Learnaboutgmp Community

Cleaning Validation MACO and LOD

My SOP is saying : “if the Minimum MACO observed from the overall matrix is found to be less than LOQof existing available Molecules then LOD Value shall be considered as MACO Value for the results verification”

MACO is in Mg/swab
and LOD/LOQ is in PPM therfore MACO is always less.

e.g.
For XYZ product:
MACO=0.27 mg/swab
LOD= 0.1 PPM
LOQ= 0.2 PPM
In this case MACO is more than LOD then MACO is considered as limit.

Till Date I was not converted this MACO value in PPM and compared; now someone suggested me, to convert MACO in PPM and then all MACO values will be less than LOD

1 Like

LOD is meaningless (it like believing in Leprechauns, the little Irish people). MACO is no longer relevant. The acceptance criteria is now based on the ADE (acceptable daily exposure, a measure of toxicity). See chapters 3 and 5 of the Eudralex.

Seems like someone is not keeping up the SOP’s!

I agree with @Boomer_Chemist. MACO should be based on ADI (acceptable daily intake) and NOEL (no observed effect limit).

Thanks,

There is a difference between the ADI (acceptable daily intake, a dietary factor) and ADE (acceptable daily exposure, a measure of toxicity)

Sorry! I misread Intake instead of exposure. I think use of ADI is considered an improvement for risk evaluation over the 10 ppm approach.
Also, sometimes ADE can give you a large MACO value that might not be acceptable for cross contamination. But again that’s subjective based on your own requirements.

Some good references: “Guide to cleaning validation in API Plants”
“Guidance on aspects fo cleaning vlalidation in active pharmaceutical ingredient plants”

Your SOP is out of date (someone is asleep at the switch!). We now use the ADE (acceptable daily exposure, a measure of toxicity) to calculate our ‘cleaning validation acceptance criteria’. Perform a ‘risk analysis’ to target the lowest ADE and molecule manufactured in your facility. Then determine which cleaning procedure is effective using the target as the ‘yardstick’.

Cite chapter 3 and 5 of the Eudralex.

I think u r misunderstanding the concept… MACO is maximum allowable in next batch. Which is calculated minimum value by toxicity or tdd or 10ppm criteria. And LOD or LOQ are represents capability of your analytcal method. If MACO is lower than LOQ; then your cleaning analytical method will not gives correct result due to its un-capability. Now if your SOP saying that if MACO less than LOQ then consider LOQ value as MACO is not true because in this case you are allowing contamination more than MACO requirement which is not acceptable.

1 Like

Agreed. I’ve used a few methods to determine “Maximum Allowable Carry Over” limit. We called the limit MACO, even though they were calculated different ways.

We used the (1) LD50 method, (2) the maximum daily dose carryover (ADE) and (3) the 10 ppm method. If I understand the ADE method you are referencing, it utelized the “daily dose” of product A and surface areas of product A and product B equipment to calculate allowable surface limits. There is no “daily dose” of cleaning agents, and so we used the LD50 method for cleaning agents. We used the 10 ppm before we had established the daily does (such as for early development activities).

For each method, whatever you calculate your limit to be - your lab method must be more accurate/precise/sensitive than your limit. That is you cannot have a Limit of Detection / Limit of Quantification to be 10 (for example) and you allowable carryover limit to be 3. If it were, you could exceed the safe limit (3), but not see it until it became so bad it was over 10.

I think no one has answered your question directly. PIC/s guide rocommends to use the LOD as limit, if your MACO is between LOD and LOQ.

Converting MACO into PPM:

Your MACO is 0.27 mg/swab.
Lets assume you would transfer your swab into 1 ml of solvent to extract the residue.
Then, your MACO = 0.27 mg/ ml
1 mg/ ml= 1000ppm
Then, 0.27 mg/ml = 270 ppm

I hope this example can answer your question.

Regards
Veerraju
nvr.veeru@gmail.com

From the MACO we shall establish the Rinse and Swab limits which will be below the MACO. Then Cleaning analytical method must able to detect the lowest value of the Rinse and swab.

Recently EU and APIC was upgraded to PDE inclusion in limits setting in Cleaning validation but practically you will get more MACO/MAR value then derived from Toxicological Data, Dose Criteria and ppm criteria.

This so called PDE calculation is helping to feed the Toxicological scientists and consultants except to make the stringent regulations in cleaning validation.