H A N D B O O K O F

PharmaceuticalManufacturingFormulationsUncompressed Solid Products

VOLUME 2

Sarfaraz K. Niazi

CRC PRESSBoca Raton London New York Washington, D.C.

Table of Contents

PartiRegulatory and Manufacturing Guidelines 1

Chapter 1Global Good Manufacturing Practices Compliance 3I. Introduction 3

A. General Provisions 5B. Organization and Personnel 5C. Buildings and Facilities 6D. Equipment 7E. Control of Components and Drug Product Containers and Closures 8F. Production and Process Controls 9G. Packaging and Labeling Controls 10H. Holding and Distribution 13I. Laboratory Controls 13J. Records and Reports 15K. Returned and Salvaged Drug Products 18

Chapter 2Compliance Program Guidance Manual for FDA Staff: Drug Manufacturing Inspections 21I. Background 21II. Implementation 21

A. Objectives 21B. Strategy 21

1. Biennial Inspection of Manufacturing Sites 212. Inspection of Systems 223. A Scheme of Systems for the Manufacture of Drugs and Drug Products 22

III. Program Management Instructions 23A. Definitions 23

1. Surveillance Inspections 232. Compliance Inspections 243. State of Control 244. Drug Process 245. Drug Manufacturing Inspection 24

B. Inspection Planning 24C. Profiles 24

IV. Inspectional Observations 25A. Investigational Operations 25

1. General 252. Inspection Approaches 253. System Inspection Coverage 264. Sampling 295. Inspection Teams 296. Reporting 29

V. Analytical Observations 30A. Analyzing Laboratories 30

B. Analysis 30VI. Regulatory /Administrative Strategy 30

Chapter 3

Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage FormsBased on a Biopharmaceutics Classification 33I. Introduction 33II. The Biopharmaceutics Classification System 33

A. Solubility 33B. Permeability 34C. Dissolution 34

III. Methodology for Classifying a Drug Substance and for Determining the Dissolution Characteristicsof a Drug Product 34A. Determining Drug Substance Solubility Class 34B. Determining Drug Substance Permeability Class 34

1. Pharmacokinetic Studies in Humans 352. Intestinal Permeability Methods 353. Instability in the Gastrointestinal Tract 36

C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity 36IV. Additional Considerations for Requesting a Biowaiver 37

A. Excipients 37B. Prodrugs 37C. Exceptions 37

1. Narrow Therapeutic Range Drugs 372. Products Designed to Be Absorbed in the Oral Cavity 37

V. Regulatory Applications of the BCS 37A. INDs/NDAs 37B. ANDAs 38C. Postapproval Changes 38

VI. Data to Support a Request for Biowaivers 38A. Data Supporting High Solubility 38B. Data Supporting High Permeability 38C. Data Supporting Rapid and Similar Dissolution 39D. Additional Information 39References 39Appendix A 39

Chapter 4

Guidelines on Formulating Uncompressed Solids 41I. Relative Humidity 41II. Surface Area 41III. Sieve Analysis 41IV. Particle Size Distribution 42V. Powder Flow Properties 42VI. Real, Tapped, and Bulk Density 43VII. Solid Handling 43VIII. Mixing of Powders 43IX. Oral Powders 43X. Capsules 43XI. FDA Classification of Capsule Types 44XII. FDA Classification of Powders 45XIII. Inhalers and Lung Delivery 45XIV. Problems in Powder Handling 45

XV. Capsulation Equipment 46XVI. Capsule Finishing 46XVII. Modified-Release Products 46XVIII. Clinical Test Supplies and Placebos 46XIX. Coated Particles 46XX. Mixing Mechanisms 46XXI. Segregation Mechanisms 46XXII. Mixing Equipment 47XXIII. Milling 47

Part IIUncompressed Solids Formulations 49

Acebutolol Hydrochloride Capsules 51Aceclofenac Instant Granules 51Acetaminophen and Diphenhydramine Hydrochloride Hot Therapy Sachet 52Acetaminophen Capsules 500 mg 52Acetaminophen, Doxylamine, and Caffeine Effervescent 53Acetaminophen Instant Granules 54Acetaminophen, Pseudoephedrine Hydrochloride, Chlorpheniramine Hot Therapy Sachet 55Acetaminophen, Pseudoephedrine Hydrochloride Hot Therapy Sachet 56Acetaminophen Swallow Capsules 56Acetazolamide Sustained-Release Capsules 57Acetylcysteine Sachets 57Acitretin Capsules 58Acrivastine and Pseudoephedrine Hydrochloride Capsules 59Acyclovir Capsules 59Adenosine Monophosphate Topical Powder 60Aluminum Acetate Powder 60Aluminum Hydroxide and Magnesium Carbonate Dry Syrup 60Aminosalicylic Acid Granules 61Amlodipine Besylate and Benazepril Hydrochloride Capsules 61Amlodipine Besylate Capsules 62Amoxicillin and Bromhexine Hydrochloride Capsules 62Amoxicillin and Clavulanic Acid Powder for Suspension, 125 mg and 31.25 mg per 5 ml 63Amoxicillin and Clavulanate Potassium for Suspension 64Amoxicillin Powder for Suspension 125 and 250 mg 65Amoxicillin Trihydrate Capsules 250 and 500 mg 65Ampicillin Powder for Suspension 66Ampicillin Trihydrate Capsules 66Ampicillin Trihydrate Capsules for Suspension 67Ampicillin Trihydrate Powder for Suspension 67Antibacterial and Bacterial Culture Capsules 68Antifungal Foot Powder 68Aspartame Granules in Sachet 69Aspartame Powder in Sachet 69Aspirin and Chlorpheniramine Powder 69Aspirin and Phenylpropanolamine Powder 70Aspirin Microencapsulated Sustained-Release Capsules 70Aspirin, Salicylamide, and Caffeine Powder 70Azithromycin Capsules 71Azithromycin Capsules and Oral Suspension 72Azithromycin for Oral Suspension "72

Azithromycin Sachet for Oral Suspension 73Balsalazide Disodium Capsules 74Benazepril Hydrochloride and Amlodipine Besylate Capsules 75Bisacodyl Colonic Delivery Capsules 76Brompheniramine and Pseudoephedrine Capsules 76Budesonide Capsules 77Budesonide Inhalation Powder 77Butalbital and Acetaminophen Capsules 77Calcitonin (Salmon) Capsules 78Calcitriol Capsules 79Calcium Carbonate Microencapsulated Sustained-Release Capsules 80Camptothecin Capsules 80Carbamazepine Extended-Release Capsules 81Cefaclor Capsules 82Cefdinir Capsules and Oral Suspension 82Cefixime for Oral Suspension 82Cefpodoxime Proxetil for Oral Suspension 82Cefprozil for Oral Suspension 83Ceftibuten Capsules and Oral Suspension 83Ceftibutin for Oral Suspension 83Cefuroxime for Oral Suspension 84Celecoxib Capsules 84Cellulose Triacetate Liquefiable Topical Powder 85Cephalexin Capsules 85Cephalexin Powder for Oral Suspension 86Cephradine Capsules 86Cephradine Powder for Suspension 87Cevimeline Capsules 87Chlordiazepoxide Hydrochloride Capsules 88Chloroxylenol and Chlorhexidine Topical Powder 88Chlorpromazine Sustained-Release Capsules 89Cimetidine Microencapsulated Sustained-Release Capsules 89Citrate Effervescent Powder 90Clindamycin Capsules 150 mg 90Clofibrate Capsules 91Clonidine Sustained-Release Capsules 91Clorazepate Dipotassium Capsules 92Cyclosporin A Capsules 92Dantrolene Sodium Capsules 93Dextroamphetamine Sulfate Capsules 93Diclofenac and Misoprostol Capsules 93Diclofenac Sustained-Release Capsules 94Didanosine Delayed-Release Capsules 95Didanosine Delayed-Release Capsules Enteric-Coated Beadlets 95Didanosine for Oral Suspension 95Diethyl Toluamide Topical Powder 96Difluoromethylornithine-Alpha Capsules 97Diltiazem Hydrochloride Extended-Release Capsules 99Diphenhydramine Hydrochloride Capsules 100Dipyridamole and Aspirin Extended-Release Capsules 100Divalproex Sodium Capsules 100Divalproex Sodium Coated Particle Capsules 100Dofetilide Capsules 100Doxepin Hydrochloride Capsules 101Doxycycline Capsules 101Doxycycline Hyclate Capsules 101

Doxycycline Hydrochloride Capsules and Oral Suspension 102Efavirenz Capsules 102Enalapril Maleate Capsules 102Erythromycin and Bromhexine Powder for Suspension 103Erythromycin and Sulfisoxazole Granules for Suspension 104Erythromycin Delayed-Release Capsules 105Erythromycin Ethylsuccinate for Oral Suspension 106Erythromycin Ethylsuccinate for Oral Suspension 200 mg/5 ml 107Erythromycin Stearate for Oral Suspension 108Erythropoietin Capsules 110Esomeprazole Magnesium Capsules I l lEstramustine Phosphate Capsules I l lEthosuximide Capsules 112Etodolac Capsules 112Eye Nutrition Supplement Capsules 112Felbamate for Oral Suspension 112Fenofibrate Capsules 113Fexofenadine Hydrochloride Capsules 114Fluconazole for Oral Suspension 114Flucytosine Capsules 114Fluoxetine Capsules 115Fluoxetine Hydrochloride Capsules 115Fluoxetine Hydrochloride Instant and Weekly Capsules 116Flutamide Capsules 116Fluticasone Propionate and Salmeterol Xinafolate Inhalation Powder 116Fluvastatin Sodium Capsules 117Formoterol Fumarate Inhalation Powder 117Formoterol Fumarate Inhaler Capsules 117Fosfomycin Tromethamine Sachets 118Gabapentin Capsules 118Ganciclovir Capsules 118Gemfibrozil Capsules 119Glycoprotein Ila/IIb Capsules 119Guaifenesin Sustained-Release Capsules 120Herbal AIDS Treatment Capsules 120Histadine Capsules 120Human Growth Hormone Capsules 121Hydrochlorothiazide and Triamterene Capsules 122Hydrochlorothiazide Capsules 122Hydroxyzine Pamoate Capsules and Oral Suspension 122Hyoscyamine Sulfate Capsules 122Ibuprofen Microencapsulated Sustained-Release Capsules 123Ibuprofen Sustained-Release Capsules 124Ifosfamide Capsules 125Imatinib Mesylate Capsules 125Indinavir Sulfate Capsules 126Indomethacin Capsules 127Indomethacin Microencapsulated Sustained-Release Capsules 129Indomethacin Sustained-Release Capsules 130Insulin Capsules '31Iron-Polysaccharide Complex Capsules 132Isometheptene Mucate, Dichloralphenazone, and Acetaminophen Capsules '32Isosorbide Mononitrate Capsules 20 mg 133Isradipine Capsules '33Itraconazole Capsules '34Ketoprofen and Misoprostol Capsules 134

Ketoprofen Capsules 135Lansoprazole Capsules 135Lansoprazole Delayed-Release Capsules 135Lincomycin Capsules 136Linezolid Oral Suspension 136Lipase, Amylase, and Protease Capsules 136Lithium Carbonate Capsules 136Lopinavir-Ritonavir Capsules 137Loracarbef Capsules and Oral Suspension 137Loxapine Capsules 137Loxapine Succinate Capsules 137Magaldrate Instant Powder or Dry Syrup 138Magnesium Oxide Capsules 138Mefenamic Acid Capsules 138Mesalamine Capsules 138Mesalamine Colonic Delivery Capsules 139Methsuximide Capsules 139Methylphenidate Capsules 140Methylphenidate Immediate- and Extended-Release Capsules 140Methyltestosterone Capsules 141Metoclopramide Hydrochloride Sustained-Release Capsules 141Metyrosine Capsules 142Miconazole Nitrate Foot and Itch Powder 142Mineral Powder for Topical Herpes Simplex 142Minocycline Hydrochloride Capsules 142Mixed Amphetamine Salt Capsules 143Mixed Amphetamine Salts Enteric-Release Capsules 143Morphine Sulfate Capsules 144Morphine Sulfate Controlled-Release Capsules 145Morphine Sulfate Sustained-Release Capsules 146Multivitamin Effervescent Granules 147Multivitamin Instant Granules 148Mycophenolate Mofetil Capsules and Oral Suspension 148Nanoparticle Polymer Particle Powders 149Nelfinavir Mesylate Oral Powder 150Nilvadipine Capsules 150Nitrofurantoin Capsules 150Nitrofurantoin Sustained-Release Capsules 151Nizatidine Capsules 151Nystatin Powder 151Omeprazole and Piroxicam Capsules 152Omeprazole Capsules 153Omeprazole Delayed-Release Capsules 153Oral Rehydration Salt 45 mEq 154Orlistat Capsules 155Oseltamivir Phosphate Capsules and Oral Suspension 156Oxcarbazepine Oral Suspension 156Oxycodone Hydrochloride and Acetaminophen Capsules 156Oxytetracycline Hydrochloride Capsules 157Oxytetracycline Hydrochloride, Sulfamethizole, and Phenazopyridine Hydrochloride Capsules 157Pancrealipase Capsules 157Pancrealipase Capsules Enteric-Coated Microspheres 158Penicillamine Capsules 158Pentosan Polysulfate Sodium Capsules 158Pentostatin Capsules 158Phenobarbital and Hyoscyamine Sulfate Capsules 158

Phenoxybenzamine Hydrochloride Capsules 159Phentermine Capsules 159Phentermine Hydrochloride Capsules 159Phenytoin Sodium Extended-Release Capsules 159Piroxicam and Beta-cyclodextrin Topical Powder 160Piroxicam Capsules 161Polyethylene Glycol 3350 Powder for Reconstitution 162Polythiazide Capsules 162Potassium Chloride Extended-Release Capsules 162Potassium Chloride for Oral Solution 162Potassium Chloride Microencapsulated Sustained-Release Capsules 163Potassium Chloride Powder 20 mEq 164Prazosin and Polythiazide Capsules 164Prednisolone Targeted-Release Capsules 165Procarbazine Hydrochloride Capsules 165Prochlorperazine Sustained-Release Capsules 165Propoxyphene Hydrochloride, Caffeine, and Aspirin Capsules 166Propoxyphene Hydrochloride Capsules 166Propranolol Hydrochloride and Hydrochlorothiazide Capsules 166Propranolol Hydrochloride Long-Acting Capsules 166Propranolol Hydrochloride Multiple Bead Capsules 167Propranolol Hydrochloride Sustained-Release Capsules 169Propranolol Timed- and Sustained-Release Capsules 170Pseudoephedrine and Guaifenesin Capsules 170Pseudoephedrine Hydrochloride Capsules 170Ranitidine Effervescent Granules 171Ribavirin Capsules 171Rifabutin Capsules 171Rifampicin Capsules 171Rifampin and Isoniazid Capsules 171Rivastigmine Tartrate Capsules 172Salmeterol Xinafolate Capsules 172Salmeterol Xinafolate Inhalation Powder 172Saquinavir Mesylate Capsules 172Selegiline Hydrochloride 173Sevelamer Hydrochloride Capsules 173Sibutramine Hydrochloride Capsules 173Stavudine Capsules '73Succimer Capsules 174Sucralafate Granules '74Tacrine Hydrochloride Capsules 174Tacrolimus Capsules '75Talc, Crospovidone, and Starch Topical Powder 175Tamsulosin Hydrochloride Capsules 176Temazepam Capsules '77Temozolomide Capsules '77Terazosin Hydrochloride Capsules 178Tetracycline Hydrochloride Capsules '78Thalidomide Capsules 17^Theophylline Sustained-Release Capsules 179Thiothixene Capsules '7 l )

Tibolone Capsules 1X()

Tiotropium Inhalation Powder l^(l

Tolmetin Sodium Capsules l x 'Tolterodine Capsules I X 'Topiramate Capsules ' x l

Tretinoin Capsules 182Triamterene and Hydrochlorothiazide Capsules 182Triamterene Capsules 182Triclosan and Zinc Undecylenate Powder 183Trientine Hydrochloride Capsules 183Trimethoprim and Sulfamethoxazole Oral Suspension 183Trimipramine Maleate Capsules 183Troleandomycin Capsules 184Typhoid Vaccine Live Oral Capsules 184Valsartan and Hydrochlorothiazide Capsules 184Valsartan Capsules 185Vancomycin Hydrochloride Capsules 185Verapamil Hydrochloride Capsules 186Verapamil Hydrochloride Sustained-Release Capsules 187Vincamine Capsules 188Vinpocetine Multiple Bead Capsules 189Vitamin B-Complex, Amino Acids, and Magnesium Effervescent Granules (Sugar-Free) 190Vitamin B-Complex and Vitamin C Instant Granules 191Vitamin C and Calcium Carbonate Effervescent Tablets 191Zanamivir Powder 192Zidovudine Capsules 192Zinc Oxide and Cornstarch Powder 192Ziprasidone Hydrochloride Capsules 193Zonisamide Capsules 194

Index 195