Understanding How Bioburden and Sterilization Affect Medical Devices

Why Understanding Bioburden and Sterilization is Key to

Successful Device Development

Presented by: Aaron Burke -Pacific BioLabs and Jeff Sauter -Nutek Corporation

Hosted by: MDMR

Why Understanding Bioburden and SterilizationIs Key to Successful Device Development – April 2, 2015

What We’ll Be Covering Today

• Bioburden: what is it and how it can affect a device development program and sterilization validation program

• Sterilization: methods and the bioburden-sterilization connection

• Benefits of minimizing the sterilization dose for your device

• Importance of monitoring bioburden

• Case study: sterilization failure and tracking down root cause

• How to monitor and reduce bioburden levels


Why You Need to Know Bioburden

Bioburden and Sterilization Validation testing are not end-stage processes in device development.

Identifying and fixing a problem earlier is almost always better.


Device development requires coordination and fearlessness. It’s like juggling cats.


Sterilization Validation Program Steps

1. Determine the bioburden of your product

2. Select your sterilization method

3. (For radiation sterilization) Dose product samples at verification dose, check for sterility

If your product passes the sterility check after the verification dose, then your sterilization process is validated.

4. Periodically check bioburden, and verify sterilization is effective


Our Ultimate Goal:

Deliver an effective product that is safe to use.


Bioburden 101

Definition: The Bioburden test determines the total number of viable microorganisms in or on a medical device, container or component. It is performed on any product that requires control and/or monitoring of bioburden counts, usually as part of a sterilization program. This test acts as an early warning system for possible production problems that could lead to inadequate sterilization. It is also used to calculate the necessary dose for effective radiation sterilization and to monitor product routinely as part of quarterly dose audits.

Bioburden is NOT a Test Your Product Passes or Fails – it is information


What are “Viable Microorganisms”

Bacteria, Fungi: Yeast/Mold

Typical Microorganisms of Concern:

• Yeast: Candida albicans

• Mold: Aspergillus Niger

• Bacteria:

° E. coli (intestinal disease)

° Pseudomonas (can cause sepsis; common on medical equipment)

° Staphylococcus aureus (staph infection)

S. Aureus from Wikipedia.org

http://en.wikipedia.org/wiki/File:Staphylococcus_aureus_VISA_2.jpg


Bioburden Sources

• Air / particulate matter

• Human handling

• Contact with surfaces

• Contact with liquids (can be particularly dangerous –endotoxins)

• Bioburden can also come from previous use of a device on humans (in the case of reusable devices)


Consequences of Nonsterile Devices:

from CNN.com:

http://www.cnn.com/2015/02/18/health/california-deadly-bacteria/

http://www.cnn.com/2015/02/18/health/california-deadly-bacteria/


Determining Bioburden – part 1

Methods described in ISO 11737

• First: Recovery (determines the best method to extract bioburden)

Factors Affecting Recovery:

° Antimicrobials

° Device geometry (nooks and crevices can impact recovery)


Determining Bioburden – part 2

• Second: Bioburden. Result reported in CFUs

CFU = a single macroscopic colony formed after the successful growth of one or more microorganisms to a solid microbiological growth medium.


Collecting Samples for Bioburden

• Select from production or representative lots

• NO special sampling methods – use product after it has gone through all production processes

Number of Samples Needed

• For large (>1000 products) and frequent production batches: 3 lots of 10 for initial bioburden

• For smaller or infrequent production batches: 10 products needed


Bacteriostasis / Fungistasis

• Some devices possess properties that inhibit the growth of microorganisms

• Bacteriostasis/ Fungistasis test is used to validate the Sterility Test (Dose Verification)

• The B-F test establishes that nothing in or on device inhibits growth of microorganisms which can cause false negatives


Verification Dose Ensures Sterility

• Study verifies irradiation dose is effective.

• Verification Dose at SAL level of 10-2.

• Sterilization Dose is established at SAL of 10-6

• Assuming all standards are met, the process is validated.


Sterilization Validation Methods and Test Samples Needed

• Validation Method

• VDmax versus Method I

• Full Validation versus Single Lot release

• Samples Needed

• Dose Map Study

• Bioburden Determination

• Verification Dosage


Most Common Sterilization Modalities

When applied correctly, EO, Gamma, E-beam/X-ray are all safe and effective technologies for sterilizing medical products, each having its own advantages and disadvantages.

• Ethylene Oxide• Highly reactive Gas Sterilant• Residuals and Environmental Concerns

• Gamma• Radioactive Cobalt 60 • Environmental and Security Concerns

• E-Beam /X-ray• Processing flexibility for Combination Devices and Sensitive Materials• Works quickly (a matter of minutes in small lots) which aids product

efficacy


How Radiation Sterilization Can Affect Devices

• Cross-Linking or Chain Scission

• Oxidation and Discoloration

Key Point: Minimizing damaging changes


Why 25 kGy is Not Always the Answer

• Combination devices and sensitive materials

• Low bioburden levels for these types of devices can be the difference in achieving successful sterilization

• Validating at 20 kGy, 17.5 kGy, 15 kGy


Optimizing Sterilization of Sensitive Materials With E-beam/X-ray

• Material Compatibility

• Customized Processing Conditions

• Dose Uniformity Ratio (DUR)

• MAP (modified atmosphere packaging)


Quarterly Bioburden and Dose Audits

• Frequency of Audits

• Quarterly, with possible reduction in frequency

• Bioburden Testing and Verification Dose

• Augmenting Dose if Product Audit Fails


Case Study-Microfluidic Plates

• Highly sensitive device

• Sterilization successful at Low Dose but not higher Dose levels

• Requires very low Bioburden levels in order to be validated at Dose level requisite for device

• ‘Spikes’ in Bioburden levels


Case Study-Microfluidic Plates

• Process Design

• Monitoring Bioburden

• Implementing Regimented Program to control Bioburden


How to Ensure a Successful Dose Audit

Q: How to we prevent events like in the case study?

A: Know as much about your production environment and process as possible, and potential sources of contamination


An effective program to control microorganism levels in the manufacturing environment is essential to minimize the bioburden on the medical device being manufactured.


Monitoring and Trending Bioburden –part 1

• Environmental Monitoring

• Air quality

• Water quality

• Surface cleanliness

• Product Bioburden Over Time

• Material / component bioburden

• Packaging bioburden



Bioburden Spikes: an unexpected bioburden level well above the mean.

• Common in manually assembled devices

• If bioburden data shows extreme variability, process should be investigated



Setting allowable limits• Alert levels: “An established microbial or nonviable particle level giving

early warning of potential drift from normal operating conditions…” (PDA TR #13)

• Action limits / levels: “An established microbial or airborne particle level that, when exceeded, indicates a process is outside of its normal operating range.” Needs investigations and corrective action.

Resources• ISO 11737 section A 8.5

• PDA Technical Report No. 13 – Fundamentals of an Environmental Monitoring Program


Changes in bioburden levels can alert you to a potential problem before it gets so large that it affects your sterility program.


How Can We Limit and Control Bioburden?

1. Personnel and training programs

• For medical devices, contamination resulting from human handling and contact makes up the bulk of bioburden

Training areas:• Personal hygiene / cleanliness• Patient safety hazards posed by a

contaminated product



2. Cleaning Processes

Areas of Focus:•Production areas•Storage areas•Production equipment

Cleaning Agents:•Sanitizers•Disinfectants •Sporicides

Cleaning agent

InSpec OX Sporicide

http://www.iab-reinraumprodukte.de/en/disinfection-hygienics/sporicide-inspec-ox.html



3. Control of the Device Itself

• Device Storage

• Components – how processed and stored before assembly

Contract manufacturing – may pose difficulties, but important to monitor



4. Device Design – what are some device design choices that can lead to greater bioburden levels?

• Adhesives – selection and use

• Small crevices and nooks in device

• Channels – these can gather microorganisms


In Summary

• Know your device bioburden!• Bioburden levels affect your sterilization program• Bioburden must be monitored and tracked on a regular

basis• Be aware and catch issues before they require corrective

action• Monitoring, training, and controlling production areas are

key

Deliver safe and effective products to people that need them

Thank you for you attention!


References

• Bioburden Testing: ISO 11737-1

• Radiation Sterilization Program Validation: ISO 11137

• Environmental Monitoring: PDA Technical Report No. 13

• General Information:

• Pacific BioLabs Sterility Assurance Compliance Booklet

• Pacific BioLabs Website

• NUTEK Corporation Website

http://www.pacificbiolabs.com/sterility_download.asp

http://www.pacificbiolabs.com/sterility_tests.asp

http://www.nutekcorp.com/

Understanding How Bioburden and Sterilization Affect Medical Devices

Science

Transcript of Understanding How Bioburden and Sterilization Affect Medical Devices