# Therapeutic dose based MACO calculation help needed

Hi,

I have questions regarding therapeutic dose. what is therapuetic dose? for example, if drug has prescribed for 3 days with 200 mg capsules two times in a day. what is the therapeutic dose? 200 mg?? is it the minimum single dose 200 mg considered therapeutic dose?

Thanks,
Patel

Dear Patel,

as you say the therapeutic dose is the minimum one. The general idea is to consider the minimum amount of drug that could potentially lead to a pharmacological action, and that is why the minimum therapeutic dose is independent from the times per day, and the period during which it is taken. Two considerations:

• If you manufacture products that have a pediatric indication, the therapeutic dose for the worst case active considere should be the pediatric dose.

• To make figures comparable, usual practice is to consider a day. So, if the product is taken once a week, the minimum therapeutic dose is 1/7 of the drug amount present in the product.

So, at least as a first approach, in your example the minimum dose is 200 mg (I assume this is the active ingredient content and not the formulated product as capsule filling).

Best regards

Alfred

Hi Alfred,

thanks for the reply. it is very useful. i have further questions on setting up MACO calculations based on therapeutic dose and toxicity.

1. If as per my example, Product A has 200mg therapeutic dose (three times in a day 200 mg) but if you consider the same product as next product B, the maximum daily dosage would be 600 mg. is that correct?

2. i work in clinical trials packaging services, where it is very rare to have therapeutic dose details available. in that case i use toxicity LD50 value to set up MACO. and i often end up having really high MACO limit. for example 2529 mg in 8129 mg. in that case what criteria i should consider to set up MACO?? 10 ppm ?? 10ppm= 10 mg/kg (A) * batch size product B

In my case, batch size for the next product is, 108,395 units of 75 mcg softgel. if i convert 108,395*75 mcg= 8129625 mcg= 8129.62 mg. which value i should use for batch size, number of units or mass to set up the MACO??

If i use mass, then 10ppm= 10 mg/kg * 8129.62 mg = 81296.2 mg2/kg
equipment shared surface area= 2785.9 in2
swab area= 4 in2

hence, (81296.2 mg2/kg / 2785.9 in2) * 4 in2 = 116.72 mg2/kg

please help me how do you do unit conversion?? why i have such a high number of MACO??

Patel

Dear Patel,

I will go through your questions:

1- It is not entirely correct. You are not specifying if the 200 mg are the amount of active ingredient, as used for the minimum dose calculation, or if the 200 mg are formulated product (with excipients). If you fill the active alone in capsules, your calculation is right.

2- If you use the toxicity (LD50), it is very unlikely to get the values you are obtaining, unless your actives are of extremely low activity. Regarding your example, I am under the impression that you are mistaking dose of active ingredient for formulated product: Are you sure your batch size is 8129 mg = 8.129 g? How do you fill 75 µg in each capsule? Even for clinical trials the dose information should be readily available, because you know exactly how much active you are giving each patient during the trial. In any case, there is an unit problem in the calculation:

Let’s assume the following (I add the product denomination , X or Y, to each unit to clarify):

• Worst case contaminant: Let’s call it X.
• Worst case contaminated product: Let’s call it Y. Its batch size is 8129 mgY/BatchY = 8,129 gY/BatchY = 108395 units of 75 µg each, taken once a day.

So the contaminant is the active X and you accept a 10 ppm = 10 mgX/kgY contamination in the next batch of Y. This is 10 mg of X contaminating 1 kg of the formulated product Y from the next batch. If in 1 kgY = 1000000 mgY you accept 10 mg of X, then in 1 mgY you will accept 10 mgX/kgY * 0.000001 kgY/mgY = 0.00001 mgX/mgY

The batch size of Y is 8129 mg = 8129 mgY/batchY. If you accept 0,0001 mgX/mgY, in 8129 mgY/batchY you will accept 0,00001 mgX/mgY * 8129 mgY/batchY = 0,08129 mgX/batchY. This is the maximum amount of X allowed to contaminate one batch Y and thus the shared equipment. If the surface of the shared equipment is 2785,9 in², this is the contamination assumed to be uniformly spread over thas 2785.9 in², and thus the contamination per surface unit is 0.08129 mgX/2785.9 in²= 0,000029 mgX/in² or 0,029 µgX/in². Calculated per 4 in² swabbed area and thus per swab, the limit is 0,117 µgX/swab.

As you see, you reach fairly low contamination limits, and this is due to the extremely small batch size of Y (check it, I cannot believe this is the real batch size). Your mistake stems from multiplying 10 mg/kg * 8129 mg disregarding the real units: 10 mgX/kgY * 8129 mgY/batchY = 81290 mgX mgY/kgY batchY. The conversion factor of 0.00001 kgY/mgY is missing, and you confounded mgX with mgY. This is why you reached the units mg²/mg, which are inconsistent with a contamination per surface unit. The last calculation has a mistake, too: the real unit of the swabbed area is not 4 in² but 4 in²/swabbed area, and the result is 0,117 µg/swabbed area.

Hope this has helped somewhat. Only for curiosity: as a feedback, tell me if the batch size of Y is really 8129 mg, or if you confused active with formulated product. How do you physically dose 75 µg?

Best regards

Alfred

Good posting

Rambabu
Kamud Drugs
09373082156