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`2 -0 TH EDITION
`
`Remington: The
`Science and
`
`Practice
`of Pharmacy
`
`ALFONSO R GENNARO
`
`Chairman of the Editorial Board
`
`and Editor
`
`MYLAN V. BAXTER
`MYLAN V. BAXTER
`IPR2016-00218
`IPR2016-00218
`EXHIBIT 2008
`EXHIBIT 2008
`’
`
`BAX-AS00006812
`
`

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`
`
`Editor: Daniel Linnner
`Managing Editor: Matthew J. Hauber
`Marketing Manager: Anne Smith
`
`Lippincott Williams 8: Wilkins
`
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`Baltimore, Maryland 21201-2436 USA
`
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`
`~
`
`All rights reserved. This book is protected by copyright. No part of this book may
`be reproduced in any form or by any means, including photocopying, or utilized
`by any information storage and retrieval system without written permission
`from the copyright owner.
`
`The publisher is not responsible (as a matter of product liability, negligence or
`otherwise) for any injury resulting from any material contained herein. This
`publication contains information relating to general principles of medical care
`which should not be construed as specific instructions for individual patients.
`Manufacturers’ product information and package inserts should be reviewed for
`current information, including contraindications, dosages and precautions.
`
`Printed in the United States ofAmerica
`
`Entered according to Act of Congress, in the year 1885 by Joseph P Remington,
`in the Oflice of the librarian of Congress, at Washington DC
`
`Copyright 1889, 1394, 1905, 1907, 1917, by Joseph P Remington
`
`Copyright 1926, 1936, by the Joseph P Remington Estate
`
`Copyright 1948, 1961, by the Philadelphia College of Pharmacy and Science
`
`Copyright 1956, 1960, 1965. 1970,‘ 1975, 1980, 1985, 1990, 1995. by the Phila-
`delphia Coliege of Pharmacy and Science
`
`Copyright 2000. by the University of the Sciences in Philadelphia
`
`All Rights Reserved
`Library of Congress Catalog Card Information is available
`ISBN 0-383-306472
`
`The publishers have made every efibrt to trace the copyright holders for borrowed
`material. lflhcy have inadvertently overlooked any, they will be pleased to make
`the necessary arrangements at the first opportunity.
`
`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 respon-
`sible 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 oflicial United States Phannacopeia (USP)
`andlor the National Forrnulaiy (NF). In the event of any difi'erence or discrep-
`ancy between the cumenl ofiicial USP or NF standards of strength. quality.
`purity, packaging and labeling for drugs and representations ofthem herein, the
`context and efibct of the official compendio shall prevail.
`
`To purchase additional copies of this book call our customer service department
`at (800) 638-3030 or fax orders to (301) 824-7390. International customers!
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`02 03 04
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`-.._s._--...e4-:
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`-
`
`CHAPTER4-0
`
`Sterilization
`
`Barry D Garfinkle. PhD
`Vice President
`Vaccine Technology and Engineering
`Manufacturing Division
`Merck 8. Co, Inc
`West Point, PA 19486
`
`Martin W Henley. Msc
`Merck Bi Co, inc (Retired)
`West Point, PA 19486
`
`The aim of a sterilization process is to destroy or eliminate
`microorganisms that are present on or in an object or prepara-
`tion, to make sure that this has been achieved with an ex-
`tremely high level of probability and to ensure that the object
`or preparation is free from infection hazards. The currently
`accepted performance target for a sterilization process is that it
`provide for a probability of finding a nonsterile unit of less than
`1 in 1 million. That is, the process (including production, stor-
`age, and shipment) will provide a Sterility Assurance Level
`(SAL) equal to or better than lO"'6.
`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 guidelines
`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 sterilization
`process. Today. qualification and validation of the equipment
`and the process carried out in that equipment is considered
`essential. This stems from the general principles of Total Qual-
`ity systems. National and international standards that define
`this system (such as ISO-9000 and EN-29000) indeed state that
`"sterilization is a special process because its eflicacy 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 equip-
`ment regularly maintained .
`. .”
`The purpose of this chapter is to provide a basic understand-
`ing of the following. sterilization methods currently being used
`in pharmaceutical technolog and the equipment employed to
`carry out these methods:
`
`Elguipment
`Saturated steam autoclaves
`Superheutod water sutoclaves
`Air over steenr autoclaves
`Batch sterilizers
`Continuous tunnel sterilizers
`Ethylene oxide
`Vaporized hydrogen peroxide
`Hydrogen peroxideisteam
`Other gaze
`Electromagnetic
`Particulate
`Membranes
`
`Method
`Moist host sterilization
`
`Dry heat sterilization
`
`Chemical cold sterilization
`
`Radiation sterilization
`lfilltration
`
`DEFINITIONS
`
`The following terms, relating to sterilization. should be under-
`stood 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 destroy-
`ing them.
`Aseptic Prooeseing—Those operations performed between the steril-
`ization of an object or preparation and the final scaling of its pack-
`age. These operations are, by definition, carried out in the complete
`absence of
`Bacterit-.ide—Any agent. that destroys microorganisms.
`Bacterioel:at——A.ny agent that arrests or retards the growth of micro-
`organisms.
`Bioburdenw-'l‘l1e number of viable mic'roorgan.isms in or on an object
`or preparation entering a sterilization step (usually expressed in
`colony forming units per unit of volume).
`Dlal.nl’ection--A process that decreases the probability of infection by
`destroying vegetative microorganisms. but not ordinarily bacterial
`spores. The term usually is applied to the use ofclremical agents on
`inanimate objects.
`Germicide-—An agent that destroys microorganisms, but not necessar-
`ily bacterial spores.
`Ste:-ility-'I‘he absence of viable microorganisms.
`Sterility Assurance Love] (SAL)—A term related to the probability
`of Ending a nonstarils unit following o sterilization step. It usually
`10‘ l.
`is egpreesed in termsoftho negative power oflfl (ie, 1 in 1 million =
`Sterill:ation—A process by which all viable microorganisms are re-
`movod or destroyed. based on I. probability function.
`Terminal Sten‘lixotion—-A process that destroys all viable microor-
`ganisms within the final, sealed package.
`Val.idm‘.ion——The act ofverifying that a procedure is capable of produc-
`ing the intended result under all
`circumstances. This usu-
`nlly is accomplished through appropriate cbsllsngelsl.
`Vi.ricide—-An agent that will destroy viruses.
`
`STERILITY AS A TOTAL SYSTEM
`
`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 washjnglrinsing agent
`-
`Packaging suitable for the product and for the sterilization process
`that will be used
`c Working environment and equipent
`u Personnel
`
`These procedures clearly have the purpose of providing the
`sterilization process with a product that has a minimum, def-
`\
`
`753
`
`
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`,W_
`
`754
`
`CHAPTER 40
`
`- Use of laminar airllow devices for certain critical operations.
`a Use of water that is of appropriate USP quality and is free of
`microbial contamination. II: is preferable to use prssterili-red water
`to avoid any possible contamination.
`
`METHODS
`
`General
`
`The procedure to be used for sterilizing a drug, a pharmaceu-
`ticsl 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 some sterilization technique cannot be applied
`universally because the unique properties of some materials
`may result in their destruction or modification. Methods of
`inactivating m.iu-oorganisms may be classified as either phys-
`ical or chemical. Physical methods include moist heat, dry heat,
`and irradiation. Sterile filtration is another process. but it only
`removes, not inactivates, microorganisms. Chemical methods
`include the use of either gaseous or liquid sterilants. Guidelines
`for the use of many types of industrial and hospital sterilizafion
`are avuilable."‘°
`Each sterilization method can be evaluated using experi-
`mentally derived values representing the general inactivation
`rates of the process. For example, a death rate or survival curve
`for a standardized species can be diagramed for different stor-
`ilization conditions. This is done by plotting the logarithm of
`surviving organisms against time of exposure to the steriliza-
`tion method. In most instances, those data show a linear rela-
`tionship, typical of first-order kinetics, and sugest that a con-
`stant proportion of a contaminant population is inactivated in
`any given time interval. Based on such inactivation curves, it is
`possible to derive values that represent the general inactiva-
`tion rutes 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 steril-
`ization exposure conditions required to reduce a surviving mi-
`crobial population by a factor of 90%.
`D values. or other expressions of sterilization process rates.
`provide a means ofsstablishing dependable sterilization cycles.
`Obviously, the initial microbial load on a product to be steril-
`ized becomes an important consideration. Beyond this, how-
`ever, kinetic data also can be used to provide a statistical basis
`finr the success of sterilization cycles. A simple example will
`suffice (Fig 40-1). When the
`microbial contamination
`level is assumed to be 10°, and iftho D value of the sterilisation
`
`LogoiNumbersolOrganisms 3.
`
`mrldadqjllfllu
`10’ gmmwouw.
`I
`
`lo
`_
`w 10'
`Exposure Time
`;.-2 104
`to avea
`=
`-3
`1CI"Proosb'IIily
`f, 1°
`‘-
`10"
`.
`_.
`. x of Sflhrlval
`E
`a. 10-: Probability clone Organism Survavang ~
`
`
`
`,
`Negative-(No Growth)
`Thermo-Chemical
`Death Tirns
`‘.40
`35 x‘
`
`‘~,
`
`‘~,
`
`5
`
`15
`
`25
`
`20
`
`30
`
`10
`
`35
`
`45
`
`40
`
`50
`
`55
`
`65
`
`60
`
`70
`
`75
`
`30
`
`Time-Minutes
`‘
`Figure 40-1. Sterilization model using D values.
`
`BAX-AS00006815
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`-
`
`inite, and consistent bioburden. There are,slso the following
`activities:
`'
`- Selection oftho 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
`selected method and of the utilities that this rnuchine requires
`Qualification and validation of the machine and of the process
`Routine checking of the process
`Checking of the rmults of the sterilization process
`Proper storage of sterile goods nnd verification that theirstcrility is
`maintained with full reliability throughout the nllowerl storage
`riod
`lleslivering, opening, and using sterile goods without rcoonta1n1'na-
`tion.
`
`an
`
`It also should be noted that, on October 11, 1991, the US
`Food nd Drug Administration (FDA) proposed new regula-
`tions for aseptic processing and terminal sterilization. The
`proposed rules require that manufacturers of sterile products
`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 Big-
`nificant detrimental elfects 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 bemperatunas
`as high as 60". Microbes vary in their oxygen requirements
`from the strict anasrobss that cannot tolerate oxygen to ser-
`obes that demand it. Slightly alkaline growth media will sup-
`port the multiplication of many microorganisms while others
`flourish in acidic environments. Some microorganisms have the
`ability to use nitrogen and carbon dioxide from the air and thus
`can actually multiply in distilled water. In general, however,
`most pathogenic bacteria have rather selective cultural re-
`quirements, with optimum temperatures of30° 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 bactoria—-among them the bacteria that cause
`anthrax, tetanus, and gas gangrene-—have the ability to as-
`sume s spore state that is very resistant to heat as well as to
`many disinfectants. For this reason, an excellent measure of
`successful sterilization is whether the highly resistant spore
`forms of nonpathoganic bacteria have been killed.
`The nature of expected contamination and the bioburdan
`are important to pharmacists preparing materials to be steril-
`ized. The raw materials they work with rarely will be sterile,
`and improper storage may increase the microbial content. Be-
`cause the pharmacist seldom handles all raw materials in a
`sterile or protected environment, the environmental 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 pre-
`sterilized and thus may contribute to the total microbial load.
`Understanding the nature of contaminants prior to steril-
`ization and application of methods for
`such con-
`tamination is vital to preparing for successful pharmaceutical
`sterilization. Examples of such methods include:
`- Maintenance of a hygienic laboratory.
`o Frequent disinfection of floors and surfaces.
`- Minimizationoftzraflicinand. outofthearsa.
`- Refiigerated storage of:-aw mateliala and preparations that support
`microbial growth.
`
`

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`
`STERILIZATION
`
`755
`
`process is 7 minutes, complete hill is approached by application
`of 6 D values (42 minutes). However, at this point reliable
`sterilization would not be assured because a few abnormally
`resistant members of the population may remain. In this ex-
`ample, by extending the process to include an additional 6 D ‘
`values, must of the remaining population is inactivated, reduc-
`ing the probability of one organism surviving to one in 1 mil-
`lion.
`
`Moist Heat
`
`ESSENTIALS OF STEAM STERILIZATION KINETICS
`
`Let us suppose a system contaminated by microorganisms
`(which we assume, for the sake of simplicity, to be pure and
`homogeneous} is immersed in pressufized saturated steam,
`at constant temperature; for example, it could be a vial con-
`taining an aqueous suspension of a certain spore~forruing
`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 reduc-
`tion of the number of microorganisms present in the system in
`each moment is proportional to the actual number itself. The
`proportionality coeflicient is typical of the species and condi-
`tions of the chosen microorganism.
`Thus, the degradation reaction (the sterilization process)
`develops like a first-order chemical reaction in which the reac-
`tion 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 ofthe first order.
`
`as the steam is present in high excess during the entire reac-
`tion and its concentration may be regarded as constant.
`The most frequently used mathematical expression of the
`above facts is
`
`N = N, 10 "D
`
`(1;
`
`where N0 is the initial number of microorganisms, t is the
`eiapsed exposure (equal to sterilization time), N is the number
`of microorganisms after the exposure time t, and D is the
`decimal decay time, defined as the time interval required, at a
`specifiedporwtant temperature. to reduce the microbial popu-
`lation being considered by 1/iu (ie, by one logarithmic value; eg,
`from 100% to 10% or from 10% to 1% of the initial value).
`The D value is inversely proportional to the first-order re-
`action coeficient and is therefore typical of the species and
`conditions of the chosen microorganism. Depending on the ini-
`tial 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 con-
`clusion: the time required to reduce the microorganism con-
`centration 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 some constant temperature will be very d.ifi'erent de-
`pending on the D value of the contaminating microbial species
`(or on the largest D value in the usual case of mixed contami-
`nation). Figure 40-2 shows that the same reduction ratio for
`different species is achieved after exposure time proportional to
`the D value of each species. The graph derives only from Equa-
`tion 1 and from the definition of D value. The basic hypothesis
`of the temperature being constant is thoroughly valid.
`
`Number of microorganisms per unit
`
`mswllllll
`‘
`III
`
`E I I I I I
`
`IEIIHIVIIIHI
`
`Sterilization time (minutes)
`
`Figure 40-2. Effect of varying D values
`on sterilization rate (courtesy, Fedegari
`Autoclavi).
`
`BAX-ASD0006816
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`

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`
`
`155
`
`CHAPTER 40
`
`Sterility Is a Probable Effect ofExposure Tll'!t(.'—l..et us now
`consider what happens within a batch ofunits I’vials, bottles, or
`others) with an initial constant unit contamination of 100 mi-
`croorganisms equal to 10“. If the D value at 121“ is assumed to
`be 1, after 1 min at 121'.
`ll reduction equal
`to 10’ = ID
`microorganisms is achieved; alter another minute. only 10" —“- 1
`microorganism is still surviving. After another minute. the
`surviving microbial population would be 10" ==
`'/m microor-
`ganirn. A contamination of 1/in must not be understood to mean
`that each unit contains trio of o microorganism, which is bio-
`logically meaningless (in this case the unit probably would be
`sterile) but that there is a probability of having l/is of the units
`still contaminated within the batch of sterilized units.
`In fact. 3 min would be the necessary time to reduce the
`microbial population to a single surviving microorganism if the
`initial population were 10 times larger than the one at issue.
`This higher initial contamination could be regarded either as n
`10 times larger number of microorganisms in the same unit, or
`as the initial contamination of a 10 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 loll. in the whole of the items
`produced. has to be increased correspondingly. The following
`example will be helpful to focus the matter.
`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 10"’. The maidmum number of
`contaminated ampules deemed to be acceptable is I0 = 1: this
`obviously means that the probability of having nonsterile am-
`pules altsr sterilization must not exceed 10‘‘°. Let us also
`suppose that the microbial population within each ampule af-
`ter the filling and the sealing does not exceed 103 microorgan-
`isms. These must be destroyed by means ofmoiet heat-terminal
`sterilization at 121°. The applicable D value is 1 m.in. The total
`number ofmicroorganisms to be destroyed during the life ofthe
`product will be
`
`101013 5 1018
`
`If this whole microbial population were exposed to moist heat
`at 121' over a period of 13 min. it would be reduced to 10*”
`times its initial number (is. to 10“"""‘ = 10” = 1. The exposure
`time of 13 min thus would be suficient (under all the other
`above hypotheses) to prevent the total number ofoontanninated
`ampules from exceeding the value of 1.
`From the point of view of each single ampule, 13 min of
`exposure would reduce the microbial population to the theoret-
`ical value of
`
`103.13 = 10-10
`
`To interpret this numeric value as the probability of still hav-
`ing one contaminated ampule in 10 billion sterilized ampules
`means that a single ampule will still be contaminated out of a
`whole lot of 10'". This probability value is defined as PNSU
`{probability of nonsterile unit).
`In recent times the PNSU as a sterility evaluation criterion
`is being replaced by the SAL. The name itself could generate
`some misunderstanding. because a level of assurance com-
`monly ie deemed to be good ifbigh, but SAL seems to have been
`defined in end: a way that its numerical value is the same as
`PNSU. This notwithstanding. it is sometimes calculated as the
`reciprocal value of PNSU. The SAP (sterility assurance proba-
`bility) criterion has been proposed as well and SAP seems for
`the moment to have been granted the some definition of PNSU.
`even if it would be better understandable if its value ap-
`proached unity after a satisfactory 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 population
`
`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.
`Effect of Temperature Changes»-All the above consider-
`ations have been developed under the basic assumption that
`the temperature is kept constant during the entire exposure
`time. It seems rather obvious that the D value will change as
`the temperature changes. If the D value experimentally ob-
`tained for a given microbial species are plotted on a sen1.iloga-
`rithmic chart as the function of the temperature T. a path
`similar to Figure 40-3 is obtained.
`ln this case. it can be seen that D value is 1 min at 121” (ie.
`the average value which very often is assumed to be acceptable
`in the absence of more exact experimental data). It also can be
`seen that D value varies by a factor of 10 if the temperature
`varies by 10°.
`The 2 value is defined as the temperature ooefflcient of
`microbial destruction, the number of degrees of temperature
`that causes a 10-fold variation of D (or, more generally, of the
`sterilization rate).
`The 2 values generally oscillate between 6 and 13 for steam
`sterilization in the range 100'‘ to 130‘, and z value often is
`assumed to be equal to 10 in the absence of more precise
`experimental dam.
`The fact that D value varies by 10 times for a variation of
`10° when 2 = 10 must not lead to the false assumption that D
`varies by one time (is, doubles) for an increase of 1'. Obviously.
`this is not true. It is actually a matter of finding the number
`which yields 10 when raised to the tenth power. This number is
`1.24.
`Therefore, a variation of 1° entails a variation of D value
`of 24%.
`This is quite a significant number, which illustrates the
`dramatic effects that are generated when the sterilization tem-
`perature is also only a few degrees lower than the expected
`value, perhaps only in some areas of the sterilizer load.
`It is also useful to remember that the efibct of temperature
`variation decreases considerably as the temperature rises and
`drop to apprmdmntely 1/2 (or even less) for dry sterilization at
`approximately 200'. Under these conditions the 2 value is
`about 20 instead of about 10. Therefore. the smell temperature
`differences that can be so dramatic in steam sterilization have
`much lees efihct in dry sterilization.
`The foregoing refers to average values because the actual D
`values and 2 values depend to a large extent on the medium
`that contains the microorganisms and on their history. At 121‘
`no microorganism has exactly D = 1 and z = 10. However, the
`combined use of these two parameters in calculating F0 and
`PNSU provides ample margins of safety with regard to the
`microorganisms with which we deal commonly.
`F0 or Equivalent Sterilization Time at 121°-—-It is of the
`utmost interest to calculate the lethal effect of the exposure of
`a microbial population to a variable temperature, T. by relating
`it to an hypothetical sterilization performed at a constant tem-
`perature. To. for the time. to. If the constant reference temper-
`ature is assumed equal to 121.1‘ (originally 250"F) and the 2
`value equal to 10, the equivalent time is termed F". Thus, F0 is
`the equivalent exposure time at 121.1‘ of the actual exposure
`time at a variable temperature, calculated for an ideal micro-
`organism with a temperature coeificient of destruction equal to
`16.
`
`First introduced in the Laboratory Manual for Food Con-
`mm: and Processors by the National Connors Association in
`1968, F0 has become a common term in pharmaceutical pro-
`duction since the FDA used it extensively in the ‘Proposed
`Rules" oi‘ June 1, I976 (21 CFR 212.3) with the Following
`meaning:
`
`F3 means the equivalent amount of time. in minutes at 121.1‘
`(250“F), which has been delivered to a product by the steriliza-
`tion prdcess.
`
`BAX-AS00006817
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`

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`
`
`Number of microorganism per unit
`
`IllIIII
`
`STERIUZATION
`
`157
`
`1G5
`
`111
`
`116
`
`121
`
`126
`
`Sterilization temperature ('C)
`
`For the calculation of it,
`A z value of 10° or 13°F is assumed; the term 2 value means the
`slope oftlie thermal death time curve and may be expressed as
`the number of degrees .
`.
`. required to bring about i1 10-fold
`change in the death rate.
`
`In practice, the knowledge of the temperature values as the
`continuous function of elapsinir time is not available, and F” is
`calculated as
`
`.F‘9*—dtE10
`
`T—l2l.!
`
`(2)
`
`where At is the time intervl between two consecutive mea-
`surements of T, T is the temperature of the sterilized product
`at time t, and z is the temperature coefficient, assumed to be
`equai to 10.
`
`Saturated Steam
`
`PRINCIPLES
`
`Sterilization with saturated steam is the method that provides
`the best combination of flexibility in operation, safe results and
`low plant and running costs. The sterilizing medium obviously
`is pressurized saturated steam and the typical operating tem-
`perature is 121" (25D"F), but higher or lower temperatures
`often are used.
`The term dry saturated steam sometimes is used: it should
`be made clear that this is an ideal condition of steam, and that
`moist saturated steam is used in practice for sterilization.
`However, the steam must entrain the smallest possible amount
`of condensate. The water vapor ratio of the steam defines the
`amount of condensate entrained by 100 parts by weight of
`moist steam; a water vapor ratio of 0.95 means that 100 g of
`steam consist of 95 g of dry saturated steam plus 5 g of eon-
`
`Figure 40-3. Effect of temperature on microbial destruction
`(courtesy, Fedegari Autoclavi).
`
`densate which is. or should be, at the same temperature as the
`steam.
`The reliability of sterilization performed with saturated
`steam is based on several particular characteristics of this
`medium.
`
`When steam condenses, it releases calories at 1: constant tem-
`perature and in a. considemble amount: 1 kg of pure saturated
`steam condensing at 121“ (turning into water at 121", thus
`without cooling) releases as much as 525 1-icai.
`The temperatures and pressures of saturated steam have a
`two-way oorrelation. Once the temperature of the steam is de-
`termined, so is its pressure. and vice versa. Saturated steam at
`121" inevitably has a pressure of 2.05 abs bar.
`
`This entails two very interesting practical possibilities:
`1. A pure saturated steam autoclave can be controlled indiflerently
`according to the temperature parameter or awarding to the pres
`sure parameter.
`2. Regardless of the parameter used for control, the second pararniator
`can be used easily to croswnoriitor the first one.
`
`A 1 gram molecule of water (13 g. or 18 mL in the liquid state)
`as steam at 121° and 2.05 abs bar occupies a volume ofa1:iprox-
`imately 15 L. This means that when stearn condenses at 121° it
`shrinks in volume by almost 1000 times. Accordingly, additional
`available steam spontaneously reaches the object to be steril-
`ized. The condensate that forms can be removed easily from Lbs
`autoclave chamber by means of a condensate disch ergo or, with
`a more modern technique. by continuous and forced bleeding (as
`occurs for example in so-called dynamic steam sterilizers).
`
`However, several other phenomena must be considered.
`
`To perform its microorganism inactivating action (coagulation
`of cellular proteins), the steam, or more generally the moist
`heat, must make contact with the microorganisms. This can
`occur directly or indirectly, For example, it occurs directly when
`the steam that is present in the autoclave chamber is in direct
`
`BAX"-ASO0D0681 8
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`

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`
`
`Figure 40-4. A modern computerized steam autoclave with hori-
`zontal sliding door (courtesy, Fedegari Autoclavi).
`
`meats in which the door engages automatically and with a. movable
`gasket activated by compressed air.
`- Vertically or laterally sliding, with retenti and gaskets as men-
`tioned immediately above.
`
`Saturated steam autoclavss generally are jacketed. There is
`no room here to discuss the various kinds of jacket and their
`purposes. However, there are two ways to feed steam into the
`jacket and into the chamber:
`
`Single F'oed—-the steam circulates first in the jacket and passes from
`the jacket into the chamber.
`Separate Feed-—usu.ally the chamber is fed pure steam and the jacket
`is fed industrial steam.
`
`Single-feed steam has some advantages in terms of control,
`but separate-feed steam is preferred because it provides
`better assurances of lack of microbiological and particle
`contamination.
`
`758
`
`CHAPTER 40
`
`contact with a surgical instrurnent.