There are many different kinds of mixers used in the manufacture of topical products. In addition to ingredient solubility/particle size, the inspection should include a review of other physical characteristics and specifications for both ingredients and finished products. For example, in one instance, residual water remaining in the manufacturing vessel, used to produce an ophthalmic ointment, resulted in partial solubilization and subsequent recrystallization of the drug substance the substance recrystallized in a larger particle size than expected and thereby raised questions about the product efficacy. Production controls should be implemented that account for the solubility characteristics of the drug substance inadequate controls can adversely affect product potency, efficacy and safety. Particle size also affects the degree to which the product may be physically irritating when applied generally, smaller particles are less irritating. Particle size can also affect the activity of the drug substance because the smaller the particle size the greater its surface area, which may influence its activity. If the active ingredient is insoluble in the vehicle, then in addition to assuring uniformity of distribution in the mix, potency uniformity depends upon control of particle size, and use of a validated mixing process. If the drug substance is soluble, then potency uniformity would be based largely upon adequate distribution of the component throughout the mix. Substances which are very soluble, as is frequently the case with ointments, would be expected to present less of a problem than if the drug substance were to be suspended, as is the case with creams. The inspection should determine if the manufacturer has data on such solubility and how that data was considered by the firm in validating the process. It is important that active ingredient solubility in the carrier vehicle be known and quantified at the manufacturing step in which the ingredient is added to the liquid phase. Crystalline form is also important where the active ingredient is dispersed as a solid phase in either the oil or water phase of an emulsion, cream, or ointment. POTENCY UNIFORMITYДЄctive ingredient solubility and particle size are generally important ingredient characteristics that need to be controlled to assure potency uniformity in many topical drug products such as emulsions, creams and ointments. Filed production control data should be specific and complete. As with other pre-approval inspections, the manufacturing and controls information filed in the relevant application should be compared with the data used for clinical batches and for production (validation) batches. If a new drug pre-approval inspection is being conducted, then an examination of the filed manufacturing and control data, and correspondence should be accomplished early in the inspection. The guide also addresses problems relating to the growing number of transdermal products. This inspectional guide addresses several problem areas that may be encountered in the production of topical drug products potency, active ingredient uniformity, physical characteristics, microbial purity and chemical purity. However, this guide does not address every problem area that the investigator may encounter, nor every policy that pertains to topical drug products.

The subjects covered in the guide are generally applicable to all forms of topical drug products, including those that are intended to be sterile. The purpose of this guide is to provide field investigators, who are familiar with the provisions of the Current Good Manufacturing Practice (CGMP) regulations for pharmaceuticals, with guidance on inspecting selected facets of topical drug product production. The document does not bind FDA, and does no confer any rights, privileges, benefits, or immunities for or on any person(s). GUIDE TO INSPECTIONS OF TOPICAL DRUG PRODUCTS Note: This document is reference material for investigators and other FDA personnel.

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