# API + Cleaning solution limits

Hi everyone! i´m new in the forum and i´d like to know if my ideas are correct or not. i have no much experience and i´m doing my first cleaning validation and i have the following question. i calculated the limit for the api and after cleaning process, i swabed the surface and calculate the residue. Then analize the final rinse looking for APi too. But i have limit for api only and i want to add limit for the cleaning solution. Said it this way, I have two different residues and two different limits. i think would not be correct.
I think it would be wrong to calculate a limit based on the API or other limit based on the cleaning solution, but should include both two.
Best regards
Fabian.

Dear Fabian…
First, clean the equipment with cleaning solution and test for the residue of API. Then, wash the equipment with water and test the residue of cleaning solution. if you are using a detergent solution as a cleaning solution, then calculate its acceptable limit using LD50 value of the detergent. if you are using an organic solvent as cleaning solution, then you can consider its ICH limit as acceptable limit.

Regards
Veerraju

In order to achieve the limit for cleaning solution, starting for its LD50 which calculate must do. I suppose must use the NOEL but i´m not so sure the factor i should use. The LD50 for the active cleaning substance is 3000mg/kg. and the subsequent product could be oral or parenteral formulations.
Best regards, and thanks again.
Fabian.

Dear Fabian…

NOEL = LD50 x Adult Average Weight / 2000 (empirical factor, derived by Layton)
So, NOEL = 3000 mg/kg x 70 kg / 2000 = 105 mg

Then, MACO = NOEL x maximum BS of next product / safety factor x Daily dose of next product
Consider the parenteral product as next product (as a worst case scenario) and use 10000 as safety factor

Regards
Veerraju

i have question about the MACO’s units that i must express for

if MACO = NOEL x maximum BS of next product / safety factor x Daily dose of next product

i.e.
MACO= 2,9225mg
and mi BS= 287,5 kg
SF=10000
Dd next rod= 10ml
then MACO = 2.9225 mg * 287m5kg / 10000 * 10ml = ?? units??
Thanks and when solve this doubt i will continue asking about MACO
Best regards
Fabian

The minimum batch size isto be converted to mg and then to be used in formula

Dear friend…

daily dose = quantity of a drug substance, in mg, given to a patient.
so, if your product strength is 10 mg / ml, then daily dose = 10 ml x 100 mg / ml = 100 mg

And, maximum batch size = quantity of API used in for formulation of next product
So, if your batch size is 10 litres, then batch size = 10 litre x 10 mg / ml = 100000 mg

then MACO = 2.9225 mg x 100000 mg / 10000 x 100 mg = 0.29225 mg = 292.25 µg
i think is clear to you…

Regards
Veerraju

Dear Veerraju! thanks lot!, I am learning as time goes by and asked more things. i´ll tell you my concern with real example to see what happens and to see what you think about.
i must calculate the limit for Detergent, so i have this data in order to calculate that limit:

LD50 = 105 mg/kg
Weigh = 40kg
Empiric constant = 2000
Then, NOEL = 2,1 mg correct me if i´m wrong please

ADI= NOEL/SF = 2,1 GM /10000 (´cos the next prod is injectable) = 0,00021 mg

Then,
LBS = 500 Liters of next product (it is a multivitamin and aminoacids mixture, injectable) with maximun daily dose of 400ml (MDD = 400ml)
my question is, if i should calculate the total amount of api´s species or may take only one of this api of the complex mixture in order to calculate LBS? and the same procedure with MDD. This concept is not yet ver clear to me, as you can see.

MACO = 0.00021 mg * LBS / MDD

Thanks again Veerraju!
Best regards!
Fabian

Dear Fabins…
I’m learning a lot while getting an answer for you
Your NOEL is 3.675 mg, since the adult average weight should be 70 kg.

MDD = 400 ml. is it correct? I never saw such a higher volume. Once recheck and get it ensured.

Then ADI = 3.675 mg / 10000 = 0.0003675 mg

Then MACO = 0.0003675 mg x 500000 ml / 400 ml = 0.46 mg (cancel the “ml” in numerator and denominator)

I think its clear to you…

Weigh is correct because is the minor weigh of specimen (ovine) cos we produce veterinary products (no human products) so if we return to the calculation then, MACO will be 0.00021 but thank you for your note and apoligize because didnt explain this before.
400ml is in fact the major daily dosis of the next product but, and here it´s my concern, this next product is a multivitamin and aminoacids injectable product. in the example you gave me MACO = ADI * Batch in ml / max dosis also in ml but, at the begining, batch is in mg because you use the dosis strenght and that´s why i´m wondering how to calculate this with this mixture of great quantity of API,
tell me what you think.
Best regards dear friend.

Dear Fabian…
If you consider your batch size in mg, then you have to consider the dosage quantity in mg. But, if your batch size is ml / litre, then dosage should also be in ml.

Since your product is veterinary, then our calculation is wrong again. We have used the adult average weight of human being and empirical factor (2000) which is an ‘extrapolation from animal studies to human beings’.

To provide apt answer in this case, I need some more data. It’s becoming a long lasting discussion. Send your facebook id to "nvr.veeru@gmail.com". We shall sit for a chat and shall derive a concrete MACO value. Sorry for unable to provide complete information in this time.

Regards
Veerraju

OK!
Regards
Fabian.