Sterile Barrier Systems. Critical to Quality Issues: Packaging & Product Sterility. John B. Kowalski, Ph.D. Principal Consultant

Transcription

1 Sterile Barrier Systems Critical to Quality Issues: Packaging & Product Sterility John B. Kowalski, Ph.D. Principal Consultant March 6-8, 2012

2 Perspective The Ultimate Customer for a Sterile Medical Product in an SBS is the Patient What Are the Critical to Quality (CTQ) Issues Relating to Packaging and Sterility? How Do You Ensure Their Attainment? 2

3 CTQ #1 SBS must allow for efficient and consistent sterilization Gaseous sterilization processes, a permeable component is required Ethylene oxide, moist heat, gas plasma, hydrogen peroxide, chorine dioxide, supercritical CO 2, ozone Radiation and dry heat, a permeable component is not required Gamma, e-beam, X-rays, dry heat 3

4 CTQ #1 Question If a component of an SBS is permeable to a gaseous sterilant, can t bacteria pass through as well? 4

5 Microbial Barrier Testing Late 70 s and early 80 s - lots of home grown methods for assessing microbial barrier properties of porous packaging materials Many contributors to the science of testing microbial barrier properties DuPont (driven by Mike Scholla) Alan Tallentire 5

6 Microbial Barrier Testing Key Learnings: There is a wide range of performance for porous SBS components when compared in laboratory tests Penetration of bacterial spores and inert particles through materials is flow rate dependent Lower performing materials, generally low basis weight uncoated papers, are perfectly functional in real world applications 6

7 Microbial Barrier Testing Key Learnings: Essentially all materials pass at least a few spores/particles Relating laboratory test conditions to real world challenges is complex Using real world flow rates is important Numbers, types, and method for microbial (particle) challenges is not easy to determine 7

8 CTQ #2 The SBS and the product it contains must survive the sterilization process and maintain their attributes over time Testing is required post-sterilization Testing is required after real time and possibly accelerated aging 8

9 CTQ #2 Questions What are the key attributes of a sterilization process used to expose the SBS/product for post-sterilization and real time/accelerated aging testing? How do you know that the product in the SBS remains sterile during its labeled shelf life? 9

10 Key Process Attributes 10 Ethylene Oxide STEP PARAMETERS DESIRED MIN MAX PRECONDITIONING TEMP 110 F 100 F 120 F RELATIVE HUMIDITY 55 % 45 % 75 % TIME 24 Hours 20 Hours 28 Hours TRANSFER TIME TIME < 60 Minutes N/A 60 Minutes PROCESS TEMPERATURE TEMP 113 F 100 F 123 F VACUUM A EVAC. TO 1.8 inhga 1.3 inhga 2.3 inhga APPROX. RATE/TIME 1 inhg/min N/A N/A LEAK TEST TOLERANCE 0.2 inhg 0.0 inhg 0.2 inhg TIME 5 minutes 5 minutes 60 minutes NITROGEN DILUTION INJECT TO 24.0 inhga 23.5 inhga 24.5 inhga APPROX. RATE / TIME 1 inhg/min N/A N/A EVAC. TO 2 inhga 1.5 inhga 2.5 inhga APPROX. RATE / TIME 1 inhg/min N/A N/A NUMBER OF REPEATS 2 ( total) HUMIDIFICATION HUMIDITY RISE 1 inhga 0.5 inhga 1.5 inhga STEAM CONDITIONING HUMIDITY TO N/A N/A N/A EVACUATE TO N/A N/A N/A TIME N/A N/A N/A HUMIDITY DWELL DWELL TIME 60 minutes 60 minutes 70 minutes

11 Key Process Attributes Ethylene Oxide STEP PARAMETERS DESIRED MIN MAX GAS A GAS TO 16.5 inhga 16.0 inhga 17.0 inhga APPROX. RATE/TIME 1 inhg/min N/A N/A Calculated gas conc. XXX mg/l GAS B NITROGEN TO N/A N/A N/A APPROX. RATE/TIME N/A N/A N/A GAS DWELL TEMP 113 F 108 F 123 F TIME 240 minutes 240 minutes 250 minutes MAINTAIN PRES. YES with EO EO MAINTAIN PRESSURE AT 16.5 inhga 16.0 inhga 17.0 inhga 11

12 Key Process Attributes Ethylene Oxide STEP PARAMETERS DESIRED MIN MAX AFTER VACUUM EVAC. TO 2 inhga 1.5 inhga 2.5 inhga APPROX. RATE / TIME 1 inhg/min N/A N/A GAS WASH A NITROGEN INJECT TO 25 inhga 24.5 inhga 25.5 inhga APPROX. RATE / TIME 1 inhg/min N/A N/A EVAC. TO 2 inhga 1.5 inhga 2.5 inhga APPROX. RATE / TIME 1 inhg/min N/A N/A TOTAL NUMBER OF WASHES 2 (total) FINAL RELEASE AIR TO 28 inhga 28 inhga ATM APPROX. RATE / TIME 1 inhg/min N/A N/A HEATED AERATION TEMP N/A 90 F 130 F TIME 48 Hours 48 Hours 60 Hours AMBIENT AERATION TIME 24 Hours 24 Hours N/A 12

13 Key Process Attributes Radiation Gamma Maximum dose Ebeam Maximum dose, dose rate 13

14 Key Process Attributes Moist Heat Process type Gravity displacement Prevacuum Exposure temperature & time 121 C, 132 C, 4 to 30 minutes Drying time? 14

15 Maintenance of Sterility Back in the day... J&J and other companies had drum tests that insulted packages with bacterial spores Not always as effective as imagined False positives due to difficulty in decontaminating the outside of the SBS 15 Recontamination tests were also used where sterilized SBS were stored in a dirty environment False positives again a problem

16 Maintenance of Sterility Contents are sterile unless SBS has been opened or damaged Event related not time related Never ever do a microbiology-based test when you can do a physical test on an SBS Prove package integrity and therefore maintenance of sterility by visual inspection, dye penetration, underwater pressure differential, etc. 16

17 Maintenance of Sterility Never ever do a product test of sterility to demonstrate maintenance of package integrity over time Baseline testing is bad, after aging is worse Never ever do a whole package microbial challenge test and test product for sterility to demonstrate maintenance of sterility over time Never ever do a whole package microbial challenge test when you think there might be or might have been a package integrity problem 17

18 Why Never Ever? Physical tests such as visual inspection, dye penetration, etc., are more sensitive than a microbial challenge test Key publications: MD&DI, 1/93, 8/95, 9/95 Testing product for sterility at baseline and after aging has non-trivial risk of getting a false positive At baseline - sterilization process ineffective? At aging - package integrity problem? 18

19 Why Never Ever? Whole package microbial challenge tests less sensitive than physical tests Statistics not very good Need to challenge 300 packages to demonstrate a defect rate is 0.01 with 95% confidence More packages tested = more risk of a false positive(s) 19

20 Ensuring Attainment of CTQs Product Concept Short and easy? Long and tortuous? Need to avoid late bad news! Market Release 20

21 Ensuring Attainment of CTQs Product Concept Product Design & Materials of Construction 21 Choices here have packaging and sterilization implications!

22 Ensuring Attainment of CTQs Rule #1 Early involvement with the right skill sets! Rule #2 Early involvement with the right skill sets!! Rule #3 Early involvement with the right skill sets!!! 22

23 Conclusions Role of microbiological testing for barrier properties of materials and whole package integrity has diminished Barrier properties can be performed with particles Whole package testing has poor sensitivity & statistical power 23

24 Conclusions Design for packaging and sterilization by use of concurrent engineering critically important SBS materials of construction and package design must be aligned with sterilant penetration needs and be resistant to sterilization process-induced damage Desired outcome is an optimal packaging system for the end user and that is resistant to transportation damage 24

25 Thank You! John B. Kowalski, Ph.D. Principal Consultant Ph