....................................................................................................................................... 193
Acetylcholine Chloride Intraocular Solution....................................................................................................... 193
Acyclovir Sodium Injection................................................................................................................................. 193
Adenosine 5′ Monophosphate Injection............................................................................................................... 194
Adenosine Injection.............................................................................................................................................. 194
Adrenal Cortex Injection...................................................................................................................................... 194
Adrenaline Tartarate Injection.............................................................................................................................. 194
Alatrofloxacin Mesylate Injection........................................................................................................................ 194
Albumin (Human)................................................................................................................................................ 195
Albumin 5% Solution........................................................................................................................................... 195
Albumin 20% Solution......................................................................................................................................... 196
Albumin 25% Solution......................................................................................................................................... 196
Albuterol Sulfate Inhalation Solution................................................................................................................... 196
Aldesleukin for Injection...................................................................................................................................... 196
Alemtuzumab Injection........................................................................................................................................ 196
Alpha-Tocopherol (Vitamin E) Injection............................................................................................................. 196
Alprostadil for Injection....................................................................................................................................... 197
Alteplase Recombinant Injection......................................................................................................................... 197
Amikacin Sulfate Injection (50 mg/mL).............................................................................................................. 197
Amikacin Sulfate Injection (250 mg/mL)............................................................................................................ 197
Amikacin Sulfate Injection................................................................................................................................... 198
Amino Acid Parenteral Nutrition Solution........................................................................................................... 199
Amino Acid Parenteral Nutrition Solution (8.5%)...............................................................................................200
Amino Acid Parenteral Nutrition Solution: 10%.................................................................................................200
Amino Acid Parenteral Injection.......................................................................................................................... 201
Aminohippurate Sodium for Injection................................................................................................................. 201
Aminophylline Injection...................................................................................................................................... 201
Amiodarone Injection...........................................................................................................................................202
Amiodarone Injection...........................................................................................................................................202
Amoxicillin Lyophilisate for Injection (250 mg).................................................................................................202
Amoxicillin-Clavulanic Acid Injection................................................................................................................202
Amoxicillin Powder for Injection......................................................................................................................... 203
Amphotericin B Cholesteryl Sulfate Complex for Injection................................................................................ 203
Amphotericin B Injection..................................................................................................................................... 203
Amphotericin B Lipid Complex Injection............................................................................................................204
Amphotericin B Liposome for Injection..............................................................................................................204
Antazoline Sulfate and Xylometazoline Hydrochloride Ophthalmic Drops........................................................ 205
Antipyrine, Phenylephrine, and Pyrilamine Maleate Ophthalmic Drops............................................................. 205
Antipyrine, Phenylephrine, and Sodium Thiosulfate Ophthalmic Solution.........................................................206
Antithymocyte Globulin (Rabbit) for Injection....................................................................................................207
Aprotinin Injection...............................................................................................................................................207
Argatroban (Thrombin Inhibitor) Injection..........................................................................................................208
Arsenic Trioxide Injection....................................................................................................................................208
Ascorbic Acid and B Complex Vitamins (Two Vials)..........................................................................................208
Ascorbic Acid and B Complex Vitamins..............................................................................................................209

xv
Contents
Ascorbic Acid and B Complex Vitamins Lyophilized in Covial..........................................................................209
Ascorbic Acid and B Complex Vitamins...............................................................................................................210
Ascorbic Acid and B Complex Vitamins Lyophilized with Diluent.....................................................................211
Ascorbic Acid and B Complex Vitamins...............................................................................................................211
Ascorbic Acid, B Complex Vitamin, with Beta-Carotene Injection..................................................................... 212
Ascorbic Acid Injection........................................................................................................................................ 212
Ascorbic Acid, USP, Injection with Disodium Edetate........................................................................................ 213
Ascorbic Acid, USP (250 mg/mL Injection)........................................................................................................ 213
Asparaginase for Injection................................................................................................................................... 213
Atropine, Chlorpheniramine Maleate, and Phenylpropanolamine Injection........................................................ 213
Atropine Sulfate Injection.................................................................................................................................... 213
Atropine Sulfate Injection.....................................................................................................................................214
Aztreonam for Injection........................................................................................................................................214
Basiliximab for Injection.......................................................................................................................................214
Benzylpenicillin + Dihydrostreptomycin Injectable Suspension (200,000 U + 200 mg/mL)..............................214
B Complex Injection: Niacinamide, Pyridoxine, Riboflavin, and Thiamine Injection........................................ 215
B Complex Injection: Niacinamide, Pantothenate, Pyridoxine, Riboflavin, Thiamine Injection........................ 215
Solution 1............................................................................................................................................................. 215
Solution 2..............................................................................................................................................................216
B Complex Injection.............................................................................................................................................217
B Complex Injection.............................................................................................................................................217
B Complex, Vitamin D, Vitamin E Lyophilized Injection.....................................................................................218
Solution 1..............................................................................................................................................................218
Solution 2............................................................................................................................................................. 220
B Complex Injection............................................................................................................................................ 220
B Complex Vitamin, Veterinary........................................................................................................................... 221
B Complex with Minerals Injection, Veterinary................................................................................................... 222
B Complex Vitamins with Hormones................................................................................................................... 222
B Complex Vitamins with Liver Extract Injection............................................................................................... 222
Benzodiazepine Injection..................................................................................................................................... 222
Benztropine Mesylate Injection........................................................................................................................... 223
Beta-Carotene Injection........................................................................................................................................ 223
Betamethasone Suspension Injection................................................................................................................... 223
Bethanechol Chloride Injection............................................................................................................................ 223
Biotin Injection..................................................................................................................................................... 223
Biperiden Lactate Injection..................................................................................................................................224
Bisantrene Emulsion Injection.............................................................................................................................224
Bisantrene Emulsion Injection.............................................................................................................................224
Borax Sodium Lubricating Ophthalmic Drops....................................................................................................224
Botulinum Toxin: Type A Purified Neurotoxin Complex..................................................................................... 225
Botulinum Toxin (Type B Injectable Solution).................................................................................................... 225
Bretylium Tosylate in Dextrose Injection............................................................................................................. 225
Buflomedil Injection............................................................................................................................................. 226
Bupivacaine Hydrochloride Injection 1: 0.75% in Dextrose 8.25% Injection..................................................... 226
Bupivacaine Hydrochloride Injection (0.25%)..................................................................................................... 226
Bupivacaine Hydrochloride Injection................................................................................................................... 227
Bupivacaine Hydrochloride Injection: Bupivacaine with Epinephrine Injection................................................. 227
Buprenorphine Hydrochloride Injectable............................................................................................................. 227
Caffeine Citrate Injection..................................................................................................................................... 228
Calcitonin Injection.............................................................................................................................................. 228
Calcitonin Injection.............................................................................................................................................. 228
Calcitriol Injection................................................................................................................................................ 228
Calcitriol Injection................................................................................................................................................ 229
Calcium Glycerophosphate Injection with Lactate.............................................................................................. 229

xvi Contents
Calcium Glycerophosphate Injection: Calcium Glycerophosphate Injection (Human and Veterinary).............. 230
Calcium Gluconate Injection................................................................................................................................ 230
Calcium Glycerophosphate Injection................................................................................................................... 230
Camphor Injection................................................................................................................................................ 231
Camptothecin Injection........................................................................................................................................ 231
Carboplatin for Infusion....................................................................................................................................... 231
Carboplatin Injection............................................................................................................................................ 231
Carprofen Injection.............................................................................................................................................. 231
Cefamandole Nafate for Injection........................................................................................................................ 232
Cefazolin Injection............................................................................................................................................... 232
Cefepime Hydrochloride for Injection................................................................................................................. 232
Cefotaxime Injection............................................................................................................................................ 232
Cefotetan Injection............................................................................................................................................... 232
Cefoxitin Injection Premixed IV Solution............................................................................................................ 233
Ceftazidime for Injection: L-Arginine Formulation............................................................................................. 233
Ceftazidime Injection Dry Powder....................................................................................................................... 233
Ceftazidime Injection Premix............................................................................................................................... 233
Ceftriaxone Injection: 500 mg Injection (IM and IV).......................................................................................... 233
Ceftriaxone Injection (250 mg Injection, IM and IV).......................................................................................... 234
Ceftriaxone Injection Premix............................................................................................................................... 234
Cefuroxime for Injection...................................................................................................................................... 234
Cetrorelix Acetate for Injection............................................................................................................................ 234
Chloramphenicol and Phenylmercuric Nitrate Ophthalmic Drops...................................................................... 235
Chloramphenicol Ophthalmic Solution (3%)....................................................................................................... 236
Chloramphenicol for Injection............................................................................................................................. 236
Chloramphenicol Injection................................................................................................................................... 236
Chloramphenicol Sodium Succinate for Injection............................................................................................... 237
Chlordiazepoxide Hydrochloride Injection.......................................................................................................... 237
Chloroprocaine Hydrochloride Injection............................................................................................................. 237
Chlorothiazide Sodium for Injection.................................................................................................................... 238
Chlorpheniramine Maleate Injection (25 mg/mL)............................................................................................... 238
Chlorpheniramine Maleate Injection (10 mg/mL)............................................................................................... 238
Chlorpromazine Hydrochloride Injection (10 mg/mL)........................................................................................ 238
Chlorpromazine Hydrochloride Injection (25 mg/mL)........................................................................................ 239
Choriogonadotropin-Alpha (Recombinant) for Injection.................................................................................... 239
Chorionic Gonadotropin for Injection (20,000 U/10 mL Covial)........................................................................ 239
Chorionic Gonadotropin for Injection (10000 U//10 mL)...................................................................................240
Chromium Chloride Additive Injection (5 mL Vial)............................................................................................240
Chromium Chloride Additive Injection (10 mL Vial)..........................................................................................240
Chromium Chloride Additive Injection (30 mL Vial)..........................................................................................240
Cidofovir Injection...............................................................................................................................................240
Cimetidine Injection............................................................................................................................................. 241
Cimetidine Injection............................................................................................................................................. 241
Ciprofloxacin Hydrochloride Ophthalmic Solution............................................................................................. 241
Ciprofloxacin Injection......................................................................................................................................... 241
Cisplatin Diaminedichloride Injection................................................................................................................. 242
Cisplatin with 2,2′-Dithio-b/s-Ethane Sulfonate Injection................................................................................... 242
Cladribine Injection Infusion............................................................................................................................... 242
Clarithromycin Injection...................................................................................................................................... 243
Lactobionic Acid (12% w/v Solution).................................................................................................................. 243
Clindamycin Injection in 5% Dextrose................................................................................................................ 243
Clindamycin Phosphate Injection 150 mg/mL (4 mL in 5 mL Vial, 600 mg; 6 mL in 10 mL vial, 900 mg)......244
Clonidine Hydrochloride Injection.......................................................................................................................244
Closantel Veterinary Injectable Solution (12–20 g/100 mL)................................................................................ 245
Coagulation Factor VIIa (Recombinant) for Injection......................................................................................... 245
Coagulation Factor IX (Recombinant) for Injection............................................................................................ 245
Colistin Sulfate, Neomycin Sulfate, Thonzonium Bromide, and Hydrocortisone Acetate Otic Suspension....... 245

xvii
Contents
Conjugated Estrogens for Injection...................................................................................................................... 245
Copper Sulfate Additive Injection (5 mL Vial)....................................................................................................246
Copper Sulfate Additive Injection (10 mL Vial)..................................................................................................246
Copper Sulfate Additive Injection (30 mL Vial)..................................................................................................246
Corticorelin Ovine Triflutate for Injection...........................................................................................................246
Cortisone Acetate Injectable Suspension.............................................................................................................246
Cosyntropin for Injection.....................................................................................................................................246
Cromolyn Sodium Ophthalmic Solution.............................................................................................................. 247
Crude Liver Extract Injection............................................................................................................................... 247
Cyanocobalamin and Thiamine Injection............................................................................................................. 247
Cyanocobalamin, Choline, and Niacinamide Injection........................................................................................ 247
Cyanocobalamin Injection.................................................................................................................................... 247
Cyanocobalamin Injection....................................................................................................................................248
Cyanocobalamin Injection for Veterinary Use.....................................................................................................248
Cyanocobalamin Repository Injection (1000 mg/mL).........................................................................................248
Cyanocobalamin, Pyridoxine, and Thiamine Injection........................................................................................ 249
Cyclosporine Ampoules for Infusion................................................................................................................... 251
Cytarabine Liposome Injection for Intrathecal Use (50 mg/5 mL Vial).............................................................. 251
Cytomegalovirus Immune Globulin IV (Human)................................................................................................ 251
Dacarbazine Injection........................................................................................................................................... 251
Daclizumab for Injection...................................................................................................................................... 252
Dactinomycin for Injection.................................................................................................................................. 252
Dalteparin Sodium Injection................................................................................................................................ 252
Danaparoid Sodium Injection............................................................................................................................... 253
Dantrolene Sodium for Injection.......................................................................................................................... 253
Dapiprazole Hydrochloride Ophthalmic Solution (0.5%).................................................................................... 253
Daunorubicin HCl Injection................................................................................................................................. 253
Daunorubicin Citrate Liposome Injection............................................................................................................ 254
Desmopressin Acetate Injection (Intranasal)........................................................................................................ 254
Dexamethasone Acetate Suspension Injection: Dexamethasone Acetate (8 mg/mL).......................................... 254
Dexamethasone Acetate/Sodium Phosphate Suspension (8/2 mg/mL)................................................................ 255
Dexamethasone Sodium Phosphate Injection...................................................................................................... 255
Dexamethasone Injection, Veterinary................................................................................................................... 256
Dexpanthenol, Niacinamide, Pyridoxine, Riboflavin, and Thiamine Injection................................................... 257
Dexrazoxane for Injection.................................................................................................................................... 258
Dextrose 25% Injection (Flexible Container)...................................................................................................... 258
Dextrose Injection (5% and 10% LVP)................................................................................................................ 258
Dextrose with Sodium Chloride Injection LVP.................................................................................................... 259
Diazepam Injectable Solution (2.5 mg/mL)......................................................................................................... 259
Diazepam Emulsion Injection.............................................................................................................................. 259
Diazepam Emulsion Injection..............................................................................................................................260
Diazepam Injection..............................................................................................................................................260
Diazepam Rectal Solution....................................................................................................................................260
Dibenzazepine Carboxamide Injection................................................................................................................ 261
Diclofenac Injectable Solution (75 mg/3 mL)...................................................................................................... 261
Diclofenac Sodium Injection................................................................................................................................ 261
Diclofenac–Lecithin Injection.............................................................................................................................. 262
Diclofenac with Acetylcysteine Injection............................................................................................................. 262
Diclofenac Lyophilized Injection......................................................................................................................... 263
Diclofenac Lyophilized Injection......................................................................................................................... 263
Dicyclomine Hydrochloride Injection.................................................................................................................. 263
Digoxin Injection.................................................................................................................................................. 263

Volume 6 : Excipients of Sterile Products _1.pdf

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