Guidance on Formulating Semisolid Drugs
size than expected and thereby raised questions about the product efﬁcacy. In addition to ingredient solubility and particle size, other physical characteristics and speciﬁcations for both ingredients and ﬁnished products are important.
The subjects covered here are generally applicable to all forms of topical drug products, including those thatare intended to be sterile. The topics given below address several problem areas that may be encountered in the production of semisolid drug products (including transdermal products) including their potency, active ingredient uniformity, physical characteristics, microbial purity, and chemical purity.
EQUIPMENT AND PRODUCTION CONTROL
There are manydifferent 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 ﬂexibleenough to remove interior material, yet not rigid enough to damage the mixer itself. In general, good design of a stainless steel mixer includes blades that are made of some hard plastic, such as Teﬂon®, which facilitates scrapping of the mixer walls without damaging the mixer. If the internal walls of the mixer are not adequately scraped during mixing and the residual material becomes part ofthe batch, the result may be nonuniformity. Such nonuniformity may occur, for example, if operators use handheld spatulas to scrape the walls of the mixer. Another mixer design concern is the presence of “dead spots” where quantities of the formula are stationary and not subject to mixing. Where such dead spots exist, there should be adequate procedures for recirculation or nonuse of the cream orointment removed from the dead spots in the tank.
Active ingredient solubility and particle size are generally important ingredient characteristics that need to be controlled to ensure 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 waterphase 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 development data should adequately demonstrate such solubility and its validation. Substances that are very soluble, as is frequently the case with ointments, would be expected topresent less of a problem than if the drug substance were to be suspended, as is the case with creams. If the drug substance is soluble, then potency uniformity would be based largely on adequate distribution of the component throughout the mix. If the active ingredient is insoluble in the vehicle, then in addition to ensuring uniformity of distribution in the mix, potency uniformity depends oncontrol of particle size and use of a validated mixing process. 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. Particle size also affects the degree to which the product may be physically irritating when applied; in general, smaller particles are less irritating. Production controlsshould be implemented that account for the solubility characteristics of the drug substance; inadequate controls can adversely affect product potency, efﬁcacy, and safety. 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...