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Cleaning Validation Acceptance Criteria - Article of the month

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I may be of some help in this case. MAC is calculated at 10 ppm approach, in my opinion. Pls comment.

Rinse sampling technique is simple & easy to understand, because the entire equipment surface gets exposed by the solvent used and the concentration of contamination in sample is representative of the overall contamination of that equipment (after adjusting with Rinse Recovery Factor). No further manupulation with test result is required to make conclusion.
But the story is some how different in case of Swab sampling. Since a limited equipment area is sampled, the result obtained from analysis is reqired to get transformed into surface contamination level (ppm to micro gram/swab to total contamination load of a perticular equipment or vise versa). Therefore to know the possible surface contamination, knowledge of equipment surface area is a must.
Secondly, in an environment of water base cleaning for insoluble contaminents (which is common in industry), sole reliability on rinse water may not be enough. In that case, swabbing method is a justified option supported by rinse & visual verification.

There are two general types of sampling that have been found acceptable. The most advantageous and desirable is the direct method of sampling from the surface of the equipment. Another method is the use of rinse solutions. In direct sampling (swab sample), the type of sampling material used and its impact on the test data is determined, since the sampling material may interfere with the test. For example, the adhesive used in swabs has been found to interfere with the analysis of samples. Therefore, early in the validation program, it is important to ensure that the sampling medium and solvent being used for extraction from the medium are satisfactory and can be readily used. Direct sampling ensures that areas hardest to clean and which are reasonably accessible can be evaluated, leading to establishing a level of contamination (residue per given surface area). Moreover, residues that are “dried out” or are insoluble can be sampled by physical removal. Whereas, rinse sampling method holds its own advantages, that is, a larger surface area may be sampled and inaccessible systems or ones that cannot be routinely disassembled can be sampled and evaluated. A disadvantage of rinse samples is that the residue or contaminant may not be soluble or may be physically occluded in the equipment, an analogy that can be used as the “dirty pot”. In the evaluation of cleaning of a dirty pot, particularly with dried out residue, one does not look at the rinse sample to see that it is clean; one looks at the pot (direct sampling). Check to see that a direct measurement of the residue or contaminant has been made for the rinse water when it is used to validate the cleaning process. For example, it is not acceptable to simply test rinse water for water quality (does it meet the compendia tests) rather than test it for potential contaminates.

Dear All
Advantages of Non Specific method over Specific method
There are two types of assay methods for determination of rinse samples and direct swab samples in cleaning validation or routine cleaning. HPLC is a lengthy analysis and delays cleaning validation analysis and routine cleaning analysis. This can lead to downtime of hours or days, contributing to high costs and limiting the amount of product reaching patients. these Specific HPLC methods are limited to the determination of one analyte and donot cover other range of products sharing the same equipment. so one need to go for the worst case for each manufacturing line. HPLC methods need development to be specific and it is to be validated. TOC Analyzer to both combustion/catalyst NDIR and combustion NDIR, including estimated monthly operating cost, gives the assurance for detecting even low levels of organic compounds, and allows for detection of contamination not possible via HPLC.
TOC is a fast and simple analytical method and has been shown to reduce downtime and method validation time by more than 75% over conventional methods. With the FDA’s recent guidance to enhance and modernize the
regulation of pharmaceutical manufacturing (cGMP’s for the 21st Century), gains in quality and efficiency have led to a growing interest in using TOC analysis for cleaning validation over a specific analytical method like HPLC.

Dear Saqib Altaf
We can choose both on the basis of 10 ppm or on minim.and maxim. daily dose calculation which is less (for safety).

Dear Shambhu You are right. In absence of any one efficiency of cleaning can not be justified.

Anand Kumar Singh
Executive _ QA

Nicholas Piramal (I) Ltd

I think both member sambhu and shahnawaz more or less talking the same thing, Rinse method is easy and simple to understand but best reliable method to perform cleaning validation is Direct sampling method.

Yes,I agree with Mr. Shahid Ali; because rinse may be easy and cover more area but not effective and reliable as much as swab but alone swab can not justified the effectiveness of cleaning.So we should consider about swab , rinse and visual verification collectivelly.

Anand kumar Singh

Executive-QA
Nicholas Piramal (I)Ltd.

Nice thread, very informative!

Dear shahid
Though TOc is simple,easy,less time consuming
results r getting eaisly.
but this method is non-specific. We r not doing Analytical method validation for all the products.AMV is general.
Is it acceptable to FDA.
TOC is giving results only in Carbon content.

pls specify,if this method is handy…

prasad
validation
NICHOLAS-PIRAMAL INDIA.

[quote=Shahid Ali]Dear All
Advantages of Non Specific method over Specific method
There are two types of assay methods for determination of rinse samples and direct swab samples in cleaning validation or routine cleaning. HPLC is a lengthy analysis and delays cleaning validation analysis and routine cleaning analysis. This can lead to downtime of hours or days, contributing to high costs and limiting the amount of product reaching patients. these Specific HPLC methods are limited to the determination of one analyte and donot cover other range of products sharing the same equipment. so one need to go for the worst case for each manufacturing line. HPLC methods need development to be specific and it is to be validated. TOC Analyzer to both combustion/catalyst NDIR and combustion NDIR, including estimated monthly operating cost, gives the assurance for detecting even low levels of organic compounds, and allows for detection of contamination not possible via HPLC.
TOC is a fast and simple analytical method and has been shown to reduce downtime and method validation time by more than 75% over conventional methods. With the FDA’s recent guidance to enhance and modernize the
regulation of pharmaceutical manufacturing (cGMP’s for the 21st Century), gains in quality and efficiency have led to a growing interest in using TOC analysis for cleaning validation over a specific analytical method like HPLC.[/quote]

Dear Prasad,
Is it acceptable to FDA? answer for your first question is below.

FDA comments below regarding Cleaning validation via TOC.

Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?
Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.
References:
21 CFR 211.67: Equipment cleaning and maintenance.
21 CFR 211.160(b): General requirements (Laboratory Controls)
USP 643 Total Organic Carbon
Guide to Inspections of Cleaning Validation, 1993


Answer for secound question is:
TOC can be used toquantify most of the impurities and residues in equipmentthat was not cleaned properly, and measures allcarbon-containing compounds: APIs (Active PharmaceuticalIngredients), cleaning agents, proteins, andintermediates. Analytical technologies utilized to measureTOC share the objective of completely oxidizing the organic molecules in an aliquot of sample water to CO2,measuring the resultant CO2 levels, and expressing this response as carbon concentration. All technologies mustdiscriminate between the inorganic carbon, which maybe present in the water from sources such as dissolved
CO2 and bicarbonate, and the CO2 generated from theoxidation of organic molecules in the sample. TOC is determined by subtracting the measured inorganic carbon (IC)
from the measured total carbon (TC), which is the sum of
organic carbon and inorganic carbon: TOC = TC - IC.
TOC analysis can be adapted to any drug compoundor cleaning agent that contains carbon. The method is sensitive to the ppb range and is less timeconsuming than HPLC

Thanks for the clarification.

pls can u tell me the procedure
of swab recovery using TOC.
is there any RSD limit for that.

prasad
executive-validation
NICHOLAS PIRAMAL INDIA LTD.PITHAMPUR
09826572940

Dear Prasad,
Is it acceptable to FDA? answer for your first question is below.

FDA comments below regarding Cleaning validation via TOC.

Can Total Organic Carbon (TOC) be an acceptable method for detecting residues of contaminants in evaluating cleaning effectiveness?
Yes. Since the publication of the inspection guide on cleaning validation in 1993, a number of studies have been published to demonstrate the adequacy of TOC in measuring contaminant residues.
TOC or TC can be an acceptable method for monitoring residues routinely and for cleaning validation. In order for TOC to be functionally suitable, it should first be established that a substantial amount of the contaminating material(s) is organic and contains carbon that can be oxidized under TOC test conditions. This is an important exercise because some organic compounds cannot be reliably detected using TOC.
TOC use may be justified for direct surface sample testing as well as indirect (rinse water) sample testing. In either case, because TOC does not identify or distinguish among different compounds containing oxidizable carbon, any detected carbon is to be attributed to the target compound(s) for comparing with the established limit. Thus, a firm should limit ‘background’ carbon (i.e., carbon from sources other than the contaminant being removed) as much as possible. If TOC samples are being held for long periods of time before analysis, a firm should verify the impact of sample holding time on accuracy and limit of quantitation.
References:
21 CFR 211.67: Equipment cleaning and maintenance.
21 CFR 211.160(b): General requirements (Laboratory Controls)
USP 643 Total Organic Carbon
Guide to Inspections of Cleaning Validation, 1993


Answer for secound question is:
TOC can be used toquantify most of the impurities and residues in equipmentthat was not cleaned properly, and measures allcarbon-containing compounds: APIs (Active PharmaceuticalIngredients), cleaning agents, proteins, andintermediates. Analytical technologies utilized to measureTOC share the objective of completely oxidizing the organic molecules in an aliquot of sample water to CO2,measuring the resultant CO2 levels, and expressing this response as carbon concentration. All technologies mustdiscriminate between the inorganic carbon, which maybe present in the water from sources such as dissolved
CO2 and bicarbonate, and the CO2 generated from theoxidation of organic molecules in the sample. TOC is determined by subtracting the measured inorganic carbon (IC)
from the measured total carbon (TC), which is the sum of
organic carbon and inorganic carbon: TOC = TC - IC.
TOC analysis can be adapted to any drug compoundor cleaning agent that contains carbon. The method is sensitive to the ppb range and is less timeconsuming than HPLC[/quote]

Dear Shahnawaz,

Thank you very much for the valuable information you have provided.
I have a question, can we correlate the tests results obtained from a specific & a nonspecific method?
My intention is to carry out cleaning validation of a perticular product on both specific & non specific analytical methods and correlating two results to draw conclusion.
Now a trend shall be established by compilling two results, on the basis of what (non specific test result) alert & action limit shall be cast.
All routine cleaning samples shall be tested (by non specific method) & verified against these set limits & any kind of OOT shall immediately be investigated.

Plz reply ASAP, I’ll be waiting for your advice.

[quote=Sambhu]Dear Shahnawaz,

Thank you very much for the valuable information you have provided.
I have a question, can we correlate the tests results obtained from a specific & a nonspecific method?
My intention is to carry out cleaning validation of a perticular product on both specific & non specific analytical methods and correlating two results to draw conclusion.
Now a trend shall be established by compilling two results, on the basis of what (non specific test result) alert & action limit shall be cast.
All routine cleaning samples shall be tested (by non specific method) & verified against these set limits & any kind of OOT shall immediately be investigated.

Plz reply ASAP, I’ll be waiting for your advice.[/quote]

If one is expecting correlation between TOC and HPLC methods on samples obtained in cleaning validation protocols, then this is an unreasonable expectation. Yes, the HPLC method will tell you how much of the target residue (for example, the active) is present. However, TOC is subject to a variety of ‘interferences’ (excipients and cleaning agent) that raise the measured carbon value. One cannot expect that the ratio of organic carbon from the active to the combined TOC is going to be constant in every sample (which could perhaps give a correlation). The bottom line is that TOC, appropriately validated, is sufficient without any correlation to a specific method.

Reference: Dispelling Cleaning Validation Myths: Part II

This is the second part of an article on common misunderstandings surrounding cleaning validation for pharmaceutical process equipment.

01 December 2005
By: Destin A. LeBlanc
Pharmaceutical Technology Europe

To me it would be more appropriate if certain API standard solutions (relevent to range of products) are checked at or around the TOC residue limit in the sample with each set of samples (for example, one check standard at the beginning of the run and one check standard at the end of the run). We should keep one thing in mind that TOC is a compendial method that is designed for the testing of Purefied water and Water for injection. For Cleaning validation it should be fully validated for accuracy and precision studies. Of course, there is no need to look for specificity, because TOC is a non-specific test (unless you really want to be technical and say that TOC is a specific method for organic carbon). In addition, measures of the limit of quantitation and limit of detection are performed differently for TOC as compared to methods like HPLC.

[quote=Sambhu]Dear Shahnawaz,

Thank you very much for the valuable information you have provided.
I have a question, can we correlate the tests results obtained from a specific & a nonspecific method?
My intention is to carry out cleaning validation of a perticular product on both specific & non specific analytical methods and correlating two results to draw conclusion.
Now a trend shall be established by compilling two results, on the basis of what (non specific test result) alert & action limit shall be cast.
All routine cleaning samples shall be tested (by non specific method) & verified against these set limits & any kind of OOT shall immediately be investigated.

Plz reply ASAP, I’ll be waiting for your advice.[/quote]
Dear Sambhu,
We cannot correlate the results of TOC and HPLC because In HPLC (Specific technique) we just targets the selective compound not other things, so it shows the API results, but in TOC analysis, it gives overall results, so results trends can be same some times but not always. Yes you can use both techniques on CLV and draw co-relation between them. Yes it a right way which you wrote here (All routine cleaning samples shall be tested (by non specific method) & verified against these set limits & any kind of OOT shall immediately be investigated.)
Thanks

Dear Shahid & Shahnawaz

Thank you very very much for your replies. You wont believe how much your advices helped me to come out from a big dilemma. As I realised the difference between knowing theories and doing practicles. I tied up all little points gathered from you people & going to start the cleaning validation study in my domain.
I’ll defenately share my experiences here after.
Once again thank you all.

[quote=Sambhu]Dear Shahid & Shahnawaz

Thank you very very much for your replies. You wont believe how much your advices helped me to come out from a big dilemma. As I realised the difference between knowing theories and doing practicles. I tied up all little points gathered from you people & going to start the cleaning validation study in my domain.
I’ll defenately share my experiences here after.
Once again thank you all.[/quote]

Dear Sambhu,
Its my pleasure to response things which i know. I always available to help u out in any problems regarding any pharmaceutical problems.

Thanks

I think MAR value is more stringent than 10 ppm criteria.

MAR value is specific for that particular product,but 10 ppm is std.limit applicable to all .

I think MAR value must be taken into consideration for cleaning validation acceptaance criteria.

Prasad
prasadaparajit@rediffmail.com