Remington: The
`Scienceand Practice
`
` .
`
`
`
`Volume II
`
`MYLAN V. BA
`
`|PR2016-
`
`R
`
`8
`
`EXHIBIT 2002
`
`

`
`1 9TH
`
`EDITION
`
`Remington:
`P ra ct i c e of
`
`ALFONSO R GENNARO
`Chairman of the Editorial Board
`and Editor
`
`

`
`The&Scienceand
`Pharmacy
`
`
`
`
`1995
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042 .
`
`

`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Office of the Librarian of Congress, at Washington DC
`
`Copyright 1889, 1894,. 1905, 1907,1917,byJ0sephPReming‘ton
`
`" Cop'y1‘ight‘1926‘; ‘I 936;.‘bythe Joseph—~P--Remingt:on-Estate -- V
`
`
`
`Copyright 1948, 1951 , by The Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965, 1970, 1975, 1980,1985, 1990, 1995, by The Philadelphia College of
`Pharmacy and Science
`
`All Riglz-ts Reserved
`
`Library of Congress Catalog Card No. 60-53834
`
`ISBN o-9127=34—o4-=3
`
`The use ofstru.ct~u:>‘alformulasfrom USAN and the USP Dictionary ofDrug Names is by
`perm-z?ssz'.on 0fThe USP Covwerzt-ion. The Convent‘.-ion is not respo-nsz'blefor any inctccu-rcz.cy
`contained herein.
`
`NOTICE~—~T/2 is text‘ is not ~t-mended to repre.se‘nt,, norshall. it be interpreted to be, the equivalent
`afar‘ a .3-ztbstz‘2‘-zztefor the ofiicviat United States Pharmatcope-z'a. (USP) and/or the National
`Frn-‘>72:z¢.lr.niy (NF").1nthe event ofcm-y cl2;1j“e1"ence or ct-z'.sc'repcLncy between the cztwent ofiicial
`USP o'rNF stat-ncla.rcl.s' 0fstrength, quality, pu7‘it;y, pa-clcaging and Labelingfor‘ drugs and
`representat-zi0n.9 ofthem herein, the context and efiect ofthe oflicial compencha shall prevail.
`
`Pri-nted in the L~'n~z‘ted States ofAmerica by the Mack Printing Compcmy, Easton, Pemzsylmn-ta
`
`

`
`Table of Contents
`
`Volume l
`
`Part 1 Orientation
`
`1
`1
`1
`.
`.
`.
`1
`1
`1
`.
`.
`.
`.
`1
`.
`.
`1
`.
`1 Scope .
`1
`1
`.
`1
`2 Evolution of Pharmacy .
`.
`.
`1
`.
`3 Ethics 1
`1
`.
`1
`1
`.
`.
`1
`1
`.
`1
`1
`.
`.
`1
`1
`.
`.
`.
`.
`4 CommunityPharmacy .
`1
`1
`1
`1
`5 Pharmacists in industry .
`6 Pharmacists in Government 1
`7 Drug information 1
`1
`1
`1
`1
`.
`1
`.
`,
`1
`8 Research 1
`1
`1
`.
`1
`.
`1
`1
`.
`1
`1
`1
`1
`1
`1
`1
`.
`
`.
`.
`1
`.
`.
`.
`.
`.
`
`1
`.
`1
`.
`.
`.
`1
`1
`
`1
`.
`.
`1
`1
`1
`.
`.
`
`1
`1
`1
`1
`.
`.
`.
`1
`
`1
`1
`.
`.
`.
`.
`1
`,
`
`1
`1
`1
`1
`.
`.
`.
`1
`
`1
`.
`.
`1
`1
`.
`.
`.
`
`.
`1
`1
`.
`1
`.
`.
`.
`
`1
`1
`1
`1
`.
`.
`.
`1
`
`1
`.
`.
`.
`.
`.
`.
`,
`
`.
`1
`.
`1
`.
`1
`.
`1
`
`.
`.
`1
`1
`1
`1
`.
`.
`
`1
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`1
`1
`.
`1
`.
`1
`
`1
`1
`1
`.
`.
`.
`.
`.
`
`1
`.
`.
`.
`.
`.
`1
`1
`
`1
`.
`.
`.
`1
`1
`.
`.
`
`.
`.
`1
`.
`1
`1
`.
`,
`
`.
`.
`1
`.
`1
`.
`1
`1
`
`1
`1
`1
`.
`1
`1
`.
`1
`
`.
`1
`1
`1
`1
`.
`. 11
`1 11
`1 11
`1
`1
`1
`.
`.1
`. 11
`
`Part 2 Pharmaceutics
`
`.
`1
`1
`.
`1
`1
`.
`1
`1
`1
`.
`1
`.
`1
`.
`.
`.
`.
`1
`.
`.
`.
`1
`9 Metrology and Calculation .
`1
`1
`1
`1
`.
`.
`1
`.
`.
`.
`.
`1
`1
`1
`.
`1
`1
`.
`.
`1
`.
`1
`1
`10 Statistics .
`.
`1
`.
`.
`1
`1
`.
`.
`1
`.
`1
`1
`.
`.
`.
`.
`1
`1
`1
`.
`.
`1
`.
`1
`1
`._.
`1
`1
`.
`1
`.
`1
`1
`1
`1
`1
`.
`.
`1 1 ComputerScience 1
`1
`1
`.
`1
`.
`.
`1
`.
`. 11
`.
`.
`1
`1
`.
`1
`.
`1
`1
`1
`1
`1
`1
`1
`.
`1
`.
`1
`.
`1
`12 Calculus 1
`1
`1
`.
`.
`.
`1
`.
`.
`1
`1
`.
`.
`1
`.
`.
`.
`13 MolecularStructute1 Properties and States of Matter. 1
`1
`.
`14 Complex Formation 1
`1
`1
`.
`1
`.
`1
`.
`.
`1
`.
`1
`.
`.
`1
`.
`.
`.
`1
`.
`1
`.
`.
`1
`.
`.
`.
`.
`1
`1
`15 Thermodynamics .
`.
`.
`1
`.
`.
`1
`.
`.
`1
`.
`1
`.
`1
`.
`.
`.
`.
`.
`.
`1
`.
`.
`1
`1
`1
`.
`1
`1
`. 1.
`...1f1§21.1§.QJHll9fl§,909.PhQ§€.EQU.'.ll9El9_;
`
`717
`1
`Ionic Solutions and Electrolytic Equilibrio .
`1
`1
`18 Reaction Kinetics .
`.
`1
`.
`,
`1
`1
`1
`.
`.
`.
`1
`1
`.
`1
`.
`1
`1
`1 1.
`.
`1
`.
`.
`1
`.
`.
`.
`.
`.
`,
`.
`19 lnterfacialPhenomeno .
`.
`1
`.
`.
`1
`.
`.
`1
`1
`.
`.
`1
`.
`1
`1
`.
`.
`.
`.
`.
`.
`.
`1
`.
`. .1
`20 Colloidal Dispersions .
`1
`.
`1
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1
`.
`1
`.
`.
`1
`.
`.
`.
`1
`1
`.
`.
`.
`.
`.
`21 Coarse Dispersions 1
`.
`1
`.
`1
`1
`.
`1
`1
`.
`1
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1
`.
`.
`.
`.
`1
`.
`.
`.
`.1
`22 Rheology .
`.
`1
`.
`.
`.
`.
`.
`.
`1
`.
`1
`.
`.
`.
`.
`.
`.
`.
`1
`1
`1
`.
`.
`.
`1
`.
`1
`.
`.
`.
`.
`.
`.
`.
`.
`. 11
`
`Part 3 Pharmaceutical Chemistry 1
`
`1
`1
`1
`1
`1 1. 1
`1
`.
`.
`1
`.
`23 inorganic Pharmaceuticalchemistry 1
`.
`1
`.
`1
`.
`1
`1
`1
`.
`.
`.
`1
`.
`24 Organic Pharmaceutical Chemistry .
`1
`.
`.
`.
`1
`1
`.
`1
`1
`.
`.
`1
`1
`.
`25 Fundamentals of Radioisotopes .
`1
`.
`.
`1
`1
`.
`.
`1
`.
`.
`1
`1
`.
`1
`1
`.
`.
`26 Natural Products .
`.
`.
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`.
`1
`1
`1
`1
`27 Drug Nomenclature——United States Adopted Names. 1
`28 Structure-Activity Relationship and Drug Design .
`.
`.
`1
`.
`1
`1
`
`.
`1
`1
`
`1
`1
`1
`
`Volume ll
`
`Part 6 Pharmaceutical and Medicinal Agents
`
`843
`1
`1
`,
`1
`1
`.
`1
`1
`1
`.
`.
`1
`1
`51 Medical Applications ofRadioisotopes 1
`866
`1
`1
`1
`.
`1
`1
`.
`1
`.
`.
`.
`.
`.
`52 Topical Drugs 1
`.
`1
`1
`1
`1
`.
`.
`.
`1
`.
`1
`1
`.
`.
`.
`1
`.
`.
`.
`.
`.
`.
`886
`1
`1
`.
`1
`1
`1
`.
`1
`.
`,
`1
`1
`1
`53 Gastrointestinal and Liver Drugs .
`.
`.
`,
`1
`1
`1
`910
`1
`1
`1
`54 Blood, Fluids, Electrolytes and Hematologic Drugs 1
`943
`. 11
`55 Cardiovascular Drugs .
`.
`.
`.
`1
`.
`1
`1
`.
`.
`.
`1
`1
`.
`1
`1
`1
`.
`.
`.
`1
`1
`.
`.
`.
`1
`971
`.
`1
`1
`56 Respiratory Drugs .
`.
`.
`1
`1
`.
`1
`1
`.
`.
`.
`.
`1
`.
`.
`.
`.
`1
`.
`.
`.
`1
`.
`.
`1
`.
`1
`1
`1
`981
`.
`1
`1
`57 Sympathomimetlc Drugs 1
`.
`1
`1
`.
`.
`1
`.
`.
`1
`.
`1
`1
`1
`1
`1
`1
`1
`.
`.
`.
`1
`1
`1000
`.
`.1
`58 Cholinomimetic Drugs 1
`.
`.
`.
`1
`1
`1
`1
`1
`.
`1
`.
`1
`1
`.
`.
`1
`.
`.
`1
`1
`1
`.
`1009
`1
`1
`1
`59 Adtenergic and Adrenergic Neuron Blocking Drugs 1
`1020
`.
`.
`1
`60 Anrimuscarinic and Antisposmodic Drugs 1
`1
`,
`1
`.
`1
`.
`.
`1
`‘ 1027
`1
`1
`1
`61 SkeletalMuscle'Re-laxonts 1
`.
`.
`.
`1
`1
`.
`.
`1
`.
`1
`1
`.
`1
`1
`1
`1
`.
`.
`.
`.
`.
`1039
`.
`1
`1
`62 Diuretic Drugs 1
`.
`1
`.
`.
`.
`1
`.
`.
`.
`.
`1
`1
`1
`1
`1
`1
`.
`.
`1
`1
`.
`.
`1
`.
`.
`.
`1
`1
`1
`.
`1
`1
`1052
`.
`1
`.
`63 Uterine and Antimigraine Drugs .
`.
`.
`1
`.
`1
`1
`.
`.
`1
`1
`.
`.
`1
`1
`1
`1
`1057
`1
`1
`.
`64 Hormones .
`.
`1
`.
`1
`1
`1
`1
`.
`.
`1
`1
`1
`1
`.
`1
`1
`.
`.
`1
`,
`.
`.
`.
`.
`.
`1
`1
`.
`.
`.
`.
`.
`.
`.
`1 106
`1
`1
`1
`65 Vitamins and Other Nutrients .
`1
`.
`.
`1
`1
`.
`1
`1
`.
`.
`.
`1
`.
`1
`.
`1
`.
`.
`1
`1137
`1 1.
`66 Enzymes 1
`1
`.
`.
`.
`.
`1
`1
`.
`.
`1
`.
`.
`1
`.
`.
`.
`1
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1
`.
`1
`.
`1
`1
`.
`1140
`67 General Anesthetic Drugs .
`1
`.
`1
`.
`.
`1
`1
`1
`.
`.
`.
`.
`1
`1
`1
`.
`.
`.
`1
`1
`1
`.
`.
`1
`1
`1 146
`1
`68 Local Anesthetic Drugs 1
`1
`1
`
`"69 "Sedativé5a‘n'dl4lypn'6tic'DrU
`.
`1
`1 "1 1543 "
`1
`1
`.
`.
`1
`,
`.
`.
`.
`.
`1
`1
`1
`1
`1
`.
`1
`1
`.
`,
`1
`1
`1
`1
`1
`70 Antiepileptic Drugs .
`.
`1
`1
`.
`1
`1171
`71 Psychopharmacolagic Agents .
`.
`.
`.
`1
`.
`1
`.
`.
`1
`.
`1
`1
`1
`1
`1
`.
`.
`.
`. .1
`1180
`72 Antipyretic and Anri—infiammatory Drugs .
`1
`1
`1
`.
`1
`.
`.
`.
`.
`.
`1
`1
`1 196
`73 Histamine and Antihistaminic Drugs 1
`1
`.
`.
`.
`1
`.
`1
`.
`.
`1
`.
`.
`1
`.
`.
`1
`1222
`74 Central Nervous System Stimulants 1
`1
`.
`1
`.
`1
`.
`.
`.
`.
`1
`1
`.
`.
`1
`.
`1
`1
`1231
`75 Antineoplastic andlmmunoactive Drugs. .
`.
`1
`1-
`.
`.
`.
`1
`.
`1
`.
`1
`1236
`76 Anti~inf1ective.Drugs. .
`1
`1
`1
`1
`1
`1
`1
`1 11.1111 1.263.
`.
`.
`77 Parasiticides 1
`1
`.
`1
`1
`.
`.
`.
`1
`.
`.
`.
`.
`1
`1
`.
`.
`.
`.
`.
`1
`1
`.
`.
`.
`1
`1
`.
`1
`1
`1
`.
`1 11
`1337
`.
`1
`78 Pesticides 1
`.
`.
`1
`.
`1
`1
`.
`.
`1
`1
`.
`.
`1
`.
`1
`.
`,
`1
`.
`.
`.
`.
`1
`.
`.
`1
`1
`.
`.
`1
`.
`1
`.
`,
`1
`1
`1343
`.
`1
`79 DiagnosticAgents .
`.
`1
`.
`1
`.
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`.
`.
`.
`1
`.
`. 1.
`1365
`80 PharmaceuticalNecessities 1
`.
`1
`1
`1
`1
`.
`1
`.
`.
`.
`1
`.
`.
`.
`1
`1
`.
`.
`.
`.
`1 1.
`1380
`81 immunizing Agents and Diagnostic Skin Antigens .
`.
`.
`1
`1
`1
`1417
`82 Allergenic Extracts .
`.
`1
`.
`1
`.
`.
`.
`1
`.
`1
`1
`,
`.
`.
`.
`1
`1
`.
`1
`1
`.
`1
`.
`1
`1
`1
`.
`.
`.
`1
`1
`1434
`
`'
`
`3
`7
`18
`25
`29
`33
`42
`52
`
`63
`94
`128
`135
`147
`169
`184
`. 1941
`213
`231
`241
`252
`278
`292
`
`315
`340
`364
`382
`413
`425
`
`Part 4 Pharmaceutical Testing, Analysis and Control
`
`1
`.
`1
`1
`1
`1
`.
`.
`1
`.
`.
`1
`1
`1
`.
`1
`.
`1
`.
`1
`.
`1
`.
`29 Analysis otMedicinals .
`1
`.
`1
`.
`1
`.
`.
`.
`.
`.
`,
`1
`1
`.
`1
`1
`1
`1
`,
`.
`.
`.
`.
`30 Biological Testing .
`,
`1
`.
`1
`.
`1
`.
`1
`.
`.
`1
`.
`1
`1
`1
`1
`1
`1
`.
`1
`1
`1
`.
`.
`.
`.
`31 Clinical Analysis 1
`.
`.
`.
`.
`1
`.
`1
`.
`.
`1
`.
`.
`.
`.
`1
`.
`.
`.
`.
`.
`1
`1
`.
`.
`.
`1
`.
`1
`32 Chromatography 1
`.
`.
`.
`1
`1
`.
`1
`1
`1
`1
`.
`1
`.
`.
`.
`1
`33 instrumental Methods of Analysis 1
`.
`1
`.
`1
`1
`.
`.
`.
`1
`.
`1
`.
`.
`34 Dissolution 1
`.
`1
`1
`.
`.
`1
`.
`1
`.
`1
`.
`.
`.
`.
`.1
`1
`.
`.
`1
`1
`.
`.
`.
`.
`35 Bioavailability and Bioequivalency Testing 1
`36 Tonlcity, Osmoticlty, Osmolality and Osmolarity .
`37 Separation .
`.
`.
`.
`1
`1
`.
`.
`.
`.
`,
`.
`.
`1
`.
`.
`.
`.
`1
`1
`1
`.
`1
`.
`1
`1
`1
`.
`.
`1
`1
`.
`1
`38 Stability ofPhormoceutical Products .
`1
`.
`.
`1
`1
`.
`1
`.
`.
`.
`.
`39 Quality Assurance and Control
`.
`1
`.
`1
`1
`1
`1
`.
`.
`.
`1
`.
`1
`.
`1
`.
`
`Part 5 Pharmacodynamics
`
`40 Diseases: Manifestations and Pathophysiology 1
`41 Drug Absorption, Action and Disposition 1
`1
`.
`.
`.
`1
`.
`42 Basic Pharmacokinetics 1
`.
`.
`.
`.
`.
`.
`1
`.
`.
`1
`.
`1
`1
`.
`.
`.
`.
`1
`.
`.
`43 Clinical Pharmacolsinetics .
`1
`.
`1
`.
`1 1, .
`1
`.
`1
`.
`1
`.
`1
`.
`.
`1
`1
`.
`44 Principles oflmmunology .
`1
`1
`1
`,
`1
`.
`1
`.
`1
`.
`1
`1
`1
`.
`1
`.
`1
`.
`1
`45 Adverse Drug Reactions 1
`1
`1
`1
`1
`.
`1
`.
`1
`1
`1
`1-
`.
`1
`1
`.
`1
`.
`.
`1
`.
`46 Pharmacogenetics .
`1
`.
`1
`1
`.
`1
`.
`.
`.
`1
`.
`1
`.
`.
`.
`.
`1
`.
`.
`.
`.
`1
`.
`.
`47 Pharmacological Aspects of Drug Abuse .
`.
`.
`1
`.
`1
`1
`48 introduction of New Drugs .
`1
`1
`1 1' .
`1
`1
`1
`.
`1
`.
`1
`1
`1
`.
`1
`1
`1
`49 Biotechnology and Drugs .
`.
`1
`1
`1
`.
`.
`1
`1
`1
`.
`.
`.
`1
`.
`1
`1
`.
`.
`.
`50 Alternative Healthcare .
`.
`1
`.
`.
`.
`1
`.
`1
`1
`.
`1
`,
`1
`.
`.
`.
`1
`.
`,
`1
`.
`
`1
`.
`1
`.
`1
`1
`1
`.
`.
`1
`.
`
`1
`.
`1
`1
`1
`.
`.
`1
`.
`.
`1
`
`.
`.
`1
`1
`1
`1
`1
`1
`1
`1
`.
`
`.
`.
`.
`1
`.
`1
`.
`.
`.
`.
`1
`
`1
`1
`1
`.
`.
`1
`.
`.
`.
`.
`.
`
`1
`1
`1
`.1
`1
`.
`1
`.
`1 .1
`.
`1
`1
`1 ..
`1
`1
`1
`.
`.
`1
`. 1.
`.
`1
`1
`1
`1
`1
`
`1
`1
`1
`1
`.
`.
`1
`1
`1
`1
`1
`1
`1
`.
`.
`.
`1
`.
`1 11
`.
`1
`1
`.
`.
`1
`1
`1
`.
`.
`1
`1
`
`437
`491
`501
`534
`559
`593
`605
`613
`628
`639
`648
`
`655‘
`697
`724
`741
`752
`761
`775
`780
`795
`809
`829
`
`vii
`
`industrial Pharmacy
`Part 7
`.
`1
`1
`.
`.
`.
`1
`1
`1
`.
`1
`.
`1
`.
`1
`1
`.
`1
`1
`1
`,
`.
`.
`.
`83 Pretormulation 1
`.
`1
`1
`1
`.
`1
`.
`.
`1
`.
`.
`.
`.
`.
`.
`.
`.
`.
`1
`.
`1
`.
`.
`1
`84 Sterilization .
`.
`.
`1
`.
`.
`1
`.
`1
`.
`5 Plastic Pocltagingn/laterials .
`1
`1
`.
`1
`.
`1
`.
`.
`.
`1
`.
`.
`.
`86 Solutions, Emulsions, Suspensions and Extracts .
`87 Parenteral Preparations 1
`.
`1
`.
`.
`.
`.
`.
`1
`1
`.
`.
`.
`.
`.
`1
`.
`1
`.
`1
`88 intravenous Admixtures .
`1
`1
`.
`.
`1
`1
`.
`1
`1
`.
`1
`1
`1
`1
`.
`1
`1
`1
`.
`89 Ophthalmic Preparations .
`1
`.
`.
`1
`1
`.
`1
`1
`.
`1
`1
`.
`1
`.
`1
`.
`.
`1
`90 Medicated Applications .
`.
`.
`.
`1
`1
`1
`.
`.
`.
`.
`1
`1
`1
`.
`.
`.
`1
`.
`.
`91 Powders .
`.
`.
`1
`.
`.
`1
`.
`1
`.
`1
`.
`.
`1
`1
`.
`1
`.
`.
`1
`1
`1
`1
`1
`.
`1
`.
`1
`1
`1
`.
`.
`.
`92 Oral Solid Dosage Forms .
`1
`1
`.
`.
`.
`1
`.
`1
`1
`1
`1
`.
`1
`1
`1
`.
`1
`.
`93 Coating of Pharmaceutical Dosage Forms .
`.
`.
`.
`94 Sustained-Release Drug Delivery Systems .
`.
`1
`,
`.
`95 Aerosols .
`.
`.
`1
`.
`.
`.
`1
`1
`1
`1
`.
`1
`1
`1
`1
`.
`.
`.
`1
`.
`1
`.
`.
`.
`1
`.
`1
`1
`.
`1
`.
`1
`
`Part 6 Pharmacy Practice
`
`.
`.
`1
`.
`.
`.
`.
`1
`1
`.
`1
`96 Ambulatory PatientCare .
`.
`.
`1
`.
`1
`.
`.
`1
`1
`.
`1
`97 Institutional ParientCare 1
`1
`1
`1
`1
`.
`.
`.
`1
`.
`.
`.
`.
`98 Long-Tetm Care Facilities .
`.
`.
`.
`1
`99 The Pharmacist and Public Health .
`100 The Patient: Behavioral Determinants 1
`101 Patient Communication 1
`.
`.
`1
`.
`1
`.
`.
`.
`.
`1
`1
`1-
`102 Drug Education .
`.
`.
`1
`1
`1
`1
`1
`.
`1
`1
`.
`1
`1
`1
`.
`1
`1
`1
`1
`103 PatientCom_t:>lionce .
`1
`1
`1
`1
`1
`.
`.
`.
`1
`.
`.
`.
`.
`.
`1
`104 The Prescription .
`1
`.
`1
`1
`1
`.
`.
`1
`1
`1
`.
`1
`.
`1 1’,
`.
`1
`.
`
`.
`1
`.
`1
`.
`.
`1
`.
`.
`
`1
`.
`.
`1
`1
`1
`.
`1
`1
`
`1
`1
`1
`.
`.
`1
`.
`.
`1
`
`.
`1
`1
`.
`1
`,
`1
`1
`.
`
`1
`.
`.
`1
`.
`1
`.
`1
`.
`
`.
`.
`1
`.
`1
`,
`1
`1
`.
`
`1
`.
`1
`1
`.
`1
`.
`.
`.
`
`.
`1
`1
`1
`1
`.
`.
`1
`.
`1
`1
`1
`1
`
`.
`1
`.
`1
`1
`_
`.
`1
`.
`
`.
`.
`1
`.
`1
`.
`1
`1
`.
`1
`1
`.
`.
`
`.
`1
`.
`.
`.
`.
`.
`.
`1
`
`1
`1
`1
`.
`1
`1
`1
`.
`1
`.
`.
`1
`.
`
`1
`.
`.
`.
`1
`.
`.
`.
`1
`
`1
`1
`1
`.
`1
`.
`.
`1
`.
`.
`.
`.
`.
`
`.
`.
`1
`1
`1
`.
`1
`1
`.
`
`. 1.
`1
`.1
`.
`1
`1
`.
`.
`1
`1 11
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`.
`.
`.
`1
`1
`1
`1
`1
`1
`1
`1
`. 11
`
`.
`1
`.
`1
`.
`.
`.
`.
`1
`1
`1
`1
`1
`1
`.
`1
`1
`.
`1
`1
`1
`1 1.
`1
`1
`1
`
`447
`463
`1487
`1495
`524
`1549
`1563
`577
`1598
`615
`650
`660
`676
`
`695
`720
`740
`1755
`1773
`1779
`1786
`1796
`1808
`
`

`
`105
`106
`107
`108
`109
`110
`M’!
`112
`
`.
`.
`_
`.
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`.
`.
`.
`.
`.
`,
`.
`.
`.
`.
`.
`.
`.
`.
`Drug interactions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`. .'.
`.
`.
`.
`.
`.
`.
`Clinical Drug Lirerarure .
`.
`.
`.
`.
`.
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`Health Accessories .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Surgical Supplies .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`i
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`.
`Poison Control .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Laws Governing Pharmacy .
`Community Pharmacy Economics and Management .
`Pharmacoeconomics .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`1822
`1887
`V 1842
`1873
`1888
`1892
`1913
`1929
`
`Appendix
`
`Dose Equivalents .
`Periodic Chart .
`.
`.
`Logariihms .
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`,
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`i
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Glossary and Index
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`i
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`i
`
`.
`.
`.
`
`.
`.
`.
`
`Alphaberic Index .
`Glossary .
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`i
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`i
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`.
`.
`
`A1_
`A2
`A4
`
`H
`G1
`
`viii
`
`

`
`
`
`CHAPTER 84
`
`Sterilization
`
` -2———*-“”
`
`rm
`nts
`or-
`zes
`;he
`to
`es
`
`in-
`ed
`ire
`IS-
`iat
`as
`Lte
`re
`
`Barry Garfinkle, PhD
`Martin Henley, PhD
`Merck 6: Co.
`West Point, PA 19486
`
`.
`
`The aim of a sterilization process is to destroy or eliminate
`microorganisms which are present on or in an object or prepa-
`ration, to make sure that this has been achieved with an
`extremely high level of probability and to assure that the
`object or preparation is free from infection hazards. The
`currently accepted performance target for a sterilization pro-
`cess is that it provide for a probability of finding a nonsterile
`unit of less than one in one million. That is, the process
`(including production, storage, shipment, etc) will provide a
`SteriLz’tyAssura7Lcc Level (SAL) equal to or better than l0“"’.
`The variety and amounts of sterile products and their pack-
`ages required for health care have increased continuously and
`been modified in recent years. Accordingly, sterilization tech-
`nologies have adapted to the changing need. Some of these
`also are brought about by changing requirements and guide-
`lines issued by regulatory or advisory bodies.
`Not many years ago, sterility testing of the finished product
`was the basic means of monitoring the success of a steriliza-
`tion process. Today, qualification and validation ofthe equip-
`ment and the process carried out in that equipment is consid-
`ered essential. This stems from the general principles of
`Total Quality systems. National and international standards
`that define this system (ISOQOOO, EN29000, etc) indeed state
`that “. . Sterilization is a special process because its efficacy
`cannot be verified by simple inspection and testing on the final
`product. .
`.
`. For this reason, sterilization processes have to
`be validated before use, the performance monitored routinely
`and the equipment regularly maintained. .
`. .”
`The purpose ofthis chapter is to provide abasic understand-
`ing of the following sterilization methods currently being used
`in pharmaceutical technology and the equipment employed to
`carry out these methods:
`
`....«.«LU
`
`Method
`Moist heat sterilization
`
`Dry heat sterilization
`
`Chemical “Cold" sterilization
`
`Radiation sterilization
`
`Filtration
`
`Definitions
`
`Equipment
`
`Saturated steam autoclaves
`Superheated water autoclaves
`Air over steam autoclaves
`Batch sterilizers
`Continuous tunnel sterilizers
`Ethylene oxide
`Vaporized hydrogen peroxide
`Hydrogen peroxide/steam
`Other gases
`Electromagnetic
`Particulate
`Membranes
`
`Bacteriostat—-Any agent which arrests or retards the growth of micro-
`organisms.
`-
`
`Bioburden—-«The number of viable microorganisms in or on an_ object
`or preparationentering a sterilization step (usually expressed in colony
`forming units per unit of volume).
`»
`Disinfection~—-A process which decreases the probability of infection
`by destroying vegetative microorganisms, but not ordinarily bacterial
`spores. The term ‘usually is applied to the use of chemical agents on
`inanimate objects.
`Germicide—An agent which destroys microorganisms, but not neces-
`sarily bacterial spores.
`Sterility——-The absence of viable microorganisms.
`Sterility Assurance Level (SAL)——-A term related to the probability of
`finding a nonsterile unit following a sterilization step.
`It usually is ex-
`pressed in terms of the negative power of 10 (ie, one in one million =
`10-5).
`.
`A
`Sterilization——A process by which all viable microorganisms are re-
`moved or destroyed, based on a probability function.
`Terminal Sterilization-—-A process which destroys all viable microor-
`ganisms within the final, sealed package.
`‘ Va1idation———’I‘he act of verifying that a procedure is capable of produc-
`ing the intended result under all expected circumstances. - This usually is '
`accomplished through appropriate challenge(s).
`Viricide~—An agent which will destroy viruses.
`
`Sterility as a Total System H
`
`It is necessary to reiterate the concept already briefly ad-
`dressed in the introduction. The task of the technology we
`are dealing with is to provide the product in sterile conditions
`to the end user.
`'
`
`It is currently acknowledged that the quality of the product
`must be “built into” the process. This concept is particularly
`true when one of the essential qualities of the product is
`sterility.
`Accordingly, the above-mentioned task is accomplished with
`a series of design, production and distribution steps that can
`be su_mmarize‘d as activities for the selection and routine check-
`ing of the following items:
`
`Active constituents, additives, raw materials in general
`Water used both as solvent and as washing/rinsing agent.
`Packaging suitable for the product and for the sterilization process that
`will be used
`,
`V
`Working environment and equipment
`Personnel
`
`These procedures clearly have the purpose of providing the
`sterilization process with a product that has a minimum, defi-
`nite and consistent bioburden. There are also the following
`activities:
`'
`
`The following terms, relating to sterilization, should be
`understood by those carrying out sterilization processes or
`handling sterile products:
`
`Antiseptic—-—A substance that arrests or prevents the growth of micro-
`organisms by inhibiting their activity without necessarily destroying them.
`Aseptic Processing———Those operations performed between the steril-
`ization of an object or preparation and the final sealing of its package.
`These operations are, by definition, carried out in the complete absence of
`microorganisms.
`-
`Bactericide——Any agent which destroys microorganisms.
`
`Selection of the sterilization method that most suits the unit formed by
`the product and its packaging, and definition of the process variables for
`obtaining the intended SAL
`Selection of the machine that is most suitable for performing the se-
`lected method and of the utilities that this machine requires
`Qualification and validation of the machine and of the process
`Routine checking of the process
`Checking of the results of the sterilization process
`Proper storage of sterile goods and verification that their sterility is
`maintained with full reliability throughout the allowed storage period
`Delivering, opening and using sterile goods without recontamination.
`
`1 463
`
`

`
`
`
`1464
`
`CHAPTER 84
`
`It also should be noted that, on October 11, 1991, the FDA
`proposed new regulations for aseptic processing and terminal
`sterilization. The proposed rules requires manufacturers of
`sterile products to use terminal sterilization Wherever possible.
`The proposal will affect 21 CFR 211, 314 and 514. Aseptic
`processing may be used only in those cases where terminal
`sterilization has significant detrimental effects on the product.
`This ruling is based on the ability to prove higher SAL’s with
`current terminal sterilization processes, thus reducing the risk
`of a nonsterile unit reaching the patient.
`
`Contamination
`
`Certain facts about microorganisms must be kept in mind
`when preparing sterile products. Some microbes (bacteria,
`molds, etc) multiply in the refrigerator, others at tempera-
`tures as high as 60°. Microbes vary in their oxygen require-
`ments from the strict anaerobes that cannot tolerate oxygen to
`aerobes that demand it. Slightly alkaline growth media will
`support the multiplication of many microorganisms while oth-
`ers flourish in acidic environments. Some microorganisms
`have the ability to utilize nitrogen and carbon dioxide from the
`air and thus can actually multiply in distilled water.
`In gen-
`eral, however, most pathogenic bacteria have rather selective
`cultural requirements, with optimum temperatures of 30 to
`37° and a pH of 7.0. Contaminating yeasts and molds can
`develop readily in glucose and other sugar solutions.
`Actively growing microbes are, for the most part, vegetative
`forms with little resistance to heat and disinfectants.
`However, some forms of bacteria-——-among them the bacteria
`that cause anthrax, tetanus and gas gangrene——have the abil- .
`ity to assume a spore state, which is very resistant to heat as
`well as to many disinfectants. For this reason, an excellent
`measure of successful sterilization is whether the highly resis-
`tant spore forms of nonpathogenic bacteria have been killed.
`The nature of expected contamination and the bioburden
`are important to the pharmacist preparing materials to be
`sterilized. Theraw materials he works with rarely will be
`sterile and improper storage may increase the microbial
`content. Because the pharmacist seldom handles all raw
`materials in a sterile or protected environment, the environ-
`mental elements of the manufacturing area (air, surfaces,
`water, etc) can be expectedto contribute to the contamination
`of a preparation. The container or packaging material may
`or may not be presterilized and thus may contribute to the
`total microbial load.
`.
`,‘__
`Understanding the nature of contaminants prior to steriliza-
`tion and application of methods for minimizing such contami-
`nation is vital to preparing for successful pharmaceutical
`sterilization. Examples of such methods include:
`Maintenance of a hygienic laboratory.
`Frequent disinfection of floors and surfaces.
`Minimization of traffic in and out of the area.
`Refrigerated storage of raw materials and preparations which support
`microbial growth.
`Use of laminar airflow devices (see page to be referenced) for certain
`critical operations.
`Use of water that is of appropriate USP quality and is free of microbial
`contamination. It is preferrable to use presterilized water to avoid any
`possible contamination.
`
`Methods
`
`General
`
`The procedure to be used for sterilizing a drug, a pharmaceu-
`tical preparation or a medical device is determined to a large
`extent by the nature ofthe product.
`It is important to remem-
`ber that the same sterilization technique cannot be applied
`universally because the unique properties of some materials
`may result in their destruction or modification. Methods of
`inactivating microorganisms may be classified as either physi-
`cal or chemical. Physical methods include moist heat, dry
`heat and irradiation. Sterile filtration is another process, but
`
`it only removes, not inactivates, microorganisms. Chemical
`methods include the use of either gaseous or liquid sterilants.
`Guidelines for the use of many types of industrial and hospital
`sterilization are avai1able.1‘1°
`Each sterilization method can be evaluated using experimen-
`tally derived values representing the general inactivation rates
`of the process. For example, a death rate or survival curve
`for a standardized species can be diagrammed for different
`sterilization conditions. This is done by plotting the loga-
`rithm of surviving organisms against time of exposure to the
`sterilization method.
`In most instances, these data show a
`linear relationship, typical of first-order kinetics and suggest
`that a constant proportion of a contaminant population is
`inactivated in any given time interval. Based on such inacti-
`vation curves, it is possible to derive values that represent the
`general inactivation rates of the process. For example, based
`on such data, it has become common to derive a decimal
`reduction time or D value, which represents the time under a
`stated set of sterilization exposure conditions required to
`reduce a surviving microbial population by a factor of 90%.
`D values, or other expressions of sterilization process rates,
`provide a means of establishing dependable sterilization
`cycles. Obviously, the initial microbial load on a product to
`be sterilized becomes an important consideration. Beyond
`this, however, kinetic data also can be used to provide a
`statistical basis for the success of sterilization cycles. A
`simple example will suffice (Fig 1). When the initial micro-
`bial contamination levelis assumed to be 10“, and if the D
`value of the sterilization process is 7 minutes, complete kill is
`approached by application of 6 D values (42 minutes). How
`ever, at this point reliable sterilization would not be assured
`because a few abnormally resistant members of the popula-
`tion may remain.
`In this example, by extending the process
`to include an additional 6 D values, most of the remaining
`population is inactivated, reducing.the.probability of. one or-
`ganism surviving to one in one million.
`'
`
`‘Moist Hear.
`
`Essentials of Steam Sterilization Kinetics—Let us sup-
`pose a system contaminated by microorganisms (which we
`assume, for the sake of simplicity, to be pure and homoge-
`neous) is immersed in pressurized saturated steam, at coir
`stant temperature; for example a vial containing an aqueous
`suspension of a certain spore-forming microorganism.
`It has been shown experimentally that, under the ab0V9
`conditions, the reaction of thermal degradation of the microor-
`ganism obeys the laws of chemical reactions:
`the rate Of
`reduction of the number of microorganisms present in W
`system in each moment is proportional to the actual numbel
`itself. The proportionality coefficient is typical of the SP9‘
`' cies and conditions of the chosen microorganism.
`
`10‘ ,
`us
`E W 105.,’
`3 g lo‘-‘
`E E 103.
`*5 g 10*
`or
`101,.
`3
`
`Negallve—(No Growllll
`Thermo-Chemical
`. Death Time
`
`
`
`20
`
`5
`
`15
`
`30
`
`‘X40
`35
`
`25
`
`I‘
`énmv
`
`,\
`
`\\
`
`\‘
`
`.
`,, 10 '
`‘ Exposur
`9 102
`to Have 3 Diliii
`lg
`1o‘°Prob”
`"fix ‘O3
`\ orsurllval
`{'3 10‘
`i 1051 Probability of One Organism Survivlng‘\
`/
`5.
`10-L-—i.r.r.vriri
`5
`15
`25
`35
`45
`10
`20
`so
`40
`so
`
`T_ime—l\/llnules
`Fig 1. Sterilization model using D valU95'
`
`.
`
`60
`
`
`.'"\'«mAé.~<¢M~»-m~m«»m.»w.v.w~/wmw»
`
`

`
`themical
`erilants.
`hospital
`
`)erimen-
`.on rates
`al curve
`iifferent
`he loga-
`'e to the
`show a
`suggest
`.ation is
`h inacti-
`sent the
`e, based
`decimal
`under a
`iired to
`90%.
`as rates,
`lization
`>duct to
`Beyond
`ovide a
`:les. A
`1 micro-
`.f the D
`te kill is
`. How
`assured
`popula-
`process
`naming
`one or-
`
`us sup-
`rich we
`:)rnoge-
`at con-
`queous
`
`above
`-.icroor-
`rate of
`in the
`lumber
`ie spe-
`
`'e_ Time
`
`babiiity
`/al
`
`80
`
`or
`
`STERILIZATION
`
`1465
`
`The degradation reaction, (the sterilization process) there-
`fore, develops like a first-order chemical reaction in which the
`‘reaction rate is proportional, in each moment, only to the
`amount of microorganisms still to be inactivated. This seems
`to be obvious for dry sterilization, but less rigorous for steam
`sterilization, in which the water vapor molecules also seem to
`take part in the reaction. Actually, this bimolecular reaction
`is of the first order, since the steam is present in high excess
`during the entire reaction and its concentration may be re-
`garded as constant.
`The most frequently used mathematical expression of the
`above facts is
`‘
`
`(1)
`N = N0 104/0
`where N0 = initial number of microorganisms, t = elapsed
`exposure (= sterilization time), N = number of microorgan-
`isms after the exposure time t andD = “decimal decay time,”
`defined as the time interval required, at a specified constant
`temperature, to reduce the microbial population being consid-
`ered by 1/10 (ie, by one logarithmic value, eg, from 100% to
`10% or from 1 0% to 1% of the initial Value).
`The D value is inversely proportional to the first-order reac-
`tion coefficient and is therefore typical of the species and
`conditions of the chosen microorganism. Depending on the
`initial hypothesis of exposure at constant temperature, each D
`value always refers to a specified temperature.
`Equation 1 allows one to draw. a first very important
`conclusion:
`the time required to reduce the microorganism
`concentration to any preset value is the function of the initial
`concentration.
`The sterilization reaction is therefore neither an “all-or-
`nothing” process nor a “potential barrier” process as was
`once thought.
`'
`It also is evident immediately that the effect of sterilization
`at the same constant temperature will be very different depend-
`ing on‘ the Dvalue of the contaminating microbial species (or
`
`on the largest D value in the usual case of mixed
`contamination). Figure 2 shows that the same reduction
`ratio for different species is achieved after exposure time
`proportional to the D value of each species. The graph de-
`rives only from Eq 1 and from the definition of D value. The
`basic hypothesis of the temperature being constant is thor-
`oughly valid.
`Sterility Is a "Probable” Efiect of Exposure Tz‘me——Let
`us now consider what happens within a batch of units (vials,
`bottles or others) with an initial constant unit contamination
`of 100 microorganisms = 102.
`If the D value at 121° is
`assumed = 1, after 1 minute at 121°, the reduction = to
`101 = 10 microorganisms is achieved; after another minute,
`only 10° = 1 microorganism is still surviving. After another
`minute the surviving microbial population would be 10*‘ =
`1/ 10 microorganism. A contamination of 1/ 10 must not be
`understood to mean that each unit contains 1/ 10 of amicroor-
`ganism, which is biologically meaningless (in this case the unit
`probably would be sterile. . .) but that there is a probability of
`having 1/ 10 of the units still contaminated within the batch of
`sterilized units.
`In fact, 8 minutes would be the necessary time to reduce the
`microbial population to a single surviving microorganism if
`the initial population were ten times larger than the one at
`issue. This higher initial contamination could be regarded
`either as a ten times larger number of microorganisms in the
`same unit, or as the initial contamination of a ten times larger
`unit.
`V
`‘
`-
`-
`If the unit is not considered any longer as the single vial or
`bottle, but as the whole of all the items produced over a period
`of time, the initial number of microorganisms present in each
`item has to be multiplied times the number of items produced,
`and the exposure time to achieve the reduction to the same
`number ofviable microorganisms left in the whole of the items
`produced, has to be increased correspondingly. The follow-
`ing example will behelpful to focus the matter.
`
`Number of microorganisms per unit
`1U'*2
`
`INHI
`INI!
`IIHI
`
`EQII
`III!
`KIII
`
`‘ Sterilization time (minutes)
`
`Fig 2. - Effect of varying D values on sterilization rate (courtesy, Fedegari Autoclavi).
`
`

`
`
`
`1466
`
`CHAPTER 84
`
`i E i
`
`~.-V~.~.<~2mr.~»<r.3>.w6sv:=\v;v
`
`
`
`2.x.~1~v-V4«ma3-'-,-we/N~e~l"-h‘(->’r1<->v-<F79')PI\\‘I*V'4r»~’K-»~r.<Ia»-.-Ii-«xv..v.-,4.»-«.v.
`
`
`
`A new sterile product in ampules has to be manufactured;
`the number of ampules to be produced over all the life period
`of the product is expected to be 1010. The maximum number
`of contaminated ampules deemed to be acceptable is 10° = 1:
`this obviously means that the probability of having nonsterile
`ampules after sterilization must not exceed, 1O“1°. Let us
`also suppose that the microbial population within each am-
`pule after the filling and the sealing does not exceed 103
`microorganisms. These must be destroyed by means of moist
`heat-terminal sterilization at 121°. The applicable D value is
`1 minute. The total number of microorganisms to be de-
`stroyed during the life of the product will be
`1010+:-3 = 1013
`
`If this whole microbial population were exposed to moist heat
`at 121° over a period of 18 minutes, it would be reduced to
`10”” times it initial number, ie, to 101343 = 10° = 1
`The
`exposure time of 13 minutes thus would be sufficient (under
`all the other above hypotheses) to prevent the total number of
`contaminated ampules from exceeding the value of one.
`From the point of View of each single ampule, 13 minutes of
`exposure would reduce the microbial population to the theo-
`retical value of
`~
`
`108-18 .___ 10-10
`
`To interpret this numeric value as the probability of still
`having one contaminated ampule in ten billion sterilized am-
`pules means that a single ampule will still be contaminated out
`of a whole lot of 101°. This probability value is defined as
`PNSU (Probability of Non Sterile Unit).
`In recent times the PNSU as a sterility evaluation criterion is
`' being replaced by the‘ SAL (Sterility Assurance Level). The
`name itself could generate some misunderstanding since a
`level of assurance commonly is deemedto be good if high, but
`SAL seems to have been defined in such away that its numeri-
`cal value is the same as PNSU. This notwithstanding, it is
`sometimes calculated as the reciprocal value of PNSU. The
`SAP (Sterility Assurance Probability) criterion has been pro-
`posed as well and SAP seems for the moment to have been
`granted the same definition of PNSU, even if it would be better
`
`understandable if its value approached unity after a satisfac.
`tory sterilization.
`The above-discussion and example lead to the conclusion
`that the optimum exposure time for a sterilization process
`must take into account not only the initial microbial popula
`tion within the single item to be sterilized and the species and
`conditions of the contaminating microorganism, but also the
`total number of items expected to be sterilized over the life of
`the product.
`Efiect of Temperatwre Chamges-——All the above consider-
`ations have been developed under the basic assumption that
`the temperature is kept constant during the entire exposure
`time.
`It seems rather obvious that the D value will change as
`the temperature changes.
`If the D values experimentally
`obtained for a given mi