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

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

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

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, ……..

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

RESPONSIBILITIES OF CONTRACT 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

RESPONSIBILITIES OF CONTRACT 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

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

TESTING LABORATORY Manufacturing Facility Contract Laboratory Contract Sterilizer

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

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

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

BIOBURDEN Webster’s Medical Device 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

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

BIOBURDEN METHODS Pour plating Spread plating Membrane filtration Automated microbiology systems

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

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

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

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

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

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

DEVICE PACKAGING 21 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”

DEVICE PACKAGING 21 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

PACKAGE INTEGRITY TESTS Dye Penetration Microbial Challenge Burst Creep Seal peal

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

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

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

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

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

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

WATER TESTS Choice of Media Choice of Incubation Temperature 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

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