Steam Sterilizer Validation Requirements Per The New Standard ISO 17665-1:2006

For decades, steam sterilization (autoclaving) has been an integral part in the manufacturing, cleanroom, and laboratory processes for the medical device, pharmaceutical, biologics, and human tissue/HCTP industries. It has been a common industry practice to validate steam sterilizers using the published guideline ISO 11134 Sterilization of health care products — Requirements for validation and routine control - Industrial moist heat sterilization,1 issued in 1994. In late 2006, AAMI released the document intended to supersede 11134, with ANSI/AAMI/ISO 17665-1:2006 Sterilization of health care products — Moist heat — Part 1: Requirements for the development, validation, and routine control of a sterilization process for medical devices.2 While other steam sterilizer guidance documents do exist,3,4 it is anticipated that the new 17665 standard will be recognized by the FDA and will be commonly employed to validate autoclave processes. The good news to manufacturers or other users of these guidelines is that many of the current validation practices are the same in the new document. This article will outline the basic requirements for steam sterilizer validation via the halfcycle overkill method, and list some of the differences between the two documents.

REQUIREMENTS PRIOR TO VALIDATION

The 17665 document makes it clear in numerous locations that the user’s quality system must adhere to ISO 13485:2003 Medical devices — Quality management system — Requirements for regulatory purposes.5 So if a user wishes to claim full compliance with the new 17665 steam standard, then their quality system must also be in compliance with ISO 13485, including items such as preventive/periodic maintenance and regular calibration for the sterilizer, documentation, change control, purchasing, etc. When compared with the previous steam document, the new 17665 also has more information on product and process characterization, sterilizing agent characterization, installation qualification/IQ, and operational qualification/OQ. The new document also states more clearly that a fully compliant validation is not just a series of successful halfcycles, but is the full complement of successful IQ, OQ, and PQ.

Sterilization agent characterization will be simple for most users — moist heat/steam at 121 or 132 °C, and cycle selection (gravity, prevacuum, etc.). Process and equipment characterization means defining and documenting items like the sterilizer cycle parameters, products (or product families) to be sterilized, load configurations and limits, placement of biological indicators or chemical indicators (BIs/CIs), process tolerances, and equipment identification. Much of this type of information would be recorded in well-written validation protocols or validation final reports. Biological indicators often use spores of the bacterial species Geobacillus stearothermophilus at a titer of greater than 106per BI, although other species or titers are sometimes used.

The new 17665 document also has more information on IQ and OQ. It defines IQ as “obtaining and documenting evidence that equipment has been provided and installed in accordance with its specification.” Autoclave installations commonly document items such as the sterilizer identification numbers, location, line voltage and amperage, water supply piping and pressure limits, steam line requirements, filtration, chamber size, structure and support, piping materials, software certification, manuals, drawings and documentation, and calibrations (temperature, pressure, and timer). The sterilizer must be installed in such a manner to facilitate any necessary maintenance, repair, adjustment, cleaning, and calibration.

OQ is defined as “obtaining and documenting evidence that the installed equipment operates within predetermined limits when used in accordance with its operational procedures.” Autoclave OQs commonly test or verify items such as cycle operation and programming instructions, safety and alarm testing, error reporting, empty chamber temperature profiling and chamber temperature limits/specifications, air removal testing, leak testing, temperature control anomalies, full cycle full-load temperature profiles (if proposed fullcycle exposure time is known), and determination of any hot or cold spots within the chamber.

The product definition and process definition sections of the new document list things such as product specifications, product families, packaging, re-sterilization issues, package moisture, stability and potency of container products, re-usable container systems, process challenge devices/PCDs, sterility assurance level/SAL, BIs and CIs, and bioburden determination if necessary. PCDs are described as products or items that provide a known resistance to the sterilization process. They are commercially available or may also be created from the user’s product line by inserting spore strips, spore dots, inoculated threads, etc. into items or locations that are determined to be the most-difficult-to-sterilize product or location in the load.

There are many other activities or decisions to be made prior to or during the IQ/OQ, that are not necessarily detailed in either standard. Items such as:

● Obtaining calibrated temperature recording devices or thermocouples

● Ordering supplies such as BIs, CIs, Bowie-Dick test packs, packaging materials, etc. and noting if adequate laboratory facilities are available

● Determining worst-case validation load and worst-case test product or PCD. The protocol or final report should contain a written rationale describing how the loads and product(s) were selected

● Selecting cycle type: 121 or 132 °C, gravity or prevacuum cycle, etc.; and determining if drying time needs to be qualified

● Is product bioburden testing necessary?

● Is product resterilization to be allowed and what are the requirements for resterilization?

● Is product stability or shelf life testing necessary for the user’s products?

● Does packaging testing or packaging validation need to be included with the protocol?

VALIDATION – PERFORMANCE QUALIFICATION

AAMI TIR #13 states “Sterilization process validation is a documented procedure for obtaining, recording, and interpreting the results required to establish that a process will consistently yield product complying with its predetermined specifications.” For the purposes of this article, the primary specification will be sterility. The performance qualification/PQ or microbiological qualification is a series of tests that establishes that the installed and properly operating sterilizer will process the users desired chamber loads to achieve the specified sterility assurance level/SAL. It must be remembered that the load is part of the validation — that is, if the user makes significant changes to the load at any point in the future — then re-validation may be necessary. The previous ISO 11134 document gave relatively little guidance information and few specifications for conducting the test cycles necessary to qualify the user’s proposed fullcycle exposure time(s). The

new 17665 steam document varies little from the previous standard in respect to the minimal PQ information that is provided. The 17665 describes bioburden validation methods and the more commonly used halfcycle “overkill” method. It should be noted that at the time this article was prepared, the proposed guidance document that is to accompany ISO 17665-1 was not yet available. This guidance document may provide more advice on microbiological qualification issues (ISO 17665-2 Sterilization of health care products — Moist heat —Part 2: Guidance on the application of ISO 17665-1). For this article, the general requirements for an overkill cycle PQ will be reviewed.

While many activities are required to complete the PQ, the primary goal for the commonly employed overkill validation is this: the user needs to complete three consecutive successful halfcycles in order to qualify their proposed fullcycle exposure for routine processing of sterilization loads. In our case, successful means all BIs are killed (no growth upon incubation) for the three consecutive halfcycles. If, for example, there was no BI growth for the three test cycles at ten minutes exposure at 121 °C, then a 20-minute exposure at the same temperature would be adequate for routine daily processing, assuming all other aspects or requirements of the IQ/OQ/PQ are successful, documented, reviewed, and approved.

But a description of the PQ needs much more detail than this. Validation protocols vary in format from company to company, but most will capture similar information for the final report. An example of validation protocol and final report sections would be:

Title page with approval signatures

         Purpose, background information, or general goal(s) of validation

         Scope with more specifics about methods, cycles, facility, SAL, products and load, exclusions, etc.         References with published standards and company SOPs         Equipment, supplies, validation loads, BIs, etc.         Rationale for selection of products, load, cycles, PCDs, etc.         Procedure or methods (more details on this below)         Acceptance criteria which list the pass/fail requirements         Deviation report which lists any unexpected results, with potential effects on the validation,

along with accept/reject rationale         Results and conclusions which assign a pass/fail decision to each acceptance criteria,

summarize study, and include any requirements for revalidation         Attachment which lists any data sheets, diagrams, certificates, temperature records, etc., for

inclusion with final report         Approvals section for final report.

To conduct the halfcycles, the user assembles the worst-case validation test load, temperature loggers, BIs/PCDs, and CIs if necessary. The temperature loggers and BIs are seeded throughout the load to represent various chamber locations, keeping in mind any cold spots or previously determined most-difficult-to-sterilize locations. For small chambers, as few as five or six BIs and temperature loggers may be needed. Ten is a common sample size for many chambers. Large, multi-pallet-sized chambers may require many more samples per run. The sterilizer is programmed for one-half of the proposed full-cycle exposure time. Upon completion of the test cycle, the BIs are immediately removed and incubated, and the test load must be allowed to return to normal temperature prior to starting another test cycle. Temperature recorder data is downloaded and printed immediately to determine if any unusual temperature conditions existed. Information is entered on the data sheets (data sheets that would have been one of the attachments to the written protocol), and all temperature records and data sheets are retained for the final report. BIs are checked regularly

throughout the http://www.cemag.us/Article_Print.asp?pid=709 (5 of 7) [13/8/2008 11:56:50 AM] Controlled Environments® | Articles | Steam Sterilizer Validation Requirements Per The New Standard ISO 17665-1:2006 incubation period, and include positive control (unprocessed) BIs which must show growth. As stated before, all processed BIs must show no growth in order for the validation runs to be considered successful.

Final reports should contain: 1) all sterilizer run data or recorder charts, signed and reviewed; 2) all temperature recorder data, signed and reviewed; 3) all data sheets with BI, CI, or any other test results, reviewed and signed; 4) any deviations recorded and investigated, with final disposition; 5) results, conclusions, and discussion; 6) calibration documents for any measuring instruments used during the study; 7) the approved full-cycle parameters and acceptable placement locations for BIs for normal processing; and 8) manufacturers’ certificates of analysis for any items such as BIs, growth media, growth promotion test cultures, etc. Including digital photographs of sterilizer, load, PCD, etc. can be quite helpful for an auditor who may be reviewing the report at a later date. The completed final report packet must then be routed for review and signed for approval.

POST-VALIDATION

There are still issues to be addressed when all activities seem to have been completed. The sterilizer must be added to a regular and documented calibration program. The sterilizer must be included in a regular and documented periodic/preventive maintenance program. And the sterilizer must be added to the validation schedule for its annual requalification. The user needs to verify that all personnel that will be using the autoclave are trained using applicable operation and safety SOPs. Untrained staff should not be allowed to run the sterilizer. Approved products, loads, cycles, and load limit information must be readily available to all operators. SOPs for daily processing must list all requirements for data that is to be reviewed and retained from the sterilizer runs, with logbook, filing system, or archive for run records. SOPs must also address items such as 1) segregation of processed and non-processed product, 2) storage requirements for processed products if necessary, 3) notification of management or maintenance if sterilizer malfunctions or if recorder chart lists any errors, cautions, or warnings, 4) immediate notification of management for BI test failure, including investigation and product quarantine procedure as appropriate, and 5) resterilization requirements if resteril-ization is to be allowed.

In summary, there seem to be no drastic or revolutionary changes in making the transition from ISO 11134 to ISO 17665. The new 17665 steam document provides more information and more guidance in some areas, while leaving other areas (such as PQ) relatively unchanged. While users would be advised to obtain the 17665-2 guidance document when it becomes available, it is anticipated that manufacturers will not find any great difficulties in applying the new standard.

This is the html version of the file http://www.aapspharmaceutica.com/meetings/files/139/James%20Gallagher.pdf.Google automatically generates html versions of documents as we crawl the web.

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Validation of Steam SterilizersArden House 2009James GallagherKalypsys Inc1Validation of Steam Sterilizers AAPS Arden House 2009

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Introduction to Validation of Steam SterilizersGoals of Presentation• Overview of basic principles for steam sterilizationand microbiology• Review key aspects of EN 285 and PDA TechnicalReport #1

• Facilitate decision making for PharmaceuticalScientists looking to Contract ManufacturingOrganization (CMO) for aseptic processing thatincludes steam sterilization2Validation of Steam Sterilizers AAPS Arden House 2009

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IntroductionOutline• Introduction• Sterilizer Design Aspects• Steam / Thermo• Micro Aspects• Validating Sterilization Cycles• Checklist / Troubleshooting• Regulatory3Validation of Steam Sterilizers AAPS Arden House 2009

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Introduction to Validation of Steam SterilizersRegulatory Drivers and GuidanceSourceDocumentFDAFDA, Guidance for IndustrySterile Drug Products Produced by Aseptic Processing —Current Good Manufacturing Practice , Sept 2004CFRRelevant Sections on Sterilization, purity and controlEN285Sterilization – Steam Sterilizers – Large Sterilizers,Amendment 1, March 2008USP <55>Biological Indicators, Resistance Performance TestsPDATechnical Report #1: Validation of Moist HeatSterilization Processes: Cycle Design, Development andOngoing ControlValidation of Steam Sterilizers AAPS Arden House 20094

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Introduction to Validation of Steam Sterilizers

Working with Contract Manufacturing Organizations (CMO)• Sponsor needs to partner with CMO• Assume aseptic process is defined, and the RFP has takeninto account the level of validation needed• Review the assumptions and risk analysis on the requiredsteam sterilization processes are included; confirmassumptions in original risk assessment are still valid• Consider including an engineering (pilot) batch in the RFP• Due Diligence: site visit, audit → Input on CMO selection• Transferring Aseptic Process Technology to the CMO5Validation of Steam Sterilizers AAPS Arden House 2009

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Introduction to Validation of Steam SterilizersThree Examples of Contract ServicesValidation of Steam Sterilizers AAPS Arden House 20096

Example of ProjectTypical Sterilization NeedsDriving ForcesEarly Phase ClinicalProgram in USReceiving Tank / BagDocumentation for INDSpeed to Clinic -- LeverageCMO’s existing cycles /programsWW Phase III ClinicalProgramFilter AssemblyFilling Line PartsDocumentation to supportNDA/ CTD and PAIScale-upSecondary source forCommercial ProductStopper processingFilling ManifoldSupplement to NDA / CTD

New facility QualificationEquivalency with existingproduct / package/ processOptimal cycles

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Sterilizer Design AspectsSterilizer interface with aseptic process• Sterilizers are acritical means toprovide access to anaseptic process• Components areprepped /cleanedprior to sterilization• Dedicated,disposable ormultiple useValidation of Steam Sterilizers AAPS Arden House 20097Prep Area (non sterile)EntrySterilizer#1Sterilizer#2Sterilizer

#3Aseptic Processing SuiteAseptic Corridor

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Sterilizer Design AspectsAutoclave DiagramValidation of Steam Sterilizers AAPS Arden House 20098

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Sterilizer Design AspectsSterilizer Design Features• Jacketed vessels, internal volume, steam trap,insulation• Filtered air (< 0.3um) with steam backflow device• Temperature sensors = Pt resistance types• 2 independent temperature sensors• Failed cycle can be vented and loading door opened,standard door interlocks

• Condensate trap within 2 meters of the connection• May have air breaks on drains to prevent backflowValidation of Steam Sterilizers AAPS Arden House 20099

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Sterilizer Design AspectsControl of a sterilizer• Critical parameters are steam quality, temperature andtime• Temperature sensor is normally in the drain• Automated cycles, sensors monitoring and alarms• Key measurements are temperature, pressure and time10Validation of Steam Sterilizers AAPS Arden House 2009

Common Indicators on Sterilizer ControllerDoor lock (both ends)Cycle in progress / Cycle Complete

FaultCycle selectedCycle counterCycle Stage Indicator

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Sterilizer Design AspectsTemp and Pressure Measurements on Sterilizer• Temperature Measurements– Jacket, Chamber, Drain, Load Probes and Recorders• Pressure Measurements– Jacket, Chamber and Recorders• Time– Exposure time, heat up timeValidation of Steam Sterilizers AAPS Arden House 200911

ParameterTemperaturePressureAccuracy of Range1% over the 50 – 150˚Crange< 1.6% over range0 to 400kPa / (-1 to 3 bar)Accuracy at Sterilization 0.5˚C at sterilization temp

+/-5 kPa (0.05 bar)Resolution0.1˚C for digital1kPa (0.01 bar)

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Steam / ThermoSteam Overview– why is steam so effective?• Condenses, collapses as wet film of condensationincreases the heat flow to sterilized item• Volume of steam ( ~6 cu ft / lb); 350x volume of water• 50 – 100 lbs of steam used in a typical cycle• The “killing power” of steam is due to its latent heat ofvaporization– 1 L water to boiling = 80 cal– 1 L boiling water to steam = 540 cal12Validation of Steam Sterilizers AAPS Arden House 2009

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Steam / ThermoSteam Enthalpy13Validation of Steam Sterilizers AAPS Arden House 2009

Temperature(C )Pressure(bar) (psig)Enthalpy of Steam(J/g) (BTU/lb)100˚ C1.013 14.72,6751,150121C2.048 29.72,7071,164126˚C2.392 34.72,7151,167134C3.039 44.12,7251,171

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Steam / Thermo

Steam Quality / Testing• Steam quality = how much water is contained in thesteam % by weight / % by volume• Dryness value = 1.0 for dry saturated steam; lesslatent heat capacity for lower steam quality• Pharma sterilization cycles use saturated steam withno superheat, minimal NCG• Clean steam used in Pharma applications;condensate complies with WFI monograph• Understand CMO’s limitations for steam production14Validation of Steam Sterilizers AAPS Arden House 2009

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Steam / Thermo

Causes of poor steam quality• Issues with clean steam generator• Water hammer – water slug moving through pipesresulting in a banging sound• Piping Insulation– prevents steam from condensing• Times of higher steam demand: winter, startup• Condensate in piping: in AM, after a shutdownValidation of Steam Sterilizers AAPS Arden House 200915

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Steam / ThermoNon-condensable gases(NCG)• Gases that cannot be liquefied by compression underthe conditions used in a sterilization cycle

• NCG do not contract / expand like steam, move to anarea of lower velocity (the sterilizer); steam/gas mix• Sources: Air: open door, piping, steam supply• Lower temperature, can insulate items → impact cycles– i.e. 10% air will lower incoming steam temp by 7F• CO2

can dissolve in the condensate → carbonic acid;corrosive to metal pipes• Oxidation from dissolved 02Validation of Steam Sterilizers AAPS Arden House 200916

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Steam / ThermoSteam Trap

• Automatic valve that drains water,vents air, but traps steam in thesystem, located on drain legs andsteam filters• Located at the bottom of thesterilizer, drains condensate fromthe jacket and the chamber• Steam traps also used on air vents• Failure mechanisms for steam trapsValidation of Steam Sterilizers AAPS Arden House 200917

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Micro AspectsOverviewValidation of Steam Sterilizers AAPS Arden House 200918

SAL = 10-6AccumulatedLethality, F0

BiologicalIndicatorsOverkill or BioburdenCycle?D, z and Fvalues

MicrobiologicalAspects ofSterilization

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Micro AspectsSterility Assurance Level (SAL)• The probability of a single viable microorganismbeing present on a sterilized unit is one in one millionafter the item has undergone a sterilization process;often called a six log reduction• PNSU (Probability of a Non-Sterile Unit)• Cannot directly measured this objective• For parenteral products, desire a SAL of 10-619Validation of Steam Sterilizers AAPS Arden House 2009

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Micro AspectsBiological Indicators (BI)• Population of microorganisms (usually spores)inoculated onto a suitable medium• Placed in sterilizer load locations to determine thesterilization cycle efficacy by deactivating BI• The challenge microorganismis selected based upon itsresistance to the givenprocess• Quality of BI defined by microbiological count and D-Value Validation of Steam Sterilizers AAPS Arden House 200920

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Micro AspectsG Stearothermophilus

• Geobacillus stearothermophilus for use in steam sterilization at 121.1°C to 135°C (275F)• Incubate at 55˚- 60°C• Thermophiles found in hot springs areas such asYellowstone NP; highly resistant to heat• Most spore forming microbes have D-value < 0.5 min;commercial spore strips have D-value 1.5 - 2 min• Desire a population of spores on a strip of ~105 or more• Direct inoculation onto test substrates (closures etc)Validation of Steam Sterilizers AAPS Arden House 200921

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Micro AspectsInoculation of BI / Positive Controls

• After the sterilization cycle, the retrieved BI is placed ina tube of growth medium and incubated per USP <55>• A color and/or turbidity change indicates the results ofthe sterilization process, no change in indicatessterilization conditions were achieved, otherwise thegrowth of the spores indicates that the sterilizationprocess has not been met.“It also should be noted that the resistance of microorganisms can vary widelydepending on the material to be sterilized. For this reason, careful considerationshould be given during sterilization validation to the nature or type of materialchosen as the carrier of the biological indicator to ensure an appropriatelyrepresentative study” Sept 2004 FDA GUIDANCE.Validation of Steam Sterilizers AAPS Arden House 200922

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Micro AspectsD-value• D value is the thermalresistance value (min) of atarget organism• D value is the time inminutes at a specifictemperature to reduce thesurviving microbialpopulation by 1-log, or 90%reduction in population.• Typical D-values forcommercial spore strip lotsare ~1.5 - 2 minValidation of Steam Sterilizers AAPS Arden House 200923

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Micro AspectsZ Value• Z value is the heat resistanceof a spore as a function of

temperature (C)• Z value is the temperaturechange required to result in a1-log reduction in D-value• Generally used standardvalue is Z= 10˚C• Z = (T2

– T1

) / (log D1

– log D2

)Thermal Resistance CurveValidation of Steam Sterilizers AAPS Arden House 200924

D121

1.6 minD131

0.16 minD111

16 min

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Micro Aspects

F value, Accumulated Lethality• Accumulated Lethality is the F value• F0

is the equivalent time that a microbial populationwith a z value of 10 has been held at 121˚C• 1 F0

= the equivalent of 1 minute at 121˚C• Equation; F = Σ 10(T-121.1)/z x tWhere T = TemperatureF0

= equivalent sterilization time (min)

• Z = 10˚C is generally usedValidation of Steam Sterilizers AAPS Arden House 200925

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Micro AspectsF, D and Z values and their relationships

• Equation #1: Log NF

= -F(T,z)

/ DT

+ log N0

• Equation #2: F(T,z)

= (Log N0

– Log NF

) x DT

• Typical D-values are ~1.5 - 2 min; natural is <0.5 min26Validation of Steam Sterilizers AAPS Arden House 2009

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Micro AspectsProduct Specific (Bioburden) Approach

• Quality attributes impacted by high thermal input • Collect detailed bioburden and D-value data• Example: Liquid Loads, terminal sterilization with abioburden of 100 CFU and D value = 0.5 min• Equation #2: F(T,z)

= (Log N0

– Log NF

) x DT

– F0

= (Log 102 – Log 10-6 ) x 0.5 min = 4.0 min at 121˚C27Validation of Steam Sterilizers AAPS Arden House 2009

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Micro AspectsOverkill Approach• Many definitions and process requirements for Overkill Cycles• Provides a minimum 12 log reduction ofmicroorganisms having a D-value of at least 1 min• Avoids collecting bioburden and D-value data byassuming extreme case conditions:– Bioburden level is 106

– D-value is 2.5 minutes• Equation #2: F(T,z)

= (Log N0

– Log NF

) x DT

F0

= 12 log (2.5 min/log) = 30 minutes at 121.1˚C28Validation of Steam Sterilizers AAPS Arden House 2009

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Micro AspectsCompare FPHY

and FBIO

• FPHY

determined from thermocouple data during heatpenetration study• FBIO

is the delivered lethality calculated by the actualkill of microorganisms in a BI system• FBIO

= DT

x LRD is the D valueLR is the log reduction of BI population during a cycle• Agreement between FPHY

and FBIOValidation of Steam Sterilizers AAPS Arden House 200929

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Micro AspectsBIER vessel• BIER (Biological Indicator Evaluator Resistometer)Systems are designed to provide environmentalconditions to evaluate the resistance of microbialpopulations to sterilization

• Confirm population of spores on strip; purity• Confirms D-values from commercial lots of sporestrips– Fractional Negative or Direct enumeration methods– Repeat value or confirm by survivor kill“The microbial count of a biological indicator should be confirmed. Biologicalindicators should be stored under appropriate conditions.” FDA, Sept 200430Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization CyclesOverviewValidation of Steam Sterilizers AAPS Arden House 200931

ThermalValidationSystemType ofGoodsWorst CaseLoad

AssessmentLoadConfigurationThermocouplesOverkill orBioburden?

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Validating Sterilization CyclesAspects of Thermal Validation System• System that meets international cGMP requirements• Performs pre and post calibration of thermocouples• Consider IRTD for reduced setup time, minimal sensor handling and automated sensor calibration• High Temperature range -195 to 420°C• 21 CFR Part 11 Compliant• Calibration Traceable to NIST

• Facilitates study data and generates regulatoryrequired reports32Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization CyclesThermocouples• Number must be documented and justified; watchacceptance criteria!• Accuracy of thermocouples = +/- 0.5˚C• Type T Class 1 thermocouple wire• Use of telemetry sensors• TCs threaded through gland to the chamber• Pre and post calibration verification“The sensing devices used for validation studies should be calibrated before andafter validation runs” FDA Sept 2004 Guidance”.33Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization CyclesType T Thermocouples• Type T Thermocouple• Wire insulation color:+ = Blue- = RedWire material:+ = Copper- = ConstantanProperties:+ = Copper colorValidation of Steam Sterilizers AAPS Arden House 200934

JunctionExposedUn-GroundedGroundedTip

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Conducting ValidationMore on Thermocouples35Validation of Steam Sterilizers AAPS Arden House 2009

• Number / access may result in failed test cycle• Can be easily damaged by autoclave cart wheels• Essential that the thermocouples do not affect airremoval or steam penetration• Label thermocouples• Conducting verification regularly (not necessarilyafter each run)• Place one near the sterilizer’s temperature sensor“In general, the biological indicator should be placed adjacent to the temperaturesensor so as to assess the correlation between microbial lethality and predictedlethality based on thermal input” FDA Sept 2004 Guidance.

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Validating Sterilization Cycles3 Classes of Goods to be sterilizedTypeGoods Sterilized

Typical Pre-VacAir RemovalHard GoodsEquipment, Piping,Glassware1 or more(3 typically)Easy air removal andsteam penetrationWrapped Goods Hoses, Gowns, Filters,Vessels with vents3 or moreMore difficult airremoval/ steampenetrationLiquidsMedia, Product(F0

> 15 min)NoneAir overpressureprocess. Heat andcool without vacuum36Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization Cycles

Establishing Load Patterns“The specific load configurations, as well as biological indicator and temperaturesensor locations, should be documented in validation records. Batch productionrecords should subsequently document adherence to the validated loadpatterns” Sept 2004 guidelines.37Validation of Steam Sterilizers AAPS Arden House 2009

LoadPositionCommentFixedFixedIdentical for all processing runsInstructions list items and position in diagramFixedVariableLocation can varyValidate positional equivalency during runsInstructions reference list of itemsVariable VariableLocation and position can varyValidate minimum and maximum loadsDemonstrate min / max are adequate in validationFlexible instructions for Operations

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Validating Sterilization Cycles

Types of Saturated Steam Processes• Pre-vacuum process is most commonly usedsaturated steam process– Removes air in vacuum pulses– Multiple pulses allow pre-conditioning of goods,reducing the equilibration time• Gravity Displacement– Steam displaces the heavier air– Air pushed out drain through steam trap– Steam distribution is criticalValidation of Steam Sterilizers AAPS Arden House 200938

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Validating Sterilization CyclesCycle development for new item• Establishing a cycle prior to validation

• Assessment of the item / current cycle adequate?– Class of goods, type of load, OK or bio?• Conduct heat penetration study• Determine equilibration time: time TREF

– time Tslow

• Drying studies if needed• Correlate FPHY

and FBIO

for cycleValidation of Steam Sterilizers AAPS Arden House 200939

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Validating Sterilization CyclesDetermination of Worst Case Load• Determine locations that are worst case with steamintegrators and/or Thermocouples

• Determine most difficult to sterilize items in load– Hoses – cut, insert, seal– Bottles – center, just above bottom– Filters – air removal• Fixed load or variable load -- degree of flexibilitydesired in CMO’s Operations• May be a destructive test ; pass through expenseValidation of Steam Sterilizers AAPS Arden House 200940

Page 41Validation of Steam Sterilizers AAPS Arden House 200941

Validating Sterilization CyclesDefinition of Loads – Contract Service ExamplesContract Service Goods TypeLoadOK or Bio?Cycle#1 VesselWrapped

FixedOverkill121˚C saturatedsteam#2 FilterWrappedFixedOverkill121˚C saturatedsteam#3 RTS ClosureWrappedVariableOverkill121˚C saturatedsteam

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Validating Sterilization CyclesExample Cycle OverviewValidation of Steam Sterilizers AAPS Arden House 200942

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Validating Sterilization CyclesTypes of StudiesCycle DescriptionStandardKey AspectsPressure Rise

(Leak Test)< 1.3mbar/minCheck prior to thermal studiesMonitors rise in pressure undervacuumTemperatureDistributionEmpty ChamberOften performed in requal programsVerifies uniform distribution of steamTemperature variation: each probe,probe to probe, probes to set pointItem Cool PointMin loadMultiple runs if neededIdentifies the most difficult to sterilizepoint in a test articleValidation of Steam Sterilizers AAPS Arden House 200943

“These uniformity or mapping studies should be conducted withcalibrated measurement devices.” FDA Sept 2004 Guidance

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Validating Sterilization CyclesTypes of StudiesCycle DescriptionStandardKey AspectsTemperatureDistribution

Min / Max Load Verifies uniform distribution of steamTemperature variation: each probe, probe toprobe, probes to set pointHeat PenetrationMax Loadsmultiple runsMap temperature with TCsTemps as aboveEquivalency of variable loads using same cycleMaximum equilibration timeUsed to calculate FPHY

Can be combined with BI challenge studyProcess LethalityBiological Qualification(BI challenge)Full Load3 consecutiverunsMap temperature with TCsPlace BI at probed locations, including mostdifficult to heatUsed to calculate FBIO

Incubate BI post cycle44Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization CyclesMinimum Acceptable Cycle

• Qualified MAC cycles confirmed biologicallyand physically• Safety margin through use of higher exposuretimes or temperatures• Total Dwell Time is additional lethality +demonstrated lethality from process validation• Half cycle methodsValidation of Steam Sterilizers AAPS Arden House 200945

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Validating Sterilization CyclesAcceptance Criteria Guide• Thermal Systems• Process Cycles• Reference Tests

• EN285 Steam quality itemsValidation of Steam Sterilizers AAPS Arden House 200946

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Validating Sterilization CyclesAcceptance Criteria–Thermal SystemsAspectStandardTC Temperatures duringDwell TimeAll temps during dwell time within 3˚C (-1˚C /+2˚C) of SPTC Temperatures duringDwell TimeFluctuation of TCs within chamber NMT 1˚CTC Temperatures duringDwell TimeAll temps measured in chamber do not differ from eachother by 2˚CSteam TemperatureCorresponds to its vapor pressure measurementEquilibration TimeLag between hottest / coldest thermocouples is NMT 30sec (15 sec for smaller chamber)Timer Accuracy+/- 1%Pre and post calibrationcheckTemp measurement system is accurate to +/-0.5˚C

Validation of Steam Sterilizers AAPS Arden House 200947

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Validating Sterilization CyclesAcceptance Criteria– Process CyclesValidation of Steam Sterilizers AAPS Arden House 200948

AspectStandardConcernsTemperature DistributionMinimum F0

met for TCsCorrelate T and PAcceptable number of TCsHeat PenetrationDetermine most difficult tosterilize item / desired loadAir removal, large mass,length of hosesF0

RangeMin F0

at end of exposureMax equilibration timeMicrobial Inactivationduring BI challenge

No BI growthGrowth with + controlSAL = 10-6

Positive control of BISOPs for handling BIComparison of FPHY

andFBIO

Agreement for minimalcycle

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Validating Sterilization CyclesAcceptance Criteria – Reference TestsAspectStandardLoad DrynessMass increase < 1% Textiles test packMass increase < 0.2% Metal test packDynamic Pressure TestAverage pressure change NMT 10 bar/min for any 3second intervalSound PowerSound level meter reading NMT 3dB change fromoriginal operating levelValidation of Steam Sterilizers AAPS Arden House 200949

• Reference tests performed during validation of cycle,revalidation and in periodic / routine tests • Most test are done on an empty chamber

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Validating Sterilization CyclesAcceptance Criteria – Reference Tests IIAspectStandardThermometric Tests(Full Load)Equilibration time NMT 30 sec (large)TCs within +3C of sterilization tempMinimum hold time at sterilization tempTemps within 2C during hold timeChamber steam temp corresponds to pressureBowie and Dick TestUniform change of indicator colorAir Leakage Flow RateNMT 1.3mbar/minAir Detector (if present)Alarms if <2C temperature difference at startof equilibration time

Hollow Load TestProcess challenge device reaches endpointValidation of Steam Sterilizers AAPS Arden House 200950

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Validating Sterilization CyclesAcceptance Criteria -- EN285 Steam QualityItemDescriptionLimitsNon condensablegases (NCG)Air and other gases, which do not condenseunder the conditions of steam sterilization andprevent the attainment of sterilizationconditions in any part of the load< 3.5%SuperheatSteam whose temperature, at any givenpressure, is higher than that indicated by theequilibration curve for the vaporization of water≤ 25CDryness ValueThe dryness fraction is a measure of theamount of moisture carried by the steam beingsupplied and used for sterilization0.90 – 0.95Contaminants

Clean steam condensate tests per EPEN285 Table E.2Validation of Steam Sterilizers AAPS Arden House 200951

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Validating Sterilization CyclesBowie-Dick Test / Steam Penetration• Test is designed to test air removal, the absence ofair leaks and steam penetration into a porous load• Test Sheet consists of chemical indicators on two testsheets positioned inside porous materials and sealedinside a disposable outer wrap• Single use packs available52Validation of Steam Sterilizers AAPS Arden House 2009

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Validation Sterilization Cycles

More on Bowie and Dick Test• Successful test indicates rapid and even penetrationof steam into the test pack. Retention of air withinthe pack due to:– adequacy of pre-vacuum– air leak– presence of NCG in steam supply• Bowie –Dick cycles: to be carried out periodically perEN285• Test pack can also be used for load dryness test(textiles)Validation of Steam Sterilizers AAPS Arden House 200953

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Validating Sterilization CyclesAssessing Limitations / Restrictions

• Qualification of multiple autoclaves,– Initial qualification– demonstration of equivalency– bracketing approach– supported by risk assessment• Ongoing monitoring of cycles• PQ studies + operational efficiencies if equivalent. Otherwise pick coolest one• Drying studies, end of cycle adjustments as neededwith post vacs, heating54Validation of Steam Sterilizers AAPS Arden House 2009

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Validating Sterilization CyclesContract Service Example #1: Post SterileFiltration Vessel (Tank / Bag)• Assumes an early phase clinical program in US

• Will an existing cycle provide sufficient assurance thatthe new load will achieve SAL? Bracketing strategy?– Overkill Cycle, Wrapped Good– 121˚C sat steam cycle with pre-vac– Fixed Load Configuration (min load)– Thermal mapping Study– Heat Penetration Study / BI Challenge Study• Include documentation for sterilization process in INDValidation of Steam Sterilizers AAPS Arden House 200955

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Validating Sterilization CyclesContract Services Example #2: Filter Assembly• Assumes a late phase WW clinical program / CTD filing• Steam sterilizer cycles will be held to EN285 standard

for Regulatory filings and PAI inspections– Overkill Cycle, wrapped good– 121˚C sat steam cycle with pre-vac– Fixed load configuration– Thermal mapping study– Heat Penetration– BI Challenge• Include documentation for sterilization process in CTDValidation of Steam Sterilizers AAPS Arden House 200956

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Validating Sterilization CyclesContract Service Example #3: RTS ClosuresValidation of Steam Sterilizers AAPS Arden House 200957

• Assumes sponsor is partnering with CMO to sourceexisting product; closures cycle not currently qualified

• WW sourcing --Steam sterilizer cycles will be held toEN285 standard for Regulatory filings and PAI inspections– OK, but may consider bioburden based cycle– Variable load, wrapped good– Thermal mapping study– Heat Penetration– BI Challenge: direct inoculation on closures– Drying studies may be needed• Include documentation for sterilization process in CTD

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ChecklistSponsor’s Checklist of CMO supplied documents• Explanation and justification of method of sterilization– Diagram showing location of load items, BI locations, TClocations, printouts

– Summary of micro results– Pre and post calibration of thermocouples• Information on preparation, cleaning sterilization andstorage of specified equipment and materials– Confirming cycle parameters are listed on MasterProduction Records– Material and Personnel flow diagramsValidation of Steam Sterilizers AAPS Arden House 200958

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ChecklistQuality and MicroQUALITY AND MICRO CHECKLISTChange control System; Cycle Description Form (CDF) for load configurationchanges covered, impact to utility system changes assessed?Type, source, concentration, D-value, Z, plant environmental isolatesHow is micro data reviewed and approved?Requalification program in place

NIST traceable standards used, review how sensors are calibratedCompare process record, SOPs, MBR for indicated product, spec for time andtemperature requirementsControl Software and documentation should be fully traceable through theproject with all documentation accurately reflecting the changes anddevelopments made throughout the project lifecycleFiling Documentation : Reports, MBR with documents for the sterilizationprocessExperience of key personnel and staffValidation of Steam Sterilizers AAPS Arden House 200959

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ChecklistSterilizer DesignSTERILIZER DESIGN ITEMSUnderstanding of sterilizer control system and parameters that will be includedon batch documentationMaterial Flow / Building: floor plan, placement of autoclaves and critical itemsUtilities: clean steam, compressed gasses free of particulates and oil vapor

Mfg of sterilizer, internal volume, jacket pressure, temp, filters used, controlsystem, materials of construction, location of controller sensor, cold spotmonitoring, alarms, and warning alarmsReview PM schedule; How often is steam trap checkedAdequate generation and distribution of Clean steam; any limitationsidentifiedIntegrity testing and sterilization of filters for vacuum breakValidation of Steam Sterilizers AAPS Arden House 200960

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ChecklistSterilization Cycle ItemsSTERILIZATION CYCLE ITEMSProtocols and data summaries that justify steam cycle, demonstrate uniformityreproducibility, conformance to specificationsSterilization process description: Validation info for BI, loading patterns, heatpenetration, results for positive controls + tested BIHeat penetration cycles: load pattern, # of runs, cold spot for each patternMin / Max load configurations: hi/low avg Temp during dwell, min/ max F0,dwell time, run date/time, ID

Time limits established, hold times, sampling instructions, compare loadpatterns with SOP and cycle forms, periodic leak testsProgram to check / monitor Steam Quality; ensure that saturated steam is usedMethods and controls to monitor routine cyclesAny adjustment to cycles for equilibration timesEmpty chamber cycles: # runs, cold spot, allowable variationValidation of Steam Sterilizers AAPS Arden House 200961

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ChecklistBusiness and SOP ChecklistBUSINESS AND SOPS CHECKLISTDocumentation to support Regulatory Filings: supplied in reports or referencedin a DMF with authorization letters; MBRs on pivotal batchesGap Analysis or Documentation that sterilizer is capable of meeting EN285List of registrations and licensesSite inspection historyPrompt delivery of reports and dataConfirm that sterile prep area has documented SOPsProcedural controls: SOP or Cycle sheets to include: load pattern, training,logbooks

Validation SOP, IQ, OQ, PQ, revalidation, Micro programsNumber and distribution of thermal monitors listed in SOPPrep Team for Pre-Approval InspectionTraining: SOPs and Operator training recordsValidation of Steam Sterilizers AAPS Arden House 200962

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RegulatorySome FDA Observations to SponsorsValidation of Steam Sterilizers AAPS Arden House 200963

According to FDA documents, the firm also was written up because equipmentand supplies used to work on, or exposed to pathogenic and potentiallypathogenic agents, were not kept separate from the supplies used in productmanufacturing as necessary to prevent cross contamination"San Diego-based _____________ has been warned by the FDA for notadhering to procedures to prevent microbial contamination of sterile

pharmaceuticals. “These deviations raise significant concerns with sterilityassurance of products that were produced under these conditions,” said theagencyConnecticut-based _______ for its sterile manufacturing practices by the FDA. The agency says the firm has not verified and validated its productionprocesses, including sterilization and packaging of devices. The violations “maybe symptomatic of serious problems in your firm's manufacturing and qualityassurance systems,” according to the letter.

• Validation of Moist Heat Sterilization Processes: Cycle Design, Development,Qualification and Ongoing Control, Technical Report No. 1 Revised 2007, PDAJournal of Pharmaceutical Science and Technology, Vol 61, No S-1• Lewis, Raymond G, Practical Guide to Autoclave Validation, PharmaceuticalEngineering, July/ Aug 2002• EN285:2006+A1, Sterilization – Steam Sterilizers – Large Sterilizers, Amendment 1,March 2008• FDA, Guidance for Industry: Sterile Drug Products Produced by AsepticProcessing — Current Good Manufacturing Practice, Sept 2004

• FDA, Guidance for Industry: Submission Documentation for Sterilization ProcessValidation in Applications for Human and Veterinary Drug Products,• Agalloco, James, Understanding Overkill Sterilization, Pharmaceutical Technology