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Definition
Sterilization
The act or process, physical or chemical, that destroys or eliminates all viable microbes including resistant bacterial spores from a fluid or a solid. Examples of sterilization methods are : steam treatment at 121, dry heat at 230, flushing with a sterilizing solution such as hydrogen peroxide (H2O2) or ozone (O3), irradiation, and filtration.
Sterility
The reduction of anticipated levels of contamination in a load to the point where the probability of survival is less than 10-6.
2013-10-22
Definition
D-value
The time in minutes required for a one-log or 90% reduction of a specific microbial population under specified lethal conditions. For steam sterilization it is determined at a constant temperature
z-value
The number of degree of temperature change necessary to change the D-value by a factor of 10.
2013-10-22
Definition
F value(lethal rate, instantaneous Fo)
The F value is a measurement of sterilization effectiveness. F(T,z) is defined as the equivalent time at temperature T delivered to a container or unit of product for the purpose of sterilization, calculated using a specific value of z.
Fo value(accumulated Fo)
The term "Fo " is defined as the number of equivalent minutes of steam sterilization at temperature 121.1C delivered to a container or unit of product calculated using a z-value of 10C. Fo = 10^((121-T)/z)*t
2013-10-22
Methodology
Overkill Sterilization
Provides a minimum 12 log reduction of a resistant BI w/ a known D-value of not less than 1 minute. Required minimal information on the bioburden
Bioburden/Bioindicator Sterilization
Provides a probability of survival of less than 1 in 106 for the bioburden as demonstrated using a resistant BI w/ a known D-value. BI may not be inactivated Requires information on the numbers and heat resistance of the BI. Requires ongoing monitoring or control over bioburden.
2013-10-22
Methodology
Bioburden Sterilization
Provides a probability of survival of less than 1 in 106 for the most resistance bioburden expected in the load. Requires information on the numbers and heat resistance of the BI. Requires ongoing monitoring or control over bioburden.
2013-10-22
Sterilizer Cycle
Gravity Displacement
Difference of density Density of air at 20 = 1.2 g/ Density of steam at 100 = 0.6 g/ Effectiveness of air elimination depends on the rate of steam supply Air pocket : too rapidly Diffusion into the steam : too slowly, more difficult to remove Specially designed steam trap permitting the passage of large volume of air
2013-10-22
Sterilizer Cycle
Prevacuum cycle
A more effective method By means of a mechanical vacuum pump or a steam eductor Vacuum as low as 15~20 mmHg, apply for 8~10 min.
Pulsing cycle
A series of alternating steam pulses followed by vacuum excursions
Air-steam mixture
Terminal sterilization of large volume parenterals Air injection required to compensate the great expansion of air or nitrogen in the head space above the liquid Well mixed chamber : fan, raining effect by external pump w/ cooling
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Cycle Development
Consider factors into account
Nature of the load : porous materials, heat sensitivity of the products Type of the sterilizer Employed containers and closures Heat stable product : overkill approach Heat liable product : bioburden approach Bioburden studies : number of microorganisms D-value studies : only highly resistant spore formers, BIER(biological indicator evaluator resistometer) Inoculate the spore into the actual solutions For solid materials, precut strips
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Temperature standards
RTD traceable to the National Bureau of Standards , IPR, HTR
Calibration of thermocouples
At two temperatures : 0 , 130 Correction factors Stability : 0.03 Accuracy : 0.5
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Validation Protocol
Protocol should include Objectives of the validation Responsibilities of validation personnel and operating department personnel Identification and description of the sterilizer and its process control Identification of SOPs :equipment Calibration of instrument : SOPs and/or description Identification and calibration of the temperature monitoring equipment
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Validation Protocol
A description of the following studies
Bioburden determination studies(if applicable) Empty chamber heat distribution studies Container mapping studies(if applicable) Loaded chamber heat penetration studies Microbiological challenge studies Evaluation of drug product cooling water(if applicable) Integrity testing of vent filter
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Container Mapping
To determine the coolest point within the liquid filled container Temperature mapping should be conducted on all the different container types, sizes and fill volume to be validated The number of the thermocouples used depends on the container volume Possible to use a single thermocouple at different positions, and can be conducted in a smaller autoclave or retort Penetration thermocouples should be positioned at the cold spot having lowest temperature or Fo
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Type of BI : Spore strips or spore suspension into the suspending medium Microbial challenge studies are conducted concurrently with the heat penetration studies
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Validation Report
Common elements of all reports :
Identification of the task report by number Reference to protocol A brief summary of the range of operational conditions experienced and how they were controlled A procedure for maintaining control within the approved range A summary and analysis of the experimental results A brief description of any deviation Conclusion Review and approval
Cycle development reports are not usually a part of the validation report
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Maintenance of Validation
A routine calibration program for all instruments critical to the operation of the sterilizer and its support system A preventative maintenance program including periodic operational rechecks and comparison to OQ record Routine monitoring of bioburden and periodic BI challenges(optionally) Operating records and equipment logs Process and equipment change control procedures including review to establish whether additional validations are required On-going validation
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Controversial Issues
Incubation of the sterility test : 7 days vs. 14 days USP provide information concerning critical parameters for Parameteric Release Reduction extent and frequency of revalidation Verification of D-value of BIs Use of alternative to B. stearothermophilus as a BI
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