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MLIBA PHARMACY COLLEGE,BARDOLI.
Introduction to Validation Stages
of qualifications of Autoclave
Protocol of Autoclave
of Dry Heat Sterilizers And Tunnel
may be defined as ” Establishing documented
evidence which provides a high degree of assurance that a specific process meeting its attributes.”
will consistently produce a product
pre-determined specifications and quality
has been made mandatory by the regulatory bodies to
prove the safety efficacy, Purity & effectiveness of the drug product, medical devices & biologics in the marketplace & health system.
Why Validation of Equipment? Equipment validation is Vital for Safety Fewer interruptions of work Lower repair costs Elimination of premature replacement Less standby equipment Identification of high maintenance cost Reduction of variation in results Greater confidence in the reliability of results .
. While IQ for a small and low cost instrument is usually done by the user. this practically limits this task to the user. complex and high cost instruments should be done by the vendor. As PQ should be done on a daily basis. DQ should always be done by the user.Who should do Equipment Validation? The vendor or the user The user has the ultimate responsibility for the accuracy of the analysis results and also for equipment qualification. PQ should always be done by the user because it is very application specific. OQ can be done by either the user or the vendor. and the vendor may not be familiar with these. IQ for large.
Analytical method validation Part 5.Validation Part 1. Qualification of systems and equipment Part 7. Computerized system validation Part 6. Overview on qualification and validation Part 2. Cleaning validation Part 4. Non sterile product process validation . Qualification of HVAC and water systems Part 3.
Validation Stages of qualification Design qualification Installation qualification Operational qualification Performance qualification Change control .
Validation Results of calibration maintenance. verification Defined schedule Frequency based on Factors Periodic Requalification After change Extent based on Risk assessment Part of Change control procedure .
Equipment qualification Equipment qualification / validation includes following things: Design qualification (DQ) qualification (IQ) qualification (OQ) Installation Operational Performance qualification (PQ) .
Description of the analysis problem Description of the intended use of the equipment Description of the intended environment .Design Qualification (DQ) "Design qualification (DQ) defines the functional and operational specifications of the instrument and details for the conscious decisions in the selection of the supplier". List below recommends steps that should be considered for inclusion in a design qualification.
Preliminary selection of the functional and performance specifications Preliminary selection of the supplier Instrument tests (if the technique is new) Final selection of the equipment Final selection of the supplier and equipment Development and documentation of final functional and operational specifications .
” The qualification involves the coordinated efforts of – vendor operating department project team (which provide input into the The The The purchase.Installation Qualification(IQ) “Installation qualification establishes that the instrument is received as designed and specified. installation. and that this environment is suitable for the operation and use of the instrument. . that it is properly installed in the selected environment. operation and maintenance of the equipment).
The A conclusion . is drawn regarding the operation of equipment after the test functions are checked and all data has been analyzed." proper operation of equipment is verified by performing the test functions specified in the protocol.Operational Qualification (OQ) "Operational qualification (OQ) is the process of demonstrating that an instrument will function according to its operational specification in the selected environment.
P’s 2.Test Instrument Calibration 6.Utilization List 3. Following are the contents of equipment operation qualification 1.Critical Parameters 7.Application S.Test Function Summaries .Process Description 4.Test Instrument Utilized To Conduct Test 5.O.Test Function (List) 8.
PQ can mean system suitability testing. where critical key system performance characteristics are measured and compared with documented. In practice. PQ should be performed on a daily basis or whenever the equipment is being used. .Performance Qualification(PQ) "Performance Qualification (PQ) is the process of demonstrating that an instrument consistently performs according to a specification appropriate for its routine use ". PQ should always be performed under conditions that are similar to routine sample analysis.
such as Freedom from micro-organisms. Extremely high standards of purity and quality. . Freedom from pyrogens.A. the ultimate goal in the manufacture of a sterile product is absolute absence of microbial contamination. Introduction Sterile products have several unique dosage form properties. Freedom from particulates. However.
To provide greater assurance and support of the results of the end product sterility test . To demonstrate to a certain maximum level of probability that the processing and sterilization methods have established sterility to all units of a product batch 3. 1. To build sterility into a product 2.Introduction(Con.) Three principles are involved in the validation process for sterile product..
The formulation components and characteristics The surface on which the micro-organism is exposed The temperature.” In other words. . gas concentration. the D value will be affected by The type of microorganism used as BI. or radiation dose of sterilization process. Quantitative expression of rate of killing of micro organism.D value “It is time required for a 90% reduction in microbial population.
Measures equivalent time . Z value is reciprocal of slope of plot of log D verses T at which D value is found i. increase in temperature required to reduce D value of organism by 90 % (1 log reduction) F value Used exclusively in validation of heat sterilization process. It is time in min required to kill all spores in suspension at 121oC.D value found by 2 methods. 1) Survivor curve method (log number of surviving organism versus time/gas concentration/radiation dose) 2) Fraction negative method Z value Used exclusively in validation of heat sterilization process.e.
Radiation Gamma Beta Ultraviolet .Heat Moist heat (autoclave) Dry heat oven or tunnel Ethylene oxide Peracetic acid 2.Methods of Sterilization of Products 1.Gas Vapor phase hydrogen peroxide Chlorine dioxide 3.
Autoclaves can also involve air–steam mixtures for Sterilizing flexible packaging systems and syringes. . Qualification and Calibration 1) Mechanically Checking. When autoclave system is used. and Qualifying the Sterilizer Unit The main concern with steam sterilization is the complete removal of air from the chamber and replacement with saturated steam. Upgrading. the unit must be installed properly and all operations qualified through installation qualification and operation qualification (IQ/OQ).B.
Thermocouple accuracy is determined using National Bureau of Standards (NBS). Copper constantan wires coated with Teflon are a popular choice as thermocouple monitors. . Temperature accuracy is especially important in steam sterilization validation.2) Selection and Calibration of Thermocouples Thermocouples must be durable for repeated use as temperature indicators in steam sterilization validation and monitoring.5°C. Accuracy of thermocouples should be 0.
3) Selection and Calibration of BI Sr. Radiation B. steriothermophillus spores B. subtilis var. Dry heat B. subtilis. subtilis var. Ethylene Oxide 4. subtilis. niger spores B. pumilus spores Micrococcus radiodurans vegetative cells . niger spores 3. coagulance spores Clostridium sporogenes spores 2. Sterilization process Autoclave Biological Indicator(BI) B. niger spores B. 5230 spores B. subtilis var. No 1. 5230 spores B.
C. Heat-Distribution Studies Heat-distribution studies include two phases: 1) Heat distribution in an empty autoclave chamber 2) Heat distribution in a loaded autoclave chamber. . The trips where the wires are soldered should not make contact with the autoclave interior walls or any metal surface.
. Greater temperature differences may be indicative of equipment malfunction.5°C .. Heat-distribution studies may employ thermocouples as the cool spot in the chamber. The difference in temperature between the coolest spot and the mean chamber temperature should be not greater than • 2. The principle is the location of the cool spot and the effect of the load size and/or configuration on the cool spot location.Cont.
Heat-Penetration Studies This is the most critical component of the entire validation process. The determined using container-mapping studies. The main purpose is to determine the F0 value of container cold spot for containers ≥100 ml is the cold spot inside the commodity. Thermocouple probes are inserted within a container and repeat cycles are run to establish the point inside the container.D. .
Cont.. F0 value will indicate whether the cycle is adequate or alterations are needed. Thermocouples will be placed both inside and outside the container at the cool spot location(s). . F0 value will be calculated based on the temperature recorded by the thermocouple inside the container at the coolest area of the load. in the steam exhaust line. and in constanttemperature baths outside the chamber.
. A design F value 3. To prove that the cool spot location has not changed or. If it has.) Three critical parameter associated with all wet heat sterilization Processes: 1. that it receives the design F0 time exposure from the sterilization cycle used. or container characteristics must be accompanied. load configuration..Heat-Penetration Studies(Con. A minimum F value 2. A sterilization process time Any changes in the load size.
it is important that the sterilizer be suitably qualified to perform its function.E.g. Typical critical requirements that are considered to the sterilization process (e.“quality” affect requirements) are: Accurate temperature and pressure measurement Air removal to some predefined level of vacuum distribution and uniformity in the Temperature chamber. Equipment Qualification Prior to the initiation of process. .
Air removal (usually measured by vacuum level achieved vs.Demonstration of the sequence of operations.Temperature distribution and uniformity .Calibration of temperature and pressure sensors (traceable to national or international standard) 2.Confirmation of alarms and interlocks 5. defined requirement) 3. 4.Precision of temperature control 6. The qualification of a sterilizer should include the following : 1.
Calibrated BIs used as bioburden models providing data that can be employed to calculate Fo. The microorganisms used to challenge moist heat sterilization cycles are G. stearothermophilus and Clostridium sporogenes.F. . Microbiological Challenge Studies Microbiological challenges studies are employed to provide additional necessary assurance that adequate lethality has been delivered to all parts of the load.
the sterilization cycle is complete, the
inoculated items or spore strips are recovered and subjected to microbiological test
are immersed in a suitable growth
medium (soybean casein digest medium is typical) and incubated for up to seven days.
G. Sterilizer Filter Evaluation
filters are employed on most parts of
sterilizers to ensure that loads are not contaminated
by air used to vent the chamber as it cools or dries.
contamination by their primary containers (vials, bags) and many nonproduct loads are protected by
wraps to provide a microbial barrier.
filters, two issues are of concern:
Sterility and Integrity.
the load will undergo a bioburden cycle, it may
be necessary to sterilize the filter in a separate
phase of the cycle.
ensure that filters will remain functional under
all expected conditions, the integrity tests should
be done following the maximum cycle time and
studies are recommended.
Introduction Mainly three types of dry-heat sterilization systems are utilized in the pharmaceutical industry today. I. Batch Sterilizer Ovens Tunnel Sterilizers III. Microwave Sterilizers .A. II.
In dry heat processes the hot air carries significantly less heat energy than an equivalent volume of saturated steam. the condensation of the steam sterilizer releases large amounts of heat energy that serves to heat the items in the sterilizer. to achieve sterilization or depyrogenation. In moist heat. and air surrounding the article. . PRINCIPLES OF HEAT TRANSFER AND CIRCULATION: The dry heat process must effectively heat the article.
Key Process Features to Control Prior to Validating Dry-Heat Sterilizer Batch(Oven) Intake air system Exhaust air system Internal air circulation Exhaust HEPA filter Tunnel Steriliser Positive pressure to entrance Even distribution of heat Belt speed recorder HEPA-filtered cooling air Static pressure gauge Heater current Exhaust HEPA filter Particulate control .
The four main mechanism through which Heat transfer occurs are: Convection Circulation Conduction Radiation .
Batch Oven Validation 1. Air balance determination: In an empty oven. data are obtained on the flow rates of both intake and exhaust air. Heat distribution of an empty chamber: Thermocouples should be situated according to a specific predetermined pattern. Repeatability of temperature attainment and identification of the cold spot can be achieved if the temperature range is • 15°C at all monitored locations.B. . Air should be balanced so that positive pressure is exerted to the nonsterile side when the door is opened 2.
and maximum temperatures as defined in the process specifications should be . Minimum studied. Thermocouples are placed in the commodities located in the areas likely to present the greatest resistance to reaching the desired temperature. Heat-penetration studies: These studies should be designed to determine the location of the slowest heating point within a commodity at various locations of a test load in the sterilizer.3.
repeatability terms temperature consistency.4. of mechanical air velocity. . and reliability and sensitivity of all the oven and instrumental controls must be verified. Mechanical repeatability: During all these in studies.
. Air Balance Determination: In this study items being sterilized are moving exposed to different air systems (e. either the items will not be cooled or they will be cooled too quickly. In the absence of a critical balance of air dynamics.C. Air flow must be balanced in order to provide a gradual decrease in air temperature as items move along the conveyor. heating zone and cooling zone). causing contamination of the entire tunnel area. . Tunnel Sterilizer Validation 1.g.
Heat-Distribution Studies: Thermocouples used in tunnel sterilizer validation must be sufficiently durable to withstand the extremely high (≥300°C) temperatures in the heating zone area of the tunnel. Peak temperature readings should remain within • 10°C across the belt for at least three replicate runs. Heat-distribution studies should determine where the cold spots are located as a function of the width of the belt and height of the tunnel chamber. .2.
Careful using 10 to 20 thermocouples distributed throughout analysis of the temperature data after each run will be invaluable in the determination of the cool spot . completed in order to identify the coolest container in the entire load.3. Three to five replicate runs for each commodity size done and every loading configuration should be the load. Heat-Penetration Studies: Prior to microbial challenge testing of the tunnel heat-penetration studies must be sterilization.
air particulates.4. temperature consistency and reliability of all the tunnel controls (heat zone temperatures. belt speed) must be proved during the physical validation studies. . Air velocity. Mechanical Repeatability: Tunnel sterilizers must demonstrate mechanical repeatability in the same manner as batch ovens.
D. The most widely used biological indicators for dry heat have been spores of B. validation studies must be done using both micro-organisms and microbial endotoxins. Subtilis. Biological Process Validation of Dry Heat Sterilization Cycles If the dry-heat process is claimed to produce both sterile and pyrogen-free commodities. . The goal is to validate a heating cycle that can produce a 12-log reduction in the biological indicator population.
Select Run the type of biological indicator to be used. Determine the number of survivors by plate-counting or fraction negative Methods. Determine the number of spore log reductions (SLRs) . a complete cycle using the desired loading pattern. Procedures for the validation of a tunnel sterilization: overkill approach is selected for the validation The study.
10–100 ng Escherichia coli lipopolysaccharide) Thermocouples should be placed in commodities containing endotoxin for adjacent to those temperature monitoring and correlation with LAL test results. .E.g. (e.. Endotoxin destruction should be ascertained at the coolest location of the load. Endotoxin challenge in Dry Heat Sterilization Inoculate commodity samples with a known amount of endotoxin.
and the studies must be adequately replicated. aseptically transfer the units containing endotoxin to an aseptic area for extraction procedures. Following the dry-heat cycle. F values required for endotoxin destruction at various temperatures and/or cycle time– temperature variations can be determined using a Z value of 54°C. . Several endotoxin challenge samples should be done per cycle.
All temperature equipment employed to perform the validation studies must be traceable and calibrated to the International Temperature Scale . OQ and PQ are discussed here.VALIDATION OF TEST EQUIPMENT Equipment required to conduct the IQ.
The equipments used for validation testing of dry heat processes are discussed here: Resistance Temperature Thermocouples Data Detectors Loggers Logger Wireless Temperature Infrared Thermometer Constant Temperature Baths Stopwatch Voltmeter or Ammeter Optical Tachometer .
. correct leveling. All equipment. and inspect for structural damage. presence of identification plates. and connections must be against the manufacturer’s checked recommendations.INSTALLATION QUALIFICATION The IQ is designed to compare the system against the manufacturer’s specifications for proper installation. proper insulation. A. Structural: Check dimensions. presence of seals. utilities.
B.g. such as those used with air (supply. water).. Filters: All filters used within the system must be recorded. . Some HEPA filters may need to be checked periodically by performing an integrity test or DOP. HVAC: Ensure the system provides the RH. Electrical: Ensure conformance to National Electrical Code Standards D. C. recirculating) or in other utilities (e. temperature. and pressure differential required. steam.
Ventilation: Check that the ventilation exhaust duct exhausts to an appropriate area (not to an aseptic environment). Air Supply: Identify source (direct from the HVAC system or room air). and identify the method used to prevent back-flow. and air classification. duct size. . duct material of construction.E. G. F. Door Gaskets: Check integrity of gaskets and materials of construction.
and that the blades rotate in the correct direction. the volute in place and correctly balanced. and wattage of the elements for the heaters. . I. Blowers: The blower must be mechanically sound. J. Lubricants: Make certain that any lubricants used cannot contaminate the material being sterilized or depyrogenated. the number of heating elements. amperage.H. and the voltage. Heaters: Record the manufacturer’s model number.
and sensors on the process equipment must be calibrated before the unit can be operated reliably. so that assurance is provided for cycle length. . recorders. C.OPERATIONAL QUALIFICATION A. B. Temperature Monitors: The temperature controllers. Door Interlocks: If a unit is equipped with double doors. Cycle Timer: The accuracy of the timer must be determined. the interlocks must operate such that the door leading to the aseptic area cannot be opened.
Recorders for charting the belt speed are recommended for units with adjustable speed settings. F. Heaters: All of the heating elements must be functional. It is preferable to have them monitored continuously with ammeters in order that burnedout elements can be immediately detected. Cooling Coils: To enable a faster cool-down cycle.D. . Belts: The belt speed is a critical operating parameter in both continuous hot-air tunnels and flame sterilizers. the air is often circulated across coolant coils. E.
H. Chamber Leaks: The perimeter of the doors for batch sterilizers should be checked for air leakage while operating. Particulate Counts: Particulate counts should be checked within the containers before and after sterilization to quantitate the particle load.G. .
QUALIFICATION TESTING Upon completion of IQ and OQ efforts and approval of the protocol. testing may begin. Loaded-chamber testing consisting of heat distribution and heat penetration studies. . The testing will include empty-chamber testing for: Heat distribution studies.
.1) Component Mapping Studies Before conducting the loaded-chamber heat penetration studies. The studies help to determine the coolest point within a specific load and item. 2) Empty-Chamber Testing The initial testing is performed on an empty oven or tunnel to establish the uniformity of temperature distribution. The thermodynamic characteristics of the empty unit are depicted in a temperature distribution profile. component mapping should be conducted.
. For tunnels. the time and temperature set points should be reduced. For ovens. the loads tested must be representative of standard items and quantities.3) Loaded-Chamber Studies For validation purposes. Ideally. the temperature set point should be reduced and the belt speed increased if possible. each size and type of material should be tested by penetration studies.
The challenge can be accomplished using commercial strips or suspensions of B. Coli endotoxin for depyrogenation. The concentration of the challenge for overkill processes must demonstrate adequate sterility assurance.4) Bio-Challenge/Pyro-Challenge Studies The challenge should demonstrate the lethality delivered by the cycle with either microorganisms or endotoxin. subtilis spores for sterilization or E. .
The following information should be provided in the process qualification validation report: 1. The results of the biochallenge studies and F value computation must demonstrate the required degree of lethality according to the protocol. Protocol achievement 2. Diagram . the data must be analyzed to ascertain that all testing requirements have been achieved. Deviations 4.QUALIFICATION REPORT After the empty and loaded-chamber studies and biochallenge studies have been completed. Summary of data 3.
”Pharmaceutical Process validation” second edition. 286-294 Groves.A.223. volume 34. Agalloco J. 2nd edition.. www.. 175. Journal of Parental Technology.A.T.J.. M. and Nash R. ”Validation of Pharmaceutical Process. Journal of Parental drug association. 83-110. Third Edition.R. Marcel Dekker series.gov Wood.A.References Berry I. Carleton F. R. revised and expanded. 432 .fda.
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