H A N D B O O K O F

PharmaceuticalManufacturingFormulations

Sterile Products

VOLUME 6

Sarfaraz K. Niazi

CRC PRESSBoca Raton London New York Washington, D.C

Table of Contents

PartiSterile Manufacturing Practice.

Chapter 1Inspection of Sterile Product Manufacturing Facilities 3I. Introduction 3II. cGMP Compliance Basics 3

A. Personnel 3B. Buildings 3C. Air 3D. Environmental Controls 4E. Equipment 4F. Water for Injection 4G. Containers and Closures 4H. Sterilization 4

1. Methods 42. Indicators 43. Filled Containers 5

I. Personnel Practices 5J. Laboratory Controls 5

1. Retesting for Sterility 52. Retesting for Pyrogens 53. Particulate Matter Testing 64. Production Records 6

III. Aseptic Processing 6A. Introduction 6B. Buildings and Facilities 6

1. Critical Area (Class 100) 72. Supporting Clean Areas 83. Clean Area Separation S4. Air Filtration S5. Design l>

C. Personnel Training. Qualification, and Monitoring 101. Manufacturing Personnel I 12. Laboratory Personnel 123. Monitoring Program 12

D. Components and Containers/Closures 121. Components 122. Containers/Closures 13

E. Endotoxin Control 14F. Time Limitations 14G. Process Validation and Equipment Qualification 14

1. Process Simulations 142. Filtration Efficacy 173. Sterilization of Equipment and Containers/Closures 1 x

H. Laboratory Controls 191. Environmental Monitoring 202. Microbiological Media and Identification 21

I. Sterility Testing 221. Choice of Methods 222. Media 223. Personnel 234. Sampling and Incubation 235. Investigation of Sterility Positives 23

J. Batch Record Review: Process Control Documentation 24IV. Processing Prior to Filling and Sealing Operations 25

A. Aseptic Processing from Early Manufacturing Steps 25B. Aseptic Processing of Cell-Based Therapy Products (or of Products Intended for Use

as Cell-Based Therapies) 25V. Aseptic Processing Isolators 25

A. Maintenance 261. General 262. Glove Integrity 26

B. Design 261. Airflow 262. Materials of Construction 263. Pressure Differential 264. Clean-Area Classifications 26

C. Transfer of Materials and Supplies 261. Introduction 262. Discharge 27

D. Decontamination 271. Surface Exposure 272. Efficacy 273. Frequency 27

E. Filling Line Sterilization 27F. Environmental Monitoring 27G. Personnel 27

VI. Blow-Fill-Seal Technology 28A. Equipment Design and Air Quality 28B. Validation and Qualification 28C. Batch Monitoring and Control 28

VII. Lyophilization of Parenterals 29A. Introduction 29B. Product Type and Formulation 29C. Filling 30D. Lyophilization Cycle and Controls 31E. Cycle Validation 32F. Lyophilizer Sterilization and Design 32G. Finished Product Testing .34

1. Dose Uniformity 342. Stability Testing ....343. Sterility Testing 34

H. Finished Product Inspection — Meltback 34VIII. High-Purity Water Systems 35

A. System Design 35B. System Validation 35C. Microbial Limits 35

1. WFI Systems 352. Purified Water Systems 35

D. WF1 Systems 37E. Still 37F. Heat Exchangers 37G. Holding Tank 3XH. Pumps ^8I. Piping 38J. Reverse Osmosis 38K. Purified Water Systems 3')L. Process Water 39M. Evaluation Strategy 39

References 40

Chapter 2New Drug Application for Sterilized Products 45I. Introduction 45II. Terminal Heat Sterilization 45

A. Description of the Process and Product 45B. Thermal Qualification of the Cycle 45C. Microbiological Efficacy of the Cycle 46D. Microbiological Monitoring of the Environment 46E. Container/Closure and Package Integrity 47F. Bacterial Endotoxins Test and Method 47G. Sterility Testing Methods and Release Criteria 47H. Evidence of Formal Written Procedures 47

III. Other Terminal Sterilization Processes 47A. Ethylene Oxide 47B. Radiation 48

IV. Aseptic Fill Manufacturing Processes 48A. Buildings and Facilities 48B. Overall Manufacturing Operation 48C. Containers and Closures 49D. Procedures and Specifications for Media Fills 49E. Actions Concerning Product when Media Fills Fail 49F. Microbiological Monitoring of the Environment 49G. Container/Closure and Package Integrity 50H. Sterility Testing Methods and Release Criteria 50I. Bacterial Endotoxins Test and Method 50J. Evidence of Formal Written Procedures 50

V Maintenance of Microbiological Control and Qualin: Stability Considerations 5(1A. Container/Closure Integrity 50B. Preservative Effectiveness 50C. Pyrogen or Endotoxin Testing 50

Chapter 3Manufacturing Formulations Template 5 1

Autoclaves 54Aseptic Contract Manufacturers 54Clean Room Design and Construction 55Clean-in-Place;Steam-in-Place (CIPISIPi 5^Closure Washing and Sterilization 56Consultants 56Disinfectants and Preservatives S6Distillation Equipment 5~Endneerine and Construction 5"

Filling Machines 57Filter Aids 58Flowmeters (Sanitary) 58Freeze-Dryers (Sterilizable) 58Microfiltration Equipment and Filters 58Pumps (Sanitary) 59Sterile Tanks and Related Stainless Equipment 60Sterility Test Equipment 60Sterilizing and Drying Tunnels (Hot Air) 60Stoppering Machines 60Vial and Bottle Washers 61

Part IISterile Pharmaceutical Formulations 63Abciximab Injection 65Acetazolamide Injection 65Acetylcholine Chloride Intraocular Solution 66Acyclovir Sodium Injection 66Adenosine Injection 67Adrenal Cortex Injection 67Adrenaline Tartarate Injection 67Alatrofloxacin Mesylate Injection 68Albumin (Human) 70Albuterol Sulfate Inhalation Solution 71Aldesleukin for Injection 71Alemtuzumab Injection 71Alpha Tocopherol (Vitamin E) Injection 72Alprostadil for Injection 72Alteplase Recombinant Injection 72Amikacin Sulfate Injection 73Amino Acid Parcnteral Nutrition Solution 75Aminohippurate Sodium for Injection 77Aminophylline Injection 78Amiodarone Injection 79Amoxiciliin-Clavulanic Acid Injection 80Amoxicillin Powder for Injection 80Amphotericin B Cholesteryl Sulfate Complex for Injection 81Amphotericin B Injection 82Amphotericin B Lipid Complex Injection 83Amphotericin B Liposome for Injection 83Antazoline Sulfate and Xylometazoline Hydrochloride Ophthalmic Drops 84Antipyrine. Phenylephrine. and Pyrilamine Maleate Ophthalmic Drops 85Antipyrine. Phenylephrine. and Sodium Thiosulfatc Ophthalmic Solution 86Antithymocyte Globulin (Rabbit) for Injection 87Aprotinin Injection 87Argatroban (Thrombin Inhibitor) Injection 88Arsenic Trioxide Injection 88Ascorbic f\cid and B-Complex Vitamins 89Ascorbic Acid. B-Complex Vitamin, with Beta Carotene Injection 93Ascorbic Acid Injection 94Ascorbic Acid. USP. Injection 94Ascorbic Acid. USP. 250 mg/mL Injection 95Asparaginase for Injection 95

Atropine. Chlorpheniramine Maleate. and Pheny lpropanolamine Inject inn 9>Atropine Sulfate Injection 9dAztreonam for Injection 97Basiliximab tor Injection 97B-Complex Injection 9SB-Complex. Vitamin D. Vitamin L Lyophili/ed Injection 103B-Complex Vitamin Veterinary 106B-Complex with Minerals Injection (Veterinary ) 107B-Complex Vitamins with Hormones 107B-Complex Vitamins with Liver Extract Injection 108Benzodiazepine Injection 108Benztropine Mesylate Injection 10SBeta-Carotene Injection 109Betamethasone Suspension Injection 109Bethanechol Chloride Injection 109Biotin Injection 110Biperiden Lactate Injection 110Bisantrenc Emulsion Injection I I IBorax Sodium Lubricating Ophthalmic Drops 1 12Botulinum Toxin 1 13Bretylium Tosylate in Dextrose Injection I I 3Buflomedil Injection 114Bupivacaine Hydrochloride Injection 115Buprenorphine Hydrochloride Injectable 1 16Caffeine Citrate Injection 116Calcitonin Injection 117Calcitriol Injection 1 18Calcium Glycerophosphate Injection 1 20Calcium Injection 121Camphor Injection 121Camptothecin Injection I 22Carboplatin for Infusion 122Carboplatin Injection 1 22Carprofen Injection I 23Cefamandole Nafate for Injection 123Cefazolin Injection 1 23Cefepime Hydrochloride for Injection I 24Cefotaxime Injection I 24Cefotetan Injection 121Cefoxitin Injection Premixed Intravenous Solution 1 24Cefta/idime for Injection — L-Arginine Formulation 125Cettazidime Injection 1 25Ceftriaxone Injection 1 26Cef urox i me for I nject ion I 2 ~CetroreIix Acetate for Injeetion 1 2 ~Chloramplienicol aiul Pheny hnercuric Nitrate Ophthalmic Drops 1 2S

Chloramphenicol for Injection 1 29Chloramphenicol Injection I 3dChloramphenicol Sodium Succinate for Injection 131Chlordiazepoxide Hydrochloride Iniection 131Chloroprocaine Hydrochloride Injection I >2Chloroquine Phosphate Injection 132Chlorothia/ide Sodium for Injection 1 ;2Chlorpheniramine Maleate Injection 1 33Chlorpromazine Hydrochloride Injection 134

Choriogonadotropin Alfa (Recombinant) for Injection 134Chorionic Gonadotropin for Injection 135Chromium Chloride Additive Injection 136Cidofovir Injection 136Cimetidine Injection 137Ciprofloxacin Hydrochloride Ophthalmic Solution 137Ciprofloxacin Injection 138Cisplatin Diaminedichloride Injection 138Cisplatin with 2,2£-Dithio-bis-Ethane Sulfonate Injection 139Cladribine Injection Infusion 139Clarithromycin Injection 140Clindamycin Injection in 5% Dextrose 141Clindamycin Phosphate Injection 142Clonidine Hydrochloride Injection 143Coagulation Factor Vila (Recombinant) for Injection 143Coagulation Factor IX (Recombinant) for Injection 143Colistin Sulfate, Neomycin Sulfate, Thonzonium Bromide, and Hydrocortisone Acetate Otic Suspension 144Conjugated Estrogens for Injection 144Copper Sulfate Additive Injection 145Corticorelin Ovine Triflutate for Injection 145Cortisone Acetate Injectable Suspension 146Cosyntropin for Injection 146Cromolyn Sodium Ophthalmic Solution 146Crude Liver Extract Injection 147Cyanocobalamin and Thiamine Injection 147Cyanocobalamin, Choline, and Niacinamide Injection 147Cyanocobalamin Injection 148Cyanocobalamin Injection for Veterinary Use 149Cyanocobalamin Repository Injection 1000 mg/mL 149Cyanocobalamin, Pyridoxine, and Thiamine Injection 150Cyclosporine Ampoules for Infusion 152Cytarabine Liposome Injection for Intrathecal Use, 50 mg/5 mL Vial 153Cytomegalovirus Immune Globulin Intravenous (Human) 153Dacarbazine Injection 154Daclizumab for Injection 154Dactinomycin for Injection 155Dalteparin Sodium Injection 155Danaparoid Sodium Injection 156Dantrolene Sodium for Injection 156Dapiprazole Hydrochloride Ophthalmic Solution, 0.57c 156Daunorubicin 157Desmopressin Acetate Injection-Intranasal 158Dexamethasone Acetate Suspension Injection 159Dexpanthenol. Niacinamide. Pyridoxine, Riboflavin, and Thiamine Injection 162Dexrazoxane for Injection 163Dextrose 25c/c Injection (Flexible Container) 163Dextrose Injection 5<7r and 107r LVP 164Dextrose with Sodium Chloride Injection LVP 164Diazepam Emulsion Injection 165Diazepam Injection 166Diazepam Rectal Solution 167Dibenzazepine Carboxamide Injection 167Diclofenac Injection 168Dicyclornine Hydrochloride Injection 170Digoxin Injection 171

Dihydroergotamine Mesylate Drops 172Dihydroergotamine Mesylate Injection 173Dihydroergotamine Mesylate Nasal Spray 173Diisopropylphenol Injection 1 74Diltiazem Hydrochloride Injection 174Dimenhydrinate Injection 175Dimethyl Sulfoxide Injection 175Dinoprostone Cervical Gel 175Diphenhydramine Hydrochloride Injection 176Diphenylmethyl Piperazine Injection 176Dipyrone Injection 1 77Dipyrone, Papaverine HC1, and Atropine Sulfate Injection 177Disodium Edetate Injection 178Disulfonic Acids Injection 178Dobutamine Injection 179Dopamine Hydrochloride Injection 180Doxapram Hydrochloride Injection, USP 181Doxercalciferol Injection 181Doxorubicin for Injection 182Doxycycline Hyclate Injection 183Doxycycline Hydrochloride Injection 184Ebselen Liposomal Injection 184Edetate Sodium, Polyvinyl Alcohol, Sodium Sulfacetamide. Sodium Thiosulfate Ophthalmic Drops 185Edrophonium Injectable 188Electrolyte Maintenance Fluid 189Electrolytes, TPN Injection 191Emetine Hydrochloride Injection 192Enalaprilat Injection 192Ephedrine and Pyrilamine Maleate Injection Veterinary 192Ephedrine Sulfate Injection 193Epinephrine Auto Injector Injection 193Epinephrine Injection 193Epoetin Alfa for Injection 194Epoprostenol Sodium for Injection 194Ergocalciferol Injection (Vitamin D) 194Ergonovine Maleate Injection 195Ergonovine Maleate Injection Veterinary 195Erythromycin Injection 196Esmolol Hydrochloride Injection 19"Estradiol Cypionate Injection 19SEstradiol Suspension Injection 198Estradiol Valerate Injection 19NEstrogenic Substances in Oil Injection 19NEstrone. Estradiol. and Cyanocobalamin Injection 199Estrone Sterile Suspension Veterinary Injection 199Ftanercept Injection 199Ftorphine Hydrochloride Veterinary 2ooExemestane Aqueous Suspension Injection 200lamotidine Injection 20 1Fenoldopam Mesy late Injection 2o 1Fentanyl Citrate Injection 201Filgrastim Injection 202Flosulide Injection 202Fluconazole Injection 202Flumazenil Injection 203

Folic Acid and Niacinamide Injection 203Follitropin Beta for Injection 204Furosemide Injection 204Gentamicin and Prednisolone Ophthalmic Drops 205Gentamicin Injection 207Gentamicin Ophthalmic Drops 209Glycine Antagonist Injection 210Glycopyrrolate Injection 210Granisetron Hydrochloride Injection 211Guaiacol-Iodide Solution Veterinary 211Haloperidol Injection 211Hemin for Injection 212Heparin Injection 213Hepatitis B Immune Globulin (Human) 214Hexamethylmelamine Injection 214Hydrochloric Acid 215Hydrocortisone Sodium Phosphate Injection 215Hydrocortisone Sodium Succinate for Injection 216Hydromorphone Hydrochloride Injection 219Hydroxycobalamin Injection 220Hydroxyprogesterone Caproate Injection 220Hydroxypropylmethylcellulose Ophthalmic Solution 221Hyoscine Butylbromide Injection 222Ibuprofen Lysinate Injection 223Ibutilide Fumarate Injection 223Idarubicin Hydrochloride Injection 223Imiglucerase for Injection 224Immune Globulin (Human) for Injection 224Infiiximab Recombinant for Injection 224Insulin Aspart Injection 225Insulin Glargine Injection 225Insulin Human 70/30 226Insulin Human Isophane Suspension (NPH) 228Insulin Lispro Injection 229Insulin Regular 230Interferon Injection 231Interleukin for Injection (IL-2) 232Iodine Intravenous Additive 233Iron Copper Solution Veterinary 233Iron Dextran Injection 233Iron Sucrose Injection 233Isometheptene Hydrochloride Veterinary Injection 234Itraconazole Injection 234Ketoprofen Lysine Injection 234Ketorolac Tromethamine Injection 235Ketorolac Tromethamine Ophthalmic Solution 235Labetalol Hydrochloride Injection 235Lactobionic Acid Injection 236Lamotrigine Injection 236La/amid Injection 237Lepirudin for Injection 237Leucovorin Calcium Injection 238Leuprolide Acetate Injection 239Levorphanol Tartarate Injection 241Levothyroxine Sodium for Injection 241

Lidocaine Hydrochloride and Epinephrine Injection 242Lidocaine Hydrochloride Injection 243Lincomycin Hydrochloride Injection 244Liothyronine Sodium Injection (T3 ) 244Lipid Emulsion 207r for Parenteral Nutrition 245Liver, Iron, and Cyanocobalamin with Procaine Injection 245Liver, Iron, and Vitamin B12 Injection Veterinary 246Lorazepam Injection 246Magnesium Sulfate 50% Injection 247Manganese Sulfate Injection 247Mechlorethamine Hydrochloride for Injection Trituration 247Medroxyprogesterone Acetate Sterile Aqueous Suspension 248Medroxyprogesterone and Estradiol Sterile Suspension 249Melphalan Hydrochloride for Injection 250Menadione Injection 250Menadione Sodium Bisulfite Injection Veterinary 251Menotropins for Injection 251Meperidine Hydrochloride Injection 252Meperidine Hydrochloride and Promethazine Hydrochloride Injection 252Mepivacaine Hydrochloride Injection 253Meropenem for Injection 253Mesoridazine Besylate Injection 254Metaraminol Bitartrate Injection 254Methandriol Dipropionate Injection 254Methocarbamol Injection 254Methohexital Sodium for Injection 255Methylprednisolone Acetate Suspension Injection 255Metoclopramide Injection 256Metolazone Injection 257Metronidazole Infusion 257Metronidazole Injection 258Metronidazole and Dextrose Infusion 259Midazolam Hydrochloride Injection 259Milrinone Lactate Injection 259Mineral Complex Injection 260Mitoxantrone for Injection 260Morphine Sulfate Infusion 260Morphine Sulfate Injection 26 1Moxidectin Injection 261Multiple Electrolytes and Dextrose Injection (Elliott's B Solution! 262Muromonab-CD3 Injection 262Nalbuphine Hydrochloride 263Naloxone Hydrochloride Injection 263Nandrolone Decanoate Injection 264Nandrolone PhenyIpropionate Injection 264Napha/oline Ophthalmic Drops 265Natamyein Ophthalmic Suspension 2MiNatural Estrogenic Substances Suspension 2w->Nedocromil Sodium Ophthalmic Solution 2f>6Neomycin and Prednisolone Acetate Ophthalmic Suspension yrNeomycin Sulfate-Polymyxin B Sulfate tor Irrigation 26>>Neostigmine Methy Isullate Injection 2 "oNesiritide for Injection 2~0Netilmicin Injection 2~lNiacinamide Injection 2~l

Nicardipine Hydrochloride for Infusion 272Nicardipine Hydrochloride Injection 272Nikethamide Injection 272Nimesulide Injection 273Nimodipine Injection 273Nystatin for Injection 273Octreotide Acetate Injection 274Ofloxacin Otic Solution 275Ondansetron Hydrochloride Injection 275Oprelvekin for Injection 276Orphenadrine Citrate Injection 276Oxacarbazepine-10 Injection 276Oxazepine Injection 277Oxendolone Injection 278Oxymorphone Hydrochloride Injection 279Oxytetracycline Injection 279Oxytocin Injection 280Oxytocin Injection, USP, 20 U/mL 280Paclitaxel Injection 281Palivizumab for Injection 281Pancuronium Bromide Injection 282Parenteral Nutrition Fat Emulsion 283Paricalcitol Injection 283Pegademase Bovine Injection 284Pegaspargase Injection 284Peginterferon Alfa-2b for Injection 284Penicillin G Benzathine and Penicillin G Procaine Injection 285Penicillin G Benzathine Injectable Suspension 285Pentobarbital Sodium Solution Injection 285Pentostatin for Injection 286Pentyienetetrazole Injection 286Pheniramine Maleate Injection 286Phenol Saline Diluent 286Phenylbutazone and Dipyrone Injection 287Phenylbutazone Injection Veterinary 287Phenylephrine and Zinc Sulfate Ophthalmic Drops 288Phenylpropanolamine Hydrochloride Injection 289Phenytoin Sodium Injection 289Phytonadione (Vitamin Kl) Injection 290Piperacillin Sodium and Tazobactam Sodium Injection 291Plicamycin for Injection 291Poly vinyl Alcohol Ophthalmic Solution 292Potassium Estrone Sulfate Injection Veterinary 293Potassium Estrone Sulfate Suspension Injection 293Potassium Phosphate Injection 294Prednisolone and Neomycin Ophthalmic Suspension 295Prednisolone Injection 298Prednisolone Ophthalmic Drops 300Procaine Hydrochloride Injection 302Prochlorperazine Injection 302Progesterone and Tocopheryl Acetate Injection 302Progesterone Injection Repository Veterinary 303Promazine Hydrochloride Injection 303Promethazine Hydrochloride Injection 304Propofol Emulsion Injection 305

Pyridoxine and Thiamine Injection '05Pyridoxine Hydrochloride Injection '06Pyrilamine Maleate and Ephedrine Injection Veterinary '07Quinidine Sulfate Injection '07Quinolone Lyophilized InjectionsQuinolone-Calcium Lactate Complex for Injection ' '08Ranitidine Injection '09Reteplase Recombinant for Injection '10Retinol (Vitamin A) InjectionRho (D) Immune Globulin (Human) InjectionRinger Lactate Solution InjectionRituximab InjectionRubella Virus Vaccine Live '12Salbutamol Aerosol for InhalationSisomicin InjectionSodium Bicarbonate and Disodium Edetate Injection 315Sodium Bicarbonate Injection 316Sodium Chloride Bacteriostatic InjectionSodium Chloride Injection 317Sodium Ferric Gluconate Complex in Sucrose Injection '17Sodium Hyaluronate Injection 'ISSodium Lactate Compound (Hartmann's) Injection MSSodium Thiosulfate Injection ' 1 8Somatropin (rDNA Origin) Injection 319Sterile Water for Injection '20Streptomycin Sulfate Injection 320Succinylcholine Chloride Injection 321Sumatriptan Succinate InjectionTenecteplase for InjectionTestosterone InjectionTetrahydrozoline Ophthalmic DropsTheophylline and Dextrose InjectionThiamine Hydrochloride InjectionThiopental Sodium for Injection '28Thiotepa for Injection '29Thiothixene Hydrochloride Injection '29Thyrotropin Alfa for injectionTimolol Ophthalmic SolutionTinzaparin Sodium InjectionTirofiban Hydrochloride Injection '3oTobramycin Solution for Inhalation '30Tobramycin Sulfate InjectionTopotecan Hydrochloride for InjectionTrace Element Concentrate InjectionTrancxamic Acid InjectionIrastu/umah for InjectionTriamcinolone Acetonide Suspension InjectionTritlupromazine Hydrochloride InjectionTripelennamine Hydrochloride Injection \eterinaryTubocurarine Chloride InjectionTyphoid Vi Polysaccharidc VaccineUndine Triphosphate InjectionL'rokinase for InjectionValproate Sodium InjectionValrubiein for Intravesical Instillation

Vancomyein for Injection 339Varicella Virus Vaccine Live 340Vasopressin (8-Arginine Vasopressin) Injection 340Vecuronium Bromide for Injection 341Verapamil Hydrochloride Injection 341Vinblastine Sulfate for Injection '. 342Vincristine Sulfate Injection 343Water for Injection 344Water for Injection. Bacteriostatic 344Zinc Sulfate Additive Injection 345Zoledronic Acid for Injection 345

Index 347