Dextroamphetamine Sulfate Capsules Diclofenac and Misoprostol Capsules Diclofenac Extended-Release Capsules Didanosine Delayed-Release Capsules. Erythromycin And Bromhexine Powder For Suspension Erythromycin And Sulfisoxazole Granules For Suspension Erythromycin Delayed Release Capsules. Prazosin and Polythiazide Capsules, Prednisolone Time-Release Capsules, Procarbazine Chloride Capsules, Prochlorperazine Extended-Release Capsules.
INTRODUCTION
Section 211.58, "Maintenance," states that: "Any building used for the manufacture, processing, packaging, or storage of a drug product shall be maintained in good repair." Section 211.150, “Distribution Procedures,” states that: “Written procedures shall be established and followed that describe the distribution of drugs. A written record of each complaint shall be kept in a file designated for drug complaints.
BACKGROUND
IMPLEMENTATION A. O BJECTIVES
Biennial Inspection of Manufacturing Sites Drugs and drug products are manufactured using many
The inspection is defined as audit coverage of two or more systems, with mandatory coverage of the Quality System (see the system definitions in Section II.B.3.). Inspection options include different number of systems to be covered depending on the purpose of the inspection. The inspection of the minimum number of systems, or more systems as deemed necessary by the FDA regional district, will provide the basis for an overall CGMP decision.
Inspection of Systems
Biennial updating of all profile classes will allow CGMP acceptability determinations to be made without delays due to company revisits. This will speed up the review process, in response to compressed timeframes for application decisions and in response to the provisions of the FDA Modernization Act of 1997 (FDAMA). This will allow pre-approval inspections/survey program inspections and post-approval audit inspections to focus on the specific issues related to a given application or the company's ability to keep applications up-to-date.
A Scheme of Systems for the Manufacture of Drugs and Drug Products
Packaging and labeling system - This system. includes measures and activities that control the packaging and labeling of drugs and drug products. The overall theme in the design of this system chart was the subchapter structure of the CGMP regulation. Production, control, or distribution records required to be maintained by the CGMP regulation and selected for review should be included for inspection audit within the context of each of the systems described previously.
PROGRAM MANAGEMENT INSTRUCTIONS A. D EFINITIONS
- Surveillance Inspections a. The Full Inspection Option
- Compliance Inspections
- State of Control
- Drug Process
- Drug Manufacturing Inspection
Coverage of these areas may be assigned under other compliance programs; however, extension of coverage to a GMP inspection must be reported under this program. A system is out of control if the quality, identity, strength and purity of the products resulting from that system(s) cannot be adequately assured. Selection of products should be made so that coverage is representative of the company's overall capabilities to manufacture within CGMP requirements.
INSPECTIONAL OBSERVATIONS A. I NVESTIGATIONAL O PERATIONS
- General
- Inspection Approaches
- System Inspection Coverage a. Quality System
- Sampling
- Inspection Teams
- Reporting
This option includes an inspection of the manufacturer to monitor the company's activities and provide input. For each of the following matters, the firm must have written and approved procedures and resulting documentation. Sanitation of the building, use of rodenticides, fungicides, insecticides and detergents and disinfectants.
ANALYTICAL OBSERVATIONS A. A NALYZING L ABORATORIES
REGULATORY/ADMINISTRATIVE STRATEGY
Pattern of failure to establish/follow a control system for implementing changes in the material handling operations. Pattern of failure to establish/follow a control system for implementing changes in the production system operations. Pattern of failure to establish/follow a control system for implementing changes in the laboratory operations.
THE BIOPHARMACEUTICS CLASSIFICATION SYSTEM
The permeability class cutoff is based indirectly on the extent of absorption (fraction of absorbed dose, not systemic BA) of the drug in humans and directly on measurements of the rate of mass transfer across the human intestinal membrane. In the absence of evidence of instability in the gastrointestinal tract, a drug substance is considered to be highly permeable if the extent of absorption in humans is found to be 90% or more of the administered dose by mass balance determination or by comparison with an intravenous reference dose. In these instructions, an IR drug is considered to be rapidly dissolved when at least 85% of the labeled amount of active ingredient is dissolved within 30 minutes, using the U.S.
METHODOLOGY FOR CLASSIFYING A DRUG SUBSTANCE AND FOR DETERMINING
Pharmacokinetic Studies in Humans
Pharmacokinetic mass balance studies with unlabeled, stable isotopes or a radiolabeled drug substance can be used to document the extent of absorption of a drug. Depending on the variability of the studies, a sufficient number of subjects should be enrolled to provide a reliable estimate of the extent of absorption. Depending on the variability of the studies, a sufficient number of subjects should be included in a study to obtain a reliable estimate of the extent of absorption.
Intestinal Permeability Methods
When it is not possible to follow this protocol, the permeability of internal standards should be determined in the same subjects, animals, tissues or monolayers after evaluation of the test drug. The permeability values of the two internal standards should not differ significantly between different tests, including those performed to demonstrate the suitability of the method. For example, a test drug substance can be determined to be highly permeable when its permeability value is equal to or greater than that of the selected high permeability internal standard.
Instability in the Gastrointestinal Tract
Sponsors may select compounds from the list of drugs and chemicals in Appendix A of this chapter, or they may choose to select other drugs for which information on the mechanism of absorption and reliable estimates of drug absorption in humans are available. The similarity factor is a logarithmic reciprocal square root transformation of the sum of the squared error and is a measure of the similarity in percent (%) of resolution between the two curves. Note that when both test and reference products dissolve 85% or more of the labeled amount of drug in ≥15 min using all three previously recommended dissolution media, the profile comparison with an f2 test is not necessary.
ADDITIONAL CONSIDERATIONS FOR REQUESTING A BIOWAIVER
Narrow Therapeutic Range Drugs
When comparing test and reference products, dissolution profiles should be compared with a similarity factor (f2). To allow the use of mean data, the coefficient of variation should not be more than 20% at the earlier times (eg 10 min) and should not be more than 10% at other times.
Products Designed to Be Absorbed in the Oral Cavity
REGULATORY APPLICATIONS OF THE BCS A. IND S /NDA S
Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms 37. BCS-based bio-release applies to the formulation to be marketed when changes in ingredients, composition or manufacturing method occur in the ingredients, composition or manufacturing method in the clinical formulation similar to the long-term trial formulations, Sections II and III). This approach is useful only when the drug substance is highly soluble and highly permeable (BCS Class 1), and the pre- and post-switch formulations are pharmaceutical equivalent (as defined in 21 CFR 320.1 (c)).
ANDA S
- DATA TO SUPPORT A REQUEST FOR BIOWAIVERS
- RELATIVE HUMIDITY
- SURFACE AREA
- SIEVE ANALYSIS
- PARTICLE SIZE DISTRIBUTION Sieving is a common method for establishing the distri-
- POWDER FLOW PROPERTIES
- REAL, TAPPED, AND BULK DENSITY Bulk or tapped density is a measure of the degree of
- SOLID HANDLING
- MIXING OF POWDERS
- ORAL POWDERS
- CAPSULES
- FDA CLASSIFICATION OF CAPSULE TYPES
- FDA CLASSIFICATION OF POWDERS
- INHALERS AND LUNG DELIVERY Key factors that contribute to the aerodynamic properties
- PROBLEMS IN POWDER HANDLING Powder materials exhibit a number of technological chal-
- CAPSULATION EQUIPMENT
- CAPSULE FINISHING
- MODIFIED-RELEASE PRODUCTS The capsulation process offers many advantages for
- COATED PARTICLES
- MIXING MECHANISMS
- SEGREGATION MECHANISMS Particulate solids tend to segregate by virtue of differences
- MIXING EQUIPMENT
A graphical representation of the mean resolution profiles of the test and reference products in the three media should also be included. The side length of the aperture in microns is inversely related to the mesh number. Calculate the mean height of the coarse powder pile and the mean angle of repose (f).
Acebutolol Hydrochloride Capsules
Aceclofenac Instant Granules
Acetaminophen and Diphenhydramine Hydrochloride Hot Therapy Sachet
Acetaminophen Capsules 500 mg
Acetaminophen, Doxylamine, and Caffeine Effervescent
Acetaminophen Instant Granules 1
Acetaminophen, Pseudoephedrine Hydrochloride, Chlorpheniramine Hot Therapy Sachet
Acetaminophen, Pseudoephedrine Hydrochloride Hot Therapy Sachet
Acetaminophen Swallow Capsules
Acetazolamide Sustained-Release Capsules
Acetylcysteine Sachets 1
Add the remaining sugar and colloidal silicon dioxide and mix until uniform (typically, this is achieved in the PK Processor® by heating the envelope to 40∞C and mixing until the product cools to 30–35∞C). Verify that the massage is adequate and note the total amount of water added. Allow the granules to cool, then sieve them in an oscillating granulator fitted with a 1.18 mm screen.
Fill the granules from step 6 into a suitable blender, add the flavor and blend until smooth (15 min.), passing through a 1.18 mm sieve if necessary.
Acitretin Capsules
Acrivastine and Pseudoephedrine Hydrochloride 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 Capsules
Amoxicillin and Bromhexine Hydrochloride Capsules
Amoxicillin and Clavulanic Acid Powder for Suspension, 125 mg and 31.25 mg per 5 ml
Amoxicillin and Clavulanate Potassium for Suspension
Amoxicillin Powder for Suspension 125 and 250 mg
Amoxicillin Trihydrate Capsules 250 and 500 mg
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
Aspartame Granules in Sachet
Aspartame Powder in Sachet
Aspirin and Chlorpheniramine Powder
Aspirin and Phenylpropanolamine Powder
Aspirin Microencapsulated Sustained-Release Capsules
Aspirin, Salicylamide, and Caffeine Powder
Azithromycin Capsules
Azithromycin Capsules and Oral Suspension
Azithromycin for Oral Suspension 1
Azithromycin Sachet for Oral Suspension
Balsalazide Disodium 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
Ceftibutin for Oral Suspension
Cefuroxime for Oral Suspension
Celecoxib Capsules
Cellulose Triacetate Liquefiable Topical Powder
Cephalexin Capsules
Cephalexin Powder for Oral Suspension
Cephradine Capsules
Cephradine Powder for Suspension
Cevimeline Capsules
Chlordiazepoxide Hydrochloride Capsules
Chloroxylenol and Chlorhexidine Topical Powder
Chlorpromazine Sustained-Release Capsules
Cimetidine Microencapsulated Sustained-Release Capsules
Citrate Effervescent Powder
Clindamycin Capsules 150 mg
Clofibrate Capsules
Clonidine Sustained-Release Capsules
Clorazepate Dipotassium Capsules
Cyclosporin A Capsules
Dantrolene Sodium Capsules
Dextroamphetamine Sulfate Capsules
Diclofenac and Misoprostol Capsules
Diclofenac Sustained-Release Capsules
The amount of coating is approximately 20% based on the weight of uncoated granules. The fine powders thus produced are processed to produce spherical granules, using 500 g of long-acting granules as a core (step 6), while a solution of 4 g of hydroxypropyl cellulose in 76 g of ethyl alcohol is dispersed.
Didanosine Delayed-Release Capsules
Didanosine Delayed-Release Capsules Enteric-Coated Beadlets
Didanosine for Oral Suspension
Diethyl Toluamide Topical Powder
Difluoromethylornithine-Alpha Capsules
The coated granules are then coated with a Eudragit S100 dispersion as done immediately above until a weight gain of 10-15% in granule weight is achieved. TEC (10 wt% based on dry polymer weight of Eudragit) is added to the suspension to yield a dispersion that is wet. Enough water is added to the powder to make a wet mass which is extruded, spheronized, dried, ground and sieved (size 14-20 mesh).
Gastric, Enteric and Colorectal Release Granules: The following procedure describes the preparation of the dosage form. Rapid gastric release granules (450 g, previously prepared), rapid enteric release granules (100 g, previously prepared) and slow colorectal release granules (450 g, previously prepared) are thoroughly mixed.
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 Hydrochloride Capsules and Oral Suspension
Efavirenz Capsules
Enalapril Maleate Capsules
Erythromycin and Bromhexine Powder for Suspension
Erythromycin and Sulfisoxazole Granules for Suspension
Erythromycin Delayed-Release Capsules
Erythromycin Ethylsuccinate for Oral Suspension
Erythromycin Ethylsuccinate for Oral Suspension 200 mg/5 ml
Erythromycin Stearate for Oral Suspension 1
Keeping the batch at 50–60∞C while stirring, slowly add the dry mixture from step D until a clear gel is obtained. Without vortexing, add erythromycin stearate to the solution from step C-2 and continue mixing until a smooth powder is formed. While mixing, add the slurry obtained from step I to the batch; rinse the dish with 5 ml of purified water and add the washings to the batch.
Erythropoietin Capsules
The amount of coating required is just enough to cover the capsule uniformly with a thin layer of the polymer layer. Usually a 3.5-4.5% weight gain of the capsule is a good indication of the amount needed as a primer. For enteric coating purposes, different polymers, such as hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate and cellulose acetate phthalate, are used.
Anionic copolymers based on methacrylic acid and methyl methycrate, commercially available as Eudragit, are also very suitable polymers for enteric coating purposes. The polymer dissolves in organic solvents such as ethyl alcohol, methyl alcohol, acetone, isopropyl alcohol. The required amount of enteric coating solution is 5-6% of the weight increase of the capsules from the original weight of the capsules before application of an enteric coating.
For a size 0 capsule, the previously mentioned enteric coating solution can be sprayed using fluid bed techniques.
Esomeprazole Magnesium Capsules
Estramustine Phosphate Capsules
Ethosuximide Capsules
Etodolac Capsules
Eye Nutrition Supplement Capsules
Felbamate for Oral Suspension
Fenofibrate 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 Xinafolate Inhalation Powder
Fluvastatin Sodium Capsules
Fosfomycin Tromethamine Sachets
Gabapentin Capsules
Ganciclovir Capsules
Gemfibrozil Capsules
Glycoprotein IIa/IIb Capsules
Guaifenesin Sustained-Release Capsules
Herbal AIDS Treatment Capsules
Histadine Capsules
Human Growth Hormone Capsules
For a size 0 capsule, the aforementioned gastroresistant coating solution can be dispersed using fluid bed techniques.
Hydrochlorothiazide and Triamterene Capsules
Hydrochlorothiazide Capsules
Hydroxyzine Pamoate Capsules and Oral Suspension
Hyoscyamine Sulfate Capsules
Ibuprofen Microencapsulated Sustained-Release Capsules
Ibuprofen Sustained-Release Capsules
Ifosfamide Capsules
Imatinib Mesylate Capsules
Indinavir Sulfate Capsules
Indomethacin Capsules
Dissolve lecithin in chloroform and wet this solution with the remaining half of the lactose.
Indomethacin Microencapsulated Sustained-Release Capsules
Indomethacin Sustained-Release Capsules
Insulin Capsules
Manufacturing Directions
Anionic copolymers based on methacrylic acid and methyl methacrylate, commercially available as Eudragit, are also very suitable polymers for enteric coating purposes. The polymer dissolves in organic solvents such as ethyl alcohol, methyl alcohol, acetone and isopropyl alcohol. The required amount of enteric coating solution is 5–6% weight gain of the capsules from the original weight of the capsules before applying the enteric coating.
Iron-Polysaccharide Complex Capsules
Isometheptene Mucate, Dichloralphenazone, and Acetaminophen Capsules
Isosorbide Mononitrate Capsules 20 mg
Isradipine 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
Lopinavir-Ritonavir Capsules
Loracarbef Capsules and Oral Suspension
Loxapine Capsules
Loxapine Succinate Capsules
Magaldrate Instant Powder or Dry Syrup
Magnesium Oxide Capsules
Mefenamic Acid Capsules
Mesalamine Capsules
Mesalamine Colonic Delivery Capsules
Methsuximide Capsules
Methylphenidate Capsules
Methylphenidate Immediate- and Extended-Release Capsules
Methyltestosterone Capsules
Metoclopramide Hydrochloride Sustained-Release Capsules
Metyrosine Capsules
Miconazole Nitrate Foot and Itch Powder
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
The coated spheres are sieved through a 1.4 mm sieve and spheres smaller than 1.4 mm are collected. The collected spheres are filled into hard gelatin capsules (hard gelatin capsule, color white, no. 2) with a normal weight of 0.17 g (net weight 108 mg).
Morphine Sulfate Sustained-Release Capsules
Multivitamin Effervescent Granules
Multivitamin Instant Granules
Mycophenolate Mofetil Capsules and Oral Suspension
Nanoparticle Polymer Particle Powders
Nelfinavir Mesylate Oral Powder
Nilvadipine Capsules
Nitrofurantoin Capsules
Nitrofurantoin Sustained-Release Capsules
Nizatidine Capsules
Nystatin Powder
Omeprazole and Piroxicam Capsules
Omeprazole Capsules
Omeprazole Delayed-Release Capsules
Oral Rehydration Salt 45 mEq
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
Pancrealipase Capsules
Pancrealipase Capsules Enteric-Coated Microspheres
Penicillamine Capsules
Pentosan Polysulfate Sodium Capsules
Pentostatin Capsules
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
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
Coating Process: Eudragit E 30D suspension with calcium stearate is sprayed onto the Methocel E4MP coated spheroids using a peristaltic pump. Capsules are filled with the powder mixture, pH sensitive coated spheroids and coated spheroids on an encapsulation machine that can double fill powders and spheroids.
Propranolol Hydrochloride Sustained-Release Capsules
Propranolol Timed- and Sustained-Release Capsules
Pseudoephedrine and Guaifenesin Capsules
Pseudoephedrine Hydrochloride Capsules
Ranitidine Effervescent Granules
Ribavirin Capsules
Rifabutin Capsules
Rifampicin Capsules
Rifampin and Isoniazid Capsules
Rivastigmine Tartrate Capsules
Salmeterol Xinafolate Capsules
Salmeterol Xinafolate Inhalation Powder
Saquinavir Mesylate Capsules
Selegiline Hydrochloride
Sevelamer Hydrochloride Capsules
Sibutramine Hydrochloride Capsules
Stavudine Capsules
Succimer Capsules
Sucralafate Granules
Tacrine Hydrochloride Capsules
Tacrolimus Capsules
Talc, Crospovidone, and Starch Topical Powder
Tamsulosin Hydrochloride Capsules
Temazepam Capsules
Temozolomide Capsules
Terazosin Hydrochloride Capsules
Tetracycline Hydrochloride Capsules
Thalidomide Capsules
Theophylline Sustained-Release Capsules
Thiothixene Capsules
Tibolone Capsules
Tiotropium Inhalation Powder
Tolmetin Sodium Capsules
Tolterodine Capsules
Topiramate Capsules
Tretinoin Capsules
Triamterene and Hydrochlorothiazide Capsules
Triamterene Capsules
Triclosan and Zinc Undecylenate Powder
Trientine Hydrochloride Capsules
Trimethoprim and Sulfamethoxazole Oral Suspension
Trimipramine Maleate Capsules
Troleandomycin Capsules
Typhoid Vaccine Live Oral Capsules
Valsartan and Hydrochlorothiazide Capsules
Valsartan Capsules
Vancomycin Hydrochloride Capsules
Verapamil Hydrochloride Capsules
Verapamil Hydrochloride Sustained-Release Capsules
Vincamine Capsules
