Setting Limits for Use in

Cleaning Validation Dawn Tavalsky

Deputy Director

Cleaning Validation

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Types of Product Limits

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Regulatory Expectations:

Cleaning Between Batches of The Same Product

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Regulatory Expectations:

Cleaning Between Batches of Different Products

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Regulatory Expectations

Analytical Methods

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Impurities and Contaminants

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Setting Limits for Impurities

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Step 2 Intra Campaign Cleaning

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Step 3: Manufacture Next Lot (lot 2)

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Setting Limits for Impurities (continued)

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Setting Limits for Contaminants

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Default versus Calculated Limits

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Maximum Allowable Carryover (MAC)

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MAC (continued)

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MAC (continued)

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MAC (continued)

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MAC (continued)

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MAC (continued)

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MAC (continued)

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Regulatory Expectations:

Routine Monitoring

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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

expectation 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.

The 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 - <500ppb

Conductivity < 2.1µcm/cm2

Bioburden <10cfu/100ml

Endotoxin < 0.25EU/ml

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Setting the non-product related limits

Setting the limits at WFI specs – pros and cons Pros

Your protocols go through your quality department without “discussions” (i.e., arguments and heated debates) about how you chose the limits

Your 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

Cons You 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)

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 job

In 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

performed 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 conductivity The cleaning that was developed consisted of a manual clean along with an in-place clean

We were cleaning first manually (tearing apart the centrifuge) and scrubbing the rotar in the sink with CP310

Sonicating all of the greasy parts in a sonicator with micro 90

Hand 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 min

We then replaced the bottle with a new bottle of cooled WFI and again let that flow around for 30 min

We 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 criteria

The KII can not handle high heat – the rotar is made of Noryl which

expands quickly at high temperatures and binds up the centrifuge

The KII has threaded fittings and small bore openings; there is a

deadleg on the top of the centrifuge where the rotary seals are

located

We were already 2 years late in completing the work we had

committed to for the FDA

The sanofi quality director at the time WOULD NOT BUDGE

We brought in Destin LeBlanc to help justify different limits

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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 sterilized

100cfu/ml (10000cfu/100ml) for equipment that is post

cleaning sterilized

FDA accepted our response to the 483 for the cleaning

of 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.

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What about TOC? Is <500ppb realistic

NO – the processing equipment is just not capable of

maintaining the same WFI specs as the piping system

designed 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 at

10ppm rinse or swab in “stage 1” equipment

5ppm rinse or swab in “stage 2” equipment

2.5ppm 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

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

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Surely I can pass the WFI spec for endotoxin

right? Wrong!

1.00E-04

1.00E-03

1.00E-02

1.00E-01

1.00E+00

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

1.00E+08

Fermenta

tion

Product

Reco

very

Low EtO

H Cent.

Low EtO

H Filt.

EtOH U

ltrafilt

ratio

n

Enzym

e Ultr

afiltra

tion

Phenol Ext

ract

ion

Phenol Ultr

afiltra

tion

Powder

EU

/mcg

Ps

UX034 (A)

UX225(W)

UX251(A)

UX303(A)

UX772(A)

UX779(A)

Target

Endotoxin levels in the process stream

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Endotoxin

At Sanofi we set the Endotoxin limits at

8EU/ml for stage 1

4EU/ml for stage 2

0.25UE/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

you have to clean to 0.25EU/ml??

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Conductivity

This one gives us the most problems during routine monitoring

Easy to contaminate sample

Conductivity level in the WFI has some variability (it may have run

around 1.2 during validation but is now running closer to 1.6

In-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 impact

BUT – just because you are below the MAC does NOT mean the

residual will have no impact on the process

EDTA example – ppt residual levels are impacting the process reaction

At 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

At Sanofi – we need to perform MAC calculations and 10ppm

calculation for (where applicable):

Product markers

Aluminum

Mercury

Detergents

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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 small

The 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

What do I do??

Dedicate equipment

Find a new marker

Get a better analytical method

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Questions – or Ideas??

What has been your experiences in setting limits?

Challenges/questions by Agencies?