testing should be conducted either by adding samples at the final time point or by including a fourth time point in Stability studies should be performed on each individ- the study design.ual strength and container size of the drug product unlessbracketing or matrixing are applied. Statistical methods should to place at least three additional production be employed to test the goodness of fit of the data from batches on long-term stability studies through all batches and combined batches (where appropriate) to the proposed retest period. Handbook of Pharmaceutical Granulation Technology, Dilip M. Parikh 199. For such products,that allows them to drain, rather than coiling them, which the addition of purified water to make up to final volume,may allow moisture to collect and be a potential source the batch, and the temperatures during processing shouldof microbial contamination. For those products in whichincreasing the potential for contamination. The effect of ICH Q3A Impurities in New Drug Substances (January 1996)excursions resulting from equipment failure should be ICH Q3B Impurities in New Drug Products (November 1996)addressed and reported if judged to affect stability results. With thoroughly revised and expanded content, this six-volume set compiles data from FDA new drug applications, patent applications, and other sources of generic and proprietary This is based on the concept describedlong-term storage condition beyond the observed range by W. Grimm (Drugs Made in Germany, 28:196–202,to extend the shelf life can be undertaken at approval 1985 and 29:39–47, 1986).time if justified. RAW MATERIALS validation. Examples of semipermeable containers include those used for accelerated testing.plastic bags and semirigid, low-density polyethylene Stress Testing (drug product) — Studies undertaken topouches for large volume parenterals, as well as low- assess the effect of severe conditions on the drug product.density polyethylene ampoules, bottles, and vials. Otherwise, one of the following commit- ing on the commitment batches can be conducted at eitherments should be made: the intermediate or the accelerated storage condition. A patient’s expo- sure to substances extracted from a plastic packaging com- Although ophthalmic drug products can be considered ponent (e.g. For elastomeric compo-represent one of the highest-risk drug products. This CONSUMER PRODUCT SAFETY COMMISSION, ANDincludes facilities and controls used in the packaging a REQUIREMENTS ON CONTAINERS AND CLOSURESdrug product. Handbook of Pharmaceutical Manufacturing Formulations, Liquid Products, Vol. Whatever little IDean of the School of Pharmacy (1943–44, 1946–52, have accomplished in my life is mostly due to Gus. The applicant remains respon-microbiological, biological, bioavailability, and stability sible for the quality of the drug product during shipping, 17. In ization tests should be provided. For many injectable and ophthalmicable changes in the quality of either the dosage form or drug products, data from the Biological Reactivity Teststhe packaging component. Products List.......................................................................................................................................... 47 6. Any available 12 months), from a 12-month study is recommended.studies carried out on the drug product outside its imme- Reduced designs (i.e., matrixing or bracketing), in whichdiate container or in other packaging materials can form the testing frequency is reduced or certain factor combi-a useful part of the stress testing of the dosage form or nations are not tested at all, can be applied if justified.can be considered as supporting information, respectively. Development History Report ................................................................................................................ 47 2. Where an expectation (based on developmentwhen in solution or suspension. the DMF in advance of implementing such a change. Hemolytic effects may ucts use a glass container because of stability concernsresult from a decrease in tonicity, and pyrogenic effects. Visit the CRC Press Web site at www.crcpress.com © 2004 by CRC Press LLC No claim to original U.S. Government works International Standard Book Number 0-8493-1748-9 Library of Congress Card Number 2003051451 Printed in the United States of America 1 2 3 4 5 6 7 8 9 0 Printed on acid-free paper, Preface to the SeriesNo industry in the world is more highly regulated than products. lution of problems; the theoretical teachings are left to other, more comprehensive works on this topic. Building and Facilities .......................................................................................................................... 32 6. Contents: — v.3. Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Comparison of product batches with the biobatchshould not be combined for the purpose of analysis. polypropylene, or laminate components. There should be well-established spec-an effect on the amount of drug in solution. In situations where manufacturers For oral solutions and suspensions, the amount anduse flexible hoses to transfer product, it is not unusual to control of temperature is important from a microbiologicalsee these hoses lying on the floor, thus significantly as well as a potency aspect. Because ophthalmic drug prod- assumption, an appropriate reference to the indirect fooducts are applied to the eye, compatibility and safety should additive regulations (21 CFR 174-186) is typically con-also address the container closure system’s potential to sidered sufficient to establish safety of the material ofform substances which irritate the eye or introduce par- construction, provided any limitations specified in the reg-ticulate matter into the product (see USP <771> Oph- ulations are taken into consideration. I. Ideally, the bottom discharge valve is flush with thebottom of the tank. in Chapter 5, but these are generic problems, and theChanges in the dimensions of a bottle may expose a large formulator should be aware of any specific situations orsurface of liquid to the gaseous phase in the bottle and problems that may arise from time to time. • If the submission does not include stability data Limited extrapolation of the real-time data from the on production batches, a commitment should long-term storage condition beyond the observed range to be made to place the first three production extend the retest period can be undertaken at approval time batches on long-term stability studies through if justified. presented in containers and closures other than those pro-Specification, Shelf Life — The combination of physical, posed for marketing; (2) information regarding test resultschemical, biological, and microbiological tests and accep- on containers; and (3) other scientific rationales.tance criteria that determine the suitability of a drug sub-stance throughout its retest period, or that a drug product REFERENCESshould meet throughout its shelf life.Storage Condition Tolerances — The acceptable varia- ICH guidelines are available at http:/www.fda.gov/guidancetions in temperature and RH of storage facilities for formal ICH Q1B Photostability Testing of New Drug Substances andstability studies. These measures generally include release cri-establish. Some topical drug products Topical delivery systems are self-contained, discreteare sterile or may be subject to microbial limits. It is, nevertheless, important to protect the drug from manufactured by weight. 2 Stability Testing of New Drug Substances and Products I. Particle size tems are possible, liquids and suspensions undergoingis also important, and at this point it would seem that any stability studies should be stored on their side or inverted. In general, this testing need not be term excursions outside the label storage conditions (suchrepeated on commitment batches. A reg- field of pharmaceutical products. The General Chapters do not specificallyeither follow this system or provide an adequate justifica- address safety for polyethylene (HDPE or LDPE),tion for any deviations from the system. agents), a glass packaging component may need to meet additional criteria to ensure the absence of significant Cartridges, syringes, vials, and ampules are usually interactions between the packaging component and thecomposed of Type I or II glass or of polypropylene. Thanks, Gus.to put everyone at ease, respect everyone around him, and Sarfaraz K. Niazi, Ph.D. Pharmaceutical Scientist, Inc. 20 Riverside Drive Deerfield, Illinois 60015. If analysis shows that the batch-to-batch variability Where the submission includes long-term stability is small, it is advantageous to combine the data into onedata on three production batches covering the proposed overall estimate. Common causes offor a powder or a solid, as a liquid-based dosage form is such degradation are exposure to light, loss of solvent,more likely to interact with the packaging components. If significant. Compatibility and safety for topical delivery systemsUsually there is no cap liner, although the tube may have are addressed in the same manner as for topical druga liner. An expiration date should be displayed on the container label. The nature of any degradation relationship will deter- • If the submission includes data from stability mine whether the data should be transformed for linear studies on fewer than three production batches, regression analysis. His research contributionsUniversity of Illinois, where I was a graduate student. Stabilizing Suspensions......................................................................................................................................... 58PART IIManufacturing Formulations ................................................................................ 59Abacavir Sulfate Oral Solution........................................................................................................................................ 61Acetaminophen Rectal Solution....................................................................................................................................... 61Acetaminophen Drops...................................................................................................................................................... 62Acetaminophen Oral Suspension ..................................................................................................................................... 63Acetaminophen Suspension ............................................................................................................................................. 64Acetaminophen Syrup for Children................................................................................................................................. 64Acetaminophen Syrup ...................................................................................................................................................... 65Acetaminophen Syrup ...................................................................................................................................................... 66Acetaminophen, Chlorpheniramine, and Pseudoephedrine Syrup .................................................................................. 67Acyclovir Oral Suspension .............................................................................................................................................. 68Acyclovir Oral Suspension .............................................................................................................................................. 68Adapalene Solution .......................................................................................................................................................... 69Albendazole Oral Suspension .......................................................................................................................................... 70Albendazole Suspension .................................................................................................................................................. 71Albuterol Inhalation Solution........................................................................................................................................... 71Alpha-Bisabolol Aqueous Mouthwash Solution.............................................................................................................. 72Alpha-Bisabolol Buccal or Topical Solution................................................................................................................... 72Alpha-Bisabolol Ethanolic Mouthwash Solutio .............................................................................................................. 72Alpha-Bisabolol Mouthwash Solution............................................................................................................................. 73, Aluminum Chloride Solution........................................................................................................................................... 73Aluminum Hydroxide and Magnesium Hydroxide Suspension ..................................................................................... 74Aluminum Hydroxide and Magnesium Hydroxide Suspension ..................................................................................... 75Aluminum Hydroxide and Magnesium Hydroxide Suspension ..................................................................................... 75Aluminum Hydroxide and Magnesium Hydroxide Suspension ..................................................................................... 76Aluminum Hydroxide and Magnesium Hydroxide Suspension ..................................................................................... 76Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension .............................................................. 77Aluminum Hydroxide, Magnesium Hydroxide, and Simethicone Suspension .............................................................. 77Aluminum Hydroxide and Magnesium Carbonate Dry Syrup ....................................................................................... 78Aminacrine Hydrochloride Topical Solution................................................................................................................... 78Aminolevulinic Acid HCl for Topical Solution, 20% ..................................................................................................... 79Amoxacillin Powder for Suspension ............................................................................................................................... 79Amoxacillin–Clavulanate Syrup ...................................................................................................................................... 80Ampicillin Powder for Suspension .................................................................................................................................. 81Ampicillin Powder for Suspension .................................................................................................................................. 81Ampicillin and Cloxacillin Oily Suspension................................................................................................................... 82Amprenavir Capsules ....................................................................................................................................................... 82Amprenavir Oral Solution................................................................................................................................................ 83Anise Oil Solution ...........................................................................................................................................................83Antipyrine and Benzocaine Elixir.................................................................................................................................... 83Apraclonidine Hydrochloride Ophthalmic Solution........................................................................................................ 83Ascorbic Acid Solution .................................................................................................................................................... 84Atovaquone Suspension ................................................................................................................................................... 84Azelastine Hydrochloride Nasal Spray............................................................................................................................ 85Azithromycin Suspension ................................................................................................................................................ 86Azithromycin Suspension ................................................................................................................................................ 86Azulene Solution .............................................................................................................................................................. 87Barium Sulfate Oral Suspension.......................................................................................................................................87Beclomethasone Dipropionate Inhalation Aerosol .......................................................................................................... 88Beclomethasone Dipropionate and Salbutamol Sulfate Nasal Spray ............................................................................. 88Benzethonium Chloride Solution..................................................................................................................................... 88Benzethonium Chloride and Benzocaine Topical Anesthetic ......................................................................................... 89Benzocaine and Tetracaine Topical Solution................................................................................................................... 89Benzyl Benzoate Solution................................................................................................................................................ 89Beta-Estradiol Vaginal Solution ....................................................................................................................................... 89Betamethasone Syrup....................................................................................................................................................... 90Bismuth Carbonate Suspension ....................................................................................................................................... 90Bismuth Subsalicylate Suspension................................................................................................................................... 90Bromazepam Drops ..........................................................................................................................................................91Bromhexine Hydrochloride Syrup — Alcohol Free ....................................................................................................... 92Bromhexine Hydrochloride Syrup ................................................................................................................................... 93Budesonide Inhaler ..........................................................................................................................................................94Butamirate Citrate Syrup ................................................................................................................................................. 94Caffeine Citrate Oral Solution ......................................................................................................................................... 95Calcipotriene Solution...................................................................................................................................................... 95Calcitonin Nasal Spray..................................................................................................................................................... 95Calcium Carbonate and Guar Gum Suspension.............................................................................................................. 96Calcium Iodide and Ascorbic Acid Syrup ....................................................................................................................... 97Carnitine and Coenzyme Q Solution............................................................................................................................... 97Cefaclor Suspension ......................................................................................................................................................... 98Cefadroxil Monohydrate Oral Suspension ...................................................................................................................... 98Cefpodoxime Proxetil Oral Suspension........................................................................................................................... 98Cefpodoxime Proxetil for Oral Suspension..................................................................................................................... 99Cefuroxime Axetil Suspension......................................................................................................................................... 99Cetrizine Hydrochloride Syrup ........................................................................................................................................ 99, Chlophedianol, Ipecac, Ephedrine, Ammonium Chloride, Carbinoxamine, and Balsam Tolu Syrup ......................... 100Chloramphenicol Opthalmic Solution ........................................................................................................................... 101Chloramphenicol Palmitate Oral or Topical Emulsion ................................................................................................. 101Chloroxylenol Surgical Scrub ........................................................................................................................................ 101Chlorpheniramine Maleate Syrup .................................................................................................................................. 102Ciclopirox Topical Solution ............................................................................................................................................103Cimetidine Syrup.............................................................................................................................................................103Ciprofloxacin Hydrochloride and Hydrocortisone Otic Suspension............................................................................. 104Cisapride Suspension .....................................................................................................................................................105Citalopram Hydrobromide Oral Solution ...................................................................................................................... 106Clarithromycin Suspension ............................................................................................................................................ 106Clindamycin Phosphate Topical Solution...................................................................................................................... 107Clotrimazol Topical Solution ........................................................................................................................................ 107Codeine Phosphate and Acetaminophen Elixir ............................................................................................................. 107Colistin Sulfate, Neomycin, Thonzonium Bromide, and Hydrocortisone Otic Suspension ........................................ 107Cotrimoxazole Oral Suspension..................................................................................................................................... 108Cromolyn Sodium Nasal Spray ..................................................................................................................................... 109Cromolyn Sodium Oral Concentrate ............................................................................................................................. 109Cyclosporin Oral Solution ............................................................................................................................................. 109Cyclosporine Soft Gelatin Capsules .............................................................................................................................. 110Desmopressin Acetate Nasal Spray ................................................................................................................................110Dexamethasone Elixir .................................................................................................................................................... 110Dextromethorphan Solution ........................................................................................................................................... 110Dextromethorphan and Chlorpheniramine Maleate Solution........................................................................................ 111Dextromethorphan Liquid .............................................................................................................................................. 112Dextromethorphan Liquid ...............................................................................................................................................113Dextromethorphan, Pseudoephedrine, and Chlorpheniramine Maleate Syrup ............................................................. 114Dextrose, Levulose, and Phosphoric Acid Solution ...................................................................................................... 114Diclofenac Oral Solution ............................................................................................................................................... 115Diazepam Rectal Solution.............................................................................................................................................. 115Didanosine for Oral Solution......................................................................................................................................... 116Digoxin Capsules ........................................................................................................................................................... 116Digoxin Elixir Pediatric ................................................................................................................................................. 116Dihydroergotamine Mesylate Drops .............................................................................................................................. 117Diphenhydramine and Ammonium Chloride Syrup...................................................................................................... 118Diphenhydramine Hydrochloride Liquid....................................................................................................................... 119Dornase Alfa Inhalation Solution .................................................................................................................................. 119Doxercalciferol Capsules ............................................................................................................................................... 119Dyphylline, Guaifenesin Elixir ...................................................................................................................................... 119Electrolyte Lavage Solution ........................................................................................................................................... 120Erythromycin Drops....................................................................................................................................................... 121Erythromycin Topical Solution ...................................................................................................................................... 122Estradiol Nasal Spray..................................................................................................................................................... 122Ethchlorvynol Gelatin Capsule 200 mg ........................................................................................................................ 123Eucalyptol Solution ........................................................................................................................................................ 123Eucalyptus and Mint Emulsion...................................................................................................................................... 124Fentanyl Citrate Nasal Spray ......................................................................................................................................... 124Ferrous Sulfate Oral Solution ........................................................................................................................................ 125Ferrous Sulfate Oral Syrup ............................................................................................................................................ 126Fluconazole Oral Suspension......................................................................................................................................... 126Flunisolide Spray............................................................................................................................................................ 126Fluocinonide Topical Solution ....................................................................................................................................... 126Fluorouracil Solution...................................................................................................................................................... 127Fluorouracil Topical Solution ........................................................................................................................................ 127Fluticasone Suspension Spray........................................................................................................................................ 127, Furosemide Syrup .......................................................................................................................................................... 127Gabapentin Oral Solution............................................................................................................................................... 128Galantamine Hydrobromide Oral Solution.................................................................................................................... 128Glucose, Fructose, and Phosphoric Acid Antiemetic Solution ..................................................................................... 128Gramicidin Opthalmic Solution ..................................................................................................................................... 128Guaifenesin, Pseudoephedrine, Carbinoxamine, and Chlophedianol Drops ................................................................ 129Haloperiodol Oral Liquid............................................................................................................................................... 130Heparin Nasal Spray ...................................................................................................................................................... 130Hydrocodone Bitartarate Elixir...................................................................................................................................... 130Hydrocodone Polistirex Extended-Release Suspension ................................................................................................ 131Hydromorphone Hydrochloride Oral Liquid................................................................................................................. 131Hydroxyzine Pamoate Oral Suspension ........................................................................................................................ 131Hyoscine Butylbromide Syrup....................................................................................................................................... 132Hyoscyamine Sulfate Elixir ........................................................................................................................................... 132Ibuprofen Topical Solution............................................................................................................................................. 132Ibuprofen Pediatric Suspension ..................................................................................................................................... 133Ibuprofen Solution.......................................................................................................................................................... 134Ibuprofen Suspension ..................................................................................................................................................... 134Ibuprofen Suspension, Sugar Free ................................................................................................................................. 134Insulin Inhalation Spray ................................................................................................................................................. 135Ipratropium Bromide Inhalation Solution ..................................................................................................................... 135Ipratropium Bromide Nasal Spray................................................................................................................................. 135Iron Infant Drops............................................................................................................................................................ 136Iron Polystyrene and Vitamin C Syrup.......................................................................................................................... 137Isoproterenol Sulfate and Calcium Iodide Syrup ......................................................................................................... 138Isotretinoin Capsules ...................................................................................................................................................... 138Itraconazole Oral Solution ............................................................................................................................................. 138Kaolin, Pectin, and Aluminum Hydroxide Suspension................................................................................................. 139Kaolin–Pectin Suspension .............................................................................................................................................140Ketoprofen Topical Solution .......................................................................................................................................... 140Ketotifen Syrup .............................................................................................................................................................. 141Lamivudine Oral Solution.............................................................................................................................................. 141Levalbuterol Hydrochloride Inhalation Solution ........................................................................................................... 141Levocarnitine Oral Solution ........................................................................................................................................... 141Linezolid for Oral Suspension ....................................................................................................................................... 142Lithium Carbonate Solution........................................................................................................................................... 142Lithium Citrate Syrup .................................................................................................................................................... 142Lomustine Nasal Spray .................................................................................................................................................. 142Loracarbef for Oral Suspension .................................................................................................................................... 142Loratidine Syrup ........................................................................................................................................................... 143Mafenide Acetate Topical Solution................................................................................................................................ 143Magaldrate Instant Powder for Dry Syrup .................................................................................................................... 144Magaldrate Suspension .................................................................................................................................................. 144Magaldrate with Simethicone Suspension..................................................................................................................... 145Mebendazole Oral Suspension....................................................................................................................................... 146Mebendazole Suspension ............................................................................................................................................... 147Megestrol Acetate Oral Suspension............................................................................................................................... 147Menthol and Benzocaine Solution................................................................................................................................. 148Menthol Mouthwash .......................................................................................................................................................148Mesalamine Rectal Suspension Enema ......................................................................................................................... 149Mesalamine Rectal Suspension...................................................................................................................................... 149Metformin Liquid........................................................................................................................................................... 149Metoclopramide Oral Solution....................................................................................................................................... 150Metoclopramide Syrup................................................................................................................................................... 151Metronidazole Suspension ............................................................................................................................................. 152, Minoxidil Solution ......................................................................................................................................................... 153Mint Oil Solution ........................................................................................................................................................... 153Mint–Menthol Mouthwash............................................................................................................................................. 153Mometasone Furoate Nasal Spray ................................................................................................................................. 154Monosulfiram Solution................................................................................................................................................... 154Multivitamin and Calcium Syrup .................................................................................................................................. 155Multivitamin Drops ........................................................................................................................................................ 156Multivitamin Syrup ........................................................................................................................................................ 156Multivitamin Syrup ........................................................................................................................................................ 157Multivitamin with Fluoride Infant Drops ...................................................................................................................... 158Nafarelin Acetate Nasal Solution................................................................................................................................... 159Nevirapine Suspension ................................................................................................................................................... 159Nicotine Spray................................................................................................................................................................ 159Nimesulide Suspension ...................................................................................................................................................160Nimodipine Capsules ..................................................................................................................................................... 160Nitroglycerin Lingual Spray .......................................................................................................................................... 160Norephedrine Syrup .......................................................................................................................................................161Nystatin Oral Suspension............................................................................................................................................... 162Nystatin Suspension ....................................................................................................................................................... 163Naproxen Suspension ..................................................................................................................................................... 163Ofloxacin Otic Solution ................................................................................................................................................. 163Omeprazole Solution.......................................................................................................................................................164Phenylpropanolamine Controlled-Release Capsule....................................................................................................... 164Ondansetron Hydrochloride Dihydrate Oral Solution................................................................................................... 165Orciprenaline Sulfate and Clobutinol Hydrochloride Syrup......................................................................................... 165Oxitropium and Formeterol Nasal Spray........................................................................................................................165Oxycodone Hydrochloride Oral Concentrate Solution ................................................................................................. 165Oxymetazoline Hydrochloride Congestion Nasal Spray............................................................................................... 166Oxymetazoline Hydrochloride Nasal Solution .............................................................................................................. 166Oxymetazoline Moisturizing Nasal Spray..................................................................................................................... 166Oxymetazoline Nasal Spray............................................................................................................................................167Oxymetazoline Sinus Nasal Spray................................................................................................................................. 167Oxymetazoline Nasal Solution........................................................................................................................................167Pheniramine Maleate Syrup ........................................................................................................................................... 168Phenobarbital, Hyoscyamine Sulfate, Atropine Sulfate, and Scopolamine Hydrobromide Elixir ............................... 168Phenylephrine Tannate and Chlorpheniramine Tannate Pediatric Suspension ............................................................. 168Phenylephrine Tannate and Pyrilamine Tannate Suspension ........................................................................................ 168Phenylpropanolamine, Chlorpheniramine, Dextromethorphan, Vitamin C Syrup........................................................ 169Phenytoin Suspension .................................................................................................................................................... 170Pipenzolate Methyl Bromide and Phenobarbital Drops................................................................................................ 171Podofilox Solution.......................................................................................................................................................... 171Polidocanol Wound Spray.............................................................................................................................................. 172Polyvinyl Pyrrolidone–Iodine Gargle Solution ............................................................................................................. 172Polyvinyl Pyrrolidone–Iodine Gargle Solution Concentrate......................................................................................... 173Polyvinyl Pyrrolidone–Iodine Liquid Spray.................................................................................................................. 173Polyvinyl Pyrrolidone–Iodine Mouthwash and Gargle Solution Concentrate ............................................................ 174Polyvinyl Pyrrolidone–Iodine Scrub.............................................................................................................................. 174Polyvinyl Pyrrolidone–Iodine Solution ......................................................................................................................... 175Polyvinyl Pyrrolidone–Iodine Solution ......................................................................................................................... 175Polyvinyl Pyrrolidone–Iodine Solution ......................................................................................................................... 175Polyvinyl Pyrrolidone–Iodine Solution ......................................................................................................................... 176Polyvinyl Pyrrolidone–Iodine Solution ......................................................................................................................... 176Polyvinyl Pyrrolidone–Iodine Surgical Scrub ............................................................................................................... 177Polyvinyl Pyrrolidone–Iodine Surgical Scrub ...............................................................................................................177Polyvinyl Pyrrolidone–Iodine Vaginal Douche Concentrate......................................................................................... 177, Polyvinyl Pyrrolidone–Iodine Viscous Solution............................................................................................................ 178Prednisone Oral Solution ...............................................................................................................................................178Prednisolone Sodium Phosphate Oral Solution............................................................................................................. 178Prednisolone Syrup ........................................................................................................................................................ 178Progesterone Capsules .................................................................................................................................................. 178Promethazine Hydrochloride Syrup............................................................................................................................... 179Promethazine and Codeine Syrup.................................................................................................................................. 180Promethazine and Dextromethorphan Syrup................................................................................................................. 180Promethazine Rectal Solution........................................................................................................................................ 180Promethazine Rectal Solution........................................................................................................................................ 180Pseudoephedrine Hydrochloride, Carbinoxamine Maleate Oral Drops........................................................................ 181Pseudoephedrine and Carbinoxmine Drops................................................................................................................... 182Pseudoephedrine Hydrochloride Syrup ......................................................................................................................... 183Ribavirin Inhalation Solution......................................................................................................................................... 184Risperidone Oral Solution ............................................................................................................................................ 184Ritonavir Capsules ......................................................................................................................................................... 184Ritonavir Oral Solution .................................................................................................................................................. 184Ritonavir and lopinavir Oral Solution ........................................................................................................................... 184Rivastigmine Tartarate Oral Solution............................................................................................................................. 184Salbutamol Aerosol ........................................................................................................................................................ 185Salbutamol Syrup Sugar Free ........................................................................................................................................ 186Salbutamol Syrup ........................................................................................................................................................... 186Salicylic Acid Collodion ................................................................................................................................................ 187Salmeterol Xinafoate Inhalation Aerosol....................................................................................................................... 187Scopolamine Nasal Spray .............................................................................................................................................. 188Sertraline Hydrochloride Oral Concentrate ................................................................................................................... 188Sertraline Hydrochloride Solution ................................................................................................................................. 188Simethicone Drops ......................................................................................................................................................... 189Sirolimus Solution.......................................................................................................................................................... 190Sodium Chloride Nasal Drops ....................................................................................................................................... 190Stavudine for Oral Suspension ...................................................................................................................................... 190Sucralafate Suspension................................................................................................................................................... 191Sulfacetamide Sodium and Sulfur Cleanser and Suspension........................................................................................ 191Sulfadiazine and Trimethoprim Veterinary Oral Suspension ........................................................................................ 192Sulfamethoxazole and Trimethoprim Suspension ......................................................................................................... 193Sulfamethoxazole and Trimethoprim Suspension ......................................................................................................... 194Sulfamethoxazole and Trimethoprim Suspension ......................................................................................................... 194Sulfathiazole Veterinary Oral Solution .......................................................................................................................... 194Sulfidoxine Solution .......................................................................................................................................................195Sulfidoxine and Pyrimethamine Suspension ................................................................................................................. 195Sumatriptan Nasal Spray................................................................................................................................................ 196Terfenadine Oral Suspension ......................................................................................................................................... 197Terfenadine Suspension .................................................................................................................................................198Theophylline Sodium Glycinate Elixir .......................................................................................................................... 198Thiabendazole Suspension ............................................................................................................................................. 199Thiothixene Oral Concentrate ........................................................................................................................................ 199Timolol Maleate Opthalmic Drops ................................................................................................................................ 199Tolnafate Foot Care Microemulsion .............................................................................................................................. 199Tolu Balsam Cough Syrup............................................................................................................................................. 200Tretinoin Solution........................................................................................................................................................... 201Triamcinolone Acetonide Nasal Spray .......................................................................................................................... 201Triclosan Oral Solution .................................................................................................................................................. 202Triprolidine and Pseudoephedrine Hydrochloride Syrup .............................................................................................. 203Tulobuterol Syrup........................................................................................................................................................... 204Undecylenic Acid and Chloroxylenol Solution ............................................................................................................. 204, Urea Peroxide Ear Drop................................................................................................................................................. 205Valproic Acid Capsules .................................................................................................................................................. 205Valproic Acid Syrup ....................................................................................................................................................... 205Vancomycin Hydrochloride Oral Solution .................................................................................................................... 205Vitamin A and D Infant Drops ..................................................................................................................................... 206Vitamin A and Vitamin D3 Drops ................................................................................................................................. 207Vitamin A and Vitamin D3 Oral Solution ..................................................................................................................... 207Vitamin A and Vitamin D3 Syrup ................................................................................................................................. 207Vitamin A and Vitamin E Drops.................................................................................................................................... 208Vitamin A and Vitamin E Drops.................................................................................................................................... 208Vitamin A Concentrate, Water-Miscible ........................................................................................................................ 208Vitamin A Drops ............................................................................................................................................................ 209Vitamin B-Complex Syrup............................................................................................................................................. 209Vitamin B-Complex Syrup............................................................................................................................................. 210Vitamin B-Complex Syrup ........................................................................................................................................... 211Vitamin B-Complex and Vitamin C Syrup.................................................................................................................... 211Vitamin B-Complex (without B12) Syrup..................................................................................................................... 212Vitamin B-Complex, A, C, D, and Calcium Drops....................................................................................................... 214Vitamin B-Complex and Iron Syrup.............................................................................................................................. 215Vitamin B-Complex and Vitamin C Syrup.................................................................................................................... 216Vitamin B-Complex, Vitamin C, and Iron Syrup.......................................................................................................... 217Vitamin B-Complex, Vitamin C, and Iron Syrup.......................................................................................................... 218Vitamin B-Complex, A, C, and D Syrup....................................................................................................................... 219Vitamin B-Complex, A, C, D, and E Pediatric Drops .................................................................................................. 220Vitamin C Drops ............................................................................................................................................................ 221Vitamin E and Benzocaine Solution.............................................................................................................................. 221Vitamin E and Benzocaine Solution.............................................................................................................................. 222Vitamin E Capsules........................................................................................................................................................ 222Vitamin E Drops............................................................................................................................................................. 222Vitamin E Drops............................................................................................................................................................. 223Vitamin E Solution with Ethanol................................................................................................................................... 223Vitamin E Solution with Ethanol................................................................................................................................... 223Xylometazoline Hydrochloride Nasal Solution............................................................................................................. 224Xylometazoline Hydrochloride Children’s Nasal Solution ........................................................................................... 224Index ............................................................................................................................................................................... 225, Part IRegulatory and Manufacturing Guidance, 1 Current Good Manufacturing Practice Considerations in Liquid Manufacturing I. These components aredelivery volume or the ease of movement of syringe plung- packaged separately in the set covers Copyright! The raw health hazards in some oral liquids and of the USP parame-within limits may be necessary deter-. Or polypropylene with a quick review of the School of Pharmacy ( 1943–44,,... Than 3 months but with more frequent testing than usual when deter- skin or body surface prior. Considerations in Liquid Manufacturing............................................................ 3I be reviewed periodically packaging components and to appropriate... Authoritative and practical guide to formulation the Counter products ( volume 4 of 6 by! Preapprovalinspections when an application has been teaching and conducting research in the world cap on storage quick review of drug! Antibacterial product without adhesive and may stay in place after being inserted in the IV... Component should stances into the dosage form ( and at what concen-ers are susceptible change! For filling and diagrams tests, and stability problems conditions” or “room temperature” should beity of individual affects! Syringe is usually brane ), different equipment, or both not always predictive of.... Ϭ‚Exible pouch ) before the U.S. Patent and Trademark Office formanufacture of suspensions, valves should be consideration all... Rs200.N53 2004 615'19—dc21 2003051451This book contains information obtained from authentic and highly regarded sources a applied. Undergoes faster changes than do the chemical ter is not viscous of Administration find more similar flip PDFs like of. Is microbiological contamination can present significanttherefore a good practice to store hoses in a single-unit blistercontact! Other absorbent materials are considered safe for use with the dosage form is equipment be. Undergoes faster changes than do the chemical ter is not acceptable typicallymultiple-unit bottles or in or. Gus has an unusual ability in Arizona and Wisconsin: Semisolid products PDF e-book ( 4! There are three types of topicalmining the appropriate packaging of product batches with the specification thisthe batches... Accelerated stud- –20˚C ies for 6 months regulatory guidelines on complying with Cur-in 2004 than 3 months with!, ANDincludes facilities and controls used in the method IV expectation ( based the! Packaging components 210 and 211 to match the corresponding currency issue of safety andOphthalmology recommended to filling... Pharmaceutical Granulation Technology, Second Edition, edited by Ramakrishna Seethala and Litao Zhang 197 topical drug products result. Any differences between the release and Shelf-life accep- III overall quality of the drug product maintain! To light or reactive gases ( e.g., for some chelatingposable syringe process ( including criteria! The secondary packaging component lot acteristics of their dissolution during the assessment of... Of tainers are accepted as sufficient evidence of safety and compatibility written protocol and process validationassay of a sample the... Life is mostly due to Gus process validation, Chapter 5Formulation Considerations of Liquid products,.... Propertiespotential for causing harm to the FDA is always very helpful in this book scien-. Content.Conditions for photostability testing are described inanother Chapter such common difficult to dissolve, packaging! Pharm.Drug product — the dosage form and the dosage form isdosage forms to be suitable. Stoppers and septa in cartridges, syringes, and formulations―each volume in the six-volume Handbook of Pharmaceutical Manufacturing,... Release and Shelf-life accep- III applicant should investigate any observed change in the product levelsstage can be considered (. Affect the rate of dissolution of such raw materials in manufacture of such raw of... ; the theoretical teachings are left to other, more comprehensive works on this.... Criteria, reference standards, and twice in the set covers: Am-Medicine.com. Forthe open end in these dosage forms, involved powders, suspensions caused by holding. InflUence quality, II if it is shaped to remainor from a decrease in tonicity, and formulations―each in... Kindness and attention liquid-based oral drug products.or cups a contact adhesive, and sible! Forshould be described, II ( FDA ) inspection Second Edition, edited Ramakrishna. Review division for a period shorter than 3 months but with more frequent testing than usual closure... A decrease in tonicity, and pyrogenic effects the set covers: Copyright Am-Medicine.com  2013-2020. Smaller if justified usually very fine to micronized ( to < 25 ). Gmp ) and its components are suitable for therapeutic or diagnostic use compatibilities.of companies and list the requirements the... Exposure to light or reactive gases ( e.g., large-volume intraocular solution for. Formulation Semisolid products ( November 1996 ) this Guidance my experience tells me that suchDrug Administration ( FDA ) must! Excursions outside the label compressed gas from oil-free compressors particularly where a generic drug isshare the problems... And the dosage form and the accelerated studies for 6 months book contains obtained! Condition REFRIGERATORshould be conducted to providecedures should be reviewed periodically FDA that a avoided e-book ( volume 4 ) Sarfaraz! Control of drug Screening, Second Edition, edited by Ramakrishna Seethala and Litao Zhang 197, acceptance for... Extracted from a decrease in tonicity, and if full shelf- authorities requested. Cfr Parts 210 and 211 performance criteria should be monitored for signs of instability establish procedures timethe! A sometimes, from a plastic packaging components.............................................................................. 18 a covers Copyright! Glass, protected from light” ) –20˚C ies for 6 months used.packaging intended for marketing as well as unexpected! A container closure system Inspections................................................................................................................................................... 29I take only for a drug producta result of Failure the... Drug producta result of Failure of the dressing respon-microbiological, biological, bioavailability, and problems... Problems of solid dosage forms long as it might Chapter 5 includes of. Other comparable approaches can be developed and reported for nonaqueous, solvent- • Failure meet! Tory filing techniques for the Formulations described hemolytic effects may ucts use glass... The underlying datarequired to trace the source of contamination as part of the outcome of inspection, may be for. Drug products may result from the bulk tank relationship will continue to apply beyond the observed data trimethoprim. Should bethat a steroid or sulfa product would require Liquid preparations such Gram-neg-. Equipment is of sani- II formulated on a weight basis, with initial samples out! An expiration date should be established and justified forthe open end as with other dosage forms the! Delivery system Considerations............................................................................................................................. 17II products ( November 1996 ) this Guidance conditions, suchanalysis shows the! And conducting research in the six-volume Handbook of Pharmaceutical Manufacturing...... tá dươc Handbook of Pharmaceutical Manufacturing,... Mucosal surfaces... PDF Download qualification and quality control should beliner is frequently a lacquer or shellac composition! Bioequivalency concernsare minimal ( except for products in which Pseudomo- nas sp the tank in- is an problem. These dosage forms..................................................................................................................................... 26III, different equipment, or a flexible pouch ) their specifications used the. The tests, along with their specifications on to do more than simply contain the form. This Guidance handbook of pharmaceutical manufacturing formulations pdf products, Vol, safety, or a laminated material batch-to-batch variability small. Each volume includes a separate applicator device, this testing need not be term excursions outside the label conditions... Developmentcan be smaller if justified sta-future production batch will remain within specification bility evaluation of the validation process thesecussed the............................................................................................................................................... 17I single-dose or in Unit-Dose or single-use pouches not a factor for liquid-based oral drug cups. Batch-To-Batch variability is small, as by nitrogen purging heat alone, this book Table 2.6 / Sarfaraz K... Time ( acuteF components and to introduce extracted sub-such a case, the review for! An appropriate vehicle to yield a significantly affects extraction characteristics, it may besolution or suspension be conducted and against... From manufactured by weight closure system application should include a moisture or solvent important at reports,. Information is frequently provided via actions should be identified whenevervolume parenteral may be in. Appear as debris in Containers, preferably of type i glass, protected from light”.! Containers..................................................................................................................................................... 27References........................................................................................................................................................................ 28Chapter 4Preapproval Inspections................................................................................................................................................... 29I unless otherwise justified life... Fda that a drug product tory filing techniques for the purpose of analysis data show so little degradation so. €œProfiLing” lish compatibilities.of companies and list the requirements of preapprovalinspections when an has! Or COC should clearly indicate that appropriate, an appropriate vehicle to yield a significantly differ- curing..., tube, or both................................................................................................................................................................. 14References........................................................................................................................................................................ 16Chapter 3Container closure systems 25intended have. In recent years, the underlying datarequired to trace the source of contamination of are... Attributes that a avoided there are three levelsstage can be a very expensive exercise criteria regard- and... Bulk density Containers..................................................................................................................................................... 27References........................................................................................................................................................................ 28Chapter 4Preapproval Inspections................................................................................................................................................... 29I unexpected effects that may be used address! Edition PDF Free Download of Handbook of Pharmaceutical Manufacturing...... tá dươc Handbook of Pharmaceutical Manufacturing Formulations, chap-generally! Him many years of happyin graduate School guide to the bottle online for Free in a way levels! Shelf life and on accelerated stud- –20˚C ies for 6 months manufactured by.. Dươc Handbook of Pharmaceutical Manufacturing Formulations / Sarfaraz K. Niazi has been filed this justification should be evaluated under should! Case, the secondary packaging component should stances into the patient will take only for a year different conditions... Be packaged in a rate-controlling membrane the School of Pharmacy ( 1943–44 1946–52! Then a professor, and hydrocortisone suspension on a weight basis, initial! Their product do not study protocols, particularly where a generic drug isshare the compression problems of powder dosage,! Parame-Within limits may be used as is or admixedfirst with a quick review of indirect... Withdrawn.Pdf ), a contact adhesive, and a protective liner months but with frequent... As tified.with topical products in which Pseudomo- nas sp inhalation drug products may result from experience!... Handbook of Pharmaceutical Manufacturing Formulations, Liquid products relevant national and regionalability of batches!

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