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دانلود کتاب Handbook of pharmaceutical manufacturing formulations Volume 1
دانلود کتاب دفترچه فرمولاسیون تولید دارویی جلد 1
مشخصات کتاب
Handbook of pharmaceutical manufacturing formulations Volume 1
ویرایش: [Third edition]
نویسندگان: Niazi. Sarfaraz
سری:
ISBN (شابک) : 9781138102804
ناشر: CRC Press
سال نشر: 2020
تعداد صفحات: [593]
زبان: English
فرمت فایل : PDF (درصورت درخواست کاربر به PDF، EPUB یا AZW3 تبدیل می شود)
حجم فایل: 8 Mb
قیمت کتاب (تومان) : 35,000
در صورت تبدیل فایل کتاب Handbook of pharmaceutical manufacturing formulations Volume 1 به فرمت های PDF، EPUB، AZW3، MOBI و یا DJVU می توانید به پشتیبان اطلاع دهید تا فایل مورد نظر را تبدیل نمایند.
توجه داشته باشید کتاب دفترچه فرمولاسیون تولید دارویی جلد 1 نسخه زبان اصلی می باشد و کتاب ترجمه شده به فارسی نمی باشد. وبسایت اینترنشنال لایبرری ارائه دهنده کتاب های زبان اصلی می باشد و هیچ گونه کتاب ترجمه شده یا نوشته شده به فارسی را ارائه نمی دهد.
توضیحاتی در مورد کتاب دفترچه فرمولاسیون تولید دارویی جلد 1
«راهنمای فرمول‌های تولید دارو، ویرایش سوم، راهنمای معتبر و کاربردی برای هنر و علم فرمول‌بندی داروها برای تولید تجاری است. این مجموعه شش جلدی، با محتوای کاملاً اصلاح‌شده و توسعه‌یافته، داده‌هایی را از برنامه‌های دارویی جدید FDA، ثبت اختراع گردآوری می‌کند. برنامه های کاربردی، و دیگر منابع فرمولاسیون های عمومی و اختصاصی برای پوشش طیف گسترده فرمول های GMP و مسائل مربوط به استفاده از این فرمول ها در یک محیط تجاری. مجموعه ای ضروری برای تولید کنندگان دارو، موسسات آموزشی و مقامات نظارتی، این یک پلت فرم عالی است. برای شرکت‌های دارویی برای محک زدن محصولات خود و برای شرکت‌های ژنریک برای فرمول‌بندی داروهایی که دارای حق ثبت اختراع هستند. -- جلد 5. محصولات بدون نسخه -- جلد 6. محصولات استریل.
توضیحاتی درمورد کتاب به خارجی
"The Handbook of Pharmaceutical Manufacturing Formulations, Third Edition is an authoritative and practical guide to the art and science of formulating drugs for commercial manufacturing. With thoroughly revised and expanded content, this six-volume set compiles data from FDA new drug applications, patent applications, and other sources of generic and proprietary formulations to cover the broad spectrum of GMP formulations and issues in using these formulations in a commercial setting. A must-have collection for pharmaceutical manufacturers, educational institutions, and regulatory authorities, this is an excellent platform for drug companies to benchmark their products and for generic companies to formulate drugs coming off patent"--;Volume 1. Compressed solid products -- volume 2. Uncompressed solid products -- volume 3. Liquid products -- volume 4. Semisolid products -- volume 5. Over-the-counter products -- volume 6. Sterile products.
فهرست مطالب
Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume One, Compressed Solid Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition Author Part I: Regulatory and Manufacturing Considerations 1: Bioequivalence Testing: Rationale and Principles I. BACKGROUND II. EVIDENCE TO MEASURE BIOEQUIVALENCE III. PIVOTAL PARAMETERS FOR BLOOD-LEVEL BIOEQUIVALENCE A. Area under the Curve Estimates IV. RATE OF ABSORPTION V. DETERMINATION OF PRODUCT BIOEQUIVALENCE VI. ERRORS IN BIOEQUIVALENCE STUDIES VII. ABSORPTION PROFILING VIII. PHARMACOKINETIC MEASURES OF SYSTEMIC EXPOSURE A. Early Exposure B. Peak Exposure C. Total Exposure IX. STATISTICAL ANALYSIS X. UNTRANSFORMED DATA XI. LOGARITHMICALLY TRANSFORMED DATA Bibliography Appendix: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs—General Considerations I. Introduction II. Background A. General B. Bioavailability C. Bioequivalence III. Methods to Document BA And BE A. Pharmacokinetic Studies B. Other Approaches to Support BA/BE IV. Documenting BA And BE For Various Dosage Forms A. Solutions and Other Solubilized Dosage Forms B. Immediate-Release Products C. Modified-Release Products D. Batch Size B. In Vitro Studies Conducted in Support of Demonstrating BA or BE VI. Special Topics A. Alcoholic Beverage Effects on MR Drug Products B. Enantiomers versus Racemates C. Drug Products With Complex Mixtures as the Active Ingredients D. Long-Half-Life Drugs E. Orally Administered Drugs Intended for Local Action F. Combination/Coadministered Drug Products G. Endogenous Substances H. Drug Products With High Intrasubject Variability Appendix A: General Study Design and Data Handling Study Conduct Sample Collection and Sampling Times Subjects with Pre-Dose Plasma Concentrations Data Deletion because of Vomiting Data Submission and Analysis Rounding Off of Confidence Interval Values 2: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System: Guidance for Industry* I. INTRODUCTION II. THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM A. Solubility B. Permeability C. Dissolution III. RECOMMENDED METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING THE DISSOLUTION CHARACTERISTICS OF A DRUG PRODUCT A. Determining Drug Substance Solubility Class B. Determining Drug Substance Permeability Class C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity7 IV. BIOWAIVERS BASED ON BCS V. ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER A. Excipients B. Prodrugs C. Fixed Dose Combinations Containing BCS Class 1, or Class 3, or a Combination of Class 1 and 3 Drugs D. Exceptions VI. REGULATORY APPLICATIONS OF THE BCS–BASED BIOWAIVERS A. INDs/NDAs B. ANDAs C. Supplemental NDAs/ANDAs (Postapproval Changes) VII. DATA TO SUPPORT A BIOWAIVER REQUEST A. Data Supporting High Solubility B. Data Supporting High Permeability C. Data Supporting Rapid, Very Rapid, and Similar Dissolution D. Additional Information ATTACHMENT A 3: Product-Specific Guidance from FDA on the Development of Compressed Dosage Forms 4: Guidance on Formulating Compressed Solids Background Tablet Types Formulation Factors I. ACTIVE PHARMACEUTICAL INGREDIENT II. BIO VERSUS PRODUCTION BATCHES III. CLEANING VALIDATION IV. COATINGS V. COMPLIANCE WITH REGULATORY REQUIREMENTS VI. COMPRESSION PROCESS CONTROL VII. CONTENT UNIFORMITY VIII. CROSS-CONTAMINATION IX. DESEGREGATION OF POWDERS X. DISINTEGRATION TEST A. Uncoated Tablets B. Plain Coated Tablets C. Delayed-Release (Enteric-Coated) Tablets D. Buccal Tablets E. Sublingual Tablets XI. DISSOLUTION XII. DISINTEGRATION AND DISSOLUTION XIII. DRUG SUBSTANCE CHARACTERIZATION XIV. DRYING PROCESS XV. DYES IN FORMULATIONS XVI. EQUIPMENT A. Blenders 1. Pony Pan 2. Ribbon 3. Tumbler 4. High Shear (High Energy) 5. Plastic Bag B. Dryers C. Tablet Compression Equipment D. Coating Equipment XVII. EXCIPIENTS A. Coating Agent B. Glidant C. Tablet Binder D. Diluent E. Disintegrant F. Lubricant XVIII. DIRECT COMPRESSION XIX. FILL WEIGHTS XX. FINAL PACKAGING XXI. FINAL TESTING XXII. FINES XXIII. FORMULA EXCESSES XXIV. GEOMETRIC DILUTION XXV. GRANULATION/MIX ANALYSIS XXVI. INGREDIENT WARNING XXVII. IN-PROCESS TESTING XXVIII. LOSS ON DRYING XXIX. MANUFACTURING YIELDS XXX. MASTER FORMULA XXXI. MULTIPLE-ITEM ENTRIES XXXII. MULTIPLE STRENGTHS OF FORMULATIONS XXXIII. NOVEL DRUG DELIVERY SYSTEMS XXXIV. PARTICLE COATING XXXV. IN COMPRESSED SOLID DOSAGE FORMULATIONS XXXVI. PUNCH SIZE AND SHAPE XXXVII. REWORKING CULLS XXXVIII. SCALE-UP XXXIX. SEGREGATION XL. SIFTING INGREDIENTS AND GRANULES XLI. SPECIFICATIONS XLII. STABILITY TESTING XLIII. STORAGE OF IN-PROCESS MATERIAL XLIV. TABLET FRIABILITY XLV. TABLET MANUFACTURING XLVI. TABLETS XLVII. WATER-PURIFIED USP XLVIII. WEIGHT VARIATION AND CONTENT UNIFORMITY XLIX. WET GRANULATION VERSUS DRY GRANULATION OR DIRECT COMPRESSION L. MULTIVARIATE METHODS IN TABLET FORMULATION LI. PHYSICAL PROPERTIES LII. PARTICLE SIZE STUDIES A. Particle Size Distribution LIII. SURFACE AREA LIV. POROSITY LV. TRUE DENSITY LVI. FLOW AND COMPACTION OF POWDERS LVII. COLOR LVIII. ELECTROSTATICITY LIX. CAKING LX. POLYMORPHISM LXI. STABILITY STUDIES TO SELECT OPTIMAL DRUG AND EXCIPIENT COMBINATIONS Appendix A GMP Audit Template GLOSSARY Appendix B Formulation Excipients Introduction Diluents Binders Lubricants Glidants and Antiadherents Disintegrants Superdisintegrants Added Functionality Excipients Colorants LIST OF EXCIPIENTS USED IN FDA APPROVED PRODUCTS Appendix C Dissolution Testing Requirements of Compressed Dosage Forms Part II: Manufacturing Formulations Compressed Solids Formulations Acetaminophen and Caffeine Tablets Acetaminophen and Caffeine Tablets Acetaminophen and Codeine Tablets (Tylenol)* Acetaminophen and Diphenhydramine Hydrochloride Tablets Acetaminophen and Orphenadrine Citrate Tablets (450 mg/35 mg) Acetaminophen and Phenprobamate Tablets (200 mg/200 mg) Acetaminophen and Pseudoephedrine Hydrochloride Tablets Acetaminophen Chewable Tablets Acetaminophen, Chlorpheniramine Maleate, and Pseudoephedrine Caplets Acetaminophen, Dextromethorphan, and Pseudoephedrine Caplets Acetaminophen, Dextropropoxyphen Hydrochloride Tablets (325 mg/32 mg) Acetaminophen Effervescent Tablets Acetaminophen Fast-Dissolving Tablet Acetaminophen, Ibuprofen, and Orphenadrine Tablets (250 mg/200 mg/200 mg) Acetaminophen, Ibuprofen, and Orphenadine Hydrochloride Tablets Acetaminophen Microsphere Tablet Acetaminophen, Norephedrine, and Phenyltoloxamine Tablets Acetaminophen, Norephedrine, and Phenyltoloxamine Tablets (300 mg/25 mg/22 mg) Acetaminophen, Phenylpropanolamine, Dextromethorphan, and Chlorpheniramine Tablets Acetaminophen, Propoxyphenazone, and Caffeine Tablets Acetaminophen, Salicylamide, Caffeine, and Codeine Tablets (150 mg/200 mg/50 mg/10 mg) Acetaminophen Sustained-Release Tablets Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets, Chewable Acetaminophen Tablets for Children Acetaminophen–Tramadol Hydrochloride Tablets Acetaminophen–Tramadol Hydrochloride Tablets Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets (Direct Compression) Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablet (250 mg/250 mg/50 mg) Acetylsalicylic Acid and Acetaminophen Tablets Acetylsalicylic Acid and Acetaminophen Tablets Acetylsalicylic Acid and Ascorbic Acid Tablets Acetylsalicylic Acid and Ascorbic Acid Tablets Acetylsalicylic Acid + Paracetamol (=Acetaminophen) Tablets (250 mg + 250 mg) Acetylsalicylic Acid Tablets (500 mg) Acetylsalicylic Acid Tablets (Direct Compression) Acetylsalicylic Acid Tablets (Direct Compression) Acetylsalicylic Acid Tablets (Direct Compression) Acetylsalicylic Acid Tablets, Buffered Acetylsalicylic Acid + Vitamin C Tablets (400 mg + 250 mg) Acyclovir Fast Melt Acyclovir Tablets (Zovirax) Acyclovir Tablets Acyclovir Water-Dispersible Tablets (800 mg) Albendazole Tablets (200 mg) Albendazole Tablets (100 mg) Alendronate Tablets (Fosamax) Alendronate Tablets, Effervescent (10 mg) Alendronate Sodium Tablets Alendronate Sodium Tablets Alendronate Sodium Tablets Manufacturing Directions Alendronate Sodium Tablets (50 mg) Allopurinol Tablets, 100 mg (Zyloric) Allopurinol Tablets (100 mg) Allopurinol Tablets (300 mg) Alprazolam Tablets (0.25 mg/0.50 mg/1.0 mg), Xanax Alprazolam Tablets (0.25 mg) Aluminum Acetylsalicylate Tablets Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets Aluminum Hydroxide and Magnesium Hydroxide Tablets Aluminum Hydroxide, Magnesium Carbonate (or Oxide), and Simethicone Tablets Aluminum Hydroxide and Magnesium Silicate Chewable Tablets Ambroxol HCl Sustained-Release Pellets Releasing Tablets Aminophylline Tablets (100 mg) 4-Amino-1-Hydroxybutylidene-1,1-Bisphosphonic Acid Tablets (5 mg) Aminosalicylic Acid Tablets Amiodarone Tablets (200 mg) Amitriptyline Tablets (50 mg), Elavil® Amitriptyline Tablets Amlodipine Besylate Tablets Amlodipine Besylate Tablets Amlodipine Free Base Tablets Amlodipine Maleate Tablets Amoxicillin and Clavulanate Potassium Tablets Amoxicillin Fast-Disintegrating Tablets Amoxicillin and Potassium Clavulanate Tablets (250 mg/62.5 mg) Amoxicillin Tablets (250 mg/500 mg/1 g), Acid Trihydrate Amoxicillin Tablets Amoxicillin Trihydrate and Clavulanate Potassium Tablets (500 mg/125 mg) Augmentin Amphetamine Salts Tablets Ampicillin Tablets (250 mg) Apomorphine and Nicotine Tablets Apomorphine and Prochlorperazine Tablets Asparagus Extract + Parsley Extract Tablets (200 mg + 200 mg) Aspartame Effervescent Tablets (20 mg) Aspartame Tablets (25 mg), DC Aspartame Tablets Aspartame Tablets Aspartame Tablets Aspartame Tablets, Effervescent Aspirin, Acetaminophen, and Caffeine Tablets Aspirin, Acetaminophen, Caffeine, and Salicylamide Tablets Aspirin Tablets Atenolol Tablets Atenolol Tablets (50 mg/100 mg), Tenormin Atenolol Tablets Atenolol Tablets (90 mg) Atorvastatin Tablets (10 mg/20 mg), Atorvastatin Calcium Lipitor Atorvastatin Calcium Tablets Attapulgite Tablets Azithromycin Chewable Tablets Azithromycin Dihydrate Tablets (600 mg) Azithromycin Tablets (250 mg), Zithromax Azithromycin Tablets Benazepril Hydrochloride Tablets Lotensin Benazepril Hydrochloride Tablets Benzafibrate Tablets (200 mg) Berberine Tablets (5 mg) Berberine Tablets Betamethasone Tablets (0.50 mg) Beta-Carotene Effervescent Tablets (7 mg) Beta-Carotene Effervescent Tablets Beta-Carotene Tablets Beta-Carotene Tablets Beta-Carotene Tablets Beta-Carotene, Vitamin C, and Vitamin E Chewable Tablets Beta-Carotene + Vitamin C + Vitamin E Chewable Tablets (10 mg + 500 mg + 250 mg) Beta-Carotene + Vitamin C + Vitamin E Effervescent Tablets (12 mg + 150 mg + 25 mg) Beta-Carotene + Vitamin C + Vitamin E Tablets (12 mg + 250 mg + 125 mg) Beta Carotene + Vitamin C + Vitamin E Tablets (7 mg + 60 mg + 25 mg) Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets BIRB 796 Tablets (100 mg) Bisacodyl Delayed-Release Tablets Bismuth Subsalicylate and Calcium Carbonate Tablets Bismuth Subsalicylate Swallow Tablets Bisoprolol Fumarate and Hydrochlorothiazide Tablets Bran Sucrose Gelatin Calcium Carbonate Tablets Bran Tablets Bromhexine Hydrochloride Tablets Bromazepam Tablets (3 mg) Bromhexine Tablets (8 mg) Bromocriptine Tablets Buflomedil Hydrochloride Tablets (150 mg/300 mg) Buflomedil Hydrochloride Tablets (600 mg) Bupropion Hydrochloride Tablets Bupropion Hydrochloride Tablets, Wellbutrin Bupropion Hydrochloride Tablets Bupropion Tablets Buspirone Fast-Melt Tablets Buspirone Hydrochloride Tablets, Buspar Buspirone Hydrochloride Tablets Buspirone Hydrochloride Tablets, Controlled-Release (30 mg) Carbenoxolone Tablets Caffeine Tablets Calcium and Vitamin D Tablets Calcium Carbonate and Glycine Tablets Calcium Carbonate and Vitamin D Tablets Calcium Carbonate Chewable Tablets Calcium Carbonate Tablets Calcium Chewable Tablets (200 mg Ca) Calcium d-Pantothenate Chewable Tablets Calcium d-Pantothenate Tablets Calcium d-Pantothenate Tablets Calcium Effervescent Tablets Calcium Gluconate Tablets Calcium Glycerophosphate Tablets Calcium Glycerophosphate Tablets Calcium Glycerophosphate Tablets (200 mg) Calcium Phosphate Tablets for Cats and Dogs Calcium Phosphate Tablets for Cats and Dogs (Direct Compression) Captopril Tablets (25 mg), Capoten Captopril Tablets Carbamazepine Tablets (200 mg) Carbamazepine Tablets (200 mg) Carbetapentane Tannate and Chlorpheniramine Tannate Tablets Carbidopa and Levodopa Tablets Sinemet Carbidopa and Levodopa Tablets Carbinoxamine Maleate, Phenylpropanolamine, and Acetaminophen Sustained-Release Tablets Carbonyl Iron, Copper Sulfate, and Manganese Sulfate Tablets Carisoprodol Tablets Soma Carvedilol Tablets Coreg Carvedilol Tablets Cefadroxil Dispersible Tablets (250 mg) Cefdinir Tablets (300 mg) Cefixime and Amoxicillin Tablets Cefixime Tablets (400 mg) Cefpodoxime Tablets Cefprozil Tablets (250 mg) Cefzil® Cefprozil Tablets Cephalexin Tablets Keflex Cetirizine and Pseudoephedrine Delayed-Release Tablets (5 mg/120 mg) Cetirizine Chewable Tablets (10 mg) Cetirizine Hydrochloride Tablets (10 mg) Zyrtec Cetirizine Hydrochloride Tablets Cetirizine Hydrochloride Tablets (5 mg) Cetirizine Tablets (5 mg) Cetirizine Hydrochloride Tablets Cetylpyridinium Lozenges (2.5 mg) Charcoal Tablets Chlorcyclizine Hydrochloride Tablets (50 mg) Chlordiazepoxide and Clinidium Bromide Tablets (5 mg/2.5 mg) Chlordiazepoxide Tablets (10 mg) Chlorhexidine Lozenges Chloroquine Tablets (250 mg) Chlorpheniramine and Pseudoephedrine Chewable Tablets Chlorpheniramine, Pseudoephedrine, and Dextromethorphan Chewable Tablets Chlorpheniramine Tablets Choline Theophyllinate Tablets (100 mg) Chymotrypsin Tablets (25 mg) Cilazapril Tablets (2.5 mg) Cimetidine Chewable Tablets Cimetidine Tablets (200 mg) Cimetidine Tablets (200 mg) Ciprofloxacin Tablets (500 mg) Cipro Ciprofloxacin Tablets Ciprofloxacin Tablets (750 mg) Cisapride Tablets Cisapride Tablets (5 mg) Cisapride Tartrate Mini Tablets Citalopram Hydrobromide Tablets Celexa Clarithromycin Tablets (250 mg/500 mg) Biaxin Clarithromycin Dispersible Tablets Clarithromycin Tablets Clarithromycin Controlled-Release Tablets Clenbuterol Tablets (20 μg) Clindamycin Tablets Clobazam Tablets (10 mg) Clomifen Citrate Tablets (50 mg) Clomipramine Hydrochloride Tablets, Buccal (10 mg) Clomipramine Hydrochloride Tablets, Effervescent (300 mg) Clonazepam Tablets (1 mg/2 mg) Clonidine Tablets (0.1 mg/0.2 mg/0.3 mg) Plavix Codeine, Acetaminophen, and Pentobarbital Tablets (15 mg/300 mg/30 mg) Conjugated Estrogens and Medroxyprogesterone Tablets, Prempro Conjugated Estrogens (0.3–2.50 mg) Premarin Coumadin Tablets Crospovidone Effervescent Tablets Cyclobenzaprine Hydrochloride Tablets (10 mg) Cyclobenzaprine Tablets Cyproheptadine Tablets (4 mg) Dapsone Tablets (50 mg) Delavirdine Mesylate Tablets Desloratadine Tablets (5 mg), Clarinex® Desogestrel and Ethinyl Estradiol Tablets (0.15 mg/0.03 mg), Ortho-Cept Diazepam Tablet (10 mg) Diazepam Tablets (2 mg/5 mg/10 mg) Diclofenac Sodium Tablets Diclofenac Sodium Tablets (50 mg) Diclofenac Sodium Tablets (100 mg) Diclofenac Sodium Dispersible Tablets (50 mg) Diclofenac Sodium Tablets (25 mg) Voltaren, Cataflam® Diclofenac Sustained-Release Tablets (100 mg) Diclofenac Tablets (50 mg) Didanosine Tablets (50 mg) Diethylcarbamazine Tablets (100 mg) Difenoxin and Atropine Tablets (0.5 mg/0.025 mg) Digoxin Tablets (0.125 mg/0.25 mg), Lanoxin Digoxin Tablets Dihydroxyaluminum Sodium Carbonate Tablets Diltiazem Hydrochloride Tablets (60 mg) Diltiazem Tablets 60 mg Cardizem Diltiazem Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets (50 mg), DC Diphenhydramine and Pseudoephedrine Chewable Tablets Diphenhydramine Hydrochloride Tablets Diphenoxylate Hydrochloride and Atropine Sulfate Tablets (2.5 mg/0.025 mg) Divalproate Sodium Tablets (125 mg), Depakote Divalproate Sodium Tablets Divalproex Sodium Tablets (400 mg) Doxazosin Mesylate Tablets (1 mg/2 mg/4 mg/8 mg) Doxycycline Hydrochloride Tablets (100 mg) Doxycycline Hydrochloride Tablets Doxycycline Monohydrate Tablets Efavirenz Tablets Eletriptan-Coated Fast-Crumbling Granule Tablets Enalapril Maleate Tablets (2.5 mg/5 mg/10 mg/20 mg) Vasotec Enalapril Maleate Tablets Enalapril Maleate Tablets (10 mg) Enoxacin Tablets (400 mg) Entacapone Tablets Eplerenone Tablets Ergotamine Tartrate Fast-Melt Tablets Erythromycin and Sulfamethoxazole Tablets Erythromycin Ethylsuccinate Tablets (400 mg) Erythromycin Particle-Coated Tablets (150 mg) Erythromycin Tablets (100 mg) Erythromycin Tablets (100 mg) Erythromycin Tablets (500 mg) Estazolam Tablets (1 mg) Estazolam Tablets (2 mg) Estradiol Tablets (0.5 mg/1 mg/2 mg), Estrace Estradiol Vaginal Tablets (25.8 μg) Estropipate Tablets (0.626 mg/1.25 mg/2.25 mg/5 mg) Ethambutol Tablets (400 mg) Ethambutol Tablets (400 mg) Ethambutol Tablets (800 mg) Etophylline and Theophylline Tablets (100 mg/22 mg) Etophylline and Theophylline Tablets (100 mg/22 mg) Ezetimibe and Simvastatin Tablets (10 mg/40 mg) Ezetimibe and Simvastatin Tablets (10 mg/80 mg) Ezetimibe Tablets (10 mg) Famciclovir Tablets (125 mg/250 mg) Famotidine Tablets (20 mg), Pepcid Famotidine Tablets Famotidine Tablets (40 mg) Fenoprofen Calcium Tablets Ferrous Fumarate Tablets Ferrous Sulfate, Manganese Sulfate, and Copper Sulfate Tablets Ferrous Sulfate Tablets Fexofenadine and Pseudoephedrine Tablets (10 mg/240 mg), Allegra Fexofenadine and Pseudoephedrine Sulfate Tablets Fexofenadine Tablets (30 mg/60 mg/180 mg) Allegra Finasteride Tablets (5 mg) Fluconazole Tablets (50 mg/100 mg/200 mg), Diflucan Fluoxetine Tablets (20 mg) Fluoxetine Hydrochloride Tablets (10 mg/20 mg/40 mg), Prozac® Fluoxetine Hydrochloride Tablets Fluoxetine Hydrochloride Tablets (12.5 mg/25.0 mg), Controlled-Release Bilayer Fluoxetine Hydrochloride Fast-Melt Tablets Fluvoxamine Maleate Tablets (50 mg) Folic Acid Tablets Folic Acid Tablets Fosinopril Tablets (20 mg), Monopril Fosinopril Tablets Fucidin Tablets (125 mg) Furazolidone Tablets (100 mg) Furosemide Tablets (40 mg), Lasix Furosemide Tablets Furosemide Tablets (40 mg) Furosemide Tablets (200 mg) Gabapentin Tablets (600 mg) Galanthamine Hydrobromide Tablets (1 mg) Garlic Extract + Thyme Extract Tablet Cores with Vitamin C (300 mg + 25 mg + 100 mg) Garlic Tablets Gemfibrozil Tablets (600 mg) Gemfibrozil Tablets Ginkgo Extract Tablets (40 mg) Glibenclamide Tablets (2.5 mg) Glibenclamide Tablets (5 mg) Gliclazide Tablets (80 mg) Glimepiride Tablets (1 mg/2 mg), Amaryl® Glimepiride Tablets Glipizide Tablets (5 mg), Glucotrol Glipizide Tablets Glipizide Tablets CR (5 mg) Glyburide and Metformin Tablets (250 mg/500 mg; 1.25 mg/2.50 mg), Glucovance Glyburide Tablets (5 mg), Micronase Griseofulvin Tablets (125 mg) Griseofulvin Tablets (500 mg) Guaifenesin Tablets Guaifenesin Tablets Heparin Tabletsa Herbal Hemorrhoid Tablets Horsetail Extract Tablets Hydrochlorothiazide and Potassium Chloride (50 mg/300 mg) Hydrochlorothiazide Fast-Melt Tablets Hydrochlorothiazide Tablets (50 mg) Hydrochlorothiazide Tablets Hydrochlorothiazide Tablets (50 mg) Hydrochlorothiazide Tablets Hydrocodone and Acetaminophen Tablets (5.0 mg/500 mg; 7.50 mg/750 mg) Hydrocodone and Acetaminophen Tablets Hydrocodone and Ibuprofen Tablets Hydromorphone Hydrochloride Fast-Melt Tablets Hydroxyzine Tablets Hyoscine Butylbromide Tablets (10 mg) Ibuprofen and Domperidone Maleate Chewable Tablets Ibuprofen and Domperidone Maleate Tablets Ibuprofen and Domperidone Sustained-Release Tablets Ibuprofen and Hydrocodone Bitartrate Tablets Ibuprofen Chewable Tablets Ibuprofen-Coated Fast-Crumbling Granule Tablets Ibuprofen Fast-Dissolve Tablets Ibuprofen Sustained-Release Bilayer Tablet Ibuprofen Tablets Ibuprofen Tablets Ibuprofen Tablets (400 mg), Motrin Ibuprofen Tablets (400 mg) Ibuprofen Tablets (400 mg) Ibuprofen Tablets (600 mg) Ibuprofen Tablets (600 mg) Imipramine Tablets (25 mg) Indomethacin Sustained-Release Tablets (75 mg) Indomethacin Tablets (50 mg), DC Indomethacin Tablets (100 mg) Inosine Tablets Irbesartan Tablets (75 mg/150 mg/300 mg), Avapro Irbesartan Tablets Iron (Polymer-Coated Particle) Tablets Isoniazid Tablets (100 mg) Isosorbide Dinitrate Tablets (5 mg) Ismo and Indur Isosorbide Dinitrate Tablets Isosorbide Dinitrate Tablets (5 mg) Isosorbide Dinitrate Tablets (10 mg) Isovaleramide Sustained-Release Tablets Kaolin-Pectin Tablets Ketotifen Tablets (1 mg) Khellin Tablets Labetalol Tablets (50 mg) Lamotrigine Tablets (100 mg) Lansoprazole Tablets (10 mg or 20 mg) Lansoprazole Tablets (10 mg or 20 mg) Lansoprazole Tablets Chewable (10 mg/20 mg) Lansoprazole Tablets, Rapid Dissolution (20 mg) Levamisole Hydrochloride Tablets (40 mg) Levamisole Tablets (150 mg) Levofloxacin Tablets (250 mg) Levaquin Levothyroxine Sodium Tablets Levothyroxine Tablets (50 μg) Synthroid Levothyroxine Tablets (0.025 mg) Levothyroxine Sodium Fast-Melt Tablets Linezolid Tablets (400 mg) Lisinopril and Hydrochlorothiazide Tablets (10/12.50) Lisinopril and Hydrochlorothiazide Tablets (20/12.5) Lisinopril and Hydrochlorothiazide Tablets (20/25) Lisinopril Tablets (10 mg), Zestril Lisinopril Tablets Lisinopril Tablets (2.5 mg) Lisinopril Tablets (5 mg) Lisinopril Tablets (10 mg) Lisinopril Tablets (15 mg) Lisinopril Tablets (20 mg) Lisinopril Tablets (40 mg) Lithium Carbonate Tablets Lomefloxacin Hydrochloride Tablets (400 mg) Loperamide Hydrochloride Fast-Melt Tablets Loperamide Hydrochloride Tablets (2 mg) Loratadine and Pseudoephedrine Sulfate Tablets Loratadine Tablets Loratadine Tablets Loratadine and Chlorpheniramine Sustained-Release Tablet Loratadine and Pseudoephedrine Sulfate Tablets (10 mg/240 mg) Claritin-D® Loratadine and Pseudoephedrine Sulfate Tablets Loratadine Fastab Loratadine Tablets (10 mg), Claritin® Loratadine Tablets Lorazepam Tablets (0.50 mg/1 mg/2 mg), Ativan Lorazepam Tablets Losartan and Hydrochlorothiazide Tablets (50 mg/12.5 mg) Losartan Potassium Tablets (50 mg), Cozaar Losartan Potassium Tablets Lycopene Tablet Cores (6 mg) Magaldrate Chewable Tablets Magaldrate Chewable Tablets (500 mg) Magaldrate Chewable Tablets (1000 mg) Magaldrate-Dispersible Tablets Magaldrate Tablets Magaldrate with Simethicone Tablets Magnesium Carbonate Tablets Mebendazole Tablets (100 mg) Meclizine Hydrochloride Tablets (25 mg) Medroxyprogesterone Acetate Tablets (2.5 mg/5 mg/10 mg), Provera Mefenamic Acid and Dicyclomine Hydrochloride Tablets (250 mg/10 mg) Mefenamic Acid Tablets (250 mg) Mefloquine Hydrochloride Tablets (250 mg) Meprobamate and Phenobarbital Tablets (400 mg/30 mg) Meprobamate and Phenobarbital Tablets (400 mg/30 mg) Meprobamate Tablets (400 mg) Meprobamate Tablets (400 mg) Metamizol Tablets (500 mg) Metamizol Tablets (500 mg) Metformin Hydrochloride Biphasic Tablets Metformin Hydrochloride Tablets Metformin Hydrochloride Tablets, Extended Release (500 mg) Metformin Tablets (500 mg) Metformin Tablets Metformin Tablets Metformin Tablets Metformin Tablets, Extended Release (500 mg) Methenamine Tablets (500 mg) Methyclothiazide and Deserpidine Tablets (5 mg/0.25 mg) Methyclothiazide Tablets (5 mg) Methyl Cysteine Tablets (100 mg) Methylergotamine Malate Tablets (0.5 mg) Methylphenidate Hydrochloride Tablets Extended Release (18 mg/36 mg), Concerta Methylprednisolone Tablets (2 mg/4 mg/8 mg/16 mg/24 mg/32 mg), Medrol Metoclopramide Tablets (10 mg), Reglan Metoclopramide Tablets Metoclopramide Hydrochloride Tablets Metoclopramide Tablets (20 mg) Metoprolol Succinate Tablets (95 mg), Toprol Metoprolol Succinate Tablets Metoprolol Tartrate Tablets Metronidazole Tablet Cores (400 mg) Metronidazole Tablets (200 mg) Metronidazole Effervescent Vaginal Tablets (500 mg) Metronidazole, Furazolidone, and Loperamide Tablets (200 mg/25 mg/2 mg) Metronidazole Tablets (200 mg) Metronidazole Tablets (200 mg/400 mg) Metronidazole Tablets (400 mg) Metronidazole Tablets (500 mg) Midodrine Hydrochloride Controlled-Release Tablets Midodrine Hydrochloride Tablets Midodrine Hydrochloride Triple-Layer Tablets Montelukast Sodium Tablets, Singulair Morphine Sulfate and Granisetron Hydrochloride Sustained-Release Tablets Morphine Sulfate Effervescent Tablets Multivitamin and Beta-Carotene Tablets Multivitamin and Carbonyl Iron Tablets Multivitamin and Fluoride Chewable Tablets Multivitamin and Mineral Tablets Multivitamin and Mineral Tablets with Beta-Carotene Multivitamin + Calcium + Iron Tablets (1 RDA of Vitamins) Multivitamin, Calcium, and Iron Tablets Multivitamin + Carbonyl Iron Tablets (1–2 RDA of Vitamins) Multivitamin Chewable Tablets for Children Multivitamin Chewable Tablets for Children Multivitamin Effervescent Tablets Multivitamin Effervescent Tablets Multivitamin Effervescent Tablets I, DC (1–2 RDA of Vitamins) Multivitamin Effervescent Tablets with Beta-Carotene Multivitamin Effervescent Tablets, DC (3–4 RDA of Vitamins) Multivitamin + Minerals Tablets with Beta-Carotene (1 RDA of Vitamins) Multivitamin Tablet Cores with Beta-Carotene (1–2 RDA of Vitamins) Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets for Dogs Multivitamin Tablets for Dogs Multivitamin Tablets with Beta-Carotene Multivitamin Tablets with Copper and Zinc Multivitamin Tablets, DC (1–2 RDA of Vitamins) Multivitamin with Beta-Carotene Tablets Multivitamin with Zinc Tablets Nalidixic Acid Tablets (500 mg) Nalidixic Acid Tablets (500 mg) Naproxen Tablets (250 mg) Naproxen Tablets Naproxen Tablets (250 mg/500 mg) Naproxen Tablets (450 mg) Nelfinavir Mesylate Tablets Neomycin Tablets (250 mg) Niacin Tablets Nicardipine Hydrochloride Sustained-Release Tablets Nicotinamide Tablets Nicotinic Acid (Niacin) Tablets Nicotinic Acid (=Niacin) Tablets (200 mg) Nicotinic Acid Tablets Nifedipine Coprecipitate Tablet Nifedipine Tablets (5 mg) Nifedipine Tablets (10 mg) Nimesulide Dispersible Tablets (100 mg) Nitrendipine Tablets (25 mg) Nitrofurantoin Tablets Nitrofurantoin Tablets (100 mg) Nitrofurantoin Tablets (100 mg) Nitroglycerin and Isosorbide Mononitrate Sustained-Release Tablets Nitroglycerin Retard Tablets Nitroglycerin Tablets (0.3 mg) Noramidopyrine Methanesulfonate and Dicyclomine Hydrochloride Tablets (500 mg/10 mg) Norephedrine and Terfenidine Tablets Norethindrone and Ethinyl Estradiol Tablets (0.75 mg/0.035 mg; 0.50 mg/0.035 mg; 1.0 mg/0.035 mg) Norfloxacin Tablets (400 mg) Norfloxacin Tablets Norgestimate and Ethinyl Estradiol Tablets (0.18 mg/0.035 mg; 0.215 mg/0.035; 0.25 mg/0.035 mg) Nystatin Tablets (50 mg) Nystatin Tablets (200 mg) Olanzapine Orally Disintegrating Tablets (5 mg) Olanzapine Tablets Olanzapine Tablets Olanzapine Tablets Zyprexa® Omeprazole and Ibuprofen Tablets (10 mg/400 mg) Omeprazole Effervescent Tablets Omeprazole Fast-Disintegrating Tablets Omeprazole Fast-Dissolving Tablets Omeprazole Tablets Omeprazole Tablets (10 mg/20 mg) Omeprazole Tablets (10 mg/20 mg) Omeprazole Tablets, Chewable (10 mg/20 mg) Omega Fatty Acids Tablets Omeprazole Tablets, Rapid Dissolution (20 mg) Orlistat Chewable Tablets Orlistat Chewable Tablets Orlistat Chewable Tablets Oxprenolol Retard Tablets Oxprenolol Retard Tablets Oxprenolol Retard Tablets Oxybutynin Chloride Tablets (5 mg/10 mg) Ditropan Oxybutynin Hydrochloride Tablets Oxybutynin Hydrochloride Tablets Oxycodone Hydrochloride and Acetaminophen Tablets (5 mg/325 mg), Percocet Oxycodone and Acetaminophen Tablets Oxycodone Hydrochloride Tablets (5 mg) Oxytetracycline Tablets (250 mg) Pancreatin and Cholic Acid Tablets Pancreatin Tablets Pancreatin Tablets Pantoprazole Tablets, Protonix Pantoprazole Tablets Pantoprazole Tablets (10 mg/20 mg) Pantoprazole Tablets, Chewable (10 mg/20 mg) Pantoprazole Tablets, Rapid Dissolution (20 mg) Papain Chewable Tablets Papaverine Hydrochloride Retard Tablets Para Amino Salicylic Acid Tablets (500 mg) Paroxetine Hydrochloride Tablets Paroxetine Hydrochloride Tablets (10 mg/20 mg/30 mg/40 mg), Paxil® Paroxetine Hydrochloride Hemihydrate Tablets Paroxetine Hydrochloride Hemihydrate Tablets Penicillin Chewable Tablets (125 mg) Penicillin Chewable Tablets Peptide Sublingual Tablets Perfloxacin Tablets (400 mg) Phendimetrazine Tablets (35 mg) Phenindione Tablets (50 mg) Phenoxymethyl Penicillin Potassium Tablets (250 mg) Phenolphthalein Tablets Phenolphthalein Tablets Phenylpropanolamine and Brompheniramine Fast-Dissolving Tablet Phenylpropanolamine Hydrochloride Tablets Phenylbutazone Tablets (100 mg) Phenylpropanolamine Hydrochloride Tablets (60 mg) Phenytoin Sodium Tablets (100 mg) Phenytoin Sodium Tablets (100 mg) Phenytoin Tablets (100 mg) Pioglitazone Hydrochloride Tablets (15 mg/30 mg/45 mg), Actos Pipemidic Acid Tablets (200 mg) Pipobroman Tablets (25 mg) Piroxicam Tablets Piroxicam Water-Dispersible Tablets (20 mg) Placebo Tablets Placebo Tablets Potassium Bicarbonate-Coated Tablet Potassium Chloride Retard Tablet Potassium Chloride Tablets (30 mg), Klor Potassium Chloride Tablets Povidone-Iodine Effervescent Vaginal Tablets Povidone-Iodine Lozenges Pravastatin Sodium Tablets (10–40 mg), Pravachol Pravastatin Tablets Prazosin Tablets (5 mg) Prednisolone Tablets (5 mg) Prednisolone Tablets (10 mg) Prednisolone Tablets (20 mg) Prednisolone Tablets (20 mg) Prednisone Tablets (10 mg) Pregabalin-Coated Granule Fast-Crumbling Tablet Probenecid Tablets (500 mg) Promethazine Hydrochloride Tablets Promethazine Hydrochloride Tablets Promethazine Hydrochloride Tablets Promethazine Hydrochloride Tablets (25 mg) Promethazine Hydrochloride Tablets (10 mg), Phenergan Propranolol Hydrochloride Tablets Propranolol Hydrochloride Tablets (10 mg) Propranolol Hydrochloride Tablets (10 mg) Propranolol Hydrochloride Tablets Propranolol HCl Sustained-Release Pellets Releasing Tablets (MUPS-Formulation) Propranolol Tablets (40 mg) Proton Pump Inhibitor Dispersible Tablets Proton Pump Inhibitor Tablets Pseudoephedrine Hydrochloride Fast-Disintegrating Tablets Pseudoephedrine Hydrochloride Tablets Pseudoephedrine Tablets Psyllium and Docusate Sodium Tablets Psyllium Husk Tablets Pyrazinamide Tablets (500 mg) Pyrazinamide Tablets (500 mg) Pyrazinamide Tablets (500 mg) Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridostigmine Bromide Tablets (10 mg) Pyridoxine Tablets Pyrilamine Tannate and Phenylephrine Tannate Tablets Quetiapine Fumarate Tablets (25 mg/100 mg/200 mg), Seroquel Quinapril Hydrochloride Tablets (5 mg/10 mg/20 mg/40 mg), Accupril Quinapril Hydrochloride Tablets Quinine Sulfate Tablets (300 mg) Quinolone Antibiotic Tablets (100 mg) Rabeprazole Sodium Tablets (20 mg) Aciphex™ Rabeprazole Tablets Raloxifene Tablets (60 mg), Evista Raloxifene Hydrochloride Tablets Ranitidine Hydrochloride Tablets Ranitidine Hydrochloride Tablets (150 mg) Ranitidine Hydrochloride Tablets Ranitidine Tablets Ranitidine Tablets Ranitidine Tablets (75 mg) Ranitidine Tablets (300 mg) Ranitidine Tablets (150 mg), Zantac Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Rifampicin, Isoniazid, Ethambutol, and Pyridoxine Tablets (300 mg/200 mg/25 mg) Rifampicin Tablets (300 mg) Rifampicin Tablets (450 mg) Risedronate Sodium Tablets (5 mg/30 mg), Actonel Risedronate Sodium Tablets Risperidone Tablets (4 mg), Risperdal Risperidone Tablets Rofecoxib Tablets (12.5 mg/25 mg/50 mg), Vioxx Rosiglitazone Maleate Tablets (2 mg/4 mg/8 mg), Avandia Roxithromycin Dispersible Tablets Roxithromycin Dispersible Tablets (200 mg) Saccharin Effervescent Tablets Saccharin Tablets Saccharin Tablets Salbutamol Tablets (2 mg) Salbutamol Tablets (4 mg) Scopolamine Tablets Selegiline Tablets (5 mg) Selegiline Tablets Serratiopeptidase Tablets (10 mg) Serratiopeptidase Tablets (10 mg) Serratiopeptidase Tablets Sertraline Hydrochloride Tablets (25 mg/50 mg/100 mg), Zoloft Sertraline l-Lactate Osmotic Tablet Sertraline Hydrochloride Tablets (25 mg) Sertraline Hydrochloride Tablets (50 mg) Sertraline Hydrochloride Tablets (100 mg) Sildenafil Tablets (25 mg/50 mg/100 mg), Viagra Sildenafil Citrate Tablets Silimarin Tablets Silimarin Tablets (35 mg) Simethicone and Magnesium Carbonate Tablets Simethicone Chewable Tablets Simethicone Chewable Tablets Simethicone Tablets Simvastatin Fast-Melt Tablet Simvastatin Tablets Simvastatin Tablets (20 mg) Simvastatin Tablets (10 mg), Zocor® Sodium Fluoride Tablets Sodium Fluoride Tablets Sotalol Hydrochloride Tablets (500 mg) Spiramycin Dispersible Tablets Spironolactone Tablets (25 mg/50 mg/100 mg), Aldactone Spironolactone Tablets Spirulina Extract Chewable Tablets Sucralfate and Sodium Alginate Tablets Sulfadimidine Tablets (500 mg) Sulfamethoxazole and Trimethoprim Tablets (400 mg/80 mg; 800 mg/160 mg; 100 mg/20 mg) Sulfamethoxazole and Trimethoprim Tablets Sulfamethoxazole and Trimethoprim Tablets (400 mg/80 mg) Sulfamethoxazole and Trimethoprim Tablets (800 mg/160 mg; 400 mg/80 mg) Sulfamethoxazole and Trimethoprim Tablets, Dispersible (800 mg/160 mg) Sulfathiazole Tablets (250 mg) Sumatriptan Succinate Fast-Melt Tablets Sumatriptan Succinate Tablets (25 mg/50 mg), Imitrex Sumatriptan Tablets Tamoxifen Tablets (10 mg/20 mg), Nolvadex Tamsulosin Hydrochloride Buccal Tablets Tannin–Crospovidone Complex Tablets Tegaserod Maleate Tablets 2 mg Tegaserod Maleate Tablets 6 mg Temafloxacin Hydrochloride Tablets (200 mg/300 mg) Tenoxicam Tablets (20 mg) Terazosin Hydrochloride Tablets Terazosin Tablets (1 mg) Terbinafine Tablets (250 mg) Terfenadine Chewable Tablets Terfenadine Tablets (60 mg) Testosterone and Norethindrone Buccal Tablets Testosterone, Estradiol, and Progesterone Buccal Tablets Tetracycline Tablets (125 mg) Tetracycline Tablets (250 mg) Tetrazepam Tablets (PAGE50 mg) Theophylline and Ephedrine Tablets (130 mg/15 mg) Theophylline Sustained-Release Tablets (500 mg) DC Theophylline Tablets (100 mg) Theophylline Tablets Theophylline Tablets Theophylline Tablets (100 mg) Theophylline Tablets CR (200 mg) Theophylline Tablets (100 mg) Thiamine and Caffeine Tablets Thiamine Hydrochloride Tablets Thiamine Hydrochloride Tablets, Sugar-Coated Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Tibolone Tablets (0.3 mg) Ticlopidine Hydrochloride Tablets (250 mg) Tinidazole Controlled-Release Tablets Tolterodine Tablets (1 mg/2 mg), Detrol® Topiramate Tablets (100 mg/200 mg), Topamax Tosufloxacin Tosylate Tablets (75 mg) Tramadol Sustained-Release Tablets (100 mg) Tramadol Hydrochloride Matrix Tablets Trazodone Hydrochloride Tablets (100 mg) Triamcinolone Tablets (4 mg) Triametrene and Hydrochlorothiazide Tablets Trifluoperazine Tablets (5 mg) Trimebutine and Ranitidine Hydrochloride Tablets Triprolidine and Pseudoephedrine Hydrochloride Tablets Tulobuterol Hydrochloride Tablets (1 mg) Valacyclovir Hydrochloride Tablets (500 mg/1 g), Valtrex Valdecoxib Tablets (10 mg/20 mg), Bextra Valeriana and Passiflora Extract Tablets Valproate Sodium Tablets Valproate Sodium Tablets (500 mg), Depakote Valproate Sodium Tablets Valsartan and Hydrochlorothiazide Tablets (80 mg/12.5 mg; 160 mg/25 mg), Diovan HCT Valsartan and Hydrochlorothiazide Tablets Venlafaxine Hydrochloride Tablets (25 mg/37.5 mg/50 mg), Effexor® Venlafaxine Hydrochloride Tablets Verapamil Sustained-Release Tablets (220 mg) Verapamil Tablets Verapamil Tablets (120 mg), Calan Verapamil Hydrochloride Tablets VESIcare Tablet 5 mg Film-Coated Tablets VESIcare Tablet (10 mg) Film-Coated Tablets Viracept 250 mg Tablets Viracept 625 mg Tablets Vitamin A and Vitamin E Tablets Vitamin A Chewable Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A, Vitamin B6, and Vitamin E Tablets Vitamin A, Vitamin C, and Vitamin D3 Chewable Tablets Vitamin A, Vitamin C, and Vitamin E Tablets (1200 IU/60 mg/30 mg) Vitamin B-Complex and Carnitine Tablets Vitamin B-Complex and Folic Acid Dragees Vitamin B-Complex and Vitamin C Effervescent Tablets Vitamin B-Complex and Vitamin C Tablets Vitamin B-Complex and Vitamin C Tablets Vitamin B-Complex Tablets Vitamin B-Complex Tablets Vitamin B-Complex Tablets Vitamin B-Complex, Choline, and Bile Tablets Vitamin B-Complex, Vitamin A, Vitamin C, and Vitamin D Tablets Vitamin B-Complex, Vitamin A, Vitamin C, Vitamin D, and Mineral Tablets Vitamin B-Complex, Vitamin C, and Calcium Effervescent Tablets Vitamin B-Complex, Vitamin C, and Ferrous Sulfate Tablets Vitamin B-Complex, Vitamin C, and Vitamin E Tablets Vitamin C and Calcium Carbonate Effervescent Tablets Vitamin C and Vitamin E Lozenges Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets with Dextrose Vitamin C Chewable Tablets with Fructose Vitamin C Chewable Tablets with Sucrose Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Tablets Vitamin C Tablets Vitamin C Tablets Vitamin C Tablets Vitamin E Chewable Tablets Vitamin E Chewable Tablets Vitamin E Chewable Tablets Vitamin E Tablets Vitamin E Tablets Voltaren Enteric-Coated Tablets (25 mg) Voltaren Enteric-Coated Tablets (50 mg) Voltaren Enteric-Coated Tablet (75 mg) Vytorin Tablets (10 mg/10 mg) Vytorin Tablets (10 mg/20 mg) Warfarin Tablets (1, 2, 2.5, 3, 4, 5, 6, 7.5, and 10 mg), Coumadin Warfarin Sodium Tablets Yasmin Tablet (3 mg/0.03 mg)—Active Film-Coated Tablets Yasmin Tablet—Inert Film-Coated Tablets Zolmitriptan Orally Disintegrating Tablets (2.5 mg) Zolmitriptan Orally Disintegrating Tablets (5 mg) Zolmitriptan Tablets (2.5 mg) Zolmitriptan Tablets (5 mg) Zolmitriptan Tablets Zolpidem Hemitartrate Tablets Zolpidem Tartrate Tablets (5 mg/10 mg), Ambien® Part III: Tablet Coating Formulations Tablet Coating Formulations INTRODUCTION CELLULOSE BASED HYDROXYPROPYL METHYLCELLULOSE (METHOCEL, HPMC) AQUEOUS COATINGS A. Brite Rose Manufacturing Directions B. Cherry Red C. Geranium Rose D. Gloss E. Red F. Moderate Red G. Clear Manufacturing Directions H. Green I. Holberry Red J. Sun Orange K. Opadry Yellow Manufacturing Directions L. Opadry Yellow M. Opadry Red N. Opadry Green Manufacturing Directions O. White Coating HYDROXYPROPYL METHYLCELLULOSE OPAQUE ORGANIC COATING A. Brite Green Manufacturing Directions B. Red Mahogany C. Sun Orange D. Dark Red E. Deep Yellow F. Pale Yellow G. Scarlet Red HYDROXYPROPYL METHYLCELLULOSE/HYDROXYPROPYL CELLULOSE (KLUCEL®) COATING A. White Manufacturing Directions HYDROXYPROPYL METHYLCELLULOSE/ETHYLCELLULOSE COATING A. Orange Opaque Manufacturing Directions B. Subcoating Solution HYDROXY METHYLCELLULOSE/HYDROXY ETHYLCELLULOSE COATING A. Blue Manufacturing Directions B. Clear (50:50) HYDROXY METHYLCELLULOSE/HYDROXY ETHYLCELLULOSE COATING A. Clear Manufacturing Directions POLYVINYLPYRROLIDONE (PVP) COATINGS A. Subcoating Manufacturing Directions B. Kollidon® VA 64 (Polyvinylpyrrolidone/Vinylacetate Copolymer, BASF) Manufacturing Directions Sugar-Coating Pan Accela Cota (Continuous Spraying) Kollidon® VA 64 and Polyvinyl Alcohol Manufacturing Directions D. Kollidon® 30 and Shellac Manufacturing Directions E. Kollidon® VA 64 and Hydroxypropyl Methylcellulose Manufacturing Directions F. Povidone, Ethylcellulose, and Talc Manufacturing Directions CELLULOSE ACETATE PHTHALATE AND CARBOWAX COATINGS A. Brite Green Manufacturing Directions B. Cherry Red C. Clear D. Orange SUGAR COATINGS A. Basic Manufacturing Directions B. Automatic Manufacturing Directions C. White Manufacturing Directions ENTERIC COATINGS A. Kollicoat® and Kollidon® Enteric Film Coating Manufacturing Directions/Conditions EUDRAGIT® ENTERIC AQUEOUS A. Brick Red Manufacturing Directions B. Yellow C. Brown D. Dark Orange E. Orange F. Dispersed Orange HYDROXYPROPYL METHYLCELLULOSE PHTHALATE ENTERIC COATING A. Clear Enteric Manufacturing Directions B. Orchid Pink Opaque C. Light Apricot Orange Part IV: Composition of Proprietary Products Approved in the United States Composition of Proprietary Products Approved in the United States Index Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume Two, Uncompressed Solid Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition Author Part I: Regulatory and Manufacturing Guidelines 1: U.S. FDA Good Manufacturing Practices I. Introduction II. U.S. FDA cGMP guidelines A. General Provisions Part 210—cGMP in Manufacturing, Processing, Packaging, or Holding of Drugs; General Part 211—cGMP for Finished Pharmaceuticals III. Amendments to Part 211 IV. U.S. FDA cGMP Overview Checklist V. Drug Master Files and Certifications A. Types of DMFs Glossary 2: Guideline on the Common Technical Document for the Registration of Pharmaceuticals for Human Use Background Scope of the Guideline General Principles Organization of the Common Technical Document Organization of the Common Technical Document for the Registration of Pharmaceuticals for Human Use Granularity of Document Definition of a Document Document Pagination and Segregation Section Numbering Within Documents Table of Contents Formatting Module 2 Module 3 Module 4 Module 5 2.3 Quality Overall Summary Introduction 2.3.S Drug Substance (Name, Manufacturer) 2.3.S.1 General Information (Name, Manufacturer) 2.3.S.2 Manufacture (Name, Manufacturer) 2.3.S.3 Characterization (Name, Manufacturer) 2.3.S.4 Control of Drug Substance (Name, Manufacturer) 2.3.S.5 Reference Standards or Materials (Name, Manufacturer) 2.3.S.6 Container Closure System (Name, Manufacturer) 2.3.S.7 Stability (Name, Manufacturer) 2.3.P Drug Product (Name, Dosage Form) 2.3.P.1 Description and Composition of the Drug Product (Name, Dosage Form) 2.3.P.2 Pharmaceutical Development (Name, Dosage Form) 2.3.P.3 Manufacture (Name, Dosage Form) 2.3.P.4 Control of Excipients (Name, Dosage Form) 2.3.P.5 Control of Drug Product (Name, Dosage Form) 2.3.P.6 Reference Standards or Materials (Name, Dosage Form) 2.3.P.7 Container Closure System (Name, Dosage Form) 2.3.P.8 Stability (Name, Dosage Form) 2.3.A Appendices 2.3.A.1 Facilities and Equipment (Name, Manufacturer) 2.3.A.2 Adventitious Agents Safety Evaluation (Name, Dosage Form, Manufacturer) 2.3.R Regional Information 2.4 Nonclinical Overview General Aspects Content and Structural Format 2.5 Clinical Overview 2.5.1 Product Development Rationale 2.5.2 Overview of Biopharmaceuticals 2.5.3 Overview of Clinical Pharmacology 2.5.4 Overview of Efficacy 2.5.5 Overview of Safety 2.5.6 Benefits and Risks Conclusions 2.5.7 Literature References 2.6 Nonclinical Written and Tabulated Summaries Nonclinical Written Summaries Content of Nonclinical Written and Tabulated Summaries 2.6.1 Introduction 2.6.2 Pharmacology Written Summary 2.6.2.1 Brief Summary 2.6.2.2 Primary Pharmacodynamics 2.6.2.3 Secondary Pharmacodynamics 2.6.2.4 Safety Pharmacology 2.6.2.5 Pharmacodynamic Drug Interactions 2.6.2.6 Discussion and Conclusions 2.6.2.7 Tables and Figures 2.6.3 Pharmacology Tabulated Summary 2.6.4 Pharmacokinetics Written Summary 2.6.4.1 Brief Summary 2.6.4.2 Methods of Analysis 2.6.4.3 Absorption 2.6.4.4 Distribution 2.6.4.5 Metabolism (Interspecies Comparison) 2.6.4.6 Excretion 2.6.4.7 Pharmacokinetic Drug Interactions 2.6.4.8 Other Pharmacokinetic Studies 2.6.4.9 Discussion and Conclusions 2.6.4.10 Tables and Figures 2.6.5 Pharmacokinetics Tabulated Summary 2.6.6 Toxicology Written Summary 2.6.6.1 Brief Summary 2.6.6.2 Single-Dose Toxicity 2.6.6.3 Repeat-Dose Toxicity (Including Supportive Toxicokinetics Evaluation) 2.6.6.4 Genotoxicity 2.6.6.5 Carcinogenicity (Including Supportive Toxicokinetics Evaluations) 2.6.6.6 Reproductive and Developmental Toxicity (Including Range-Finding Studies and Supportive Toxicokinetics Evaluations) 2.6.6.7 Local Tolerance 2.6.6.8 Other Toxicity Studies (If Available) 2.6.6.9 Discussion and Conclusions 2.6.6.10 Tables and Figures 2.6.7 Toxicology Tabulated Summary (See Appendix B) 2.7 Clinical Summary 2.7.1 Summary of Biopharmaceutical Studies and Associated Analytical Methods 2.7.1.1 Background and Overview 2.7.1.2 Summary of Results of Individual Studies 2.7.1.3 Comparison and Analyses of Results Across Studies 2.7.1.4 Appendix 2.7.2 Summary of Clinical Pharmacology Studies 2.7.2.1 Background and Overview 2.7.2.2 Summary of Results of Individual Studies 2.7.2.3 Comparison and Analyses of Results Across Studies 2.7.2.4 Special Studies 2.7.2.5 Appendix 2.7.3 Summary of Clinical Efficacy 2.7.3.1 Background and Overview of Clinical Efficacy 2.7.3.2 Summary of Results of Individual Studies 2.7.3.3 Comparison and Analyses of Results across Studies 2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations 2.7.3.5 Persistence of Efficacy and/or Tolerance Effects 2.7.3.6 Appendix 2.7.4 Summary of Clinical Safety 2.7.4.1 Exposure to the Drug 2.7.4.2 Adverse Events 2.7.4.3 Clinical Laboratory Evaluations 2.7.4.4 Vital Signs, Physical Findings, and Other Observations Related to Safety 2.7.4.5 Safety in Special Groups and Situations 2.7.4.6 Postmarketing Data 2.7.4.7 Appendix 2.7.5 Literature References 2.7.6 Synopses of Individual Studies Module 3: Quality Scope of the Guideline 3.1 Table of Contents of Module 3 3.2 Body of Data 3.2.S Drug Substance (Name, Manufacturer) 3.2.S.1 General Information (Name, Manufacturer) 3.2.S.1.1 Nomenclature (Name, Manufacturer) 3.2.S.1.2 Structure (Name, Manufacturer) 3.2.S.1.3 General Properties (Name, Manufacturer) 3.2.S.2 Manufacture (Name, Manufacturer) 3.2.S.2.1 Manufacturer(s) (Name, Manufacturer) 3.2.S.2.2 Description of Manufacturing Process and Process Controls (Name, Manufacturer) 3.2.S.2.3 Control of Materials (Name, Manufacturer) 3.2.S.2.4 Controls of Critical Steps and Intermediates (Name, Manufacturer) 3.2.S.2.5 Process Validation and/or Evaluation (Name, Manufacturer) 3.2.S.2.6 Manufacturing Process Development (Name, Manufacturer) 3.2.S.3 Characterization (Name, Manufacturer) 3.2.S.3.1 Elucidation of Structure and Other Characteristics (Name, Manufacturer) 3.2.S.3.2 Impurities (Name, Manufacturer) 3.2.S.4 Control of Drug Substance (Name, Manufacturer) 3.2.S.4.1 Specification (Name, Manufacturer) 3.2.S.4.2 Analytical Procedures (Name, Manufacturer) 3.2.S.4.3 Validation of Analytical Procedures (Name, Manufacturer) 3.2.S.4.4 Batch Analyses (Name, Manufacturer) 3.2.S.4.5 Justification of Specification (Name, Manufacturer) 3.2.S.5 Reference Standards or Materials (Name, Manufacturer) 3.2.S.6 Container Closure System (Name, Manufacturer) 3.2.S.7 Stability (Name, Manufacturer) 3.2.S.7.1 Stability Summary and Conclusions (Name, Manufacturer) 3.2.S.7.2 Postapproval Stability Protocol and Stability Commitment (Name, Manufacturer) 3.2.S.7.3 Stability Data (Name, Manufacturer) 3.2.P Drug Product (Name, Dosage Form) 3.2.P.1 Description and Composition of the Drug Product (Name, Dosage Form) 3.2.P.2 Pharmaceutical Development (Name, Dosage Form) 3.2.P.2.1 Components of the Drug Product (Name, Dosage Form) 3.2.P.2.2 Drug Product (Name, Dosage Form) 3.2.P.2.3 Manufacturing Process Development (Name, Dosage Form) 3.2.P.2.4 Container Closure System (Name, Dosage form) 3.2.P.2.5 Microbiological Attributes (Name, Dosage Form) 3.2.P.2.6 Compatibility (Name, Dosage Form) 3.2.P.3 Manufacture (Name, Dosage Form) 3.2.P.3.1 Manufacturer(s) (Name, Dosage Form) 3.2.P.3.2 Batch Formula (Name, Dosage Form) 3.2.P.3.3 Description of Manufacturing Process and Process Controls (Name, Dosage Form) 3.2.P.3.4 Controls of Critical Steps and Intermediates (Name, Dosage Form) 3.2.P.3.5 Process Validation and/or Evaluation (Name, Dosage Form) 3.2.P.4 Control of Excipients (Name, Dosage Form) 3.2.P.4.1 Specifications (Name, Dosage Form) 3.2.P.4.2 Analytical Procedures (Name, Dosage Form) 3.2.P.4.3 Validation of Analytical Procedures (Name, Dosage Form) 3.2.P.4.4 Justification of Specifications (Name, Dosage Form) 3.2.P.4.5 Excipients of Human or Animal Origin (Name, Dosage Form) 3.2.P.4.6 Novel Excipients (Name, Dosage Form) 3.2.P.5 Control of Drug Product (Name, Dosage Form) 3.2.P.5.1 Specification(s) (Name, Dosage Form) 3.2.P.5.2 Analytical Procedures (Name, Dosage Form) 3.2.P.5.3 Validation of Analytical Procedures (Name, Dosage Form) 3.2.P.5.4 Batch Analyses (Name, Dosage Form) 3.2.P.5.5 Characterization of Impurities (Name, Dosage Form) 3.2.P.5.6 Justification of Specification(s) (Name, Dosage Form) 3.2.P.6 Reference Standards or Materials (Name, Dosage Form) 3.2.P.7 Container Closure System (Name, Dosage Form) 3.2.P.8 Stability (Name, Dosage Form) 3.2.P.8.1 Stability Summary and Conclusion (Name, Dosage Form) 3.2.P.8.2 Postapproval Stability Protocol and Stability Commitment (Name, Dosage Form) 3.2.P.8.3 Stability Data (Name, Dosage Form) 3.2.A Appendices 3.2.A.1 Facilities and Equipment (Name, Manufacturer) 3.2.A.2 Adventitious Agents Safety Evaluation (Name, Dosage Form, Manufacturer) 3.2.A.3 Excipients 3.2.R Regional Information 3.3 Literature References Module 4: Nonclinical Study Reports General Principles of Nonclinical Overview and Summaries 4.1 Table of Contents of Module 4 4.2 Study Reports 4.3 Literature References Module 5: Clinical Study Reports 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports 5.3.1 Reports of Biopharmaceutical Studies 5.3.1.1 Bioavailability (BA) Study Reports 5.3.1.2 Comparative BA and BE Study Reports 5.3.1.3 In Vitro–In Vivo Correlation Study Reports 5.3.1.4 Reports of Bioanalytical and Analytical Methods for Human Studies 5.3.2 Reports of Studies Pertinent to Pharmacokinetics Using Human Biomaterials 5.3.2.1 Plasma Protein Binding Study Reports 5.3.2.2 Reports of Hepatic Metabolism and Drug Interaction Studies 5.3.2.3 Reports of Studies Using Other Human Biomaterials 5.3.3 Reports of Human PK Studies 5.3.3.1 Healthy Subject PK and Initial Tolerability Study Reports 5.3.3.2 Patient PK and Initial Tolerability Study Reports 5.3.3.3 Intrinsic Factor PK Study Reports 5.3.3.4 Extrinsic Factor PK Study Reports 5.3.3.5 Population PK Study Reports 5.3.4 Reports of Human Pharmacodynamic (PD) Studies 5.3.4.1 Healthy Subject PD and PK/PD Study Reports 5.3.4.2 Patient PD and PK/PD Study Reports 5.3.5 Reports of Efficacy and Safety Studies 5.3.5.1 Study Reports of Controlled Clinical Studies Pertinent to the Claimed Indication 5.3.5.2 Study Reports of Uncontrolled Clinical Studies 5.3.5.3 Reports of Analyses of Data from More than One Study 5.3.5.4 Other Study Reports 5.3.6 Reports of PostMarketing Experience 5.3.7 Case Report Forms and Individual Patient Listings 5.4 Literature References 1 General Questions Format or Content? 2 Questions Regarding Location Issues 3 Associated Information Located in Different Sections 3.1 Polymorphism 3.2 Particle Size 3.3 Impurities 3.4 New Location of Quality Information for Investigational Formulations 3.5 Where Would the Information Related to Nonviral Adventitious Agents be Placed Within Module 3.2? 3.6 Location Issues Questions in Drug Substance: 3.2.S 4 Location Issues in Drug Product: 3.2.P 6 Safety 7 Efficacy 8 ISS/ISE 3: Process Validation: General Principles and Practices I. Introduction II. Background III. Statutory and Regulatory Requirements for Process Validation IV. Recommendations A. General Considerations for Process Validation B. Specific Stages and Activities of Process Validation in the Product Lifecycle 1 Stage 1—Process Design 2 Stage 2—Process Qualification 3 Stage 3—Continued Process Verification V. Concurrent Release of Performance Qualification Batches VI. Documentation VII. Analytical Methodology Bibliography 4: Bioequivalence Regulatory Compliance I. Background II. Regulatory Aspects III. Equivalence Documentation for Marketing Authorization IV. Therapeutic Classification V. Topics Related to Regulatory Compliance A. Is a BE Study Required? B. Prior Review VI. Record Maintenance VII. Clarification on Requirements A. In which cases is it allowed to use a wider acceptance range for the ratio of Cmax? B. When can subjects classified as outliers be excluded from the analysis in be studies? C. If one side of the 90% CI of a PK variable for testing BE lies on 0.80 or 1.25, can we conclude that the products are bioequivalent? D. In which cases may a nonparametric statistical model be used? E. When should metabolite data be used to establish BE? F. When using metabolite data to establish BE, may one use the same justification for widening the Cmax acceptance criteria as in the case of the parent compound? G. What is a “highly variable drug or drug product”? H. What are the conditions for using urinary PK data for BE assessment? I. Standardization of BE studies with regard to food intake. how strictly should the guideline be interpreted? J. Worldwide considerations VIII. Postapproval Changes A. NDAs: BA and BE studies B. Waivers of in vivo BE studies (Biowaivers): NDAs and aNDAs 1 Beaded capsules-lower strength 2 Tablets-lower strength C. Risk-based BE D. Typical examples of complex BE 1 Digoxin 2 Levothyroxine 3 Warfarin sodium 4 Albuterol metered-dose inhalers E. General PK study design and data handling 1 Study conduct 2 Sample collection and sampling times 3 Subjects with predose plasma concentrations 4 Data deletion due to vomiting 5 PK information recommended for submission 6 BE demonstration measures 7 CI values 8 Statistical information for AUC0-T, AUC0-°, and Cmax F. Measurement indices G. Dose selection H. Multiple strengths of solid oral dosage forms I. Manufacturing of pilot batch (“biobatch”) J. Dosing by labeled concentration K. Single dose vs. multiple dose studies L. Guidelines on the design of a single-dose study M. Guidelines for multiple-dose study N. Fed vs. fasted state O. Pharmacological end-point studies P. Clinical end-point studies Q. Analytical methods Assay consideration R. Sampling time considerations S. Protein binding T. Subject number U. Crossover and parallel design considerations V. Duration of washout time for crossover study W. Fed BE studies X. Food effects on drug products Y. Recommendations for immediate-release drugs: Z. Recommendations for modified-release products 1 Study design 2 General design 3 Subject selection 4 Dosage strength 5 Test meal 6 Administration 7 Sample collection 8 Data analysis and labeling Parent drug vs. metabolites Enantiomers vs. racemates Drug products with complex mixtures as the active ingredients Long half-life drugs First-point Cmax Orally administered drugs intended for local action Sprinkles Special vehicles Locally acting GI drugs Animal drug BE testing Reference product Reference 5: Bioequivalence Regulatory Review Process and Audit Background Protocols Productivity Documentation Methods Validation for Abbreviated New Drug Applications Good Laboratory Practices Types of Inspections Inspections FDA Audit Plans Part I—Background Part II—Implementation Objective Program Management Instructions Part III—Inspectional Operations Part IV—Analytical Part V—Regulatory/Administrative Strategy Clinical Testing Analytical Testing Bioequivalence Inspection Report Part I—Facilities and Procedures (Clinical and Analytical) Electronic Records and Signatures Clinical Data and Operations General Inspection Procedures Study Responsibility and Administration Protocol Subjects’ Records Other Study Records Consent of Human Subjects Institutional Review Board Sponsor Test Article Accountability Records Retention Abbreviated Report Format Analytical Data and Operations Bibliography 6: EU Guidelines to Good Manufacturing Practice: Active Drug Substance 1.1 Objective 1.2 Scope 2 Quality Management 2.1 Principles 2.2 Responsibilities of the Quality Unit(s) 2.3 Responsibility for Production Activities 2.4 Internal Audits (Self-Inspection) 3 Personnel 3.1 Personnel Qualifications 3.2 Consultants 4 Buildings and Facilities 4.1 Design and Construction 4.2 Utilities 4.3 Water 4.4 Containment 4.5 Lighting 4.6 Sewage and Refuse 4.7 Sanitation and Maintenance 5 Process Equipment 5.1 Design and Construction 5.2 Equipment Maintenance and Cleaning 5.3 Calibration 5.4 Computerized Systems 6 Documentation and Records 6.1 Documentation System and Specifications 6.2 Equipment Cleaning and Use Record 6.3 Records of Raw Materials, Intermediates, API Labeling, and Packaging Materials 6.4 Master Production Instructions (Master Production and Control Records) 6.5 Batch Production Records (Batch Production and Control Records) 6.6 Laboratory Control Records 6.7 Batch Production Record Review 7 Materials Management 7.1 General Controls 7.2 Receipt and Quarantine 7.3 Sampling and Testing of Incoming Production Materials 7.4 Storage 7.5 Reevaluation 8 Production and In-Process Controls 8.1 Production Operations 8.2 Time Limits 8.3 In-Process Sampling and Controls 8.4 Blending Batches of Intermediates or APIs 8.5 Contamination Control 9 Packaging and Identification Labeling of APIs and Intermediates 9.1 General 9.2 Packaging Materials 9.3 Label Issuance and Control 9.4 Packaging and Labeling Operations 10 Storage and Distribution 10.1 Warehousing Procedures 10.2 Distribution Procedures 11 Laboratory Controls 11.1 General Controls 11.2 Testing of Intermediates and APIs 11.3 Validation of Analytical Procedures 11.4 Certificates of Analysis 11.5 Stability Monitoring of APIs 11.6 Expiry and Retest Dating 11.7 Reserve/Retention Samples 12 Validation 12.1 Validation Policy 12.2 Validation Documentation 12.3 Qualification 12.4 Approaches to Process Validation 12.5 Process Validation Program 12.6 Periodic Review of Validated Systems 12.7 Cleaning Validation 12.8 Validation of Analytical Methods 13 Change Control 14 Rejection and Reuse of Materials 14.1 Rejection 14.2 Reprocessing 14.3 Reworking 14.4 Recovery of Materials and Solvents 14.5 Returns 15 Complaints and Recalls 16 Contract Manufacturers (including Laboratories) 17 Agents, Brokers, Traders, Distributors, Repackers, and Relabellers 17.1 Applicability 17.2 Quality Management 17.3 Repackaging, Relabeling, and Holding of APIs and Intermediates 17.4 Stability 17.5 Transfer of Information 17.6 Handling of Returns 18 General 18.1 Cell Bank Maintenance and Record Keeping 18.2 Cell Culture/Fermentation 18.3 Harvesting, Isolation, and Purification 18.4 Viral Removal/Inactivation steps 19 APIs for Use in Clinical Trials 19.1 General 19.2 Quality 19.3 Equipment and Facilities 19.4 Control of Raw Materials 19.5 Production 19.6 Validation 19.7 Changes 19.8 Laboratory Controls 19.9 Documentation Glossary 7: FDA Pre-approval Inspections I. Introduction A. Background B. Objective C. Triggering of Inspections D. Inspections/Audits 1 Manufacturing Process 2 Reprocessing 3 Laboratory 4 Components 5 Building and Facilities 6 Equipment 7 Packaging and Labeling Controls II. Regulatory/Administrative Strategy A. General B. Process Validation C. Key Elements D. Strategies for Pre-Inspection E. International Inspection F. Product Stability Data G. Validation of Processes H. Change Control 1 Cleaning Validation 2 Analytical Methods Validation 3 Computer System Validation Part 11—Electronic Records; Electronic Signatures Subpart A—General Provisions Sec. 11.1 Scope. Sec. 11.2 Implementation. Sec. 11.3 Definitions. Subpart B—Electronic Records Sec. 11.10 Controls for closed systems. Sec. 11.30 Controls for open systems. Sec. 11.50 Signature manifestations. Sec. 11.70 Signature/record linking. Subpart C—Electronic Signatures Sec. 11.100 General requirements. Sec. 11.200 Electronic signature components and controls. Sec. 11.300 Controls for identification codes/passwords. Documentation Standards 1 Development History Report 2 Deviation Records 3 Installation, Operational, and Performance Qualification 4 Organizational Chart 5 Products List 6 Drawings 7 Stability Data 8 SOPs 9 Training Records 10 Validation Records 11 Technology Transfer and Scale-Up 12 Quality Policy 13 Vendor Approval 14 Outside Contractors 8: Formulation Factors in Uncompressed Dosage Forms Introduction Capsules Manufacture of Hard Gelatin Shells Hard-Gelatin Capsule Filling Oral Powders Nasal Powders Formulation and Manufacturing Considerations Relative Humidity Surface Area Sieve Analysis Particle Size Distribution Powder Flow Properties Real, Tapped, and Bulk Density Mixing Mixing Mechanisms Segregation Mechanisms Mixing Equipment Milling Powder Handling References 9: Solid-State Properties 1 Introduction 2 Crystal Morphology 3 Polymorphism 4 High-Throughput Crystal Screening 5 Solvates Hydrates 6 Amorphous Forms 7 Hygroscopicity 8 Solubility 8.1 Salt Form 8.2 Melting Point 8.3 Dissolution 9 Study Methods Thermal Analysis 9.1 Differential Scanning Calorimetry 9.2 Hot-Stage Microscopy 9.3 Thermogravimetric Analysis 9.4 Solution Calorimetry 9.5 Isothermal Microcalorimetry 9.6 Infrared Spectroscopy 9.7 X-Ray Powder Diffraction 9.8 Phase Solubility Analysis 9.9 Dynamic Vapor Sorption 9.10 Dissolution Testing 9.11 High-Performance Liquid Chromatography Web References Reading Recommendations 10: Formulation of Flavor 1 Introduction 2 Taste-Concealing Goals 3 Fluid Bed Coating 3.1 Filmcoat Parameters 3.2 Filmcoat Formulations 3.3 Other Considerations 4 Spray Drying or Spray Congealing 5 Coacervation 6 Inclusion Complexes 7 Ion Resin Technology 8 Taste Conceal Performance Specifications Appendix A Appendix B Appendix C Part II: Manufacturing Formulations Uncompressed Solids Formulations Acebutolol Hydrochloride Capsules Aceclofenac Instant Granules Acetaminophen and Diphenhydramine Hydrochloride Hot Therapy Sachets Acetaminophen Capsules (500 mg) Acetaminophen, Doxylamine, and Caffeine Effervescent Acetaminophen Instant Granules Acetaminophen Instant Granules Acetaminophen Instant Granules Acetaminophen, Pseudoephedrine Hydrochloride, Chlorpheniramine Hot Therapy Sachet Acetaminophen, Pseudoephedrine Hydrochloride Hot Therapy Sachet Acetaminophen Swallow Capsules Acetazolamide Sustained-Release Capsules Acetylcysteine Sachets Acitretin Capsules Acrivastine and Pseudoephedrine Hydrochloride Capsules Acrivastine and Pseudoephedrine Hydrochloride Capsules Acyclovir Capsules Acyclovir Capsules Adenosine Monophosphate Topical Powder Aluminum Acetate Powder Aluminum Hydroxide and Magnesium Carbonate Dry Syrup Aminosalicylic Acid Granules Amlodipine Besylate and Benazepril Hydrochloride Capsules Amlodipine Besylate and Benazepril Hydrochloride Capsules Amlodipine Besylate Capsules Amlodipine Free Base Capsules Amlodipine Maleate Capsules Amoxicillin and Bromhexine Hydrochloride Capsules Amoxicillin and Clavulanic Acid Powder for Suspension, 125 mg and 31.25 mg per 5 mL (Amoxil)* Amoxicillin and Clavulanic Acid Powder for Suspension Amoxicillin and Clavulanate Potassium for Suspension* Amoxicillin and Clavulanate Potassium for Suspension* Amoxicillin Powder for Suspension (125 and 250 mg) Amoxicillin Trihydrate Capsules (250 and 500 mg) Ampicillin Dry Syrup (5% = 500 mg/10 mL) Ampicillin Powder for Suspension Ampicillin Trihydrate Capsules Ampicillin Trihydrate Capsules for Suspension Ampicillin Trihydrate Powder for Suspension Antibacterial and Bacterial Culture Capsules Antifungal Foot Powder Antioxidant Eye Nutrition Supplement Capsules Aspartame Granules in Sachets Aspartame Powder in Sachets Aspirin and Chlorpheniramine Powder Aspirin-Coated Crystals Aspirin and Phenylpropanolamine Powder Aspirin Microencapsulated Sustained-Release Capsules Aspirin, Salicylamide, and Caffeine Powder Azithromycin Suspension Azithromycin Capsules Azithromycin Capsules Azithromycin Capsules Azithromycin Capsules and Oral Suspension Azithromycin for Oral Suspension Azithromycin for Oral Suspension Azithromycin Sachets for Oral Suspension Balsalazide Disodium Capsules Benazepril Hydrochloride and Amlodipine Besylate Capsules Benazepril Hydrochloride and Amlodipine Besylate Capsules Bisacodyl Colonic Delivery Capsules Brompheniramine and Pseudoephedrine Capsules Budesonide Capsules Budesonide Inhalation Powder Butalbital and Acetaminophen Capsules Calcitonin (Salmon) Capsules Calcitriol Capsules Calcium Carbonate Microencapsulated Sustained-Release Capsules Camptothecin Capsules Carbamazepine Extended-Release Capsules Cefaclor Capsules Cefdinir Capsules and Oral Suspension* Cefixime for Oral Suspension* Cefpodoxime Proxetil for Oral Suspension* Cefprozil for Oral Suspension* Ceftibuten Capsules and Oral Suspension* Ceftibuten for Oral Suspension Cefuroxime for Oral Suspension* Celecoxib Capsules Celecoxib Tablets Celebrex* Cellulose Triacetate Liquefiable Topical Powder Cephalexin Capsules Cephalexin Powder for Oral Suspension Cephradine Capsules Cephradine Powder for Suspension Cevimeline Capsules Cevimeline Capsules Chlordiazepoxide Hydrochloride Capsules* Chlordiazepoxide Hydrochloride Capsules Chloroxylenol and Chlorhexidine Topical Powder Chlorpromazine Sustained-Release Capsules* Cimetidine Microencapsulated Sustained-Release Capsules Citrate Effervescent Powder Clindamycin Capsules* Clindamycin Capsules (150 mg) Clofibrate Capsules Clonidine Sustained-Release Capsules Clorazepate Dipotassium Capsules Coated Spheroids Crospovidone Water-Dispersible Tablets Cyanocobalamin Tablets Cyclosporin A Capsules Dantrolene Sodium Capsules* Dextroamphetamine Sulfate Capsules* Diclofenac and Misoprostol Capsules Diclofenac Spheronized Pellets for Sustained-Release Coating (30%) Diclofenac Sustained-Release Capsules Diclofenac Granules Didanosine Delayed-Release Capsules* Didanosine Delayed-Release Capsules Enteric-Coated Beadlets* Didanosine for Oral Suspension Diethyl Toluamide Topical Powder Difluoromethylornithine-Alpha Capsules Diltiazem Hydrochloride Extended-Release Capsules* Diphenhydramine Hydrochloride Capsules* Dipyridamole and Aspirin Extended-Release Capsules* Divalproex Sodium Capsules* Divalproex Sodium Coated Particle Capsules Dofetilide Capsules* Doxepin Hydrochloride Capsules* Doxycycline Capsules* Doxycycline Hyclate Capsules* Doxycycline Hyclate Capsules Doxycycline Hydrochloride Capsules and Oral Suspension* Efavirenz Capsules* Enalapril Maleate Capsules Enalapril Maleate Capsules Eplerenone Capsules Erythromycin and Bromhexine Powder for Suspension Erythromycin and Sulfisoxazole Granules for Suspension Erythromycin Delayed-Release Capsules* Erythromycin Delayed-Release Capsules Erythromycin Ethylsuccinate for Oral Suspension Erythromycin Ethylsuccinate for Oral Suspension (200 mg/5 mL) Erythromycin Stearate for Oral Suspension Erythromycin Stearate for Oral Suspension Erythropoietin Capsules Esomeprazole Magnesium Capsules* Estramustine Phosphate Capsules* Ethosuximide Capsules* Etodolac Capsules* Felbamate for Oral Suspension* Fenofibrate Capsules* Fenofibrate Capsules Fexofenadine Hydrochloride Capsules* Fexofenadine Hydrochloride Capsules Fluconazole for Oral Suspension* Flucytosine Capsules* Fluoxetine Capsules Fluoxetine Hydrochloride Capsules Fluoxetine Hydrochloride Instant and Weekly Capsules* Flutamide Capsules* Fluticasone Propionate and Salmeterol Xinafoate Inhalation Powder* Fluvastatin Sodium Capsules* Fluvastatin Sodium Capsules Formoterol Fumarate Inhalation Powder* Formoterol Fumarate Inhaler Capsules* Fosfomycin Tromethamine Sachets* Gabapentin Capsules* Gabapentin Capsules Ganciclovir Capsules* Ganciclovir Capsules Gemfibrozil Capsules Glycoprotein IIa/IIb Capsules Guaifenesin Sustained-Release Capsules Herbal AIDS Treatment Capsules Histidine Capsules Human Growth Hormone Capsules Hydrochlorothiazide and Triamterene Capsules* Hydrochlorothiazide Capsules* Hydroxyzine Pamoate Capsules and Oral Suspension* Hyoscyamine Sulfate Capsules* Ibuprofen Microencapsulated Sustained-Release Capsules Ibuprofen and Domperidone Maleate Capsules Ibuprofen and Domperidone Maleate Effervescent Granules Ibuprofen Sustained-Release Capsules Ifosfamide Capsules Imatinib Mesylate Capsules* Indinavir Sulfate Capsules* Indinavir Sulfate Capsules Indomethacin Capsules Indomethacin Capsules* Indomethacin Capsules Indomethacin Capsules (25 mg) Indomethacin Capsules (50 mg) Indomethacin Powder for Hard Gelatin Capsules (160 mg) Indomethacin Microencapsulated Sustained-Release Capsules Indomethacin Sustained-Release Capsules Insulin Capsules Iron-Polysaccharide Complex Capsules* Isometheptene Mucate, Dichloralphenazone, and Acetaminophen Capsules* Isosorbide Mononitrate Capsules (20 mg) Isradipine Capsules* Itraconazole Capsules* Itraconazole Capsules Ketoprofen and Misoprostol Capsules Ketoprofen Capsules* Lansoprazole Capsules Lansoprazole Delayed-Release Capsules* Lincomycin Capsules Linezolid Oral Suspension Lipase, Amylase, and Protease Capsules Lithium Carbonate Capsules Loperamide and Trimebutine Capsules Lopinavir-Ritonavir Capsules* Loracarbef Capsules and Oral Suspension* Loxapine Succinate Capsules Magaldrate Instant Powder or Dry Syrup Magaldrate Instant Powder or Dry Syrup Magnesium Oxide Capsules Mefenamic Acid Capsules Mesalamine Capsules* Mesalamine Colonic Delivery Capsules Methsuximide Capsules* Methylphenidate Capsules Methylphenidate Capsules Methylphenidate Immediate- and Extended-Release Capsules Methyltestosterone Capsules* Metoclopramide Hydrochloride Sustained-Release Capsules Metyrosine Capsules* Miconazole Nitrate Foot and Itch Powder Midodrine Capsules Mineral Powder for Topical Herpes Simplex Minocycline Hydrochloride Capsules* Mixed Amphetamine Salt Capsules* Mixed Amphetamine Salts Enteric-Release Capsules Morphine Sulfate Capsules* Morphine Sulfate Controlled-Release Capsules Morphine Sulfate Sustained-Release Capsules* Multivitamin Effervescent Granules Multivitamin Effervescent Granules Multivitamin Instant Granules Multivitamin Instant Granules Mycophenolate Mofetil Capsules and Oral Suspension* Nanoparticle Polymer Particle Powders Nelfinavir Mesylate Oral Powder* Nelfinavir Mesylate Oral Powder Nilvadipine Capsules Nitrofurantoin Capsules* Nitrofurantoin Sustained-Release Capsules Nizatidine Capsules* Nizatidine Capsules* Nystatin Powder* Omeprazole and Piroxicam Capsules Omeprazole Capsules Omeprazole Capsules Omeprazole Delayed-Release Capsules* Oral Rehydration Salt (45 mEq) Orlistat Capsules* Orlistat Capsules Oseltamivir Phosphate Capsules and Oral Suspension* Oxcarbazepine Oral Suspension* Oxycodone Hydrochloride and Acetaminophen Capsules Oxytetracycline Hydrochloride Capsules Oxytetracycline Hydrochloride, Sulfamethizole, and Phenazopyridine Hydrochloride Capsules* Pancrelipase Capsules Pancrelipase Capsules Enteric-Coated Microspheres Penicillamine Capsules* Pentosan Polysulfate Sodium Capsules Pentostatin Capsules pH-Sensitive Coated Spheroids Phenobarbital and Hyoscyamine Sulfate Capsules Phenoxybenzamine Hydrochloride Capsules Phentermine Capsules Phentermine Hydrochloride Capsules Phenytoin Sodium Extended-Release Capsules* Piroxicam and Beta-Cyclodextrin Topical Powder Piroxicam Capsules Piroxicam Capsules Piroxicam Capsules Polyethylene Glycol 3350 Powder for Reconstitution Polythiazide Capsules Potassium Chloride Extended-Release Capsules Potassium Chloride for Oral Solution Potassium Chloride Microencapsulated Sustained-Release Capsules Potassium Chloride Powder (20 mEq) Prazosin and Polythiazide Capsules* Prednisolone Targeted-Release Capsules Procarbazine Hydrochloride Capsules* Prochlorperazine Sustained-Release Capsules Propoxyphene Hydrochloride, Caffeine, and Aspirin Capsules* Propoxyphene Hydrochloride Capsules Propranolol Hydrochloride and Hydrochlorothiazide Capsules Propranolol Hydrochloride Long-Acting Capsules* Propranolol Hydrochloride Multiple Bead Capsules Propranolol Hydrochloride Sustained-Release Capsules Propranolol Timed- and Sustained-Release Capsules Proton Pump Inhibitor Powder for Reconstitution for Oral Use Proton Pump Inhibitor Powder for Reconstitution for Oral Use Pseudoephedrine Hydrochloride Capsules Pseudoephedrine Hydrochloride Capsules Pseudoephedrine and Guaifenesin Capsules Pseudoephedrine Hydrochloride Capsules Psyllium and Dioctyl Sodium Sulfosuccinate Powder Psyllium and Docusate Sodium Wafer Psyllium Husk Granules Ranitidine Effervescent Granules* Ribavirin Capsules Rifabutin Capsules Rifampicin Capsules Rifampin and Isoniazid Capsules Rivastigmine Tartrate Capsules* Salmeterol Xinafoate Capsules Salmeterol Xinafoate Inhalation Powder* Salmeterol Xinafoate Inhalation Powder Saquinavir Mesylate Capsules* Selegiline Hydrochloride Sevelamer Hydrochloride Capsules* Sibutramine Hydrochloride Capsules* Sibutramine Hydrochloride Capsules Simethicone Instant Granules (60 mg and 120 mg) Stavudine Capsules* Succimer Capsules* Sucralafate Granules Sulfamethoxazole + Trimethoprim Dry Syrup (400 mg + 80 g/10 mL) Tacrine Hydrochloride Capsules Tacrolimus Capsules* Tacrolimus Capsules* Talc, Crospovidone, and Starch Topical Powder Tamsulosin Hydrochloride Capsules* Tamsulosin Hydrochloride Capsules Temazepam Capsules Temozolomide Capsules* Terazosin Capsules (1–10 mg) Hytrin* Terazosin Capsules Terazosin Hydrochloride Capsules Terfenadine Oral Granules Tetracycline Hydrochloride Capsules Thalidomide Capsules Theophylline Sustained-Release Capsules Thiothixene Capsules* Tibolone Capsules Tiotropium Inhalation Powder Tolmetin Sodium Capsules* Tolterodine Capsules* Tolterodine Capsules Topiramate Capsules* Tretinoin Capsules Triamterene and Hydrochlorothiazide Capsules Triamterene Capsules* Triclosan and Zinc Foot Deodorant Powder Triclosan and Zinc Undecylenate Powder Trientine Hydrochloride Capsules* Trimebutine Capsules Trimethoprim and Sulfamethoxazole Oral Suspension* Trimipramine Maleate Capsules* Troleandomycin Capsules Typhoid Vaccine Live Oral Capsules Valsartan and Hydrochlorothiazide Capsules Valsartan Capsules* Valsartan Capsules Vancomycin Hydrochloride Capsules* Venlafaxine Capsules Verapamil Hydrochloride Capsules* Verapamil Hydrochloride Capsules Verapamil Hydrochloride Sustained-Release Capsules Vincamine Capsules Vinpocetine Multiple Bead Capsules Vitamin B Complex, Amino Acids, and Magnesium Effervescent Granules (Sugar-Free) Vitamin B Complex + Amino Acid + Magnesium Effervescent Granules (Sugar-free) Vitamin B Complex and Vitamin C Instant Granules Vitamin C and Calcium Carbonate Effervescent Powder Zanamivir Powder* Zanamivir Powder Zidovudine Capsules Zidovudine Capsules Zinc Oxide and Cornstarch Powder Ziprasidone Hydrochloride Capsules* Ziprasidone Hydrochloride Capsules Zonisamide Capsules* Zonisamide Capsules Part III: Commercial Pharmaceutical Formulations Commercial Pharmaceutical Formulations Index Handbook of Pharmaceutical Manufacturing Formulations, Third Edition_ Volume Three, Liquid Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition Author Part I: Regulatory and Manufacturing Guidance Chapter 1: Manufacturing Considerations in Liquid Formulations I. Introduction II. Facilities III. Equipment IV. Raw Materials V. Compounding VI. Microbiological Quality VII. Oral Suspensions VIII. Product Specifications IX. Process Validation X. Stability XI. Packaging Chapter 2: Oral Solutions and Suspensions I. Introduction II. Facilities III. Equipment IV. Raw Materials V. Compounding VI. Microbiological Quality VII. Oral Suspension Uniformity VIII. Product Specifications IX. Process Validation X. Stability XI. Packaging Chapter 3: The FDA Drug Product Surveillance Program I. Background II. Implementation A. Objectives B. Strategy 1. Biennial Inspection of Manufacturing Sites 2. Inspection of Systems 3. A Scheme of Systems for the Manufacture of Drugs and Drug Products III. Program Management Instructions A. Definitions 1. Surveillance Inspections 2. Compliance Inspections 3. State of Control 4. Drug Process 5. Drug Manufacturing Inspection B. Inspection Planning C. Profiles IV. Inspectional Observations A. Investigational Operations 1. General 2. Inspection Approaches 3. System Inspection Coverage 4. Sampling 5. Inspection Teams 6. Reporting V. Analytical Observations A. Analyzing Laboratories B. Analysis VI. Regulatory/Administrative Strategy Chapter 4: Changes to Approved NDAs and aNDAs I. Introduction II. Reporting Categories III. General Requirements IV. Assessing the Effect of Manufacturing Changes A. Assessment of the Effects of the Change 1. Conformance to Specifications 2. Additional Testing B. Equivalence C. Adverse Effect V. Components and Composition VI. Manufacturing Sites A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) VII. Manufacturing Process A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) VIII. Specifications A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) IX. Package A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) X. Labeling A. General Considerations B. Major Changes (Prior Approval Supplement) C. Moderate Changes (Supplement—Changes Being Effected) D. Minor Changes (Annual Report) XI. Miscellaneous Changes A. Major Changes (Prior Approval Supplement) B. Moderate Changes (Supplement—Changes Being Effected) C. Minor Changes (Annual Report) XII. Multiple Related Changes Glossary Chapter 5: Formulation Considerations of Liquid Products I. Solubility II. Chemical Modification III. Preservation IV. Sweetening Agents V. Flavors VI. Viscosity VII. Appearance VIII. Chemical Stability IX. Physical Stability X. Raw Material XI. Manufacturing Equipment XII. Manufacturing Directions XIII. Packaging XIV. Particle Size and Shape XV. Suspensions XVI. Emulsions Emulsions XVII. Powder for Reconstitution XVIII. Nasal Spray Products A. Inhalation Solutions and Suspensions B. Inhalation Sprays C. Pump Delivery of Nasal Products D. Spray Content Uniformity for Nasal Products E. Spray Pattern and Plume Geometry of Nasal Products F. Droplet-Size Distribution in Nasal Products G. Particle-Size Distribution for Nasal Suspensions XIX. Emulsification and Solubilization XX. Complexing XXI. Hydrophilization XXII. Stabilizing Suspensions Chapter 6: Container Closure Systems I. Introduction A. Definitions B. Current Good Manufacturing Practice, the Consumer Product Safety Commission, and Requirements on Containers and Closures C. Additional Considerations II. Qualification and Quality Control of Packaging Components A. Description B. Information about Suitability C. Stability Data (Packaging Concerns) D. Inhalation Drug Products E. Injection and Ophthalmic Drug Products F. Liquid-Based Oral and Topical Drug Products and Topical Delivery Systems G. Solid Oral Dosage Forms and Powders for Reconstitution 1. Polyethylene Containers (USP <661>) 2. Single-Unit Containers and Unit-Dose Containers for Capsules and Tablets (USP <671>) 3. Multiple-Unit Containers for Capsules and Tablets (USP <671>) H. Other Dosage Forms III. Postapproval Packaging Changes IV. Type III Drug Master Files V. Bulk Containers Bibliography Chapter 7: Material for Containers I. Glass Containers II. Nonplasticized Poly(Vinyl Chloride) for Containers for Noninjectable Aqueous Solutions III. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use IV. Nonplasticized Poly(Vinyl Chloride) for Containers for Dry Dosage Forms for Oral Administration V. Plasticized Poly(Vinyl Chloride) for Containers for Aqueous Solutions for Intravenous Infusion VI. Polyethylene Terephthalate for Containers for Preparations Not for Parenteral Use VII. Polyolefins VIII. Polyethylene with Additives for Containers for Parenteral Preparations and for Ophthalmic Preparations IX. Polypropylene for Containers and Closures for Parenteral Preparations and Ophthalmic Preparations X. Poly(Ethylene/Vinyl Acetate) for Containers and Tubing for Total Parenteral Nutrition Preparations XI. Plastic Containers for Aqueous Solutions for Infusion XII. Sterile Single-Use Plastic Syringes XIII. Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders, and for Freeze-Dried Powders XIV. Silicone Oil Used as a Lubricant XV. Silicone Elastomer for Closures and Tubing Chapter 8: Stability Testing of New Drug Substances and Products I. Introduction A. Objectives of the Guideline B. Scope of the Guideline C. General Principles II. Guidelines A. Drug Substance 1. General 2. Stress Testing 3. Selection of Batches 4. Container Closure System 5. Specification 6. Testing Frequency 7. Storage Conditions 8. Stability Commitment 9. Evaluation 10. Statements/Labeling B. Drug Product 1. General 2. Photostability Testing 3. Selection of Batches 4. Container Closure System 5. Specification 6. Testing Frequency 7. Storage Conditions 8. Stability Commitment 9. Evaluation 10. Statements/Labeling Glossary Bibliography Chapter 9: Stability Testing: Photostability Testing of New Drug Substances and Products I. General A. Preamble B. Light Sources C. Procedure II. Drug Substance A. Presentation of Samples B. Analysis of Samples C. Judgement of Results III. Drug Product A. Presentation of Samples B. Analysis of Samples C. Judgement of Results IV. Annex A. Quinine Chemical Actinometry Chapter 10: Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products I. Introduction A. Objectives of the Guideline B. Background C. Scope of the Guideline II. Guidelines A. General B. Applicability of Reduced Designs C. Bracketing 1. Design Factors 2. Design Considerations and Potential Risks 3. Design Example D. Matrixing 1. Design Factors 2. Design Considerations 3. Design Examples 4. Applicability and Degree of Reduction 5. Potential Risk E. Data Evaluation Chapter 11: Evaluation of Stability Data I. Introduction A. Objectives of the Guideline B. Background C. Scope of the Guideline II. Guidelines A. General Principles B. Data Presentation C. Extrapolation D. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products Intended for Room-Temperature Storage 1. No Significant Change at Accelerated Condition 2. Significant Change at Accelerated Condition E. Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products Intended for Storage below Room Temperature 1. Drug Substances or Products Intended for Storage in a Refrigerator 2. Drug Substances or Products Intended for Storage in a Freezer 3. Drug Substances or Products Intended for Storage below −20°C F. General Statistical Approaches Appendices Appendix A: Decision Tree for Data Evaluation for Retest Period or Shelf-Life Estimation for Drug Substances or Products (Excluding Frozen Products) Appendix B: Examples of Statistical Approaches to Stability Data Analysis B.1. Data Analysis for a Single Batch B.2. Data Analysis for One-Factor, Full-Design Studies B.3. Data Analysis for Multifactor, Full-Design Studies B.4. Data Analysis for Bracketing Design Studies B.5. Data Analysis for Matrixing Design Studies References Chapter 12: Stability Data Package for Registration Applications in Climatic Zones III and IV I. Introduction A. Objectives of the Guideline B. Background C. Scope of the Guideline II. Guidelines A. Continuity with the Parent Guideline B. Storage Conditions 1. General Case 2. Aqueous-Based Drug Products Packaged in Semipermeable Containers 3. Tests at Elevated Temperature and/or Extremes of Humidity C. Additional Considerations References Chapter 13: EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use I. Introduction Part I: Chapter 1: Quality Management Principle Quality Assurance Good Manufacturing Practice for Medicinal Products (GMP) Quality Control Product Quality Review Quality Risk Management Chapter 2: Personnel Principle General Key Personnel Training Personnel Hygiene Chapter 3: Premises and Equipment Principle Premises Production Area Storage Areas Quality Control Areas Ancillary Areas Equipment Chapter 4: Documentation Principle General Specifications for Starting and Packaging Materials Specifications for Intermediate and Bulk Products Specifications for Finished Products Manufacturing Formula and Processing Instructions Packaging Instructions Batch Processing Records Batch Packaging Records Procedures and Records Sampling Testing Other Chapter 5: Production Principle General Prevention of Cross-Contamination in Production Validation Starting Materials Processing Operations: Intermediate and Bulk Products Packaging Materials Packaging Operations Finished Products Rejected, Recovered, and Returned Materials Chapter 6: Quality Control Principle General Good Quality Control Laboratory Practice Documentation Sampling Testing Ongoing Stability Program Chapter 7: Contract Manufacture and Analysis Principle General The Contract Giver The Contract Acceptor The Contract Chapter 8: Complaints and Product Recall Principle Complaints Recalls Chapter 14: Impurities: Guideline for Residual Solvents I. Introduction II. Scope of the Guideline III. General Principles A. Classification of Residual Solvents by Risk Assessment B. Methods for Establishing Exposure Limits C. Options for Describing Limits of Class 2 Solvents D. Analytical Procedures E. Reporting Levels of Residual Solvents IV. Limits of Residual Solvents A. Solvents to Be Avoided B. Solvents to Be Limited C. Solvents with Low Toxic Potential D. Solvents for Which No Adequate Toxicological Data Were Found Glossary Appendix 1 List of Solvents Included in the Guideline Appendix 2 Additional Background A2.1 Environmental Regulation of Organic Volatile Solvents A2.2 Residual Solvents in Pharmaceuticals Appendix 3 Methods for Establishing Exposure Limits Chapter 15: Electronic Records and Signatures (CFR 21 Part 11 Compliance) Sec. 11.2 Implementation Sec. 11.3 Definitions Subpart B: Electronic Records Sec. 11.10 Controls for Closed Systems Sec. 11.30 Controls for Open Systems Sec. 11.50 Signature Manifestations Sec. 11.70 Signature/Record Linking Subpart C: Electronic Signatures Sec. 11.100 General Requirements Sec. 11.200 Electronic Signature Components and Controls Sec. 11.300 Controls for Identification Codes/Passwords Chapter 16: Product-Specific Bioequivalence Testing Protocols Chapter 17: Formulation Considerations 1. Background 2. Ion Resin Complexes 3. Ion Exchange Resins 3.1 Drug Loading 3.2 Coating Drug–Resin Complexes 4. Cyclodextrins Chapter 18: Pediatric Pharmaceutical EU Legislation Background The Main Points in the Regulation Implications Chapter 19: Pediatric Formulations Specific Considerations on Formulations for Neonates Collaboration on Pediatric Formulations Conclusions Bibliography Chapter 20: SOP and Specification to Establish Electronic Submission to Regulatory Agencies 1. Purpose 2. Scope 3. Definitions and Abbreviations 4. Responsibilities 4.1 Information Technology 4.2 Regulatory Affairs 4.3 Publishing 5. Materials and Equipment 5.1 Materials 5.2 Equipment 6. Health and Safety 7. Procedure 7.1 Secure E-mail Setup 7.2 Requesting a Pre-Assigned Application Number 7.3 ESG Account Setup 8. References 9. Exhibits Exhibit I—Pre-Assigned Application Number Request Exhibit II – Sample Letters of Non-Repudiation Agreement 10. Revision History 11. ICH eCTD Specification 11.1 Introduction 11.2 Background 11.3 Scope 11.4 Requirements 11.5 Change Control 11.5.1 Introduction 11.5.2 Process 11.5.3 Procedure 11.6 Approach to Documentation and Use of the eCTD Specification Appendix 1: Overall Architecture 1.1 Guiding Design Principles 1.2 Business Model 1.3 Modular Structure of the eCTD 1.4 XML-Based eCTD 1.5 Multiple Region Support 1.6 Life Cycle Management Appendix 2: The eCTD Submission 2.1 Introduction 2.2 The eCTD Submission 2.2.1 Directory Structure 2.2.2 XML eCTD Instance 2.3 eCTD Template 2.4 Logical Documents and Files 2.5 Formats 2.6 Common Formats 2.7 Regional Use of Other Formats 2.8 Links 2.9 Presentation 2.10 Checksums 2.11 Element to file directory mapping 2.12 File extension 2.13 Name Character encoding 2.14 References Appendix 3: General Considerations for the CTD Modules 3.1 Introduction 3.2 Folder and File Naming Conventions 3.3 Screenshots and Folder Hierarchy 3.4 Module 1 Administrative Information and Prescribing Information 3.5 Module 2 Summaries 3.6 Module 3 Quality 3.7 Module 4 Nonclinical Study Reports 3.8 Module 5 Clinical Study Reports Appendix 4: File Organization for the eCTD Appendix 5: Region-Specific Information Including Transmission and Receipt 5.1 Introduction 5.2 Region-Specific Information: Module 1 5.3 Submission Addresses 5.4 Media 5.5 Cover Letter 5.6 Preparing the Media 5.7 Transport 5.8 Security 5.9 Receipt 5.10 Acknowledgment Appendix 6: The eCTD XML Submission 6.1 Background 6.2 File Names and Directory Structure 6.3 Life Cycle Management 6.4 Operation Attribute 6.5 DTD Content Model 6.6 eCTD Element/Attribute Instructions 6.7 Instructions for a Simple New Submission 6.8 Instructions for an Amendment, Supplement, or Variation 6.9 Instructions for Multiple Indications 6.10 Instructions for Multiple Drug Substances, Manufacturers, and Products 6.11 Instructions for extending XML eCTD DTD elements 6.12 Instructions for Submitting Sections as Paper Appendix 7: Specification for Submission Formats 7.1 Introduction 7.2 PDF 7.2.1 Version 7.2.2 Fonts 7.2.3 Use of Color Fonts 7.2.4 Page Orientation 7.2.5 Page Size and Margins 7.2.6 Source of Electronic Document 7.2.7 Methods for Creating PDF Documents and Images 7.2.8 Hypertext Linking and Bookmarks 7.2.9 Page Numbering 7.2.10 Document Information Fields 7.2.11 Open Dialog Box 7.2.12 Security 7.2.13 Indexing PDF Documents 7.2.14 Use of Acrobat Plug-Ins 7.3 XML Files 7.4 SVG Files Appendix 8: XML eCTD DTD Appendix 9: Glossary Logical Document Appendix A: GMP Audit Template GLOSSARY Appendix B: Dissolution Testing Appendix C: Excipients Part II: Manufacturing Formulations Liquid Formulations Abacavir Sulfate Oral Solution Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup Acetaminophen Drops Acetaminophen Oral Suspension Acetaminophen Rectal Solution Acetaminophen Suspension Acetaminophen Syrup Acetaminophen Syrup Acetaminophen Syrup for Children Acetaminophen Syrup Acetaminophen Syrup Acne Scrub Acyclovir Oral Suspension (2% = 200 mg/10 mL) Acyclovir Oral Suspension Acyclovir Oral Suspension Adapalene Solution Albendazole Oral Suspension Albendazole Suspension Albuterol Inhalation Solution Albuterol Inhalation Solution Alginic Acid + Aluminum Hydroxide + Magnesium Silicate Tablets (500 mg + 100 mg + 25 mg) Alpha-Bisabolol Aqueous Mouthwash Solution Alpha-Bisabolol Buccal or Topical Solution Alpha-Bisabolol Ethanolic Mouthwash Solution Alpha-Bisabolol Mouthwash Solution Aluminum Hydroxide + Magnesium Silicate Chewable Tablets (120 mg + 250 mg) Aluminum Chloride Solution Aluminum Hydroxide and Magnesium Carbonate Dry Syrup Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Tablets Aminacrine Hydrochloride Topical Solution Amoxicillin Powder for Suspension Amoxicillin–Clavulanate Syrup Amoxicillin–Clavulanate Syrup Ampicillin Powder for Suspension Ampicillin Powder for Suspension Ampicillin and Cloxacillin Oily Suspension Amprenavir Capsules Amprenavir Capsules Amprenavir Oral Solution Anise Oil Solution Antipyrine and Benzocaine Elixir Antiseptic Wet Wipes Apraclonidine Hydrochloride Ophthalmic Solution Ascorbic Acid Solution Atovaquone Suspension Atovaquone Suspension Azelastine Hydrochloride Nasal Spray Azelastine Hydrochloride Nasal Spray Azithromycin Suspension Azithromycin Suspension Azulene Solution Azulene Solution (1%) Barium Sulfate Oral Suspension Beclomethasone Dipropionate Inhalation Aerosol Beclomethasone Dipropionate Inhalation Aerosol Beclomethasone Dipropionate and Salbutamol Sulfate Nasal Spray Benzethonium Chloride Solution Benzethonium Chloride and Benzocaine Topical Anesthetic Benzocaine and Tetracaine Topical Solution Benzyl Benzoate Solution Beta-Estradiol Vaginal Solution Betamethasone Syrup Bismuth Carbonate Suspension Bismuth Subsalicylate Suspension Bromazepam Drops Bromhexine Hydrochloride Syrup Bromhexine Hydrochloride Syrup—Alcohol Free Bromhexine Hydrochloride Syrup Budesonide Inhaler Butamirate Citrate Syrup Caffeine Citrate Oral Solution Calcipotriene Solution Calcitonin Nasal Spray Calcitonin Nasal Spray Calcium Carbonate and Guar Gum Suspension Calcium Iodide and Ascorbic Acid Syrup Carbamazepine Oral Suspension 2% Carbetapentane Tannate and Chlorpheniramine Suspension Carnitine and Coenzyme Q Solution Cefaclor Suspension Cefadroxil Monohydrate Oral Suspension Cefpodoxime Proxetil Oral Suspension Cefpodoxime Proxetil Oral Suspension Cefpodoxime Proxetil for Oral Suspension Cefuroxime Axetil Suspension Cetirizine Hydrochloride Syrup Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup Chloramphenicol Palmitate Oral or Topical Emulsion (2.5% = 250 mg/10 mL) Chloramphenicol Palmitate Oral or Topical Emulsion (5% = 500 mg/10 mL) Chloramphenicol Ophthalmic Solution Chloramphenicol Palmitate Oral or Topical Emulsion Chlorhexidine Gel Chlorpheniramine Maleate Syrup Chloroxylenol Surgical Scrub Ciclopirox Topical Solution Cimetidine Syrup Ciprofloxacin Hydrochloride and Hydrocortisone Otic Suspension Cisapride Suspension Citalopram Hydrobromide Oral Solution Clarithromycin Suspension, 125 mg/5 ml reconstituted Clindamycin Phosphate Topical Solution Clotrimazole Topical Solution Clotrimazole Topical Solution (3%) Codeine Phosphate and Acetaminophen Elixir Colistin Sulfate, Neomycin, Thonzonium Bromide, and Hydrocortisone Otic Suspension Cotrimoxazole Oral Suspension Cromolyn Sodium Nasal Spray Cromolyn Sodium Oral Concentrate Crospovidone Oral Suspension (2000 mg/10 mL) Cyclosporin Oral Solution Cyclosporin Soft Gelatin Capsules Desmopressin Acetate Nasal Spray Dexamethasone Elixir Dextromethorphan and Chlorpheniramine Maleate Solution Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup Dextromethorphan Liquid Dextromethorphan Liquid Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup Dextromethorphan Solution Diazepam Rectal Solution Diclofenac Oral Solution Didanosine for Oral Solution Digoxin Elixir Pediatric Dihydroergotamine Mesylate Drops Diphenhydramine and Ammonium Chloride Syrup Diphenhydramine Hydrochloride Liquid Dornase-Alpha Inhalation Solution Doxercalciferol Capsules Dyphylline, Guaifenesin Elixir Electrolyte Lavage Solution Eplerenone Solution Erythromycin Drops Erythromycin Topical Solution Estradiol Nasal Spray Ethchlorvynol Gelatin Capsule (200 mg) Eucalyptol Solution Eucalyptol Solution (8%) Eucalyptus and Mint Emulsion Fentanyl Citrate Nasal Spray Ferrous Sulfate Oral Solution Ferrous Sulfate Oral Syrup Fir Needle Oil Solution Fluconazole Oral Suspension Flunisolide Spray Fluocinonide Topical Solution Fluorouracil Solution Fluorouracil Topical Solution Fluticasone Suspension Spray Foot Bath Furosemide Syrup Gabapentin Oral Solution Galantamine Hydrobromide Oral Solution Glucose, Fructose, and Phosphoric Acid Antiemetic Solution Glycol Foam, Nonaqueous Gramicidin Ophthalmic Solution Guaifenesin, Pseudoephedrine, Carbinoxamine, and Chlophedianol Drops Haloperidol Oral Liquid Heparin Nasal Spray Hydrocodone Bitartrate Elixir Hydroxyzine Pamoate Oral Suspension Hyoscine Butylbromide Syrup Hyoscyamine Sulfate Elixir Ibuprofen Topical Solution Ibuprofen Pediatric Suspension Iron Infant Drops Iron Polystyrene and Vitamin C Syrup Ibuprofen Solution Ibuprofen Suspension Ibuprofen Suspension, Sugar Free Ibuprofen and Domperidone Maleate Suspension Insulin Inhalation Spray Ipratropium Bromide Inhalation Solution Ipratropium Bromide Nasal Spray Isoproterenol Sulfate and Calcium Iodide Syrup Isotretinoin Capsules Itraconazole Oral Solution Kaolin, Pectin, and Aluminum Hydroxide Suspension Kaolin–Pectin Suspension Kaolin–Pectin Suspension Ketoprofen Topical Solution Ketotifen Syrup Lamivudine Oral Solution Levalbuterol Hydrochloride Inhalation Solution Levocarnitine Oral Solution Linezolid for Oral Suspension Lithium Carbonate Solution Lithium Citrate Syrup Lomustine Nasal Spray Loracarbef for Oral Suspension Loratadine Syrup Mafenide Acetate Topical Solution Magaldrate Instant Powder for Dry Syrup Magaldrate Suspension Magaldrate with Simethicone Suspension Magaldrate with Simethicone Suspension Mebendazole Oral Suspension Mebendazole Suspension Megestrol Acetate Oral Suspension Menthol and Benzocaine Solution Menthol Mouthwash Mesalamine Rectal Suspension Enema Mesalamine Rectal Suspension Metformin Liquid Metoclopramide Oral Solution Metoclopramide Syrup Metronidazole Suspension Mineral and Multivitamin Syrup Minoxidil Solution Mint–Menthol Mouthwash Mint Oil Solution Mometasone Furoate Nasal Spray Monosulfiram Solution Multivitamin and Calcium Syrup Multivitamin and Mineral Syrup Multivitamin Drops Multivitamin Infant Drops Multivitamin Infant Drops Multivitamin Mineral Syrup Multivitamin Syrup Multivitamin Syrup Multivitamin with Fluoride Infant Drops Multivitamin Drops Multivitamin Syrup Multivitamin Syrup Multivitamin with Fluoride—Infant Drops Nafarelin Acetate Nasal Solution Naproxen Suspension Nevirapine Suspension Nicotine Spray Nimesulide Suspension Nimodipine Capsules Nitroglycerin Lingual Spray Norephedrine Syrup Norephedrine Syrup Nystatin Oral Suspension Nystatin Suspension Ofloxacin Otic Solution Omeprazole Solution Ondansetron Hydrochloride Dihydrate Oral Solution Orciprenaline Sulfate and Clobutinol Hydrochloride Syrup Oxitropium and Formoterol Nasal Spray Oxymetazoline Hydrochloride Nasal Solution Oxymetazoline Moisturizing Nasal Spray Oxymetazoline Nasal Spray Oxymetazoline Sinus Nasal Spray Oxymetazoline Nasal Solution Peptide Topical Liquid Pheniramine Maleate Syrup Phenobarbital, Hyoscyamine Sulfate, Atropine Sulfate, and Scopolamine Hydrobromide Elixir Phenylephrine Tannate and Chlorpheniramine Tannate Pediatric Suspension Phenylephrine Tannate and Pyrilamine Tannate Suspension Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, and Vitamin C Syrup Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, and Vitamin C Syrup Phenylpropanolamine Controlled-Release Capsules Phenytoin Suspension Phenytoin Suspension Pipenzolate Methyl Bromide and Phenobarbital Drops Podofilox Solution Polidocanol Wound Spray Polyvinylpyrrolidone–Iodine Gargle Solution Polyvinylpyrrolidone–Iodine Gargle Solution Concentrate Polyvinylpyrrolidone–Iodine Liquid Spray Polyvinylpyrrolidone–Iodine Mouthwash Polyvinylpyrrolidone–Iodine Mouthwash and Gargle Solution Concentrate Polyvinylpyrrolidone–Iodine Scrub Polyvinylpyrrolidone–Iodine Solution Polyvinylpyrrolidone–Iodine Solution Polyvinylpyrrolidone–Iodine Solution Polyvinylpyrrolidone–Iodine Solution Polyvinylpyrrolidone–Iodine Solution Polyvinylpyrrolidone–Iodine Surgical Scrub Polyvinylpyrrolidone–Iodine Surgical Scrub Polyvinylpyrrolidone–Iodine Vaginal Douche Concentrate Polyvinylpyrrolidone–Iodine Viscous Solution Polyvinylpyrrolidone–Iodine Mouthwash Povidone–Iodine Concentrates for Broilers and Cattle Povidone–Iodine Foam Spray Povidone–Iodine Gargle Povidone–Iodine Gargle Solution Concentrate Povidone–Iodine Liquid Spray Povidone–Iodine Mouthwash and Gargle Solution Concentrate Povidone–Iodine Powder Spray Povidone–Iodine Pump Spray Povidone–Iodine Shampoo Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Scrub Povidone–Iodine Surgical Scrub Povidone–Iodine Surgical Scrub Povidone–Iodine Vaginal Douche Concentrate Povidone–Iodine Viscous Solution Prednisone Oral Solution Prednisolone Sodium Phosphate Oral Solution Prednisolone Syrup Progesterone Capsules Promethazine and Codeine Syrup Promethazine and Dextromethorphan Syrup Promethazine Hydrochloride Syrup Promethazine Hydrochloride Syrup Promethazine Rectal Solution Promethazine Rectal Solution Pseudoephedrine Hydrochloride Syrup Pseudoephedrine Hydrochloride and Carbinoxamine Maleate Oral Drops Pseudoephedrine and Carbinoxamine Drops Pseudoephedrine Hydrochloride Syrup Ribavirin Inhalation Solution Risperidone Oral Solution Ritonavir Capsules Ritonavir Oral Solution Ritonavir and Lopinavir Oral Solution Rivastigmine Tartrate Oral Solution Salbutamol Aerosol Salbutamol Syrup Sugar Free Salbutamol Syrup Salicylic Acid Collodion Salmeterol Xinafoate Inhalation Aerosol Salmeterol Xinafoate Inhalation Aerosol Scopolamine Nasal Spray Selenium Sulfide Shampoo with Conditioner Sertraline Hydrochloride Oral Concentrate Sertraline Hydrochloride Solution Simethicone Drops Sirolimus Solution Sodium Chloride Nasal Drops Stavudine for Oral Suspension Sucralfate Suspension Sulfacetamide Sodium and Sulfur Cleanser and Suspension Sulfadiazine and Trimethoprim Veterinary Oral Suspension Sulfamethoxazole and Trimethoprim Suspension Sulfamethoxazole and Trimethoprim Suspension Sulfathiazole Veterinary Oral Solution Sulfidoxine Solution Sulfidoxine and Pyrimethamine Suspension Sumatriptan Nasal Spray Terfenadine Oral Suspension Terfenadine Suspension Theophylline Sodium Glycinate Elixir Thiabendazole Suspension Thiothixene Oral Concentrate Timolol Maleate Ophthalmic Drops Tolnaftate Foot Care Microemulsion Tolu Balsam Cough Syrup Tretinoin Solution (50 mg/100 g) Tretinoin Solution Triamcinolone Acetonide Nasal Spray Triclosan Oral Solution Triprolidine and Pseudoephedrine Hydrochloride Syrup Tulobuterol Syrup Tolnaftate Foot Care Microemulsion Triprolidine and Pseudoephedrine Hydrochloride Syrup Undecylenic Acid and Chloroxylenol Solution Urea Peroxide Ear Drops Valproic Acid Capsules Valproic Acid Syrup Vancomycin Hydrochloride Oral Solution Vitamin A and Vitamin D Infant Drops Vitamin A and D Infant Drops Vitamin A and Vitamin D3 Drops Vitamin A and Vitamin D3 Oral Solution Vitamin A and Vitamin D3 Syrup Vitamin A and Vitamin E Drops Vitamin A and Vitamin E Drops Vitamin A and Vitamin E Drops Vitamin A Concentrate, Water-Miscible Vitamin A Drops Vitamin B Complex Syrup Vitamin B Complex Syrup Vitamin B Complex and Vitamin C Syrup Vitamin B Complex (without B12) Syrup Vitamin B Complex, A, C, D, and Calcium Drops Vitamin B Complex and Iron Syrup Vitamin B Complex and Vitamin C Syrup Vitamin B Complex, A, C, and D Syrup Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Vitamin E Pediatric Drops Vitamin B Complex, Vitamin C, and Iron Syrup Vitamin C Drops Vitamin E and Benzocaine Solution Vitamin E Concentrate, Water-Miscible Vitamin E Drops Vitamin E Soft Gel Capsules Vitamin E Solution with Ethanol Xylometazoline Hydrochloride Nasal Solution Xylometazoline Hydrochloride Children’s Nasal Solution Zinc Pyrithione Shampoo Part III: Commercial Pharmaceutical Products Commercial Pharmaceutical Products Index Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume Four, Semisolid Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition About the Author Part I: Regulatory and Manufacturing Guidance Chapter 1: Waiver of In Vivo Bioequivalence Study I. Introduction II. The Biopharmaceuticals Classification System A. Solubility B. Permeability C. Dissolution III. Methodology for Classifying a Drug Substance and for Determining the Dissolution Characteristics of a Drug Product A. Determining Drug Substance Solubility Class B. Determining Drug Substance Permeability Class 1. Pharmacokinetic Studies in Humans 2. Intestinal Permeability Methods 3. Instability in the Gastrointestinal Tract C. Determining Drug Product Dissolution Characteristics and Dissolution Profile Similarity IV. Additional Considerations for Requesting a Biowaiver A. Excipients B. Prodrugs C. Exceptions 1. Narrow Therapeutic Range Drugs 2. Products Designed to Be Absorbed in the Oral Cavity V. Regulatory Applications of the BCS A. INDs/NDAs B. aNDAs C. Post-Approval Changes VI. Data to Support a Request for Biowaivers A. Data Supporting High Solubility B. Data Supporting High Permeability C. Data Supporting Rapid and Similar Dissolution D. Additional Information 1. Excipients 2. Prodrugs 3. Exceptions Bibliography Chapter 2: Quality Risk Management I. Introduction II. Scope III. Principles of Quality Risk Management IV. General Quality Risk Management Process A. Responsibilities B. Initiating a Quality Risk Management Process C. Risk Assessment D. Risk Control E. Risk Communication F. Risk Review V. Risk Management Methodology VI. Integration of Quality Risk Management into Industry and Regulatory Operations Glossary Annex I: Risk Management Methods and Tools I.1 Basic Risk Management Facilitation Methods I.2 Failure Mode Effects Analysis Potential Areas of Use(s) I.3 Failure Mode, Effects, and Criticality Analysis Potential Areas of Use(s) I.4 Fault Tree Analysis Potential Areas of Use(s) I.5 Hazard Analysis and Critical Control Points Potential Areas of Use(s) I.6 Hazard Operability Analysis Potential Areas of Use(s) I.7 Preliminary Hazard Analysis Potential Areas of Use(s) I.8 Risk Ranking and Filtering Potential Areas of Use(s) I.9 Supporting Statistical Tools Annex II: Potential Applications for Quality Risk Management II.1 Quality Risk Management as Part of Integrated Quality Management Documentation Training and Education Quality Defects Auditing/Inspection Periodic Review Change Management/Change Control Continual Improvement II.2 Quality Risk Management as Part of Regulatory Operations Inspection and Assessment Activities II.3 Quality Risk Management as Part of Development II.4 Quality Risk Management for Facilities, Equipment, and Utilities Design of Facility/Equipment Hygiene Aspects in Facilities Qualification of Facility/Equipment/Utilities Cleaning of Equipment and Environmental Control Calibration/Preventive Maintenance Computer Systems and Computer-Controlled Equipment II.5. Quality Risk Management as Part of Materials Management Assessment and Evaluation of Suppliers and Contract Manufacturers Starting Material Use of Materials Storage, Logistics, and Distribution Conditions II.6. Quality Risk Management as Part of Production Validation In-Process Sampling and Testing Production Planning II.7. Quality Risk Management as Part of Laboratory Control and Stability Studies Out of Specification Results Retest Period/Expiration Date II.8. Quality Risk Management as Part of Packaging and Labeling Design of Packages Selection of Container Closure System Label Controls Bibliography Chapter 3: Pharmaceutical Quality System I. Pharmaceutical Quality System A. Introduction B. Scope C. Relationship of ICH Q10 to Regional GMP Requirements, ISO Standards, and ICH Q7 D. Relationship of ICH Q10 to Regulatory Approaches E. ICH Q10 Objectives 1. Achieve Product Realization 2. Establish and Maintain a State of Control 3. Facilitate Continual Improvement F. Enablers: Knowledge Management and Quality Risk Management 1. Knowledge Management 2. Quality Risk Management G. Design and Content Considerations H. Quality Manual II. Management Responsibility A. Management Commitment B. Quality Policy C. Quality Planning D. Resource Management E. Internal Communication F. Management Review G. Management of Outsourced Activities and Purchased Materials H. Management of Change in Product Ownership III. Continual Improvement of Process Performance and Product Quality A. Lifecycle Stage Goals 1. Pharmaceutical Development 2. Technology Transfer 3. Commercial Manufacturing 4. Product Discontinuation B. Pharmaceutical Quality System Elements 1. Process Performance and Product Quality Monitoring System 2. Corrective Action and Preventive Action System 3. Change Management System 4. Management Review of Process Performance and Product Quality IV. Continual Improvement of the Pharmaceutical Quality System A. Management Review of the Pharmaceutical Quality System B. Monitoring of Internal and External Factors Impacting the Pharmaceutical Quality System C. Outcomes of Management Review and Monitoring Glossary Annex 1 Annex 2 Chapter 4: Pharmaceutical Development I. Introduction A. Approaches to Pharmaceutical Development II. Elements of Pharmaceutical Development A. Target Product Profile B. Critical Quality Attributes C. Linking Material Attributes and Process Parameters to CQAs—Risk Assessment D. Design Space 1. Selection of Variables 2. Defining and Describing a Design Space in a Submission 3. Unit Operation Design Space(s) 4. Relationship of Design Space to Scale and Equipment 5. Design Space vs. Proven Acceptable Ranges 6. Design Space and Edge of Failure E. Control Strategy F. Product Lifecycle Management and Continual Improvement III. Submission of Pharmaceutical Development and Related Information in CTD Formats A. Quality Risk Management and Product and Process Development B. Design Space C. Control Strategy D. Drug Substance Related Information Glossary Appendix 1: Differing Approaches to Pharmaceutical Developmenta Appendix 2: Illustrative Examples Example of Use of a Risk Assessment Tool Example of Depiction of Interactions Illustrative Examples of Presentation of Design Space Chapter 5: Scale-Up and Post-Approval Changes for Nonsterile Semisolid Dosage Forms: Manufacturing Equipment I. Preservative II. Manufacturing Changes III. Process A. Batch Size (Scale-Up or Scale-Down) IV. Manufacturing Site Manufacturing Equipment I. Introduction II. Particle Size Reduction and Separation A. Definitions 1. Unit Operations 2. Operating Principles B. Equipment Classifications 1. Fluid Energy Mills 2. Impact Mills 3. Cutting Mills 4. Compression Mills 5. Screening Mills 6. Tumbling Mills 7. Separators III. Mixing A. Definitions 1. Unit Operation 2. Operating Principles B. Equipment Classification 1. Convection Mixers, Low Shear 2. Convection Mixers, High Shear 3. Roller Mixers (Mills) 4. Static Mixers 5. Low-Shear Emulsifiers IV. Transfer A. Definitions 1. Unit Operation 2. Operating Principles B. Equipment Classification 1. Low Shear 2. High Shear V. Packaging A. Definitions 1. Unit Operation 2. Operating Principles B. Equipment Classification 1. Holders 2. Fillers 3. Sealers Chapter 6: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients 1. Introduction 1.1. Objective 1.2. Regulatory Applicability 1.3. Scope 2. Quality Management 2.1. Principles 2.2. Responsibilities of the Quality Unit(s) 23. Responsibility for Production Activities 2.4. Internal Audits (Self-Inspection) 2.5. Product Quality Review 3. Personnel 3.1. Personnel Qualifications 3.2. Personnel Hygiene 3.3. Consultants 4. Buildings and Facilities 4.1. Design and Construction 4.2. Utilities 4.3. Water 4.4. Containment 4.5. Lighting 4.6. Sewage and Refuse 4.7. Sanitation and Maintenance 5. Process Equipment 5.1. Design and Construction 5.2. Equipment Maintenance and Cleaning 5.3. Calibration 5.4. Computerized Systems 6. Documentation and Records 6.1. Documentation System and Specifications 6.2. Equipment Cleaning and Use Record 6.3. Records of Raw Materials, Intermediates, API Labeling and Packaging Materials 6.4. Master Production Instructions (Master Production and Control Records) 6.5. Batch Production Records (Batch Production and Control Records) 6.6. Laboratory Control Records 6.7. Batch Production Record Review 7. Materials Management 7.1. General Controls 7.2. Receipt and Quarantine 7.3. Sampling and Testing of Incoming Production Materials 7.4. Storage 7.5. Reevaluation 8. Production and In-Process Controls 8.1. Production Operations 8.2. Time Limits 8.3. In-Process Sampling and Controls 8.4. Blending Batches of Intermediates or APIs 8.5. Contamination Control 9. Packaging and Identification Labeling of APIs and Intermediates 9.1. General 9.2. Packaging Materials 9.3. Label Issuance and Control 9.4. Packaging and Labeling Operations 10. Storage and Distribution 10.1. Warehousing Procedures 10.2. Distribution Procedures 11. Laboratory Controls 11.1. General Controls 11.2. Testing of Intermediates and APIs 11.3. Validation of Analytical Procedures (see Section 12) 11.4. Certificates of Analysis 11.5. Stability Monitoring of APIs 11.6. Expiry and Retest Dating 11.7. Reserve/Retention Samples 12. Validation 12.1. Validation Policy 12.2. Validation Documentation 12.3. Qualification 12.4. Approaches to Process Validation 12.5. Process Validation Program 12.6. Periodic Review of Validated Systems 12.7. Cleaning Validation 12.8. Validation of Analytical Methods 13. Change Control 14. Rejection and Reuse of Materials 14.1. Rejection 14.2. Reprocessing 14.3. Reworking 14.4. Recovery of Materials and Solvents 14.5. Returns 15. Complaints and Recalls 16. Contract Manufacturers (Including Laboratories) 17. Agents, Brokers, Traders, Distributors, Repackers, and Relabelers 17.1. Applicability 17.2. Traceability of Distributed APIs and Intermediates 17.3. Quality Management 17.4. Repackaging, Relabeling, and Holding of APIs and Intermediates 17.5. Stability 17.6. Transfer of Information 17.7. Handling of Complaints and Recalls 17.8. Handling of Returns 18. Specific Guidance for APIs Manufactured by Cell Culture/Fermentation 18.1. General 18.2. Cell Bank Maintenance and Record Keeping 18.3. Cell Culture/Fermentation 18.4. Harvesting, Isolation, and Purification 18.5. Viral Removal/Inactivation Steps 19. APIs for Use in Clinical Trials 19.1. General 19.2. Quality 19.3. Equipment and Facilities 19.4. Control of Raw Materials 19.5. Production 19.6. Validation 19.7. Changes 19.8. Laboratory Controls 19.9. Documentation Glossary Chapter 7: Validation of Analytical Procedures I. Introduction II. Types of Analytical Procedures to Be Validated Validation Methodology Overview I. Introduction II. Specificity A. Identification B. Assay and Impurity Test(s) 1. Impurities Are Available 2. Impurities Are Not Available III. Linearity IV. Range V. Accuracy A. Assay 1. Drug Substance 2. Drug Product B. Impurities (Quantitation) C. Recommended Data VI. Precision A. Repeatability B. Intermediate Precision C. Reproducibility D. Recommended Data VII. Detection Limit A. Based on Visual Evaluation B. Based on Signal-to-Noise C. Based on the Standard Deviation of the Response and the Slope 1. Based on the Standard Deviation of the Blank 2. Based on the Calibration Curve D. Recommended Data VIII. Quantitation Limit A. Based on Visual Evaluation B. Based on Signal-to-Noise Approach C. Based on the Standard Deviation of the Response and the Slope 1. Based on Standard Deviation of the Blank 2. Based on the Calibration Curve D. Recommended Data IX. Robustness X. System Suitability Testing A. Introduction B. Background C. Bioanalytical Method Development and Validation 1. Guiding Principles 2. Bioanalytical Parameters of CCs and LBAs 3. Validated Methods: Expectations of In-Study Analysis and Reporting D. Incurred Sample Reanalysis E. Additional Issues 1. Endogenous Compounds 2. Biomarkers 3. Diagnostic Kits 4. Bridging Data from Multiple Bioanalytical Technologies 5. Dried Blood Spots F. Documentation 1. Summary Information 2. Documentation for Method Validation and Bioanalytical Reports G. APPENDIX Glossary References Chapter 8: Bioequivalence Testing of Topical Drugs I. Inactive Ingredients II. Waiver of Bioequivalence III. Bioequivalence Approaches A. Dermatopharmacokinetic Approaches 1. Performance and Validation of the Skin Stripping Technique IV. Sample Pilot Study A. DPK Bioequivalence Study Protocol 1. Protocol and Subject Selection 2. Application and Removal of Test and Reference Products 3. Sites and Duration of Application 4. Collection of Sample 5. Procedure for Skin Stripping B. Metrics and Statistical Analyses V. Pharmacodynamic Approaches A. In Vitro Release Approaches (Lower Strength) B. In Vitro Release: Extension of the Methodology C. Systemic Exposure Studies Chapter 9: Active Pharmaceutical Ingredients: GMP Compliance and Inspection Compliance I. Introduction II. FDA’s Risk-Based, Systems Approach to API Inspections The Quality System Manufacturing Facility Inspection Part I—Background General Scope of APIs Covered by This Program Part II—Implementation Objective Program Management Instructions Inspection Planning Profile Classes Types of Inspections Part III—Inspectional Inspection Approaches Full Inspection Option A Full Inspection Is Appropriate Abbreviated Inspection Option Compliance Inspections Selecting Systems for Coverage Preparing the Inspection Strategy Special Inspection Reporting Instructions Special Instructions for Foreign Drug Inspections Part IV—Analytical Part V—Regulatory/Administrative Strategy Part VI—References, Attachments, and Program Contacts Bibliography Part VII—Center Responsibilities Appendix A: Description of Each System and Areas of Coverage Quality System Facilities and Equipment System Materials System Production System Packaging and Labeling System Laboratory Control System Glossary Chapter 10: Test Procedures and Acceptance Criteria for New Chemical Drug Substances and Drug Products I. Introduction A. Objective of the Guideline B. Background C. Scope of the Guideline II. General Concepts A. Periodic or Skip Testing B. Release vs. Shelf Life Acceptance Criteria C. In-Process Tests D. Design and Development Considerations E. Limited Data Available at Filing F. Parametric Release G. Alternative Procedures H. Pharmacopoeial Tests and Acceptance Criteria I. Evolving Technologies J. Impact of Drug Substance on Drug Product Specifications K. Reference Standard III. Guidelines A. Specifications: Definition and Justification 1. Definition of Specifications 2. Justification of Specifications B. Universal Tests/Criteria 1. New Drug Substances 2. New Drug Products C. Specific Tests/Criteria 1. New Drug Substances 2. New Drug Products Glossary IV. Attachments Bibliography Chapter 11: Topical Testing of Transdermal Drug Products I. Study Designs A. Recommendations for a Cumulative Skin Irritation Study 1. Sample Size 2. Exclusion Criteria 3. Duration of Study 4. Study Design 5. Patch Application 6. Evaluations 7. Data Presentation and Analysis B. Recommendations for a Skin Sensitization Study (Modified Draize Test) 1. Sample Size 2. Exclusion Criteria 3. Duration of Study 4. Study Design 5. Patch Application 6. Data Presentation and Analysis C. Combined Studies Appendix A: Skin Irritation Scoring Systems Appendix B: Adhesion Score Appendix C: Statistics Bibliography Chapter 12: Drug Substance I. Preamble II. Classification of Impurities III. Rationale for the Reporting and Control of Impurities A. Organic Impurities B. Inorganic Impurities C. Solvents IV. Analytical Procedures V. Reporting Impurity Content of Batches VI. Listing of Impurities in Specifications VII. Qualification of Impurities Glossary Attachment 1: Thresholds Attachment 2: Illustration of Reporting Impurity Results for Identification and Qualification in an Application Attachment 3: Decision Tree for Identification and Qualification Chapter 13: Impurities in New Drug Products I. Introduction A. Objective of the Guideline B. Background C. Scope of the Guideline II. Rationale for the Reporting and Control of Degradation Products III. Analytical Procedures IV. Reporting Degradation Products Content of Batches V. Listing of Degradation Products in Specifications VI. Qualification of Degradation Products Glossary Attachment 1: Thresholds for Degradation Products in New Drug Products Attachment 2: Illustration of Reporting Degradation Product Results for Identification and Qualification in an Application Attachment 3: Decision Tree for Identification and Qualification of a Degradation Product Chapter 14: Formulation Factors in Semisolid Dosage Forms I. Potency Uniformity II. Equipment and Production Control A. Mixers B. Filling and Packaging C. Process Temperature Control III. Cleaning Validation A. Detailed Cleaning Procedures B. Sampling Plan for Contaminants C. Equipment Residue Limits IV. Microbiological A. Controls (Nonsterile Topicals) 1. Deionized Water Systems for Purified Water 2. Microbiological Specifications and Test Methods B. Preservative Activity V. Change Control VI. Transdermal Topical Products A. General Considerations B. The Role of In Vitro Release Testing C. In Vivo Bioequivalence Studies VII. Chewing Gum Composition Manufacture of Chewing Gum Fusion Method Direct Compression Evaluation Tests Release of Drug Chapter 15: Pediatric Research Equity Act (PREA) Compliance Introduction I. Background II. Overview—Requirements of PREA A. PREA Statutory Requirements B. Scope of Requirements 1. Applications Affected by PREA 2. Orphan Drugs 3. Generic Drugs Under 505(j) of the Act [21 U.S.C. 355(j)] III. The Pediatric Assessment A. What Is the Pediatric Assessment? [Section 505B(a)(2) of the Act] B. When to Submit the Pediatric Assessment in Compliance wit C. What Types of Data Are Submitted as Part of the Pediatric IV. The Pediatric Plan and Submissions A. When to Develop a Pediatric Plan B. What Ages to Cover in a Pediatric Plan C. Must the Sponsor Develop a Pediatric Formulation? D. When to Initiate Pediatric Studies E. What Information Must Be Submitted to FDA V. Waivers and Deferrals A. What Is a Waiver? B. How to Apply for a Waiver 1. Criteria for Full Waiver [Section 505B(a)(4)(A) of the Act] 2. Criteria for Partial Waiver [Section 505B(a)(4)(B) of the Act] 3. Information in a Waiver Request 4. Waiver Decision C. What Is a Deferral? D. How to Apply for a Deferral 1. Criteria for Deferral [Section 505B(a)(3) of the Act] 2. Information in a Deferral Request 3. Deferral Decision VI. Compliance with PREA VII. PREA and Pediatric Exclusivity VIII. Information A. Additional Information Concerning PREA B. Additional Information Concerning Pediatric Exclusivity Attachment A—Sample Waiver Request Attachment B—Sample Deferral Request Attachment C—Compliance Dates for Applications Subject to PREA Chapter 16: Global Regulatory Guidance on Bioequivalence Testing Background Global Diversity Global Agencies General Assessment of Bioequivalence Pharmacokinetic Endpoint Studies Pharmacodynamic Endpoint Studies Clinical Endpoint Studies or Comparative Clinical Trials In Vitro Endpoint Studies Design and Analysis Study Design Bioanalysis Selection of Appropriate Analyte(s) Parent Drug vs. Metabolite(s) Enantiomers vs. Racemates Drug Products with Complex Mixtures Bioequivalence Metrics and Data Treatment Statistical Approaches Study Power 75/75 Rule 90% Confidence Interval Acceptance Criteria for Bioequivalence General For Highly Variable Drugs For Narrow Therapeutic Index Drugs (NTIDs) The World Health Organization Guidelines Bibliography Chapter 17: Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs—General Considerations I. Introduction II. Background A. General B. Bioavailability C. Bioequivalence 1. Preapproval Changes 2. Post-Approval Changes 3. BE Considerations III. Methods to Document BA and BE A. Pharmacokinetic Studies 1. General Considerations 2. Pilot Study 3. Full-Scale Study 4. Study Population 5. Single-Dose and Multiple-Dose (Steady-State) Testing 6. Bioanalytical Methodology 7. Administration Under Fasted/Fed Conditions 8. Moieties to Be Measured 9. Measures of Systemic Exposure 10. Comparison of PK Measures in BE Studies B. Other Approaches to Support BA/BE 1. In Vitro Tests Predictive of Human In Vivo BA 2. Pharmacodynamic Studies 3. Comparative Clinical Studies 4. In Vitro Studies IV. Documenting BA and BE for Various Dosage Forms A. Solutions and Other Solubilized Dosage Forms B. Immediate-Release Products 1. Preapproval Changes 2. Post-Approval Changes C. Modified-Release Products 1. Preapproval: BA and BE Studies 2. Post-Approval Changes D. Batch Size V. Additional Information on In Vitro Approaches A. In Vitro Studies Conducted in Support of a Waiver of an In Vivo BA or BE Data Requirement B. In Vitro Studies Conducted in Support of Demonstrating BA or BE 1. Immediate-Release Formulations (Capsules, Tablets, and Suspensions) 2. Modified-Release Formulations VI. Special Topics A. Alcoholic Beverage Effects on MR Drug Products B. Enantiomers vs. Racemates C. Drug Products with Complex Mixtures as the Active Ingredients D. Long-Half-Life Drugs E. Orally Administered Drugs Intended for Local Action F. Combination/Co-administered Drug Products G. Endogenous Substances H. Drug Products with High Intrasubject Variability Appendix A: General Study Design and Data Handling Study Conduct Sample Collection and Sampling Times Subjects with Pre-Dose Plasma Concentrations Data Deletion because of Vomiting Data Submission and Analysis Rounding off of Confidence Interval Values Notes Chapter 18: FDA 483 Observations Chapter 19: WHO Good Manufacturing Guidelines Quality Management in the Drug Industry: Philosophy and Essential Elements 1. Quality Assurance 2. GMPs for Pharmaceutical Products 3. Sanitation and Hygiene 4. Qualification and Validation 5. Complaints 6. Product Recalls 7. Contract Production and Analysis General The Contract Giver The Contract Accepter The Contract 8. Self-Inspection and Quality Audits Items for Self-Inspection Self-Inspection Team Frequency of Self-Inspection Self-Inspection Report Follow-Up Action Quality Audit Suppliers’ Audits and Approval 9. Personnel General Key Personnel 10. Training 11. Personal Hygiene 12. Premises General Ancillary Areas Storage Areas Weighing Areas Production Areas Quality Control Areas 13. Equipment 14. Materials General Starting Materials Packaging Materials Intermediate and Bulk Products Finished Products Rejected, Recovered, Reprocessed, and Reworked Materials Recalled Products Returned Goods Reagents and Culture Media Reference Standards Waste Materials Miscellaneous 15. Documentation General Documents Required Specifications and Testing Procedures Specifications for Starting and Packaging Materials Specifications for Intermediate and Bulk Products Specifications for Finished Products Master Formulae Packaging Instructions Batch Processing Records Batch Packaging Records Standard Operating Procedures and Records 16. Good Practices in Production General Prevention of Cross-Contamination and Bacterial Contamination During Production Processing Operations Packaging Operations 17. Good Practices in Quality Control Control of Starting Materials and Intermediate, Bulk, and Finished Products Test Requirements In-Process Control Finished Products Batch Record Review Stability Studies WHO Inspections Summary Bibliography Appendix A Appendix B Appendix C Part II: Manufacturing Formulations Semisolid Formulations Aceclofenac Gel Cream Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetylsalicylic Acid Suppositories Acne Cover Cream Acne Treatment Cream Acyclovir Cream Acyclovir Ointment Adapalene Cream Alclometasone Dipropionate Cream and Ointment Aloe Vera Gel Alum Cream 6-Aminonicotinamide Ointment 6-Aminonicotinic Acid Methyl Ester Ointment 6-Aminonicotinic Acid Ointment Aminacrine Hydrochloride Cream Amoxicillin Lotion Ampicillin Lotion Analgesic Clear Gel Analgesic Cream Analgesic Lotion Anthralin Cream Antiacne Gel Antifungal Foot Powder Antifungal Topical Cream Antiseptic Cream Antiseptic Lotion Antiseptic Lotion Arginine and Oleoresin Capsicum Cream Arginine Cream Arginine–Aspartate Cream Atropine Opthalmic Ointment Azelaic Acid Cream and Gel Baby Cream, Benzalkonium Chloride, and Zinc Oxide Baby Lotion Baby Lotion Baby Shampoo Bacitracin Zinc and Polymyxin B Sulfate Opthalmic Ointment Base Cream Base Ointment Base Ointment Base Ointment Base Ointment Becaplermin Gel (0.01%) Benzalkonium Chloride and Zinc Oxide Cream Benzalkonium Chloride Contraceptive Gel Benzocaine Cream Benzoyl Peroxide and Alpha-Bisabolol Gel Benzoyl Peroxide Antiacne Microemulsion Benzoyl Peroxide Cream Benzoyl Peroxide Gel Benzoyl Peroxide Lotion Benzoyl Peroxide Lotion Betamethasone and Cinchocaine Suppositories Betamethasone and Neomycin Gel Cream Betamethasone and Salicylic Acid Lotion Betamethasone Cream Betamethasone Cream Betamethasone Dipropionate Cream, Lotion, and Ointment Betamethasone Dipropionate Ointment Betamethasone Gel Betamethasone Opthalmic Ointment Betamethasone Valerate and Cinchocaine Ointment Betamethasone Valerate Cream Betamethasone Valerate Foam Betamethasone Valerate Ointment Betamethasone Valerate Ointment Bifonazole Cream (1%) Bisacodyl Suppositories Bisacodyl Suppositories Biscarboxychromonyloxy Propanol Ointment Bleaching and Antimicrobial Dentifrice Breast Care Cream Budesonide Cream Budesonide Ointment Buprenorphine Hydrochloride Suppository Burn Cream Burn Cream Butenafine Hydrochloride Cream Butesin Picrate and Metaphen Ointment Butesin Picrate Ointment Butoconazole Nitrate Vaginal Cream Calamine and Diphenhydramine Hydrochloride Lotion Calamine and Pramoxine Hydrochloride Lotion Calamine Cream Calamine Cream Calamine Lotion Calcipotriene Cream Calcipotriene Cream Calcium Carbonate Ointment Camphor, Eucalyptus Oil, and Menthol Ointment Carbamazepine Cream Carbamazepine Gel Carbamazepine Ointment Carbamide Peroxide Chewing Gum 2-Carbamoylpyrazinamide Ointment Castor Oil Ointment Cefaclor and Benzoyl Peroxide Gel Cefaclor and Benzoyl Peroxide Lotion Cetrimide Antiseptic Cream Cetrimonium Bromide Cream Chloramphenicol Opthalmic Ointment Chlorhexidine and Cetrimonium Bromide Cream Chlorhexidine Gel Chlorpromazine Suppositories Ciclopirox Cream, Lotion, and Gel Ciclopirox Nail Varnish Ciclopirox Nail Varnish Ciprofloxacin Hydrochloride Opthalmic Ointment Clindamycin Gel Clindamycin Lotion and Gel Clindamycin Phosphate Suppository Clindamycin Phosphate Topical Gel Clindamycin Phosphate Vaginal Cream Clindamycin Phosphate Vaginal Suppository Clobetasol Propionate Cream Clobetasol Propionate Cream, Ointment, and Gel Clobetasol Propionate Ointment Gel Clotrimazole and Betamethasone Cream and Lotion Clotrimazole Cream Clotrimazole Lotion Clotrimazole Lotion Clotrimazole Vaginal Cream Clotrimazole Vaginal Cream Clotrimazole Vaginal Cream Inserts Clotrimazole and Clindamycin Cream Clotrimazole and Clindamycin Suppositories Clotrimazole and Clindamycin Suppositories Coal Tar and Allantoin Cream Coal Tar and Allantoin Cream Coal Tar Cream Collagenase Ointment Conjugated Estrogens Vaginal Cream Cyanocobalamin Gel DBcAMP Ointment Desonide Cream, Ointment, and Lotion Desoximetasone Emollient Cream, Gel, and Ointment Dexamethasone Sodium Phosphate Ointment Dexpanthenol Cream Dexpanthenol Gel Cream Diclofenac Diethylamine Gel Diclofenac Diethylammonium Gel Diclofenac Sodium Suppositories Diclofenac Sodium Suppositories Diclofenac Sodium Suppositories Diclofenac Sodium Suppositories Dichlorobenzyl Alcohol Tooth Gel Dienestrol Vaginal Cream Diethylamine Salicylate Cream Diflorasone Diacetate Cream and Ointment Dimethicone and Zinc Oxide Ointment Dinoprostone Cervical Gel Dinoprostone Vaginal Insert and Suppositories Diphenhydramine Hydrochloride and Zinc Acetate Ointment Docosanol Lotion Econazole Nitrate and Benzoyl Peroxide Cream Econazole Nitrate and Benzoyl Peroxide Lotion Eflornithine Hydrochloride Cream Enzyme Extract Ointment Erythromycin and Neomycin Ointment Erythromycin Gel Erythromycin Ointment Erythromycin Ointment Estradiol and Norethindrone Acetate Transdermal System Estradiol Transdermal System Estradiol Vaginal Cream Estradiol Vaginal Cream Ethylenediamine Tetracetate Ointment Eucalyptus and Mint Ointment Foot Freshener Cream Foot Mousse Fluocinonide Cream Fluocinonide Cream, Ointment, and Gel Fluorometholone Opthalmic Ointment Fluorouracil Cream Flurandrenolide Lotion Flurandrenolide Topical Film Fluticasone Ointment Fluticasone Propionate Ointment Fluticasone Propionate Cream Fluticasone Propionate Cream Folic Acid Suppository 6-Formylaminonicotinamide Ointment and Lotion Foscarnet Cream Gamma Benzene Hexachloride Lotion Gentamicin Sulfate Cream Gentamicin Sulfate Ointment Gentamicin Sulfate Ointment Glycerin Suppositories Glycerin Suppositories Glycolic Acid Cream Gramicidin, Neomycin, Nystatin, and Triamcinolone Ointment Halobetasol Propionate Cream and Ointment Hemorrhoid Cream Heparin Gel Cream Hexachlorophene Cream Hydrocortisone Acetate and Pramoxine Hydrochloride Cream and Lotion Hydrocortisone Acetate Suppositories Hydrocortisone and Nitrofurazone Cream Hydrocortisone Butyrate Cream and Ointment Hydrocortisone Cream Hydrocortisone Cream Hydrocortisone Cream Hydrocortisone Cream and Ointment Hydrocortisone Gel Hydrocortisone Gel Hydrocortisone Gel Hydrocortisone Ointment Hydrogen Peroxide and Carbamide Peroxide Bleaching Oral Dentifrice Hydrogen Peroxide Bleaching Dentifrice Paste Hydrogen Peroxide Ointment Hydrophilic Ointment USP Hydroquinone Cream Hydroquinone Cream and Gel Hydroquinone Gel Ibuprofen and Domperidone Maleate Suppository Ibuprofen Cream Ibuprofen Gel Ibuprofen Gel Ibuprofen Gel Ibuprofen Gel Cream Ibuprofen Gel Cream Ibuprofen Gel Cream Imiquimod Cream Indomethacin Gel Indomethacin Gel Indomethacin Gel Indomethacin Suppositories Indomethacin Suppositories Insect Bite Cream Keratolytic Cream Ketoconazole Cream Ketoconazole Cream Kojic Dipalmitate Cream Lactic Acid Cream Lanolin Cream Lidocaine Adhesive System Gel Lidocaine and Prilocaine Topical Adhesive System Cream Lidocaine and Tribenoside Cream Lidocaine and Tribenoside Ointment Lidocaine and Tribenoside Suppositories Lidocaine Anorectal Cream Lidocaine, Eugenol, and Menthol Dental Ointment Lidocaine Gel Lidocaine Gel Lidocaine Ointment Lindane Lotion Mafenide Acetate Cream Malathion Lotion Mandelic Acid Cream Medicated Foot Cream Menthol, Methyl Salicylate, and Menthol Cream and Ointment Mercuric Oxide Ointment Mesalamine Suppository Methotrexate Cataplasms Methotrexate Cream Methotrexate Gel Methotrexate Lotion Methoxsalen Lotion Methyl Salicylate and Menthol Cream Methyl Salicylate and Menthol Lotion Methyl Salicylate and Menthol Lotion Methyl Salicylate and Menthol Ointment Methyl Salicylate Clear Gel Methyl Salicylate Cream Methyl Salicylate Cream Methyl Salicylate Heat Rub Lotion Methyl Salicylate Lotion Methyl Salicylate, Thyme, Pine, and Menthol Foot Cream Metoclopramide Suppositories Metoclopramide Suppositories Metoclopramide Suppositories Metoclopramide Suppositories Metronidazole Cream Metronidazole Gel Solution Metronidazole Lotion Metronidazole Vaginal Gel Miconazole Cream Miconazole Mouth Gel Miconazole Nitrate Cream Miconazole Nitrate Vaginal Suppositories Miconazole Nitrate Vaginal Suppositories (400 mg) Minoxidil Gel Minoxidil Gel Minoxidil Gel Minoxidil Gel Mometasone Furoate Cream Mometasone Furoate Lotion Monobenzone Cream Multivitamin Oral Gel Veterinary Multivitamin Oral Gel with Linoleic and Linolenic Acid Mupirocin Calcium Cream Mupirocin Ointment Mupirocin Ointment Naftifine Hydrochloride Cream Naftifine Hydrochloride Cream Nanoxynol Suppository with Bacterial Culture Neomycin and Bacitracin Ointment Neomycin Gel Neomycin, Polymyxin B Sulfate, and Bacitracin Zinc Opthalmic Ointment Nicotine Polymer Gel Nitrofurazone Cream Nondetergent Neutral Dry Skin Cream Nystatin Cream Nystatin Ointment Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment Octyl Metlioxycinnainate, Octyl Salicylate, and Oxybenzone Gel Olibanum Gum Cream Oxiconazole Cream and Lotion Oxymorphone Hydrochloride Suppositories Oxytetracycline Ointment Panthenol and Chlorhexidine Lotion Panthenol Ointment Panthenol Lotion Pantoprazole–Cholesterol Complex Suppository Papain Chewing Gum Papain Ointment Penciclovir Cream Peppermint Cream Permethrin Cream and Lotion Petrolatum and Lanolin Ointment Phenylephrine Ointment, Cream, Suppositories, and Gel Piroxicam Ointment Piroxicam and Dexpanthenol Gel Polymyxin, Bacitracin, Hydrocortisone, and Zinc Ointment Povidone–Iodine and Lidocaine Gel Povidone–Iodine Bar Soap Povidone–Iodine Bar Soap Povidone–Iodine Bar Soap Povidone–Iodine Cream Povidone–Iodine Cream Povidone–Iodine Cream Povidone–Iodine Gel Povidone–Iodine Gel Povidone–Iodine Gel Povidone–Iodine Gel Cream Povidone–Iodine Gels Povidone–Iodine Glucose Ointment Povidone–Iodine Glucose Ointment Povidone–Iodine Mastitis Cream for Cattle Povidone–Iodine Soft Gel Povidone–Iodine Transparent Ointment Povidone–Iodine Vaginal Ovule Povidone–Iodine Vaginal Ovule Povidone–Iodine Vaginal Ovules Povidone–Iodine Vaginal Ovules Pramoxine Cream Pramoxine Hydrochloride and Zinc Acetate Lotion and Ointment Pramoxine Suppositories Pramoxine Suppositories Pranoprofen Ointment Prednicarbate Emollient Cream Prochlorperazine Suppositories Progesterone Gel Promethazine Hydrochloride Suppositories Promethazine Suppository Psoriasis Cream Psoriasis Cream Resorcinol Acne Cream Rubefacient Analgesic Ointment Salicylic Acid Cream Salicylic Acid Cream Salicylic Acid Gel Scopolamine Transdermal Therapeutic System Selenium Sulfide Detergent Lotion Selenium Sulfide Lotion Silicone Cream Silver Sulfadiazine Cream Silver Sulfadiazine Cream Sodium Chloride Ointment Sodium Sulfacetamide Lotion Spermatocidal Effervescent Suppository Squalene Cream Starch Ointment Sucralafate and Hyaluronic Acid Ointment Sucralafate Ointment Sucralafate Opthalmic Ointment Sulfacetamide Ointment Sulfacetamide Sodium and Prednisolone Acetate Opthalmic Ointment Sulfanilamide Suppositories Sulfathiazole Cream Sulfur Ointment Tacrolimus Ointment Terconazole Vaginal Cream Terconazole Vaginal Suppositories Testosterone Gel Testosterone Transdermal System Tetracaine Gel and Cream Tetracycline Hydrochloride Ointment TGF Alpha-Ointment Therapeutic Skin Lotion Tolnaftate and Undecylenate Cream Tretinoin and Alpha-Bisabolol Gel Tretinoin and Dexpanthenol Gel Tretinoin Cream Tretinoin Cream Tretinoin Gel Tretinoin Gel Microsphere Triacontanol Ointment Triclosan Foot Care Cream Triclosan Foot Cream Tridax procumbens Ointment Trolamine Salicylate Cream Ulinastatin Suppository Ultrasonic Adhesive Gel Vitamin A Ointment Vitamin A Suppositories Vitamin C Vaginal Ointment Vitamin E Gel Cream Wound Debriding Ointment Zinc Oxide and Vitamin E Cream Zinc Oxide Lotion Zinc Oxide Ointment Zinc Oxide Ointment Zinc Oxide Ointment with Vitamin E and Aloe Zinc Pyrithione Detergent Lotion Zinc Undecylenate Cream Zirconium Oxide Lotion Part III: Commercial Pharmaceutical Formulations Commercial Pharmaceutical Formulations Index Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume Five, Over-the-Counter Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition Author Part I: Regulatory Guidance Chapter 1: European Directorate for the Quality of Medicines (EDQM) Certification 1.2.3.S Drug Substance A.2.3.S.1 General Information 1.2.3.S.1.1 Nomenclature 1.2.3.S.1.2 General Properties 2.3.S.2 Manufacture 2.3.S.2.1 Manufacturer(s) (Name, Manufacturer) and Sites Involved in the Entire Process 2.3.S.2.2 Description of Manufacturing Process and Process Controls 2.3.S.2.3 Control of Materials 2.3.S.2.4 Controls of Critical Steps and Intermediates 2.3.S.2.5 Process Validation and/or Evaluation 2.3.S.3 Characterization 2.3.S.3.1 Impurities 2.3.S.4 Control of the Drug Substance 2.3.S.4.1 Specification 2.3.S.4.2 Analytical Procedures 2.3.S.4.3 Validation of Analytical Procedures 2.3.S.4.4 Batch Analyses 2.3.S.4.5 Justification of Specification 2.3.S.5 Reference Standards or Materials 2.3.S.6 Container Closure System 2.3.S.7 Stability 2.3.S.7.1 Stability Summary and Conclusions 2.3.S.7.2 Postapproval Stability Protocol and Stability Commitment Chapter 2: Solid Oral Dosage Forms Validation I. Introduction II. Background III. Product Development A. Product Development Reports 1. Drug Substance Characterization 2. Manufacturing Procedures 3. In-Process Testing 4. Finished Product Testing 5. Dissolution Profile 6. Stability B. Preapproval Inspections 1. Master Formula 2. History Section of the Application 3. Development Data (Product Development Report) 4. Inspection of the Facilities 5. Raw Materials 6. Laboratory 7. Equipment IV. Validation Protocols V. Demonstration Runs (Validation Of The Process) A. Test Batch Relationships B. Postapproval Prospective Validation Inspections 1. Raw Materials 2. Manufacturing Procedures and Equipment 3. Granulation/Mix Analysis 4. In-Process Testing 5. Test Results 6. Investigations and Product Failures 7. Site Review Chapter 3: Current Regulatory Status of Over-the-Counter Products Background Regulatory Definitions Appendix I OTC Ingredient List Appendix II Unproven Safety of OTC Ingredients Chapter 4: Bioequivalence of Complementary and Alternative Medicines Background Appendix A: GMP Audit Template Appendix B: OTC Process and Ingredients Part II: Manufacturing Formulations Over-the-Counter Formulations Acetaminophen and Caffeine Tablets Acetaminophen and Caffeine Tablets Acetaminophen and Diphenhydramine Hydrochloride Hot Therapy Sachets Acetaminophen and Pseudoephedrine Hydrochloride Hot Therapy Sachets Acetaminophen and Diphenhydramine Hydrochloride Tablets Acetaminophen Sustained-Release Tablets Acetaminophen and Pseudoephedrine Hydrochloride Tablets Acetaminophen Chewable Tablets Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup Acetaminophen, Chlorpheniramine Maleate, and Pseudoephedrine Caplets Acetaminophen, Dextromethorphan, and Pseudoephedrine Caplets Acetaminophen, Doxylamine, and Caffeine Effervescent Granules Acetaminophen Drops Acetaminophen Effervescent Tablets Acetaminophen Fast-Dissolving Tablets Acetaminophen, Ibuprofen, and Orphenadrine Hydrochloride Tablets Acetaminophen Instant Granules Acetaminophen Instant Granules Acetaminophen Instant Granules Acetaminophen Microsphere Tablets Acetaminophen, Norephedrine, and Phenyltoloxamine Tablets Acetaminophen Oral Suspension Acetaminophen, Phenylpropanolamine, Dextromethorphan, and Chlorpheniramine Tablets Acetaminophen, Propoxyphenazone, and Caffeine Tablets Acetaminophen, Pseudoephedrine Hydrochloride, and Chlorpheniramine Hot Therapy Sachet Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suppositories Acetaminophen Suspension Acetaminophen Syrup Acetaminophen Syrup Acetaminophen Syrup for Children Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets Acetaminophen Tablets for Children Acetylcysteine Sachets Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets (250 mg + 250 mg + 50 mg) Acetylsalicylic Acid + Paracetamol (=Acetaminophen) Tablets (250 mg + 250 mg) Acetylsalicylic Acid + Vitamin C Tablets (400 mg + 250 mg) Acetylsalicylic Acid Tablets (500 mg) Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets Acetylsalicylic Acid, Acetaminophen, and Caffeine Tablets (Direct Compression) Acetylsalicylic Acid and Acetaminophen Tablets Acetylsalicylic Acid and Acetaminophen Tablets Acetylsalicylic Acid and Ascorbic Acid Tablets Acetylsalicylic Acid and Ascorbic Acid Tablets Acetylsalicylic Acid Suppositories Acetylsalicylic Acid Tablets (Buffered) Acetylsalicylic Acid Tablets (Direct Compression) Acetylsalicylic Acid Tablets (Direct Compression) Acetylsalicylic Acid Tablets (Direct Compression) Acne Cover Cream Acne Scrub Acne Treatment Cream Alginic Acid + Aluminum Hydroxide + Magnesium Silicate Tablets (500 mg+100 mg+25 mg) Aloe Vera Gel Alpha-Bisabolol Aqueous Mouthwash Solution Alpha-Bisabolol Buccal or Topical Solution Alpha-Bisabolol Ethanolic Mouthwash Solution Alpha-Bisabolol Mouthwash Solution Aluminum Acetylsalicylate Tablets Aluminum Hydroxide + Magnesium Silicate Chewable Tablets (120 mg+250 mg) Aluminum Hydroxide and Magnesium Carbonate Dry Syrup Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets Aluminum Hydroxide and Magnesium Hydroxide Chewable Tablets Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension Aluminum Hydroxide and Magnesium Hydroxide Antacid Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Suspension Aluminum Hydroxide and Magnesium Hydroxide Tablets Aluminum Hydroxide and Magnesium Silicate Chewable Tablets Aluminum Hydroxide, Magnesium Carbonate (or Oxide), and Simethicone Tablets Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Tablets Analgesic Clear Gel Analgesic Cream Analgesic Lotion Anise Oil Solution Antazoline and Xylometazoline Eye Drops Antiacne Gel Antifungal Foot Powder Antiseptic Cream Antiseptic Lotion Antiseptic Lotion Antiseptic Wet Wipes Asparagus Extract + Parsley Extract Tablets (200 mg+200 mg) Aspartame Effervescent Tablets (20 mg) Aspartame Granules in Sachets Aspartame Powder in Sachets Aspartame Tablets (25 mg), DC Aspartame Tablets Aspartame Tablets Aspartame Tablets Aspartame Tablets, Effervescent Aspirin, Acetaminophen, and Caffeine Tablets Aspirin, Acetaminophen, Caffeine, and Salicylamide Tablets Aspirin Tablets Aspirin-Coated Crystals Attapulgite Tablets Azulene Solution (1%) Baby Cream, Benzalkonium Chloride and Zinc Oxide Baby Lotion Baby Shampoo Barium Sulfate Oral Suspension (23%) Basic Cream for Various Active Ingredients Benzalkonium Chloride Contraceptive Gel Benzoyl Peroxide and Alpha-Bisabolol Gel Benzoyl Peroxide Antiacne Cream Benzoyl Peroxide Antiacne Gel Benzoyl Peroxide Antiacne Lotion Benzoyl Peroxide Antiacne Microemulsion Benzyl Benzoate Solution Berberine Tablets Beta-Carotene + Vitamin C + Vitamin E Chewable Tablets (10 mg + 500 mg + 250 mg) Beta-Carotene + Vitamin C + Vitamin E Effervescent Tablets (12 mg + 150 mg + 25 mg) Beta-Carotene + Vitamin C + Vitamin E Tablets (7 mg + 60 mg + 25 mg) Beta-Carotene + Vitamin C + Vitamin E Tablets (12 mg + 250 mg + 125 mg) Beta-Carotene Effervescent Tablets (7 mg) Beta-Carotene Effervescent Tablets Beta-Carotene Tablets Beta-Carotene Tablets Beta-Carotene Tablets Beta-Carotene, Vitamin C, and Vitamin E Chewable Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Beta-Carotene, Vitamin C, and Vitamin E Tablets Betamethasone and Neomycin Gel Cream Betamethasone Cream Betamethasone Gel Betamethasone Valerate Cream Betamethasone Valerate Ointment Bisacodyl Delayed-Release Tablets Bisacodyl Suppositories Bismuth Carbonate Suspension Bismuth Subsalicylate and Calcium Carbonate Tablet Bismuth Subsalicylate Suspension Bismuth Subsalicylate Swallow Tablets Bleaching and Antimicrobial Dentifrice Bran–Sucrose–Gelatin–Calcium Carbonate Tablet Bran Tablets Breast Care Cream Bromhexine Hydrochloride Syrup Bromhexine Hydrochloride Syrup (Alcohol Free) Bromhexine Hydrochloride Tablets Burn Cream Burn Cream Caffeine Tablets Calamine Cream Calamine Cream Calamine Lotion Calcium and Vitamin D Tablets Calcium Carbonate and Glycine Tablets Calcium Carbonate and Vitamin D Tablets Calcium Carbonate Chewable Tablets Calcium Carbonate Tablets Calcium Chewable Tablets (200 mg Ca) Calcium d-Pantothenate Chewable Tablets Calcium d-Pantothenate Tablets Calcium d-Pantothenate Tablets Calcium Effervescent Tablets Calcium Gluconate Tablets Calcium Glycerophosphate Tablets Calcium Glycerophosphate Tablets Calcium Glycerophosphate Tablets (200 mg) Calcium Iodide and Ascorbic Acid Syrup Calcium Phosphate Tablets for Cats and Dogs (Direct Compression) Calcium Phosphate Tablets for Cats and Dogs Carbamide Peroxide Chewing Gum Carbamide Peroxide and Hydrogen Peroxide Bleaching Oral Dentifrice Carbinoxamine Maleate, Phenylpropanolamine, and Acetaminophen Sustained-Release Tablets Carbonyl Iron, Copper Sulfate, and Manganese Sulfate Tablets Carnitine and Coenzyme Q Solution Cetirizine Hydrochloride Tablets Cetrimide Antiseptic Cream Cetylpyridinium Lozenges (2.5 mg) Charcoal Tablets Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup Chlorhexidine Gel Chlorhexidine Lozenges Chlorpheniramine Tablets Chlorpheniramine Maleate Syrup Chlorpheniramine and Pseudoephedrine Chewable Tablets Chlorpheniramine, Pseudoephedrine, and Dextromethorphan Chewable Tablets Chymotrypsin Tablets Cimetidine Tablets (200 mg) Cimetidine Chewable Tablets Citrate Effervescent Powder Crospovidone Effervescent Tablets Crospovidone Oral Suspension (2000 mg/10 mL) Crospovidone Water-Dispersible Tablets Cyanocobalamin Tablets Dexpanthenol Gel Cream Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup Dihydroxyaluminum Sodium Carbonate Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets Dimenhydrinate Tablets (50 mg), DC Diphenhydramine and Pseudoephedrine Chewable Tablets Diphenhydramine Hydrochloride Tablets Econazole Nitrate and Benzoyl Peroxide Antiacne Cream Econazole Nitrate and Benzoyl Peroxide Antiacne Lotion Eucalyptol Solution Eucalyptol Solution (8%) Eucalyptus and Mint Emulsion Eucalyptus and Mint Ointment Ferrous Fumarate Tablets Ferrous Sulfate, Manganese Sulfate, and Copper Sulfate Tablets Ferrous Sulfate Oral Solution Ferrous Sulfate Oral Syrup Ferrous Sulfate Tablets Fir Needle Oil Solution Folic Acid Tablets Folic Acid Tablets Foot Bath Foot Freshener Cream Foot Mousse Garlic Extract + Thyme Extract + Vitamin C (300 mg + 25 mg + 100 mg) Garlic Tablets Ginkgo Extract Tablets (40 mg) Glycerin Suppositories Glycerin Suppositories for Children Glycol Foam (Nonaqueous) Guaifenesin, Pseudoephedrine, Carbinoxamine, and Chlophedianol Drops Guaifenesin Tablets Guaifenesin Tablets Hemorrhoid Cream Herbal Hemorrhoid Tablets Horsetail Extract Tablets Hydrocortisone Aqueous Gel Hydrocortisone Aqueous Gel Hydrocortisone Cream Hydrocortisone Cream Hydrocortisone Ethanolic Gel Hydrocortisone Ointment Hydrogen Peroxide Bleaching Dentifrice Paste Ibuprofen Fast-Dissolve Tablets Ibuprofen-Coated Fast-Crumbling Granule Tablets Ibuprofen Pediatric Suspension Ibuprofen Chewable Tablets Ibuprofen Sustained-Release Bilayer Tablets Ibuprofen Tablets Inosin Tablets Insect Bite Cream Iron Infant Drops Iron (Polymer-Coated Particle) Tablets Iron Polystyrene and Vitamin C Syrup Kaolin-Pectin Suspension Kaolin-Pectin Tablets Keratolytic Cream Khellin Tablets Lidocaine Gel Lidocaine Gel Cream Lidocaine Ointment Lidocaine, Eugenol, and Menthol Dental Ointment Loperamide Hydrochloride Fast-Melt Tablet Loratadine and Pseudoephedrine Sulfate Tablets Loratadine Tablets Loratadine Fastab Loratadine Tablets Lycopene Tablet Cores (6 mg) Magaldrate Chewable Tablets Magaldrate Chewable Tablets (500 mg) Magaldrate Chewable Tablets (1000 mg) Magaldrate Dispersible Tablets Magaldrate Instant Powder or Dry Syrup Magaldrate Suspension Magaldrate Tablets Magaldrate with Simethicone Suspension Magaldrate with Simethicone Tablets Magnesium Carbonate Tablets Medicated Foot Cream Menthol Mouthwash Methyl Salicylate Analgesic Cream Methyl Salicylate Analgesic Cream Methyl Salicylate and Menthol Gel Methyl Salicylate Heat Rub Lotion Metoclopramide Tablets Miconazole Nitrate Cream Mineral and Multivitamin Syrup Mint-Menthol Mouthwash Mint Oil Solution Multivitamin and Beta-Carotene Tablets Multivitamin and Calcium Syrup Multivitamin and Carbonyl Iron Tablets Multivitamin and Fluoride Chewable Tablets Multivitamin and Mineral Syrup Multivitamin and Mineral Tablets Multivitamin and Mineral Tablets with Beta-Carotene Multivitamin, Calcium, and Iron Tablets Multivitamin + Calcium + Iron Tablets (1 RDA of Vitamins) Multivitamin + Carbonyl Iron Tablets (1–2 RDA of Vitamins) Multivitamin Chewable Tablets for Children Multivitamin Chewable Tablets for Children Multivitamin Drops Multivitamin Effervescent Granules Multivitamin Effervescent Tablets Multivitamin Effervescent Tablets Multivitamin Effervescent Tablets I, DC (1–2 RDA of Vitamins) Multivitamin Effervescent Tablets II, DC (3–4 RDA of Vitamins) Multivitamin Effervescent Tablets with Beta-Carotene Multivitamin Infant Drops Multivitamin Infant Drops Multivitamin Instant Granules Multivitamin Mineral Syrup Multivitamin + Minerals Tablets with Beta-Carotene (1 RDA of Vitamins) Multivitamin Oral Gel Multivitamin Oral Gel Veterinary Multivitamin Oral Gel with Linoleic and Linolenic Acid Multivitamin Syrup Multivitamin Syrup Multivitamin Tablet Cores with Beta-Carotene (1–2 RDA of Vitamins) Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets Multivitamin Tablets, DC (1–2 RDA of Vitamins) Multivitamin Tablets for Dogs Multivitamin Tablets for Dogs Multivitamin Tablets with Beta-Carotene Multivitamin Tablets with Copper and Zinc Multivitamin with Beta-Carotene Tablets Multivitamin with Fluoride Infant Drops Multivitamin with Zinc Tablets Naphazoline Eye Drops Neomycin Gel Niacin Tablets Nicotinamide Tablets Nicotinic Acid Tablets Nicotinic Acid (Niacin) Tablets Nicotinic Acid (Niacin) Tablets (200 mg) Nondetergent Neutral Dry Skin Cream Norephedrine Syrup Nystatin Cream Nystatin Ointment Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Cream Nystatin, Neomycin Sulfate, Gramicidin, and Triamcinolone Acetonide Ointment Omega Fatty Acids Tablets Oral Rehydration Salt (45 mEq) Orlistat Chewable Tablets Orlistat Chewable Tablets Orlistat Chewable Tablets Pancreatin Tablets Pancreatin Tablets Pancreatin and Cholic Acid Tablets Panthenol Lotion Panthenol Ointment Papain Chewable Tablets Papain Chewing Gum Peppermint Rub Cream Peptide Sublingual Tablet Peptide Topical Liquid Phenindione Tablets Phenolphthalein Tablets Phenolphthalein Tablets Phenylpropanolamine and Brompheniramine Fast-Dissolving Tablets Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, Vitamin C Syrup Phenylpropanolamine Hydrochloride Tablets Placebo Tablets Polidocanol Wound Spray Potassium Bicarbonate–Coated Tablet Povidone–Iodine and Lidocaine Gel Povidone–Iodine Bar Soap Povidone–Iodine Bar Soap Povidone–Iodine Bar Soap Povidone–Iodine Concentrates for Broilers and Cattle Povidone–Iodine Cream Povidone–Iodine Effervescent Vaginal Tablets Povidone–Iodine Foam Spray Povidone–Iodine Gargle Povidone–Iodine Gargle Solution Concentrate Povidone–Iodine Gel Cream Povidone–Iodine Gels Povidone–Iodine Glucose Ointment Povidone–Iodine Liquid Spray Povidone–Iodine Lozenges Povidone–Iodine Mastitis Cream for Cattle Povidone–Iodine Mouthwash and Gargle Solution Concentrate Povidone–Iodine Powder Spray Povidone–Iodine Pump Spray Povidone–Iodine Shampoo Povidone–Iodine Soft Gel Povidone–Iodine Solution Povidone–Iodine Scrub Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Solution Povidone–Iodine Surgical Scrub Povidone–Iodine Surgical Scrub Povidone–Iodine Transparent Ointment Povidone–Iodine Vaginal Douche Concentrate Povidone–Iodine Vaginal Ovule Povidone–Iodine Vaginal Ovule Povidone–Iodine Viscous Solution Promethazine Hydrochloride Syrup Promethazine Hydrochloride Tablets Promethazine Hydrochloride Tablets Pseudoephedrine Hydrochloride Capsules Pseudoephedrine Hydrochloride, Carbinoxamine Maleate Oral Drops Pseudoephedrine Hydrochloride Fast–Disintegrating Tablets Pseudoephedrine Hydrochloride Syrup Pseudoephedrine Hydrochloride Tablets Pseudoephedrine Tablets Psoriasis Cream Psoriasis Cream Psyllium and Dioctyl Sodium Sulfosuccinate Powder Psyllium and Docusate Sodium Tablets Psyllium and Docusate Sodium Wafer Psyllium Husk Granules Psyllium Husk Tablets PVP–Iodine Mouthwash Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Pyridoxine Tablets Ranitidine Hydrochloride Tablets Ranitidine Tablets Ranitidine Tablets Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Riboflavin Tablets Rubefacient Analgesic Ointment Saccharin Effervescent Tablets Saccharin Tablets Saccharin Tablets Salicylic Acid Cream Scopolamine Tablets Selegiline Tablets Selenium Sulfide Shampoo with Conditioner Serratiopeptidase Tablets Sertraline l-Lactate Osmotic Tablets Silicone Protective Cream Silymarin Tablets Simethicone and Magnesium Carbonate Tablets Simethicone Chewable Tablets Simethicone Chewable Tablets Simethicone Instant Granules (60 mg and 120 mg) Simethicone Tablets Sodium Fluoride Tablets Sodium Fluoride Tablets Spirulina Extract Chewable Tablets Sucralfate and Sodium Alginate Tablets Sulfur Antiseptic Ointment Tannin–Crospovidone Complex Tablets Tetrahydrozoline Eye Drops Thiamine and Caffeine Tablets Thiamine Hydrochloride Tablets Thiamine Hydrochloride Tablets (Sugar-Coated) Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine, Pyridoxine, and Cyanocobalamin Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Thiamine Tablets Tolnaftate and Undecylenate Foot Care Cream Tolnaftate Foot Care Microemulsion Tolu Balsam Cough Syrup Triclosan and Zinc Foot Deodorant Powder Triclosan Foot Care Cream Triprolidine and Pseudoephedrine Hydrochloride Syrup Triprolidine and Pseudoephedrine Hydrochloride Tablets Trolamine Salicylate Cream Ultrasonic Adhesive Gel Urea Peroxide Ear Drops Valeriana and Passiflora Extract Tablets Vitamin A and Vitamin D Infant Drops Vitamin A and Vitamin D3 Drops Vitamin A and Vitamin D3 Oral Solution Vitamin A and Vitamin D3 Syrup Vitamin A and Vitamin E Drops Vitamin A and Vitamin E Drops Vitamin A and Vitamin E Tablets Vitamin A Chewable Tablets Vitamin A Concentrate (Water-Miscible) Vitamin A Drops Vitamin A Suppositories Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A Tablets Vitamin A, Vitamin B6, and Vitamin E Tablets Vitamin A, Vitamin C, and Vitamin D3 Chewable Tablets Vitamin A, Vitamin C, and Vitamin E Tablets (1200 IU, 60 mg, 30 mg) Vitamin B Complex, Amino Acids, and Magnesium Effervescent Granules (Sugar-Free) Vitamin B Complex + Amino Acid + Magnesium Effervescent Granules (Sugar-free, 1 RDA of vitamins + 500 mg carnitine + 20 mg glutamine) Vitamin B Complex and Carnitine Tablets Vitamin B Complex and Folic Acid Dragées Vitamin B Complex and Iron Syrup Vitamin B Complex and Vitamin C Effervescent Tablets Vitamin B Complex and Vitamin C Instant Granules Vitamin B Complex and Vitamin C Syrup Vitamin B Complex and Vitamin C Syrup Vitamin B Complex and Vitamin C Tablets Vitamin B Complex and Vitamin C Tablets Vitamin B Complex, Choline, and Bile Tablets Vitamin B Complex Syrup Vitamin B Complex Syrup Vitamin B Complex Syrup (without B12) Vitamin B Complex Tablets Vitamin B Complex Tablets Vitamin B Complex Tablets Vitamin B Complex, Vitamin A, Vitamin C, and Vitamin D Syrup Vitamin B Complex, Vitamin A, Vitamin C, and Vitamin D Tablets Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Calcium Drops Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Mineral Tablets Vitamin B Complex, Vitamin A, Vitamin C, Vitamin D, and Vitamin E Pediatric Drops Vitamin B Complex, Vitamin C, and Calcium Effervescent Tablets Vitamin B Complex, Vitamin C, and Ferrous Sulfate Tablets Vitamin B Complex, Vitamin C, and Iron Syrup Vitamin B Complex, Vitamin C, and Iron Syrup Vitamin B Complex, Vitamin C, and Vitamin E Tablets Vitamin C and Calcium Carbonate Effervescent Tablets Vitamin C and Vitamin E Lozenges Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets Vitamin C Chewable Tablets with Dextrose Vitamin C Chewable Tablets with Fructose Vitamin C Chewable Tablets with Sucrose Vitamin C Drops Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Effervescent Tablets Vitamin C Tablets Vitamin C Tablets Vitamin C Tablets Vitamin E and Benzocaine Solution Vitamin E Chewable Tablets Vitamin E Chewable Tablets Vitamin E Chewable Tablets Vitamin E Concentrate (Water-Miscible) Vitamin E Drops Vitamin E Gel Cream Vitamin E Softgel Capsules Vitamin E Solution with Ethanol Vitamin E Tablets Vitamin E Tablets Zinc Oxide Lotion Zinc Oxide Ointment Zinc Pyrithione Shampoo Zinc Undecylenate Cream Zirconium Oxide Lotion Part III: Cosmetic Formulations Cosmetic Formulations Light Lip Gloss Heavy Lip Gloss Lip Care Paste Lipstick, Basic Lipstick, Light Glossy Lipstick, Clear Lipstick, Smooth Lipstick (Moisture-Rich Lipstick) Base Cream Oil-Based Foundation Sunscreen (Moisture Type) Sunscreen (Fresh Type) Manufacturing Directions WaterProof Eye Liner Oil-Based Facial Cleanser (Available in Wet Condition) Manufacturing Directions Oil-Based Facial Cleanser (for Heavy Make-Up) Oil-Free Facial Cleanser (Liquid) Oil-Free Facial Cleanser (Gel) Make-Up Remover (Separate Type) Cleansing Paste Massage Gel Part IV: Tablet Coating Formulations Introduction Approved Drug Colorants for Internal Use in Japan-1a Approved Drug Colorants for Internal Use in Japan-2a Approved Drug Colorants for Use in Canada I. Colorants Approved for Internal and External Drug Use II. Colorants Approved for External Drug Use Approved Drug Colorants Listed by the European Union Color Additives Exempt from Certification Permitted for Use in the United Statesa Provisionally Listed Color Additives Subject to U.S. Certificationa List of Permanently Listed Color Additives Subject to U.S. Certificationa Cellulose Based Hydroxypropyl Methylcellulose (Methocel, HPMC) Aqueous Coatings A. Brite Rose B. Cherry Red C. Geranium Rose D. Gloss E. Red F. Moderate Red G. Clear H. Green I. Holberry Red J. Sun Orange K. Opadry Yellow L. Opadry Yellow M. Opadry Red N. Opadry Green O. White Coating Hydroxypropyl Methylcellulose Opaque Organic Coating A. Brite Green B. Red Mahogany C. Sun Orange D. Dark Red E. Deep Yellow F. Pale Yellow G. Scarlet Red Hydroxypropyl MethylCellulose/Hydroxypropyl Cellulose (Klucel®) Coating A. White Hydroxypropyl MethylCellulose/EthylCellulose Coating A. Reddish Orange Opaque B. Subcoating Solution Hydroxy Methylcellulose/Hydroxy Ethyl-Cellulose Coating A. Blue B. Clear (50:50) Hydroxy Methylcellulose/Hydroxy Ethylcellulose Coating A. Clear Polyvinylpyrrolidone (PVP) Coatings A. Subcoating B. Kollidon® VA 64 (Polyvinylpyrrolidone/Vinylacetate Copolymer, BASF) Sugar-Coating Pan Accela Cota (Continuous Spraying) Kollidon® VA 64 and Polyvinyl Alcohol A. Kollidon® 30 and Shellac B. Kollidon® VA 64 and Hydroxypropyl Methylcellulose C. Povidone, Ethylcellulose, and Talc Cellulose Acetate phthalate and Carbowax Coatings A. Brite Green B. Cherry Red C. Clear D. Orange Sugar Coatings A. Basic B. Automatic C. Manual, White Enteric Coatings A. Kollicoat® and Kollidon® Enteric Film Coating Eudragit® Enteric Aqueous A. Brick Red B. Yellow C. Brown D. Dark Orange E. Orange F. Dispersed Orange Hydroxypropyl Methylcellulose Phthalate enteric Coating A. Clear Enteric B. Orchid Pink Opaque C. Light Apricot Orange Index Handbook of Pharmaceutical Manufacturing Formulations, Third Edition-Volume Six, Sterile Products-CRC Press (2019) Cover Half Title Title Page Copyright Page Dedication Contents Preface to the Series—Third Edition Preface to the Series—Second Edition Preface to the Series—First Edition Preface to the Volume—First Edition About the Author Part I: Regulatory and Manufacturing Chapter 1: Sterile Manufacturing Formulations Template I. Autoclaves II. Aseptic Contract Manufacturers A. Manufacturing Formulations Template III. Clean-Room Design and Construction IV. Clean-in-Place/Steam-in-Place (CIPISIP) V. Closure Washing and Sterilization VI. Consultants VII. Disinfectants and Preservatives VIII. Distillation Equipment IX. Engineering and Construction X. Filling Machines XI. Filter Aids XII. Flowmeters (Sanitary) XII. Freeze-Dryers (Sterilizable) XIII. Microfiltration Equipment and Filters A. Manufacturing Formulations Template XIV. Pumps (Sanitary) XV. Sterile Tanks and Related Stainless Equipment XVI. Sterility Test Equipment XVII. Sterilizing and Drying Tunnels (Hot Air) XVIII. Stoppering Machines Chapter 2: Inspection of Sterile Product Manufacturing Facilities I. Introduction II. cGMP Compliance Basics A. Personnel B. Buildings C. Air D. Environmental Controls E. Equipment F. Water for Injection G. Containers and Closures H. Sterilization 1. Methods 2. Indicators 3. Filled Containers I. Personnel Practices J. Laboratory Controls 1. Retesting for Sterility 2. Retesting for Pyrogens 3. Particulate Matter Testing 4. Production Records III. Aseptic Processing A. Introduction B. Buildings and Facilities 1. Critical Area (Class 100) 2. Supporting Clean Areas 3. Clean Area Separation 4. Air Filtration 5. Design C. Personnel Training, Qualification, and Monitoring 1. Manufacturing Personnel 2. Laboratory Personnel 3. Monitoring Program D. Components and Containers/Closures 1. Components 2. Containers/Closures E. Endotoxin Control F. Time Limitations G. Process Validation and Equipment Qualification 1. Process Simulations 2. Filtration Efficacy 3. Sterilization of Equipment and Containers/Closures H. Laboratory Controls 1. Environmental Monitoring 2. Microbiological Media and Identification I. Sterility Testing 1. Choice of Methods 2. Media 3. Personnel 4. Sampling and Incubation 5. Investigation of Sterility Positives J. Batch Record Review: Process Control Documentation IV. Processing Prior to Filling and Sealing Operations A. Aseptic Processing from Early Manufacturing Steps B. Aseptic Processing of Cell-Based Therapy Products (or of Products Intended for Use as Cell-Based Therapies) V. Aseptic Processing Isolators A. Maintenance 1. General 2. Glove Integrity B. Design 1. Airflow 2. Materials of Construction 3. Pressure Differential 4. Clean-Area Classifications C. Transfer of Materials and Supplies 1. Introduction 2. Discharge D. Decontamination 1. Surface Exposure 2. Efficacy 3. Frequency E. Filling Line Sterilization F. Environmental Monitoring G. Personnel VI. Blow-Fill-Seal Technology A. Equipment Design and Air Quality B. Validation and Qualification C. Batch Monitoring and Control VII. Lyophilization of Parenterals A. Introduction B. Product Type and Formulation C. Filling D. Lyophilization Cycle and Controls E. Cycle Validation F. Lyophilizer Sterilization and Design G. Finished Product Testing 1. Dose Uniformity 2. Stability Testing 3. Sterility Testing H. Finished Product Inspection—Meltback VIII. High-Purity Water Systems A. System Design B. System Validation C. Microbial Limits 1. WFI Systems 2. Purified Water Systems D. WFI Systems E. Still F. Heat Exchangers G. Holding Tank H. Pumps I. Piping J. Reverse Osmosis K. Purified Water Systems L. Process Water M. Evaluation Strategy Relevant Guidance Documents (FDA) Glossary Bibliography Chapter 3: New Drug Application for Sterilized Products I. Introduction II. Terminal Heat Sterilization A. Description of the Process and Product B. Thermal Qualification of the Cycle C. Microbiological Efficacy of the Cycle D. Microbiological Monitoring of the Environment E. Container/Closure and Package Integrity F. Bacterial Endotoxins Test and Method G. Sterility Testing Methods and Release Criteria H. of Formal Written Procedures III. Other Terminal Sterilization Processes A. Ethylene Oxide B. Radiation IV. Aseptic Fill Manufacturing Processes A. Buildings and Facilities B. Overall Manufacturing Operation C. Containers and Closures D. Procedures and Specifications for Media Fills E. Actions Concerning Product When Media Fills Fail F. Microbiological Monitoring of the Environment G. Container/Closure and Package Integrity H. Sterility Testing Methods and Release Criteria I. Bacterial Endotoxins Test and Method J. Evidence of Formal Written Procedures V. Maintenance of Microbiological Control and Quality: Stability Considerations A. Container/Closure Integrity B. Preservative Effectiveness C. Pyrogen or Endotoxin Testing Chapter 4: Validation of Cleaning Process I. Introduction II. Background III. General Requirements IV. Evaluation of Cleaning Validation A. Equipment Design B. Cleaning Process, Written Procedure, and Documentation C. Analytical Methods D. Sampling 1. Direct Surface Sampling 2. Rinse Samples 3. Routine Production In-Process Control Monitoring V. Establishment of Limits VI. Other Issues A. Placebo Product B. Detergent C. Test Until Clean Chapter 5: Viral Safety Evaluation of Biotechnology Products Derived from Cell Lines of Human or Animal Origin I. Introduction II. Potential Sources of Virus Contamination A. Viruses That Could Occur in the Master Cell Bank B. Adventitious Viruses That Could Be Introduced during Production III. Cell Line Qualification: Testing for Viruses A. Suggested Virus Tests for MCB, Working Cell Bank, and Cells at the Limit of In Vitro Cell Age Used for Production 1. Master Cell Bank 2. Working Cell Bank 3. Cells at the Limit of In Vitro Cell Age Used for Production B. Recommended Viral Detection and Identification Assays 1. Tests for Retroviruses 2. In Vitro Assays 3. In Vivo Assays 4. Antibody Production Tests C. Acceptability of Cell Lines IV. Testing for Viruses in Unprocessed Bulk V. Rationale and Action Plan for Viral Clearance Studies and Virus Tests on Purified Bulk VI. Evaluation and Characterization of Viral Clearance A. The Choice of Viruses for the Evaluation and Characterization of Viral Clearance 1. “Relevant” Viruses and “Model” Viruses 2. Other Considerations B. Design and Implications of Viral Clearance Evaluation and Characterization Studies 1. Facility and Staff 2. Scaled-Down Production System 3. Analysis of Step-Wise Elimination of Virus 4. Determining Physical Removal vs. Inactivation 5. Inactivation Assessment 6. Function and Regeneration of Columns 7. Specific Precautions C. Interpretation of Viral Clearance Studies 1. Acceptability D. Limitations of Viral Clearance Studies E. Statistics F. Reevaluation of Viral Clearance VII. Summary Glossary Appendix 1: Products Derived from Characterized Cell Banks which Were Subsequently Grown In Vivo Appendix 2: The Choice of Viruses for Viral Clearance Studies Appendix 3: Statistical Considerations for Assessing Virus Assays Probability of Detection of Viruses at Low Concentrations Appendix 4: Calculation of Reduction Factors in Studies to Determine Viral Clearance Appendix 5: Calculation of Estimated Particles per Dose Chapter 6: Analysis of the Expression Construct in Cells Used for Production of rDNA-Derived Protein Products I. Introduction II. Rationale for Analysis of the Expression Construct III. Characterization of the Expression System A. Expression Construct and Cell Clone Used to Develop the Master Cell Bank B. Cell Bank System C. Limit for In Vitro Cell Age for Production IV. Conclusion Glossary Chapter 7: Stability Testing of Biotechnological/Biological Products I. Preamble II. Scope of the Annex III. Terminology IV. Selection of Batches A. Drug Substance (Bulk Material) B. Intermediates C. Drug Product (Final Container Product) D. Sample Selection V. Stability-Indicating Profile A. Protocol B. Potency C. Purity and Molecular Characterization D. Other Product Characteristics VI. Storage Conditions A. Temperature B. Humidity C. Accelerated and Stress Conditions D. Light E. Container/Closure F. Stability after Reconstitution of Freeze-Dried Product VII. Testing Frequency VIII. Specifications IX. Labeling Glossary Chapter 8: Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products I. Introduction A. Objective B. Rationale C. Scope II. Guidelines A. Source, History, and Generation of the Cell Substrate 1. Introduction 2. Origin, Source, and History of Cells 3. Generation of the Cell Substrate B. Cell Banking 1. Cell Banking System 2. Cell Banking Procedures C. General Principles of Characterization and Testing of Cell Banks 1. Tests of Identity 2. Tests of Purity 3. Cell Substrate Stability 4. Tests for Karyology and Tumorigenicity Glossary BIBLIOGRAPHY Appendix 1: Primary Cell Substrates Introduction Source Tissue and Other Raw Materials Preparation of Primary Cell Substrates Testing of Primary Cell Substrates Chapter 9: Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process I. Introduction A. Objectives of the Guideline B. Background C. Scope D. General Principles II. Guidelines A. Considerations for the Comparability Exercise B. Quality Considerations 1. Analytical Techniques 2. Characterization 3. Specifications 4. Stability C. Manufacturing Process Considerations D. Demonstration of Comparability during Development E. Nonclinical and Clinical Considerations 1. Factors to be Considered in Planning Nonclinical and Clinical Studies 2. Type of Studies Glossary Bibliography Chapter 10: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products I. Introduction A. Objective B. Background C. Scope II. Principles for Consideration in Setting Specifications A. Characterization 1. Physicochemical Properties 2. Biological Activity 3. Immunochemical Properties 4. Purity, Impurities, and Contaminants 5. Quantity B. Analytical Considerations 1. Reference Standards and Reference Materials 2. Validation of Analytical Procedures C. Process Controls 1. Process-Related Considerations 2. In-Process Acceptance Criteria and Action Limits 3. Raw Materials and Excipient Specifications D. Pharmacopoeial Specifications E. Release Limits vs. Shelf Life Limits F. Statistical Concepts III. Justification of Specification IV. Specifications A. Drug Substance Specification 1. Appearance and Description 2. Identity 3. Purity and Impurities 4. Potency 5. Quantity B. Drug Product Specification 1. Appearance and Description 2. Identity 3. Purity and Impurities 4. Potency 5. Quantity 6. General Tests 7. Additional Testing for Unique Dosage Forms Glossary References Appendices 6.1 Appendix for Physicochemical Characterization 6.1.1 Structural Characterization and Confirmation 6.1.2 Physicochemical Properties 6.2 Appendix for Impurities 6.2.1 Process-Related Impurities and Contaminants 6.2.2 Product-Related Impurities Including Degradation Products Chapter 11: Essential Clean-Room Design Elements I. Optimized Designs II. Turbulent Type Clean Rooms III. Vertical Flow Clean Rooms IV. Laminar Flow Clean Rooms V. Horizontal Laminar Flow Clean Rooms A. Design of Class 500,000 Rooms B. Design of Class 100,000 Rooms C. Design of Class 10,000 Clean Rooms VI. The USP <797> Guidelines A. Issues B. Definitions C. Recommendations Appendix: Air-Handling Unit AHU Data Sheet Nonhazardous Clean Room—Room Data Sheet PEC and Buffer Room (Nonhazardous Clean Room)—Room Data Sheet Anteroom (Nonhazardous Clean Room)—Room Data Sheet Hazardous Clean Room—Room Data Sheet PEC and Buffer Room (Hazardous Clean Room)—Room Data Sheet Controlled Substance Vault and Secured Dispensing Receiving Area—Room Data Sheet Dispensing, Prepacking and EXTEMP—Room Data Sheet Appendix A Appendix B Part II: Manufacturing Formulations Sterile Product Formulations Abciximab Injection Acetazolamide Injection Acetylcholine Chloride Intraocular Solution Acyclovir Sodium Injection Adenosine 5′ Monophosphate Injection Adenosine Injection Adrenal Cortex Injection Adrenaline Tartarate Injection Alatrofloxacin Mesylate Injection Alatrofloxacin Mesylate Injection Alatrofloxacin Mesylate Injection Alatrofloxacin Mesylate Injection Albumin (Human) Albumin 5% Solution Albumin 20% Solution Albumin 25% Solution Albuterol Sulfate Inhalation Solution Aldesleukin for Injection Alemtuzumab Injection Alpha-Tocopherol (Vitamin E) Injection Alprostadil for Injection Alteplase Recombinant Injection Amikacin Sulfate Injection (50 mg/mL) Amikacin Sulfate Injection (250 mg/mL) Amikacin Sulfate Injection Amino Acid Parenteral Nutrition Solution Amino Acid Parenteral Nutrition Solution (8.5%) Amino Acid Parenteral Nutrition Solution: 10% Amino Acid Parenteral Injection Aminohippurate Sodium for Injection Aminophylline Injection Amiodarone Injection Amiodarone Injection Amoxicillin Lyophilisate for Injection (250 mg) Amoxicillin-Clavulanic Acid Injection Amoxicillin Powder for Injection Amphotericin B Cholesteryl Sulfate Complex for Injection Amphotericin B Injection Amphotericin B Lipid Complex Injection Amphotericin B Liposome for Injection Antazoline Sulfate and Xylometazoline Hydrochloride Ophthalmic Drops Antipyrine, Phenylephrine, and Pyrilamine Maleate Ophthalmic Drops Antipyrine, Phenylephrine, and Sodium Thiosulfate Ophthalmic Solution Antithymocyte Globulin (Rabbit) for Injection Aprotinin Injection Argatroban (Thrombin Inhibitor) Injection Arsenic Trioxide Injection Ascorbic Acid and B Complex Vitamins (Two Vials) Ascorbic Acid and B Complex Vitamins Ascorbic Acid and B Complex Vitamins Lyophilized in Covial Ascorbic Acid and B Complex Vitamins Ascorbic Acid and B Complex Vitamins Lyophilized with Diluent Ascorbic Acid and B Complex Vitamins Ascorbic Acid, B Complex Vitamin, with Beta-Carotene Injection Ascorbic Acid Injection Ascorbic Acid, USP, Injection with Disodium Edetate Ascorbic Acid, USP (250 mg/mL Injection) Asparaginase for Injection Atropine, Chlorpheniramine Maleate, and Phenylpropanolamine Injection Atropine Sulfate Injection Atropine Sulfate Injection Aztreonam for Injection Basiliximab for Injection Benzylpenicillin + Dihydrostreptomycin Injectable Suspension (200,000 U + 200 mg/mL) B Complex Injection: Niacinamide, Pyridoxine, Riboflavin, and Thiamine Injection B Complex Injection: Niacinamide, Pantothenate, Pyridoxine, Riboflavin, Thiamine Injection Solution 1 Solution 2 B Complex Injection B Complex Injection B Complex, Vitamin D, Vitamin E Lyophilized Injection Solution 1 Solution 2 B Complex Injection B Complex Vitamin, Veterinary B Complex Vitamin, Veterinary B Complex Vitamin, Veterinary B Complex Vitamin, Veterinary B Complex with Minerals Injection, Veterinary B Complex Vitamins with Hormones B Complex Vitamins with Liver Extract Injection Benzodiazepine Injection Benztropine Mesylate Injection Beta-Carotene Injection Betamethasone Suspension Injection Bethanechol Chloride Injection Biotin Injection Biperiden Lactate Injection Bisantrene Emulsion Injection Bisantrene Emulsion Injection Borax Sodium Lubricating Ophthalmic Drops Botulinum Toxin: Type A Purified Neurotoxin Complex Botulinum Toxin (Type B Injectable Solution) Bretylium Tosylate in Dextrose Injection Buflomedil Injection Bupivacaine Hydrochloride Injection 1: 0.75% in Dextrose 8.25% Injection Bupivacaine Hydrochloride Injection (0.25%) Bupivacaine Hydrochloride Injection Bupivacaine Hydrochloride Injection: Bupivacaine with Epinephrine Injection Buprenorphine Hydrochloride Injectable Caffeine Citrate Injection Calcitonin Injection Calcitonin Injection Calcitriol Injection Calcitriol Injection Calcium Glycerophosphate Injection with Lactate Calcium Glycerophosphate Injection: Calcium Glycerophosphate Injection (Human and Veterinary) Calcium Gluconate Injection Calcium Glycerophosphate Injection Camphor Injection Camptothecin Injection Carboplatin for Infusion Carboplatin Injection Carprofen Injection Cefamandole Nafate for Injection Cefazolin Injection Cefepime Hydrochloride for Injection Cefotaxime Injection Cefotetan Injection Cefoxitin Injection Premixed IV Solution Ceftazidime for Injection: L-Arginine Formulation Ceftazidime Injection Dry Powder Ceftazidime Injection Premix Ceftriaxone Injection: 500 mg Injection (IM and IV) Ceftriaxone Injection (250 mg Injection, IM and IV) Ceftriaxone Injection Premix Cefuroxime for Injection Cetrorelix Acetate for Injection Chloramphenicol and Phenylmercuric Nitrate Ophthalmic Drops Chloramphenicol Ophthalmic Solution (3%) Chloramphenicol for Injection Chloramphenicol Injection Chloramphenicol Sodium Succinate for Injection Chlordiazepoxide Hydrochloride Injection Chloroprocaine Hydrochloride Injection Chlorothiazide Sodium for Injection Chlorpheniramine Maleate Injection (25 mg/mL) Chlorpheniramine Maleate Injection (10 mg/mL) Chlorpromazine Hydrochloride Injection (10 mg/mL) Chlorpromazine Hydrochloride Injection (25 mg/mL) Choriogonadotropin-Alpha (Recombinant) for Injection Chorionic Gonadotropin for Injection (20,000 U/10 mL Covial) Chorionic Gonadotropin for Injection (10000 U//10 mL) Chromium Chloride Additive Injection (5 mL Vial) Chromium Chloride Additive Injection (10 mL Vial) Chromium Chloride Additive Injection (30 mL Vial) Cidofovir Injection Cimetidine Injection Cimetidine Injection Ciprofloxacin Hydrochloride Ophthalmic Solution Ciprofloxacin Injection Cisplatin Diaminedichloride Injection Cisplatin with 2,2\'-Dithio-b/s-Ethane Sulfonate Injection Cladribine Injection Infusion Clarithromycin Injection Lactobionic Acid (12% w/v Solution) Clindamycin Injection in 5% Dextrose Clindamycin Phosphate Injection 150 mg/mL (4 mL in 5 mL Vial, 600 mg; 6 mL in 10 mL vial, 900 mg) Clonidine Hydrochloride Injection Closantel Veterinary Injectable Solution (12–20 g/100 mL) Coagulation Factor VIIa (Recombinant) for Injection Coagulation Factor IX (Recombinant) for Injection Colistin Sulfate, Neomycin Sulfate, Thonzonium Bromide, and Hydrocortisone Acetate Otic Suspension Conjugated Estrogens for Injection Copper Sulfate Additive Injection (5 mL Vial) Copper Sulfate Additive Injection (10 mL Vial) Copper Sulfate Additive Injection (30 mL Vial) Corticorelin Ovine Triflutate for Injection Cortisone Acetate Injectable Suspension Cosyntropin for Injection Cromolyn Sodium Ophthalmic Solution Crude Liver Extract Injection Cyanocobalamin and Thiamine Injection Cyanocobalamin, Choline, and Niacinamide Injection Cyanocobalamin Injection Cyanocobalamin Injection Cyanocobalamin Injection for Veterinary Use Cyanocobalamin Repository Injection (1000 mg/mL) Cyanocobalamin, Pyridoxine, and Thiamine Injection Cyanocobalamin, Pyridoxine, and Thiamine Injection Cyanocobalamin, Pyridoxine, and Thiamine Injection Cyanocobalamin, Pyridoxine, and Thiamine Injection Cyclosporine Ampoules for Infusion Cytarabine Liposome Injection for Intrathecal Use (50 mg/5 mL Vial) Cytomegalovirus Immune Globulin IV (Human) Dacarbazine Injection Daclizumab for Injection Dactinomycin for Injection Dalteparin Sodium Injection Danaparoid Sodium Injection Dantrolene Sodium for Injection Dapiprazole Hydrochloride Ophthalmic Solution (0.5%) Daunorubicin HCl Injection Daunorubicin Citrate Liposome Injection Desmopressin Acetate Injection (Intranasal) Dexamethasone Acetate Suspension Injection: Dexamethasone Acetate (8 mg/mL) Dexamethasone Acetate/Sodium Phosphate Suspension (8/2 mg/mL) Dexamethasone Sodium Phosphate Injection Dexamethasone Sodium Phosphate Injection Dexamethasone Injection, Veterinary Dexamethasone Sodium Phosphate Injection Dexpanthenol, Niacinamide, Pyridoxine, Riboflavin, and Thiamine Injection Dexrazoxane for Injection Dextrose 25% Injection (Flexible Container) Dextrose Injection (5% and 10% LVP) Dextrose with Sodium Chloride Injection LVP Diazepam Injectable Solution (2.5 mg/mL) Diazepam Emulsion Injection Diazepam Emulsion Injection Diazepam Injection Diazepam Rectal Solution Dibenzazepine Carboxamide Injection Diclofenac Injectable Solution (75 mg/3 mL) Diclofenac Sodium Injection Diclofenac–Lecithin Injection Diclofenac with Acetylcysteine Injection Diclofenac Lyophilized Injection Diclofenac Lyophilized Injection Dicyclomine Hydrochloride Injection Digoxin Injection Dihydroergotamine Mesylate Drops Dihydroergotamine Mesylate Injection Dihydroergotamine Mesylate Nasal Spray Diisopropylphenol Injection Diltiazem Hydrochloride Injection Dimenhydrinate Injection Dimethyl Sulfoxide Injection Dimethyl Sulfoxide Irrigation Dinoprostone Cervical Gel Diphenhydramine Hydrochloride Injection Diphenylmethyl Piperazine Injection Dipyrone Injection Dipyrone, Papaverine HCl, and Atropine Sulfate Injection Disodium Edetate Injection (150 mg/mL) Disulfonic Acids Injection Dobutamine Injection Dopamine Hydrochloride Injection Doxapram Hydrochloride Injection, USP Doxercalciferol Injection Doxorubicin for Injection Doxycycline Hyclate Injection Doxycycline Hyclate Injection Doxycycline Hydrochloride Injection Ebselen Liposomal Injection Edetate Sodium, Polyvinyl Alcohol, Sodium Sulfacetamide, Sodium Thiosulfate Ophthalmic Drops with Thimerosal Edetate Sodium, Polyvinyl Alcohol, Sodium Sulfacetamide, Sodium Thiosulfate Ophthalmic Drops with Benzalkonium Chloride Edrophonium Injectable Electrolyte Maintenance Fluid (For Maintenance) Electrolyte Maintenance Fluid (For Rehydration) Electrolyte Maintenance Fluid (Maintenance, Pediatric) Electrolyte Maintenance Fluid Electrolyte Maintenance Fluid Rehydration (75 mEq) Electrolyte Maintenance Fluid Rehydration (90 mEq) Electrolytes, TPN Injection Emetine Hydrochloride Injection Enalaprilat Injection Ephedrine and Pyrilamine Maleate Injection Veterinary Ephedrine Sulfate Injection Epinephrine Auto Injector Injection Epinephrine Injection Epoetin-Alpha for Injection Epoprostenol Sodium for Injection Ergocalciferol Injection (Vitamin D) Ergonovine Maleate Injection Ergonovine Maleate Injection Veterinary Erythromycin Injection Esmolol Hydrochloride Injection Infusion Concentrate Estradiol Cypionate Injection Estradiol Suspension Injection Estradiol Valerate Injection Estrogenic Substances in Oil Injection Estrone, Estradiol, and Cyanocobalamin Injection Estrone Sterile Suspension Veterinary Injection Etanercept Injection Etorphine Hydrochloride Veterinary Exemestane Aqueous Suspension Injection Famotidine Injection Fenoldopam Mesylate Injection Fentanyl Citrate Injection Filgrastim Injection Flosulide Injection Fluconazole Injection Flumazenil Injection Folic Acid and Niacinamide Injection Follitropin-Beta for Injection Furaltadone Injectable Solution (50 mg/mL) Furosemide Injection Gentamicin and Prednisolone Ophthalmic Drops Gentamicin Injection (20 mg/2 mL) Gentamicin Injection (80 mg/2 mL) Gentamicin Ophthalmic Drops Glycine Antagonist Infusion Glycine Antagonist Infusion Glycopyrrolate Injection Gramicidin Ophthalmic Solution (1.3 mg/10 mL) Granisetron Hydrochloride Injection Single Dose Granisetron Hydrochloride Injection Multiple Dose Guaiacol–Iodide Solution Veterinary Haloperidol Injection Hemin for Injection Heparin Injection Hepatitis B Immune Globulin (Human) Hexamethylmelamine Injection Hydrochloric Acid Hydrocortisone Sodium Phosphate Injection Hydrocortisone Sodium Succinate for Injection (Single-Unit System Lyophilized) Hydrocortisone Sodium Succinate for Injection (Nonlyophilized) Hydrocortisone Sodium Succinate for Injection Hydromorphone Hydrochloride Injection Single Dose Hydromorphone Hydrochloride Injection Multiple Dose Hydroxycobalamin Injection Hydroxyprogesterone Caproate Injection Hydroxypropylmethylcellulose Ophthalmic Solution Hyoscine Butylbromide Injection Ibuprofen Lysinate Injection Ibutilide Fumarate Injection Idarubicin Hydrochloride Injections Imiglucerase for Injection Immune Globulin (Human) for Injection Infliximab Recombinant for Injection Insulin Aspart Injection Insulin Glargine Injection Insulin Human 70/30 Insulin Human Isophane Suspension (NPH) Insulin Lispro Injection Insulin Regular Interferon Injection Interferon Alpha-2a Interferon Injection Interferon Alpha-2a (Prefilled Syringe) Interferon Beta-1b Injection Interferon Beta-1a Injection Interferon Alpha-n3 Injection Interferon Alphacon-1 Injection Interferon Gamma-1b Injection Interleukin Eye drop Interleukin for Injection (IL-2) Iodine IV Additive Iron Copper Solution Veterinary Iron Dextran Injection Iron Sucrose Injection Isometheptene Hydrochloride Veterinary Injection Itraconazole Injection Ketoprofen Lysine Injection Ketorolac Tromethamine Injection Ketorolac Tromethamine Ophthalmic Solution Labetalol Hydrochloride Injection Lactobionic Acid Injection Lamotrigine Injection Lazaroid Injection Lepirudin for Injection Leucovorin Calcium Injection (50 mg/5 mL, 10 mL Vial Lyophilized) Leucovorin Calcium Injection (3 mg/ml, 2 mL Vial) Leuprolide Acetate Injection (5 mg/mL Injection) Leuprolide Acetate Injection: Depot Preparation (3.75 and 7.50 mg for Injecting Every Month) Leuprolide Acetate Injection (11.25 and 22.50 mg for Injecting Every 3 Months) Leuprolide Acetate Injection (30 mg for Injecting Every 4 Months) Leuprolide Acetate Implant Levorphanol Tartarate Injection Levothyroxine Sodium for Injection Lidocaine Hydrochloride and Epinephrine Injection Lidocaine Hydrochloride and Epinephrine Injection Lidocaine Hydrochloride and Epinephrine Injection Lidocaine Hydrochloride Injection (1% or 1.5% 20 mL) Lincomycin Hydrochloride Injection Liothyronine Sodium Injection (T3) Lipid Emulsion 20% for Parenteral Nutrition Liver, Iron, and Cyanocobalamin with Procaine Injection Liver, Iron, and Vitamin B12 Injection Veterinary Liver, Iron, and Vitamin B12 Injection Veterinary Lorazepam Injection Magnesium Sulfate 50% Injection Manganese Sulfate Injection (5 mL Vial) Manganese Sulfate Injection (10 mL Vial) Manganese Sulfate Injection (30 mL Vial) Mechlorethamine Hydrochloride for Injection Trituration Medroxyprogesterone Acetate Sterile Aqueous Suspension Medroxyprogesterone Acetate Sterile Aqueous Suspension Medroxyprogesterone Acetate Sterile Aqueous Suspension Medroxyprogesterone and Estradiol Sterile Suspension Melphalan Hydrochloride for Injection Menadione Injection Menadione Sodium Bisulfite Injection Veterinary (50 mg/mL) Menadione Sodium Bisulfite Injection Veterinary (5 mg/mL) Menotropins for Injection Meperidine Hydrochloride Injection Meperidine Hydrochloride and Promethazine Hydrochloride Injection Mepivacaine Hydrochloride Injection Single-Dose Vials Mepivacaine Hydrochloride Injection Multidose Vials Meropenem for Injection Mesoridazine Besylate Injection Metaraminol Bitartrate Injection Methandriol Dipropionate Injection Methocarbamol Injection Methohexital Sodium for Injection Methylprednisolone Acetate Suspension Injection Methylprednisolone Acetate Suspension Injection Metoclopramide Injection: Preservative Formula Metoclopramide Injection: Preservative-Free Formula Metolazone Injection Metronidazole Infusion Metronidazole Injectable Solution (500 mg/10 mL) Metronidazole Injection Metronidazole and Dextrose Infusion Midazolam Hydrochloride Injection Milrinone Lactate Injection Mineral Complex Injection Miconazole Injectable Solution (1%) Mitoxantrone for Injection Morphine Sulfate Infusion Morphine Sulfate Injection Moxidectin Injection Multiple Electrolytes and Dextrose Injection (Elliott’s B Solution) Muromonab-CD3 Injection Nalbuphine Hydrochloride Naloxone Hydrochloride Injection (1 mg/mL) Naloxone Hydrochloride Injection (0.04 mg/mL) Naloxone Hydrochloride Injection (0.02 mg/mL) Nandrolone Decanoate Injection Nandrolone Phenylpropionate Injection Naphazoline Ophthalmic Drops Natamycin Ophthalmic Suspension Natural Estrogenic Substances Suspension Nedocromil Sodium Ophthalmic Solution Neomycin and Prednisolone Acetate Ophthalmic Suspension Neomycin Sulfate–Polymyxin B Sulfate for Irrigation Neostigmine Methylsulfate Injection Single-Dose Vial Neostigmine Methylsulfate Injection Multidose Vial Nesiritide for Injection Netilmicin Injection Netilmicin Sulfate Injection Niacinamide Injection Nicardipine Hydrochloride for Infusion Nicardipine Hydrochloride Injection Nikethamide Injection Nimesulide Injection Nimodipine Injection Nystatin for Injection Octreotide Acetate Injection Single-Dose Ampoule Octreotide Acetate Injection Multidose Vial Octreotide Acetate Injection Depot Ofloxacin Otic Solution Ondansetron Hydrochloride Injection Single-Dose Vial Ondansetron Hydrochloride Injection Multidose Vial Ondansetron Hydrochloride Injection Premixed for Infusion Oprelvekin for Injection Orphenadrine Citrate Injection Oxacarbazepine-10 Injection Oxazepine Injection Oxendolone Injection Oxymorphone Hydrochloride Injection Oxytetracycline Injection Oxytetracycline Injectable Solution for IM + IV Veterinary Application (500 mg/10 mL) Oxytetracycline Sustained-Release Injectable for IM Veterinary Application (2.2 g/10 mL) Oxytocin Injection Oxytocin Injection, USP (20 U/mL) Paclitaxel Injection Palivizumab for Injection Pancuronium Bromide Injection Parenteral Nutrition Fat Emulsion Paricalcitol Injection Pegademase Bovine Injection Pegaspargase Injection Peginterferon Alpha-2b for Injection Penicillin G Benzathine and Penicillin G Procaine Injection Penicillin G Benzathine Injectable Suspension Pentobarbital Sodium Solution Injection Pentostatin for Injection Pentylenetetrazol Injection Pheniramine Maleate Injection Phenol Saline Diluent Phenylbutazone and Dipyrone Injection Phenylbutazone Injection Veterinary Phenylephrine and Zinc Sulfate Ophthalmic Drops Phenylpropanolamine Hydrochloride Injection Phenytoin Sodium Injection Phytonadione (Vitamin K1) Injection Phytonadione (Vitamin K1) Injection Phytonadione Injection—Aqueous Colloidal Solution of Vitamin K1 Piperacillin Sodium and Tazobactam Sodium Injection Plicamycin for Injection Polyvinyl Alcohol Ophthalmic Solution Potassium Estrone Sulfate Injection Veterinary Potassium Estrone Sulfate Suspension Injection Potassium Phosphate Injection Prednisolone and Neomycin Ophthalmic Suspension Prednisolone Injection: Acetate/Phosphate Injection Acetate Suspension Injection (50 mg/mL) Acetate Suspension Injection (10 mg/mL) Prednisolone Acetate Suspension with Niacinamide Injection (20 mg/mL) Prednisolone Ophthalmic Drops Procaine Penicillin Injectable Suspension (300 mg/mL) Procaine Hydrochloride Injection Prochlorperazine Injection Progesterone and Tocopheryl Acetate Injection Progesterone Injection Repository Veterinary Promazine Hydrochloride Injection Promethazine Hydrochloride Injection Vial Promethazine Hydrochloride Injection Cartridge Unit Propanidid Injectable Solution (50 mg/mL) Propofol Emulsion Injection Pyridoxine and Thiamine Injection Pyridoxine Hydrochloride Injection (100 mg/mL, 30 mL vial) Pyridoxine Hydrochloride Injection (100 mg/mL, 1 mL Ampoule) Pyrilamine Maleate and Ephedrine Injection Veterinary Quinidine Sulfate Injection Quinolone Lyophilized Injections Quinolone-Calcium Lactate Complex for Injection Ranitidine Injection Ampoule Ranitidine Injection Ampoule (50 mL Flexible Plastic Container) Reteplase Recombinant for Injection Retinol (Vitamin A) Injection Rho (D) Immune Globulin (Human) Injection Ringer Lactate Solution Injection Rituximab Injection Rubella Virus Vaccine Live Salbutamol Aerosol for Inhalation Sisomicin Injection Sobrerol Injectable Solution (75 mg/5 mL) Sodium Bicarbonate and Disodium Edetate Injection Sodium Bicarbonate Injection Sodium Chloride Bacteriostatic Injection Sodium Chloride Injection Sodium Ferric Gluconate Complex in Sucrose Injection Sodium Hyaluronate Injection Sodium Lactate Compound (Hartmann’s) Injection Sodium Thiosulfate Injection Somatropin (rDNA Origin) Injection (4- or 8 mg Vials, ca. 12 or 24 IU) Somatropin (rDNA Origin) Injection (5 mg/1.5 mL, 10 mg/1.5 mL, or 15 mg/1.5 mL Cartridge) Sterile Water for Injection Streptomycin Sulfate Injection Succinylcholine Chloride Injection: Lyophilized Succinylcholine Chloride Injection: Ampoule Succinylcholine Chloride Injection: Veterinary Nonsterile Sulfadimethoxine Veterinary Injectable Solution (2.5% = 250 mg/10 mL) Sulfadoxine + Trimethoprim Veterinary Injectable Solution (1000 mg + 200 mg/10 mL) Sulfadoxine solution (2% = 20 mg/mL) Sulfamoxole + Trimethoprim Veterinary Injectable Solution (400 mg + 80 mg/10 mL) Sulfathiazole Veterinary Injectable and Oral Solutions (0.8% = 8 mg/mL) Sumatriptan Succinate Injection Tenecteplase for Injection Testosterone Suspension Injection Testosterone Cypionate Injection Testosterone Enanthate–Estradiol Valerate Injection Testosterone Enanthate Injection Testosterone Repository Veterinary Injection Testosterone Propionate Injection Testosterone Propionate Injection Tetrahydrozoline Ophthalmic Drops Theophylline Injectable Solution (4% = 200 mg/5 mL) Theophylline and Dextrose Injection Thiamine Hydrochloride Injection: Unbuffered Thiamine Hydrochloride Injection: with Citric Acid and Gelatin Thiamine Hydrochloride Injection: Buffered Thiamine Hydrochloride Injection: with Sodium Formaldehyde Sulfoxylate Thiamine Hydrochloride Injection: Buffered and Gelatin Thiopental Sodium for Injection Thiotepa for Injection Thiothixene Hydrochloride Injection Thyrotropin-Alpha for Injection Timolol Ophthalmic Solution Tinzaparin Sodium Injection Tirofiban Hydrochloride Injection Tobramycin Solution for Inhalation Tobramycin Sulfate Injection Tobramycin Sulfate Injection Topotecan Hydrochloride for Injection Trace Element Concentrate Injection: (1- or 10 mL Vial) Trace Element Concentrate Injection (3- or 10 mL Vial) Tranexamic Acid Injection Trastuzumab for Injection Triamcinolone Acetonide Suspension Injection Triflupromazine Hydrochloride Injection Triflupromazine Hydrochloride Injection Triflupromazine Hydrochloride Injection Tripelennamine Hydrochloride Injection Veterinary Tubocurarine Chloride Injection Typhoid Vi Polysaccharide Vaccine Uridine Triphosphate Injection Urokinase for Injection Valproate Sodium Injection Valrubicin for Intravesical Instillation Vancomycin for Injection Varicella Virus Vaccine Live Vasopressin (8-Arginine Vasopressin) Injection Vecuronium Bromide for Injection Verapamil Hydrochloride Injection Vinblastine Sulfate for Injection Vincristine Sulfate Injection Vincristine Sulfate Injection Vitamin C Vaginal Ointment Water for Injection Water for Injection, Bacteriostatic Zinc Sulfate Additive Injection (5 mL Vial) Zinc Sulfate Additive Injection (10 mL Vial) Zinc Sulfate Additive Injection (30 mL Vial) Zoledronic Acid for Injection Part III: Commercial Pharmaceutical Formulations Commercial Pharmaceutical Formulations Index
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