The document discusses the concept of Maximum Allowable Carryover (MACO) in pharmaceutical cleaning validation, which is crucial to prevent contamination from residual products. It outlines the two-tiered approach for calculating MACO as per APIC guidelines, emphasizing the use of No Observed Effect Level (NOEL) and various formulas for determining acceptable levels of carryover. The document further provides calculations for MACO based on the total daily dose and maximum batch size of a subsequent product.

1. NOEL and MACO for
wash method
By Pankaj Gawate.

2. What is MACO?
 Maximum Allowable Carryover (MACO) is the highest amount of
residue from a previous product that is acceptable to remain on
equipment or surfaces after cleaning before manufacturing a new
product.
 It is a critical parameter in cleaning validation studies.
 MACO helps to ensure that the new product is not contaminated
with residual amounts of the previous product that could be
harmful or affect the quality of the new product. Establishing an
appropriate MACO level is essential for safeguarding product
purity and efficacy.

3. Importance of MACO in Pharmaceutical
industry
 Cleaning validation is one of the most important aspects in
Pharmaceutical world.
 Accurate determination of cleaning validation limits based
on the maximum allowable carryover (MACO) of a marker
compound between successive products is crucial to ensure
the effectiveness and reliability of the cleaning validation
program in a multiproduct facility with shared equipment,
mitigating the risk of cross-contamination.
 MACO is a critical component of ensuring product quality
and safety in pharmaceutical manufacturing.

4. APIC Guidelines for MACO Calculation
 The APIC guideline recommends a two-tiered approach for calculating MACO:
o Tier 1: Health-Based Approach
o Tier 2: Toxicological Approach (if Tier 1 is not feasible)
 The APIC guidelines provide a structured framework for calculating MACO.
The preferred method is the Tier 1, Health-Based Approach, which
leverages the concept of Acceptable Daily Exposure (ADE) of the previous
product. If sufficient data is not available for the Tier 1 approach, then
the Tier 2, Toxicological Approach, based on safety factors and potential
toxicity of the residue, can be employed.

5. NOEL
 “ NO OBSERVED EFFECT LEVEL ” of any pharmaceutical Drug.
 It is also used to calculate the MACO ( Maximum Allowable Carry Over).
 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.
 LD 50 is the amount of drug that kills the 50% population of the animal used in
the Test.

6. NOEL formula
NOEL
(LD 50 x 70 kg)
---------------------
2000
=
Where,
LD 50 – Lethal dose.
70 kg – Average adult weight.
2000 – Constant Value.

7. Calculation with example
 If any drug has (LD 50) 300 mg/kg
 Then NOEL will be calculated as:-
NOEL
(300 x 70 kg)
---------------------
2000
=
21000
---------------------
2000
= = 10.50

8. MACO Value Calculation:
 Now this NOEL value will be used for calculation of MACO value
MACO
(NOEL x MBS)
---------------------
(SF x TDD)
=
Where,
MBS – Maximum Batch Size
SF – Safety Factor (1000 for Oral Dose)
TDD – Total Daily Dose of next product.

9. Calculation with example
 If the total Daily dose of the next product is 500mg and batch size is 400 kg
then CACO Calculated as:
 400 kg is equivalent to 400000000 mg
MACO
(10.50 x 400000000 mg)
---------------------------------
(1000 x 500 mg)
=
= 8400 mg
= 8.400 gm

10. It shows that the drug with
300 mg/kg LD50 should not
be carried over more than
8.4000 gm in next batch
having 500 mg daily dose and
400 kg batch size.
This Calculation is used to
calculate the cleaning
validation limit.

11. “Before putting ink to paper, contemplate the footprint on nature’s canvas”