Setting Limits for Use inCleaning Validation Dawn Tavalsky Deputy Director Cleaning Validation 2 3 4 . 5 . 6 . 7 . Types of Product Limits 8 . Regulatory Expectations: Cleaning Between Batches of The Same Product 9 . Regulatory Expectations: Cleaning Between Batches of Different Products 10 . Regulatory Expectations Analytical Methods 11 . Impurities and Contaminants 12 . Setting Limits for Impurities 13 . Step 2 Intra Campaign Cleaning 14 . Step 3: Manufacture Next Lot (lot 2) 15 . Setting Limits for Impurities (continued) 16 . Setting Limits for Contaminants 17 . Default versus Calculated Limits 18 . Maximum Allowable Carryover (MAC) 19 . MAC (continued) 20 . MAC (continued) 21 . MAC (continued) 22 . MAC (continued) 23 . MAC (continued) 24 . MAC (continued) 25 . Regulatory Expectations: Routine Monitoring 26 . 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 27 . <500ppb Conductivity < 2.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 .25EU/ml 28 .1µcm/cm2 Bioburden <10cfu/100ml Endotoxin < 0. 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. 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 29 .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.. The KII Centrifuge 30 . The response to FDA was that validation to support the cleaning and sanitization of the KII centrifuge was targeted for completion by Q4 2005.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. 31 . 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.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. We were getting hits of 20cfu/100ml to 120 cfu/100ml during our validation attempts 32 . 33 . .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.KII Example So we were getting way more than a 3 log reduction in bioburden during our cleaning…. 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 34 . KII Example 35 . 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. 36 . the equipment. the detergent 37 . my product (we will talk about product specific limits a little later).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. TOC 38 . TOC 39 . TOC 40 . 41 . 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!! 42 .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. Surely I can pass the WFI spec for endotoxin right? Wrong! Endotoxin levels in the process stream 1.00E+08 UX034 (A) 1.00E+00 1. H Fi C en t.00E-04 Fe rm EU/mcg Ps UX772(A) 1. H tO E Lo w P ro du c tR ec ov en ta tio n er y 1.00E+04 .00E-01 1.00E+03 Target 1.00E-03 ltr af il U no l P he P ow de r tra tio n n ct io xt ra no l P he ltr U ym e nz E tO H 43 E af il fil t U ltr a tO E Lo w tra tio n ra tio n lt.00E+06 UX251(A) UX303(A) 1.00E+07 UX225(W) 1.00E+01 1.00E+05 UX779(A) 1.00E+02 1.00E-02 1. 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.25EU/ml?? 44 . If you depyrogenate after cleaning – why would you have to clean to 0. 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 45 . 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 46 . 47 . 48 . 49 . 50 51 52 53 . 54 . 55 . 56 . 57 . 58 . 59 . 60 . 61 . Sanofi Example 62 . 63 . 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 0.5ppm For example.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 0.009ug/ml What do I do?? Dedicate equipment Find a new marker Get a better analytical method 64 . Final formulate Flu has an average TOC concentration of 400ppm (400ug/ml). Questions – or Ideas?? What has been your experiences in setting limits? Challenges/questions by Agencies? 65 .
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