Setting Cleaning Validation Acceptance Limits for Topical Formulations - Pharmaceutical Technology

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Setting Cleaning Validation Acceptance Limits for Topical Formulations
There is a need for current cleaning validation methods to be used for topical formulations. The authors highlight the issues and challenges encountered.


Pharmaceutical Technology
Volume 32, Issue 1

The method uses permitted daily exposure (PDE) values, the criteria commonly used for determining occupational and environmental health hazards. There are two ways to set PDE values. One of the approaches is based on the "no observed effect level/safety factor" (NOEL/SF) approach. In this approach, all of the pertinent animal and human studies are reviewed, and the highest dose that did not cause an effect in the most sensitive health endpoint (the NOEL) is identified. Once a NOEL has been identified, a set of uncertainty (or safety) factors are applied to this value to compensate for limitations in the data and ensure that safe MACO values are obtained. If a NOEL is not available, then a lowest observed effect level (LOEL) can be used. The LOEL value is the lowest dose that causes an effect in the most sensitive health endpoint. A safety factor from 1 to 10 may be considered for extrapolating a LOEL to a NOEL.

The no observed adverse effect level (NOAEL) or lowest observed adverse effect level (LOAEL), are often used interchangeably with the NOEL or LOEL, respectively. For TFs, using NOAEL and LOAEL values is more logical when dealing with local toxic effects caused by the active ingredient.

An equation to determine PDE value for a pharmaceutical can be represented as follows:

PDE =NOEL HBW SF

in which, NOEL is typically in units of milligram of active ingredient administered per kilogram of animal body weight per day (mg/kg-bw/day). NOEL values obtained from human toxicity data and reported in milligrams per day need not to be multiplied by human body weight (HBW), and a safety factor of 0.1 is used to account for the human variability in response. HBW typically is assumed to be 60 kg for an adult male. SF, which is the safety factor for accommodating limitations in the data, is usually 0.01 for converting NOEL to a PDE for topical products.

The second method of calculating PDE is to convert the LD50 value to a NOEL value by applying an empirical factor. This empirical factor is derived from animal models developed by Layton et al. and can range from 0.0005 to 0.001 (8). The NOEL thus obtained is converted to a PDE value by using the previous equation.

It is important that the NOEL and LD50 values be obtained from dermal toxicity studies. NOEL/LD50 values reported in mg/m2 /day, the PDE (mg/kg) can be calculated by using the following equation:

PDE (mg/day) = NOEL (mg/m2 /day) HSA (m2 ) SF

in which, HSA is the average human body surface area, typically assumed to be 1.62 m2.

In addition, a few drugs have NOEL/LD50 values reported in parts per million (ppm), which can be converted to mg/kg-bw/day on the basis that 1000 ppm equals 25 mg/kg-bw/day for an average 60-kg adult.

MACO(mg/swab area) values based on toxicity data may be calculated as

MACO = (PDE BS SA) / (MA ESA)

in which PDE is the permitted daily exposure for active A1 (mg/day), BS is the number of fingertip units per batch of final mixture of product B (FTUs), SA is the swab area (cm2 ), MA is the maximum number of FTUs of product B applied on the skin per day (FTUs/day) as described under criteria based on the strength of product, and ESA is the equipment surface area shared by product A and product B (cm2 ).

For this example, if the PDE value for active A1 = 0.35 mg/day, and assuming BS = 200,000 FTUs, MA = 162 FTUs/day, SA= 25 cm2 , and ESA = 6000 cm2 , then the MACO (mg/swab area) value is


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