Friday, September 24, 2010

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.
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 withinthe chamber.
The product definition and process definition sections of the new document list things such as product specifications, product families, packaging, re-sterilizationissues, package moisture, stability and potency of container products, re-usablecontainer systems, process challenge devices/PCDs, sterility assurance level/SAL,BIs and CIs, and bioburden determination if necessary. PCDs are described asproducts or items that provide a known resistance to the sterilization process.They are commercially available or may also be created from the user’sproduct line by inserting spore strips, spore dots, inoculated threads, etc.into items or locations that are determined to be the most-difficult-to-sterilizeproduct 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?
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 thedata 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 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 runsto 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 instrumentsused during the study; 7) the approved full-cycle parameters and acceptable placementlocations for BIs for normal processing; and 8) manufacturers’ certificatesof analysis for any items such as BIs, growth media, growth promotion test cultures,etc. Including digital photographs of sterilizer, load, PCD, etc. can be quitehelpful for an auditor who may be reviewing the report at a later date. The completedfinal report packet must then be routed for review and signed for approval.
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 readilyavailable 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 isto 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.
  1. ISO 11134:1994. Sterilization of health care products — Requirements for validation and routine control — Industrial moist heat sterilization.
  2. 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.
  3. AAMI TIR No. 13-1997. Principles of Industrial Moist Heat Sterilization.
  4. PDA Technical Report #1. Validation of Steam Sterilization Cycles. Parenteral Drug Association.
  5. ISO 13485:2003. Medical devices — Quality management systems — Requirements for regulatory purposes.


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    1. Focuses on the validation of laboratory equipments used in the production of pharmaceutical products.
      Determination the requirements of the end user,
      which are often defined in the User Requirements validation is a part of the design validation for a finished device,
      but is not separately defined in the Quality System regulation.

      equipment validation