An Overview of the Validation Approach for Moist Heat Sterilization, Part I B.M.. Boca,E. Pret B.M Pretoriu orius*,R. s*,R. Goch Gochin, in, R. Chap Chapoull oullie,and ie,and Z. Z. Apos Apostolid tolides es
The sterility concept and sterilizati sterilization on principles This article illustrates a qualification– validation strategy for moist heat sterilization and briefly discusses the sterility concept and common sterilization principles. In Part I, the authors present present examples for cycle types, parameter requirements requirements for a standard cycle as defined by pharmacopeias, methods used to design sterilization cycles, and various approaches used to measure the efficiency of the sterilizatio sterilization n process.
T
his article article provides provides an update update of of the validation validation of moist heat sterilization. It brings together practical information information one needs when validating an autoclave, from procureprocurement throu through gh routine routine use. use. In Part Part I of this article, article, the sterility sterili ty concept, concept, sterili sterilization zation principle principles, s, develo development pment of steril steriliization cycles, cycles, and the measurement of sterilization efficiency efficiency are discussed.. Part II will be published discussed published in Pharmaceutical Technology ’s ’s October issue and will review the qualification–validation procedur proc eduree and the probability probability of nonst nonsterility erility of a load during the validation of the steam sterilization process.
B.M. Boca is a doctoral student at the University of Pretoria in South Africa; E. Pretorius, PhD, is a senior lecturer in the Department of Anatomy, Faculty of Medicine, University of Pretoria 0002, Pretoria, South Africa, tel. 27 12 319 2533, fax 27 12 319 2240,
[email protected]; R. Gochin is the quality assurance manager of the Pharma Division at Roche Products Pty Ltd.; R. Chapoullie is the quality manager at Steren Support Systems CC; and Z. Apostolides, DSc, is senior lecturer in the Department of Biochemistry, University of Pretoria. *To whom all correspondence should be addressed. 62
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Sterility is defined as the absence of any microorganism Sterility is microorganism capable of repr reproducti oduction on (1). Sterili Sterility ty can be achieved achieved through through the destruction of all viable life forms by by applying a lethal agent agent to the item that must be sterilized. sterilized. Several sterilization principles principles exist according according to the lethal agent used (2). Each treatment destroys microorganisms in a unique manner and with a different degree degree of effec effective tiveness. ness.A A few examples examples of these treatment treatmentss are G heat sterilization with dry or moist heat G radiation sterilization sterilization with gamma and X-rays, which produce positively charged ions in their passage through the matter,, thereby further generating free radicals with lethal effects ter in the cells chemical cal sterilization sterilization with glutaral glutaraldehy dehyde, de, chlo chlorine, rine, iodin iodine, e, G chemi hydrogen hydrog en peroxid peroxide, e, quaternary ammonium salts, ozone, peracetic acid, and phenolic compounds compounds G gaseous sterilization with chemical agents such as ethylene oxide, oxi de, prop propylene ylene oxide oxide,, and formaldeh formaldehyde, yde, all of which have have a lethal effect effect that consists consists of the alkylation alkylation of prote proteins, ins, DNA, and RNA physically removes removes micromicroG filtration sterilization, which physically organisms from the product product by means of retentive filters. filters. New technologies also have have been developed, including sterilization with free radicals generated by the combination of UV irradiation with hydrogen peroxide and sterilization with chlorine dioxide. The sterility criterion is a mandatory requirement for parenteral products, products, ophthalmic preparations, preparations, and products products applied to injured skin or used to irrigate the body cavities. All products that must be manufactured as sterile should pass the sterility test described by the pharmacopeias. When exposing exposing homogenous populations populations of microorgan microorgan-isms to a sterilizing agent, the microbial inactivation inactivation follows an exponential decrease decrease curve (see Equation 1). Mathematically,, the inactivation cally inactivation of micro microorganis organisms ms can be expressed expressed as a first-order first-order kinetic kinetic process. process. A finite probability probability of of surviving organisms, organis ms, indepe independent ndent from from the magnitude magnitude of the delivered delivered sterilizing sterilizi ng agent, can be expressed expressed as: www.pharmtech.com
Heating phase
Exposure phase
Cooling phase
Sterilizing temperature
T0
) C ( e r u F 1 F 2 F 3 F 4 t a r T100 C e p m e T
F n 1F n
Vent closure t 0
t 1
t 2
t 3
t 4
t n 1 t n
Time (s)
Figure 1: The temperature profile for a saturated steam–vented cycle. t 0 to t n is the time interval in the computation of the F value. F 1 to F n areas represent the lethal rates in the product calculated for each discrete time interval. The shaded area under the cur ve obtained through graphical summation of F 1 to F n values represents the total calculated F value per cycle. In the heating phase, phase, saturated steam is admitted into the chamber, chamber, displacing the cold air until the exposure temperature and corresponding saturated steam pressure are attained. In the exposure phase, the sterilizing temperature is maintained in the chamber by saturated steam for the prescribed exposure time. The cooling phase can be achieved by slow exhaust (for containers filled with liquids) or fast exhaust (for goods required to be dry after sterilization). This phase is completed when the pressure in the chamber reaches atmospheric pressure.
Heat can be used either alone alone or mixed mixed with steam. In the autoclave chamber, chamber, terminal sterilization is based on highly efficient heat transfer from the saturated steam to the autoclave load (6). Heat transfer transfer occurs occurs by the release release of the latent latent heat from saturated steam under pressure as it condenses. Heat transfer has maximum maximum efficiency efficiency if the steam is kept kept along the phase phase separation line line of the water–steam phase diagram. Heat transfer from saturated steam steam to the chamber environment is much more effective and timely for the coagulation and denaturation of nucleic acids and proteins than from from dry heat or superheated superheated heat heat (7). Moist heat heat in the form form of saturated steam under pressure is therefore the most reliable sterilizing agent and is the method method of choic choicee whenever it can be used, especially for aqueous preparations preparations (2,8).
Types of cycles used in moist heat sterilization
For saturated steam sterilizers, the physical parameters governing the efficiency of the sterilization sterilization process are exposure exposure time, temp temperatur erature, e, and pressure pressure.. The last two parameter parameterss vary in a direct proportional relationship to each other. Generally,, a cycle Generally cycle comprises comprises heating, sterilizin sterilizing, g, and cooling cooling phases (9). The choice choice of a cycle for for a particular load depends on the heat sensitivity of the load material and on the knowledge of the heat heat penetration penetration in the article articles. s. Figur Figures es 1 and and 2 illustrate the cycles typically used in the moist heat sterilization process. For a saturated steam-vented cycle (see Figure 1) the steam is injected at the top of the chamber and displaces displaces the cold air, air, which exits through a trap. This cycle is recommended for containers filled with aqueous preparations preparations (i.e., parenterals, ophthalmics,, media, and buffers). thalmics buffers). The prevacuum prevacuum cycle (see FigFigNt N0e kt [1] ure 2) ensures a more effective effective penetration of the load by saturated steam and is generally used for porous loads (e.g., in which Nt is the number number of surviving organisms after time t , surgical dressings and wrapped materials). N0 is the number of micr microorg oorganism anismss at time zero (i.e., (i.e., the For moist moist heat sterilization, the accepted accepted range of sterilizing bioburden), t t is is the exposure exposure time, time, and k is a microbial inacti- temperatures is 118 – 134 C. Th Thee US Pharmacopeia (USP) exvation rate constant. plains in a footnote that “an autoclave cycle, cycle, where specified in For a given given process, process, the probability probability of survival is determined determined the compendi compendiaa for media or reagent reagents, s, is a period of 15 min at by the number, number, type, and resistance resistance of of the microorgani microorganisms sms prepre- 121 C, unless otherwise otherwise indicated indicated” (10 (10). ). The European Pharsent and by the environment in which the organisms exist dur- macopoeia (EP ) and the British Pharmacopoeia (BP ) recoming the treatment treatment (e.g., mois moisture ture conten content, t, therm thermal al energy, energy, and mend a heating process process at a minimum minimum of 121 C for 15 min as time for steam sterilization) (3). For pharmaceutical pharmaceutical products, a reference condition for aqueous preparations (3 –4). The text text the term sterile is applied to products that have been treated in of both books books states that other conditi conditions ons of time and temperatemperasuch a manner manner that, that, on completi completion on of the process, process, indivi individual dual ture may be used provided that the process chosen has been satitems have a probability of being nonsterile or have have a sterility isfactorily demonstrated to deliver an adequate and reproducible 6 assurance level (SAL) equal to 1 10 or more (4). (4). Such a level level of lethality when operating routinely within the estabof sterility assurance is required required for terminally terminally sterilized injectable injectable lished tolerances (3–4). products. prod ucts. This definition definition of of sterili sterility ty as a probability probability function does not assume that one in a million products is allowed to be Development of sterilization cycles nonsterile but admits a finite statistical probability that a micro- Theor Theoretical etically ly,, the timing of the exposure exposure phase begins when the organism may survive the sterilizing process (3). temperature sensor placed placed in the chamber drain (i.e., the coldest spot, theoretically) reaches the set sterilizing temperature. Experiments using thermocouples have shown that the temSterilization Sterilizatio n by saturated steam in the autoclave When heat is used as a sterilizing sterilizing agent, the vibratory motion perature profile profile of the chamber under loaded conditions conditions is difof every molecule molecule of a microorganism microorganism is is increased increased to levels levels that ferent from the one obtained for the empty chamber. chamber. The rate induce the cleavage of intramolecular hydrogen bonds between of heating and cooling cooling a product in a container is a function of proteins. Death is therefore therefore caused by an accumulation accumulation of irre- the container container type and size, size, the viscosity viscosity of liquids, and the size versible damage damage to all metabolic functions of the organism (5). and arrangement arrangement of the load load (2). There Therefore, fore, to ensure ensure sterilisterili64
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l a g n v i o t a m e e r H T0 i r ) A C ( e r u t a r e T100 C F 1 F 2 F 3 F 4 p m e T
Exposure Sterilizing temperature
t s u a h x E
t 0
t 1
t 2
t 3
g n i y r D
f e i l e r m u u c a V
F n 1F n
t 4
t n 1 t n
Time (s)
Figure 2: The temperature profile for a saturated-steam with forced air– air –removal cycle. t 0 to t n is the time interval in the computation of the F value. F 1 to F n areas represent the lethal rates in the product calculated for each discrete time interval. The shaded area under the curve obtained through graphical summation of F 1 to F n values represents the total calculated F value per cycle. In the air-removal air-removal phase, phase, air is removed from the chamber and load by several vacuum pulses. In the exhaust phase, steam is exhausted from the chamber chamber until the atmospheric pressure is reached. In the drying phase, the temperature in the jacket and the vacuum in the chamber are maintained for a predetermined time period for products required to be dry. In the vacuum-relief phase, phase, air is admitted to the chamber through a microbiologically retentive filter until atmospheric pressure is reached.
zation efficiency, efficiency, sterilization must begin after a certain certain equilibration time when the temperature temperature of the material being sterilized has reached the the set sterilizing temperature. temperature. This means that a lag time must be added to the cycle exposure time that represents the time necessary for the coldest spot inside the load to reach the sterilizing temperature. The lag time must be determined experimentally and validated with each loading configuration that will be used in the autoclave for any further routine sterilization. The larger the containers containers and the volumes to to be sterilized are, the longer the lag time is. The modern design of a sterilization cycle can be based on on either the initial population of microorganisms in the product that is examined during a suitable time period or on the measurement of the physical parameters attained in the load during the sterilization process. BP BP indicates indicates that “sterilization methods must be validated with respect to both the assurance of sterility and integrity of the product and to ensure that the final product complies complies with the requirements requirements of the monograph” (4). USP USP states states that “the design or choice of of a cycle for given products or components components depends on a number of factors, including the heat heat lability of the material, material, knowledg knowledgee of heat penepenetration into the articles, and other factors described under the validation program” (10). Three approaches are used in designing sterilization cycles: the bioburden approach, the overkill overkill approach appr oach,, and a combination combination of the two approaches approaches.. The bioburden bioburden approach is based on determination determination of the 66
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number, type, and resistanc number, resistancee characteristi characteristics cs of of the organisms organisms contained in the bioburden (11). For heat-sensitive products, the heat exposure must be minimized in such a way to reach an optimum balance balance between an acceptable degree of sterilizatio sterilization n and an acceptable acceptable stability of the product after after its sterilization (12). In the bioburden approach, approach, the process process will provide provide less 6 than 1 10 prob probability ability of micr microorgan oorganism ism survival.The survival. The sterilizing conditions used for the bioburden approach are less extreme than the conditions used for an overkill approach. The design of a sterilization sterilization cycle also can be based based on the heating characteristics of the containers located located in the slowest slowest heating zone of of the load. The overkill overkill approach approach stems from from the concept that the sterilization process will inactivate a high microbiological challenge with an additional safety factor. factor. The microbiological challenge will consist of a biological indicator with a specific number number of micr microorgan oorganisms isms (103–106), and a worstworstcase assumption is made made that the heat resistance of the bioburden is equivalent equivalent to that of the biological indicator indicator.. Therefore, the cycle conditions established are more severe than those required to inactivate inactivate the real product bioburden, and a theoretical spore spore reductio reduction n of 1012 is expected to prove the overkill assurance. Considerably exceeding exceeding the sterilization time is recommended for heat-resistant products products (10). Therefore, F 0 values (see definition in the “Mathematical approach” section) in the rang rangee of 30–60 are expected. The bioburden bioburden approach emphasizes emphasizes the stability of the final product while the optimum sterility is achieved by knowing the characteristic charact eristicss of the bioburden; bioburden; howev however er,, the overkill overkill approach approach places the emphasis on sterility. A combination of the two apapproaches is sometimes useful to reach a balance between the maximum acceptable SAL and the maximum allowable concomitant adverse effect upon the material to be sterilized.
Measuring the efficiency of the sterilization process Assessment of sterili Assessment sterility ty is based on the demonstra demonstration tion of the absence of growth followi following ng the sterility sterility test. Pe Perform rformance ance of the sterility test is not always a guarantee guarantee of sterility for a product product (13). Therefore, two methods that incorporate microbial inacinactivation data have have been developed developed to measure, measure, contro control, l, and demonstrate the efficiency of a sterilization process. approach, h, known also Biological approach. In the biological approac as the Latin approach, approach, one determines the lowest lowest probability to detect a nonsterile unit in a sterile load and uses biological indicators (BIs) (BIs) (14). BIs are are standardized standardized preparations preparations of microorganisms specific specific to the type of sterilization process process being studied. These BIs are used to show a reproducible reproducible logarithmic inactivation. inactivat ion. Many types of of BIs consi consist st of a given given populatio population n of bacterial spores spores considered considered to be the most resistant resistant forms against a particular sterilization principle. In sterilization microbiology the D value is frequently used instead of k of k as a measur measuree of the rate rate of micr microbial obial death death.. Equation 1 can be formulated in a logarithmic manner as follows: log
N 0 N t
kt
2.303
t D
[2]
The D value represents the temperature coefficient for the lethal process and is the exposure time in minutes required to www.pharmtech.com
Table I: Combinations of temperature and time calculated calcul ated to provide F 0 values of 8- and 12-min equivalents based on reference spores of Bacillus stearothermophilus with a D 121 of 1.5 min and a Z value of 10 C.
cause a 1-logarithm or 90% reduction in the population ulatio n of a particular particular microorgan microorganism ism (9,10). (9,10). The resistance of of an organism changes with alterations alterations in temperature. The smaller the D value, the more more Steriliz iza ati tio on Ex Exposure Ste terril iliizatio ion n Ex Exposure sensitive the organism is to the lethal agent. Time (min) for Time (min) for The Z The Z value value is defined as the number of degrees Temperature ( C) F 0 8-min Equivalents F 0 12-min Equivalents of temperature required required for a 1-logarithm change 110 103.05 154.58 in the D val value. ue. The The Z and D values are significant Z and 115 32.59 48.88 only under precisely defined experimental condi118 16.34 24.50 tions and are generally assumed for aqueous solu121 8.18 12.27 tions. For saturated-st saturated-steam eam sterilization, sterilization, a BI concon124 4.10 6.15 taining spores of Bacillus of Bacillus stearothermophilus strain 126 2.58 3.88 ATTC 7953 with a D value greater than 1.5 min, a 130 1.03 1.54 Z val Z value ue of of 10 C, and a population population greater greater than 5 temperature data accumulated during the entire process are 105 is recommended (15). B. stearothermophilus is considered the reference organism for saturated-steam sterilization converted to the equivalent lethality at 121.1 C. For practi practical cal because it is known for its great resistance to the lethal agent purposes purposes,, tempera temperatures tures higher than 100 C are considered in when compared with the organisms contained in the biobur- calculations. It should be emphasized that that the F 0 value must be den (4). For a standard standard cycle, cycle, as recommended recommended by BP by BP , no growt growth h calculated at 121.1 C, not at at 121 C, because the difference of should be recorded recorded for the BI after an exposure exposure time of 15 min 0.1 C introduces introduces an an error of of 2.4% in the the computatio computation n of the at 12 121 1 ± 1 C and a poststudy incubation period. USP USP states states F 0 value. that for B. stearothermophilus spores with a D value of 1.5 min t n under total process process parameters (i.e., 121 C), if the theyy are treate treated d (T z121.1 ) 10 dt F 0 for 12 minutes, minutes, the lethality input is 8D 8D (10) (10).. Ho Howeve weverr, it is not [3] specified speci fied that, that, after 15 min, min, no growth growth of the reference reference micromicrot 0 organism should exist. For meaningful results, at least 20 BIs per cycle should should be In a nonmandatory nonmandatory section section of the EP , General Text Text 5.1.5 ofused to ensure that statistical distribution is differentiated from fers guidance concerning concerning the validation of the steam sterilizatrue deviations to demonstrate homogenous conditions within tion process process by means means of the F 0 concept, whose value can be dethe chamber autoclave. Although the biological approach approach pre- termined from Equation 4 (3). D121 is the exposure time at the sents difficulties specific specific to statistical methods, methods, it allows the de- indicated temperature required to cause a 90% reduction in the termination of the lethality effect within the loads in which it spore population. population. The text of of BP states that the application of BP states is difficult or impossible to place temperature temperature probes (e.g., in- the F 0 concept requires microbiological validation. side ampuls). F value value is a unit of letha lethality lity and [4] Mathematical approach. The F F 0 D 121 log N 0 log N t is a measure measure of the microbial microbial inactivat inactivation ion capability capability of a heat sterilization process. process. It is defined as “the equivalent in minutes The lethality of the sterilization process process is influenced by by the at 250 F of all heat considered considered with respect respect to its capacity capacity to effectiveness of heat penetration into into actual articles and the destroy spores spores or vegetative vegetative cells of a particular organism” (2) time of of ste steriliz rilizatio ation. n. Pfei Pfeiffer ffer,, quot quoting ing BP BP 1983, 1983, indicate indicatess that and allows the comparison comparison of lethal effects at various temper- the steam sterilization process must be sufficient to produce an atures. Sterilization cycle parameters can be found by using F 0 value of at least 8-min 8-min equivalents equivalents (17). (17). This means means that the other temperatures than 121 C with the the help of the F 0 concept. coolest location in the autoclave loading configuration must be F 0, as defined defined by by USP USP (10) (10) at a particular temperature other expo exposed sed to an equivalent equivalent time time of at least 8 min of expo exposure sure to than 121 C, is the time (in minutes) minutes) required to provide provide the a temperature temperature of of 121. 121.1 1 C. This represents represents the most conservaconservalethality equivalent to that which is provided at 121 C for a tive estimate of the lethality and therefore therefore the safest conditions conditions stated time. The temp temperatur eraturee of 250 F or 121.1 C represents for determining cycle times. the temperature temperature of saturated water water vapor at 100 kPa kPa.. The An F 0 of 8-min equivalents is considered considered a realistic minimum F value allows the comparison comparison of lethal effects at various value because most mesophilic spore-forming microorganisms temperatures. have D values between 30 s and 1 min at 121.1 C. Whe When n deThe total F F value value of a process can can be calculated by the inte- signing a cycle, one should introduce introduce an additional safety facgration of lethal rates with respect to time at discrete discrete tempera- tor that takes into account the extra time that may be required Z ture intervals (16). Integrating the lethality constant constant 10(T T 0)/ Z for steam to penetrate certain containers in the middle or cool between two time points, t 0 and t n, will yield the shaded area locations of the chamber. chamber. For practical purposes one should deunder the curves indicated in Figures 1 and 2. sign sterilization cycles with an F 0 value of of 12-min equivalents equivalents.. The mathematical approach, approach, also known as the Anglo-Saxon the Anglo-Saxon Depending Depen ding on the nature nature of the load, one may use nonstannonstanuses es the the F 0 value as the reference reference unit of lethali lethality. ty. dard conditions conditions and try to achieve an equivalent level level of kill approach,, us approach The F 0 value can be calculated calculated using Equation Equation 3. Product- from new conditions conditions (18). A high activation energy needed to
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kill spores can lead to chemical chemical changes, especially in aqueous preparations (2). To avoid product degradation, a longer cycle at lower temperatures is recommended. recommended. For other products such as vitamins media that may suffer decomposition processes from a prolonged prolonged treatment at a lower temperature, it would be more advantageous to apply a short-time exposure at a higher temperature tempera ture (19). To evaluate the effect of the killing process process at a temperature different from 121.1 C, the following following equation can be used when calculating the lethality factor, F T : z F T
F 0
10
(T 121.1)
(min)
[5]
Z
in which D and and Z Z values values are known for a given microorganism,, and F ism F is is the effectiveness of killing at the specified process process temperature, T T ((C). Table I presents equivalent combinations of temperature and time, pro providing viding the F 0 value of 8- and 12-min 12-min equival equivalents. ents. The use of 11 110 0 C as a sterilizing temperature requires very long exposure times to reach the target F 0 values. Such exposure exposure times would be unrealistic. The biological and mathematical approaches are complementary to each other. other. Lethality using physical process process data should be determined in conjunction with appropriate microbiological studies.
Qualifying an autoclave and validating the sterilization process Absolute sterility cannot be practically demonstrated without the complete complete destruction destruction of the load. For practical practical purposes, purposes, the industry and regulatory agencies approach the concept of sterility on a probabilistic basis. Validation must prove that the sterilization process delivers a treatment that ensures a certain statistical probability of sterility for an intially intially nonsterile unit. Therefore,, any sterilization process Therefore process must be validated before use and must be routinely monitored as required by many official texts (3,4,10). It should be emphasized that the terms qualification and validation are not identical. Equipment is qualified, qualified, and processes processes are validated. Qualificatio Qualification n provides assurance that the autoclave can consistently kill kill a microbial microbial load of 1 106 colony-forming units per container during a defined cycle by using a specific loading configuration. configuration. The actual process process validation validation of the cycles cycles is performed by recording and interpreting the physical parameters (i.e., time, temperature, and pressure pressure for steam steam sterilization) sterilization) required to prove that the process will consistently yield a product that complies with previously established specifications. During routine routine monitoring, monitoring, the assurance assurance of sterility is gained gained by demonstrating that validated conditions, conditions, known to produce the required level level of micro microbial bial inactivation, inactivation, have been attained. attained. Therefore, the careful design and validation of of the sterilization process enables sterility to be addressed with an increasing probability of succes successs (12). Such a system system is called called parametric parametric release and has been defined as a “sterility release procedure based upon effective effecti ve control, control, monit monitoring, oring, and documentatio documentation n of a validated sterilization process process in lieu of release based upon end-product end-product sterility testing” (20). 70
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Part II of this article will be published published in Pharmaceutical Technology ’s October issue and will review the qualification – validation procedur proceduree and the probability probability of nonsterility of a load during the validation validation of the steam sterilization process.
Acknowledgment Roche Products Roche Products Pty. Pty. Ltd. Ltd.,, Isan Isando, do, South Africa Africa,, is greatly greatly acknowledged for sponsoring this work. References 1. W.D .D.. Bi Bige gelo low w, “Logarithmic Nature Nature of Thermal Death Time Curves, Curves,”” J. Infect. Dis. 29, 528 528– –536 (1921). 2. C.J C.J.. Sop Soper er and D.J .J.G. .G. Da Davie vies, s, “Principles of Sterilization Sterilization”” in Guide to Microbiological Control in Pharmaceuticals, S. Den Denyer yer and and R. Bair Baird, d, Eds.. (El Eds (Ellis lis Ho Horwo rwood, od, Lon London don,, 199 1990), 0), pp pp.. 157 157– –181. 3. European Pharmacopoeia (Co (Counci uncill of Eur Europe, ope,Stra Strasbo sbourg, urg,3d 3d ed., 1997 1997), ), –285. pp. 283 283– 4. British Pharmacopoeia, Volume II (The Stationary Office, London, 2001), 200 1), pp.A332 pp.A332– –A335. 5. P. De Santi Santiss and and V.S. Rud Rudo, o,““Validation of Steam Sterilization in Autoclaves,”” in Validation of Aseptic Pharmaceutical Processes, F.J. Carleton claves, and J.P J.P.. Agall Agalloco oco,, Eds. (Mar (Marcel cel Dekke Dekker, r, New York, 2d ed., 1986), pp. –317. 279– 279 6. S. S.W W.B .B.. Ne Newso wsom, m,““Steam Sterilization— Sterilization—A Historical Perspective,” Perspective,” CPD Infection 1 (3) (3),, 95 95– –98 (2000). 7. J. J.P P. Aga Agallo lloco co,, “Steam Sterilization and Steam Quality,” Quality,” PDA J. Pharm. –63 (2000). Sci. Technol. 54 (1 (1), ), 59 59– 8. A.K A.K.. Na Nagpal gpal and A.K A.K.. Shr Shrini iniwas was,, “Principles of Steam Sterilization, Sterilization,”” Health Popul. Perspect. Issue 1 (1) (1),, 40 40– –50 (1978). 9. Americ American an National National Standard Standard ANSI/AAMI ANSI/AAMI/ISO /ISO 11134,“ 11134, “Sterilization of Health Care Products: Products: Requir Requirements ements for Validatio Validation n and Routin Routinee Control— Control —Industrial Moist Heat Sterilization,” Sterilization,” (American National –763. Standards Stan dards Institut Institute, e, 16 December December 1993), pp. 737 737– 10. USP 24–NF 19 (United States Pharmacopeial Convention, Convention, Rockville, MD,, 200 MD 2000), 0), pp. 181 1813, 3, 181 1819, 9, 214 2143 3–2145. 11. I.J I.J.. Pfl Pflug ug and and K.D. K.D. Ev Evans ans,, “Carrying Out Biological Qualification: Qualification: The Control Operation of Moist-H Moist-Heat eat (Steam Sterilization) Processes for Producing Sterile Pharmaceuticals and Medical Devices,” Devices,” PDA J. Pharm. Sci. Technol. 54 (2) (2),, 117 117– –135 (2000). 12. “Validation of Steam Sterilization Cycles, Cycles,”” Technical Monograph No. 1, Parenteral Drug Association, Philadelphia, PA (1978). 13.. P. Ho 13 Hoet et,, “Validation and Parametric Release for a Sterile Product,” Product,” –374 (1997). S.T.P S.T .P.. Pharma Practiques 7 (5) (5),, 372 372– –29 14.. F. Ga 14 Galt ltie ierr, “Que Signifie F o?” Labo-Pharma-Probl. Tech. 30 (316 (316), ), 21 21– (1982). 15.. M.Pfe 15 M.Pfeif iffe ferr, “Shelf Life of Bioindicators for Steam Sterilization, Sterilization,”” Pharm. –717 (2000). Ind. 62 (9) (9),, 713 713– 16. M.J M.J.. Ak Akers ers and N.R.Ande N.R.Anderso rson, n,““Sterilization Validation Validation of Sterile Products”” in Fundamentals in Pharmaceutical Process Validation, I.R.Berry ucts and R.A. R.A. Na Nash, sh, Eds. (Ma (Marce rcell Dekker Dekker,, Ne New w York York,, 2d ed., 1993 1993), ), pp. 25– 25 –87. 17. M.Pfei M.Pfeiff ffer er,, “Microbio Microbiological logical Validation Validation of the F 0 Concept for the Steam Sterilization Steriliz ation of Aqueou Aqueouss Preparations Preparations Using Spores of Bacillus stearothermophilus as Biological Indicator Organism,” Organism,” Drugs Made in Germany 41 (3) (3),, 77 77– –80 (1998). 18.. M. Pf 18 Pfei eiff ffer er,, “F 0-Concept in Steam Sterilization and the Connected –296 (2001). Sterilization Safety,” Safety,” Pharm Pharm.. Ind. 63 (3) (3),, 291 291– 19. E. Dew Dewhur hurst st and and E.V. E.V. Ho Hoxey xey,, “Sterilization Methods” Methods ” in Guide to Microbiological Control in Pharmaceuticals, S. Den Denyer yer and R. Bair Baird, d, Eds. –218. (Elliss Horwood, (Elli Horwood, Lond London, on, 1990) pp. pp. 182 182– 20. Code of Federal Regulations, Tit Title le 21, Foo Food d and Drugs (Office (Office of Federal Register National Archives and Records Administration Washington, ingt on, DC, 1989) 1989),, Part 211, 211,““Current Good Manufacturing Practices for Finished Pharmaceuticals Pharmaceuticals,,” Subpart I— I—Laboratory Controls, Controls, Section 167— 167—Special Testing Requirements. PT
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