Critical Quality Attributes for Topical Dosage Forms

A recently issued USP stimuli article describes advances in product quality and performance tests for topical drug products. The comment deadline is 30 November 2023. In particular, the article published in Pharmacopeial Forum (PF) 49(5) focuses on the following:

  • In vitro adhesion tests for transdermal and topical delivery systems (collectively called TDS)
  • In vitro quality and performance tests for microneedle array systems
  • Physicochemical and structural characterization tests for topical drug products

Characterization of Topical Dosage Forms

The critical quality attributes (CQAs) of semisolid dosage forms (e.g., lotions, gels, creams), usually consider the type, amount, and arrangement of matter in the dosage form:

  • The type of matter is described by its ingredients, typically specified further in terms of a particular grade of that ingredient.
  • The amount of each type of matter is described by a galenic recipe that defines the relative proportion of each of the ingredients in the formulation.
  • The arrangement of matter can be influenced by manufacturing process parameters which are usually controlled within specified limits.

Thus, ensuring consistency in these attributes helps ensure consistent product performance. Regulatory concepts are described in FDA’s Draft Guidance for Physicochemical and Structural Characterization of Topical Drug Products. In addition, there are established compendial standards to characterize the type, grade, and purity/potency of many ingredients which are commonly utilized in topical drug products.

The authors of the article emphasize that "the characterization of topical dosage forms is particularly important because their physicochemical and structural features may not be evident from their dosage form nomenclature. For example, a lotion may actually be a viscous single-phase solution, a gel may be an emulsion, a cream may not have globules, an ointment may or may not contain any petrolatum, and any of these may contain fully dissolved or partially suspended drug".

According to the article, the following parameters may be considered for the characterization of semisolid drug products:

  • Human sensory assessments that describe the look and feel of a product as well as its smell.
  • Microscopic examination of the product can help to characterize the number and type of phase states, describing features like globules and suspended particles.
  • Rheological characterization of a topical drug product reflects how the system responds to stress - this typically involves using a rheometer. it is important to characterize the apparent viscosity at low-, medium-, and high-shear rates. The authors point out that the best way to visualize comparative rheology data for a test and reference product is by plotting the data for both, shear stress versus shear rate, and viscosity versus shear rate.
  • Solvent (water) activity, or measurements of the drying rate, at relevant temperatures.
  • The pH of a product can have a substantial impact on a variety of potentially CQAs, such as the viscosity of a gel or the ionization state of the drug. It may also be important to characterize any buffer systems as well (the pH of the product following application on the skin may be dependent on how well the product is buffered).
  • For products comprised of more than 70% lipophilic contents (like many petrolatum-based ointments), it is recommended to characterize the product using the tests provided in the USP monograph for Petrolatum (e.g. tests such as the actual pH of the pooled washings during an alkalinity test, or the melting point test according to USP general chapter <741> Melting Range or Temperature). 
  • Dose delivery: Different manufacturing process parameters (e.g., mixing rate and duration) may have the potential to alter the amount of entrapped air in a product formulation, which may impact the delivered dose, so it may be considered important to characterize the specific gravity of a semisolid product.
  • Influence of the container closure system on the attributes of the dispensed product.

In conclusion the authors state that the challenge is that compendial test methods do not yet exist for many of the tests that may be utilized to facilitate characterization. For example, there are different methods, equipment, and test conditions that may be utilized to characterize attributes as simple as pH, or as complex as rheological behavior. Therefore, "public input is sought from investigators who work with topical and transdermal products to clarify whether it is challenging to identify appropriate test methods, equipment, and conditions, and to determine the appropriate number of replicate measurements or the relevant data analysis and reporting considerations".

More information is available in the Stimuli Article "Advances in Product Quality and Performance Tests for Topical and Transdermal Products—View of the USP Expert Panel" after registration to the Pharmacopeial Forum.

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