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CALCULATION OF LIMIT BASED ON TOXICITY CLEANING VALIDATION

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This method of calculation is based on the use of animal toxicity data to determine limits. As mentioned earlier, this method is particularly suited for determining limits for materials that are not used medically. This method is based upon the concepts of acceptable daily intake (ADI) and no observed effect level (NOEL) developed by scientists in the Environmental Protection Agency, the U.S. Army Medical Bio engineering Research and Development Laboratory, and the toxicology department at Abbott Laboratories. This method has also been recently used to calculate the limits of organic solvent residues allowed in APIs.

Basically, these workers were attempting to determine the amounts of chemicals that the human body could ingest on a daily basis without undue risk and toxicity. In the process, they found that a level of “acceptable daily intake” could be calculated from the toxicity of the materials expressed as an LD50. These data are widely available on material safety data sheets and other references on which toxicity data can be found. The NOEL is calculated from the LD50 by the mathematical relationship as follows:

 

NOEL = LD50 × 0.0005

 

where the 0.0005 is a constant derived from a large toxicology database.

 

Once the NOEL is known, then the ADI can be calculated by the relationship: –

 

ADI = NOEL/SF

 

where SF is an appropriate safety factor

 

Finally, the maximum allowable carryover (MACO) can be calculated from the relationship: –

 

MACO = ADI × B/(LDD)

 

where

B is defined as the smallest batch size of any other product made in the same equipment

LDD is the largest normal daily dosage of any product made in the same equipment.

 

 

 

 

 

 

 

 

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