21ST EDITION
`
`Remington
`
`The Science and Practice
`of Phar111acy
`
`,~ LIPPINCOTT WILLIAMS & WILKINS
`A Wolters Kluwer Company
`•
`Philadelphia • Baltimore • New York • London
`Buenos Aires • Hong Kong • Sydney • Tokyo
`
`Nexus Ex. 1014
`Page 1 of 11
`
`

`

`ber
`Editor: David B. Troy
`Managing Editor: Matthe~v J. H~~Brien
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`1. b·l·t negligence or otherwise or any mJury resulting fro
`f product ia 1 1 Y,
`rn any
`.
`. 1
`.
`d.
`f
`tte
`r O
`t· n relating to general prmc1p es o me 1cal care which h
`The publisher is not responsible (as a ma
`• r:.
`•
`• fi
`.
`s ould
`f
`.
`.
`.
`bl.
`ntams m1orma 10
`d
`.
`tea _10n_ c~
`not
`t Manufacturer's product m ormabon an package mserts h
`material con tamed herem. This pu
`.
`8 ould be
`be construed as specific instructions for individual _pa~ient· s. dosages and precautions.
`. 1 d.
`.
`.
`ontramd1ca 10ns,
`reviewed for current mformation, me u mg c
`
`Printed in the United States of America
`. h
`Entered according to Act of Congress, m t e year
`Washington DC
`
`1885 by Joseph p Remington, in the Office of the Librarian of Congr
`ess, at
`
`Copyright 1889, 1894, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`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
`
`Copyright 2000, 2006, by the University of the Scie'nces in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available ·
`ISBN 0-7817-4673-6
`
`h
`The publishers have made every effort to t
`.
`race t e copyright holders for borrowed
`any, they will be pleased to make th
`e necessary arrangements at th fi
`material. If they have inadvertently overlooked
`e irst opport
`·t
`uni y.
`The use of structural formulas from USAN
`.
`.
`Convention is not responsible for a
`and the USP Dictionary of Dru
`g Names is by permission of The USP Convention. The
`.
`.
`ny inaccuracy contained herein.
`Notice-This text is not intended t
`h l .
`U ·t d S
`o represent n
`' ors a l it be interpreted t b
`tates Pharmacopeia (USP)
`d
`ni e
`curr~nt official USP or NF stand dan fl or the National Formulary (NF'~ I e, the equivalent of or a substitute for the official
`en ° any difference or discrepancy betwee
`n the
`1 ·
`.
`1. n the ev
`t
`f
`ar s O strength
`herein th
`'
`e context and effect of the offi • l
`' qua ity, purity pack
`.
`aging and l b z·
`f h n
`'
`cia compe d .
`To purchase ddit·
`.
`n ia shall prevail.
`a e mg for drugs and representations o t er
`wnal copies of th· b
`a
`824-7390. International customers i:h oolk call our customer servic d
`ou d call (30l) 714-2324.
`e epartment at (800) 638-3030 or fax orders to (301)
`
`Nexus Ex. 1014
`Page 2 of 11
`
`

`

`
`
`Contents
`
`
`
`Neeeee rTTEEIEEIIEEIEIEEEEneee
`
`Biotechnology and Drugs ......-6.. eee ee eens976
`49
`=
`Part 1__ Orientation
`3
`a
`Heros0lS...ccunas cena ssa aee see Sawa Pee1000
`50
`Scope of Pharmacy
`
`1ScopeofPharmacy... 6c. scu cere e tees aes ets end eae 4 Quality Assurance and Control .........+-+42e09e5 1018
`
`
`Evolution of Pharmacy .....0.66000 00 bee eee ee eee eee z
`a
`.
`1025
`2
`i
`52
`Stability of Pharmaceutical Products
`.....--.++++++5
`3
`Ethics and Professionalism... 2.0.00... 0 00:25 ee eeee20
`y
`‘lability
`and Bioequivalency Testing
`.......- ++ 1037
`The Practice of Community Pharmacy .............-..30
`33
`Bigavallaninty'e
`q
`ene
`4
`1047
`I
`Plastic Packaging Materials ........-2+ee00002000>
`54
`5
`Pharmacists in Industry... 0.066. ee eee 35
`aral NareselOS...
`iascaiaadienvewsgad 1058
`6
`Pharmacists in Government........................40
`55
`Pharmaceutical
`N@C@SSINES
`«+. +e secre e reece
`Pharmacokinetics and Pharmacodynamics
`7
`Pharmacists and Public Health bret Obed UEEE BAe ta eee51
`Part6
`
`Diseases: Manifestations and Pathophysiology ...-.-- 1095
`8
`information Resources in Pharmacy and the
`56
`Pharmaceutical Sciences .....-.... 2.0020 cb cee e wees 64
`:
`-
`doen
`1142
`ini
`i
`57
`Drug Absorption, Action, and Disposition .....-.-.--
`:
`CUR BRIEREIANS yr psc a4 cawilnset bee rear ye:m
`58
`Basic Pharmacokinetics and Pharmacodynamics ...... 1171
`Me
`RSIS) oS aith acatiaxt ieee nthe selahienenea
`59
`Clinical Pharmacokinetics and Pharmacodynamics.... .ee
`ici
`ara
`rt2
`Pharmaceutics
`60
`Priniciples of Immunology ....-.+++-+ee
`=
`‘
`;
`5
`61
`Adverse Drug Reactions and Clinical Toxicology .....-1221
`11 Aig and Pharmaceutical Calculations ......... ae
`62
`Pharmacogenomics ....-22+0sssessnecesvnncenes 1230
`Pharmacokinetics/Pharmacodynamics in
`TaHStS ius fe eiteas cies cums coke Wace nn naeks
`12
`13
`Molecular Structure, Properties, and States of Matter
`...162
`Drug Development .......--+52000 ester eee e ees 1249
`14
`Complex Formation 2.00... eee 186
`ag
`15
`Thermodynamics ......- <i haa Stara pad
`aad eal
`Pharmaceutical and MedicinalAgents
`
`Diagnostic Drugs and Reagents ............00e005 1261
`16
`Solutions and Phase Equilibria... 2.00.0... 020025...211
`17
`lonic Solutions and Electrolytic Equilibria... ....
`0. 237
`ToitDGS ad na cis core ar aksedam tesbwaeis 1277
`18
`Tonicity, Osmoticity, Osmolality, and Osmolarity .....
`..250
`Gastrointestinal and Liver Drugs .......--++-0+-05- 1294
`19
`Chemical KINGS «xs se eee veee yen
`nde cienurin
`nese 268
`Blood,Fluids, Electrolytes, and Hematological Drugs .
`. .1318
`20
`Interfacial Phenomena ..... +++ +2 +s2e0eer eres
`+
`+ 0280
`Cardiovascular Drugs
`...- 2.0.0 ssseeee eee eee es 1350
`21
`Colloidal Dispersions .........++. +++
`Leaareven® ee
`Respiratory Drugs .....--.00eceeeeeeeeeesee ene 1371
`22
`Coarse Dispersions... si0 ses seen nares -
`ele
`Sympathomimetic Drugs .......-000-0eeee erences 1379
`23
`Rheology... 1... eevee sree eee Regd
`Ge BF oe 338
`Cholinomimetic Drugs .......-0 2600 e eee eee 1389
`i
`4
`ic Antagonists and Adrenergic
`Part'3|_
`Pharmaceutical Chennst
`Macoaecenabens
`2 jot Haters iheoy vas 1399
`24
`Inorganic Pharmaceutical Chemistry... 2... ee ees361
`Antimusearinic and Antispasmodic Drugs ........... 1405
`25
`Organic Pharmaceutical Chemistry .....+.-+-0-05-5-386
`Skeletal Muscle Relaxants .........-00000ee eee eee 1411
`26
`Natural Products... 00.0.4 eae cee eee ... 410
`PiureHe DS se 2e2 cee ee baad ewan pee aetees A 1422
`27
`Drug Nomenclature—United States Adopted Names. .
`. .443
`Uterine and Antimigraine Drugs ........--.+--0.- 1432
`28
`Structure-Activity Relationship and Drug Design .......468
`Hormones and Hormone Antagonists .............. 1437
`29
`Fundamentals of Medical Radionuclides .....-.......479
`General Anesthetics .........00 006 cece eee eens 1474
`.
`.
`Local Anesthetics 2.04. ..5.e4 seas ect ee scene es 1479
`Pharmaceutical Testing, Analysis, and Control
`Antianxiety Agents and Hypnotic Drugs ............ 1486
`Analysis of Medicinals ........- 00s eee eee eee eee495
`Antiepileptic Drugs... 6.66. e ever renee eee ee eens 1501
`Biological Testing ........ 02s se sce eee e ene enees 553
`Psychopharmacologic Agents ..........-.......55 1509
`Clinica Analysis: oc. s5 5 sce see aeereesaseedenunaes 565
`Analgesic, Antipyretic, and Anti-Inflammatory Drugs .
`. .1524
`Chromatography ........0eeeeceeeeeeeeeeneeees599
`Histamine and Antihistaminic DUQS.
`i cas cea agieaices 1543
`Instrumental Methods of Analysis ............2000+633
`Central Nervous System Stimulants ................ 1551
`DISGGIUPON! Geiacces hres ess creer eneemacegip ia672
`Antineoplastic Drugs .....--...++++seeeees seers 1556
`Immunoactive Drugs .. 2... 0.00.0. c eee eee 1588
`PAPASGS a2 ate teesce olan aos wie ee SS aoe se 1595
`Immunizing Agents and Allergenic Extracts .......... 1600
`;
`6%
`Anti-infectives ...... 0.0... cseceeeeeseeeeeeees 1626
`Enteymes
`aes
`ee eee Phe Pete as Pee eld vate
`Nutrients and Associated Substances .............. 1688
`ba
`Pesticides... eee eee eee eee aes 1719
`
`Part4__
`30
`31
`32
`33
`34
`35
`
`Part5
`
`36
`37
`eS
`39
`40
`41
`42
`43
`44
`45
`46
`47
`48
`
`63
`
`Part7
`64
`65
`66
`67
`68
`69
`70
`71
`7
`:
`73
`74
`75
`76
`77
`78
`79
`80
`81
`82
`83
`84
`85
`86
`87
`88
`89
`90
`91
`92
`93
`
`Part8
`
`Pharmacy Practice
`
`94
`95
`96
`97
`98
`99
`
`A Fundamentals of Pharmacy Practice
`Application of Ethical Principles to Practice Dilemmas . .1745
`Technology and Automation ........-......-.0.+5 1753
`The Patient: Behavioral Determinants ...........-.+- 1762
`Patient Communication ...........0.0000 eee eens 1770
`Patient Compliance ...... 00... cee ees 1782
`Drug Equeatiori se sa sg ee Ghee ey eee ES hve dale BYES 1796
`
`xxi
`
`Nexus Ex. 1014
`Page 3 of 11
`
`Pharmaceutical Manufacturing
`j
`Asa Abe isaan ad 691
`Separation... .sreseerereree
`POWGERS & pecnc al Ok ea Rae VETO eae coe beg TMT702
`ign
`and Preformulation ....... 720
`Fioperty pased png Design a
`Solutions, Emulsions, Suspensions, and Extracts .......745
`Sans
`ia
`Storligatn: poiG be iiaceis aa poceliilenpaaereeicins776
`Parenteral Preparations ... 0... 0.000 eee eee eee eens802
`Intravenous Admixtures ....... 60000 e eee eee eee 837
`Ophthalmic Preparations ..... 6-4 cee eee eee eee850
`Medicated Topicals ... 2... cece eee cece eens871
`Oral Solid Dosage Forms ...- 1.1.0 cece eee ee eee ees889
`Coating of Pharmaceutical Dosage Forms ........--.-929
`Extended-Release and Targeted Drug Delivery Systems . .939
`The New Drug Approval Process and
`Clinical Trial Design... 0... eee eee eee een eens965
`
`Nexus Ex. 1014
`Page 3 of 11
`
`

`

`117
`
`118
`119
`
`120
`121
`122
`
`xxii
`
`CONTENTS
`
`100
`101
`102
`
`Documenting,Billing, and Reimbursement for
`Professional Communications ............ 000.0008 1808
`Pharmaceutical Care Services .........-..... +++ .2114
`The Prescription ........c.ccccceeeueucueeeeres 1823
`Pharmaceutical Risk Management bb Sete 4.64.02. 2124
`Providing a Frameworkfor Ensuring
`Medication Use Safety ........0. 00.0. cece cece 1840
`Integrated Health Care Delivery Systems ..........2139
`103
`Poison Control «2.0... cece cece eee e ees 1881
`104
`Cc Patient Care
`DrugInteractions 22. cece eee ees 1889
`105
`Specialization in Pharmacy Practice .............., 2158
`ExtemporaneousPrescription Compounding ......... 1903
`106
`Pharmacists and Disease State Management ........ .2163
`Nuclear Pharmacy Practice .........,............ 1913
`107
`Development of a Pharmacy Care Plan and
`Nutrition in Pharmacy Practice.................... 1925
`108
`Patient Problem-Solving ............0-ee000000.,2170
`Pharmacoepidemiology......................... 1958
`109
`123
`Surgical Supplies... 02... 1968
`Ambulatory Patient Care... 0... .....0-.0.0..00.,2179
`110
`124
`Health Accessories 2.0... 1979
`SelCaNe sce eiearetadnisjaivaia a cuca sida Sha GeeEent -2197
`125
`Diagnostic Self-Care ic csancccsaswwsenenednne ge 2206
`B Social, Behavioral, Economic, and
`126
`Preventive Cares. i:ii6. vv cidw'edie cage ase manera Gece2223
`Administrative Sciences
`127
`111
`Hospital Pharmacy Practice .............0..000..., 2247
`Laws Governing Phanmagy:
`tas cy pehnt co fae acess:2015
`112
`128
`Emergency Medicine Pharmacy Practice ............2265
`Re-engineering Pharmacy Practice.................2055
`113
`129
`LONQ-Term Care. vi. tvalics kw cad accneninenede nes2272
`Pharmacoeconomics
`
`BeMGS:Seda tit stewing 55-4 GR sagt ides!2070
`114
`130
`Community Pharmacy Economics and Management .
`. .2082
`Aseptic Processing for Home Infusion Pharmaceuticals
`.2290
`115
`131
`The Pharmacist’s Role in Substance Use Disorders... _2303
`Product Recalls and Withdrawals..... 00.2098
`116
`132
`Marketing Pharmaceutical Care Services ......0 6,2107
`Complementary and Alternative Medical Health Care ..2318
`133
`Chronic Wound Care .............0.. cca cess, 2342
`
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`
`Nexus Ex. 1014
`Page 4 of 11
`
`
`
`Nexus Ex. 1014
`Page 4 of 11
`
`

`

`Parenteral Preparatior,,s
`
`Michael J Akers, PhD
`
`Parenteral (Gk,para enteron, beside the intestine) dosa~e ~orms
`differ from all other drug dosage forms because they are mJected
`directly into body tissue through the primary protective system
`of the human body, the skin, and mucous membranes. ~hey
`must be exceptionally pure and free from physical, chemical,
`and biological contaminants. These requirements place a heavy
`responsibility on the pharmaceutical industry to practice cur(cid:173)
`rent good manufacturing practices (cGMPs) in the manufacture
`of parenteral dosage forms and upon pharmacists and other
`health care professionals to practice good aseptic practices
`(GAPs) in dispensing them for administration to patients.
`Certain pharmaceutical agents, particularly peptides, pro(cid:173)
`teins, and many chemotherapeutic agents, can only be given
`parenterally because they are inactivated in the gastrointesti(cid:173)
`nal tract when given by mouth. Parenterally administered
`drugs are relatively unstable and generally high potent drugs
`that require strict control of their administration to the patient.
`Because of the advent of biotechnology, parenteral products
`have grown in number and usage around the world.
`This chapter will focus on the unique characteristics of par(cid:173)
`enteral dosage forms and the basic principles for formulating,
`packaging, manufacturing, and controlling the quality of these
`unique products. The references and bibliography at the end of
`this chapter contain the most up-to-date texts, book chapters,
`and review papers on parenteral product formulation, manu(cid:173)
`facture, and quality control.
`
`OVERVIEW OF UNIQUE
`CHARACTERISTICS OF PARENTERAL
`DOSAGE FORMS
`Parenteral products are unique from any other type of phar(cid:173)
`maceutical dosage form for the following reasons:
`
`• All products must be sterile.
`• All products must be free from pyrogenic (endotoxin) contamina(cid:173)
`tion.
`• Injectable solutions must be free from visible particulate matter
`This includes reconstituted sterile powders.
`·
`• Products should be isotonic although strictness of isotonicity de(cid:173)
`rends on the route _of admi~istration. Products to be administered
`mto the _cerebrospmal flmd must be isotonic. Ophthalmic prod(cid:173)
`ucts,_ ~h1le not parent:r~l, also must be isotonic. Products to be
`admm1ster~d by bolus mJection by routes other than intravenous
`(IV) essentially should be isotonic or at least very close t
`·
`0 iso-
`tonicity. IV infusions must be isotonic.
`
`Th~ a~th~r recognizes the long time contributions of Dr. Kenneth Avis Dr
`· •
`·
`Avis died m January 1999. Dr. Avis authored this chapter in Rem·
`t
`h ·
`1965 ,,, h
`mg on since
`• .1. o onor is memory, the author has maintained most of h ·
`·
`· h
`.
`.
`{th " h
`is orgamza-
`t·
`. is c apter wit new material and revised information add d h
`ion o
`appropriate.
`e w ere
`
`802
`
`•
`
`ducts must be stable (not only chemically and ph
`.
`All
`pro
`b t 1 " t bl "
`. b"
`Ysical! l
`all other dosage forms, u _a so s ~ . e micr~ rnlogically ie Y it~
`·t freedom from pyrogemc and visible particulate cont' :s~nl.
`i y, t be maintained throughout the shelflife of the prodarninatiun
`r bl )
`"bl Cf
`mus
`.
`uct)
`• Products must be compati e i app ica e with IV diiuen~s
`livery systems, and other drug products co-administered.
`,de.
`
`FORMULATION PRINCIPLES
`Parenteral drugs are fo~mulated as solutions, suspensions
`emulsions, liposo~es, m1crosp~eres, n~nosys~ems, and pow'.
`ders to be reconstituted as solutions. This sect10n will describe
`the components that are commonly used in parenteral formul .
`tions focusing on solutions and freeze-dried products. Gener~
`guidance also will be provided or_i ~~propriate selection of the
`finished sterile dosage form and mitial approaches used to de(cid:173)
`velop the optimal parenteral formulation.
`
`s
`C
`el
`p:
`tl
`p
`g
`jE
`li
`ii
`V
`F
`t
`
`VEHICLES
`WATER-Since most liquid injections are quite dilute, the
`component present in the highest proportion is the vehicle. The
`vehicle of greatest importance for parenteral products is water.
`Water of suitable quality for compounding and rinsing product
`contact surfaces may be prepared either by distillation or byre·
`verse osmosis, to meet United States Pharmacopeia (USP1
`specifications for Water for Injection (WFI). Only by these two
`methods is it possible to separate adequately various liquid.
`gas, and solid contaminating substances from water. These two
`~ethods for preparation of WFI and specifications for W~l are
`discussed later in this chapter. With the possible exception of
`freeze-drying, there is no unit operation more important and
`none more costly to install and operate than the one for the
`preparation of WFI.
`WATER-MISCIBLE VEHICLES-A number of solventE
`tha~ are_ miscible with water have been used as a portion of~:
`vehicle _m the formulation of parenterals. These solvents • J·
`used pnmar·1 t
`1 b" •
`.
`.
`s vehic e
`i Y o so u ihze certam drugs m an aqueou . this
`and to reduce hydrolysis. The most important solvents 10
`1·.
`roup l are ethyl alcohol, liquid polyethylene glycol, and pr~\~n
`efne lg y_col. Ethyl alcohol is used particularly in the prepa_ran· of
`f
`o so ut10n
`d"
`·
`lutio ~
`s O car iac glycosides and the glycols in 50 . • such
`b b.
`ar itur~tes, certain alkaloids and certain antibiotic~- !i!ll•
`preparations us
`11
`.
`1 There are d
`?
`ua Y are gwen mtramuscular y.
`·t t·
`bell·
`1 ~ i_onts with the amount of these co-solvents that cant1·al for
`m1ms ered be
`f
`. .
`oten
`.
`cause o tox1c1ty concerns greater P
`•te of1n·
`.
`h
`1
`emo ys1s and
`t
`·
`. .'
`·
`t the s1
`f
`.,,0re 0
`·
`1 '
`po ential for drug prec1p1tation a
`t·
`Jee 10n. Form 1 t·
`e or w
`d
`.
`u a ion scientists needing to use on
`th
`2) aP
`1
`to:sc:fi ~~nts must consult the literature (eg, refet~~:0ivef
`gis s to ascertain the maximum amount O c
`
`Nexus Ex. 1014
`Page 5 of 11
`
`

`

`"de an efficient rejection of
`.
`cont
`d t prov1
`selecte ? w water. The mo ecu es most d1fficu1t atnina
`1 1
`•c ones such as sodium chlor·d t0 teh, nt
`molecules 1? ra
`i e fl ·•1<iv\
`11 norgan1
`.
`.
`.
`are sma 1 embranes in series is sometimes used t~ . as8an
`through ~wo m of removal of th~se small molecules a ineret
`f tructural failure of a membran nd 4J d~
`the effic1enc1
`•
`d
`e to
`th nsk o s
`c.
`crease
`e
`.
`ts such as bacteria an pyrogens
`tetii0,
`b th R
`·
`·1·
`taminan
`'
`
`O and d' .
`other con WFI . stallations uti ize o
`.
`1.stil!ati
`mtion of the highest quality water 8
`Several
`systems fo~ ~~fie~fon units can be heavily contamin;;eerbf:d~
`water to dis~ a eration of the still, water is first ru ed, an0
` 0 ~nate contaminants. For additiona]n_throu~
`thus, affect t e
`RO units to e 1m1 is
`infol'Jli.
`·1 bl
`e Collentro.
`·
`~-
`·
`tion, se
`i·s systems are avai a e m a range f
`F" A
`R erse osmos
`o pro~
`inn- qua, Meco, M'[ '."l!Jt.
`(AMSCO, Aqua-Chem,
`.
`e~
`1 ltpore
`tion sizes
`ystem is used for the preparation of WFJ
`'
`etc).
`.
`Whichever s
`h t th
`t
`, va1·
`e sys em, consiste ti
`. d to be sure t a
`.
`.
`1-
`da~10n is r~tiui;~duce the chemical, physical, and micr~/ ana
`rehabl~,-t1 f~ater required. Such validation should sta~olo~.
`cal qua 1
`Y ? d characteristics of the source water and • \\'JI tn
`the determine
`.
`d
`.
`inc ua
`treatment production, storage, an distribution
`t
`I a·
`.
`t e pre
`,
`h
`·
`syi.
`h
`All f these systems toget er, me u mg their prop
`-
`er op(cid:173)
`tems.
`o
`.
`h
`l .
`eration and maintenance, determme t e u timate qualityoftht
`
`1.
`
`1'
`
`WF~TORAGE AND _DISTRIBU:ION-The rate of produc.
`f WFI usually 1s not sufficient to meet processing d
`t .
`d .
`h 1a·
`rnn o
`e(cid:173)
`mands; therefore, it is col~ecte m a
`~ mg tank for subse-
`quent use. In large operations, the holdmg tanks may have a
`capacity of several thousand gallo~s and be a part of a continu.
`ously operating system. In such mstances t~e USP require5
`that the WFI be held at a temperature too high for microbial
`growth. Normally, this temperature is a constant 80°C.
`The USP also permits the WFI to be stored at room temp€r(cid:173)
`ature but for a maximum of 24 hours. Under such conditions.
`the WFI usually is collected as a batch for a particular use with
`any unused water being discarded within 24 hours. Sucha sys•
`tern requires frequent sanitization to minimize the risk of ii(cid:173)
`able microorganisms being present. The stainless-steel storage
`tanks in such systems usually are connected to a welded stain(cid:173)
`less-steel distribution loop supplying the various use sites with
`a continuously circulating water supply. The tank is provided
`with a hydrophobic membrane vent filter capable of excluding
`bacteria and nonviable particulate matter. Such a vent filter~
`necessary to permit changes in pressure during filling and em~
`tying. The construction material for the tank and connect!Dg
`lines usually is electropolished 316L stainless steel with welded
`P_ipe. The tanks also may be lined with glass or a coatingofp~
`tm. Such systems are very carefully designed and co~st~ct
`and often constitute the most costly installation within tbe
`plant.
`When the water cannot be used at 80°C heat exchang:f.
`'
`· t of u:e,
`t b ·
`mus ~ mstalle~ to reduce the temperature at the p01n
`,:·
`Bacterial retentive filters should not be installed in suc~ ; 0
`terns because of the risk of bacterial buildup on the filter~
`the consequent release of pyrogenic substances.
`lud!fRITY-While certain purity requirements h~ve ~:~re-
`
`to above, the USP and EP monographs provide · ction
`.
`c1al standards of purity for WFI and Sterile Water for InJe
`J
`(SWFI).
`· 1
`The ch
`h echaJl,
`• th
`emica and physical standards for WFI av e!llain·
`e past few
`· 1 tests r
`m
`T
`_r
`years. he only physical/chem1ca
`1·.,,jt~
`•
`·th a 1'"
`mg are the
`.
`new total organic carbon (TOC)_, \~! fl.3 µSlc0
`500
`b (O
`at 2§Pc
`·
`5
`mg/L), and conductivity, with a hnut_ 0 tru!lleot~
`1
`·1 µS/cm at 20°C. The former is an ins t and~1
`meth d or
`latt o. capable of detecting all organic carbon pres_en 'the con·
`ducte_r _its a three-tiered instrumental test measurins~e!lleJl5or
`1v1 y contr"b t db .
`.
`.
`·
`·cro 1 11,f
`1 u e Y 10mzed particles (m n~1
`. te<11"il l. ,:
`micromh
`t H
`os) relativ
`.
`· ·t 1s 1n
`e,· ·;1t1"
`. us rev1
`lated to pH th
`e O P
`. Smee conduct1v1 Y
`•. 01
`has been eli
`. e pH requirement of 5 to 7 in _P:ev:pecificil~:tii
`mmated. The TOC and conduct1v1tY d" tor, o
`are no
`·e 1c
`w consid
`d
`. .
`l
`to be adequate mmuna P1
`ere
`
`~(cid:173)
`
`ACTURING
`PART 5: PHARMACEUTICAL MANUF
`
`808
`
`-
`
`'l!!rRFl.OW ,APPROX . T • iO•F .
`FEED APPROX, T • e,o•F .
`•
`_,. ~NSATEAPPf3OX T•74 F.
`
`L-~------~
`
`Figure 41 .2. Vapor compressor still.
`
`ciple it is simply a series of single-effect stills or columns tt
`ning'at differing pressures where phase changes oftat~[h ~h=
`
`lace. A series of up to seven effects may be use ' w1
`hrst effect operated at the highest pressure ~nd the l~st e!~ec!
`at atmospheric pressure. See a schematic drawing
`multiple-effect still in Figure 41-3. Steam from an external
`source is used in the first effect to generate steam under pr~s(cid:173)
`sure from feed water- it is used as the power source to dnve
`the second effect. Th~ steam used to drive the second effect
`condenses as it gives up its heat of vaporization and forms a
`distillate. This process continues until the last effect, when
`the steam is at atmospheric pressure and must be condensed
`in a heat exchanger.
`The capacity of a multiple-effect still can be increased by
`adding effects. The quantity of the distillate also will be affected
`by the inlet steam pressure; thus, a 600-gal/hr unit designed to
`operate at 115 psig steam pressure could be run at approxi(cid:173)
`mately 55 psig and would deliver about 400 gal/hr. These stills
`have no moving parts and operate quietly. They are available in
`capacities from about 50 to 7000 gal/hr (AMSCO, Barnstead,
`Finn-Aqua, Kuhlman, Vaponics).
`REVERSE OSMOSIS (RO)-As the name suggests, the
`natural process of selective permeation of molecules through a
`semipermeable membrane separating two aqueous solutions of
`different concentrations is reversed. Pressure, usually between
`200 and 400 psig, is applied to overcome osmotic pressure and
`force pure water to permeate through the membrane. Mem(cid:173)
`branes, usually composed of cellulose esters or polyamides, are
`
`Figure 41-3. Multiple effect still (courtesy, Getinge) S C
`· ee olor Plate 6.
`
`Nexus Ex. 1014
`Page 6 of 11
`
`

`

`CHAPTER 41: PARENTERAL PREPARATIONS
`
`809
`
`chemical/physical purity of WFI. However the wet chemistry
`tests still are used when WFI is packaged for commercial dis(cid:173)
`tribution and for SWFI.
`Biological requir~ment~ continue to be, for WFI, not more
`than ~0 col?ny-formmg umts (CFUs)/100 mL and 0.25 USP en(cid:173)
`dotoxm umts/mL. The SWFI requirements differ in that since
`it is a final product, it must pass the USP Sterility Test.
`WFI and SWFI may not contain added substances. Bacte(cid:173)
`riostatic Water for Injection (BWFI) may contain one or more
`
`suitable antimicrobial agents in containers of 30 mL or less.
`This restriction is designed to prevent the administration of a
`large quantity of a bacteriostatic agent that probably woul~ be
`toxic in the accumulated amount of a large volume of solution,
`.
`.
`even though the concentration was low.. .
`The USP also provides monographs givmg the spec1ficab_ons
`for Sterile Water for Inhalation and Sterile Water for Irriga(cid:173)
`tion. The USP should be consulted for the minor differences be(cid:173)
`tween these specifications and those for SWFI.
`
`Injectable formulations are packaged into containers made of
`glass or plas~ic. Container systems include ampoules, vials, sy(cid:173)
`ringes, cartridges, bottles, and bags (Fig 41-4).
`Ampoules are all glass while bags are all plastic. The other
`containers can be composed of glass or plastic and must include
`rubber materials such as rubber stoppers for vials and bottles
`and rubber plungers and rubber seals for syringes and car(cid:173)
`tridges. Irrigation solutions are packaged in glass bottles with
`aluminum screw caps.
`Table 41-2 provides a generalized comparison of the three
`compatibility properties-leaching, permeation, and adsorp(cid:173)
`tion-of container materials most likely to be involved in the
`formulation of aqueous parenterals. Further, the integrity of
`the container/closure system depends upon several characteris(cid:173)
`tics, including container opening finish, closure modulus,
`durometer and compression set, and aluminum seal application
`force. Container-closure integrity testing will be discussed in
`the Quality Assurance and Control section.
`
`CONTAINER TYPES
`
`Glass
`Glass is employed as the container material of choice for most
`SVIs. It is composed principally of silicon dioxide, with varying
`amounts of other oxides such as sodium, potassium, calcium,
`magnesium, aluminum, boron, and iron. The basic structural
`network of glass is formed by the silicon oxide tetrahedron.
`
`Boric oxide will enter into this structure, but most of the other
`oxides do not. The latter are only loosely bound, are present in
`the network interstices, and are relatively free to migrate.
`These migratory oxides may be leached into a solution in con(cid:173)
`tact with the glass, particularly during the increased reactivity
`of thermal sterilization. The oxides thus dissolved may hy(cid:173)
`drolyze to raise the pH of the solution and catalyze or enter into
`reactions. Additionally, some glass compounds will be attacked
`by solutions and, in time, dislodge glass flakes into the solution.
`Such occurrences can be minimized by the proper selection of
`the glass composition.
`TYPES-The USP has aided in this selection by providing a
`classification of glass:
`
`Type I, a borosilicate glass
`Type II, a soda-lime treated glass
`Type III, a soda-lime glass
`NP, a soda-lime glass not suitable for containers for parenterals
`
`Type I glass is composed principally of silicon dioxide ( ~81 %)
`and boric oxide ( ~ 13%), with low levels of the non-network(cid:173)
`forming oxides (eg, sodium and aluminum oxides). It is a chem(cid:173)
`ically resistant glass (low leachability) also having a low ther(cid:173)
`mal coefficient of expansion (68 X 10- 7 cm/cm-°C).
`Types II and III glass compounds are composed ofrelatively
`high proportions of sodium oxide ( ~ 14%) and calcium oxide
`( ~8%). This makes the glass chemically less resistant. Both
`types melt at a lower temperature, are easier to mold into var(cid:173)
`ious shapes, and have a higher thermal coefficient of expansion
`than Type I (eg, 90 x 10-7 cm/cm-°C for Type III). While there
`is no one standard formulation for glass among manufacturers
`
`A
`
`8
`
`figure 41-4. Various types of packaging for parenterals (courtesy, Kimble, Baxter) .
`
`Nexus Ex. 1014
`Page 7 of 11
`
`

`

`810
`
`PART 5: PHARMACEUTICAL MANUFACTURING
`
`rt·es of Container Materials
`. . .
`Table 41-2. Comparative Compat1b1hty Prope •
`LEACHING
`
`EXTENT 6
`
`PERMEATION
`
`POTENTIAL AGENTS
`
`EXTENT•
`
`POTENTIAL LEACHABLES
`
`Glass
`Borosilicate
`
`Soda-lime
`
`Plastic polymers
`Polyethylene
`Low density
`High density
`PVC
`
`Polyolefins
`Polypropylene
`Rubber polymers
`Natural and related synthetic
`
`Butyl
`
`Silicone
`
`Alkaline earth and heavy metal
`oxides
`1
`Alkaline earth and heavy meta
`oxides
`
`Plasticizers, antioxidants
`Antioxidants
`HCI, especially plasticizers, ..
`antioxidants, other stabilizers
`Antioxidants
`Antioxidants, lubricants
`
`Heavy metal salts, lubricants,
`reducing agents
`Heavy metal salts, lubricants,
`reducing agents
`Minimal
`
`0
`
`0
`
`5
`3
`5
`
`2
`4
`
`3
`
`5
`
`5
`
`2
`1
`4
`
`2
`2
`
`5
`
`3
`
`2
`
`a Approximate scale of 1 to 5, with 1 as the lowest.
`
`NIA
`
`N/A
`
`2
`
`2
`
`Gases, water vapor, other molecules 2
`Gases, water vapor, other molecules 2
`Gases, especially water vapor and
`2
`other molecules
`Gases, water vapor, other molecules
`Gases, water vapor
`
`2
`1
`
`Gases, water vapor
`
`Gases, water vapor
`
`Gases, water vapor
`
`3
`
`2
`
`of these USP type categories, Type II glass usually has a lower
`concentration of the migratory oxides than Type III. In addi(cid:173)
`tion, Type II has been treated under controlled temperature
`and humidity conditions with sulfur dioxide or other dealkaliz(cid:173)
`ers to neutralize the interior surface of the container. While it
`remains intact, this surface will increase substantially the
`chemical resistance of the glass. However, repeated exposures
`to sterilization and alkaline detergents will break down this
`dealkalized surface and expose the underlying soda-lime com(cid:173)
`pound.
`The glass types are determined from the results of two USP
`tests: the Powdered Glass Test and the Water Attack Test. The
`latter is used only for Type II glass and is performed on the
`whole container, because of the dealkalized surface; the former
`is performed on powdered glass, which exposes internal sur(cid:173)
`faces of the glass compound. The results are based upon the
`amount of alkali titrated by 0.02 N sulfuric acid after an auto(cid:173)
`claving cycle with the glass sample in contact with a high-pu(cid:173)
`rity distilled water. Thus, the Powdered Glass Test challenges
`the_ leaching potential of the interior structure of the glass
`while the Water Attack Test challenges only the intact surface
`of the container.
`Selecti~g. the appropriate glass composition is a critical facet
`of deter~mmg the overall specifications for each parenteral
`formulation.
`In general, the following rules apply with respect to glass
`leachables:
`• Relatively low levels of leachables at pH 4-8
`• Rel~tively high levels of leachables at pH > 9
`• MaJor extractables are silicon and sodium
`• M~nor extractables include potassium, barium calci
`l
`d
`um, an a u-
`mmum.
`'
`• Trace extractables include iron, magnesium and zi
`• Treated glass gives less extractables if pH < 8
`nc.
`TyP~ I glass will be suitable for all products, althou h
`
`lfi
`
`d10xide treatment sometimes is used for even gr f SU ur
`
`tance to glass leachables. Because cost must be con=·~ er Jesis(cid:173)
`of the other, less-expensive types may be acceptab~ e~ one
`glass may be suitable, for example, for a solutio: th e ~I
`buffered, has a pH below 7, or is not reactive with th at IS
`'J)P~ III glass usually will be suitable principally for
`; glass.
`liquids or dry substances. However some
`f:an ydrous
`manu acturer-to-
`'
`
`manufacturer variation in glass composition should be antici(cid:173)
`pated within each glass type. _ The~efore, for highly chemically
`sensitive parenteral formulat10ns 1t may