`

`

`

`
`
`Contents
`
`NeETTEEEEEIEEEEEnees
`
`Biotechnology and Drugs ......-6.. eee ee eens976
`49
`—_
`Part1_ Orientation
`Heros0lS...ccunas cena ssa aee see Sawa Pee1000
`50
`1
`Scope of Pharmacy)... 2a. eee ace ee eae cae eae ged vee3
`Quality Assurance and Control ......- +2625 eeeee es1018
`31
`2
`Evolution of Pharmacy 22.6.6. 0 0000s b ieee e eee eee ee7
`Stability of Pharmaceutical Products
`....-.--++++++>1025
`52
`3
`Ethics and Professionalism... 0.0.0. ee eee ee20
`Bioavailability and Bioequivalency Testing .---...----1037
`53
`4
`The Practice of Community Pharmacy ................30
`Plastic Packaging Materials aE Wines ele ESET EE 1047
`54
`5
`Pharmacists in Industry .. 6.0.6...35
`Pharmaceutical Necessities .......-- 06s ee eee eee1058
`55
`6
`Pharmacists in Government... 2... 0.4.0. e ee eee
`AO
`Pharmacokinetics and Pharmacodynamics
`Part6
`7
`Pharmacists and Public Health ............0...000-00551
`
`:
`8
`Information Resources in Pharmacy and the
`Diseases: Manifestations and Pathophysiology Latin’1095
`56
`Pharmaceutical Sciences . 2.0.0.0 .0 ccc cece cece veces64
`Drug Absorption, Action, and Disposition ......-.-.+ 1142
`57
`Clinical Drug Literature . 2.0.0.0. occ cece eee74
`9
`Basic Pharmacokinetics and Pharmacodynamics aged ace 1171
`58
`Paced#6 ct fa sadn oad Aba har sclahaalamn es87
`10
`Clinical Pharmacokinetics and Pharmacodynamics.... . 1191
`59
`Priniciples of Immunology ....-.+-.--e eres e eee ee1206
`60
`Pharmaceutics
`Part2
`2 Saget: reen eee en
`Metrology and Pharmaceutical Calculations .......... .99
`"1
`63
`Pharmacokinetics/Pharmacodynamicsin
`StatistiGS ius ce aeacee as eiSe 127
`12
`Drug Development ..-....2++sssseeeeeneeeeeees 1249
`MolecularStructure, Properties, and States of Matter. . 162
`13
`Complex Formation 2... 20.0. . eee 186
`14
`
`
`
`15 Thermodynamics ....... G2 tial Btw aaleeae sae Part 7 Pharmaceutical and MedicinalAgents
`
`(7
`fonieSohtns and ecrobicEquitis =. 23t
`6
`SammonRanges 00000 Tan
`.
`‘
`16
`Solutions and Phase Equilibria... 2.2... ....202.25. 211
`fe Reeee Osmolality, and Osmolarity .. ..
`- = 66
`Gastraintestinal and Liver Drugs .......mewn wnen ee1294
`20
`interfacial Bhiariena, eer EP Te a Ea re! Y 380
`67
`Blood, Fluids, Electrolytes, and Hematological Drugs .
`. .1318
`
`21 Colloidal Dispersions «0. emseaan+ee,~/eeaentaes diet iicise oleate
`22
`Coarse Disdersions ... ++ 0120+ ss eereres m
`319
`70
`Sympathomimetic DAIQS «sre eu i ES 1379
`23
`Rheology... 1+. eee reese eens es Sages
`te 338
`71
`Cholinomimetic Drugs ........ 0-2 ee eee e eee e eee 1389
`Gist ea of
`
`Pharmaceutical Chemist 72Part3. Adrenergic Antagonists and Adrenergiccedeaaeey Neuron Blocking Drugs... 0... 2.54 sce cence nes 1399
`
`
`24
`Inorganic Pharmaceutical Chemistry... 6-0... 00 555361
`73
`Antimuscarinic and Antispasmodic Drugs .........-. 1405
`25
`Organic Pharmaceutical Chemistry ....-+--. +0 serene386
`74
`Skeletal Muscle Relaxants ...........0-0..000 eee 1411
`26
`Natural Products .......- +... sere eee ee ees
`..» 410
`75
`DiureHO DOS vase ccs eos bade ov aang eee deatee es 1422
`27
`Drug Nomenclature—United States Adopted Names. .
`. .443
`76
`Uterine and Antimigraine Drugs ..............0.-- 1432
`28
`Structure-Activity Relationship and Drug Design .......468
`77
`Hormones and Hormone Antagonists .............. 1437
`29
`Fundamentals of Medical Radionuclides .....-.......479
`78
`renefal AWAshetes nis sicos cg r de dear iae racket ns 1474
`
`
`
`paid.Phertaseautleal Tasting, Anaivats; and Control 79 Local Anesthetics bth mala RR bieabet ener eens 1479_Pham
`
`
`esting,Analysis,and-ontrol_80 Antianxiety Agents and Hypnotic Drugs ............ 1486
`
`30
`Analysis of Medicinals ....... 000.2. ce eeeen eee eees495
`81
`Antiepileptic Drugs ....... 26-6. eee eee eee eee 1501
`31
`Biological Test,
`6 ice ssa cea c ea ce sven ned eeeanes 553
`82
`Psychopharmacologic Agents ...........--...--.. 1509
`32
`ClOANALYSIS: ko eee ee seen cease ces aagumies 565
`83
`Analgesic, Antipyretic, and Anti-Inflammatory Drugs .
`. .1524
`33
`Chromptography:
`is iccicceeyscvinrsoneed anaaaaes599
`84
`Histamine and Antihistaminic Drugs ............... 1543
`34
`Instrumental Methodsof Analysis ...........0-20055633
`85
`Central Nervous System Stimulants ............0055 1551
`35
`DIGEGIUPON! veias ccs sede veces ceewr ene rmauenen in672
`86
`Antineoplastic Drugs... 66... eee ee eee eee ee eee 1556
`87
`Immunoactive Drugs .. 2... 0.00.0. c eee eee 1588
`88
`PACASIHEIIGS
` m.. vis.d ace
`tesce mins ee eate ele vale OR Faw ee EG 1595
`Pharmaceutical Manufacturing
`Part5
`89
`GecatatOll abcieois G4 veveen tanh ea wotsanised691
`36
`Immunizing Agents and Allergenic Extracts ..........1600
`
`BY.©POWMd w-auinad sags rangerdes sstre a area702-90 AnnttHinfectives. 0... 26. v cece e eee reese ees 1626
`38
`Property-Based Drug Design and Preformulation.......720
`91
`Enzymes ........ee1685
`39
`Solutions, Emulsions, Suspensions, and Extracts .......745
`92
`Nutrients and Associated Substances ..............1688
`MO
`“Sega so 5G 23 opens capaci rsayresen776
`93
`Pesticides... seen e eee eee eee e eens1719
`
`4] Parenteral Preparations ....... 50000 e eee erences802Part8PharmacyPractice
`42
`Intravenous Admixtures
`......02: 02002 terre ee 837
`43
`Ophthalmic Preparations... 0... eee eee eee850
`S
`datapoageams ssicesccieoeseaay:
`See eee tenes
`46
`Coating of Pharmaceutical Dosage Forms ........-.--929
`47
`Extended-Release and Targeted Drug Delivery Systems . .939
`48
`The New Drug Approval Process and
`Clinical Trial Design... 6.6 eee eee eee eens965
`
`A Fundamentals of Pharmacy Practice
`MRAMRION EWAMONEAISEccorrowdernec ATES
`WAG Siig CS Fe eit ee
`The Patient: Behavioral Determinants ...........-.+- 1762
`Patient Communication ...........0.0000 eee eens 1770
`Patient Compliance’. .....--4--.c4e0eeeceeneeees 1782
`Drug Equeatiori se sa sg ee Ghee ey eee ES hve dale BYES 1796
`
`AG.
`96
`97
`98
`99
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`Eton Ex. 1014
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`Eton Ex. 1014
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`xxii
`
`CONTENTS
`
`100
`101
`102
`
`103
`104
`105
`106
`107
`108
`109
`110
`
`117
`
`118
`119
`
`120
`121
`122
`
`Documenting,Billing, and Reimbursementfor
`Professional Communications ............ 000.0008 1808
`Pharmaceutical Care Services
`....--.0--0. 2.000000,2114
`The Prescription:
`2.2. ...05c00cc.eceecsneceeeas 1823
`Pharmaceutical Risk Management .........-...., 2124
`Providing a Frameworkfor Ensuring
`Medication Use Safety ........0. 00.0. cece cece 1840
`Integrated Health Care Delivery Systems ..........2139
`Poison Control «2.0... cece cece eee e ees 1881
`Cc Patient Care
`DrugInteractions 22. cece eee ees 1889
`Specialization in Pharmacy Practice .....-........, 2155
`ExtemporaneousPrescription Compounding ......... 1903
`Pharmacists and Disease State Management ........2163
`Nuclear Pharmacy Practice .........,............ 1913
`Development of a Pharmacy Care Plan and
`Nutrition in Pharmacy Practice.................... 1925
`Patient Problem-Solving ..........-.22-00.0000.,2170
`Pharmacoepidemiology......................... 1958
`123
`Surgical Supplies... 02... 1968
`Ambulatory Patient Care ............02.0.2..000.,2179
`124
`Health Accessories 2.0... 1979
`SelPCaMG sc ouieaeta a csjaiciiss deanaa esaee Hees ents.2197
`125
`Diagnostic Self-Care ..... 0.0.0.0... 0. eee ee ee. 2206
`B Social, Behavioral, Economic, and
`126
`PREVENTIVE CATES. b)56.
`6 oid wisdin abies aad aateraeh Cane2223
`Administrative Sciences
`127
`111
`Hospital Pharmacy Practice ..............020....., 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 tvalies Se cn acene ened ea 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 ..........00. cece eee, 2342
`
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`Eton Ex. 1014
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`Eton Ex. 1014
`4 of 11
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`CHAPTER 41: PARENTERAL PREPARATIONS
`
`813
`
`nuents (lipopolysaccharides, LPS) of the cell wall of gram(cid:173)
`~:gative ba~teria (eg, P~e_udomona~ sp, Salmonella sp, Es(cid:173)
`cherichia colzJ. Gram-positive bacten~ and fungi also produce
`yrogens but oflower potency and of different chemical nature.
`~ram-positive bacteria produc~ peptidoglycans wherease fungi
`roduct ~-glucans, both of which can cause non-endotoxin py(cid:173)
`~ogenic res~on~es. Endotoxins a7e lipopolysaccharides that typ(cid:173)
`ically exist m h1g~ molecul_ar weight aggregate forms. However,
`the monomer umt of LPS 1s less than 10,000 daltons, enabling
`endotoxin easily to pass through sterilizing 0.2 micron filters.
`Studies have shown that the lipid portion of the molecule is re(cid:173)
`sponsible for the biological activity. Since endotoxins are the
`most potent pyrogens and gram-negative bacteria are ubiqui(cid:173)
`tous in the environment, especially water, this discussion fo(cid:173)
`cuses on endotoxins and the risk of their presence as contami(cid:173)
`nants in sterile products.
`Pyrogens, when present in parenteral drug products and
`injected into patients, can cause fever, chills, pain in the back
`and legs, and malaise. Although pyrogenic reactions are rarely
`fatal, they can cause serious discomfort and, in the seriously
`ill patient, shock-like symptoms that can be fatal. The inten(cid:173)
`sity of the pyrogenic response and its degree of hazard will be
`affected by the medical condition of the patient, the potency of
`the pyrogen, the amount of the pyrogen, and the route of ad(cid:173)
`ministration (intrathecal is most hazardous followed by intra(cid:173)
`venous, intramuscular, and subcutaneous). When bacterial
`(exogenous) pyrogens are introduced into the body, LPS tar(cid:173)
`gets
`circulating mononuclear
`cells
`(monocytes
`and
`macrophages) that, in turn, produce pro-inflammatory cy(cid:173)
`tokines such as interleukin-2, interleukin-6, and tissue necro(cid:173)
`sis factor. Besides LPS, gram-negative bacteria also release
`many peptides (eg, exotoxin A, peptidoglycan, and muramuyl
`peptides) that can mimic the activity of LPS and induce cy(cid:173)
`tokine release. The Limulus Amebocyte Lysate (LAL) test, dis(cid:173)
`cussed later, can only detect the presence of LPS. It has been
`suggested that a new test, called Monocyte Activation Test,
`replace LAL as the official pyrogen test because of its greater
`sensitivity to all agents that induce the release of cytokines
`that cause fever and a potential cascade of other adverse
`physiological effects. 19
`CONTROL OF PYROGENS-In general, it is impractical,
`if not impossible, to remove pyrogens once present without ad(cid:173)
`versely affecting the drug product. Therefore, the emphasis
`should be on preventing the introduction or development ofpy(cid:173)
`rogens in all aspects of the compounding and processing of the
`product.
`Pyrogens may enter a preparation through any means that
`will introduce living or dead microorganisms. However, current
`technology generally permits the control of such contamination,
`and the presence of pyrogens in a finished product indicates
`processing under inadequately controlled conditions. It also
`should be noted that time for microbial growth to occur in(cid:173)
`creases the risk for elevated levels ofpyrogens. Therefore, com(cid:173)
`pounding and manufacturing processes should be carried out as
`expeditiously as possible, preferably planning completion of the
`~rocess, including sterilization, within the maximum allowed
`bme according to process validation studies. Aseptic processing
`guidelines require establishment of time limitations through(cid:173)
`out processing for the primary purpose of preventing the in(cid:173)
`crease of endotoxin (and microbial) contamination that subse(cid:173)
`quently cannot be destroyed or removed.
`t Pyrogens can be destroyed by heating at high tempera(cid:173)
`u~es. A typical procedure for depyrogenation of glassware
`;~00 equipment is maintaining a dry heat temperature of
`4 h C _for ~5 mi1:. Exposure for 650°C for 1 min or 180°C for
`{ h~ew1se will destroy pyrogens. The usual autoclaving
`~~fu~_wdl n~t do so. Heating with strong alkali or oxidizing
`th
`ions will destroy pyrogens. It has been claimed that
`py°rough washing with detergent will render glassware
`frerogen-free if subsequently rinsed thoroughly with pyrogen(cid:173)
`des~r wa~er. Rubber stoppers cannot withstand pyrogen-
`uctive temperatures, so reliance must be placed on an
`
`effective sequence of washing, thorough rinsing with WFI,
`prompt sterilization, and protective st?rage t~ ensure ade(cid:173)
`quate pyrogen control. Similarly, plastic cont~me:s and ?e(cid:173)
`vices must be protected from pyrogenic contammat10n dur~ng
`manufacture and storage, since known ways of destroymg
`pyrogens affect the plastic adversely._ ~t has been reported
`that anion-exchange resins and positively charged mem(cid:173)
`brane filters will remove pyrogens from water. Also, al(cid:173)
`though reverse osmosis membranes will eliminate them, t~e
`most reliable method for their elimination from water is
`distillation.
`A method that has been used for the removal of pyrogens
`from solutions is adsorption on adsorptive agents. Ho~ever,
`since the adsorption phenomenon also may c~use se~ective re(cid:173)
`moval of chemical substances from the solut10n, this m~thod
`has limited application. Other in-proc_ess metho~s for their de-
`struction or elimination include selective extract!on proc_edur~s
`and careful heating with dilute alkali, dilute acid, or mild ~x1-
`dizing agents. In each instance, the method must be studied
`thoroughly to be sure it will not have an adverse effe~t on the
`constituents of the product. Although ultrafiltra~10n no~
`makes possible pyrogen separation on a molecular-weight basis
`and the process of tangential flow is making; la:g~-scale pro(cid:173)
`cessing more practical, use of this technology 1s limited, except
`in biotechnological processing.
`SOURCES OF PYROGENS-Through understanding the
`means by which pyrogens may contaminate parenteral prod(cid:173)
`ucts their control becomes more achievable. Therefore, it is im(cid:173)
`port;nt to know that water is probably the greatest potential
`source of pyrogenic contamination, since water is essential for
`the growth of microorganisms and frequently contaminated
`with gram-negative organisms. When microorganisms metabo(cid:173)
`lize, pyrogens will be produced. Therefore, raw water can be ex(cid:173)
`pected to be pyrogenic and only when it is appropriately treated
`to render it free from pyrogens, such as WFI, should it be used
`for compounding the product or rinsing product contact sur(cid:173)
`faces such as tubing, mixing vessels, and rubber closures. Even
`when such rinsed equipment and supplies are left wet and im(cid:173)
`properly exposed to the environment, there is a high risk that
`they will become pyrogenic. Although proper distillation will
`provide pyrogen-free water, storage conditions must be such
`that microorganisms are not introduced and subsequent
`growth is prevented.
`Other potential sources of contamination are containers
`and equipment. Pyrogenic materials adhere strongly to glass
`and other surfaces, especially rubber closures. Residues of so(cid:173)
`lutions in used equipment often become bacterial cultures,
`with subsequent pyrogenic contamination. Since drying does
`not destroy pyrogens, they may remain in equipment for long
`periods. Adequate washing will reduce contamination and
`subsequent dry-heat treatment can render contaminated
`equipment suitable for use. However, all such processes must
`be. val~dated to. ensur~ th~ir effectiveness. Aseptic processing
`gmdelmes :r:eqmre validation of the depyrogenation process by
`demonstratmg at least 3-log reduction in an applied endotoxin
`challenge.
`Solutes ~ay be a source of pyrogens. For example, the
`ma1:ufacturmg of bulk chemicals may involve the use of pyro(cid:173)
`ge~1c water for process steps such as crystallization, precipi(cid:173)
`tation, or washmg. Bulk drug substances derived from cell
`cult_ure fermentation will almost certainly be heavily pyro(cid:173)
`gemc. Therefore, all lots of solutes used to prepare parenteral
`p:r:oducts should be tested to ensure that they will not con(cid:173)
`tnbute unacceptable quantities of endotoxin to the finished
`product. It is standard practice today to establish valid endo(cid:173)
`toxin limits on active pharmaceutical ingredients and most so(cid:173)
`lute additives.
`The manufacturing process must be carried out with great
`care and as rapidly as possible, to minimize the risk of micro(cid:173)
`bial contamination. Preferably, no more product should be pre(cid:173)
`pare~ than can be processed completely within one working
`day, mcluding sterilization.
`
`(cid:141)
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`Eton Ex. 1014
`11 of 11
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