MACO Calculation in Cleaning Validation

Maximum allowable carryover (MACO) means an acceptable transferred amount from the previous product into the next product. There are a few different methods which have been used to calculate the maximum allowable carry over.

Calculation of MACO limit for cleaning validation studies (maximum allowable carry over of the target residue in the subsequently manufactured product) based on the following criteria: 

• NMT 0.1 % of the minimum daily dose, 
• 10 ppm and 
• PDE / HBELs.

This MACO limit should be greater than LOQ (obtained from AMV of the product under study). But, If calculations for the MACO limit of the active ingredient is not measurable by validated analytical methods (MACO Less than LOQ) There are several options to solve such situation :

• 1st option: is to dedicate the equipment to that one product, thereby reducing the need to measure the active ingredient except by a visually clean criterion. 

• 2nd option: is to modify the parameters of the next manufactured product such that the limit is higher. For example, raising the minimum batch size of the next product will increase the limit.

• 3rd option: is to modify the sampling parameters. For example, for swab sampling, sampling a larger area (100 cm² rather than 25 cm²) or extracting the swab with a smaller amount of solvent will result in an increased limit in the analytical sample.

• 4th option: is lower the rinse volume for rinse sampling.

• 5th option: is to concentrate the rinse sample by a technique such as vacuum evaporation.

MACO Calculation Using PDE

MACO = (PDE × MBS) / MDD

Where,

• MACO: Maximum allowable carry over in mg
• PDE: Permitted daily exposure of the previous product
• MBS: Minimum batch size for the next product in mg
• MDD: Maximum Daily dose of the next product in mg 

MACO Calculation Using LD50 and NOEL

MACO (mcg) = (NOEL previous × MBS next × 1000) / (SF × TDD next)

Where,

• NOEL (No observed effect level in mg/day) = [LD 50 × BW Avg. Wt. of a human: 70 kg)] / 2000
• MBS: Minimum batch size of next product in mcg
• TDD next: Therapeutic daily dose of next product in mg
• SF: Safety factor [Topical: 10-100; Oral Products: 100-1000; Parenteral: 1000-10000]

 

Current cGMP Practice for MACO Calculation

For all critical effects identified, a NOAEL should be established. The NOAEL is the highest tested dose at which no “critical” effect is observed. If the critical effect is observed in several animal studies, the NOAEL occurring at the lowest dose should be used for calculation of the PDE value. If no NOAEL is obtained, the lowest-observed-adverse-effect level (LOAEL) may be used.

• F1 = A factor to account for extrapolation between species.
• F2 = A factor of 10 to account for variability between individuals.
• F3 = A variable factor to account for toxicity studies of short-term exposure.
• F4 = A factor that may be applied in cases of severe toxicity, e.g., carcinogenicity, neurotoxicity or teratogenicity.
• F5 = A variable factor that may be applied if the no-effect level was not established (Q3C).

Example of PDE ≈ ADE Value Calculation

In the new approach, the PDE will be usually calculated on the basis of the pre-clinical data (Toxicological studies on animals) and clinical studies data (pharmacology and adverse effects). But the general principle for the therapeutical and toxicological approaches does not change.

 

One should perform MACO for Active Pharmaceutical Ingredients, microbial residue, cleaning agent residue and disinfectants where applicable.

Read also: 

• Permitted Daily Exposure (PDE) Calculation
• Cleaning Validation Limits or Acceptance Criteria
  

Reference: 

• ISPE
• PDA TRS No. 29