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Slide 1 of 27
Why Low-Temperature?
A frozen bubble created at -9F by Angela Kelly using homemade bubble solution near her home in Arlington, Washington.
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Sterilization Methods
Traditional
• Dry Heat• Ethylene Oxide• Moist heat or steam• Radiation
Non-Traditional
• Hydrogen Peroxide Gas Plasma (H2O2)
• Ozone (O3)
Novel Non-Traditional
• Chlorine Dioxide• EtO in a bag• High Intensity or
Pulse Light• Microwave Radiation• Sound Waves• UV Light• Vaporized Chemical
Sterilants
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Slide 3 of 27
1976 1997 2002 2008 2011PMN
(510K)K97 510K Guidance
K90 Sterile
Guidance
K90 Sterile
Comment
K97 510K Comment
FDA 510K – Sterilization Guidance Timeline
Food, Drug and Cosmetic Act - Section 510K Pre Market Notification
Medical Device Amendments to Food, Drug and Cosmetic Act of 1997 *1
Clarification on traditional and non-traditional
sterilization methods
Addition of novel non-traditional category
When to submit a 510K for a change to
an existing device*1 Clinton, William J. (21 November 1997). "Statement on Signing the Food and Drug Administration Modernization Act of 1997
Evolution of Submission Process Driven by Technological Innovation
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FDA 2008 - Recommended Review Routing
http://bit.ly/Sterility-Info-for-510k
Early Consultation with FDA: Key to QS Inspection Success
INCB = Infection Control Devices Branch
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Recommended & Required Testing for FDA Submissions
# Test Name # Cycles # Of Samples Notes RequiredOptional
1 Residual 2X 5 samples Run with CytoTox test R
2 CytoTox 2X 5 samples Run with residual test R
3 Animal testing 2X 5 samples Only if CytoTox fails O
4 Physical QC 2X 5-10% of load Verify product & packaging functional after 2X sterilization
R
5 Accelerated Aging 2X Amount product in one shipping carton
Run ASTM “Shake & Bake” test immediately after
R
6 ASTM Shake 1X Amount of product in one shipping carton
Verify package integrity R
7 % Efficiency of Recovery 1X 5 samples minimum non sterile product
Validate extraction method for the Bioburden test method
R
8 Product Bioburden 3X 10 samples each lot Run three different lots, non sterile product
R
9 Product Bioburden versus BI/PCD
1X 20 samples – 10 TSB / 10- FTM
Compare product Bioburden against BI/PCD
O
10 PQ Micro per ISO 14937 Full load with packaging - 3 ½ cycles- 1 sublethal cycle- 3 full production runs
R
11 BI Titer Perform on every BI lot Initial validation lot, all production lots
O
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Medical Device Approval Process
CDRHCenter Director
Communication
Compliance
Device Evaluation
In Vitro
Management Ops
Science
Surveillance
FDA
Commissioner
CBER
CDRH
CDER
Food
Tobacco
Vet Med
Toxicology
Regulatory
ODEDirector
Division of Surgical, Orthopedic and Restorative Devices
Division Of Cardiovascular Devices
Division of Opthalmic, Neurologic and ENT Devices
Division of Reproductive, Gastro-Renal & Urological Devices
Division of Anesthesiology, General Hospital, Infection Control & Dental Devices
Identifying the Right Offices within FDA Critical to Success
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SAL and OverkillSterility Assurance Level (SAL)• Microbiology term to describe the
probability of a single unit being non-sterile after it has been subjected to the sterilization process
• SALs can be used to describe the microbial population that was destroyed by the sterilization process. Each log reduction (10−1) represents a 90% reduction in microbial population.
• A 10−6 SAL (12-log reduction) will reduce a population from a million organisms (106) to very close to zero, theoretically.
Overkill Cycle
3MTM Attest™ Products Sterile U Network - T U T O R I A L SLiving Organisms for Sterility Assurance— Biological Indicators
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ISO 14937:2009 http://bit.ly/ISO14937
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Other ISO Standards
• ISO 11737-1: 2006 – Sterilization of medical devices – Microbiological methods – Part 1: Determination of a population of microorganisms on products
• ISO 11737-2: 2009 – Sterilization of medical devices – Microbiological methods – Part 2: Tests of sterility performed in the definition, validation and maintenance of a sterilization process
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Low-Temp Steam & Formaldehyde• EN 14180:2003 - Sterilizers for medical purposes. Low
temperature steam and formaldehyde sterilizers. Requirements and testing
• BS EN ISO 25424:2011 - Sterilization of medical devices. Low temperature steam and formaldehyde. Requirements for development, validation and routine control of a sterilization process for medical devices
• BS EN ISO 11138-5:2006 - Sterilization of health care products. Biological indicatorsBiological indicators for low-temperature steam and formaldehyde sterilization processes
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Microbial Load Determination(ISO 11737-1:2006)
Packaged Product(non-sterile)
Sample ImmersionIn Media
(sterile container)
Extraction of Bioburden
(shaker)
MembraneFiltration
AerobicBacteria
AnaerobicBacteria
Fungal
Bioburden Enumeration
Transfer
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Sterility Test(ISO 11737-2:2009)
Packaged Product(non-sterile)
Sample ImmersionIn Sterile Media Incubation (14 Days)
PassFail
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Cycle Development• Processes developed are specific to
product/packaging combination. • BIs placed in most difficult to kill
location.• Product, load configuration and
packaging fixed. Bioburden is monitored and controlled.
• No surviving microorganisms after exposure to a reduced level of treatment (as per AAMI/ISO 14937).
• Demonstration that BI is highly resistant to the sterilizing agent relative to the product bioburden (as per AAMI/ISO 14937).
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Process Challenge Devicehttp://bit.ly/Process-Challenge-Devices
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Incubator Validation
What’s different?
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Chemical IndicatorsWarnings:• These are not to be used instead of BIs• Be careful how you store these
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H202 Cycle Safety Margins – 4 Injection
0
1
2
3
4
51 84 167
250
333
416
499
582
665
748
831
914
997
1080
1163
1246
1329
1412
Time
Pero
xide
Con
c.
Dose ResponseSafety
Half-CycleSafety
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Sterilization Validation StepsMaterial
Compatibility
Cycle Development(i.e., fractional cycles)
Calibration & IQ
1 Fractional or Sub-lethal Cycle& 3 Half-Cycles
3 Full-Cycles
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Incubation Reduction StudyBiological Indicator (BI)
With Spores
BI In Sterile Media
IncubationNo Growth
Growth
http://bit.ly/Incubation-Reduction
(3 lots min. of 100)
FractionalCycle
≤80 BIs
≥30 BIs
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Slide 20 of 27
UV Light
Booth 1655 – American Ulraviolethttp://bit.ly/Lesco-UV
http://bit.ly/Honle-UV
Booth 760 – Honle UV America Inc.
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Slide 21 of 27
EtO in a Bag
Booth 3092 – Anderson Productshttp://bit.ly/Anprolene
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Slide 22 of 27
NO2 Sterilization OverviewFeature Parameter Range
Nitrogen dioxide gas sterilant Boiling point 21C
Low sterilant concentration 10 mg/L – 15 mg/L (less than 1%)
Room temperature process Consistent results from 10C to 65C
Humidity reduces cycle time 70% - 80% RH provides rapid lethality, 0% RH requires longer exposure time
Fast cycle exposure times Typically less than 20 minutes, 2.5 hour average total cycle time
Low sterilant residuals Residuals often not measureable, no increase in cytotoxicity observed
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Slide 23 of 27
Noxilizer Booth #675 MDM West
Michael ValentineVP, NA Sales
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H2O2 Sterilization OverviewFeature Parameter Range
Hydrogen peroxide gas sterilant
Boiling point 150.2C
High sterilant concentration 35-90%
Room temperature process Operating temperature of <55C
Humidity reduces effectiveness
Peroxide reacts with moisture and results in positive BIs
Fast cycle exposure times Total cycle times as short as 28 min.
Safe sterilant residuals Residuals are safe at low concentrations (<3%)
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Slide 25 of 27
H2O2 Sterilizers
http://bit.ly/Steris-Amsco
VHP – Vapor Hydrogen Peroxide
Gas Plasma
Booth 2109 – Steris Isomedix
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Q&A
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Slide 27 of 27
Need help with process validation?
Rob Packard
+1.802.258.1881
rob13485
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