NO 2 Gas Sterilization and Decontamination: Keeping Pace, from Start to Finish

Transcription

1 NO 2 Gas Sterilization and Decontamination: Keeping Pace, from Start to Finish Evan Goulet, Ph.D., VP of Microbiology Applications Laboratory PDA Midwest: Sterility Assurance and Risk Mitigation October 6, 2016 Page 1

2 Agenda Noxilizer Company Overview About Nitrogen Dioxide (NO 2 ) Current Product Portfolio & Solutions From Start: Biodecontamination of RTF Syringe Tubs To Finish: Secondary Sterilization of Prefilled Syringes Page 2

3 Noxilizer Company Overview Providing Decontamination & Sterilization Solutions Ultra-low temperature decontamination & sterilization using Nitrogen Dioxide (NO 2 ) Terminal sterilization of medical devices Secondary sterilization of drug delivery devices administered in the sterile field Decontamination of biopharmaceutical equipment and containers Page 3

4 About Nitrogen Dioxide (NO 2 ) Chemical Decontamination & Sterilization Complementary to H 2 O 2 & Ethylene Oxide, but with important benefits: Ultra-low temperature (10 C 30 C) Works with or without vacuum for many products Excellent small lumen efficacy & complex geometries Rapid process, typically 2 hours (sterilization) Safe To Use In-House, Inline with production How Is NO 2 Delivered And Used? Decontamination equipment Sterilization equipment Consumables or On Demand Page 4

5 Applications Bio-Pharma Production Page 5

6 NO 2 Sterilization Solutions From Start Page 6

7 Bio-Pharma Production Component Preparation / Infeed Moduline TM -BioDecontamination: Rapid Biodecontamination Process SCF / RTF Tubs (syringes or other containers) Transfer into RABS or Class B / A filling area Reduces Risk Eliminates manual wipe down: spray and pray Eliminates risk of shadowing with e-beam NO 2 diffuses into the seams of tub lids Key Benefits Achieves 10 6 biodecontamination of tubs Keeps pace with low and medium speed filling lines 20 tubs in 20 minutes Room temperature process No hot equipment to handle or HVAC issues Only electrical power required (no drain) Page 7

8 Concentration (ppm) Biodecontamination With Nitrogen Dioxide Faster Aeration is the Key to Matching Filling Line Output The H 2 O 2 level reaches a plateau Chart Title FTIR Data EC Cell Draeger Tube 10 HPV Peroxide Plateau Time (Minutes) Aeration of NO 2 is significantly faster, allows for rapid processing. Page 8

9 NO 2 Diffuses into Narrow Gaps, Minimizing Risk in Seams Head-to-Head with HPV Page 9

10 NO 2 Diffuses into Narrow Gaps, Minimizing Risk in Seams Test Fixture and Gas Flow This test is meant to show diffusion into small spaces 3-mm gap between two plates This simulates closely positioned components in a filling line Gas enters down-wind side Gas Flow Box sealed on 3 sides Air Lock Page 10

11 NO 2 Diffuses into Narrow Gaps, Minimizing Risk in Seams Test Fixture and Gas Flow Hydrogen Peroxide Vapor Exposure BI Time Carrier 3 cm 8 cm 2 min. SS N P Q N N 4 min. SS P P Q N P 6 min. SS P P Q N P 8 min. SS N P Q N P 16 min. SS P P Q N P 24 min. SS P P Q N P NO 2 Gas Processing Exposure BI Data Carrier 3 cm 8 cm 10 mg/l, 4 min. SS N N 75% RH Q N N 10 mg/l, 10 min. SS N N 75% RH Q N N 10 mg/l, 16 min. SS N N 75% RH Q N N 10 mg/l, 24 min. SS N N 75% RH Q N N Page 11

12 NO 2 Sterilization Solutions To Finish Page 12

13 NO 2 Sterilization Solutions Critical Process Parameters and Their Ranges Page 13 Process Parameter Temperature 10 C to 30 C Vacuum (Optional) NO 2 Concentration Relative Humidity Dwell Time Exposure Pulses 1 to 6 Aeration PFS: 700 Torr to Devices: 20 Torr 5 mg/l to 20 mg/l Range PFS: 80% RH to Sensitive Devices: 40% RH PFS: Typically 60 min to Devices: 10 min to 240 min 60 to 120 min

14 NO 2 Sterilization Solutions Vacuum Applications Typical cycle for devices that can withstand pressure changes Page 14

15 NO 2 Sterilization Solutions Minimal-Vacuum Applications Typical prefilled syringe applications Page 15

16 Sterilization of Prefilled Syringes Regulatory Driving Force FDA has requested sterilization of the external surfaces of prefilled syringes in Ophthalmics or Sterile Field Applications Even external surfaces of vials for surgical applications 2004 Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing Current Good Manufacturing Practices Sensitive drugs/biologics prevent terminal sterilization Design of delivery devices can also prevent terminal sterilization FDA recommends that manufacturers employ an adjunct sterilization process to mitigate risk to the patient Page 16

17 Validation of the NO 2 Sterilization Process Follows ISO 14937:2009 for Medical Devices ISO is a general sterilization standard for med device Closely aligned with ISO Standard governing EO sterilization Governs validation of sterilization process: Product Definition Bioburden Estimation (typically vary low for parenteral products) Includes packaging, fixturing, load size, etc. Process Definition Identify the extent of treatment that provides a 6-log reduction Performance Qualification Demonstrate repeatability, product quality and safety Also provides guidance for routine monitoring Page 17 ISO 13485:2003 FM

18 Validation of the NO 2 Sterilization Process Product Definition Prefilled Syringe Glass, 1-mL long syringe Staked needle Rigid needle shield Pharma rubber plunger PP Plunger rod Tyvek-Mylar pouch Configuration for clinical trials BI in the most challenging location Next to the plunger, inside of the syringe barrel 10 6 G. stearothermophilus spores Page 18

19 Validation of the NO 2 Sterilization Process Process Definition Prefilled Syringe BIs in syringes located throughout the load 10 BIs in total (Follow guidance in ISO 11135) 10 samples for product tests of sterility (PToS) Dunnage was used for the balance of the load Simulated a load of 300 syringes Clinical trial-sized batch Load volume of 360 liters Follows Overkill Approach Conservative method Annex D of ISO SAL of 10-6 Page 19

20 Validation of the NO 2 Sterilization Process Process Definition 6-Log Reduction Was Achieved NO 2 dose was 5 mg/l NO 2, RH was 70% RH Dwell Time was the process variable Prefer to add a safety factor into the process Page 20

21 Validation of the NO 2 Sterilization Process Sterilization Process Specification Parameter Load Size Set Point 300 syringes Temperature 20 C (+/- 2) Thermal Equilibration Time 120 min (+/- 4) BIs per load 10 Relative Humidity 75% RH (+/- 10) NO 2 Dose (2X Safety Factor) 10 mg/l (+/- 1) Dwell Time 60:00 (+/- 00:10) Aeration Time 90:00 (+/- 00:10) Page 21

22 Validation of the NO 2 Sterilization Process Process Definition Prefilled Syringe Follows a very conservative approach SAL of Half-cycle BIs and PToS samples are required Follow the USP <71> guidance for sampling plans Full-cycle BIs only are required Product quality samples are exposed to both cycles Meet lot release criteria Page 22

23 Single Batch Release with NO 2 Sterilization Ideal for Clinical Trials Follows a very conservative approach: SAL Follow guidance in AAMI TIR16 and USP <71> Half-cycle is performed first BIs and product test of sterility samples external surfaces Full-cycle is performed next Fresh BIs are the microbiological challenge Product and samples for release testing see 1.5 cycles Product stability, NO 2 ingress, sterility (contents), etc. Page 23

24 NO 2 Sterilization of Prefilled Syringes Top Three Questions Asked 1. What happens when NO 2 diffuses into water? 2 NO 2 (g) + H 2 O (l) HNO 2 (aq) + HNO 3 (aq) HNO 2 (aq) H + (aq) + NO 2 (aq) HNO 3 (aq) H + (aq) + NO 3 (aq) 2. If NO 2 ingress does occur, what will happen to my product? Spiking of product with HNO 3 or NO 2 to provide a signal for quality testing what to look for? 3. How can you prove that NO 2 ingress does not occur? Page 24

25 NO 2 Sterilization of Prefilled Syringes Detection of NO 2 Ingress Noxilizer employs a colorimetric assay for nitrate. Page 25

26 NO 2 Sterilization of Prefilled Syringes Detection of NO 2 Ingress Limit of Detection ppm NO 3 - Limit of Quantification ppm NO 3 - The LOD is 8X lower than European Pharmacopoeia limit of 0.2 ppm NO 3 - COP Syringes Staked needles Rubber needle shield NO 3- < LOD Glass Syringes Staked needles Rigid needle shield NO 3- < LOD This data can be coupled with stability and shelf-life tests to remove doubt about the quality of the product. Page 26

27 Contact Information North America Evan Goulet, PhD VP Microbiology Applications Lab Office: Mike Valentine Vice President, North American Sales Office: Angie Kearns Midwest Sales Representative Office: Page 27