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US FDA Guideline for Topical Drug Products (7/94)


A topical drug product is a medication that is applied to a particular place on body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes including creams, foams, gels, lotions, and ointments.

The purpose of this guide is to provide the Current Good Manufacturing Practice (CGMP) regulations for pharmaceuticals, with guidance on inspecting selected topics of topical drug product production. The subjects covered in the guide are generally applicable to all forms of topical drug products, including those that are intended to be sterile. However, this guide does not address every problem area that the investigator may encounter, nor every policy that pertains to topical drug 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. The guide also addresses problems relating to the growing number of transdermal products.


Active 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. 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.

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. 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.

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.



There are many different kinds of mixers used in the manufacture of topical products. It is important that the design of a given mixer is appropriate for the type of topical product being mixed. One important aspect of mixer design is how well the internal walls of the mixer are scraped during the mixing process. This can present some problems with stainless steel mixers because scraper blades should be flexible enough to remove interior material, yet not rigid enough to damage the mixer itself. Generally, good design of a stainless steel mixer includes blades which are made of some hard plastic, such as teflon, which facilitates scrapping of the mixer walls without damaging the mixers.

Filling and Packaging

Suspension products often require constant mixing of the bulk suspension during filling to maintain uniformity. When inspecting a suspension manufacturing process determine how the firm assures that the product remains homogeneous during the filling process and audit the data that supports the adequacy of the firm's process. When the batch size is large and the bulk suspension is in large tanks, determine how the firm deals with low levels of bulk suspension near the end of the filling process.

Process Temperature Control

Typically, heat is applied in the manufacture of topicals to facilitate mixing and/or filling operations. Heat may also be generated by the action of high energy mixers. It is important to control the temperature within specified parameters, not only to facilitate those operations, but also to assure that product stability is not adversely affected.

Temperature control is also important where microbial quality of the product is a concern. The processing of topicals at higher temperatures can destroy some of the objectionable microorganisms that may be present. However, elevated temperatures may also promote incubation of microorganisms.


It is CGMP for a manufacturer to establish and follow written SOPs to clean production equipment in a manner that precludes contamination of current and future batches. This is especially critical where contamination may present direct safety concerns, as with a potent drug, such as a steroid (e.g., cortisone, and estrogen), antibiotic, or a sulfa drug where there are hypersensitivity concerns.

Microbiological Specifications and Test Methods

During inspections it is important to audit the microbiological specifications and microbial test methods used for each topical product to assure that they are consistent with any described in the relevant application, or USP. It is often helpful for the inspection to include an FDA microbiologist.


As with other dosage forms, it is important for the firm to carefully control how changes are made in the production of topical products. Firms should be able to support changes which represent departures from approved and validated manufacturing processes.

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