Lai Yeo Lian

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 area. 

This article uses the same principles to generate cleaning validation residue acceptance levels for TFs. 

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.  

 refers to the product being cleaned, active 

 to the subsequently produced formulation, then the MACO calculation based on ADI values can be expressed as 

in which ADI is the acceptable daily intake of the active 

1 (%) and is equal to the minimum therapeutic daily dose × safety factor; MDD is the maximum daily dose for product 

 (mg); BS is the batch size of the product 

 is the equipment surface area shared with product 

For the MACO calculation using therapeutic dose unit and safety factor approach, different safety factors have been suggested for various formulation types (see Table I). Nonetheless, a safety factor of 1000 is widely used because it can be thought of as comprising a factor of 10 for adjusting a therapeutically effective dose to a therapeutically noneffective dose, a factor of 10 to accommodate for individual variability in response, and a factor of 10 for making cleaning validation studies robust. The dose-reduction fraction is a measure of the risk involved and is assessed by the manufacturer depending on the actual manufacturing situation.  

Table I: Safety factors for the determination of cleaning validation acceptance limits. 

When it comes to TFs, applying the ADI or therapeutic dose–safety factor approach for MACO calculations is challenging for several reasons, including:  

TFs are not divided into individual dosage units, unlike solid and liquid formulations.

Dose size per application varies depending upon the total lesion area. Hence, it becomes difficult to establish minimum or maximum daily doses.

No standardized approach exists for determining dose size. That is, the amount of product recommended to be applied per area of skin per treatment varies from manufacturer to manufacturer.

The pharmacological effects produced by systemic absorption of the API through oral ingestion are taken into consideration when determining ADIvalues. In the case of TFs, occasionally enough API is absorbed to cause systemic effects. TFs produce local toxicity even at low doses.

Therefore, a need arises for establishing a rational method to determine cleaning validation acceptance limits for TFs. This article establishes a method for the calculation of MACO for the APIof a subsequently manufactured TF by taking into account possible worst cases. 

1 is marketed in strengths of 2%, 3%, and 5% and that product 

 can be applied on the entire body two to four times per day. The criterion set by Long and Finley can be used to determine the total amount of TF (e.g., cream and ointment) applied on the entire body in one application (6). The criterion describes the dosage of TFs in terms of fingertip units (FTUs). One adult FTU is the amount of ointment or cream expressed from a tube with a standard 5-mm diameter nozzle, applied from the distal crease to the tip of the index finger. One FTU contains approximately 0.5 g of cream, and it is assumed that approximately 20.25 g (~40.5 FTUs) of cream is needed to cover an adult body. On the basis of the these assumptions, the maximum amount of product 

20.25 g/application × 4 application/day = 81 g/day 

To determine the maximum amount of product applied per treatment for other TFs such as medicated shampoos, lotions, toothpaste, and mouthwash, one could consult the European Commission's 

Guidance for the Testing of Cosmetic Ingredients and their Safety Evaluation 

 or the manufacturer's in-house criteria (7). For these formulations, the amount of product applied per treatment is fixed; therefore, the maximum amount of product applied per day depends on the maximum number of times the product is used daily. 

1 in the TF is 2%. This means that approximately 1.62 g (2% of 81 g) of active 

 will produce its pharmacological effects. Taking into account a safety factor of 1000, active 

1 should not exceed 0.00162 g (1.62 g divided by 1000) in 81 g of product 

 Assuming that the batch size for product 

 should not be more than 0.1% of the lowest marketed strength–concentration for active 

1. For the example above, MACO can also be calculated by 

From the previous example, it is clear that to calculate MACO of the API in any subsequently manufactured TF, the only information needed is the lowest marketed strength of the API in the TF being cleaned and the batch size of subsequently manufactured finished product. The MACO calculation is independent of minimum and maximum daily dose for product 

MACO in terms of amount of API per surface area of equipment (for swab sampling) can be determined by using the following equation: 

 is the lowest available strength of the API in the product A (%), 

 ); ESA is the equipment surface area shared by product 

 ). This equation can be further modified to calculate the residue limits (mg/mL) in the rinse sample by using total volume (TV) of rinse or wash solvent portion (mL) and volume (

) of rinse sample collected (mL) in place of ESA and SA, respectively. 

Following the same assumptions and examples described in worst case I, therapeutic doses for TFs may be established in terms of mg/kg body weight/day or mg/cm

 /day units. According to Long and Finley, 1 FTU covers about 286 cm

  of skin surface area. This implies that approximately 1.75 mg of the TF is applied per each square centimeter of skin surface area. The dose size for TF may be calculated using the following equation, 

in which, A is the amount of TF applied in one application per unit area of skin (mg/cm

 is the concentration of the API in the TF (%), and 

 is the frequency of application per day (day

For calculating minimum daily dose for product A, 

 = lowest available strength/concentration of the API in the product 

 ). Therefore, the minimum daily dose for product 

 /day, and the maximum daily dose for product 

 = maximum number of times product B is applied per day = 4). One point to remember is that the calculation for the maximum daily dose for product 

 is independent of the concentration of API present. Therefore, for a batch size of 300 kg (product 

) / (safety factor × maximum daily dose for product 

Comparing the previous cases, one can observe that the MACO value obtained from the second worst-case scenario is four times less than the value obtained from the first worst case. After thorough analysis of the calculations, however, it can be concluded that the MACO value obtained from worst case II is equal to the MACO value from worst case I divided by the maximum number of applications per day for product 

. Therefore, if MF is the maximum number of times product 

 that can be applied daily, the MACO value from worst case II can be mathematically expressed as: 

Therefore, it is the concentration (i.e., percentage) of active 

1 and the number of doses per day for product 

 make a difference when it comes to the calculation of MACO values. 

Criterion based on permitted daily exposure

Another approach for determining MACO uses toxicity data. This strategy is generally used in the industry when dealing with contaminants for which therapeutic doses are not known (e.g., intermediates, precursors, and cleaning agents).  

For many drugs, using a safety factor of 0.1% of the lowest recommended therapeutic dose may be reasonable and will produce MACO values at a safe level. This approach cannot be used indiscriminately, however, for several reasons. First, for topical products, the therapeutic doses are not well defined, as discussed previously. A second issue is the mechanism by which toxic effects are produced by the drug. For many drugs, the mechanism by which the toxic effects are produced might be unrelated to the mechanism of pharmacological action. For instance, a drug may cause developmental toxicity (e.g., birth defects) or cancer by a mechanism unrelated to its pharmacological effects. In these cases, using the 0.1% safety factor on the therapeutic dose may still be appropriate but would need to be used with greater caution because the toxic effects may be produced below the safe therapeutic levels. 

For these reasons, many manufacturers also include an approach based on toxicity data to calculate MACO values. For many drugs, this approach may be reasonable and has produced 

 values similar to the traditional therapeutic dose/safety factor approach. The basic value of this approach is that a limit can be calculated for cleaning validation purposes based solely on the toxicity of the API present in the TF. 

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.  

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There is a need for current cleaning validation methods to be used for topical formulations. The authors highlight the issues and challenges encountered.