Remington: The
`Science and Practice
`‘
`of Pharmacy
`
`Volume II
`
`MYLAN V. BAXTER
`MYLAN V. BAXTER
`IPR2016-00217
`|PR20’|6-0021 7
`EXHIBIT 2002
`EXHIBIT 2002
`
`

`
`19m
`
`EDITION
`
`Remington:
`Practice of
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`and Editor
`
`

`
`The Science and
`Pharmacy
`
`1995
`
`MACK PUBLISHING COMPANY
`
`Easton, Pennsylvania 18042
`
`

`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Oifice of the Librarian of Congress, at Washington DC
`
`Copyright 1889. 1894,1905, 1907,19 1 T, by Joseph P Remington
`
`Copyright 1926, 1 9-36, 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, byThe Philadelphia College of
`Pharmacy and Science
`
`All Rz'ghz‘.s Resemred
`
`Library of Congress Catalog Card No. 60-53834
`
`ISBN O-912 7311-04-33
`
`The use ofstru,ctu,ral.fornzulasfrom. USAN and the USP Dict2'on.ary 0fDrug Names is by
`pe7"m.z’.ss'z'on of The USP Convention, The Convention is not responsiblefor any inaccuracy
`conta 2'ned herein.
`
`NOTIC ——”'h 27.9 text is not ivntended to represent, nor shall it be interpreted to be, the equ'z'.val.ent
`ofm" a 57/.bstz' ratefor the ofiicial United States Pharmacopeia. (USP) and /07‘ the National
`Fornzzzlcnty (NF). In the event ofayny cZv2jTe"rence or discrepancy between the cuwent ofiicial
`USP or NF sta.ncla.rd.s 0fstrength, quc/..l_it;y, pusrzty, packaging and labelingfor drugs and
`rep7*esen.Zat2I0ns ofthem herein, the context and efiect ofthe oficial compendia shall prevail.
`
`Pflhted in the -Urzzite/J. States ofA'men'ca by the Mack Printing Company, Easton, Pennsylltranzia
`
`

`
`Table of Contents
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`Volume I
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`Part 1 Orientation
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`1
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`1 Scope .
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`2 Evolution of Pharmacy .
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`3 Ethics .
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`4 Community Pharmacy .
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`5 Pharmacists in industry .
`6 Pharmacists in Government .
`7 Drug information .
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`8 Research 1
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`Part 2 Pharmaceutics
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`Volume II
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`Part 6 Pharmaceutical and Medicinal Agents
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`51 Medical Applications of Radioisotopes .
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`52 Topical Drugs .
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`53 Gastrointestinal and LiverDrugs .
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`54 Blood, Fluids, Electrolytes and Hematologic Drugs 1
`55 CardiovascularDrugs .
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`56 Respiratory Drugs .
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`57 Sympathomimetic Drugs .
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`58 Cholinomimetic Drugs .
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`59 Adrenergic and Adrenergic Neuron Blocking Drugs 1
`60 Anrimuscarinic and Antispasmodic Drugs .
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`61 SkeletalMuscle Relaxants .
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`62 Diuretic Drugs .
`63 Uterine and Antimigraine Drugs .
`64 Hormones .
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`65 Vitamins and Other Nutrients .
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`9 Metrology and Calculation .
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`10 Statistics .
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`1 1 Computerscience .
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`12 Calculus .
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`13 MolecularStructure, Properties and States of Matter. .
`14 Complex Formation .
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`15 Thermodynamics .
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`16 Solutions and Phase Equilibria .
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`17 ionic Solutions and Electrolytic Equilibria .
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`18 Reaction Kinetics .
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`19 lnterfacial Phenomena .
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`20 Colloidal Dispersions .
`21 Coarse Dispersions .
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`22 Rheology .
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`252
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`Part 3 Pharmaceutical Chemistry
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`66 Enzymes .
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`67 General Anesthetic Drugs .
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`68 Local Anesthetic Drugs .
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`69 Sedative and Hypnotic Drugs .
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`70 Antiepileptic Drugs .
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`71 Psychopharmacologic Agents .
`72 Antipyretic and Anti—inflammatory Drugs .
`78 Histamine and Antihistaminic Drugs .
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`74 Central Nervous System Stimulants .
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`75 Antineoplastic and lmmunoactive Drugs .
`76 Anti—infectlve Drugs 1
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`77 Parasiticides .
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`78 Pesticides .
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`843
`866
`886
`910
`943
`971
`981
`000
`009
`020
`027
`’ 039
`052
`057
`106
`137
`140
`146
`154
`171
`180
`196
`222
`231
`236
`1263
`337
`1343
`365
`380
`417
`434
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`-447
`-463
`487
`495
`524
`549
`563
`577
`1598
`1615
`.650
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`676
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`23 inorganic Pharmaceutical Chemistry .
`24 Organic Pharmaceutical Chemistry .
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`25 Fundamentals of Radioisotopes .
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`26 Natural Products .
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`27 Drug Nomenclature-~United States Adopted Names. .
`28 Structure-Activity Relationship and Drug Design .
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`315
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`Part 4 Pharmaceutical Testing, Analysis and Control
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`29 Analysis of Medicinals .
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`30 BiologicalTesting .
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`31 ClinicalAna|ysis .
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`32 Chromatography .
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`33 instrumental Methods of Analysis 1
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`34 Dissolution .
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`35 Bioavoilability and Bioequivalencyiesting .
`36 Tonicity, Osmoticity, Osmolality and Osmolarity .
`37 Separation .
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`88 Stability of Pharmaceutical Products 1
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`39 Quality Assurance and Control
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`Part 5 Pharmacodynamics
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`79 Diagnostic Agents .
`80 PharmaceuticalNecessities .
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`81 immunizing Agents and Diagnostic Skin Antigens .
`82 Allergenic Extracts .
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`industrial Pharmacy
`Part 7
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`88 Pretormulation .
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`84 Sterilization .
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`5 Plastic Packaging Materials .
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`86 Solutions, Emulsions, Suspensions and Extracts .
`87 Parenteral Preparations .
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`88 Intravenous Admixrures .
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`89 Ophthalmic Preparations .
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`90 Medicated Applications .
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`91 Powders .
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`1
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`1
`1
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`1
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`1
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`92 Oral Solid Dosage Forms .
`1
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`1
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`1
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`1
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`1
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`98 Coating of Pharmaceutical Dosage Forms _
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`94 Sustained~Release Drug Delivery Systems .
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`95 Aerosols .
`1
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`1
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`40 Diseases: Manifestations and Pathophysiology .
`41 Drug Absorption, Action and Disposition .
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`42 Basic Pharmacokinetics .
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`1
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`1
`1
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`43 Clinical Pharmacokinetics .
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`1
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`44 Principles oflmmunology .
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`45 Adverse Drug Reactions .
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`46 Pharmacogenetics .
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`47 Pharmacological Aspects of Drug Abuse .
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`48 introduction of New Drugs .
`1
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`1
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`1
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`49 Biotechnology and Drugs 1
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`50 Alternative Heaithcare .
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`Part 8 Pharmacy Practice
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`Ambulatory Patient Care .
`institutional Patient Care .
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`1
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`Long—Term Care Facilities .
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`The Pharmacist and Public Health .
`The Patient; Behavioral Determinants .
`Patient Communication 1
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`1
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`1
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`Drug Education ,
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`PorientCompliance .
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`The Prescription 1
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`1695
`1720
`1740
`1755
`1773
`1779
`1786
`1796
`1808
`
`655‘
`697
`724
`741
`752
`761
`775
`780
`795
`809
`829
`
`vii
`
`96
`97
`98
`99
`100
`101
`102
`103
`104
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`

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`105
`106
`107
`105
`109
`110
`111
`112
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`Drug interactions .
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`Clinical Drug Literature .
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`Health Accessories .
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`A
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`c
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`A
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`Surgical Supplies .
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`Poison Control .
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`Laws Governing Pharmacy .
`Community Pharmacy Economics and Management .
`Pharmacoeconomics .
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`1822
`1837
`1642
`1873
`1883
`1892
`1913
`1929
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`Appendix
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`Dose Equivalents .
`Periodic Chart
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`Logarithms .
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`Glossary and Index
`
`Alphabetic index .
`Glossary .
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`A1
`A2
`A4
`
`l1
`G1
`
`viii
`
`

`
`CHAPTER 84
`
`Sterilization
`
`
`Barry Gorfinkle. PhD
`Martin Henley, PhD
`Merck 6 Co.
`West Point, PA 19466
`
`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
`Sterility/Assuraitce Level (SAL) equal to or better than 1 O‘‘‘.
`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 of the 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 eificacy
`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 a basic understand-
`ing of the following sterilization methods currently being used
`in pharmaceutical technology and the equipment employed to
`carry out these methods:
`Method
`
`Equipment
`
`Moist heat sterilization
`
`Dry heat sterilization
`
`Chemical “Cold” sterilization
`
`Radiation sterilization
`
`Filtration
`
`Definitions
`
`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
`
`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.
`
`Bacteriostat—-Any agent which arrests or retardsthe growth of micro-
`organisms.
`Bioburden—-The number of viable microorganisms in or on ar; object
`or preparation entering 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 un.it following a sterilization step.
`It usually is ex-
`pressed in terms of the negative power of 10 (ie, one in one million =
`1045).
`.
`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.
`Validation—The act of verifying that a procedure is capable of produc-
`ing the intended result under all expected circumstances. This usually is
`accomplished through appropriate chal1enge(s).
`Viricide—An agent which will destroy viruses.
`
`Sterility as a Total System A
`
`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 summarized 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
`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:
`
`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.
`
`1463
`
`
`
`
`
`\4\LwLid
`
`

`
`
`
`1 464
`
`CHAPTER 84
`
`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 available.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 suflice (Fig 1). When the initial micro-
`bial contamination level is assumed to be 105, 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 Heat
`
`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 C011‘
`stant temperature; for example a vial containing an aqueous
`suspension of a certain spore-forming microorganism.
`It has been shown experimentally that, under the above
`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 lh‘?
`system in each moment is proportional to the actual numbe’
`itself. The proportionality coefficient is typical of the SP9‘
`cies and conditions of the chosen microorganism.
`
`106 1
`.5
`<3 U) 105'.
`3 E 10‘ 1
`:5 K2
`3 Q 103.
`Z S?
`3 5 109»
`U)
`1Ol
`3
`
`_
`Negatlve—(No Growth)
`Thermo—Chemical
`, Death Time
`
`mzv/I{«/J¢«é»r:«\~r«~>®,V‘¢.Vs7waevIn¢ia&<:tér4n-9evA»s~¢za«~n~«»\vm;nv>v;«/aw»;-»:¢»oe«o«;s
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`
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`35
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`
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`
`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. The raw 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 expected to 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 of the 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
`
`10
`
`20 ' so
`25
`
`15
`
`5
`
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`i
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`Expos‘
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`24
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`to Have
`pill”
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`I
`10.5 Probgl‘
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`olsuf‘/“'3
`5 10”‘,
`n. 105; Probability of One Organism Surviving \\
`/ I
`106}
`H
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`r
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`1 W O
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`35
`45
`55
`65 70
`9
`10
`20
`30
`40
`50
`60
`Time—Minules
`
`Fig 1. Sterilization model using D values-
`
`

`
`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 = No 10-5/0
`Where N0 = initial number of microorganisms, t = elapsed
`exposure (2 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 ccmstcmt
`temperature, to reduce the microbial population being consid-
`ered by 1/10 (ie, by one logarithmic value, eg, from 100% to
`1 0% 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 D value 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 T7jme—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 12 1° is
`assumed = 1, after 1 minute at 12 1°, 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 =
`1/ 10 microorganism. A contamination of 1/ 10 must not be
`understood to mean that each unit contains 1/ 1 O of a microor-
`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.
`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 of viable microorganisms left in the Whole of the items
`produced, has to be increased correspondingly. The follow-
`ing example will be helpful to focus the matter.
`
`Number of microorganisms per unit
`10*2
`
`Sterilization time (minutes)
`
`Fig 2. Effect of varying D values on sterilization rate (courtesy, Fedegari Autoclavi).
`
`hemical
`erilants.
`hospital
`
`>erimen-
`on rates
`al curve
`lifferent
`1e loga-
`'e to the
`show a
`suggest
`ation is
`J inacti-
`sent the
`e, based
`decimal
`under a
`iired to
`90%.
`as rates,
`lization
`)dl.lCt to
`Beyond
`ovide a
`:les. A
`. micro-
`.f the D
`be kill is
`How
`assured
`popula-
`arocess
`
`naining
`one or-
`
`us sup-
`iich We
`3moge-
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`
`above
`.icroor-
`rate of
`in the
`number
`16 spe-
`
`'e Time
`
`bability
`
`“U
`80
`
` iE2E
`
`i:
`
`ziE
`
`
`
`

`
`
`
`1466
`
`CHAPTER 84
`
`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 10”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 12 1°. The applicable D value is
`1 minute. The total number of microorganisms to be de-
`stroyed during the life of the product will be
`10104-23 = 1013
`
`If this whole microbial population were exposed to moist heat
`at 121° over a period of 13 minutes, it would be reduced to
`10‘13 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, 1 3 minutes of
`exposure would reduce the microbial population to the theo-
`retical value of
`
`103—13 = 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 1010. 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 deemed to be good if high, but
`SAL seems to have been defined in such a way 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 Temperature Chcmges—Al1 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 w