New Applications of the VDmax Approach to Substantiation of...
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New Applications of the VDmax Approach to Substantiation of Preselected Sterilization Doses: VDmax
12.5, VDmax Values Derived for Specific Product Use, and Sterility Assurance Levels Greater than 10-6 John B. Kowalski, Ph.D. Principal Consultant
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Topics
• Rationale for and evolution of Method VDmax
• Substantiation of 25 kGy and sterilization doses less than and greater than 25 kGy
• VDmax12.5
• Product-specific VDmax “tables”
• VDmax approach for sterility assurance values greater than 10-6
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Rationale for Method VDmax • Change in the “landscape” of sterilization of
medical devices:
• Late 1970’s – 25 kGy widely used, needed methods to validate
lower doses, some products required >25 kGy
• Middle 1990’s – Need for a method for substantiation of 25 kGy
and desire for a lower number of samples
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• Further change in the “landscape” – Complex drug/device and convergent-
technology products
• Middle 2000’s – Method VDmax applied to doses other than 25
kGy • Today
– Product-specific applications and use for SAL values >10-6
Evolution of Method VDmax
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• Maintain the conservativeness of Method 1 – Been effectively and safely used 20+ years
• Have a direct linkage between the outcome of the verification dose experiment and the attainment of an SAL of 10-6 at a 25 kGy sterilization dose
• Perform the verification dose experiment at an SAL of 10-1
• Maintain as much as possible the procedural steps of Method 1
Foundations of Method VDmax
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• Computer evaluations – Showed safe and unambiguous outcomes with
the SDR – Concluded Method VDmax was “conservative and
credible”
• Field evaluations – Evaluated a wide range of medical devices from
three manufacturing facilities – No failures in ~500 verification dose experiments
Substantiation of 25 kGy
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• The VDmax approach not limited to substantiation of 25 kGy
– VDmax values can be calculated for the substantiation of sterilization doses within the range covered by Method 1
• Average bioburden values from 0.1 to 106
• Sterilization doses from 11.0 to 36.3 kGy
Doses Other Than 25 kGy
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• Computer and field evaluations performed for doses <25 kGy and also for doses >25 kGy – Method VDmax is both safe and robust for doses
below and above 25 kGy
• Values of VDmax for sterilization doses of 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, and 35 kGy published in AAMI TIR33:2005
• VDmax15 and VDmax
25 published in ISO 11137-2
• All above doses called out in ISO TS 13004
Doses Other Than 25 kGy
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• Needs to be very low – Generally this does not happen by
accident! • You need to prove it! • Need high efficiency of recovery! • Need low dilution factor!
VDmax12.5 - Bioburden Issues
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Measuring Very Low Bioburden
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Product Item Aerobic Yeasts/Molds Anaerobic
CFU / Plate 1 0 0 0 2 0 0 0 3 0 0 0 4 0 0 0 5 0 0 0 6 0 0 0 7 0 0 0 8 0 0 0 9 0 0 0
10 0 0 0
No CFU observed!
Measuring Very Low Bioburden
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Product Item Aerobic Yeasts/Molds Anaerobic
Batch Average Bioburden = 9 1 <3 <3 <3 2 <3 <3 <3 3 <3 <3 <3 4 <3 <3 <3 5 <3 <3 <3 6 <3 <3 <3 7 <3 <3 <3 8 <3 <3 <3 9 <3 <3 <3
10 <3 <3 <3
No CFU observed; bioburden = 9? (1.0 correction factor)
Measuring Very Low Bioburden
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• Pool 10 samples? – Need validated method, high efficiency
• Use MPN approach? – CFU on product items that are positive for growth?
• Use one plating medium with temperature shift for aerobic & yeasts/molds? – Demonstrate lack of strict anaerobes & spores
• More than one of the above??
• Poisson distribution & and one-half limit of detection substitution for “zero CFU” findings
Very Low Bioburden: Statistical Approach
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• Unique combination of bioburden level and low maximum dose requirement - in this example, a biologically-derived product, xenograft
– Bioburden too high to use VDmax15
– Bioburden acceptable for VDmax17.5 but use of
this minimum dose risked exceeding the product maximum dose requirement during irradiation
Product-Specific VDmax Values
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• VDmax16.1 look-up table developed, bioburden from
0.1 to 3.5
• Supporting documentation supplied for auditor review
• Such tables of VDmax values accepted in FDA and Notified Body reviews
• Product-specific VDmax values derived for sterilization doses from 11.9 to 36.4 kGy
Product-Specific VDmax Values
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• VDmax “look-up tables” derived for substantiation of 10-3 SAL sterilization doses – 7.5, 10, 12.5, and 15 kGy doses
VDmax for Other Values of SAL
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10-3 SAL Dose (kGy)
Maximum Bioburden (CFU)
7.5 7 10 45
12.5 300 15 1700
10-4 VDmax
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• VDmax verification doses have been developed for an SAL of 10-4
• Could be viewed as an: “Aseptic Processing Equivalent Dose”
• The probability of a nonsterile unit (PNSU) for aseptic processing ≅ 0.0001
• No increased patient risk and “substantially equivalent” to aseptic processing
• VDmax & Population A? – Population A could be an appropriate
assumption for low bioburden combination products
Future State
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Bioburden 10-4 SAL Dose (kGy)
10 6.6
5 6.0
1 4.7
.2 3.5
• Method VDmax is a safe and robust method for substantiation of a radiation sterilization dose
• Requires relatively few product items, minimizing costs for complex products
• Functions over a wide range of bioburden level and sterilization dose
• Can be customized for product-specific situations • Can be used at SAL values other than 10-6
Conclusions
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