Considerations in Pre-Use Post-Sterilization Integrity … Millipore designed specifically for...

Considerations in Pre-Use

Post-Sterilization Integrity Test

(PUPSIT) Implementation

PDA Midwest Conference

Oct 6th, 2016

Jeff Gaerke P.E.

10/10/2016 Company Confidential © 2015 Eli Lilly and Company 2

Agenda

• Overview of integrity testing and the

requirement for PUPSIT

• Considerations in designing a filtration

scheme with the ability to perform PUPSIT

• Questions


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 0.22µm or less are considered “sterilizing”


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


Two common methods to perform

IT on wetted filter media

[Diagram used with permission from

Guillaume Lesage from Millipore Sigma]

IT result is used as an indication

of bacteria retention capability


[Diagram used with permission from

Guillaume Lesage from Millipore Sigma]


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 determine whether or not PUPSIT

compliant

– Common within industry to perform pre-use

integrity testing prior to sterilization when

sterilization method is via autoclave


Requirement listed in

EU Annex 1

• Performing pre-use testing prior to sterilization doesn’t align with EU Annex 1

• The word “sterilised” from EU Annex 1 indicates that pre-use integrity testing should be performed post-sterilization

• EU Annex 1 is currently in the process of being revised. There is the potential that the requirements regarding PUPSIT may be modified.


Agenda





• Questions


Design considerations for

PUPSIT

• Use of single sterilizing filter vs. dual filter

(backup) filtration scheme

• Wetting filter for pre-use integrity testing

with water or product

• Use of traditional stainless assemblies vs.

single use assemblies and method of

sterilizing the filter assembly

• Ability to rotate filter assembly for air

removal and product recovery


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

– Helpful to quantify this risk

• The addition of a backup filter increases the

complexity of the performing PUPSIT

significantly

– Area between the two filters must be maintained

sterile while performing PUPSIT on both filters


Providing “backup” capability

increases the complexity significantly

Millipak barrier filter

• Specialized sterilizing grade filter

from Millipore designed

specifically for PUPSIT

• Single filter that contains both

hydrophobic and hydrophilic

membrane

– Allows passage of both liquid and air

(required for wetting and venting

during integrity testing)



How much risk reduction does a

backup filter provide?• Calculations used for filter reliability analysis

– For this evaluation, it is important to understand

the impact of filters in “series” vs. filters in

“parallel” in terms of resulting in a loss of sterility

• Two filters in “series” = post-use integrity test failure

on either filter results in potentially non-sterile product

• Two filters in “parallel” = post-use integrity test failure

on a single filter does not result in potentially non-

sterile product. Potentially non-sterile product occurs

only if have post-use integrity test failure of both filters

Series reliability model

The system fails if any component fails.

BUT

Series reliability equation

Series systems fail to function if any one of the components fail.

For a system of three series components, the equation is:

The general equation is:

Where:

• n = # of components in series

• R = the reliability of an individual component

Rseries =R1 x R2 x R3

R1 R2 R3

ni

iiseries RtR

1)(

Represented as an

electrical circuit

Parallel reliability model

Parallel or redundant system design means that the system will not

fail if a specific component fails.

Parallel reliability equation

Parallel systems continue to function as long as one of the components survives.

For a system of three parallel components, the equation is:

The general equation is:

Where:

• n = # of components in parallel

• R = the reliability of an individual component

Rparallel = 1 - ((1-R1) x (1-R2)x (1-R3))

)1(1)(1

iparallel RtRni

i

R1

R2

R3

Represented as an

electrical circuit


Plug in the estimated failure rates

to determine risk• For this example the following

assumptions are made:

– 1/1,500 = failure rate of post-use integrity test

in product filter that previously passed an in

house pre-use integrity test

– 1/500 = failure rate of post-use integrity test in

air/vent/Millipak filter that was not previously

pre-use integrity tested in house.


Dual filter (backup) option–

discard 1 lot every 321,613 lots


Single filter option –

discard 1 lot every 1,500 lots

Prod

flush

bag

(X? L

)

Spare Lynx S2S (F)

Lynx S2S (F)

4 sam

ple b

ags

(~ 2

00 ml)

Bleed

bag

(0.5

L)

vent to room

Reliability indicated as a circuit

FLT-402 millipak

FLT-401 product

FLT-401

Reliability equations:

RCUM= R401

# of occurrences between failure = 1/(1-RCUM)

Note: confirm that integrity test of FLT-402 (millipak) passes prior to filter being used on product – therefore FLT-402 has no impact on this evaluation


Summary of expected batch

discard rate of 2 options


Single vs. dual filter (backup)

considerations

• Risk of discarding lot due to post-use

integrity test failure(s)

• Process complexity

– Consider automating filtration steps with dual

filter to minimize potential errors

• Product loss due to holdup in filters/filter

assembly



PUPSIT











Wetting filter for pre-use integrity

testing with water or product• Water Pro’s:

– Enables off-line integrity testing• Cycle time/capacity advantage

– 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.


Wetting filter for pre-use integrity

testing with water or product• Product Pro’s:

– Design 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

– Important that product wetted integrity test parameters are robust

– Impact of failed pre-use integrity test is more significant (reset manufacturing operation)

– Depending on how product wetting is performed (to waste or downstream vessel) – might be driver to limit volume used for wetting operation



PUPSIT











Use of stainless vs. disposable &

sterilization method• Considerations

– Cabinet washer/autoclave capacity

– Operations personnel time to prep

– Ease to automate if desired

– Fabricated in a controlled manner

– Gamma radiated single use assemblies may offer advantages

• 2 yr shelf life for sterilized assemblies

• Ability to utilize expandable bleed/purge bags without vent filters on them


Design considerations for PUPSIT











Consider ideal filter orientation at

different times• Ideal orientation to perform integrity test is

~opposite of ideal orientation for air removal from core of filter element

• Ideal orientation for air removal from core of filter element is ~ opposite of ideal orientation for product recovery at end of filtration operation

• Providing the ability to rotate the filter assembly to the best orientation for the step in the overall filtration operation offers several advantages


Ability to rotate filter assembly

provides advantages


Agenda





• Questions

Jeff Gaerke P.E.

Eli Lilly & Company

[email protected]

(317)276-6621

mailto:[email protected]

Considerations in Pre-Use Post-Sterilization Integrity … Millipore designed specifically for...

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