Dose Audits 101 Copyright 2016 Quality Tech …...Your production dose is always a range, for...
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Copyright 2016 Quality Tech Services, Inc. Dose Audits 101 February 4, 2016
Dose Audits 101 Copyright 2016 Quality Tech …...Your production dose is always a range, for example 25-40 kGy. The dose substantiation study seeks to prove that if the minimu\൭
• Member of AAMI working groups • WG2 – Radiation Sterilization
• WG8 – Microbiological Methods
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• Section 1: What is a Dose Audit? • Section 2: Why are Dose Audits Required? • Section 3: How are Dose Audits Performed? • Section 4: Timing and Scheduling • Section 5: Challenges with Dose Audits
Outline
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What?
Ethylene Oxide (EO)
Gamma
E-Beam X-Ray Other
Medical Device Sterilization Methods (single-use)
Presenter
Presentation Notes
Before we get into directly answering what a dose audit is, we’ll go over some background in sterilization and how dose audits fit into the grand scheme of things Here’s a chart of the most common sterilization methods for medical devices that are terminally sterilized – this would not include reusable devices that you might see in hospitals Common industry knowledge puts the breakdown in sterilization methods anywhere from 50-55% EO, 40-45% Gamma, 3% E-Beam, 1% other (Steam, Chemical, X-Ray) Everyone that is currently sterilizing their product by radiation (gamma, e-beam, & x-ray) is performing dose audits on a routine basis – that’s a lot of medical device companies!
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• Purpose of sterilization is to prove a Sterility Assurance Level (SAL)
• Radiation sterilization = dosage (measured in kGy)
What?
106
101
100
10-1
10-6
Sterilization Dose (or Time)
Ster
ility
Ass
uran
ce L
evel
(SAL
)
1 in 10 are non-sterile
1 in 1,000,000 are non-sterile
pre-sterilization
Presenter
Presentation Notes
The reason you sterilize your medical devices is that you need them to be sterile for patients. Today we’re focusing on one of the most common ways to sterilize medical devices, radiation, which is measured by dosage being radiated or penetrating into the product. The measurement units used in radiation are KiloGray, abbreviated kGy. Sterility Assurance Level (SAL) is a probability. When you hear someone say they’re looking for a 10-6 SAL, that means that they’re looking for the probability that 1 in 1 million devices has a single microorganism on it / is non-sterile. Dosage to product depends on how long you expose it to radiation, which is directly proportional to your SAL. Longer exposure to irradiation means that the greater the sterility chances for each device become. Looking at the chart, we’re focusing on a couple points: 10-1 means 1 in 10 would be non-sterile 10-6, which is the most commonly accepted for production devices means that 1 in 1 million devices would be non-sterile
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• Audit of the sterilization Dose
• Dose audits prove efficacy of radiation sterilization through an abbreviated sterilization event, followed by tests of sterility
What?
106
101
100
10-1
10-6
Sterilization Dose (or Time)
Ster
ility
Ass
uran
ce L
evel
(SAL
)
1 in 10 are non-sterile
1 in 1,000,000 are non-sterile
pre-sterilization
Dose Audits Performed Here
Routine Sterilization
Presenter
Presentation Notes
How it gets its name is that it is an AUDIT of the sterilization DOSE Looking again at the graph, your dose audit samples are sterilized at a much lower dose (10-1), and then the dose audit results mathematically prove the sterility odds for your 10-6 production dose.
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• Section 1: What is a Dose Audit? • Audit of the sterilization Dose • Longer/higher exposure increases sterilization probability
• Section 2: Why are Dose Audits Required? • Section 3: How are Dose Audits Performed? • Section 4: Timing and Scheduling • Section 5: Challenges with Dose Audits
Outline
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• Production dosage is always a range (e.g. 25-40 kGy) • Dose substantiation study is completed to establish the
minimum sterilization dose (e.g. 25 kGy) • Following completion of dose substantiation study, dose
audits are required by the ISO standard.
Establish Families
Establish Bioburden
(3 Lots)
Initial Verification
(1 Lot)
Dose Audit Bioburden
(1 Lot)
Dose Audit Verification
(1 Lot)
Dose Substantiation Study Dose Audits
Why?
Presenter
Presentation Notes
Your production dose is always a range, for example 25-40 kGy. The dose substantiation study seeks to prove that if the minimum dose of that range is delivered to the product (for example 25 kGy), your product would still be sterile. As a general note, the Dose substantiation study is often referred to as the “sterilization validation”. It’s not quite the sterile validation because it doesn’t include all steps that would make it a full validation. This would apply to all radiation - gamma, e-beam, and X-Ray. Following the completion of your dose substantiation study, you’d do dose audits routinely per the standard. Visualizing this sequentially, your dose substantiation study would cover the establishment of family, 3 lots of bioburden, 1 lot of sterility, then your dose audits would be just 1 lot of bioburden and 1 lot sterility (it’s essentially the same testing, just abbreviated).
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• ISO 11137-1 – Sterilization of health care products – Radiation – Part 1: Requirements for development, validation and routine control of a sterilization process for medical devices Section 12.1.1: The continued effectiveness of the established sterilization dose shall be demonstrated through the conduct of A) Determinations of bioburden to monitor the number of
microorganisms on product B) Sterilization dose audits to monitor the radiation resistance of the
bioburden on product
Why?
Presenter
Presentation Notes
Here’s the exact verbiage from the ISO standard that says you have to do dose audits. In ISO Standards, whenever it uses the term “Shall”, it means you have to do it.
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• Effectiveness of radiation sterilization is dependent on bioburden
• Dose audits can detect shifts in bioburden counts and/or resistance
Why?
Increased Resistance Increased Counts
Presenter
Presentation Notes
You need to continually audit your dose because the sterility of your product depends on it. Your dose substantiation study evaluated 3 separate lots of bioburden and their expected radiation resistance in order to substantiate that minimum dose. Bioburden can change over time, dose audits are effective for monitoring any potential shifts. Examples: Increased Counts: The microorganism is starting to invite his friends over to a party happening on your device. Increased Resistance: The microorganism didn’t invite any friends over, but he started hitting the gym, so he gets more resistant to sterilization. Either of these shifts might lead to your product being more difficult to sterilize. Dose audits can prove that neither of these shifts have caused that to happen.
First you need to select your samples. 20 samples required if you use Vdmax. Vdmax is by far the most common dose audit method, because it is the most cost effective and requires the fewest number of samples. If you use another method like method 1, method 2a, or method 2b, the sample requirements would be much higher but the same principles would apply. It is required that samples are all from the same lot. Example: You have a family of 1000 screws configurations that only differ by size. You would NOT need to do a dose audit on every configuration to mark them sterile. You would pick representatives (determined in initial dose substantiation study), selected through one of three methods – master product, equivalent product, or simulated product.
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• All the same general features and materials • Bigger, more bioburden • “worst case”
How? Master Product
Presenter
Presentation Notes
Master Product – all same general features, materials, vendors, but one product captures everything or is biggest. One product is a “worst case” scenario. Example: A QTS customer produces a product that has configurations that come in 1, 5, and 10 packs. We always test the 10 packs since it is worst-case.
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How? Equivalent Product
• Same but slightly different • Mirror images • Different finishes
Presenter
Presentation Notes
Equivalent Product – the only differences are just different anodizing finishes, thread patterns, etc. but each would have the same bioburden. Example: QTS works with an orthopedic company that has around 200 screw configurations that are basically the same, so whenever a dose audit is due we just test whatever is currently in production.
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• Something you wouldn’t normally produce/sell • Represents equal or greater bioburden for each product
being represented
How? Simulated Product
Presenter
Presentation Notes
Simulated Product – manufacture something you wouldn’t normally sell, but it is representative of the product family and its bioburden. Maybe it is more cost effective for you to produce this and it can save you long term costs vs. doing separate dose audits on each product. Example: QTS customer produces two products that aren’t very similar. One of the products happens to be a lot smaller, so for their dose audits they use a simulated product which is a big product packaged together with a small product. As you can see in the picture, the small product is packaged in a pouch and inserted into the tray.
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• 10 samples • Used for monitoring/trending purposes • NEVER used as Pass/Fail criteria for a dose audit
How? Test Component 1: Bioburden
Presenter
Presentation Notes
Once you have selected your samples via one of those three methods, there are two tests they are used for: Bioburden and Sterility. Bioburden: 10 samples (quantities for Method Vdmax, which is the most common) Bioburden is just for monitoring Even if you had a really high Bioburden count, it wouldn’t necessarily fail your dose audit General Process: Place device in media Agitate the media to shake any bugs off of the device Filter the media and then plate it and incubate to see what grows After a few days, you’d be able to count the colonies. And look, here’s Bob that came off your device and is now making a colony on that plate.
How? Test Component 2: Sterility • 10 samples • Samples sterilized at verification dose (e.g. 7-9 kGy),
NOT at production dose (e.g. 25-40 kGy) • Measures resistance of bioburden • These results determine the success or failure of the
dose audit
Presenter
Presentation Notes
Sterility: Following abbreviated sterilization event, place devices in growth media and test for sterility. You’re checking the radiation resistance of your product. Sterility is your pass/fail criteria. Process: Aseptically put your device in growth media Seal it up for at least 14 days Incubate, and then check for growth/turbidity See if bioburden on your device survived the abbreviated sterilization event. If it’s cloudy, that means something is still living and growing. Looks like a positive sample on the right test tube (cloudy).
0/10 or 1/10 positive = Pass 2/10 positive = Confirmatory dose experiment 3/10 or more positive = Fail
CALCULATE
PROVES
Presenter
Presentation Notes
Here’s a diagram of how everything we just reviewed fits together. Audit of the sterilization Dose Purpose of sterilization is to prove a 10-6 SAL (using VDmax) Bioburden results in initial dose substantiation study are used to calculate the dose to the product to achieve a 10-1 SAL (i.e. the verification dose) Verification dose is therefore much lower (e.g. 7-9 kGy) than production dose When you are doing your sterility testing on your samples that were exposed to the verification dose, you are actually expecting occasional positives in the tests of sterility. Pass/Fail criteria: 0/10 or 1/10 positive = Pass 2/10 positive = Confirmatory dose experiment 3/10 or more positive = Fail
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• Section 1: What is a Dose Audit? • Audit of the sterilization Dose • Longer/higher exposure increases sterilization probability
• Section 2: Why are Dose Audits Required? • Bioburden can change or shift over time
• Section 3: How are Dose Audits Performed? • Sterility results determine the success of your dose audit • Bioburden results are just for monitoring purposes
• Section 4: Timing and Scheduling • Section 5: Challenges with Dose Audits
Outline
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• Once completed, 3 month window until next dose audit • Can produce and sterilize any amount of product during
that period • Example: Dose audit is completed on January 1st. You
would have until April 1st to sterilize product before the next dose audit would be due.
1/1/16 4/1/16
Scheduling
Presenter
Presentation Notes
Once you complete a dose audit, you have 3 months until your next one is due. At QTS we interpret due dates and scheduling in an end to end manner, meaning the last completion/fulfilled date would be when the lab testing ended, and then the due date for the next dose audit would be 3 months from that date.
Example: Completed last dose audit on January 1st and your next one is due April 1st Standard lead times would mean you’d have to start manufacturing samples by around February 1st.
Example: Completed last dose audit on January 1st and your next one is due April 1st Expedited timeline would mean you’d have to start manufacturing samples by the middle or end of February. Dose audits should be part of your routine production planning if you want to avoid delays in releasing your product. Due dates can be easy to forget, so QTS will send out notifications to help remind you to plan for them. We’ve heard about some companies who don’t follow this sort of strict schedule and have been hit with regulatory warnings. Dose audits are important because the sterility of your product can directly affect the health of the patient. We take dose audits and their scheduling very seriously.
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• Section 1: What is a Dose Audit? • Audit of the sterilization Dose • Longer/higher exposure increases sterilization probability
• Section 2: Why are Dose Audits Required? • Bioburden can change or shift over time
• Section 3: How are Dose Audits Performed? • Sterility results determine the success of your dose audit • Bioburden results are just for monitoring purposes
• Section 4: Timing and Scheduling • Dose audits are valid for 3 months, but take a long time to perform • You need to think about them when forecasting production
• Section 5: Challenges with Dose Audits
Outline
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Challenges Result Generation & Interpretation
Presenter
Presentation Notes
For someone with no background in sterilization or microbiology, seeing these results could be pretty confusing and overwhelming. Our goal at QTS is to take all the detailed information and break it down for you in a manageable and understandable way.
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Challenges Result Generation & Interpretation
Presenter
Presentation Notes
Here’s an example from what the end of a QTS report might look like – easy to understand conclusion section – simply whether the dose audit was successful or not, as well as giving you your next due date.
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• Sample preparation can be costly (need at least 20)
• Testing can vary between two seemingly similar product lines
Challenges Sample Manufacturing & Testing Costs
Presenter
Presentation Notes
Sample manufacturing can get expensive, especially if you’re building smaller lots and then have to take at least 20 of them and essentially scrap them for testing. We’ve seen cost differences between products at the laboratory and at the sterilizer. If 2 of your products or their packaging are different, or there are special testing circumstances, there might be varying dose audit costs between 2 of your products. Here’s an example of 2 products, they’re very similar (spherical) and the same tests are being performed. Size differences lead to more media being used, and therefore a higher cost for product B. QTS can help walk you through the costs and any differences between products so you understand what is required in each dose audit.
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• Long periods between production
• Skipped dose audits
1/1/16 4/1/16 7/1/16 10/1/16 …TBD 3 months after
Dose Audit Completed
Challenges Production Timing
Presenter
Presentation Notes
What if you aren’t frequently in production, maybe you only build product a couple times a year? Say you finished your last dose audit in January, but your next production build isn’t scheduled until November… If you weren’t building product throughout the year, you would NOT need to do dose audits, simple as that. However, in order to release your November build you would need to take some of those samples and perform a dose audit. Don’t be scared off from radiation sterilization because you think you need to keep building samples and doing dose audits year round. Dose Audit “skipping” is okay if you are NOT in production, however, product cannot be certified sterile until a dose audit is complete.
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From ISO 11137-1:
Challenges Product or Manufacturing Changes
Presenter
Presentation Notes
What if you make changes to the device or any aspect of its manufacturing? This is pretty common if you might have identified a cheaper supplier, material, or maybe just improved on your design over time. If you make changes to the product, you would be required to do a change assessment per the ISO Standards. QTS is experienced in performing these assessments, which would document the changes and recommend testing as needed (which may include a dose audit if there are major changes that might affect its sterilization). Pretend these iPods are actually medical devices: These are both called “iPods” – one is from approximately 2003 and the other is the most recent model. Although the name remains the same, there have been tons of changes over the past decade that have made these almost completely different products. If they were medical devices, Apple would likely have assessed each change along the way.
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• Bioburden “Spike” • Dose Audit affected?
• Over alert or action limits? • Investigation required?
• Dose Audit Failure • Too many positives? • Impacts
• Dose augmentation • Dose reestablishment
Challenges Testing Failures & Complications
Presenter
Presentation Notes
Dose audit affected by a Bioburden Spike? As discussed previously, bioburden testing is only included for monitoring purposes. Simply having an elevated result would not automatically fail your dose audit. However, as good practice, QTS sets alert and action limits to evaluate results against acceptance criteria. If you are above either of those limits, an investigation might be required into the possible source of the bioburden spike. These limits are like your early warning signal. Dose audit failure would only be if you have too many positives in the tests of sterility. First you would want to do a laboratory investigation for contamination. If you found proof of contamination, you’d be able to repeat your sterility testing. If no contamination, you’d have to either augment the dose (for example you were sterilizing product at 25-40 KGY, your new minimum might be around 30 KGY). You would then need to repeat your dose substantiation study. If you get 7+ positives, you would need to discontinue production immediately, and repeat your dose substantiation study before producing again. Dose audit failures don’t happen often, but we have seen them on occasion. QTS would work with the lab to investigate the failure and work through the best solutions, which may result in temporary or permanent changes to the device manufacturing or sterilization process.
At QTS we can take most of the stress out of dose audit issues and help explain them to you in plain English. Hopefully we can make you feel less like the picture on the left and more like the one on the right. Failures are serious, we have an obligation to ensure devices are sterile. At QTS we call it “Quality for Life”.
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• Section 1: What is a Dose Audit? • Audit of the sterilization Dose • Longer/higher exposure increases sterilization probability
• Section 2: Why are Dose Audits Required? • Bioburden can change or shift over time
• Section 3: How are Dose Audits Performed? • Sterility results determine the success of your dose audit • Bioburden results are just for monitoring purposes
• Section 4: Timing and Scheduling • Dose audits are valid for 3 months, but take a long time to perform • You need to think about them while forecasting
• Section 5: Challenges with Dose Audits • Radiation sterilization and dose audits can be challenging; QTS is
the perfect partner to take all of the stress out of them
Outline
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• Section 1: What is a Dose Audit? • Audit of the sterilization Dose • Longer/higher exposure increases sterilization probability
• Section 2: Why are Dose Audits Required? • Bioburden can change or shift over time
• Section 3: How are Dose Audits Performed? • Sterility results determine the success of your dose audit • Bioburden results are just for monitoring purposes
• Section 4: Timing and Scheduling • Dose audits are valid for 3 months, but take a long time to perform • You need to think about them while forecasting
• Section 5: Challenges with Dose Audits • Radiation sterilization and dose audits can be challenging; QTS is
the perfect partner to take all of the stress out of them
Outline
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Questions & Answers Session
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Contact information: Jade Schiesser Work: 952-942-8321 [email protected] Slide Deck: Available at QTSpackage.com Resources Educational Materials
Additional Resources • ANSI/AAMI/ISO 11137-1:2006 – Sterilization of health care products – Radiation – Part 1:
Requirements for development, validation, and routine control of a sterilization process for medical devices
• ANSI/AAMI/ISO 11137-2:2013 – Sterilization of health care products – Radiation – Part 2: Establishing the sterilization dose
• ANSI/AAMI/ISO TIR13004:2013 – Sterilization of health care products – Radiation – Substantiation of a selected sterilization dose: Method VDmax
SD
• ANSI/AAMI/ISO 11737-1:2006 – Sterilization medical devices – Microbiological methods – Part 1: Determination of a population of microorganisms on products
• ANSI/AAMI/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
• AAMI TIR29:2012 – Guide for process characterization and control in radiation sterilization of medical devices
• AAMI TIR33:2005 – Sterilization of health care products – Radiation – Substantiation of a selected sterilization dose – Method Vdmax
• AAMI TIR 35: 2006 – Sterilization of health care products – Radiation sterilization – Alternative sampling plans for verification dose experiments and sterilization dose audits
