Freedom from Contamination

Particulates

Numerous topical preparations contain finely dispersed solids. Pastes, for example, contain as much or more than 50% solids dispersed in an ointment medium. Powders themselves are used topically. Many dermatological liquids and semisolids contain suspended matter. However present, the particles should be impalpable, that is, incapable of being individually perceived by touch, so that the formulations do not feel gritty. The palpability of a particle is a function of its hardness, shape, and size. The pharmacist can only manipulate the latter, and thus it is important to prepare or use finely subdivided solids when making topical dosage forms. Individual particles greater than 50 |im in their longest dimension can be individually perceived by touch. The surface of the eye is substantially more sensitive and a 10 |im particle can be distinguished here. Clearly, the presence of hard, palpable particulates in semisolids makes them abrasive, particularly when applied to disease or damage-sensitized skin. Severe eye irritation is possible if ophthalmic ointments contain them. One particularly troublesome source of particulate contamination is flashings (tiny metal slivers and shavings) left over from the production of tin and aluminum-collapsible tubes. These often adhere electrostatically and tenaciously to tubing walls following cutting of the containers down to a particular size. Some escape removal in washing and rinsing done to cleanse the empty containers. Consequently, a jet of exceedingly high velocity air is blown into the open end of tubes just prior to their filling to remove all particulates. If this precaution is not taken, tiny metal slivers may be packaged with the product, posing the threat that they will become dislodged and instilled into the eye while the product is in use. For reasons as this, the

United States Pharmacopoeia/National Formulary (USP/NF) has a particulate test for ophthalmic ointments. In this test, the ointments are liquefied in a petri dish at high temperature, 85°C, for two hours, and then solidified by cooling. Particles that have settled to the bottom of the shallow glass container are counted by microscopic scanning at 30 times magnification. The requirements are met if the total number of particles 50 |im or larger in any dimension does not exceed 50 in the 10 tubes tested and if not more than eight particles are found in a single tube. Products that are put into the distribution channels have to meet this test. Nevertheless, the pharmacist should be on the lookout for particulate problems associated with commercial products. The pharmacist must also take measures to ensure that extemporaneously compounded formulations are free of particulates. Particular attention must be paid to the cleaning of collapsible tubes and other package parts prior to their use.

Microbial Specifications and Sterility

As of the USP XIX, ophthalmic ointments have to be prepared and dispensed as sterile products (until opened for use). Presently in the United States, nonophthalmic topical preparations do not need to be sterile, although they cannot contain pathogens and must have low microbe counts. The reasons ophthalmic sterility requirements were broadened to cover ointments are enlightening. In the mid-1960s, there was an outbreak of extremely serious Pseudomonas eye infections in the Scandinavian block of countries, in some instances with loss of sight. The source of the contamination was traced to antibiotic-containing ophthalmic ointments made by a regional manufacturer known for its high standards of manufacturing and quality control (83). Pathogenic Pseudomonas organisms were found in both the products and in the manufacturing facilities where the ointments were prepared. It was widely believed up until this time that pathogens could not and would not survive and grow in ointments and similar media. The presence of antibiotics in the preparations could only have added to the false sense of security this company had. This incident sent shock waves throughout the pharmaceutical world and spawned revisions in all world compendia. In the United States, ophthalmic ointments have to be sterile when dispensed. In Europe, dermatological products that are to be used over broken skin also have to be sterile.

The foregoing incident has special meaning to the dispensing pharmacist. Unopened ophthalmic ointments should be dispensed for each condition and should be given very short shelf life datings. Patients should be advised to discard unused quantities of old preparations and to return for fresh supplies if and when chronic symptoms reappear. Similar advice and precautions are good practice with dermatological products like ointments that do not ordinarily contain microbial preservatives. Lotions, creams, and topical solutions that contain preservatives tend to remain pathogen free after their packages have been opened, providing an extra measure of safety.

Preservatives have an important purpose in topical medications. Systems containing them tend to remain aseptic. Even if a few organisms subsist in the presence of the preservatives, these tend to be nonvegetative. Importantly, no pathogenic forms survive to cause problems. Preservatives are necessary for systems that have an aqueous phase, for water offers an environment that is particularly conducive for microbial growth. Therefore, all emulsions and aqueous solutions and suspensions should be preserved. However, choosing a preservative is no easy task, for the physical systems tend to be compositionally complex and polyphasic, affording many possible means for specific preservatives to be inactivated. In mass-produced products, the effectiveness of the preservation system of formulations is checked by the USP preservative challenge tests.

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