REUSABLE MEDICAL DEVICE VALIDATION

All sterilization processes require validation of the efficacy and reproducibility of the process. Depending on the type of sterilization, this may be accomplished by partial, sub-lethal, or repetitive processing, using representative product and/or biological indicators. AppTec offers a full range of services in this area, from testing alone to full management of the validation. REUSABLE MEDICAL DEVICE VALIDATION The FDA expects manufacturers to validate all reuse instructions including cleaning and disinfection procedures, cycle parameters, and aeration times, if applicable. AppTec offers a comprehensive program for evaluation of cleaning and sterilization processes for reusable medical devices. Your AppTec Account Manager can provide you with initial information regarding any of these testing programs. Also working closely with you will be a highly trained and knowledgeable technical expert. IN THIS SECTION EO Half Cycle Sterilization Validation Determination of Bioburden Bioburden Recovery Validation Repetitive Recovery Bioburden Recovery Validation Inoculation method Fractional Cycle Studies Inoculated Biological Indicators USP Product Sterility Test Bacteriostasis/Fungistasis Terminal Sterilization Studies Biological Indicators EO Residual Testing EO Residual Panel Water Extraction EO Residual Panel Headspace Extraction ISO 11135 Performance Qualifications: Sensor and BI Requirements [Chart] Radiation Sterilization Validation Testing Requirements (per ISO and AAMI Standards) [Chart] AppTec s Radiation Sterilization Validation Programs AppTec s Dose Audit Programs Reusable Medical Device Validation H-1

EO HALF CYCLE For validation of ethylene oxide (EO) sterilization, certain steps must be followed as outlined in ISO and AAMI standards. As part of the performance qualification, a microbiological challenge must be performed to demonstrate the adequacy of the process to achieve the desired sterility assurance level (SAL). One of the most utilized methods is the half-cycle (overkill) method, which uses a biological indicator (BI) challenge, typically 10 6 spores of Bacillus subtilis. Complete EO validation studies can be designed for a particular product and process, and all aspects of the studies follow the requirements of ISO and AAMI standards. NOTE: Samples for EO Half Cycle Sterilization Validation testing should be shipped to AppTec s St. Paul facility. ESTIMATED TOTAL TESTING TIME: 4-6 weeks DETERMINATION OF BIOBURDEN 1601000 Bioburden Recovery Efficiency - Repetitive Recovery Method OR 1602000 Bioburden Recovery Efficiency Spore Inoculation Method Devices are selected at random for the bioburden recovery validation. They must be representative of the Worst Case Representative Family Designs being tested, but need not be identified with the production batches being used for validation. 5-10 products For more information on these tests, see Page A-3. 1603010 Non-sterile devices are tested for bioburden. Aerobic Bioburden Panel Minimum 10 products FRACTIONAL CYCLE STUDIES [1 PARTIAL AND 3 HALF CYCLES] 1203000 Inoculated Biological Indicators Twenty (20) samples will contain the microbial challenge system (process challenge device) inoculated in the device's most difficult area to sterilize. The BI seeded samples can be simulated products if they are wholly representative of the actual finished product. 80 products (four sets of 20) [See table on next page for sample size if chamber is larger than two (2) pallets.] USP Product Sterility Test 1220010 Extra Small [ 100 ml of media] Twenty (20) product samples are removed from the load for sterility testing. (A minimum of 40 extra samples should be retained in the event a retest is required.) 20 products 1220000 Small [101 to 200 ml of media] 1226000 Medium [201 to 400 ml of media] 1227000 Large [401 to 600 ml of media] 1228000 Extra Large [601 to 1200 ml of media] H-2

EO HALF CYCLE Sample device or material is tested for growth inhibition using the current USP organisms for Soybean-Casein Digest Medium (SCDM) and Fluid Thioglycollate Medium (FTM). (Additional organisms available upon request.) 6 products 190105 Bacteriostasis/Fungistasis TERMINAL STERILIZATION STUDIES A minimum of five samples per pallet, but at least 10 samples per cycle will contain inoculated carriers (spore strips). These carriers will be tested for sterility according to client specifications and/or the USP. Set of 10 [See table below for sample size if chamber is larger than two (2) pallets.] 1201000 Biological Indicators EO RESIDUAL TESTING Samples from the terminal sterilization cycle will be tested for ethylene oxide residuals at incremental time periods. Suggested time periods are: immediately after sterilization, one day post-sterilization, three days post-sterilization, five days post-sterilization, and seven days post-sterilization. Additional time increments may be required and will be identified in the final report. Varies 195000 EO Residual Panel Water Extraction OR 194500 EO Residual Panel Headspace Extraction ISO 11135 Performance Qualifications: Sensor and BI Sample Requirements LOAD DIMENSIONS 15 11 9 7 3 2 30 Cu. Ft. 25 Cu. Ft. Width 48 48 48 48 42 42 21 23 Length 48 48 48 48 48 48 60 51 Height 78 78 78 75 72 72 30 35 Cubic Feet 1560 1144 936 700 252 168 22 24 PERFORMANCE QUALIFICATIONS COMMISSIONING/PHYSICAL Preconditioning: TC/RH Sensor 40/19 29/14 25/12 19/9 9/4 7/3 5/2 5/2 Empty Chamber Temperature Profile: TC Sensor 20 20 20 20 12 10 10 10 Conditioning: TC/RH Sensor 20/19 20/14 20/12 20/9 12/4 10/3 10/2 10/2 MICROBIOLOGICAL Biological Indicators (BI) 54 42 37 30 24 20 20 20 ROUTINE PROCESS Biological Indicators (BI) 27 21 19 15 12 10 10 10 TC = Thermocouples RH = Relative Humidity H-3

RADIATION STERILIZATION VALIDATION For validation of radiation (gamma, electron beam or x-ray) sterilization, certain steps must be followed as outlined in ISO and AAMI standards. As part of the performance qualification, a dosesetting or dose substantiation study must be performed to demonstrate the adequacy of the minimum dose to achieve the desired sterility assurance level (SAL). Several methods are available for validation of the minimum SAL dose, and the choice of method is dependent on a number of variables. Complete radiation validation studies can be designed for a particular product and process, and all aspects of the studies follow the requirements of ISO and AAMI standards. AppTec offers three levels of service programs for sterilization validations, as well as two levels of service programs for dose audits. For descriptions of these programs, see following pages. NOTE: Samples for radiation sterilization validation testing should be shipped to AppTec s Atlanta facility. TEST NAME SAMPLES REQUIRED TEST DESCRIPTION AAMI/ISO 11137 Method 1 Validation TOTAL TURNAROUND TIME: 4-6 weeks Total Bioburden Panel 10 products from first batch Page A-3 Aerobic Bioburden Panel 10 products each from 2nd & 3rd batches Page A-2 Bioburden Recovery Efficiency Test 3-5 products from any batch Page A-3 Bacteriostasis / Fungistasis One Medium 3 products from any batch Page A-8 Product Test of Sterility 100 samples from one batch Page G-6 Dose Audit Aerobic Bioburden Panel 10 products from one batch Page A-2 Product Test of Sterility 100* samples from one batch Page G-6 AAMI/ISO Method 2 Validation TOTAL TURNAROUND TIME: 6-7 weeks The requirements of Method 2 are not outlined here because of the complexity of the sampling scheme. Please contact the laboratory for more information. Dose Audit Aerobic Bioburden Panel 10 products from one batch Page A-2 Product Test of Sterility 100* samples from one batch Page G-6 * Reduced number of samples may apply. Contact laboratory. H-4

RADIATION STERILIZATION VALIDATION TEST NAME SAMPLES REQUIRED TEST DESCRIPTION AAMI TIR 27 (25 kgy) Validation TOTAL TURNAROUND TIME: 4-6 weeks Total Bioburden Panel 10 products from one batch Page A-3 Aerobic Bioburden Panel 10 products each from 2nd & 3rd batches Page A-2 Bioburden Recovery Efficiency Test 5-10 products from one batch Page A-3 Bacteriostasis / Fungistasis One Medium 3 products from any batch Page A-8 Product Test of Sterility 10 samples from one batch Page G-6 Quarterly Dose Audit Aerobic Bioburden Panel 10 products from one batch Page A-2 Product Test of Sterility 10 samples from one batch Page G-6 ISO/TR 13409 (25 kgy) Validation TOTAL TURNAROUND TIME: 4-6 weeks Total Bioburden Panel 10 products from one batch Page A-3 Bioburden Recovery Efficiency Test 5-10 products from one batch Page A-3 Bacteriostasis / Fungistasis One Medium 3 products from any batch Page A-8 Product Test of Sterility 10 samples from one batch Page G-6 Quarterly Dose Audit Aerobic Bioburden Panel 10 products from one batch Page A-2 Product Test of Sterility 10 samples from one batch Page G-6 AAMI/ISO 15844 Single-Batch Validation TOTAL TURNAROUND TIME: 4-6 weeks Total Bioburden Panel 10 products from batch Page A-3 Bioburden Recovery Efficiency Test 5-10 products from batch Page A-3 Bacteriostasis / Fungistasis One Medium 3 products from batch Page A-8 Product Test of Sterility 100* samples from batch Page G-6 H-5

RADIATION STERILIZATION VALIDATION PROGRAMS To help clients get their products through the validation process, AppTec offer three levels of service options for validation studies and two levels of service options for dose audits each with varying degrees of involvement. Your choice of service levels would depend on how much of your company s time, manpower and expertise you want to commit to your validation program. With the Level 1 option, we provide only the testing services. You schedule and manage all aspects of the irradiation services and you pull together all the documentation to present an organized study. With Level 2, in addition to the testing, we handle all the irradiation services. However, you are still responsible for producing the final documentation. With Level 3, we take care of everything. You simply choose the validation method, give us your product samples, and 4 to 6 weeks later we give you a completed validation and finished manual. These programs are conducted by AppTec s Atlanta facility. Contact your Account Manager for more information. : Dependent on method. See charts on Pages H4 H5. VALIDATION PROGRAMS LEVEL 1 Testing Services We perform the full panel of the specific tests required by the particular validation method you have chosen AAMI/ISO Method 1, Method 2, the 25 kgy Method, or the Single-Batch Method. [See charts on Pages H-4 and H-5.] LEVEL 2 Testing Services + Irradiation Services We perform all the required testing plus we provide the verification irradiation services we compute the dose calculations, coordinate all interaction with the sterilizer, ensure that samples are irradiated at the verification dose, and provide the confirmation of irradiation. LEVEL 3 Total Management of the Validation Study We perform all the required testing, provide verification irradiation services and produce a manual that includes the protocol, test reports and supporting documents as attachments to protocol, the official AAMI / ISO standards, irradiation documentation (instructions, dose certificates, etc.), and a final report summarizing the study. H-6 RADIATION STERILIZATION

VALIDATION PROGRAMS Most products that are validated for radiation sterilization require periodic dose audits. AppTec offers two levels of service options for performing these audits. DOSE AUDIT PROGRAMS Testing Services We perform all the tests required for a particular dose audit. LEVEL 1 Testing Services + Irradiation Services We perform all the required testing plus we provide dose audit irradiation services and a dose audit summary. The summary contains the steps of the dose audit, provides a conclusion, and includes reports and supporting documents. LEVEL 2 DOSE AUDIT REMINDER PROGRAM The dose audit requirements for Method 1 and Method 2 validations now allow for reduction in the number of verification samples as well as a reduction in the frequency, based on certain criteria. AppTec offers a dose audit reminder program that informs clients of their options and issues reminders when dose audits are due for each product or family of products. TEST CODES VALIDATION METHOD CODES DOSE AUDIT CODES LEVEL 1 LEVEL 2 LEVEL 3 LEVEL 1 LEVEL 2 AAMI/ISO 11137 Method 1 200100 200110 200120 200130 200140 AAMI/ISO 11137 Method 2 200300 200400 200600 200800 200900 AAMI TIR 27 (25 kgy) Method 200101 200102 200121 200131 200141 ISO13409 (25 kgy) Method 200150 200160 200170 200180 200190 AAMI/ISO 15844 Single-Batch Method 200200 200500 200700 N/A N/A NOTE: These test codes are for prepackaged/bundled programs. Clients may select services within any level. REUSABLE MEDICAL DEVICE VALIDATION H-7

When reusable medical devices are cleaned and sterilized in a health care facility, manufacturers are responsible for providing their customers with complete and comprehensive written instructions for handling, cleaning, disinfection and sterilization. The FDA expects manufacturers to validate all reuse instructions including cleaning and disinfection procedures, cycle parameters, and aeration times, if applicable. AppTec offers a comprehensive program for evaluation of cleaning and sterilization processes for reusable medical devices. Testing follows the guidelines outlined in the AAMI Technical Information Report No. 12 ( Designing, Testing & Labeling Reusable Medical Devices for Reprocessing in Health Care Facilities: A Guide for Device Manufacturers ). This program assists the manufacturer in meeting the requirements of the FDA Reviewer Guidance: Labeling Reusable Devices for Reprocessing in a Health Care Facility. All samples for reusable medical device testing should be shipped to AppTec s St. Paul facility. Protocol Development A custom protocol is written for each study, tailored specifically to the device and the manufacturer s instructions for reuse. AppTec s scientific staff assists clients in designing cleaning processes and developing protocols. Cleaning Efficacy Studies Manufacturers must verify the efficacy of their recommended cleaning processes. Following the manufacturer s cleaning instructions, this study tests those processes using simulated soil inoculated with bacterial spores. Sterilization Efficacy Studies Manufacturers must provide health care facilities with detailed sterilization instructions for their particular medical device. Sterilization parameters are tested to determine capability of producing a sterility assurance level of at least 10-6. Studies are available to evaluating the following sterilization processes: Liquid chemical sterilants Sterrad (H 2 O 2 ) Ethylene Oxide (EO) Pre-vacuum, steam (121-123 C and 132-135 C) Gravity, steam (121-123 C and 132-135 C) Support for Functionality Studies These studies involve exposure to multiple cleaning and or sterilization cycles as part of the functionality studies required to determine the useful life of a device. For more information on reusable device validation testing, contact your Account Manager. H-8