steam sterilization validation

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 fullload 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, multipallet-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.

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Validation of Steam Sterilizers Arden House 2009 James Gallagher Kalypsys Inc 1 Validation of Steam Sterilizers AAPS Arden House 2009 Page 2

Introduction to Validation of Steam Sterilizers Goals of Presentation • Overview of basic principles for steam sterilization and microbiology • Review key aspects of EN 285 and PDA Technical

Report #1 • Facilitate decision making for Pharmaceutical Scientists looking to Contract Manufacturing Organization (CMO) for aseptic processing that includes steam sterilization 2 Validation of Steam Sterilizers AAPS Arden House 2009 Page 3

Introduction Outline • Introduction • Sterilizer Design Aspects • Steam / Thermo • Micro Aspects • Validating Sterilization Cycles • Checklist / Troubleshooting

• Regulatory 3 Validation of Steam Sterilizers AAPS Arden House 2009 Page 4

Introduction to Validation of Steam Sterilizers Regulatory Drivers and Guidance Source Document FDA FDA, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice , Sept 2004 CFR Relevant Sections on Sterilization, purity and control EN285 Sterilization – Steam Sterilizers – Large Sterilizers, Amendment 1, March 2008 USP Biological Indicators, Resistance Performance Tests PDA Technical Report #1: Validation of Moist Heat Sterilization Processes: Cycle Design, Development and Ongoing Control Validation of Steam Sterilizers AAPS Arden House 2009

4 Page 5

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 taken into account the level of validation needed • Review the assumptions and risk analysis on the required steam sterilization processes are included; confirm assumptions 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 CMO 5 Validation of Steam Sterilizers AAPS Arden House 2009 Page 6

Introduction to Validation of Steam Sterilizers Three Examples of Contract Services Validation of Steam Sterilizers AAPS Arden House 2009 6

Example of Project Typical Sterilization Needs Driving Forces Early Phase Clinical Program in US Receiving Tank / Bag Documentation for IND Speed to Clinic -- Leverage CMO’s existing cycles / programs WW Phase III Clinical Program

Filter Assembly Filling Line Parts Documentation to support NDA/ CTD and PAI Scale-up Secondary source for Commercial Product Stopper processing Filling Manifold Supplement to NDA / CTD New facility Qualification Equivalency with existing product / package/ process Optimal cycles Page 7

Sterilizer Design Aspects Sterilizer interface with aseptic process • Sterilizers are a critical means to provide access to an aseptic process • Components are prepped /cleaned

prior to sterilization • Dedicated, disposable or multiple use Validation of Steam Sterilizers AAPS Arden House 2009 7 Prep Area (non sterile) Entry Sterilizer #1 Sterilizer #2 Sterilizer #3 Aseptic Processing Suite Aseptic Corridor

Page 8

Sterilizer Design Aspects Autoclave Diagram Validation of Steam Sterilizers AAPS Arden House 2009 8 Page 9

Sterilizer Design Aspects Sterilizer 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 backflow Validation of Steam Sterilizers AAPS Arden House 2009 9 Page 10

Sterilizer Design Aspects Control of a sterilizer • Critical parameters are steam quality, temperature and time

• Temperature sensor is normally in the drain • Automated cycles, sensors monitoring and alarms • Key measurements are temperature, pressure and time 10 Validation of Steam Sterilizers AAPS Arden House 2009

Common Indicators on Sterilizer Controller Door lock (both ends) Cycle in progress / Cycle Complete Fault Cycle selected Cycle counter Cycle Stage Indicator Page 11

Sterilizer Design Aspects Temp 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 time Validation of Steam Sterilizers AAPS Arden House 2009 11

Parameter Temperature Pressure Accuracy of Range 1% over the 50 – 150˚C range < 1.6% over range 0 to 400kPa / (-1 to 3 bar) Accuracy at Sterilization 0.5˚C at sterilization temp +/-5 kPa (0.05 bar) Resolution 0.1˚C for digital 1kPa (0.01 bar) Page 12

Steam / Thermo Steam Overview– why is steam so effective? • Condenses, collapses as wet film of condensation increases 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 of vaporization – 1 L water to boiling = 80 cal – 1 L boiling water to steam = 540 cal 12 Validation of Steam Sterilizers AAPS Arden House 2009 Page 13

Steam / Thermo Steam Enthalpy 13 Validation of Steam Sterilizers AAPS Arden House 2009

Temperature (°C ) Pressure (bar) (psig) Enthalpy of Steam (J/g) (BTU/lb)

100˚ C 1.013 14.7 2,675 1,150 121° C 2.048 29.7 2,707 1,164 126˚C 2.392 34.7 2,715 1,167 134°C 3.039 44.1 2,725 1,171 Page 14

Steam / Thermo Steam Quality / Testing • Steam quality = how much water is contained in the steam % by weight / % by volume • Dryness value = 1.0 for dry saturated steam; less

latent heat capacity for lower steam quality • Pharma sterilization cycles use saturated steam with no superheat, minimal NCG • Clean steam used in Pharma applications; condensate complies with WFI monograph • Understand CMO’s limitations for steam production 14 Validation of Steam Sterilizers AAPS Arden House 2009 Page 15

Steam / Thermo Causes of poor steam quality • Issues with clean steam generator • Water hammer – water slug moving through pipes resulting in a banging sound

• Piping Insulation– prevents steam from condensing • Times of higher steam demand: winter, startup • Condensate in piping: in AM, after a shutdown Validation of Steam Sterilizers AAPS Arden House 2009 15 Page 16

Steam / Thermo Non-condensable gases(NCG) • Gases that cannot be liquefied by compression under the conditions used in a sterilization cycle • NCG do not contract / expand like steam, move to an area 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 7°F • CO 2

can dissolve in the condensate → carbonic acid; corrosive to metal pipes • Oxidation from dissolved 0 2 Validation of Steam Sterilizers AAPS Arden House 2009 16 Page 17

Steam / Thermo Steam Trap • Automatic valve that drains water, vents air, but traps steam in the system, located on drain legs and

steam filters • Located at the bottom of the sterilizer, drains condensate from the jacket and the chamber • Steam traps also used on air vents • Failure mechanisms for steam traps Validation of Steam Sterilizers AAPS Arden House 2009 17 Page 18

Micro Aspects Overview Validation of Steam Sterilizers AAPS Arden House 2009 18

SAL = 10-6 Accumulated Lethality, F0 Biological Indicators Overkill or Bioburden Cycle?

D, z and F values Microbiological Aspects of Sterilization

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Micro Aspects Sterility Assurance Level (SAL) • The probability of a single viable microorganism being present on a sterilized unit is one in one million after 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 10-6 19 Validation of Steam Sterilizers AAPS Arden House 2009 Page 20

Micro Aspects Biological Indicators (BI)

• Population of microorganisms (usually spores) inoculated onto a suitable medium • Placed in sterilizer load locations to determine the sterilization cycle efficacy by deactivating BI • The challenge microorganism is selected based upon its resistance to the given process • Quality of BI defined by microbiological count and D-Value Validation of Steam Sterilizers AAPS Arden House 2009 20 Page 21

Micro Aspects G Stearothermophilus • Geobacillus stearothermophilus

for use in steam sterilization at 121.1°C to 135°C (275°F) • Incubate at 55˚- 60°C • Thermophiles found in hot springs areas such as Yellowstone NP; highly resistant to heat • Most spore forming microbes have Dvalue < 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 2009 21 Page 22

Micro Aspects Inoculation of BI / Positive Controls

• After the sterilization cycle, the retrieved BI is placed in a tube of growth medium and incubated per USP • A color and/or turbidity change indicates the results of the sterilization process, no change in indicates sterilization conditions were achieved, otherwise the growth of the spores indicates that the sterilization process has not been met. “It also should be noted that the resistance of microorganisms can vary widely depending on the material to be sterilized. For this reason, careful consideration should be given during sterilization validation to the nature or type of material chosen as the carrier of the biological indicator to ensure an appropriately representative study” Sept 2004 FDA GUIDANCE.

Validation of Steam Sterilizers AAPS Arden House 2009 22 Page 23

Micro Aspects D-value • D value is the thermal resistance value (min) of a target organism • D value is the time in minutes at a specific temperature to reduce the surviving microbial population by 1-log, or 90% reduction in population. • Typical D-values for commercial spore strip lots are ~1.5 - 2 min Validation of Steam Sterilizers AAPS Arden House 2009 23 Page 24

Micro Aspects

Z Value • Z value is the heat resistance of a spore as a function of temperature (°C) • Z value is the temperature change required to result in a 1-log reduction in D-value • Generally used standard value is Z= 10˚C • Z = (T 2

–T 1

) / (log D 1

– log D 2

) Thermal Resistance Curve Validation of Steam Sterilizers AAPS Arden House 2009 24

D 121

1.6 min D 131

0.16 min D 111

16 min Page 25

Micro Aspects F value, Accumulated Lethality • Accumulated Lethality is the F value •F 0

is the equivalent time that a microbial population with a z value of 10 has been held at 121˚C •1F 0

= the equivalent of 1 minute at 121˚C • Equation; F = Σ 10(T-121.1)/z x t Where T = Temperature F 0

= equivalent sterilization time (min)

• Z = 10˚C is generally used Validation of Steam Sterilizers AAPS Arden House 2009

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Micro Aspects F, D and Z values and their relationships • Equation #1: Log N F

= -F (T,z)

/D T

+ log N 0

• Equation #2: F (T,z)

= (Log N 0

– Log N F

)xD T

• Typical D-values are ~1.5 - 2 min; natural is 15 min) None Air overpressure process. Heat and cool without vacuum 36 Validation of Steam Sterilizers AAPS Arden House 2009 Page 37

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

Load Position Comment Fixed Fixed Identical for all processing runs Instructions list items and position in diagram Fixed Variable Location can vary Validate positional equivalency during runs Instructions reference list of items Variable Variable Location and position can vary Validate minimum and maximum loads Demonstrate min / max are adequate in validation Flexible instructions for Operations Page 38

Validating Sterilization Cycles Types of Saturated Steam Processes • Pre-vacuum process is most commonly used saturated 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 critical Validation of Steam Sterilizers AAPS Arden House 2009 38 Page 39

Validating Sterilization Cycles Cycle 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 T REF

– time T slow

• Drying studies if needed • Correlate F PHY

and F BIO

for cycle Validation of Steam Sterilizers AAPS Arden House 2009 39 Page 40

Validating Sterilization Cycles Determination of Worst Case Load • Determine locations that are worst case with steam integrators 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 flexibility desired in CMO’s Operations • May be a destructive test ; pass through expense Validation of Steam Sterilizers AAPS Arden House 2009 40 Page 41 Validation of Steam Sterilizers AAPS Arden House 2009 41

Validating Sterilization Cycles Definition of Loads – Contract Service Examples Contract Service Goods Type Load OK or Bio? Cycle #1 Vessel Wrapped Fixed Overkill 121˚C saturated steam #2 Filter Wrapped

Fixed Overkill 121˚C saturated steam #3 RTS Closure Wrapped Variable Overkill 121˚C saturated steam Page 42

Validating Sterilization Cycles Example Cycle Overview Validation of Steam Sterilizers AAPS Arden House 2009 42 Page 43

Validating Sterilization Cycles Types of Studies Cycle Description Standard Key Aspects Pressure Rise (Leak Test) < 1.3mbar/min Check prior to thermal studies Monitors rise in pressure under vacuum

Temperature Distribution Empty Chamber Often performed in requal programs Verifies uniform distribution of steam Temperature variation: each probe, probe to probe, probes to set point Item Cool Point Min load Multiple runs if needed Identifies the most difficult to sterilize point in a test article Validation of Steam Sterilizers AAPS Arden House 2009 43

“These uniformity or mapping studies should be conducted with calibrated measurement devices.” FDA Sept 2004 Guidance Page 44

Validating Sterilization Cycles Types of Studies Cycle Description Standard Key Aspects Temperature Distribution Min / Max Load Verifies uniform distribution of steam Temperature variation: each probe, probe to probe, probes to set point

Heat Penetration Max Loads multiple runs Map temperature with TCs Temps as above Equivalency of variable loads using same cycle Maximum equilibration time Used to calculate F PHY

Can be combined with BI challenge study Process Lethality Biological Qualification (BI challenge) Full Load 3 consecutive runs Map temperature with TCs Place BI at probed locations, including most difficult to heat Used to calculate F BIO

Incubate BI post cycle 44 Validation of Steam Sterilizers AAPS Arden House 2009 Page 45

Validating Sterilization Cycles Minimum Acceptable Cycle

• Qualified MAC cycles confirmed biologically and physically • Safety margin through use of higher exposure times or temperatures • Total Dwell Time is additional lethality + demonstrated lethality from process validation • Half cycle methods Validation of Steam Sterilizers AAPS Arden House 2009 45 Page 46

Validating Sterilization Cycles Acceptance Criteria Guide • Thermal Systems • Process Cycles

• Reference Tests • EN285 Steam quality items Validation of Steam Sterilizers AAPS Arden House 2009 46 Page 47

Validating Sterilization Cycles Acceptance Criteria–Thermal Systems Aspect Standard TC Temperatures during Dwell Time All temps during dwell time within 3˚C (-1˚C /+2˚C) of SP TC Temperatures during Dwell Time Fluctuation of TCs within chamber NMT 1˚C TC Temperatures during Dwell Time All temps measured in chamber do not differ from each other by 2˚C Steam Temperature Corresponds to its vapor pressure measurement Equilibration Time Lag between hottest / coldest thermocouples is NMT 30 sec (15 sec for smaller chamber) Timer Accuracy

+/- 1% Pre and post calibration check Temp measurement system is accurate to +/-0.5˚C Validation of Steam Sterilizers AAPS Arden House 2009 47 Page 48

Validating Sterilization Cycles Acceptance Criteria– Process Cycles Validation of Steam Sterilizers AAPS Arden House 2009 48

Aspect Standard Concerns Temperature Distribution Minimum F 0

met for TCs Correlate T and P Acceptable number of TCs Heat Penetration Determine most difficult to sterilize item / desired load Air removal, large mass, length of hoses F 0

Range

Min F 0

at end of exposure Max equilibration time Microbial Inactivation during BI challenge No BI growth Growth with + control SAL = 10-6 Positive control of BI SOPs for handling BI Comparison of F PHY

and F BIO

Agreement for minimal cycle Page 49

Validating Sterilization Cycles Acceptance Criteria – Reference Tests Aspect Standard Load Dryness Mass increase < 1% Textiles test pack Mass increase < 0.2% Metal test pack Dynamic Pressure Test Average pressure change NMT 10 bar/min for any 3

second interval Sound Power Sound level meter reading NMT 3dB change from original operating level Validation of Steam Sterilizers AAPS Arden House 2009 49

• Reference tests performed during validation of cycle, revalidation and in periodic / routine tests • Most test are done on an empty chamber Page 50

Validating Sterilization Cycles Acceptance Criteria – Reference Tests II Aspect Standard Thermometric Tests (Full Load) Equilibration time NMT 30 sec (large) TCs within +3°C of sterilization temp Minimum hold time at sterilization temp Temps within 2°C during hold time

Chamber steam temp corresponds to pressure Bowie and Dick Test Uniform change of indicator color Air Leakage Flow Rate NMT 1.3mbar/min Air Detector (if present) Alarms if