A Journey in Global PUPSIT Implementation with Benchmarking. PDA Midwest Event Oct 5th, 2017 Jeff Gaerke P.E.

Transcription

1 A Journey in Global PUPSIT Implementation with Benchmarking PDA Midwest Event Oct 5th, 2017 Jeff Gaerke P.E.

2 Purpose Share learning on ongoing global implementation of PUPSIT for parenteral operations. Share results of recent PDA benchmarking survey on PUPSIT. 2

3 Agenda Overview of integrity testing and the requirement for PUPSIT Considerations in implementing a PUPSIT capable filtration scheme Benchmarking results integrated Questions 3

4 Filters are used as a means to sterilize liquid products Where the final product stream can not be terminally heat sterilized (eg. via autoclave), filtration is commonly the means to ensure sterility. Liquid product stream is passed through filter element designed to retain microorganisms so that the resulting effluent is free of organisms (sterile) Filters with a pore size of 0.22 µm or less are considered sterilizing 4

5 Integrity testing (IT) of filters performed to Ensure integrity of the filter media Provide assurance that there isn t a tear, hole, defect in the filter media that could allow a micro-organism to pass through. Check correct filter installation Detect leaks due to seals, O-rings Determine if filter was damaged during filtration operation assures integrity both before and after use 5

6 Two common methods to perform IT on wetted filter media Diffusion Test Method Bubble Point Test Method [Diagram used with permission from Guillaume Lesage from Millipore Sigma] 6

7 IT result is used as an indication of bacteria retention capability [Diagram used with permission from Guillaume Lesage from Millipore Sigma] 7

8 How IT has commonly been implemented IT performed pre-use to confirm that filter starts out integral IT performed post-use to confirm that filter remained integral during filtration operation The details around the timing of the pre-use IT determines whether or not PUPSIT compliant Common within industry to perform pre-use integrity testing prior to sterilization (particularly if sterilization method was not SIP). 8

9 Requirement listed in EU Annex 1 The word sterilised from EU Annex 1 indicates that preuse integrity testing should be performed post-sterilization PUPSIT = Pre-Use Post-Sterilization Integrity Testing Performing pre-use testing prior to sterilization does not align with EU Annex 1 Note: EU Annex 1 is currently in the process of being revised. 9

10 Decision to implement PUPSIT across all Lilly parenteral mfg sites Prompted by feedback during a regulatory inspection. Increased challenge in global implementation due to the fact that multiple sterile filtration designs/different infrastructures exist at different sites. 10

11 Agenda Overview of integrity testing and the requirement for PUPSIT Considerations in implementing a PUPSIT capable filtration scheme Benchmarking results integrated Questions 11

12 Benchmarking PDA PUPSIT Survey completed April big pharma companies responded Most (7/9) responded for entire global company Note: limited to one response per company Benchmarking slides that follow include comments from survey questions. 12

13 Benchmarking #11 Why does your company perform PUPSIT 13

14 Benchmarking #13 has company performed sterility risk assessment on PUPSIT implementation? 14

15 Benchmarking #14 If performed risk assessment does PUPSIT result in or less sterility risk? 15

16 Benchmarking #12 Does company feel that decision to perform PUPSIT belongs to end user? 16

17 Benchmarking #8 PUPSIT performed on commercial manufacturing? 17

18 Considerations in implementing a PUPSIT capable filtration scheme Use of a single filter vs. dual filter (backup) filtration scheme Wetting fluid used for PUPSIT Wetting method used for PUPSIT Integrity test method to use Use of stainless steel vs. disposable components and sterilization method Need for ability to rotate the filter assembly 18

19 Use of single sterilizing filter vs. dual filter (backup) filtration scheme Backup filter provides insurance against having to discard a batch due to failing the post-use integrity test of a single sterilizing filter (business risk) Helpful to quantify this risk The addition of a backup filter increases the complexity of performing PUPSIT significantly Area between the two filters must be maintained sterile while performing PUPSIT on both filters 19

20 Providing backup with PUPSIT capability increases the complexity significantly 20

21 Single vs. dual filter (backup) considerations Risk of discarding lot due to post-use integrity test failure(s) Process complexity Ongoing product loss due to holdup in filters/filter assembly 21

22 Benchmarking #33 Does your site have dual sterilizing filters (backup) 22

23 Benchmarking #34 If have dual (redundant) sterilizing filter, is PUPSIT performed on both filters? 23

24 Wetting filter for pre-use integrity testing with water or product Water Pro s: Enables off-line integrity testing Cycle time/capacity advantage Know that filter passed PUPSIT before introducing product Water flush can serve as flush for extractables/leachables No concern about limiting volume to wet filter Water Con s: Leaves filter wet after integrity testing To minimize impact of residual water, common to perform air blow/drying of filter assembly after pre-use integrity test completed. Difficult to get filter completely dry; storage of partially wetted membrane represents potential bioburden concern. Creates requirement for expiration time of wetted filter assembly before use. Potential concern of diluting product in subsequent product filtration operation. 24

25 Wetting filter for pre-use integrity testing with water or product Product Pro s: Design for IT can be more straightforward Wetting in place just prior to mfg operation (less filter movement) Product Con s May not have product wetted integrity test parameters for development products (~1.5 L product per lot tested to obtain parameters, time, $) Generally want to limit interaction between protein products and air during IT, air passes through the product. Impact of failed pre-use integrity test is more significant (reset manufacturing operation) Depending on how product wetting is performed (product sent to waste or downstream vessel) might be driver to limit volume used for wetting operation 25

26 Benchmarking #22 If PUPSIT performed, what fluid is used to wet the filter? 26

27 Benchmarking #23/24 Has company performed testing to determine if there are negative consequences to performing product wetted PUPSIT 27

28 Drying - if requirement is to remove residual water down to a low level, consider design of filter/housing liquid hold up zone - area where liquid will pool and not easily dry when in the downward flow orientation indicated in red highlighting Due to design / fabrication of capsule filters, pockets are created where liquid is held up Picture to left indicates filter in vertical position. With this orientation, it can be difficult to remove water from trapped zone Ability to rotate filter can facilitate efficient water removal. 28

29 Residual water in filter element (grams) Residual water in filter vs. cumulative air blow time (~ 25 scfm through 10 filter) 20 Cumulative air blow duration vs. residual water in 10" filter (testing ) y = x x R² = Cumulative air blow duration (minutes) 29

30 Study performed using D 2 O to understand impact of 15 min air blow/drying of 10 filter on the flush volume required to reduce product dilution caused by residual water in filter to < 0.5% Hydrogen Deuterium 30

31 Benchmarking #25/26 If wetting with water, is element blown down above bubble point to dry afterwards? 31

32 Considerations in wetting method used for PUPSIT Is it important to minimize the volume of liquid used in the wetting process More of a concern with product wetting. Attributes that can impact the volume of liquid required to wet the filter. Hold time between wetting and performing PUPSIT Pressurization of the filter between wetting and performing PUPSIT The orientation of the filter during wetting. The filter manufacturer 32

33 Benchmarking #27 If wetting with product, describe wetting method 33

34 Considerations with test method used when performing PUPSIT Diffusion/forward flow vs. bubble point Size of filter being tested Impact of temperature on acceptance criteria Probability of failing integrity test due to poor wetting 34

35 Benchmarking #29 What automated integrity test method is used to perform PUPSIT? 35

36 Considerations in use of stainless steel vs. disposable components and sterilization method All stainless steel Sterilized via SIP Purchased pre-assembled single use assembly installed in rack Sterilized off-site via gamma radiation Combination of stainless and single use components assembled on site Sterilized via autoclave 36

37 Additional considerations in use of stainless steel vs. disposable components and sterilization method Cabinet washer/autoclave capability/capacity Operations personnel time to prepare assembly Level of automation Cleaning validation requirements Cycle time for batch/product changeover Is there a requirement to rotate filter assembly Ability to perform pressure hold test on filtration assembly to test system integrity prior to use Shelf life of sterilized assemblies Ability to utilize expandable bags 37

38 Benchmarking #10 impact of sterilization method on whether or not PUPSIT performed 38

39 Considerations in determining need to rotate the filter assembly Is it important to easily displace air from the core of the filter assembly Improves ability to wet the filter with minimal volume Limits air/product interaction during filtration If wetting with water, is it important to dry filter down to low level prior to use? The ability to rotate can improve drying efficiency Level of automation required Automating valves on a rotating panel would be difficult 39

40 Filtration assembly with ability to rotate (utilizes single use components) Lynx Product Outlets Lynx.2µ Millipak Barrier Filter Bag Bag WFI Inlet Flex tubing Legend: Integrity Test Inlet Product/Drying Air Inlet Pinch valve (manual) 40

41 Steps associated with PUPSIT filtration process 3 rotation positions 41

42 Agenda Overview of integrity testing and the requirement for PUPSIT Considerations in implementing a PUPSIT capable filtration scheme Benchmarking results integrated Questions Jeff Gaerke Eli Lilly & Company J.Gaerke@Lilly.com (317)

43 Acknowledgements Lilly Andrew Mouat Michael Walsh Shane Fox PDA Valeria Shirviani Richard Levy 43