Cleaning validation is documented evidence that provides a high degree of assurance that a cleaning procedure consistently removes residues to predetermined acceptable levels. These acceptable residue limits (ARL) for drug products are often based on health and adulteration criteria (1–3). The limit used to determine the appropriate cleaning level is the lower of the two criteria. A health-based limit is generated from toxicity data, which can be expressed as acceptable daily intake (ADI) (4, 5). The health limit is calculated using the ADI, or an alternative toxicity factor, and the parameters of the equipment used to manufacture the formulation (2, 6). For example, a health-based limit can be calculated as follows:
(ADI ÷ MDD) × (DUB ÷ SSA) = (μg/cm2)
where the ADI units are μg/day of the residue in question, which would have no pharmacological effect; MDD is the maximum daily dose (units per day) of the product manufactured in the equipment; DUB is the dose units per batch (units) of the subsequent product; and SSA is the shared surface area (cm2) for the product contact surface area of the manufacturing equipment.For the adulteration-based limit, a carryover limit of 10 ppm or a baseline limit of 100 μg/swab is often used in industry. The following equation provides an example:
10 μg/g × (MBS ÷ SSA) = ARL (μg/cm2)
where 10 μg/g (10 ppm) is the adulteration-based limit; MBS is the minimum batch size (g) of the product; and SSA is the shared surface area (cm2) for the product contact surface area of the manufacturing equipment. Alternatively, an adulteration limit of 4 μg/cm2 or 100 μg/swab can be used as an adulteration-based cleaning limit (7).
A third level of acceptance criteria of any cleaning evaluation is that all equipment surfaces must be visibly clean. The visual cleanliness of the equipment must be established before any swabbing can take place to confirm compliance with a health-based or adulteration-based cleaning limit.
The 10-ppm limit
The concept of the 10-ppm carryover limit has been used since the beginning of cleaning validation. The idea of a carryover adulteration limit goes back much further. The latter is used in conjunction with a health-based residue limit; together, the two limits provide a well-defined residue limit to prevent carryover that causes adulteration in pharmaceutical formulation manufacturing. A defined limit of carryover adulteration makes sense for compounds, which have a relatively high health-based residue limit. Not only does this limit prevent unacceptable carryover, but it also ensures a pharmacologically safe formulation.
Fourman and Mullin popularized the 10-ppm criterion for cleaning validation (6). Their program was the first to couple the health-based and carryover criteria in a logical, straightforward manner. They took the 10-ppm limit, calculated it with the equipment-product contact-surface area and the subsequent batch size, and arrived at a swab limit for carryover. It has since been demonstrated that a flat, unadjusted 10-ppm or 100 μg/swab limit can also be appropriate for some applications without affecting compliance, which accompanies a constantly changing cleaning limit in a clinical-manufacturing facility (7). The US Food and Drug Administration cited the 10-ppm limit in its guide to Inspection of Validation of Cleaning Processes as one of several appropriate options for cleaning limits (8). Health Canada and the Pharmaceutical Inspection Cooperation Scheme also use the 10 ppm limit in their cleaning validation guidelines (9, 10). The European Medicines Agency uses similar wording regarding cleaning-validation limits, although the agency does not specifically use the 10 ppm limit (11). Several literature references (12–14) refer to the use of the 10-ppm limit and numerous commercial and research facilities (2, 15–17) have adopted the 10-ppm carryover limit as part of their internal cleaning validation programs.
The 10-ppm limit is used when it is lower than the corresponding health-based limit for the residue of interest. Although the 10-ppm limit has some historic precedent, there is a lack of scientific justification and validation as a limit for cleaning validation. However, the idea of a carryover limit was logical to industry and the 10-ppm limit not only filled this need but also made sense.