Why Low-Temperature?

Robert Packard, Consultantwww.MedicalDeviceAcademy.com

[email protected] 12, 2014

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.

http://www.medicaldeviceacademy.com/




Slide 2 of 27

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





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



http://www.presidency.ucsb.edu/ws/index.php?pid=53607

http://www.presidency.ucsb.edu/ws/index.php?pid=53607



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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



http://bit.ly/Sterility-Info-for-510k



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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



http://bit.ly/ISO14937

http://bit.ly/ISO14937



Slide 9 of 27

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



http://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



http://bit.ly/Incubation-Reduction



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UV Light

Booth 1655 – American Ulraviolethttp://bit.ly/Lesco-UV

http://bit.ly/Honle-UV

Booth 760 – Honle UV America Inc.



http://bit.ly/Lesco-UV

http://bit.ly/Honle-UV



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EtO in a Bag

Booth 3092 – Anderson Productshttp://bit.ly/Anprolene



http://bit.ly/Anprolene



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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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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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H2O2 Sterilizers

http://bit.ly/Steris-Amsco

VHP – Vapor Hydrogen Peroxide

Gas Plasma

Booth 2109 – Steris Isomedix



http://bit.ly/Steris-Amsco



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Q&A





Slide 27 of 27

Need help with process validation?

Rob Packard

[email protected]

+1.802.258.1881

rob13485



Why Low-Temperature?

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