1. Validating Sterilization of Medical Devices
CDR Martha O’Lone, RN, BSN
Infection Control Devices Branch
DAGID / ODE / FDA
Good Morning- I am Martha O’Lone, a medical device reviewer in FDA’s Office of Device Evaluation /Infection Control Devices Branch.
Ms. Lillian Gill, our Senior Associate Director for Science, gave an introduction to FDA medical device reviews.
I am going to discuss approaches to reviewing medical device reprocessing and how that might relate to devices that would require reprocessing after exposure or potential exposure to CJD.
Hopefully this information will reinforce current knowledge that you have about medical device reviews and will assist with your discussion on the questions that will be presented later in this section.

2. Objectives
Provide background information on sterilization validation for medical devices
Obtain panel guidance on how to design and interpret sterilization validation studies for medical devices after exposure to TSE material
These are the objectives that I hope to accomplish.

3. Questions For prion contaminated critical medical devices:
What is the acceptable sterilization process for prion removal/ inactivation?
What endpoint is appropriate?
Log reduction of infectivity?
Is there an indicator agent for prions?
When I complete this presentation we will hopefully have enough information to address the questions at the end of the time allotted for CDRH.

4. Validating Sterilization of Medical Devices
Spaulding Classification of Medical Devices
Sterilization Methods
Medical Device Reprocessing Steps
Healthcare Sterilization Processes
Medical Device Reprocessing Review
Validation
Available Recommendations/Guidelines
These are the topics that I plan to cover during this presentation

5. Spaulding Classification of Medical Devices
BASED ON RISK OF INFECTION
Critical devices
Enter normally sterile body tissue: e.g., surgical instruments
-Sterilization
Semi- critical devices
Contact mucous membranes: e.g., flexible endoscopes
-Sterilization, if not feasible- Minimally high level disinfection
Non- critical devices
Contact intact skin: e.g., stethoscopes, electrocardiogram electrodes
-Intermediate or Low level disinfection Block, 5th edition
The science behind instrument classification has been described by Spaulding.. Spaulding Instrument Classification is based on risk of infection.
This classification is used in medical device reviews to determine if devices should be subject to sterilization or high level disinfection before use -depending on the area that the device will contact as shown here.
The medical device or product classification that the FDA uses aligns with the Spaulding classification.
Critical devices are those devices that enter normally sterile body tissues- surgical instruments such as scalpels, neuro burrs are an example of devices that would be subject to sterilization prior to use.
Most of this presentation will center on critical devices because areas of concern for CJD such as brain tissue are considered sterile body tissue.
When medical devices are used, their reuse is determined by their design and materials but most heavily by the ability to validate that these devices can be reprocessed.

6. Descending Order of Resistance
???? Prions ????
Bacterial Spores
Mycobacteria
Non-lipid or Small Viruses
Fungi
Vegetative Bacteria
Lipid or Medium-Size Viruses
After considering the Spaulding Classification in medical device sterilization validation reviews, the potential level of resistance of the infectious organism is considered.
This order of resistance provides additional information that should be considered when determining the resistance to reprocessing and the level of resistance that should be validated for a review of a medical device that is to be reprocessed for multiple use.
This slide is not new- it shows that the order of resistance to Prions is thought to be higher than bacterial Spores.
Currently there have been no studies submitted that attempt to validate the safe reuse of medical devices after contamination with CJD.

7. Steps for Medical Device Reprocessing
Cleaning
Required for effective disinfection or sterilization
Goal: Reduce bioburden
Remove organic / inorganic clinical contaminants
High Level Disinfection-semi critical devices
Endpoint- To kill mycobacteria and some spores
Sterilization- critical devices
Validated process used to render a product free of all forms of viable microorganisms (AAMI)
Endpoint- To kill spores (as an indicator microorganism)
The STEPS for Medical Device Reprocessing may include the items in bold: Cleaning, High Level Disinfection or Sterilization.
CLEANING- No standard definition/No standard procedure. Goal is to reduce bioburden by removal of organic and inorganic clinical contaminants.
Next is High Level Disinfection-Although high level disinfection is mentioned in this slide, the focus for this discussion is on reprocessing that is used for critical devices which would be reprocessed after exposure to potential or known CJD
Sterilization for critical device reprocessing as defined by AAMI is a validated process used to render a product free of all forms of viable microorganisms.
Currently the sterilization endpoint is to kill spores, but as the previous slide showed, resistance to prions is thought to be higher than spores.

8. Sterilization Processes Currently Used in Healthcare Settings
Steam (Moist Heat) Sterilization
Gravity displacement cycles - 121ºC, min
Prevacuum cycles – ºC, 3-5 min
Dry Heat Sterilization
Ethylene Oxide (EtO) Sterilization
Liquid Chemical Sterilization
Gas Plasma Hydrogen Peroxide Sterilization Process
These are the sterilization processes that are used in health care settings to reprocess medical devices that are currently on the market and available to the user. The FDA has reviewed devices according to these methods.
Bring to your attention that Steam or Moist heat sterilization is the most common method recommended for prion deactivation and removal.
It is also the most common method used for sterilization of medical devices.
For the Gravity displacement cycles, steam is used at a temperature of 121C for minutes.
The prevacuum cycles use steam temperatures of C for 3 to 4 minutes
It is important to remember that in the U.S., these cycles are fixed in health care and it is rare for the healthcare user to reprogram the sterilizers- This will be important when discussing recommendations for reprocessing devices that are contaminated or potentially contaminated with CJD.

9. Review of Reusable Medical Device Reprocessing
FDA Guidance: Labeling Reusable Medical Devices for Reprocessing In Health Care Facilities: FDA Reviewer Guidance, April, 1996
Labeling for a reusable device that contacts the patient in some manner must include reprocessing instructions
The instructions must indicate the appropriate microbicidal process for the device
Critical - Sterilization
Semicritical – At least high level disinfection
Noncritical – Intermediate or low level disinfection
The reprocessing process must be feasible considering the intended location of reprocessing (e.g., health care facility or home use)
Reprocessing instructions must be validated
If the manufacturer wants to label their product reusable, FDA will ask the manufacturer to follow this 1996 Reusable Labeling guidance.
This guidance recommends clear instructions to the user so that user can properly follow the manufacturers recommendations.
Instructions must include appropriate microbicidal processes for the device
Those reprocessing processes must be feasible- for example- users don’t have access to radiation so that is not a viable method.
The Reprocessing instructions must be validated.

10. Sterilization Validation
Sterilization of critical medical devices
Objective: sterilization process should demonstrate a spore (BI) kill to achieve a sterility assurance level (SAL) of 1x10-6
Standards/Guidance available to provide validation methods for traditional sterilization processes utilizing bacterial spores
As has been stated for medical device reprocessing, the sterilization process should demonstrate a spore (BI) kill to achieve a sterility assurance level (SAL) of 10-6 or twelve log kill as its endpoint for conventional critical medical devices.
For medical devices exposed to potential or known CJD, this current approach to sterilization validation for medical device reprocessing with spores does not provide information that can be applied to removal/ inactivation of prions.
These questions remain- what endpoint is appropriate?
Can log reduction be applied to determine safe use of a medical device and prevent transmission of prion infectivity?
What indicator agent similar to the use of spores should be used for safe validation of sterilization of prion contaminated devices?
Can prion contaminated medical devices and the equipment used in reprocessing in health care facilities be safely used?

11. Sterilization Validation
For prion contaminated critical medical devices:
What is the acceptable sterilization process for prion removal/ inactivation?
What endpoint is appropriate?
Log reduction of infectivity?
Is there an indicator agent for prions?

12. Virus Validation
For medical devices incorporating animal derived tissue
Objective: final product below one infectious particle per 106 devices
Similar to SAL 1 X 10-6 in traditional medical devices sterilization processes
CDRH requires a virus validation study for medical devices that incorporate animal derived tissue.
Since Virus Validation studies for medical devices with animal derived tissues were discussed at this panel’s July 2002 meeting I will not cover it in detail.
For medical devices incorporating animal derived tissue the objective is a final product that is below one infectious particle per devices.
This is similar to an Sterility Assurance Level of 1X10-6 in traditional sterilization processes.
In the case of bacteria, fungi and yeast there are published methods by the FDA, but for virus validation there are published standards but no accepted methods- virus validation is a step by step evaluation of an overall inactivation process that is carried out in a controlled manufacturing setting.
The sterilization of reusable critical medical devices is performed in healthcare settings.

13. Virus Validation Studies
Scaled down (e.g.1/100) manufacturing procedures
Relevant model viruses (DNA, RNA, single and double stranded enveloped and non- enveloped)
Spike virus in different steps in the manufacturing process and determine post- step PFU
Sum the viral clearance values for each manufacturing step
With bacterial inactivation or traditional sterilization of medical devices it’s a full scale sterilization process. These are the details
Virus validation is a model or scaled down approach with different steps in the manufacturing process to inactivate the virus. Then the steps are summarized for a total inactivation process.

14. WHO Recommendations Annex III (For reprocessing CJD contaminated instruments)
Disposable Instruments: Incinerate (and all instruments exposed to high infectivity tissues.)
Heat Resistant Instruments:
Immerse in 1N NaOH
Heat in a gravity displacement autoclave at 121°C for 30 min, or 132º C for 3-5 min
Rinse in water
Routine sterilization process
For Reprocessing CJD Contaminated Medical Devices, The WHO has provided recommendations. These recommendations begin with incineration for disposable instruments and those exposed to high infectivity tissues such as brain.
The most stringent method is listed on this slide.
Yesterday Dr. Brown mentioned his findings and recommendations on device material compatibility with reprocessing in Na OH.
These included the potential for damage or residue on many of the medical device materials tested.
What the list does not do is provide an endpoint or indicator for the heat resistant instruments. No validation method.

15. Draft CDC HICPAC Guidelines for CJD Decontamination
Critical or Semicritical Devices Exposed to High Risk Tissues and/or High Risk patients
Keep instruments wet or damp until they are decontaminated
Options:
1. Clean and sterilize the contaminated devices by immersion in 1N NaOH, remove, rinse in water and autoclave (sterilizer) in an open pan as recommended by WHO at 121° C or 134°C depending on type of sterilizer- gravity displacement or prevac- for 1hr
2. OR immerse instruments in 1N NaOH for 1 hour and heat in a gravity displacement sterilizer at 121°C for 30 minutes, clean; and subject to routine sterilization
3. Clean thoroughly, then autoclave at 134°C for 18 minutes in a prevacuum sterilizer or 132°C for 1 hour in a gravity displacement sterilizer.
Discard contaminated medical devices that are impossible or difficult to clean
Recently CDC’s HICPAC has also made recommendations for CJD contaminated devices. These guidelines are not final.
They do provide some different information such as discard contaminated medical devices that are impossible or difficult to clean.
Options 1& 2 are similar to WHO recommendations. Option #3 is a new recommendation from HICPAC.
HICPAC Health Care Infection Control Practice Advisory Committee