NOEL and MACO Calculations in Cleaning Validation : Pharmaceutical Guidelines

NOEL and MACO Calculations in Cleaning Validation

Calculations of NOEL and MACO, those are important factors in cleaning validation of pharmaceutical equipments.
NOEL is “No Observed Effect Level” of any pharmaceutical drug. It is determined to calculate the MACO (Maximum Allowable Carry Over) in cleaning validation. NOEL is the amount of drug in mg that does not have any effect on the human health.

NOEL is calculated by using Lethal Dose 50 (LD50) of the drug. Lethal Dose 50 is the amount of drug that kills the 50% population of the animals used in the test.

Cleaning Validation SamplingNOEL = (LD50 x 70kg)/2000
LD50 – Lethal Dose
70kg – Average adult weight
2000 – Constant
For Example: If any drug has LD50 331 mg/kg, then its NOEL will be calculated as below.
NOEL = 331x70/2000
= 23170/2000
= 11.58 mg

Now this value of NOEL is used to calculate the MACO (Maximum Allowable Carry Over)

MBS – Maximum Batch Size
SF – Safety Factor (1000 for oral drugs)
TDD – Total Daily Dose of Next Product

For Example: If Total Daily Dose of the next product is 500 mg and batch size is 400 kg then MACO can be calculated as below.
MACO = (11.58 mg x 400000000 mg)/(1000 x 500 mg)  -------- 400 kg = 400000000 mg
= 4632000000/500000
= 9264 mg
= 9.264 gm

It shows that the drug with 331 mg/kg LD50 should not be carried over more than 9.264 gm in next batch having 500 mg daily dose and 400 kg batch size. This criterion is used to calculate the cleaning validation limits.

Ankur Choudhary is India's first professional pharmaceutical blogger, author and founder of Pharmaceutical Guidelines, a widely-read pharmaceutical blog since 2008. Sign-up for the free email updates for your daily dose of pharmaceutical tips.
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10 comments: Post Yours! Read Comment Policy ▼

  1. What approach shall be adopted in case of MACO value is less than LOQ?

    1. Concentrate samples of rinsing water by evaporation in 5, 10, 20 ... times to achieve a measurable value

    2. then, use LOQ as limit, and justification is the limitation of instrument used

  2. How i can do cleaning validation for Topical formulations, Is there any procedures?

  3. MBS stands for minimum batch size of the subsequent product if i am not wrong

    1. yes, MBS in here means batch size for following product, following product means product which will be produced in that equipment after cleaning procedure has been performed in that equipment

  4. MBS stands for Minimum Batch Size

  5. the problem in this approche i mean application of toxicological data is critical because we dont have a real toxic dose date of APIs human vody

  6. How to calculate MACO for drug substance.

    TThanks andregards, A. Prabhakar

  7. hi,
    regarding B.Size, 400kg is considered but this comprises both API & excipients,to my knowledge we need to consider 500mg X NO. Of tablets, then it gives the whole API quantity in the minimum b.size.
    what do you say, replay is awaited.


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