New Applications of the VD max Approach to Substantiation of Preselected Sterilization Doses: VD max

Transcription

1 New Applications of the VD max Approach to Substantiation of Preselected Sterilization Doses: VD max 12.5, VD max 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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3 Topics Rationale for and evolution of Method VD max Substantiation of 25 kgy and sterilization doses less than and greater than 25 kgy VD max 12.5 Product-specific VD max tables VD max approach for sterility assurance values greater than

4 Rationale for Method VD max 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 4

5 Further change in the landscape Complex drug/device and convergenttechnology products Middle 2000 s Method VD max applied to doses other than 25 kgy Today Evolution of Method VD max Product-specific applications and use for SAL values >10-6 5

6 Foundations of Method VD max 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 6

7 Substantiation of 25 kgy Computer evaluations Showed safe and unambiguous outcomes with the SDR Concluded Method VD max was conservative and credible Field evaluations Evaluated a wide range of medical devices from three manufacturing facilities No failures in ~500 verification dose experiments 7

8 Doses Other Than 25 kgy The VD max approach not limited to substantiation of 25 kgy VD max values can be calculated for the substantiation of sterilization doses within the range covered by Method 1 Average bioburden values from 0.1 to 10 6 Sterilization doses from 11.0 to 36.3 kgy 8

9 Doses Other Than 25 kgy Computer and field evaluations performed for doses <25 kgy and also for doses >25 kgy Method VD max is both safe and robust for doses below and above 25 kgy Values of VD max for sterilization doses of 15, 17.5, 20, 22.5, 25, 27.5, 30, 32.5, and 35 kgy published in AAMI TIR33:2005 VD max 15 and VD max 25 published in ISO All above doses called out in ISO TS

10 10 Doses Other Than 25 kgy

11 VD max 12.5 Products with very low average bioburden 11

12 12 VD max 12.5

13 VD max Bioburden Issues 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! 13

14 Measuring Very Low Bioburden Product Item Aerobic Yeasts/Molds Anaerobic CFU / Plate No CFU observed! 14

15 Measuring Very Low Bioburden 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) 15

16 Measuring Very Low Bioburden 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?? 16

17 Very Low Bioburden: Statistical Approach Poisson distribution & and one-half limit of detection substitution for zero CFU findings 17

18 Product-Specific VD max Values Unique combination of bioburden level and low maximum dose requirement - in this example, a biologically-derived product, xenograft Bioburden too high to use VD max 15 Bioburden acceptable for VD max 17.5 but use of this minimum dose risked exceeding the product maximum dose requirement during irradiation 18

19 Product-Specific VD max Values VD max 16.1 look-up table developed, bioburden from 0.1 to 3.5 Supporting documentation supplied for auditor review Such tables of VD max values accepted in FDA and Notified Body reviews Product-specific VD max values derived for sterilization doses from 11.9 to 36.4 kgy 19

20 VD max for Other Values of SAL VD max look-up tables derived for substantiation of 10-3 SAL sterilization doses 7.5, 10, 12.5, and 15 kgy doses 10-3 SAL Dose (kgy) Maximum Bioburden (CFU)

21 VD max

22 10-4 VD max VD max 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 No increased patient risk and substantially equivalent to aseptic processing 22

23 VD max 15

24 VD max & Population A? Future State Population A could be an appropriate assumption for low bioburden combination products Bioburden 10-4 SAL Dose (kgy)

25 Conclusions Method VD max 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