SELECTING AND MANAGING CONTRACT STERILIZERS AND TESTING LABORATORIES

1. SELECTING AND MANAGING CONTRACT STERILIZERS AND TESTING LABORATORIES Pacific BioLabs Inc. (510) 964-9000 info@PacificBioLabs.com

2. CONTRACT STERILIZERS • Written agreement between the contract sterilizer and the device manufacturer is required by 21 CFR- 801-150(e), Medical Devices, processing, labeling or repacking

3. WRITTEN AGREEMENT MUST INCLUDE: • Instructions for maintaining proper records • Acknowledgement that the device is non-sterile and awaiting processing • Detailed specifications for the sterilization process • Division of responsibilities

4. DIVISION OF RESPONSIBILITY • The device manufacturer is ultimately responsible for the sterility of its products • The contract sterilizer is responsible for a quality control system for steps under its control • Therefore, ……..

5. RESPONSIBILITIES OF MANUFACTURER • Ensure devices are sterile by confirming quality control system of contractor • Validation of the process • Ensure process controls are appropriate • Maintain records of specification & evidence they were followed • Product release

6. RESPONSIBILITIES OFCONTRACT STERILIZER • All requirements of the quality system regulation that apply to its operations • Equipment installation, maintenance, and equipment calibration • Installation and operation qualifications • Building adequacy • Personnel training • Environmental controls

7. RESPONSIBILITIES OFCONTRACT STERILIZER (cont.) • Quality system requirements: • Process controls • Documentation and record keeping • Acceptance of manufacturing materials • Procedures for handling process deviations • Any other requirement of the written agreement

8. COMMON PROBLEMS FOUND BY FDA • Manufacturer does not assume responsibility for sterilization performed by the contract sterilizer • Communication between the two parties of changes • Product is released following sterilization without approval of device manufacturer

9. TESTING LABORATORY • Manufacturing Facility • Contract Laboratory • Contract Sterilizer

10. LAB ATTRIBUTES • Quality System • SOP • Calibrated equipment • Training • FDA Track Record • Experienced Personnel • Industry Reputation • Committed Client Services

11. STERILIZATION QUALITY TESTS • Bioburden • Bioburden Recovery Validation • Sterility • Bacteriostasis and Fungistasis • Biological Indicators • Pyrogen or Bacterial Endotoxin • Inhibition and Enhancement

12. STERILIZATION QUALITY TESTS (cont.) • Package Integrity • Chemical Residuals • Environmental Monitoring • Microbial Identification

13. BIOBURDEN • Webster’s • bio (Greek) – life, living • burden – that which is carried, load • Medical Device • Population (number and types) of viable microorganisms on a product and/or a package

14. BIOBURDEN TEST • Three steps • Removal of microbes from a product • Culturing on a medium appropriate for growth • Enumeration • Bioburden Recovery Validation • Demonstrates the adequacy of the steps above

15. BIOBURDEN METHODS • Pour plating • Spread plating • Membrane filtration • Automated microbiology systems

16. STERILITY TESTS • Product Sterility • Membrane filtration • Direct transfer • Biological Indicators (BI) Sterility • Testing the BI by placing it in microbiological growth medium

17. STERILITY TEST VALIDATION • Bacteriostasis and Fungistasis (B & F) • Test using known organisms to demonstrate whether the combination of the product and sterilization method do or do not inhibit microbial growth

18. STERILITY TESTUSP vs. AAMI/ISO • USP • Two microbiological media • SCDM and FTM • B&F (6 organisms) • AAMI/ISO • One microbiological medium • SCDM • B&F (3 organisms)

19. BIOLOGICAL INDICATOR TESTS • Three quality attributes may be measured: • Species identification • Population • Resistance • D-Value • Z-Value

20. BACTERIAL ENDOTOXIN TEST • Endotoxin = Pyrogen • Bacterial Endotoxin Test = LAL Test • Gel clot method • Photometric techniques • Photochromogenic • Turbidimetric

21. INHIBITION AND ENHANCEMENT TEST • Validation of the LAL test • 3 lots of product must be tested

22. DEVICE PACKAGING21 CFR 820.130 “Each manufacturer shall ensure that device packaging and shipping containers are designed and constructed to protect the device from alteration or damage during the customary conditions of processing, handling, and distribution”

23. DEVICE PACKAGING21 CFR 820.130 • Package integrity is required to maintain the microbial barrier and sterility of the product • Expiration dating • Required for IVD’s and certain other devices that may degrade over time • If label includes expiration, you must have data to back it up

24. PACKAGE INTEGRITY TESTS • Dye Penetration • Microbial Challenge • Burst • Creep • Seal peal

25. CHEMICAL RESIDUALS(EO ONLY) • EO (ethylene oxide) • ECH (ethylene chlorohydrin) • EG (ethylene glycol) • No longer required

26. ENVIRONMENTAL MONITORING • Conducted in-house • Laboratory field technicians conduct sampling at manufacturing facility • Samples collected by sponsor’s personnel and incubated/counted at testing laboratory

27. ENVIRONMENTAL MONITORING TESTS • Non-viable particles • Viable particles • Bacteria • Soybean Casein Digest Medium (SCDM) • 30 – 35 °C • Yeast and Mold • Sbouraud Dextrose Agar (SDA) • 20 – 25 °C • Growth promotion required

28. MICROBIAL IDENTIFICATION • Morphological characterization • Colony description, Gram stain • Identification to genus and species level • Phenotypic • Genotypic

29. MICROBIAL IDENTIFICATION • Biochemical Tests • Vitek • Fatty Acid Analysis • MIDI • Carbon Utilization • Biolog • Genetic Based Technology (preferred) • RiboPrinter

30. MICROBIAL WATER TESTS • Total Heterotrophic Counts • Yeast and Mold Counts • Coliform Determinations • Thermophiles Counts • Anaerobes counts • Pseudomonas screening

31. WATER TESTS • Choice of Media • Plate Count Agar • Soybean Casein Digest Agar • R2A • Tryptone Glucose Extract • Choice of Incubation Temperature 30-35°C, 20-25°C • Choice of Incubation Times 2, 3, 5 or 7 days

32. THANK YOU Q & A