Can any one tell me how to calculate the limit for the detergent residue for the detergent used in cleaning of equipment.
Not more than 10ppm/cm2 should be present in cleaned area.
Well what technique you are using for detecting the detergent residues??? can u share this.
Thanks for reply .
How this limit is fixed as NMT 10ppm/ cm2 ?
Is there any literature in suuport of this ?
Is this limit is irrespective of the detergent used for cleaning?
We are using UV spectrophotometer for detergent residue analysis .
Dear Tapan Kumar Panda,
to set the limit for the detergent residue unfortunately you have to rely on the detergent manufacturer. The, in my opinion, best way to set the residue limit is based on the toxicity data of all the components of the detergent formulation (that´s where the detergent manufacturer comes in!), and assuming that there is no significant difference in the “rinsability” of the different components (they all should be very soluble).
Our approach is based on an article of William Hall: “Validation of Cleaning Processes for Bulk Pharmaceutical Chemical Processes” in a publication of the IVT: “Cleaning Validation - An Exclusive Publication”, 1997.
Using the LD50 of the most toxic component, the NOEL (No Observed Effect Level) is estimated as:
NOEL=LD50 x 0,0005 x 70
0,0005 is a safety factor, according to the above mentioned publication, derived from toxicological data bases.
70 is the average weight of a normal adult, to convert the LD50-figure, which is expressed per kg weight, into an absolute figure of intake of the detergent component. Obviously, for parenteral formulations a lower weight should be used.
The NOEL now takes the place of the minimum pharmacological dosage of any active in the classical acceptance criteria calculation, to calculate the ADI (Accepted Daily Intake) as:
ADI = NOEL x 0,001
0,001 is the “usual” safety factor we use, in this case for oral formulations. For topic formulations it is 0,01 and for parenterals 0,0001. These safety factors can vary among different companies and publications.
With the ADI, the MACO is calculated using the minimum batch size and the maximum daily intake of the “contaminated” product.
This approach naturally gives levels that are comparable to the usually calculated API levels, and thus quite sensitive analytical methods need to be used. It is quite complicated to develop these methods, so i strongly recommend to ask the detergent manufacturer. The manufacturers specialized in the pharmaceutical industry (Alconox, Ecolab, etc.) have the toxicological data and the analytical methods at disposal for their clients, after some hassle with contracts, secrecy agreements and similar legal requirements.
Best regards
Alfred
So , based on LD 50 if we will calculate the detergent limit, then do we need to prepare a matrix as we prepare in case of calculation for chemical limit?
Because the previous product and next product will change every time.
Please suggest can we fix a certain limit for detergent?
[quote=Tapan Kumar Panda]So , based on LD 50 if we will calculate the detergent limit, then do we need to prepare a matrix as we prepare in case of calculation for chemical limit?
Because the previous product and next product will change every time.
Please suggest can we fix a certain limit for detergent?[/quote]
Dear Tapan Kumar Panda,
i don´t think there is a need for a complex matrix if you use a “worst case” approach. In that case, the most toxic detergent component takes the place of the contaminant, so there is no need for considering the “previous product”, which after all only serves to determine which is the contaminant. For the “next” product, and going ahead with the worst case approach, the product that will transfer the highest contamination to the patient is the one with the worst combination of daily intakes (maximum) and batch size (minimum). As an example, consider Ibuprofen 200 mg tablets, batch size 500000 tablets, maximum daily dosage 1200 mg/day (equivalent to 6 tablets/day), and Atenolol 50 mg tablets, batch size 800000 tablets, maximum daily dosage 200 mg/day (equivalent to 4 tablets/day): The worst case is Ibuprofen tablets, because the ratio 500000/6 is smaller than the ratio 800000/4, so with similar levels of detergent contamination in the equipment, with the Ibuprofen the patient could potentially take more detergent than with the Atenolol. This is one possible approach, there are many others, but in any case you will come out with one worst case next product.
Best regards
Alfred
Thanks for your valuable suggestion.
[quote=pharmacist48]Not more than 10ppm/cm2 should be present in cleaned area.
Well what technique you are using for detecting the detergent residues??? can u share this.[/quote]
Hi,
Usually commercially available , detergent contains one or more PHOSPHATE, in form of orthophosphate. So we are quantifying the amount of phosphate from calibration curves determined at preset levels.(ie), from LOQ level to 150% of target level. These calibration methods are locked in software, which becomes automatically invalidated after 30 Days or as user entered days.So in real time situations, we run blank and samples, which will be correlated to the ppm, by the recent calibration curves.
Simple technique>
Phosphates, particularly Orthophosphate in acidic conditions forms Phoshomolybadate, which is further reduced to MOLYBENUM BLUE[COLOURED COMPOUND] which can be determined colourimetrically. The said reagents are available as Test kits, so no need to prepare.
We are employing a Lambda 35 [UV-Vis Spectrophotometer], since this gives us detection upto 0.174ppm of phosphate. when same methodology, we are trying in SPECTROQUANT, we are able to obtain detection limit 0.219ppm
Other detection techniques include, Vanadium [Yellow method], but when compared for running cost of chemicals, instruments, MOLYBEDNUM BLUE method is cheap, accurate and very sensitive.
Hi all,
what about setting as ‘Not detected’ level since it should not be there in the first place? i.e LOD (limit of detection level) of a method.
Regards
Hi,
The value 10ppm/cm2 is proportional to the surface area of the production train,thus this value will change whenever the train changes.
for example if for the same batch size we have a train surface of 80000cm2 the total amount of residue will be 800000ppm.And if the train surface is 5000cm2 the total amount of residue will be 50000ppm ,and this will be of no sens if we consider the same active and the same batch size…
is there any colorimetric detection method for CIP100 residue? I have HPLC method but this takes too long .
Thanks
[quote=thami13]Hi,
The value 10ppm/cm2 is proportional to the surface area of the production train,thus this value will change whenever the train changes.
for example if for the same batch size we have a train surface of 80000cm2 the total amount of residue will be 800000ppm.And if the train surface is 5000cm2 the total amount of residue will be 50000ppm ,and this will be of no sens if we consider the same active and the same batch size…
is there any colorimetric detection method for CIP100 residue? I have HPLC method but this takes too long .
Thanks[/quote]
Dear thami13,
I don’t think a 10 ppm/cm² makes any sense, because ppm is a concentration unit. The limit used is 10 ppm of analyte in contaminated batch, and thus is not dependant from surface of equipment train. To obtain an “analytical” limit the absolute amount of contaminant in the equipment train (for a limit of 10 ppm and a batch size of 300 kg, it is 3000 mg) is divided by the train surface.
Best regards
Alfred