USP〈1664.3〉 ASSESSMENT OF LEACHABLES IN TOPICAL OPHTHALMIC DRUG PRODUCTS

1. INTRODUCTION

This section addresses considerations for leachables in topical ophthalmic drug products (ODPs), including solutions, suspensions, emulsions, and ointments. Although other dosage forms (e.g., injectables, implants, inserts) also exist in ophthalmology, the scope of this discussion is limited to topical products. Regulatory guidance and detailed best practice recommendations for treating leachables in ODPs have become available in recent years (1–2).

Topical ophthalmic products are dosage forms designed to be administered topically to the eye (principally the conjunctiva or the eyelid) for the treatment of primarily local disorders. Glaucoma, a disease of the interior of the eye, may also be treated using these dosage forms.

Four main types of topical ophthalmic dosage forms are clinically used:

Solutions

Suspensions (including gels)

Emulsions

Ointments

Leaching of substances from packaging components will be significantly affected by the ingredients present in the formulation. The first three dosage forms listed above typically have water as the primary phase (continuous phase) in direct contact with the primary packaging. Ointment formulations will have an oil phase (typically mineral oil and petrolatum) in direct contact with the product packaging. The addition of other ingredients to the water or oil phase of the drug product may enhance the solubility of extractable materials and affect the rate of migration.

Most topical ODPs are solutions, suspensions, and emulsions that are often filled into semipermeable plastic container closure systems. These formulations are sterile, isotonic, largely aqueous products that typically include tonicity agents, surfactants, preservatives, and may include some oil phase ingredients (in the case of emulsions). These ingredients have the potential to increase the solubility of extractable substances and affect the rate of leaching into the drug product. Some nonionic tonicity agents may be added to ODPs with the potential to enhance leaching that include propylene glycol, glycerin, and polyethylene glycol. Surfactants (e.g., polysorbate 80, poloxamer, tyloxapol) may be added as suspending agents, solubilizing agents, or wetting agents to help the product spread on the surface of the eye. Regardless of their function in the drug product, these surfactants may affect the solubility of extractable substances and increase observed leachable levels. Oils present in an emulsion may increase the solubility of extractable materials in the drug product, even if they are not in direct contact with the packaging. This may not increase the rate of leaching from a package, but it may increase the maximum amount of material that can be extracted from a packaging system. Some preservatives may also have significant effects—benzalkonium chloride (BAK) is a common preservative with surfactant properties that can solubilize some low-solubility materials, and chlorobutanol is known to migrate into some plastic packaging materials over time. The presence and concentration of these ingredients in the drug product should be considered when selecting ODP packaging and designing extractables and leachables studies.

Ophthalmic ointments have an oil phase as the continuous phase in direct contact with the primary packaging. The oil phase for an ointment is typically comprised of mineral oil and petrolatum, but may also contain triglyceride oils, lanolin, and lanolin alcohols. Mineral oil and petrolatum are nonpolar oils, and the addition of other polar oils may significantly affect the extraction or leaching from the packaging. Additionally, some ointments may contain surfactants added as emulsifiers to either stabilize the aqueous phase in the ointment or to enhance the ability of water to diffuse into the ointment after application. All of these additional ingredients have the potential to affect the type and concentration of leachables that may migrate into a drug product.

eye drop bottles

2. PACKAGING SYSTEMS FOR ODPS

Multidose solution, suspension, and emulsion ODPs are commonly stored and administered using dropper bottles (also called droptainers), which typically consist of a bottle containing the drug product, a dropper tip, and a screw cap closure to seal the container closure system. Patients squeeze the inverted bottle to administer the ODP directly to the eye, which places mechanical requirements around the physical properties of the bottle material for effective dose administration. In common use for many years, these systems supplanted glass bottles fitted with glass pipettes and elastomeric bulb droppers due to their simplicity, shatter resistance, and ability to serve as effective sterile containers.

Droptainer components are primarily fabricated from polyolefins, for example, low-density polyethylene (LDPE), high-density polyethylene (HDPE), or polypropylene (PP). For dosing, the container must be soft enough to allow facile squeezing by patients. As a result, many ODP bottles a

re made of LDPE, although exceptions exist. In some cases, more rigid polymers may be used for the bottle, but thinned significantly to facilitate dosing. In either case, dropper bottles are often semipermeable. Lacking a requirement for flexibility, dropper tip and closure components are often molded from harder plastics. Closures for pharmaceutical ODPs are colored to correspond with the class of active ingredient contained within, per American Academy of Ophthalmology (AAO) recommendations (3). More recently, specialized closures that prevent microbial ingress during dosing have allowed the distribution of preservative-free formulations in multidose bottles. These closures contain a greater diversity of materials than droptainers, including elastomers.

In some cases, solution, suspension, and emulsion ODPs are filled into single-dose unit vials. This is an alternative means of storing and delivering preservative-free formulations, in which a small volume (i.e., no more than 0.5 mL) is filled into a container closure system that is opened once by the patient, dispensed to the eye, and then discarded. More often than not, these single-dose units are created using a blow-fill-seal process, in which LDPE resin is molded, the product is filled aseptically, and the vial is sealed in a single operation. Water loss from these low-volume, semipermeable vials can limit ODP shelf life, often necessitating the enclosure of the single-dose unit vial in an impermeable foil laminate pouch that serves as functional secondary packaging.

Ointments are typically packaged in flexible plastic or collapsible metal tubes, which include the tube itself, a delivery nozzle, and a screw cap closure. These tubes can be made from metal (such as tin or aluminum) or laminate structures, which typically consist of a polyolefin product contact layer, an aluminum barrier layer, and a printable polyolefin exterior. Metal tubes, especially those made of aluminum, are often coated with lacquer to minimize interactions between the metal substrate and the drug product. Additionally, a crimp sealant may be applied at the distal end of the tube from the nozzle to ensure container closure integrity. Both lacquers and crimp sealants can be sources of extractables from these packaging systems. Screw cap closures are typically molded from polyolefins and are color-coded according to the class of active pharmaceutical ingredient, following AAO recommendations (3).

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