A Journey in Global PUPSIT

Implementation with Benchmarking

PDA Midwest Event

Oct 5th, 2017
Jeff Gaerke P.E.
Purpose
• Share learning on ongoing global
implementation of PUPSIT for parenteral
operations.
• Share results of recent PDA benchmarking
survey on PUPSIT.

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

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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 micro-
organisms so that the resulting effluent is
free of organisms (sterile)
– Filters with a pore size of 0.22 µm or less are
considered “sterilizing”
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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
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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]
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IT result is used as an indication
of bacteria retention capability
[Diagram used with permission from
Guillaume Lesage from Millipore Sigma]

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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).
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Requirement listed in
EU Annex 1

• The word “sterilised” from EU Annex 1 indicates that pre-

use 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.
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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.

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

11
 Benchmarking PDA PUPSIT
Survey completed April 2017

• 9 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.

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Benchmarking #11 Why does your
company perform PUPSIT

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

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

15
Benchmarking #12 Does company feel that decision to
perform PUPSIT belongs to end user?

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Benchmarking #8 PUPSIT performed
on commercial manufacturing?

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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
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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

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Providing “backup” with PUPSIT capability
increases the complexity significantly

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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

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

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

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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.

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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

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

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

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Drying - if requirement is to remove residual water
down to a low level, consider design of filter/housing

• Due to design /
fabrication of capsule
“liquid hold up zone” - area
filters, pockets are
where liquid will pool and not created where liquid is
easily dry when in the
“downward” flow orientation held up
indicated in red highlighting
• 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.

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Residual water in filter vs. cumulative air
blow time (~ 25 scfm through 10” filter)
Cumulative air blow duration vs. residual water in 10" filter (testing 04-17-17)
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16.86

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Residual water in filter element (grams)

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12

10

8
6.26
6

y = 0.0027x2 - 0.9309x + 80.39

4 R² = 0.9997

2 1.38
0.37
0
80 90 100 110 120 130 140 150 160 170 180
Cumulative air blow duration (minutes)

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Study performed using D2O 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

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

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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

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Benchmarking #27 If wetting with product,
describe wetting method

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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

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

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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 36
Sterilized via autoclave
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
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Benchmarking #10 impact of sterilization
method on whether or not PUPSIT performed

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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

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 Filtration assembly with ability to rotate
(utilizes single use components)

Product
Lynx Outlets Lynx

.2µ
Millipak
Bag Bag
Barrier
Filter
WFI
Inlet

Product/Drying
Air Inlet
Legend:
Flex tubing Integrity
Test Inlet
Pinch valve (manual)

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Steps associated with PUPSIT filtration
process – 3 rotation positions

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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) 319-0391

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

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