What do u mean by MACO calculation.

Dear sanmut,

MACO is the Maximum Allowable CarryOver, it is the maximum amount of contaminant that is accepted to contaminate the equipment and thus carried over to the next batch.

Best regards

Alfred

Dear Alfred,

i would like to know more about MACo calculation. Could you please illustrate it with simple example?

thank you

SUNITA

Dear sunita,

I’ll try to make it as simple as possible, but there are many variables and decision points which may be different for your scenario. To make it simpler, I will take a real life example.

Equipment: Bohle MCG 1000 bin, product exposed surface: 60910 cm²

Actives manufactured in the equipment: Alprazolam, Atenolol, Thioctic acid

Minimum therapeutic dosage: Alprazolam: 0,25 mg / Atenolol: 25 mg / Thioctic acid: 25 mg. Most active: Alprazolam.

Solubilities: Alprazolam: 0,1 mg/ml / Atenolol: 13,5 mg/ml / Thioctic acid: 0,4 mg/ml. Most insoluble: Alprazolam.

Worst case of contaminant: Alprazolam (Abbreviation: A). In case that the most active is not the most insoluble, solibility overruns activity. Weighing: 95% solubility in mg/ml, 5% activity in mg. This weighing is arbitrary!

Worst case of contaminated product: This is the most complicated part: The worst case is the product which minimizes the factor (Batch size[tablets])/(maximum daily intake[tablets/day]*manufacturing train surface[cm²]) Units between square brackets[]. The units are essential for consistency.
So, worst case contaminated product is product B with 50 mg Thioctic acid as the active. Batch size: 600000 tablets (177 kg). Maximum daily dosage of Thioctic acid: 300 mg/day equivalent to 6 tablets/day with 50 mg Thioctic acid. Shared equipment train product exposed surface: 334391 cm. The aforementioned factor is 600000/(6*334391)=0,3 cm-².

MACO calculation: So, based on the minimum therapeutic dosage and a safety factor of 1/1000=0,001): Maximum amount of Alprazolam per day allowed to be ingested is:

0,25mgA/day* 0,001= 0,00025 mgA/day ≡ 0,25 µgA/day. This is the amount allowed to be contaminating 6 tablets of the product B because it is the daily intake of B, so per tablet of B the contamination is:

(0,00025 mgA/day)/(6 tablets B/day)=0,00004 mgA/tablet B,

To compare this limit against the dEfault limit of 10 ppm the batch size of b in kg is needed: Per batch B, the amount of contamination is:

(0,00004µgA/tablet B)*(600000 tablets B/batchB)= 25 mgA/batchB ≡ 25 mgA/177kgB = 0,14 mgA/kgB = 0,14 ppm < 10 ppm, so we can go without the default level. The MACO is then 25 mgA/batch B

Equipment contamination limit: Allowed maximum contamination per batch B is 25 mgA/batchB, which is in contact with the shared equipment train surface. Per unit of surface the contamination is then:

(25mgA/batch B)/(334391 cm²/batchB)=0,000075 mgA/cm² ≡ 0,075 µgA/cm². So, in the Bohle MCG 1000 bin with a surface of 60910 cm², the allowed contamination is 4568 µgA or 4,5 mgA.

If you put all the figures in one formula, you will see that the aforementioned factor appears multiplying the minimum therapeutic dosage and the safety factor. Thus, minimizing this factor the most stringent level of contamination is obtained, and that is the reason for the choice of the product which minimizes this factor. This is especially useful to automate the calculation with a spreadsheet.

Try repeating the calculation with your figures, and if there are further questions, simply contact me.

Best regards

Alfred

Dear alfred sir,

as u mentioned above,

worst case of contaminated product is pdt B, and is the product which is having minimum factor value.

what this factor indicates?

Dear nil,

the factor mentioned is the one used to choose the worst case contaminated product (the product which minimizes the factor):

f= BS/(MDI*S)

BS = Batch size (in tablets)

MDI = Maximum daily intake (in tablets/day)

S = Manufacturing train surface (in cm²)

The units are essential for consistency.

This factor represents the inverse of the fraction of the “contaminated” batch taken per day that makes contact with the entire surface of the shared equipment train. At the same time this is the fraction that is allowed to carry the maximum of contaminant.

The complete calculation for the maximum allowed contamination (MAC) per surface unit is then:

MAC = mdta * 0,001 * f

mdta = minimum therapeutic dosage of worst case contaminant.

0,001: Safety factor

The most challenging MAC is obtained with the minimum f, this is why the minimum f is chosen.

Best regards

Alfred

Thank you, Alfred sir!