دانلود کتاب Handbook of Pharmaceutical Manufacturing Formulations (Full 6 Volume)

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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-Ami​no-1-​Hydro​xybut​ylide​ne-1,​1-Bis​phosp​honic​ 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