Hi All,
In cleaning validation study, what is the Minimum daily dosage and Maximum daily dosage for a specific product, there is an equation to calculate MACO
TD X SF X BS / LDD how to get the data for TD (Minimum daily dosage for product A) and LDD (Maximum Daily dosage for product B)
if we consider the result for swab = 1.12 ug/100 cm2 after cleaning the equipment. the next batch size is 360 kg, surface area = 67500 cm2 and dosage unit is 500 mg.
Thanks all,
Dear Bluesky,
for the calculation of the MACO there are two figures missing:
-The minimum daily dosage of the contaminant (of which you found 1,12 µg/100 cm², i will call it “A”). For the calculation i will assume that the minimum daily dosage of A is 5 mgA/day of a solid dosage form.
As safety factor for solids 0,001 is currently used. So if the minimum daily dosage is 5 mg A/day, a “safe” contamination is 5 mg A/day x 0,001=0,005 mg A/day. This is the amount of active A that can be taken “safely” together with the product B, both per day. So, if you can take 3 dosage units of B per day, this is the amount of A in that 3 dosage units, or, per dosage unit, (0,005mgA/day)/(3 unitsB/day)=0,00167 mgA/unitB ≡ 1,67 µA/unit B.
The batch size of B is 360 kg and the dosage unit weight 500 mg, so batch size of B in units is (360 kg/Batch B x 1000000 mg/kg)/(500 mg/unit B)= 720000 units B/Batch B.
So, if 1,67 mg A were allowed in each unit B, in one batch of 720000 units B you can have (0,00167 mgA/unitB) x (720000 units b/Batch B)= 1202,4 mg A/Batch B, being this your MACO.
This figure assumes homogeneous distribution of contaminating A in the batch of B (which is only reasonable to assume until the last step with mixing action). This contamination is taken from the surfaces of the shared equipment (67500 cm²) by the product B, so the maximum allowed contamination per unit of surface is (1202,4 mg A/Batch B)/(67500 cm²/Batch B)=0,0178 mgA/cm² ≡ 17,8 µgA/cm², and this is the limit against which you compare the contamination of 1,12 µgA/100cm² ≡ 0,0112 µgA/cm² you found.
To compare this limit with the MaxRL: (1202,4 mg A/Batch B)/(360 kgB/Batch B) = 3,34 mgA/kgB=3,34 ppm < 10 ppm.
Hope this answered your question.
Best regards
Alfred
Dear Alfred,
Thank you, can you please tell me how to get Minimum and Maximum daily doses for Product A and B, can we do calculation without these data .
I know this equation MAC= TD X BS X SF / LDD that is what you said. with your data is 1202.4 mg A/Batch B
the other thing my result is 1.12 u/swab (100 cm2) how can I compare my result to MaxRL and how to find the MACO or ECO
for total surface area that means 1202.4 mg A/Batch B x 67500 cm2/batch B = 0.0178 mgA/cm2 = 17.8 ug/cm2
All thoughts are appreciated.
Regards,
Bluesky
Dear Bluesky,
the calculation cannot be performed without these data, unless you set arbitrary worst case figures so as to be on the safe side may come what may. It is not worth the effort, for the maximum and minimum daily dosages can be taken from the product leaflet, from the literature (e.g. Martindale) or through the internet. Some considerations:
The minimum daily dosage used should be made dependant form the product use: if there are pediatric dosages manufactured in the equipment, the minimum pediatric dosage should be used for the calculation of the allowed contamination.
Same applies to the targeted market: in many eastern countries, the minimum dosages are lower than in western countries, so take into consideration the potential export of the manufactured products. A little search in foreign vademecums will do no harm.
The other issue is the comparison of the result with the limit. Take into account that you began with the end of the story: usually the limit calculation is first and the swab result is the final outcome, and is then compared to the previously performed limit calculation. In your case you got a result of 0,0112 µgA/cm² (1,12 µg/100 cm²), which has to be compared to the calculated limit of 17,8 µgA/cm². In other words: You are far below the limit, probably because the drug is very soluble in water.
The MACO is what you call MAC. I do not like these acronyms because they are not standardized and can lead to confusion. Same applies to formulas: try reasoning the calculation and don´t apply the formula blindly (in fact the above formula is wrong: To calculate the MAC the equipment train surface is in the denominator and not in the numerator). Only as a personal advice.
Best regards
Alfred
Dear Alfred,
Thanks for your answer, now I have better idea for my study and I try to figure out the way to get these data, but if there is other way to calculate MACO please tell me. I remember we can do calcualtion based on MaxRl and DL of active to find out if our eqiupment is fail or pass , once again thanks a lot for your help.
Best Regards,
Bluesky
Dear Bluesky,
of course, there are other ways to calculate the MACO (or better, other figures to base the calculation on), but the use of the drug activity is the most widely used and recognized, albeit readily at hand. The use of other data (I don´t know what the acronym MaxRI stands for) like the toxicity has the disadvantage that you assume that the drug has a lower than common activity/toxicity relationship, like the case of oncology drugs, which in case of antibiotics is questionable (typically, an inspector will require you to perform calculations with both figures to see if you tried to tackle a non compliant cleaning using a more “favourable” figure to calculate your limit with). The use of toxicity data is normally limited to entities that are not part of the formulation (cleaning agents, lubricants, etc), and to drugs like the aforementioned, or which could cause other effects like allergenic drugs.
Best regards
Alfred
Dear Alfred,
Thanks a lot, actually MaxRL is Maximum Residue limit. In some companies, the acceptance limits for active ingredients residues are calculated by using therapeutic dosage information or LD50. If the MaxRL is greater than 10 ug then a default value is 10 ug and for less than 10 ug , the MaxRL is considered as a limit for Estimated Carry Over (ECO) . please tell me if you have any idea about this way and how we can calculate MaxRL .
Also ED50 is defined as 50% minimum effective dose or 50% of minimum dose manufactured (if minimum effective dose is not known).
If dosage information is not applicable, LD50 will be used to calculate acceptance limits for drug product. In practice ED50 is always lower than
LD50.
For calculation:
Actual amount of drug residue remaining on equipment after cleaning (Tr)=
S X R / 100 R = the highest detected amount of drug residue per swab
ECO= Tr / # of doses
Any idea about this calculation.
Best Regards,
Blue sky
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