`
`1D40002.HbmEaCeneZartSA
`aCeneZaHSAV.CLLg.mSne.wLmmhPOm
`5090nw71mPI
`
`

`

`
`
`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, by Joseph P Remington
`
`Copyright 1926, 1936, by Joseph P Remington Estate
`
`Copyright 1948, 1951, by The Philadelphia College of Pharmacy and Science
`
`Copyright © 1956, 1960, 1965, .1970, 1975, 1980, 1985, 1990, by The Philadelphia College of
`Pharmacy and Science
`-
`
`All Rights Reserved
`
`Library of Congress Catalog Card No. 60-53334
`ISBN 0-912734-04-3
`
`The use of structural formulas from USAN and the USP Dictionary of Drug Names is by
`permission of The USP Convention. The Convention is not responsible for any inaccuracy
`contained herein.
`
`NOTICE—This text is not intended to represent, nor shall it be interpreted to be, the equivalent
`of or a substitute for the official United States Pharmacopeia (USP) and/or the National
`Formalary (NF). In the event of any difference or discrepancy between the current official
`USP or NF standards of strength, quality, purity. packaging and labeling for drugs and
`representations of them herein, the context and effect of the official campendia shall
`prevail.
`
`Printed in the United States of America by the Mach Printing Company, Easton, Pennsylvania
`
`
`
`AstraZeneca Exhibit 2084 p. 2
`
`

`

`Table of Contents
`
`Part 1
`
`Orientation
`
`.
`.
`.
`.
`. . . . . . .
`.
`.
`.
`.
`. .
`. . . . . .
`.
`. . . .
`. . . . .
`.
`.
`Scope .
`1
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`2 Evolution of Pharmacy .
`. . . . . .
`. . .
`.
`. . . . . . . .
`.
`.
`.
`3 Ethics
`.
`.
`.
`. . . . .
`. . . .
`.
`. . . . . . . .
`4 The Practice of Community Pharmacy . . . . . . . .
`. .
`5 Opportunities for Pharmacists in the Pharmaceuti-
`cal Industry . . . . . . . .
`.
`. . . . . . .
`. . .
`.
`. . . . . . .
`. .
`. .
`6 Pharmacists in Government
`. . . .
`.
`. . . . . . . . . .
`.
`. .
`7 Druglnformatlon...........................
`6 Research . . .
`. . . . .
`
`Part 2
`
`Pharmaceutics
`
`.
`. . .
`. . . . . . .
`.
`.
`.
`.
`9 Metroiogy and Calculation . . . .
`.
`.
`.
`.
`. . . . . .
`. .
`.
`.
`10 Statistics . . . . . . . . . .
`. . . . . . . . . .
`.
`.
`.
`.
`. . . . . . . .
`.
`.
`11 Computer Science . .
`.
`. . . . . . . . .
`. . .
`. . . . . . . . . ..
`12 Calculus . .
`. . . . . . .
`13 Molecular Structure. Properties and States of
`. .
`.
`.
`Matter
`. .
`. . . . . . . . . .
`.
`. . . . . . .
`. .
`.
`.
`. . . . . . .
`. ..
`.
`14 Complex Formation .
`. .
`. . . . .
`.
`.
`. . .
`.
`15 Thermodynamics...........................
`16 Solutions and Phase Equilibria .
`.
`. .
`.
`. . . . . . . . .
`. .
`17
`Ionic Solutions and Electrolytic Equilibrla . . . . . .
`. .
`16 Reaction Kinetics .
`.
`.
`.
`. . . . . . . .
`.
`.
`.
`. . . . . . . . . .
`. .
`19 Disperse Systems . . .
`. . . .
`. . . . . . .
`.
`. . . . . . . . .
`.
`. .
`20 Rheology . . . . . .
`. . . .
`. .
`. . . . . .
`.
`.
`. . .
`. . . . . .
`.
`.
`. .
`
`Part 3
`
`Pharmaceutical Chemistry
`
`. . . . .
`Inorganic Pharmaceutical Chemistry . . .
`21
`. . . . .
`22 Organic Pharmaceutical Chemistry . . . .
`23 Natural Products
`. . .
`.
`. . . .
`. . . . . . .
`.
`. . . . . . . .
`24 Drug Nomenclature—United States Adopted
`Names . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . . .
`. . . . . . . . . . .
`25 Structure-Activity Relationship and Drug
`Design . .
`. . .
`. . . . . . .
`.
`. . . . . . . . . .
`.
`. . . . . . . .
`
`.
`.
`.
`
`.
`.
`.
`
`.
`.
`.
`
`.
`
`. .
`
`Part 4
`
`Testing and Analysis
`
`.
`. .
`
`.
`.
`
`26 Analysis of Medicinals
`27 Biological Testing
`. .
`26 CllnicalAnalysis
`.
`29 Chromatography . . .
`.
`30 instrumental Methods of Analysis
`31 Dissolution . . . .
`. . . .
`.
`. . . . . . . .
`. . .
`
`. . . . . . .
`. . .
`.
`.
`
`. . . .
`. . .
`.
`. . . . . .
`
`. .
`. .
`
`. . . .
`. .
`. .
`
`.
`.
`
`. . . . . . . .
`. . . . . . . .
`
`.
`.
`
`. .
`.
`.
`
`3
`8
`20
`28
`
`33
`36
`49
`60
`
`69
`104
`136
`145
`
`156
`162
`197
`207
`226
`247
`257
`310
`
`329
`356
`360
`
`412
`
`422
`
`435
`464
`495
`529
`555'
`589
`
`Part 5
`
`Iladioisotopes in Pharmacy and Medicine
`
`.
`32 Fundamentals of Rodioisotopes . . . . . . . . . . . .
`33 Medical Applications of Radiolsotopes
`. . . . . . .
`
`. .
`. .
`
`605
`624
`
`Pharmaceutical and Medicinal Agents
`Part 6
`34 Diseases: Manifestations and Patho-
`physiology 655
`35 Drug Absorption. Action and Disposition . . . .
`.
`.
`.
`.
`697
`36 Basic Pharmacakinetics . . . . .
`. .
`.
`. . . . . . . . . .
`. . .
`.
`725
`37 Clinical Pharmacokinetics . . . . .
`.
`. . .
`. . . . .
`. . . .
`.
`.
`746
`36 Topical Drugs . . . . .
`. .
`. .
`. . . . . .
`.
`. . .
`. . . . .
`. . . . . .
`757
`39 Gastrointestinal Drugs . . . . . . . . .
`.
`.
`. . . . . . . . . . .
`.
`774
`40 Blood, Fluids. Electrolytes and Hematologic
`.
`.
`Drugs
`. . .
`. . . . . . . . . .
`.
`.
`. . . . . . . . .
`.
`. . . . . . . . .
`‘41
`Cardiovascular Drugs
`. .
`. t . . . .
`.
`.
`.
`.
`. . . . .
`. . . . . .
`42 RespiratoryDrugs
`.
`. . . . ..
`43 Sympathomimetic Drugs . . . . . .
`. . . . .
`. . . .
`.
`.
`
`.
`
`. . .
`
`600
`631
`860
`670
`
`44
`45
`
`46
`47
`46
`49
`50
`51
`52
`53
`54
`55
`56
`57
`56
`59
`60
`61
`62
`63
`64
`65
`66
`67
`66
`69
`70
`
`71
`72
`
`73
`74
`
`75
`76
`77
`76
`79
`60
`61
`62
`63
`
`64
`65
`66
`67
`66
`69
`90
`9 1
`92
`
`93
`94
`95
`96
`
`xv
`
`. . . .
`
`669
`. . . . . .
`. . . . . .
`. . .
`Cholinomimetic Drugs . . . .
`‘
`Adrenergic and Adrenergic Neuron Blocking
`Drugs 698
`Antlmuscarinic and Antispasmodic Drugs
`. . . . . . .
`907
`Skeletal Muscle Relaxants . . .
`. . . . .
`. . . . -.
`.
`. . . . .
`916
`DiureticDrugs
`. . . .
`929
`. . . . . . . . . . . . . .
`Uterine and Antlmlgralne Drugs
`943
`Hormones . . . .
`. .
`. . . .
`. . . .
`. .-.
`. . . . . . . . . . . .
`. . . .
`948
`Vitamins and Other Nutrients .
`. . .
`. . . . . . . . . . t . .
`1002
`Enzymes
`. . . . .
`.
`. . . . .
`. . . .
`.
`.
`. . .
`. . . . . . . . . . . . .
`1035
`General Anesthetics . .
`. . . . . .
`. . .
`. . . . . .
`.
`.
`. . . . .
`1039
`Local Anesthetics . . . . . . . . . . .
`. . .
`. . . . . .
`. . . . . . .
`1046
`Sedatives and Hypnotic: . .
`. . .
`. .
`. . .
`. . . .
`.
`.
`. . . . .
`1057
`Antleplleptics
`. . . . . . . . . ..
`1072
`. . .
`Psychopharmacologic Agents
`. . . . . .
`.
`. . . . . .
`1062
`Analgesics and Antipyreiics .. . . .
`. . .
`. . .
`.
`. .
`. . . .
`1097
`Histamine and Antihistamines . . .
`. . .
`. . .
`.
`. . . . . .
`1123
`Central Nervous System Stimulants . . . . . .
`.
`. . . . .
`1132
`Antlneoplastic and lmmunosuppressive Drugs . . .
`1136
`Antimicrobial Drugs . . . . . . .
`.
`.
`. . . . . . . . .
`.
`.
`. . . . .
`1163
`Parasiticides . .
`.
`. .
`. . . . . . .
`. . .
`. . . . . . . . .
`.
`. . . . . .
`1242
`Pesticides . . .
`.
`. . . .
`. . . .
`. .
`.
`.
`.
`. . . . . . . . . . . . . . . .
`1249
`Diagnostic Drugs
`. .
`. . . . . . . . . . . . .
`. . . . .
`.
`.
`. . . . .
`1272
`Pharmaceutical Necessities
`. . . . . .
`. . . . .
`.
`.
`. . . . .
`1266
`Adverse Drug Reactions .
`. . . . . . . . . . . . .
`.
`.
`. . . . .
`1330
`_Pharmacogenetics
`1344
`. . . . . . .
`Pharmacological Aspects of Drug Abuse .
`1349
`introduction of New Drugs
`.
`.
`. .
`. . . . . . . . . . . . . . .
`1365
`
`Part 1
`
`Biological Products
`
`. . .
`. . .
`. .
`. .
`Principles oi Immunology . . .
`lmmunlzing Agents and Diagnostic Skin
`Antigens
`AllergenicExtracts
`Biotechnology and Drugs . .
`
`.
`
`.
`
`. . .
`
`. . . .
`
`. .
`
`.
`
`.
`
`. . . . .
`
`1379
`
`1369
`1405
`1416
`
`.
`
`.
`
`. . . . .
`
`Part 3
`
`Pharmaceutical Preparations and Their
`Manufacture
`
`. . . . . . . . . . ..
`Preformulatlon
`Bloavailability and Biaequivalency Testing . . . . .
`Separation . . .
`. .
`. . . .
`. . . .
`. .
`.
`. . . . .
`. . . . . .
`. . . . .
`Sterilization . . . .
`. . . . . . . . .
`.
`. . .
`. . . . .
`. . . . . . . . .
`Tonlclty, Osmoticity, Osmoiality and Osmolority .
`Plastic Packaging Materials
`.
`.
`. .
`. . . . . . .
`.
`.
`. . . . .
`Stability of Pharmaceutical Products
`. . . . . .
`. . . . .
`Quality Assurance and Control
`. . . . . . . .
`.
`. .
`. . . .
`Solutions, Emulsions, Suspensions and
`Extractives .
`. . . . .
`.
`.
`. . . .
`. . . . .
`.
`.
`. . . . . . .
`Parenteral Preparations . . . . . .
`.
`. .
`. . . . . .
`Intravenous Admixtures . . . . . .
`. . .
`. . . . . .
`Ophthalmic Preparatlons . . .
`.
`.
`. . .
`. . . . . .
`Medicated Applications .
`. .
`. . .
`.
`. .
`. . . . . .
`Powders . . . . . .
`.
`. . .
`. . . . . . .
`.
`.
`.
`. . . . . . . .
`Oral Solid Dosage Forms .
`. . . . .
`.
`. . . . . . . .
`Coating of Pharmaceutical Dosage Forms .
`Sustalned-Release Drug Delivery Systems
`Aerosols
`
`. . .
`.
`. .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`.
`. . . . .
`. . . . . .
`. . . . . .
`
`1435
`1451
`1459
`1470
`1461
`1499
`1504
`1513
`
`1519
`1545
`1570
`1561
`1596
`1615
`1633
`1666
`1676
`1694
`
`Part 9
`
`Pharmaceutical Practice
`
`. . .
`. .
`Ambulatory Patient Care . . . .
`. . .
`Institutional Patient Care .
`.
`.
`. . .
`Long-Term Care Facilities . . . .
`. . . . .
`The Pharmacist and Public Health . .
`
`. . . .
`. . . .
`. . . .
`. .
`. .
`
`.
`.
`.
`.
`
`.
`.
`.
`.
`
`. . . . .
`. . . . .
`. . . . .
`. . . . .
`
`1715
`1737
`1756
`1173
`
`AstraZeneca Exhibit 2084 p. 3
`
`

`

`
`
`. . . . .
`. . .
`.
`.
`. . . .
`. . . . .
`.
`.
`.
`.
`.
`106 Poison Control
`. . . . . . . .
`.
`.
`107 Laws Governing Pharmacy . . .
`106 Community Pharmacy Economics and
`. . . . . .
`Management
`. .
`. .
`.
`.
`. . . . . . . .
`. .
`.
`. . .
`109 Dental Services .
`.
`.
`.
`-. . .’.
`. . . . . .
`.,
`. . .
`. . . . .
`.
`.
`
`.
`.
`
`Index
`
`.
`97 The Patient: Behavioral Determinants . .
`96 Patient Communication . . . .
`. . . .
`.
`.
`.
`. . .
`99 Drug Education . . . .
`.
`. . . . . .
`. . . .
`.
`.
`.
`. . .
`100 Patient Compliance
`.
`.
`. .
`. . . . . . .
`.
`.
`.
`. . .
`101 The Prescription . . . .
`.
`. . . . . ._ . . . .
`. . .
`. . .
`102 Drug interactions . . .
`.
`.
`. . . . . . . . .
`. . .
`. .
`.
`103 Clinical Drug Literature . .
`. . .
`. . . .
`.
`.
`.
`. . .
`104 Health Accessories
`.
`.
`. . . . . .
`. . . .
`.
`.
`.
`. . .
`
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`. . . . . . .
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.
`. . . . .
`.
`.-
`
`1758
`1796
`1800
`1813
`1628
`1642
`1859
`1664
`
`.
`.
`
`. . .
`. . .
`
`. . .
`. . .
`
`1905
`1914
`
`1940
`1957
`
`105 Surgical Supplies . . . . .
`
`. . . . . . . . .
`
`. . .
`
`. .
`
`. . . . . .
`
`. .
`
`1895'
`
`Alphabetic index .
`
`. . . . . . . . . . .
`
`.
`
`.
`
`. . . .
`
`. . . . .
`
`.
`
`. .
`
`1967
`
`xvi
`
`AstraZeneca Exhibit 2084 p. 4
`
`

`

`CHAPTER 64
`
`Parenteral Preparations
`
`Kenneth E Avls, D5:
`Emeritus Professor. Pharmaceutics
`College of Pharmacy
`University of Tennessee. Memphis
`The Health Science Cenler
`Memphls. TN 38163
`
`Dosage forms of drugs are designed to make it possible to
`introduce a drug into the body of a human or animal patient.
`Since the well-being, or even the life, of the patient may be
`affected, the dosage form must be designed and prepared in
`a manner intended to promote the safety of the patient.
`Concurrently, it is essential that the dosage form compli—
`ment or enhance the therapeutic effectiveness of the drug.
`Parenteral (Gk, para entcron = beside the intestine) is the
`route of administration of drugs by injection under or
`through one or more layers of the skin or mucous mem-
`branes. Since this route circumvents these highly efficient
`protective barriers of the human body, exceptional purity of
`the dosage formrnust be achieved. The processes used in
`preparing it must embody good manufacturing practices
`that will produce and maintain the required quality of the
`product. New developments in process technology and
`quality control should be adopted as soon as their value and
`reliability have been established as a means for further im-
`proving the quality of the product.
`
`History1
`
`One of the most significant events in the beginnings of
`parenteral therapy was the first recorded injection of drugs
`into the veins of living animals, in about 1657, by the archi-
`tect Sir Christopher Wren. From such a very crude begin-
`ning, the technique for intravenous injection and knowledge
`of the implications thereof developed slowly during the next
`century and a half.
`In 1855 Dr Alexander Wood of Edin-
`burgh described what was probably the first subcutaneous
`injection of drugs for therapeutic purposes using a true hy-
`podermic syringe.
`The latter half of the 19th century brought increasing
`concern for safety in the administration of parenteral solu-
`tions, largely because of the work of Robert Koch and Louis
`Pasteur. While Charles Chamberland was developing both
`hot-air and steam sterilization techniques and the first bac-
`teria-retaining filter (made of unglazed porcelain), Stanis-
`laus Limousin was developing a suitable container, the all-
`glass ampul.
`In the middle 1920s Dr Florence Seibert pro-
`vided proof that the disturbing chills and fever which often
`followed the intravenous injection of drugs was caused by
`patent products of microbial growth, pyrogens, which could
`be eliminated from water by distillation and from glassware
`by heating at elevated temperatures.
`0f the recent developments that have contributed to the
`high quality standards currently achievable in the prepara-
`tion of parenteral dosage forms, the two that have probably
`contributed most are the development of HEPA-filtered
`laminar airflow and the development of membrane microfil-
`tration for solutions. The former made it possible 'to
`achieve ultraclean environmental conditions for processing
`sterile products, and the latter made itpossible to remove
`from solutions by filtration both viable and nonviable parti-
`
`cles of microbial size and smaller. However, many other
`developments in recent years have produced an impressive
`advance in the technology associated with the safe and reliL
`able preparation of parenteral dosage forms. The following
`list identifies a few of the events which have contributed to
`that development.
`1926—Parenterals were accepted for inclusion in the fifth
`edition of the National Formulary.
`1933—The practical application of freeze-drying to clinical
`materials was accomplished by a team of scientists at
`the University of Pennsylvania.
`.1938w—The Food, Drug and Cosmetic Act was passed by
`Congress, establishing the Food and Drug Adminis-
`tration (FDA).
`1944—The sterilant ethylene oxide was discovered.
`1946—The Parenteral Drug Association was organized.
`1961—The concept of laminar airflow was developed by WJ
`Whitfield.
`1962—The FDA was authorized by Congress to establish
`current good manufacturing practices (CGMP) regu-
`lations.
`'
`1965—Total parenteral nutrition (TPN) was developed by
`SJ Dudrick.
`1972—The Limulus Amebocyte Lysate test for pyrogens in
`parenteral products was developed by JF Cooper.
`
`Administration
`
`Injections may be classified in five general categories:
`1. Solutions ready for injection.
`2. Dry, soluble products ready to be combined with a olvent just
`prior to use.
`3. Suspensions ready for injection.
`4. Dry, insoluble products ready to be combined with a vehicle just
`prior to use.
`5. Emulsions.
`
`These injections may be administered by such routes as
`intravenous, subcutaneous, intradermal, intramuscular, in-
`traarticular and intrathecal. The nature of the prodirct will
`determine the particular route of administration that may
`be employed. Conversely, the desired route of administra-
`tion will place requirements on the formulation. For exam-
`ple, suspensions would not be administered directly into the
`blood stream because of the danger of insoluble particles
`blocking capillaries. Solutions to be administered subcutav
`neously require strict attention to tonicity adjustment, oth-
`erwise irritation of the plentiful supply of nerve endings in
`this anatomical area would give-rise to pronounced pain.
`Injections intended for intraocular, intraspinal, intracister-
`nal and intrathecal administration require the highest puri-
`ty standards because of the sensitivity of nerve tissue to
`irritant and toxic substances.
`When compared with other dosage forms, injections pos-
`sess select advantages.
`If immediate physiological action is
`
`1545
`
`
`
`AstraZeneca Exhibit 2084 p. 5
`
`

`

`1546
`
`CHAPTER 84
`
`needed from a drug, it usually can be provided by the intra-
`venous injection of an aqueous solution. Modification of
`the formulation or another route of injection can be used to
`slow the onset and prolong the action of the drug. The
`therapeutic response of a drug is controlled more readily by
`parenteral administration since the irregularities of intesti-
`nal absorption are circumvented Also, since the drug nor-
`mally is administered by a professionally trained person, it
`confidently may be expected that the dose was actually and
`accurately administered. Drugs can be administered paren-
`terally when they cannot be given orally because of the
`unconscious or uncooperative state of the patient, or because
`of inactivation or lack of absorption in the intestinal tract.
`Among the disadvantages of this dosage form are the re-
`quirement of asepsis at administration, the risk of tissue
`toxicity from local irritation, the real or psychological pain
`factor and the difficulty in correcting an error, should one be
`made.
`In the latter'situation, unless a direct pharmacologi—
`cal antagonist is immediately available, correction of an er—
`ror may be impossible. One other disadvantage is that daily
`or frequent administration poses difficulties, either for the
`patient to visit a professionally trained person or to learn to
`inject oneself.
`
`Parenteral Combinations
`
`Since there is a degree of discomfort for the patient with
`each injection, a physician frequently will seek to reduce this
`by combining more than one drug in one injection. This is
`encountered most commonly when therapeutic agents are
`added to large-volume solutions of electrolytes or nutrients,
`commonly called “IV additives,” during intravenous admin-
`istration. Since these are aqueous solutions, there is a high
`potential for chemical and physical interactions. See Chap-
`ter 85. The pharmacist is the professional best qualified to
`cope with these incompatibilities. However, in the past,
`these have been handled largely at the patient’s bedside by
`the nurse and physician. Only recently has it been recog-
`nized that this professional area is the proper function of a
`pharmacist and has been so stated by the Joint Commission
`on Accreditation of Hospitals}-3
`As pharmacists have assumed increasing responsibility in
`this area, awareness has developed gradually of the wide-
`spread occurrence of visible, as well as invisible, physical,
`chemical and therapeutic incompatibilities when certain
`drugs are combined or added to intravenous fluids.
`The development of a precipitate or a color change when
`preparations are combined is an immediate warning that an
`alteration has occurred. Such a combination should not be
`administered to the patient because the solid particles may
`occlude the blood vessels, the therapeutic agent may not be
`available for absorption or the drug may have been degraded
`into toxic substances. Moreover,
`in other instances,
`changes not visually apparent may have occurred which
`could be equally or more dangerous to the welfare of the
`patient.
`The almost innumerable potential combinations present a
`complex situation even for the pharmacist. To aid him in
`making rapid decisions concerning potential problems, a
`number of charts have been compiled based on the visible
`changes that may be observed when two or more prepara-
`tions are combined. However, the advent of data storage
`and retrieval systems using computers has provided a means
`to organize and gain rapid access readily to such informa-
`tion. The value of such information is limited by such
`factors as frequent changes in commercial products, varia-
`tions in order of mixing or the proportions in the mixture,
`differences in concentration of each ingredient or variations
`in the period of time that the combination is held before use.
`
`As studies have been undertaken and more information
`has been gained, it has been shown that knowledge of vari-
`able factors such as pH and the ionic character of the active
`constituents aids substantially in understanding and pre-
`dieting potential incompatibilities. Kinetic studies of reac-
`tion rates may be used to describe or predict the extent of
`degradation. Ultimately, a thorough study should be un-
`dertaken of each therapeutic agent in combination with oth-
`er drugs and IV fluids, not only of generic but of commercial
`preparations, from the physical, chemical and therapeutic
`aspects.
`Ideally, no parenteral combination should be adminis-
`tered unless it has been studied thoroughly to determine its
`effect on the therapeutic value and the safety of the combi-
`nation. However, such an ideal situation does not and may
`never exist. Therefore, it is the responsibility of the phar-
`macist to be as familiar as possible with the physical, chemi-
`cal and therapeutic aspects of parenteral combinations and
`to exercise the best possible judgment as to whether or not
`the specific combination extemporaneously prescribed is
`suitable for use in a patient. A service to pharmacists has
`been provided through reviews of this subject.4
`
`General Requirements
`
`An inherent requirement for parenteral preparations is
`that they be of the very best quality and provide the maxi-
`mum safety for the patient. Therefore, the pharmacist,
`being responsible for‘their preparation, must use his skills
`and resourcefulness at the highest level of efficiency to
`achieve this end. Among the areas requiring dedicated at-
`tention are the following:
`1. Possession and application of high moral and professional ethics.
`Even the thought of using inferior techniques or ingredients in a manu-
`facturing process must not be countenanced. The proper attitude ofthe
`person responsible for the—preparation of the product is its most vital
`ingredient.
`2. The pharmaceutical training received must be used to the fullest
`vane .
`measgre. The challenges to this knowledge bank will be many and
`3. Specialized techniques will be required for 'the manufacture ‘of
`sterile preparations, employing them with alertness and sound judg-
`ment. These must be subjected to continuous critical review for faults,
`omissions and improvements.
`4.
`Ingredients of the highest quality obtainable must be used. At
`times, ingredients may require special purification beyond that of the
`commercial supply. This normally will require that cost factors be given
`second place in importance.
`5. The stability and effectiveness of the product must be established
`with substantiating data, either from original or published sources.
`This must take into account process variations and differences in ingre-
`dient specifications from one production site to another.
`6. A well-defined and controlled program must be established to
`assure the quality of the product and the repetition of valid production
`procedures. This involves the evaluation of all ingredients, vigilant
`controls of all steps in the production procedures and careful evaluation
`of the finished product.
`
`Injections or other sterile products rarely are prepared in
`the community pharmacy because of the lack of adequate
`facilities and trained personnel necessary to prepare a reli-
`able and safe product.
`_
`In some hospital pharmacies injections are prepared from
`raw materials for research purposes or in the early phases of
`clinical studies.
`In most hospital pharmacies aseptic pro-
`cessing often is used for adding commercially available par-
`enteral drug products to IV solutions for an individual pa-
`tient.
`Increasingly, hospital pharmacies or independent
`units are dispensing parenterals for the home care of pa-
`tients. Since the products dispensed most frequently are to
`provide the total parenteral nutrition (TPN) requirements
`of a patient, and these are excellent nutritional preparations
`for microorganisms as well, strict requirements for sterility
`must be met in preparation and packaging.
`
`AstraZeneca Exhibit 2084 p. 6
`
`
`
`

`

`
`
`The preparation of the vast majority of injectable prod-
`ucts used clinically occurs in the highly technologically ad-
`vanced plants of the pharmaceutical industry. The opera-
`tions are subject to the oversite of the Food and Drug Ad-
`ministration (FDA) through the application of the Current
`Good Manufacturing Practices (CGMPs) Regulations.5
`These regulations are discussed more fully in Chapter 107.
`While the oversite by the FDA has encouraged strongly the
`achieving of the essential high quality of parenterals today,
`the parenteral industry has taken the leadership and initia-
`tive in the extensive technological development and im-
`provement in the quality, safety, effectiveness and adminis-
`trative proficiency of parenteral dosage forms in recent
`years.
`
`General Process
`
`The preparation of a parenteral product may be consid-
`ered to encompass fou: general areas as follows:
`
`PARENTERAL PREPARATIONS
`
`1547
`
`Procurement and selection of the components and containers.
`Production facilities and procedures.
`Control of quality.
`Packaging and labeling.
`
`$93.“?
`
`The components of the product to be procured include
`vehicles, solutes, containers and closures. The steps consti-
`tuting production include maintaining facilities and equip-
`ment, preparing and controlling the environment, cleaning
`the containers and equipment, preparing the product, filter-
`ing the solution, filling containers with the product, sealing
`the containers and sterilizing the product. The control of
`‘quality includes the evaluation of the components, valida-
`tion of equipment and processes, determination that the
`production has been executed within prescribed require-
`ments, and performance of necessary evaluative tests on the
`finished product. The final area of packaging and labeling
`includes all steps necessary to identify the finished product
`and enclose it in such manner that it is safely and properly
`prepared for sale and delivery to the user.
`
`Vehicles
`
`Since most liquid injections are quite dilute, the compo-
`nent present in the highest proportion is the vehicle. A
`vehicle normally has no therapeutic activity and is nontoxic.
`However, it is of great importance in the formulation since it
`presents to body tissues the form of the active constituent
`for absorption. Absorption normally occurs most rapidly
`and completely when a .drug is presented as an aqueous
`solution. Modification of the vehicle with water-miscible
`liquids or substitution with water-immiscible liquids nor-
`mally decreases the rate of absorption. Absorption from a
`suspension may be affected by such factors as the viscosity
`of the vehicle, its capacity for wetting the solid particles, the
`solubility equilibrium produced by the vehicle and the dis-
`tribution coefficient between the vehicle and aqueous body
`systems.
`The vehicle of greatest importance for parenteral prod-
`ucts is water. Water of suitable quality for parenteral ad-
`ministration must be prepared either by distillation or by
`reverse osmosis. Only by these means is it possible to sepa-
`rate adequately various liquid, gas and solid contaminating
`substances from water.
`
`*
`
`*
`
`1. The quality ofthe raw water will affect the quality of the distillate.
`It may be necessary that the raw water he first softened, deionized or
`treated by reverse osmosis to obtain a final distillate of adequate quality. *
`2. The size of the evaporator will affect the efficiency. It should be
`large enough to provide a low vapor velocity, thus reducing the entrain-
`ment of the distilland either as a film on vapor bubbles or as separate
`droplets.
`3. The baffles (condensing surfaces) determine the effectiveness of
`refluxing. They should be designed to remove efficiently the entrain—
`ment at optimal vapor velocity, collecting and returning the heavier
`droplets contaminated with the distilland.
`4. Redissolving volatile impurities in the distillate reduces its purity.
`Therefore, they should be separated efficiently from the hot water vapor
`and eliminated by aspirating them to the drain or venting them to the
`atmosphere.
`5. Contamination of the vapor and distillate from the metal parts of
`the still can occur. Present standards for high-purity stills are that all
`parts contacted by the vapor or distillate should be constructed of metal
`coated with pure tin, 304 or 31.6 stainless steel or chemically resistant
`glass.
`
`The design features of a still also influence its efficiency of
`operation, relative freedom from maintenance problems or
`extent of automatic operation. Stills may be constructed of
`varying size, rated according to the volume of distillate that
`can be produced per hour of operation under optimum con-
`ditions. Only stills designed to produce high-purity water
`may be considered for use in the production of WFI.
`Conventional commercial stills designed for the produc-
`tion of high—purity water, such as shown in Fig 84-1, are
`available from several supplierslAMSCO, Barnstead, Cor-
`ning, Finn-Aqua, Vaponics).
`
`AstraZeneca Exhibit 2084 p. 7
`
`Components and Containers
`Establishing specifications to insure the quality of each of
`Preparation of Water
`the components of an injection is an essential first step.
`These Specifications will be courdinated with the require-
`ments of the specific formulation and necessarily will not be
`identical for a particular component if used in several differ-
`ent formulations.
`The most stringent requirements normally will be encoun-
`tered with aqueous solutions, particularly if the product is to
`be sterilized at an elevated temperature where reaction rates
`will be accelerated greatly. Modification of aqueous vehi—
`cles to include a glycol, or replacement with a nonaqueous
`vehicle, usually will reduce reaction rates. Dry preparations
`pose relatively few reaction problems but may require defin—
`itive physical specifications for ingredients that must have
`certain solution or dispersion characteristics when a vehicle
`is added.
`Containers and closures are in prolonged, intimate contact
`with the product and may release substances or remove
`ingredients from the product. While not usually considered
`a part of a container, administration devices are a part of a
`container System and their effect upon the product must be
`assessed even though the contact period is usually brief.
`
`In general, a conventional still consists of a boiler (evapo-,
`rator) containing raw water (distilland), a source of heat to
`vaporize the water in the evaporator, a headspace above the
`level of distilland with condensing surfaces for refluxing the
`vapor and thereby returning nonvolatile impurities to the
`distilland, a means for eliminating volatile impurities before
`the hot water vapor is condensed and a condenser for remov-
`ing the heat of vaporization, thereby converting the water
`vapor to a liquid distillate.
`The specific construction features of a still and the process
`specifications markedly will affect the quality of distillate
`obtained from a still. Those required for producing high— -
`purity water, such as Water for Injection USP (WFI), must
`be considerably more stringent than those required for Puri-
`fied Water USP. Among the factors that must be consid—
`ered are:
`
`

`

`
`
`1548
`
`CHAPTER 84
`
`
`
`Fig 84-1. High-purity still and sealed water—storage system. A:
`evaporator; B:
`high-purity baffle unit; 0.
`condenser; D:
`storage
`tank with ultraviolet lamp; E: control panel (courtesy, Giba-Geigy).
`
`Compression Distillation—The vapor-compression
`still, primarily designed for the productionof large volumes "
`of high-purity distillate with low consumption of energy and
`water, is illustrated diagrammatically in Fig 84—2. To start,
`the feed water is heated in the evaporator to boiling. The
`vapor produced in the tubes is separated from the entrained
`distilland in the separator and conveyed to a compressor
`which compresses the vapor and raises its temperature to
`approximately 224°F.
`It then flows to the steam chest
`where it condenses on the outer surfaces of the tubes con-
`taining the distilland; thereby the vapor is condensed and
`drawn off as a distillate while giving up its heat to bring the
`distilland in the tubes to the boiling point.-
`Vapor-compression stills are available in capacities from
`50 to 2800 gal/hr (Aqua-Chem, Barnsteod, Mecol.
`Multiple-Effect Stills—The multiple-effect still also is
`designed to conserve energy and water usage.
`In principle,
`
`it is simply a series of single-effect stills running at differing i
`pressures. A series of up to seven effects may be used, with
`the first effect operated at the highest pressure and the last
`effect at atmospheric pressure. Steam from an external
`source is used in the first effect to ‘generate steam under
`pressure from raw water; it is used as the power source to
`drive the second effect. The 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
`becondensed in a heat exchanger.
`The capacity of a multiple—effect still can be increased by
`adding effects. The quality of the distillate also will be
`affected by the inlet steam pressure; thus, a SOD-gal/hr unit
`designed to operate at 115 psig steam pressure could be run
`at approximately 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, Bernstead, Finn-Aqua, Vaponics).
`Reverse Osmosis—Reverse