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Setting Limits for Use inSetting Limits for Use in Cleaning ValidationDawn TavalskyDeputy DirectorCleaning Validation

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But we aren’t just worried about product residues

We have to set limits / acceptance criteria for product residues and cleaning residues – but the clear

t ti i th t l t li it / texpectation is that we also set limits / acceptance criteria for bioburden and endotoxin – and other measures of general cleanliness (as appropriate for your soils/equipment (sanofi uses TOC and Conductivity) as well

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Setting the non-product related limits

Some – especially your Quality counterpart – may want you to set your limits at WFI spec.

Th i “ h fi l i iThe common statement is “the final rinse water coming out of the equipment should meet the same specifications as the water being put into the system to do the rinse”This would mean (if you use WFI for your final rinse)

TOC - <500ppbConductivity < 2.1µcm/cm2

Bioburden <10cfu/100ml

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Endotoxin < 0.25EU/ml

Setting the non-product related limits

Setting the limits at WFI specs – pros and cons

ProsYour protocols go through your quality department without “discussions”Your protocols go through your quality department without discussions (i.e., arguments and heated debates) about how you chose the limitsYour discussion with the auditors during audits is very easy and, in my experience, when you tell them you have set your limits at WFI specs they back off the topic and move on

ConsYou will have to go to monumental efforts/have long wash and flush times/have very short clean hold times to meet these limits

Translation –development and validation take 3x’s longer (so your project manager hates you)the cycle you validate in the end uses tons more WFI (so your utility manager hates you)the cycle you validate is very long to run (so your operations manager hates you)

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the cycle you validate is very long to run (so your operations manager hates you)you get more “alert” hits during routine monitoring which puts product on hold (so your site vice president of operations hates you)

Ultra Translation – you better look for a new jobIn some cases with some equipment designs – you just won’t be able to meet these limits

KII centrifuge example

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The KII Centrifuge

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KII Example

The project was in response to a March 2005 FDA observation that stated that no studies had been

f d t lid t th l i d iti ti fperformed to validate the cleaning and sanitization of the KII centrifuge utilizing the K-3 rotors used in the zonal centrifugation step. The response to FDA was that validation to support the cleaning and sanitization of the KII centrifuge was targeted for completion by Q4 2005.

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KII Example

With a monumental effort – we were passing cleaning validation for TOC, endotoxin, and conductivityThe cleaning that was developed consisted of a manual clean along with an in-place cleanan in place clean

We were cleaning first manually (tearing apart the centrifuge) and scrubbing the rotar in the sink with CP310Sonicating all of the greasy parts in a sonicator with micro 90Hand wiping the inside of the centrifuge

We then put the centrifuge back together and attached a bottle of hypochlorite/hydroxide mix to the centrifuge and, using a peristaltic pump, pumped the flow around for approx 1 hr (with the rotar spinning slowly)Then we put cooled WFI in a bottle attached that and let that flow around for about 30 minWe then replaced the bottle with a new bottle of cooled WFI and again let th t fl d f 30 i

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that flow around for 30 minWe repeated the cooled WFI for a third time and took samples

Bioburden still was NOT passing 10cfu/100ml. We were getting hits of 20cfu/100ml to 120 cfu/100ml during our validation attempts

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KII Example

So we were getting way more than a 3 log reduction in bioburden during our cleaning…..but we weren’t meeting the WFI bioburden spec that the site had set as the acceptance criteriap pThe KII can not handle high heat – the rotar is made of Noryl which expands quickly at high temperatures and binds up the centrifugeThe KII has threaded fittings and small bore openings; there is a deadleg on the top of the centrifuge where the rotary seals are locatedWe were already 2 years late in completing the work we had committed to for the FDA

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committed to for the FDAThe sanofi quality director at the time WOULD NOT BUDGEWe brought in Destin LeBlanc to help justify different limits

KII Example

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KII Example

In the end – our site acceptance criteria for bioburden during cleaning validation was modified site-wide to

10cfu/ml (1000cfu/100ml) for equipment that is NOT post cleaning sterilized100cfu/ml (10000cfu/100ml) for equipment that is post cleaning sterilized

FDA accepted our response to the 483 for the cleaning

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accepted ou espo se to t e 83 o t e c ea gof the KII’s. Our bioburden acceptance criteria has not been challenged by the FDA in 2 inspections and 4 PAI’s since the criteria was modified.

What about TOC? Is <500ppb realistic

NO – the processing equipment is just not capable of maintaining the same WFI specs as the piping system d i d ifi ll f i t i i WFIdesigned specifically for maintaining WFI specs.

How do I set the limits for TOC then?TOC is coming from: the water, the equipment, my product (we will talk about product specific limits a little later), the detergent

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TOC

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TOC

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TOC

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TOC

At Sanofi we set the TOC limits at10ppm rinse or swab in “stage 1” equipment5 i b i “ t 2” i t5ppm rinse or swab in “stage 2” equipment2.5ppm rinse or swab in “stage 3” equipment

These numbers are based upon cleaning capability and the risk to the next batch from leaving this level of soil behind

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This one is hard to talk to the auditor about!!

Surely I can pass the WFI spec for endotoxin right? Wrong!

Endotoxin levels in the process stream

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

1.00E+08

EU/m

cg P

s

UX034 (A)

UX225(W)

UX251(A)

UX303(A)

UX772(A)

UX779(A)

Target

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1.00E-04

1.00E-03

1.00E-02

1.00E-01

1.00E+00

n

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Endotoxin

At Sanofi we set the Endotoxin limits at8EU/ml for stage 14EU/ml for stage 24EU/ml for stage 20.25UE/ml for stage 3

These numbers are based upon cleaning capability and the risk to the next batch from leaving this level of soil behind

We are planning to add a modification to the limits incorporating depyrogenation. If you depyrogenate after cleaning – why would

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depyrogenation. If you depyrogenate after cleaning why would you have to clean to 0.25EU/ml??

Conductivity

This one gives us the most problems during routine monitoringEasy to contaminate sampleConductivity level in the WFI has some variability (it may have run around 1.2 during validation but is now running closer to 1.6around 1.2 during validation but is now running closer to 1.6In-line conductivity probe may be solidly passing but we still get a barely failing results from our grab sample

So – WHY do I have to rinse to 2.1µsm/cm2?Detergent carryover MAC calcs correlated to conductivity tell me I can be closer to 5µsm/cm2 with no impactBUT – just because you are below the MAC does NOT mean the residual will have no impact on the process

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EDTA example – ppt residual levels are impacting the process reactionAt Sanofi we plan to do more work to set limits for conductivity that are correlated with MAC calculations and process impact assessments

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Product Specific Residues

MAC (Maximum allowable Carryover) calculation or 10ppm calculation

A S fi d f MAC l l i d 10At Sanofi – we need to perform MAC calculations and 10ppm calculation for (where applicable):

Product markersAluminumMercuryDetergents

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Sanofi Example

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Problem

The marker for the final formulated products we are trying to use right now is TOC

The amount of TOC in the final formulated product is VERY smallThe validated TOC analytical method for detecting the product in the final rinse water has an LOD of 0.5ppm

For example, Final formulate Flu has an average TOC concentration of 400ppm (400ug/ml). In other words – 1ml of flu contains 400ug carbon

Flu has a MAC of 3.5ug/ml (previous page)Doing the math – that means the MAC in terms of TOC is 0.009ug/ml

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gWhat do I do??

Dedicate equipmentFind a new markerGet a better analytical method

Questions – or Ideas??

What has been your experiences in setting limits?

Ch ll / ti b A i ?Challenges/questions by Agencies?

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