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ASHP Technical Assistance Bulletin on Compounding Nonsterile Products in Pharmacies

Introduction

Pharmacists are the only health care providers formally trained in the art and science of compounding medications.^1,2 Therefore pharmacists are expected, by the medical community and the public, to possess the knowledge and skills necessary to compound extemporaneous preparations. Pharmacists have a responsibility to provide compounding services for patients with unique drug product needs.

This Technical Assistance Bulletin is intended to assist pharmacists in the extemporaneous compounding of nonsterile drug products for individual patients. Included in this document is information on facilities and equipment, ingredient selection, training, documentation and record keeping, stability and beyond-use dating, packaging and labeling, and limited batch compounding. This document is not intended for manufacturers or licensed repackagers.

Facilities and Equipment

Facilities. It is not necessary that compounding activities be located in a separate facility; however, the compounding area should be located sufficiently away from routine dispensing and counseling functions and high traffic areas. The area should be isolated from potential interruptions, chemical contaminants, and sources of dust and particulate matter. To minimize chemical contaminants, the immediate area and work counter should be free of previously used drugs and chemicals. To minimize dust and particulate matter, cartons and boxes should not be stored or opened in the compounding area. The compounding area should not contain dust-collecting overhangs (e.g., ceiling utility pipes, hanging light fixtures) and ledges (e.g., windowsills). Additionally, at least one sink should be located in or near the compounding area for hand washing before compounding operations. Proper temperature and humidity control within the compounding area or facility is desirable.

Work areas should be well lighted, and work surfaces should be level and clean. The work surface should be smooth, impervious, free of cracks and crevices (preferably seamless), and nonshedding. Surfaces should be cleaned at both the beginning and the end of each distinct compounding operation with an appropriate cleaner or solvent. The entire compounding facility should be cleaned daily or weekly (as needed) but not during the actual process of compounding.

Equipment. The equipment needed to compound a drug product depends upon the particular dosage form requested. Although boards of pharmacy publish lists of required equipment and accessories, these lists are not intended to limit the equipment available to pharmacists for compounding.² Equipment should be maintained in good working order. Pharmacists are responsible for obtaining the required equipment and accessories and ensuring that equipment is properly maintained and maintenance is documented.

Weighing Equipment. In addition to a torsion balance, pharmacists who routinely compound may need to use a top-loading electronic balance that has a capacity of at least 300 g, a sensitivity of ±1 mg (or 0.1 mg), and 1-mg, 100-mg, 1-g, and 100-g weights for checking. Balances should be maintained in areas of low humidity and should be stored on flat, nonvibrating surfaces away from drafts. At least annually, the performance of balances should be checked according to the guidelines found in Remington’s Pharmaceutical Sciences,³ USP XXII NF XVII: The United States Pharmacopeia–The National Formulary (USP–NF),⁴ or USP DI Volume III: Approved Drug Products and Legal Requirements⁵ or the instructions of the balance manufacturer. Performance should be documented.

Weights should be stored in rigid, compartmentalized boxes and handled with metal, plastic, or plastic-tipped forceps—not fingers—to avoid scratching or soiling. Since most Class III prescription balances are only accurate to ±5 or 10 mg, Class P weights may be used for compounding purposes.⁴ The USP–NF recommends that the class of weights used be chosen to limit the error to 0.1%. In practical terms this means that Class P weights can be used for weighing quantities greater than 100 mg.

The minimum weighable quantity must be determined for any balance being used for compounding. To avoid errors of 5% or more on a Class III balance with a sensitivity requirement of 6 mg, quantities of less than 120 mg of any substance should not be weighed. Smaller quantities may be weighed on more sensitive balances. If an amount is needed that is less than the minimum weighable quantity determined for a balance, an aliquot method of measurement should be used.

Measuring Equipment. The pharmacist should use judgment in selecting measuring equipment. The recommendations given in the USP–NF General Information section on volumetric apparatus should be followed. For maximum accuracy in measuring liquids, a pharmacist should select a graduate with a capacity equal to or slightly larger than the volume to be measured. The general rule is to measure no less than 20% of the capacity of a graduate. Calibrated syringes of the appropriate size may be preferred over graduated cylinders for measuring viscous liquids such as glycerin or mineral oil, since these liquids drain slowly and incompletely from graduated cylinders. Viscous liquids may also be weighed if this is more convenient, provided that the appropriate conversions from volume to weight are made by using the specific gravity of the liquid. Thick, opaque liquids should be weighed. For example, if a formulation specifies 1.5 mL of a liquid, it is better to use a 3-mL syringe with appropriate graduations to measure 1.5 mL than to use a 10-mL graduated cylinder, since quantities of less than 2.0 mL cannot be accurately measured in a 10-mL graduate. Also, if an opaque, viscous chemical, such as Coal Tar, USP, must be measured, it is more accurate to weigh the substance than to try to read a meniscus on a graduated cylinder or a fill line on a syringe.

For volumes smaller than 1 mL, micropipettes are recommended, in sizes to cover the range of volumes measured. Two or three variable pipettes can usually cover the range from about 50 μL to 1 mL.

Although conical graduates are convenient for mixing solutions, the error in reading the bottom of the meniscus increases as the sides flare toward the top of the graduate. Therefore, for accurate measurements, cylindrical graduates are preferred. Conical graduates having a capacity of less than 25 mL should not be used in prescription compounding.⁴

Compounding Equipment. Pharmacists need at least two types of mortars and pestles—one glass and one Wedgwood or porcelain. The sizes of each will depend on the drug products being compounded. Glass mortars should be used for liquid preparations (solutions and suspensions) and for mixing chemicals that stain or are oily. Generally, glass mortars should be used for antineoplastic agents. Because of their rough surface, Wedgwood mortars are preferred for reducing the size of dry crystals and hard powder particles and for preparing emulsions. Porcelain mortars have a smoother surface than Wedgwood mortars and are ideal for blending powders and pulverizing soft aggregates or crystals. When Wedgwood mortars are used for small amounts of crystals or powders, the inside surface may first be lightly dusted with lactose to fill any crevices in which the crystals or powders might lodge. If the contact surfaces of the mortar and pestle become smooth with use, rubbing them with a small amount of sand or emery powder may adequately roughen them. Over extended use, a pestle and a mortar become shaped to each other’s curvature. Thus, to ensure maximum contact between the surface of the head of each pestle and the interior of its corresponding mortar, pestles and mortars should not be interchanged.³

The compounding area should be stocked with appropriate supplies. Although supply selection depends on the types of products compounded, all areas should have weighing papers, weighing cups, or both to protect balance pans and spatulas. Glassine weighing papers (as opposed to bond weighing paper) should be used for products such as ointments, creams, and some dry chemicals. Disposable weighing dishes should also be stocked for substances like Coal Tar, USP.

Each compounding area should have stainless steel and plastic spatulas for mixing ointments and creams and handling dry chemicals. The pharmacist should exercise judgment in selecting the size and type of spatula. Small spatula blades (6 inches long or less) are preferred for handling dry chemicals, but larger spatula blades (>6 inches) are preferred for large amounts of ointments or creams and for preparing compactible powder blends for capsules. Plastic spatulas should be used for chemicals that may react with stainless steel blades. A variety of spatulas should be stocked in the compounding area, including 4-, 6-, and 8-inch stainless steel spatulas (one each) and 4- and 6-inch plastic spatulas (one each). Imprinted spatulas should not be used in compounding, since the imprinted ink on the spatula blade may contaminate the product.

The compounding area should contain an ointment slab, pill tile, or parchment ointment pad. Although parchment ointment pads are convenient and reduce cleanup time, parchment paper cannot be used for the preparation of creams because it will absorb water. Therefore, an ointment slab or pill tile is necessary. If suppositories are compounded, appropriate suppository molds, either reusable or disposable, should be available.

Other useful equipment and supplies may include funnels, filter paper, beakers, glass stirring rods, a source of heat (hot plate or microwave oven), a refrigerator, and a freezer—in some cases, an ultrafreezer capable of maintaining temperatures as low as –80 °C.

Ingredients

Ideally, only USP or NF chemicals manufactured by FDA-inspected manufacturers should be used for compounding. Although chemicals labeled USP or NF meet USP–NF standards for strength, quality, and purity for human drug products, the facilities in which the chemicals were manufactured may not meet FDA Good Manufacturing Practice (GMP) standards. In the event that a needed chemical is not available from an FDA-inspected facility, the pharmacist should, by next best preference, obtain a USP or NF product. If that is not available, the pharmacist should use professional judgment and may have to obtain the highest-grade chemical possible. Chemical grades that may be considered in this situation are ACS grade (meeting or exceeding specifications listed for reagent chemicals by the American Chemical Society) and FCC grade (meeting or exceeding requirements defined by the Food Chemicals Codex). Additional professional judgment is especially necessary in cases of chemical substances that have not been approved for any medical use. Particularly in these cases, but also in others as needed, the pharmacist, prescriber, and patient should be well informed of the risks involved.

Selection of ingredients may also depend on the dosage form to be compounded. In most cases, the prescriber specifies a particular dosage form, such as a topical ointment, oral solution or rectal suppository. Sometimes, however, the prescriber relies on the pharmacist to decide on an appropriate form. Irrespective of how the drug order is written, the pharmacist should evaluate the appropriateness of ingredients and the drug delivery system recommended. Factors to consider in selecting the dosage form include (1) physical and chemical characteristics of the active ingredient, (2) possible routes of administration that will produce the desired therapeutic effect (e.g., oral or topical), (3) patient characteristics (e.g., age, level of consciousness, ability to swallow a solid dosage form), (4) specific characteristics of the disease being treated, (5) comfort for the patient, and (6) ease or convenience of administration.

In checking the physical form of each ingredient, the pharmacist should not confuse drug substances that are available in more than one form. For example, coal tar is available as Coal Tar, USP, or Coal Tar Topical Solution, USP; phenol is available as Liquified Phenol, USP, or Phenol, USP; sulfur is available as Precipitated Sulfur, USP, or Sublimed Sulfur, USP. If ingredients are liquids, the pharmacist should consider compounding liquid dosage forms such as solutions, syrups, or elixirs for the final product. If ingredients are crystals or powders and the final dosage form is intended to be a dry dosage form, options such as divided powders (powder papers) or capsules should be considered. If ingredients are both liquids and dry forms, liquid formulations such as solutions, suspensions, elixirs, syrups, and emulsions should be considered.

Care must be exercised when using commercial drug products as a source of active ingredients. For example, extended-release or delayed-release products should not be crushed. Also, since chemicals such as preservatives and excipients in commercial products may affect the overall stability and bioavailability of the compounded product, their presence should not be ignored. Information on preservatives and excipients in specific commercial products can be found in package inserts and also in the dosage form section of selected product monographs in USP DI Volume I.⁶

If an injectable drug product is a possible source of active ingredient, the pharmacist should check the salt form of the injectable product to make sure it is the same salt form ordered. If it is necessary to use a different salt because of physical or chemical compatibility considerations or product availability, the pharmacist should consult with the prescriber. Some injectable products contain active constituents in the form of prodrugs that may not be active when administered by other routes. For example, if an injectable solution is a possible source of active ingredient for an oral product, the pharmacist must consider the stability of the drug in gastric fluids, the first-pass effect, and palatability. Also, if injectable powders for reconstitution are used, expiration dating may have to be quite short.

Storage

All chemicals and drug products must be stored according to USP–NF

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