A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment - Pharmaceutical Technology

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A Single Adulteration Limit for Cleaning Validation in a Pharmaceutical Pilot-Plant Environment


Pharmaceutical Technology


Health-based risk assessment

To implement an adulteration limit, it must be lower than the associated health-based ARL. The adulteration limit would be lower at the level at which compounds are not likely to be potent, highly toxic, or carcinogenic. A corresponding allowable daily intake (ADI) for this category of material is 100 μg/day (0.1 mg/day) (8).

The calculation for the health-based ARL with an ADI of 0.1 mg/day includes:















in which ADI is the allowable daily intake for the compound, SSA is the shared product-contact surface areas of the manufacturing equipment train, and recovery is the percentage of spiked material recovered for assay.


Table I: Calculated health-based acceptable residue limit (μg/swab).
Table I shows the health-based ARLs with associated parameters for an ADI of 0.1 mg/day, tablet weight from 0.1–1.5 g and maximum daily dose from 1–10 tablets. The number of tablets per batch ranged from 266–10,000 (small) to 3600–160,000 (medium) to 46,666–1,000,000 (large), based on batch sizes of 0.4–1 kg (small), 5.4–16 kg (medium), and 70–100 kg (large), respectively. It was assumed that the next batch was manufactured in equipment with the same SSA.

The shaded portions of the small, medium, and large batch ranges in Table I fell below the proposed limit of 100 μg/swab (4 μg/cm2 ). The low end of each range assumed the smallest batch size, the largest tablet weight (1500 mg), and the highest number of tablets dosed (10).

In the pilot plants, about 5% of manufactured batches fell below the 100 μg/swab (4 μg/cm2 ) limit. The batches that fell below the 4 μg/cm2 limit were typically for clinical studies with large tablet sizes (>1000 mg), multiple-tablet doses (>6 tablets/dose) or small batch sizes (<500 g). Small batch sizes generally are for first-in-man studies or preclinical and Phase I studies. These clinical-trial programs are dosed on small populations to establish dose levels.

The risk of falling below the 4 μg/cm2 limit for compounds with ADIs >100 μg/day was small, based on the site data. Also, of the 1225 swab samples taken in support of cleaning validation, none failed the ARL for the compound tested, greater than 98% of the swabs were below 1 μg/cm2 , and more than 99.5% were below 4 μg/cm2 , further reducing potential risk.

Finally, a continuing program for monitoring cleaning effectiveness using visible residue limits (VRL) was conducted. Of the manufactured batches that fell below the 100 μg/swab (4 μg/cm2 ) limit, the highest VRL was 1.23 μg/cm2 , which is well below the health-based limit. Therefore, for compounds with ADIs >100 μg/day, it is extremely unlikely that the adulteration limit selected will be greater than the health-based limit.


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