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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Doses Other Than 25 kGy

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•  Products with very low average bioburden

VDmax12.5

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VDmax12.5

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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

10-3 VDmax

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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

10-4 VDmax15

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•  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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