Different MACO Calculations for Topical Products - Which One to Use? HELP!

[Josephine Miles]

Hi,

I was after some help with figuring out what calculation to use when determine the MACO for topical products... I am trying to determine the surface limit (mg/100cm2) for 0.1% of the normal therapeutic dose of any product appearing in the maximum daily dose of the following product. I have 2 formulas but am not sure which one to use as they give different results...

First formula =
(0.1% x lowest therapeutic dose (A) x batch size (B) x swab area) / (maximum daily dose (B) x total equipment surface area)

Second forumla =
(0.1% x lowest available strenth of API in the product A (%) x batch size (B) x swab area) / (total equipment surface area)

The first formula is in terms of dosages (eg. 0.025g therapeutic dose) where as the second formula is in terms of the overall strength of API in the batch of A (eg. 5% API).

I have seen both formulas used before but am not clear on which one is the correct way to determine the 0.1% carry over limit.

If anyone could shed some light on this it would be great.

Thanks!!

Josephine

[ramyaraj725]

Dear Joseph...
How you derived 0.025 mg therapeutic dose? I think you might use 1 FTU (0.5g of total formulation) as minimum daily dose. But, according to Long and Finley, 1.75 mg of cream / ointment can be applied for cm2 of body surface. So, minimum dose of A = 1.75 mg x 5% = 0.087 mg. Formula which I have used in my company is...

MACO = (0.1% x concentration of API in formulation x batch size of next product x swab area) / (Max. No. of application of B per day x equipment surface area)

Pls find the attached article for more information on this subject.

Regards
Veerraju

[Josephine Miles]

Thanks Veerraju,

Yes, I used 1FTU=0.5g as the minimum dosage for A (1FTU=1 single dose). As the cream (A) contains 5% active, 0.5g x 5% = 0.025g is the minimum therapeutic dose of A... Why is it necessary to convert to 1.75mg of cream per cm2 of body surface? Why not just stick with the 1FTU=0.5g single dose?

Also, in your formula you use the 'concentration of API in forumlation', will that be 5%? As the total concentration of active in the batch of A is 5%? If that is the case what is the need for the (1.75mg x 5%) 0.087mg minimum dose of A calculation?

Thanks so much for your help.

Josephine

[ovais]

Dear Ms Josephine,

The estimation of CV acceptance limit for topical formulation is based on either of following two approaches:
a. Minimum daily dose: which is estimated based on minimum amount applied topically in one application and
b. Lowest available strength of product multiplied by appropriate safety factor (I prefer using this approach as this will give lower MACO values compared to former).

For more information about the approaches, you may refer to my article here: http://pharmtech.findpharma.com/phar.../detail/481947

I use approach no. "b" for estimation of CV limits.

Hope this is will be useful.

Regards,

Ovais

[ramyaraj725]

Same article was attached in PDF format in my previous reply.
I learned "cleaning valdiaiton of topical formulations" form ovais' article only
As per his recommendations, you can use second formula, which was defined by you in your question.

[Josephine Miles]

Thank you very much to both of you for all your help. Great article too, I have been using it for all my MACO work so far, thank you!

Just to clarify, there is no single forumla everyone should use when calculating MACO. So long as the calculated limit is justified.

One other question... for the 'therapeutic dose' of a cream, is that the single daily dose for that product (eg. 0.5g) OR the amount of therapeutic agent (API) in that single dose (eg. for a cream containing 5% active, 0.5g x 5% = 0.025g).

If there is no defined maximum and minimum dosages for the product, is a maximum application of 4 times per day a safe assumption to make for most creams/ointments??

Thank you once again for all your help!

[ramyaraj725]

Dear Joseph...

You can use any of the two formulas. But, to get the lesser MACO value, use the second one. For oral products, you can calculate MACO based on dose, or 10 ppm assumption or 1/1000th minimum dose basis.

For any kind of formulation, when you are calculating MACO, single daily dose (for previous product) should be the quantity of API. And, for next product, maximum daily dose should be the quantity of complete formulation.

Generally, for any topical product (creams, ointments, lotions, beauty creams, make up items etc.), there is no defined dosage. So, as a worst case scenario, you can consider "minimum doses per day (previous product) = 1 time" and "maximum doses per day (next product) = 4 times

Regards
Veerraju

[bujjikanchi]

Can you please explain the Difference between maximum dialy dose and Minimum dialy dose ?

[ramyaraj725]

Sorry for the delayed reply
I'm on leave due to a major surgery to my left ear
pls see the below example


Product: Omeprazole
Permitted dose = 10 mg & 20 mg
No. of time that the drug can be given to patient in a day = 3
So, minimum single dose = 10 and maximum daily dose = 20 mg x 3 = 60 mg

Veerraju