Cleaning Validation (TOC)

GOOD VALIDATION PRACTICE (cGVP) CLEANING VALIDATION
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Good morning , this is my first topic here and hope to be as clear as possible . I 'm doing the CV of our new plant and have a two questions.

The worst case is luckily solube in water and I will analyze it by TOC.

I realize the recovery test and gives me greater than 75 % , this was made by HPLC.

There is a TOC calibration curve ranging from 50 ppb to 1000 ppb used to read the daily water laboratory.

Is some other test required in TOC to ensure that it is feasible to use in the validation?

Conductivity, its possible to reach the ´less than 1,3 us/cm´ to ensure the absence of detergent?

Thanks a lot…

Regards…

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OK. I have a few questions to help answer your questions:
1 - What sampling method will you be proposing to use? Rinsate or swabbing or something else?
2 - Is the HPLC used to sample for product, while the TOC is used to sample for detergent? Is that why you are looking at two different methods? Later on you mention conductivity. Is this also being examine to determine residual cleaning agent, or residual product?
3 - Did you use a “coupon” study to determine the recovery test? You said you used HPLC for this method. If so then you will likely need to continue to use HPLC and swabbing to do your actual cleaning test sampling and analysis.

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Hi…
1 - we are going to use swabbing and rinsate.
2 - No, we want to use TOC for the analysis of detergent and product, we only made the recovery by HPLC because it was the easiest way in that moment. But I think that i can use HPLC when we have a sample that is upper the limit for TOC, so there we can discriminate between our sample and exipients and dont stop the production (i dont know if this is possible). I think we can use the conductivity to determine the presence of detergent, so it can be a rapid analysis for support of the TOC.
3 - If when you said ¨Coupon¨ it means recovery simulating surfaces, yes, i use glass and metal. Ok, so then i need to make the recovery in TOC to use it.

A last question. In our new plant we have 2 different equipment in the same room (i know this is no the best choice). So, is it possible to make a CV so we can pass the audit or it will be very difficult to make it?

Thanks a lot!

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All good comments

So it sounds like you will use a tiered approach, in that you will use conductivity first, because it is the quickest, and will tell you if you are close (to remove detergent). Then you will use TOC to determine if you have removed detergent and product. Then, if you are on the upper limit for TOC, then you will perform HPLC testing, to see what the amount of product you have, and by calculation how much detergent you have (TOC - HPLC results = detergent results).

First of all, do you need to go through three tiers, or will conductivity tell you enough, is the method sensitive enough? Because conductivity iis non-specific, you will have to see what your conductivity will be at your MACO for product, and your conductivity for your MACO for detergent. The smallest conductivity will then be your acceptance limit.

If you want to use three methods, you will need to develop and validate chemistry tests for all three methods (HPLC, conductivity, and TOC).

Also, one thing you cannot do, and this is in the regulations, but I acknowledge that many people still do this. You cannot do cleaning, then test and then clean some more, then test, then clean some more. Your cleaning process should be reliable enough so that you get passing results after the 1st cleaning, otherwise your cleaning method is not considered “controlled” or “reliable” which is what validation ultimately is showing. The reason I bring this up, is because of your comment to do conductivity, then proceed to TOC.

Regarding having 2 equipment in the same room. Are the equipment is the same room for processing/manufacturing, or for cleaning? If together for cleaning, then I don’t see an issue. For manufacturing, the this is allowable, but you have to have procedures in place to avoid cross contamination. The audits might take into consideration the type/nature of products, and if proliferation is a concern (powder, aerosols).

I think this is a rather big topic, and it seems you understand a lot of the risks. Let me know if you have more/other details to go over.

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Hi, thanks for the quickly answer.

First, my intention wasnt to use a tiered aproach but i didnt know if only with toc its enough to perform the CV so i propose to use conductivity AND toc, because conductivity its a rapidly test for detergent (they will use SDS 5% in water) and toc can analyze all the organic compounds. A question is that if a need to validate the conductivity test or i can use the ¨Less than 1,3 us/cm¨ that is what we are using to control de mili q water.

The analysis by hplc was only because my boss wanted it , but its not my intention to put it in the CV protocol.

I know clean until it is clean is not GMP, and isnt my intention to do it, i pray to make a good CV :smile:

From what i know they want to have two processing/manufacturing equipment in the same room. The only thing that can be done, i think, is to make CV for the equipment that was not in use while a batch of the worst case was in progress. In this we need to put all the conditions ¨the not in use equipment¨ must have to be in the same room when a batch is in progress.

I hope you can understand what i mean.

Thanks in advice (Yep, this is a big topic and i hope can help somone in my possition)

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HPLC and swabbing is the best method, and I can see why your boss requested it. Swabbing is best because you are testing the actual surfaces of the equipment, and not the water where the contaminate may have been washed into (for rinsate). Also HPLC is better because it is specific, and looks for just the API, while TOC is generic and can easily become contaminated during sampling/handling (even by IPA which is used when donning/doffing gloves in the lab); but TOC is quicker turnaround.

In my past life, HPLC was used to test for API, and TOC was used to test for detergent. Regarding conductivity, i think it is good to ensure your water sample meets the Milli Q water standard, but this might not tell you with enough detail if the sample is clean enough. For example, if it takes a lot of product to raise the conductivity at all, then you might not “see” the product even though the conductivity reads 1.3 microSiemens / cm. Its likely that conductivity will be useful for monitoring cleaning agent as typical cleaning agents affect the conductivity a lot and can thus be measured with some accuracy using conductivity.

But in another previous life, conductivity was useful for determining cleaning. This application was for automated CIP cycles, where the conductivity was taken in real time.

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Ok, so can i said that if conductivity gives me less than 1,3 uS/cm then its absence of detergent?

Ok, so can i said if conductivity gives me less than 1,3 uS/cm is the detergent (SDS) in acceptable level? And if the TOC gives me less ppb C than the calculated i have the active in acceptable level and, in that way, pass the CV?
One last question, is this way of calculating the limit in the swab ok?

SWAB

Active in the next batch [mg] (RPPB): limit concentration of the active (CLA) x batch size (l)

Average active in the surface [mg/cm2] (PRS): RPPB x surface of the equipment (cm2)

swab content in the measured area[mg] (CHAM): PRS x Swab measured area [cm2] (SH)

Concentration of the swab area [PPM] (CAH): CHAM / dilution (ml)

Limit by TOC[PPB] (MCOT): (CAH x %C) x 10

The MCOT is the limit that we are going to use for the TOC

RINSE WATER

Active in the next batch [mg] (RPPB): limit concentration of the active (CLA) x batch size (l)

Average content in the total volume [mg/cm3] (PRVT): RPPB x volume equipment (cm3)

Content of the rinse water [mg] (CAEM): PRVT x sampled volume [cm3] (VM)

Concentration of the rinse water [PPM] (CEH): CAEM / dilution (ml)

Limit by TOC [PPB] (MCOT): (CEH x %C) x 10

El MCOT is the limit that we are going to use for the TOC

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Ok, so can i said that if conductivity gives me less than 1,3 uS/cm then its absence of detergent? Likely. This has to be confirmed by developing and validating a lab test method. You should get a response curve/reliationship, which shows that at X concentration you get Y conductivity, and create a profile for this. And this conductivity must be sensitive enough to show that you haven’t exceeded your detergent limit when you are at 1.3 microSiemens/cm

Ok, so can i said if conductivity gives me less than 1,3 uS/cm is the detergent (SDS) in acceptable level? And if the TOC gives me less ppb C than the calculated i have the active in acceptable level and, in that way, pass the CV? Yes, you have met the acceptance limit for that run, for that location…
One last question, is this way of calculating the limit in the swab ok? Sorry, I’m going to have to refer you to other discussions in this form to answer that question. The discussion about allowable carryover limit is very well discussed there - sorry not to answer your question - but I think you can easily find the answers there without too much extra work.

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Here is one of the few discussions on how to calculate carryover limit calculations

http://community.learnaboutgmp.com/t/cleaning-validation-maco-and-lod/5129/7

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I have only used conductivity of rinse water to confirm the end of the cleaning process (CIP). TOC can be used as a quick screening procedure but it will eventually end up as an HPLC analysis since it is more selective and many non-toxic molecules do have a TOC signature.

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Agreed. HPLC is the eventual test method in my experience also. There are too many ways for TOC to give you a false failure, and then you spend too much time investigating deviations.

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