Pharmaceutical manufacturing requires the selection of residue acceptance levels for potential residues such as active pharmaceutical
ingredients (APIs), excipients, degradation products, cleaning agents, bioburden substances, and endotoxins when carrying
out cleaning validation studies. These levels are determined according to the potential pharmacological, safety, toxicity,
stability, and contamination effects on the next product produced with the same surface or equipment. The USFood and Drug
Administration's guidance for determining residue limits states that residue limits should be logical, practical, achievable,
and verifiable (1). Limits are typically set for visual, chemical, and microbiological residues by taking into consideration
the batch size, dosing, toxicology, and surface area for the equipment.
In contrast to solid and liquid formulations, topical semi-solid formulations such as creams and ointments pose far more difficulty
in cleaning because they contain greasy ingredients such as waxes and oils. These ingredients may inhibit wetting by cleaning
agents, thereby limiting the ability to clean–rinse the residual product away.
Topical formulations (TFs) generally are considered to be safe and less potent than oral or injectable formulations. Nonetheless,
the APIs and excipients commonly used in TFs may produce significant adverse effects in the form of skin irritation, skin
sensitization, hypersensitivity, and photosensitivity reactions. Therefore, one must determine the carryover of residues from
one product to another in a scientifically justified manner to limit the chances of adverse reactions and possibility of synergistic
pharmacological effects between products and their ingredients.
The available guidelines and literature on cleaning validation provide possible approaches for setting the residual acceptance
levels for APIs and finished products but contain little or no guidance regarding the ways to use these approaches for TFs
(2–5). Although the existing approaches are more logical and appropriate for generating residual acceptance levels for solid
and liquid formulations, they can also be applied to TFs with logical modifications. This article discusses the possible ways
to set the residual acceptance levels for APIs present in TFs as a prerequisite for conducting cleaning validation studies.
The method widely used within the pharmaceutical industry for setting residual acceptance levels is the one provided by Fourman
and Mullen, whose paper is listed in the reference section of the FDA cleaning validation guidance document (2). The method
is based on the following criteria:
- The dose criterion is based on the principle that an API should not be present in a subsequently produced product at levels
higher than 1/1000 of the minimum daily dose of the API in a maximum daily dose of the subsequent product.
- The 10-ppm criterion is based on the principle that any API should not be present in a subsequently produced product at levels
higher than 10 ppm.
- The visually clean criterion states that the equipment should have a fixed value of no higher than 100 μg per 2 × 2 in. swab
This article uses the same principles to generate cleaning validation residue acceptance levels for TFs.
Criterion based on product strength
One basis for establishing limits is a mathematical calculation that allows a certain fraction of the therapeutic dose to
carry over into the maximum daily dose of the following product. The dose fraction allowed to carry over is referred to as
maximum allowable carryover (MACO) and is based on the acceptable daily intake (ADI) of the API being cleaned. Industry uses
various approaches to determine the ADI values for active ingredients and involve using minimum recommended therapeutic daily
dose, lowest marketed dose, or no observable effect level (NOEL)/LD50 (lethal dose 50%) values divided by a safety factor
(5). Some manufacturers use an occupational exposure limit (OEL) value to calculate ADI.
If A refers to the product being cleaned, active A1 to the API present in product A, and product B to the subsequently produced formulation, then the MACO calculation based on ADI values can be expressed as
MACO = (ADI × BS × SA)/(MDD × ESA)