Drug Distribution and Control: Preparation and Handling … Compounding Set 1.pdf · · 2016-08-20ASHP Technical Assistance Bulletin on! Compounding Nonsterile Products in Pharmacies!!!

Drug Distribution and Control: Preparation and Handling–Technical Assistance Bulletins 73

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, compartmental- ized 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.

74 Drug Distribution and Control: Preparation and Handling–Technical Assistance Bulletins 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 inte- rior 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 maintain- ing 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 and manufacturer specifications. Most chemicals and drug products marketed for compounding use are packaged by the manufacturer in tight, light-resistant containers. Chemicals intended for compounding should be purchased in small quantities and stored in the manufacturer’s original container, which is labeled with product and storage information. This practice fosters the use of fresh chemicals and ensures that the manufacturer’s label remains with the lot of chemical on hand. Certificates of purity for chemical ingredients should be filed for a period of time no less than the state’s time requirement for retention of dispensing records.

The manufacturer’s label instructions for storage should be followed explicitly to ensure the integrity of chemicals and drug products and to protect employees. Most chemicals and commercial drug products may be stored at controlled room temperature, between 15 and 30 °C (59 and 86 °F); however, the pharmacist should always check the manufacturer’s label for any special storage requirements. Storage information provided for specific commercial drug products in USP DI Volume I and on product labels follows the definitions for storage temperatures found in the General Notices and Requirements section of USP–NF. An acceptable refrigerator maintains temperatures between 2 and 8 °C (36 and 46 °F); an acceptable freezer maintains temperatures between –20 and –10 °C (– 4 to +14 °F)

To protect pharmacy employees and property, hazardous products such as acetone and flexible collodion must be stored appropriately. Safety storage cabinets in various sizes are available from laboratory suppliers.

Personnel Compounding personnel include pharmacists and supportive personnel engaged in any aspect of the compounding procedures. Training. The pharmacist—who is responsible for ensuring that the best technical knowledge and skill, most careful and accurate procedures, and prudent professional judgment are consistently applied in the compounding of pharmaceuticals—must supervise all compounding activities and ensure that supportive personnel are adequately trained to perform assigned functions. Both pharmacists and the compounding personnel they supervise should participate in programs designed to enhance

and maintain competence in compounding. Training programs should include instruction in the following areas: · Proper use of compounding equipment such as bal-

ances and measuring devices—including guidelines for selecting proper measuring devices, limitations of weighing equipment and measuring apparatus, and the importance of accuracy in measuring.

· Pharmaceutical techniques needed for preparing compounded dosage forms (e.g., levigation, trituration, methods to increase dissolution, geometric dilution).

· Properties of dosage forms (see Pharmaceutical Dosage Forms in USP–NF) to be compounded and related factors such as stability, storage considerations, and handling procedures.

· Literature in which information on stability, solubility, and related material can be found (see suggested references at the end of this document).

· Handling of nonhazardous and hazardous materials in the work area, including protective measures for avoiding exposure, emergency procedures to follow in the event of exposure, and the location of Material Safety Data Sheets (MSDSs) in the facility.7–10

· Use and interpretation of chemical and pharmaceutical symbols and abbreviations in medication orders and in product formulation directions.

· Pharmaceutical calculations. Procedures should be established to verify the ability of staff to meet established competencies. These procedures may include observation, written tests, or quality control testing of finished products. Attire. Personnel engaged in compounding should wear clean clothing appropriate for the duties they perform. Protective apparel, such as head, face hand, and arm coverings, should be worn as necessary to preclude contamination of products and to protect workers.

Generally, a clean laboratory jacket is considered appropriate attire for most personnel performing nonsterile compounding activities. Personnel involved in compounding hazardous materials should wear safety goggles, gloves, a mask or respirator, double gowns, and foot covers as required, depending on the substance being handled. To avoid microbial contamination of compounded drug products, written policies should be established that address appropriate precautions to be observed if an employee has an open lesion or an illness. Depending on the situation, an affected employee may be required to wear special protective apparel, such as a mask or gloves, or may be directed to avoid all contact with compounding procedures.

Reference Materials Pharmacists and supportive personnel must have ready access to reference materials on all aspects of compounding (see suggested references at the end of this document). Earlier editions of some references, such as Remington’s Pharmaceutical Sciences, provide more comprehensive compounding information than do the later editions. Information on compounding extemporaneous dosage forms from commercially available products can sometimes be obtained from the product’s FDA- approved labeling (package insert), the manufacturer, a local pharmacy college, or a drug information center. It is essential

76 Drug Distribution and Control: Preparation and Handling–Technical Assistance Bulletins that the stability and proper storage conditions for extemporaneous products be thoroughly researched. Therefore, the availability of adequate references and appropriate training in the use of the references is important.

Documentation and Record Keeping Each step of the compounding process should be documented. Pharmacists should maintain at least four sets of records in the compounding area: (1) compounding formulas and procedures, (2) a log of all compounded items, including batch records and sample batch labels (see section on packaging and labeling), (3) equipment-maintenance records, including documentation of checks of balances, refrigerators, and freezers, and (4) a record of ingredients purchased, including certificates of purity for chemicals (see section on ingredient selection) and MSDSs.

Compounding procedures should be documented in enough detail that preparations can be replicated and the history of each ingredient can be traced. Documentation should include a record of who prepared the product (if the compounder is not a pharmacist, the supervising pharmacist should also sign the compounding record); all names, lot numbers, and quantities of ingredients used; the order of mixing, including any interim procedures used (such as preparing a solution and using an aliquot); the assigned beyond-use date; and any special storage requirements (see section on stability and expiration dating). Compounding formulas and procedures should be written in a typeface that can be read easily. If formulas originate from published articles, copies of the articles should be attached to or filed with the written procedures.

Equipment maintenance and calibrations should be documented and the record maintained in an equipment-maintenance record file. Refrigerator and freezer thermometers should be checked and documented routinely, as should alarm systems indicating that temperatures are outside of acceptable limits.

Follow-up contact with patients who have received extemporaneously compounded products is recommended to as- certain that the product is physically stable and that no adverse effects have occurred from use of the product. Documentation of the contact and the findings is recommended.

Stability, Expiration, and Beyond-Use Dating

The USP–NF 4 defines stability as the extent to which a dosage form retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of its preparation. The USP–NF lists the following five types of stability: · Chemical · Physical · Microbiological · Therapeutic · Toxicological

Factors affecting stability include the properties of each ingredient, whether therapeutically active or inactive. Environmental factors such as temperature, radiation, light, humidity, and air can also affect stability. Similarly, such factors as particle size, pH, the properties of water and other solvents employed, the nature of the container, and the presence of other

substances resulting from contamination or from the intentional mixing of products can influence stability.4

Since compounded drug products are intended for con- sumption immediately or storage for a very limited time, stability evaluation and expiration dating are different for these products than for manufactured drug products. According to criteria for assigning dating in the USP–NF 4 General Notices and Requirements section and the Code of Federal Regulations,11 the pharmacist labeling extemporaneously compounded drug products should be concerned with the beyond-use date as used by USP–NF or the expiration date as used by the Code of Federal Regulations. For uniformity, the term beyond-use date will be used in the remainder of this bulletin. The beyond-use date is defined as that date after which a dispensed product should no longer be used by a patient.

Determination of the period during which a compounded product may be usable after dispensing should be based on available stability information and reasonable patient needs with respect to the intended drug therapy. When a commercial drug product is used as a source of active ingredient, its expiration date can often be used as a factor in determining a beyond-use date. For stability or expiration information on commercial drug products, the pharmacist can refer to USP DI Volume I.6 If no information is available, the manufacturer should be contacted. When the active ingredient is a USP or NF product, the pharmacist may be able to use the expiration dating of similar commercial products for guidance in assigning a beyond-use date. In addition, the pharmacist can often refer to published literature to obtain stability data on the same active ingredient under varying conditions and in different formulations.12

The pharmacist must assess the potential for instability that may result from the new environment for the active ingredients—from the combination of ingredients and the packaging materials. According to USP–NF,4 hydrolysis, oxidation-reduction, and photolysis are the most common chemical reactions that cause instability. When the possibility of such reactions exists, the pharmacist should seek additional stability data or consider other approaches. These could, in extreme cases, include the preparation and dispensing of more than one compounded drug product or the use of alternative methods of dosing. For some drugs, the lat- ter methods might include, for example, crushing a tablet or emptying the contents of a hard gelatin capsule into an appropriate food substance at each dosing time.

In assigning a beyond-use date for compounded drug products, the pharmacist should use all available stability information, plus education and experience in deciding how factors affecting product stability should be weighted. In the absence of stability data to the contrary or any indication of a stability problem, the following general criteria for assigning maximum beyond-use dates are recommended. It must be em- phasized that these are general criteria. Professional judgment as discussed elsewhere in this section must be used in deciding when these general criteria may not be appropriate. · When a manufactured final-dosage-form product is

used as a source of active ingredient, use no more than 25% of the manufacturer’s remaining expiration dating or six months, whichever is less;

· When a USP or NF chemical not from a manufactured final-dosage-form product is used, use no more than six months;


· In other cases, use the intended period of therapy or no

more than 30 days, whichever is less. All compounded products should be observed for signs of instability. Observations should be performed during preparation of the drug product and any storage period that may occur before the compounded drug product is dispensed. A list of observable indications of instability for solid, liquid, and semisolid dosage forms appears in USP–NF.

Packaging and Labeling The packaging of extemporaneously compounded products for ambulatory patients should comply with regulations pertaining to the Poison Prevention Packaging Act of 1970. These regulations can be found in USP–NF.4

Containers for compounded products should be appropriate for the dosage form compounded. For example, to minimize administration errors, oral liquids should never be packaged in syringes intended to be used for injection.

The drug product container should not interact physically or chemically with the product so as to alter the strength, quality, or purity of the compounded product. Glass and plastic are commonly used in containers for compounded products. To ensure container inertness, visibility, strength, rigidity, moisture protection, ease of reclosure, and economy of packaging, glass containers have been the most widely used for compounded products.3 Amber glass and some plastic containers may be used to protect light-sensitive products from degradation; however, glass that transmits ultraviolet or violet light rays (this includes green, blue, and clear [“flint”] glass) should not be used to protect light-sensitive products.

The use of plastic containers for compounded products has increased because plastic is less expensive and lighter in weight than glass. Since compounded products are intended for immediate use, most capsules, ointments, and creams should be stable in high-density plastic vials or ointment jars. Only plastic containers meeting USP–NF standards should be used.4 Reclosable plastic bags may be acceptable for selected divided powders that are intended to be used within a short period of time.

Each compounded product should be appropriately labeled according to state and federal regulations. Labels should include the generic or chemical name of active ingredients, strength or quantity, pharmacy lot number, beyond-use date, and any special storage requirements. If a commercial product has been used as a source of drug, the generic name of the product should be used on the label. The trade name should not be used because, once the commercial drug product has been altered, it no longer exists as the approved commercial product. Listing the names and quantities of inactive ingredients on labels is also encouraged. The coining of short names for convenience (e.g., “Johnson’s solution”) is strongly discouraged; these names provide no assistance to others who may need to identify ingredients (e.g., in emergency circumstances).

Capsules should be labeled with the quantity (micro- grams or milligrams) of active ingredient(s) per capsule. Oral liquids should be labeled with the strength or concentration per dose (e.g., 125 mg/5 mL or 10 meq/15 mL). If the quantity of an active ingredient is a whole number, the number should not be typed with a decimal point followed by a zero. For example, the strength of a capsule containing 25 mg of active ingredient should be labeled as 25 mg and not 25.0 mg. In

cases where the dosage strength is less than a whole number, a zero should precede the decimal point (e.g., 0.25 µg).3

In expressing salt forms of chemicals on a label, it is permissible to use atomic abbreviations. For example, HCl may be used for hydrochloride, HBr for hydrobromide, Na for sodium, and K for potassium.

Vehicles should also be stated on labels, especially if similar products are prepared with different vehicles. For example, if a pharmacist prepares two potassium syrups, one using Syrup, USP, as the vehicle and one using a sugar-free syrup as the vehicle, the name of the vehicle should be included on the labels.

Liquids and semisolid concentrations may be expressed in terms of percentages. When the term “percent” or the symbol “%” is used without qualification for solids and semi- solids, percent refers to weight in weight; for solutions or suspensions, percent refers to weight in volume; for solutions of liquids in liquids, percent refers to volume in volume.4

Labels for compounded products that are prepared in batches should include a pharmacy-assigned lot number. Assignment of a pharmacy lot number must enable the history of the compounded product to be traced, including the person compounding the product and the product’s formula, ingredients, and procedures. Being able to trace the history of a batch is essential in cases of a drug product recall or withdrawal.

In the preparation of labels for batches of compounded products, all extra labels should be destroyed, since pharmacy lot numbers change with each batch. If computers, memory typewriters, or label machines are used to print batch labels, care must be taken to ensure that the memory and printing mechanism have been cleared and the correct information is programmed before any additional labels are made. It is a good practice to run a blank label between each batch of labels to ensure that the memory has been erased or cleared. To document the information printed on each set of labels, a sample label printed for the batch should be attached to the compounded-product log. If labels are sequentially prepared for different drug products, procedures should exist to minimize the risk of mislabeling the compounded products. These procedures should ensure, for example, that labels for one drug product are physically well separated from labels for any other drug product.

Auxiliary labels are convenient for conveying special storage or use information. Auxiliary labels should be attached conspicuously to containers, if possible. If the container is too small for both a general label and an auxiliary label, special storage and use instructions should appear on the label in a format that will emphasize the instructions.

Limited Batch Compounding The purpose of extemporaneously compounding products is to provide individualized drug therapy for a particular patient. When a pharmacist is repeatedly asked to prepare identical compounded products, it may be reasonable and more efficient for the pharmacist to prepare small batches of the compounded product.

Batch sizes should be consistent with the volume of drug orders or prescriptions the pharmacist receives for the compounded product and the stability of the compounded product. The pharmacist should use judgment in deciding reasonable batch sizes. Product assays should be performed by a chemical analysis laboratory on a regular basis to ensure product

78 Drug Distribution and Control: Preparation and Handling–Technical Assistance Bulletins consistency among various lots, product uniformity, and stability. Analyses should be repeated every time an ingredient (active or inert) or procedure is changed. Documentation of as- say findings should be filed for a period no less than the state’s time requirement for the retention of dispensing records. General Compounding Considerations To provide the patient with the most stable drug product, the pharmacist should take the following steps upon receiving a prescription order that requires compounding.

First, the pharmacist should determine if a similar commercial product is available. A pharmacist can refer to various reference texts to check the availability of identical or similar products. Package inserts from commercially available products also contain information on inactive ingredients that can be compared with the requested formulation. If there is a commercially manufactured identical product, the local availability of the product should be determined.

When a similar product is commercially available, the pharmacist should determine which ingredients are different from the requested formulation to decide whether or not the commercial product can be used. At this stage, the pharmacist should seek answers to the following questions: · Are all of the ingredients appropriate for the condition

being treated? · Are the concentrations of the ingredients in the drug

order reasonable? · Are the physical, chemical, and therapeutic proper-

ties of the individual ingredients consistent with the expected properties of the ordered drug product?

If the answers to these questions are positive, the pharmacist should consult the prescriber about the possibility of dispensing the commercial product. (In some states, pharmacists may not be required to obtain permission from the prescriber to dispense a commercial product if the formulation is identical to the drug order.) Dispensing a commercial product is preferable to extemporaneously compounding a drug product because commercial products carry the manufacturer’s guarantee of labeled potency and stability.

If there is not a commercial product available with the same or similar formulation, the pharmacist should consider asking the prescriber the following questions: · What is the purpose of the order? There may be another

way to achieve the purpose without compounding a product.

· Where did the formula originate (article, meeting, col- league)?

· How will the drug product be used? · Does the patient have other conditions that must be

considered? · For how long will the drug product be used? If possible, the pharmacist should obtain a copy of the original formula to determine the extent to which the formulation has been tested for stability. When documentation is not available, the pharmacist should review the ingredients for appropriateness and reasonable concentrations.

For drug products that must be compounded, the pharmacist should closely observe the compounded drug product

for any signs of instability. Such observations should be performed during preparation of the drug product and during any storage period that may occur before the compounded drug product is dispensed.

If specific packaging information is not available, a light-resistant, tight container, such as an amber vial or bottle, should be used to maximize stability (see section on packaging and labeling).

The pharmacist should label the compounded drug product, including an appropriate beyond-use date and storage instructions for the patient.

Specific Compounding Considerations Accepted, proven compounding procedures for products including solutions, suspensions, creams, ointments, capsules, suppositories, troches, emulsions, and powders may be found in reference sources or the pharmacy literature. For additional information, pharmacists should check references cited in this document or consult colleagues or colleges of pharmacy with known expertise in compounding.

Glossary For the purposes of this document, the following terms are used with the meanings shown. Active Ingredient: Any chemical that is intended to furnish

pharmacologic activity in the diagnosis, cure, mitigation, treatment, or prevention of disease or to affect the struc- ture or function of the body of man or other animals.4

Batch: Multiple containers of a drug product or other material with uniform character and quality, within specified limits, that are prepared in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns.

Cold: Any temperature not exceeding 8 °C (46 °F).4 Commercially Available Product: Any drug product manu-

factured by a producer registered with the Department of Health and Human Services as a pharmaceutical manufacturer.

Compounding: The mixing of substances to prepare a drug product.

Container: A device that holds a drug product and is or may be in direct contact with the product.3

Cool: Any temperature between 8 and 15 °C (46 and 59 °F).4 Drug Product: A finished dosage form that contains an active

drug ingredient usually, but not necessarily (in the case of a placebo), in combination with inactive ingredients.4

Extemporaneous: Impromptu; prepared without a standard formula from an official compendium; prepared as required for a specific patient.

Inactive Ingredient: Any chemical other than the active ingredients in a drug product.4

Manufacturer: Anyone registered with the Department of Health and Human Services as a producer of drug products.14

Sensitivity Requirements: The maximal load that will cause one subdivision of change on the index plate in the position of rest of the indicator of the balance.4

Stability: The chemical and physical integrity of a drug product over time.4


Trituration: The reducing of substances to fine particles by rubbing them in a mortar with a pestle.3

Warm: Any temperature between 30 and 40 °C (86 and 104 °F).4

Suggested References Product Availability

American Drug Index Drug Facts & Comparisons Physicians’ Desk Reference The Extra Pharmacopoeia (Martindale) CHEMSOURCES AHFS Drug Information

Compounding Techniques

Compounding Companion PC-Based Software King’s Dispensing of Medications Remington’s Pharmaceutical Sciences Contemporary Compounding column in U.S. Pharmacist

Pharmaceutical Calculations

Stoklosa and Ansel’s Pharmaceutical Calculations Math—Use It or Lose It column in Hospital Pharmacy Calculations in Pharmacy column in U.S. Pharmacist

Drug Stability and Compatibility

American Journal of Hospital Pharmacy ASHP’s Handbook on Extemporaneous Formulations ASHP’s Handbook on Injectable Drugs International Pharmaceutical Abstracts Journal of the Parenteral Drug Association (now Journal of Pharmaceutical Science and Technology)

Canadian Society of Hospital Pharmacists Extempora- neous Oral Liquid Dosage Preparations

Pediatric Drug Formulations Physicians’ Desk Reference Contemporary Compounding column in U.S. Phar- macist

AHFS Drug Information The Merck Index

References

1. Pancorbo SA, Campagna KD, Devenport JK, et al.

Task force report of competency statements for pharmacy practice. Am J Pharm Educ. 1987; 51:196–206.

2. Allen LV Jr. Establishing and marketing your extem-

poraneous compounding service. US Pharm. 1990; 15(Dec):74–7.

3. Remington’s pharmaceutical sciences. 18th ed. Gennaro AR, ed. Easton, PA: Mack Publishing; 1990; 1630–1, 1658, 1660.

4. The United States Pharmacopeia, 22nd rev., and The National Formulary, 17th ed. Rockville, MD: The United States Pharmacopeial Convention; 1989.

5. USP DI Volume III: Approved drug products and legal requirements. 14th ed. Rockville, MD: The United States Pharmacopeial Convention; 1994.

6. USP DI Volume I: Drug information for the health care professional. 14th ed. Rockville, MD: The United States Pharmacopeial Convention; 1994.

7. 29 §C.F.R. 1910. 1200(1990). 8. ASHP technical assistance bulletin on handling cyto-

toxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033–49.

9. Feinberg JL. Complying with OSHA’s Hazard Communication Standard. Consult Pharm. 1991; 6:444, 446, 448.

10. Myers CE. Applicability of OSHA Hazard Communi- cation Standard to drug products. Am J Hosp Pharm. 1990; 47:1960–1.

11. 21 C.F.R. §211.137. 12. Connors KA, Amidon GL, Stella VJ. Chemical stabil-

ity of pharmaceuticals: a handbook for pharmacists. 2nd ed. New York: Wiley; 1986.

13. American Society of Hospital Pharmacists. ASHP guidelines on preventing medication errors in hospi- tals. Am J Hosp Pharm. 1993; 50:305–14.

14. Fitzgerald WL Jr. The legal authority to compound in pharmacy practice. Tenn Pharm. 1990; 26(Mar): 21–2.

Approved by the ASHP Board of Directors, April 27, 1994. Developed by the Council on Professional Affairs. Copyright © 1994, American Society of Hospital Pharmacists, Inc. All rights reserved. The bibliographic citation for this document is as follows: American Society of Hospital Pharmacists. ASHP technical assistance bulletin on compounding nonsterile products in pharmacies. Am J Hosp Pharm. 1994; 51:1441–8.

SecundumArtem

VOLUME 4 NUMBER 3

Current & Practical CompoundingInformation for the Pharmacist.

PHARMACY COMPOUNDING EQUIPMENTLoyd V. Allen, Jr., Ph.D.

INTRODUCTIONThe “tools of the trade” for most professions

have changed over the years. Physicians arenow using computers, laser light, high technol-ogy communications systems andbiotechnology-derived drug products; lawyersare extensively using computers and largedatabase search methods in the courtroom andpharmacists are using computers for suchapplications as dispensing, patient monitoring,patient counseling, drug preparation activities,high technology communications, access todata bases and drug delivery (pumps).

As one observes the changes that haveoccurred over the past 25 years in the deliveryof medical and pharmaceutical care, it is evi-dent that the equipment and supplies that arehandled on a daily basis have changed. It isalso notable that in many state boards of phar-macy regulations, changes are being made toreflect current practice activities, especially asthey apply to the preparation of drug products.

As one looks at change in pharmacy, itbecomes apparent that the rate of change isincreasing, especially with new technology.New methods and techniques must be learnedand mastered as they replace older ones.However, many time-honored methods andtechniques are still valuable and appropriatetoday and should be maintained as long asthey are useful and contribute to patient thera-py. It is imperative, as one looks at current andfuture practice activities in pharmacy, to becognizant of the role that computerization androbotics play. These will impact counseling,drug utilization review, medication manage-ment and dispensing activities. As

Loyd V. Allen, Jr., Ph.D., Professor and Head,Pharmaceutics, University of Oklahoma, HSCCollege of Pharmacy, Oklahoma City, OK 73190.

pharmacists, it is important to know whatequipment is available, how to use and main-tain it, and to be aware of changingresponsibilities and opportunities in health-care. As long as there is drug therapy,pharmacists must be involved in the prepara-tion and/or provision and appropriate use ofthe product to meet the specific needs of thepatient. This is especially true for the newerand biotechnology-derived medications andfor providing patient-specific products whichmust be compounded.PURPOSE

The purpose of this issue of SecundemArtem is to describe the different types ofequipment and supplies that are now availablefor the compounding of drug products.Obviously, this will not be a complete list asthere are differences in practices of pharmacythroughout the U.S. and many of these requiredifferent equipment and techniques. The intentis to present the more common items and topresent novel uses for alternative equipment.

HISTORICAL REVIEWHistorical records reveal that apothecaries

began by using very simple equipment andtools. Common dosage forms included oint-ments, oils, powdered extracts from plants, etc.Mortars and pestles were common, as wereknives and axes for obtaining the plants andplant parts. Other equipment included mixingvessels and drying tables. Later, processes suchas distillation and extraction were introduced,resulting in more complex equipment require-ments.

Equipment used by pharmacists for com-pounding during the 1940s, 1950s and 1960swas basic, consisting of mortars and pestles,beakers, conical graduates, prescription bal-ances, hot plates, refrigerators, pill tiles andspatulas. During the 1970s, with the advent ofpharmacist’s responsibility for intravenous

As long as there is drug therapy,

pharmacists must be involved in

the preparation and/or

provision and appropriate use

of the product to meet the

specific needs of the patient.

Pharmacists are becoming

involved in a higher level of

technology-based pharmacy.

admixture services, additional equipment was introducedinto the pharmacy, including laminar flow hoods, aseptictransfer devices/pumps and sterile filtration units.

In the 1980s and 1990s, the resurgence of compounding hasresulted in a large increase in the diversity of equipment inpharmacies, depending upon the scope of practice. From tra-ditional compounding activities in the preparation of syrups,suppositories, troches and ointments to the high-tech asepticcompounding of total parenteral nutrition solutions contain-ing 20 or more ingredients and even the programming ofambulatory pumps capable of predetermined delivery of aweeks supply of drugs contained in a small reservoir, phar-macists are becoming involved in a higher level oftechnology-based pharmacy.

Despite the tremendous changes in the equipment require-ments of today’s practicing pharmacists, many regulatoryagencies have not “kept up with the profession” in updatingpractice regulations. Since the practice of pharmacy is sodiverse, we have probably passed the time in which a Board-defined single list of items will suffice for all practice settings;rather, different lists must be developed dependent upon thetype of practice, i.e., community, hospital, home healthcare,nuclear, traditional compounding and aseptic compounding.Many regulatory bodies are now looking at this subject so wewill probably see increased activity in the future. Until thattime, this issue will serve as a reference for some of the equip-ment and supplies that pharmacists are using, dependingupon their practice activities.COMPOUNDING EQUIPMENT AND SUPPLIES

The approach taken in this presentation is to divide theequipment into four areas of pharmacist involvement, as fol-lows:

1. General nonsterile product compounding equipment2. Advanced nonsterile product compounding equip-

ment3. General sterile product compounding equipment4. Advanced sterile product compounding equipmentThe costs presented for some items are only approximate

and will vary greatly depending upon their source, qualityand design. Many routine items are simply listed without costand discussion, as use of these has become common.Discussion will usually be limited to those items for which theapplications and use may be unclear or for those in whichthere is an unusual application. Many items are actually usedfor both nonsterile and sterile product compounding.NONSTERILE PRODUCTCOMPOUNDING EQUIPMENTGeneral Nonsterile ProductCompounding EquipmentBalance—Prescription, TorsionBalance—Triple BeamBeaker Hot StandBeaker TongsBeakers—50, 100, 150, 250, 400, 600,

1000 mL Glass/Plastic/Stainless Steel

Beakers—With/Without Handles,1000, 2000, 3000 mL Glass/Plastic/Stainless Steel

Capsule Filling EquipmentCylinders—Graduated 5 to 2000

mL—Glass/PlasticDesiccators—Glass/PlasticDesiccant (Drier-Rite®)Dishes—Evaporating, Porcelain—

with/without Handles

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Funnels—Glass/Plastic—2", 3", 4",5", 6"

Graduates—Pharmaceutical/Conical 10, 25, 50, 100, 250, 500and 1000 mL, Glass/Plastic

Hotplates, Various Sizes andFeatures

Glasses—SafetyGraters, Hand—Fine, Medium,

Coarse, CombinationMortars/Pestles—Glass and

Porcelain—2, 4, 8 oz.Openers—Jar/Bottle/TubeOvens—DryingPill Tiles—Glass, FrostedRacks, Drying—Plastic or Epoxy

Resin MaterialRefrigerator with FreezerSpatulas—4", 6"—Plastic and

Stainless Steel, AssortedStir Plate—Magnetic with Stir BarsStirring RodsStrainers—Small, Medium, LargeSuppository Molds (rectal, vaginal,

urethral)Thermometers—GlassThermometer ClipsTroche MoldsWeighing Dishes—Plastic and

AluminumWeighing PapersWeight Sets

Advanced Nonsterile ProductCompounding Equipment(in addition to those listed above)Balance, Electronic—Minimum

sensitivity of 10 mg.Balance, Electronic—Minimum

sensitivity of 1 mg.Bath, Dry—Heater/IncubatorBeakers, InsulatedBeakers, TeflonBeakers, Heat-resistant plasticBlender

Liquefy, Puree, Mix12 mL to 4,000 mL capacitiesTemperature controlled, Foam

arrestorBlender, Hand—Variable speed

Mixing container, stand, variousblades, at least 2 speeds.

Blender, Hand—Two Speed LabThree blades, with stand

Boiling Chips or BeadsBottles, Drop Dispensing—Plastic or

GlassBottles, Dispensing Fluid—Plastic or

GlassBrushes, Cleaning—Nylon—Various

sizes/shapes to fit equipmentBuckets with Lids—PlasticBurets, 10-50 mLBurners, Bunsen or Similar (natural

gas or propane)Carboys with/without spigotsCarts, Plastic/Metal

CentrifugeChopper/GrinderCoffee GrinderCrimper, Hand operatedDesiccatorDesiccator/MicroMarinader

Creates vacuum. . . desiccator applications

Dispensing Pumps, Variable SpeedPipet bulbsFat/oil separator (Gravy separator)Food Processor

Slice, Grate, Chop, Puree, Mix,Knead: various blades

Heat Gun, Variable Heat OutputsHomogenizers, Hand operatedLead Sticks, flexibleLight boxesMagnetic StirrersMicrospatulas, Stainless Steel, Teflon

CoatedMotorized StirrerMalt Shop Mixer (2 speed motor,

stainless steel cup 28 oz.)Mixer—Orbital, Single/Variable

SpeedMixer, Professional—KitchenMortar/Pestle, wide shapepH Meters, Variable Sizes/StylesPipets, 1-100 mLPipet Fillers, Hand OperatedPipettors/Micropipettors—Variable

Size: 5-200 µL, 200-1000 µLPipettors—MultichannelPipettor, MotorizedPitcher, Stirring

2000 mL capacity, Blades attachedto handle, plastic

Powder BlenderBlends powders in dust-freeenvironment and protects operatorfrom powder dust.

Repeating Dispensers for LiquidsSealers, bag or suppositorySealers, tubeSieves, 3", 5", 7", various mesh sizesSolvent Dispensing/Spray BottlesSpatulas, Stainless Steel, Teflon-

coated, Porcelain, Plastic.Sprayer BottlesTablet Press, single punchTea/Spice BallThermometer, Hi-Lo AlarmThermometer, Digital ProbeThermometers with alarmTest-tube rack, four-sidedTongs, Beaker/Flask/TubeTool Set, Cooks’

Heavy gauge stainless steelPasta fork, turner, solid spoon, ladle, server, skimmer and hanging rack.

Tubing, various sizes/typesTubing clamps, various sizes/typesVortex MixersUltrasonic Cleaner, Various

Capacities

Workbench protector sheets (plastic, rubber, absorbable paper, matted)

Wash BottlesWater systemSTERILE PRODUCTCOMPOUNDING EQUIPMENTGeneral Sterile ProductCompounding EquipmentLaminar Flow Hood, Horizontal

(Class 100)Laminar Flow Hood, Vertical (Class

100)RefrigeratorAnemometer, Direct ReadingAmpule Openers, DisposableApparel for Clean Rooms (Class

10,000)Aprons, Sleeves, Gloves, Hoods—Open Face, Hoods—Face Mask,Boot Covers, Shoe Covers, Frocks,Coveralls, Head Coverings, LabCoats, Smocks, Shirts/Pants, Hats/ Caps, Facemasks, Beard Covers

Autoclave TapeBiohazard Autoclave BagsBiohazard Bag HoldersAutoclave BagsBaggies/Pouches/Pouch SealersCleaning Materials

Pickup Roller-WallPickup Roller-FloorPickup Roller-Cabinet/Work

SpaceHazardous materials handling

equipmentFilter Units, Vacuum—DisposableFilters, Sterilizing—Numerous types/

shapes/applicationsFilter Unit—Repeating Syringe with

Three-Way connector and Check Valve

ForcepsImpulse or Induction Sealer for plastic

overwrapsNeedle DestroyerPumps, VacuumPump-Vacuum, Hand OperatedPumps, PressureRefrigerator with FreezerSharps Disposal UnitStainless Steel Pressure Filter Holders—

Various CapacitiesStainless Steel Pressure VesselsTacky MatsTrash Container—Gowns/Apparel ArticlesTrash Container—Plastic/Paper ArticlesWire Racks/Shelving

Advanced Sterile ProductCompounding Equipment(in addition to the above)AutoclaveFiltration, Sterile—EquipmentCooler/Heater for medication transportin automobile, 30 L

Crimper, Hand OperatedDecappersIce Replacement Gel—Various Forms/TypesOsmometersParticle CounterParticulate Testing EquipmentPump, Pressure—VacuumPyrogen Test MaterialsQuality Control EquipmentSample Transporter Coolant—Pouch

Maintains sample at about 50˚ F (below 10˚ Cfor 30 minutes)

Smoke SticksSpatulas and Spoons, Sterile—Plastic for weighing

and obtaining drugsSterility Test Equipment Ultra-Freezer (Capable of about -80˚ C)

DISCUSSIONGeneral Nonsterile Product CompoundingEquipment

Beaker Hot Stand is a rubber or plastic molded handprotector that is convenient for picking up hot or verycold beakers, flasks, etc.

Capsule Filling Devices are available in numerous for-mats. From inexpensive plastic units ($20) for 25 or 50capsules to the more rugged 100-capsule machines ($500-$1500), these are timesavers if a large number of capsulesis being prepared. The 100-capsule units can be used forpreparing smaller numbers and work well with lockingcapsules.

Desiccators ($50-100) containing a desiccant areimportant for storing drug products that require a verydry atmosphere. Desiccators are available in glass orplastic and may have a port for a vacuum.

Glass Pill Tiles ($35) customarily are used for thepreparation of many different dosage forms. Many comewith graduated markings on one end for measuringlengths of suppositories, pill pipes, etc. Most glass pilltiles also have a “frosted” portion which is to be used asthe primary work area. This area also provides a goodworking surface for comminution with a stainless steelspatula, and for mixing ointments.

Ovens-Drying ($600-1000) are often required for thedrying of various compounded products and for the dry-ing of products that might have adsorbed or absorbedmoisture over time. As the potency of drugs increases,the sorption of moisture will become even more danger-ous due to weighing errors which may occur if the drugis not dried before weighing due to the apparentlygreater weight of the material.

Stir plates (magnetic with stir bars) are becoming com-monplace in pharmacies involved in compounding alarge number of fluid preparations. This frees up phar-macists time to do other duties while ingredients aredissolving and mixing. If the plate has a heating element,melted ointments and suppository bases will be moreeasily mixed to uniformity.

Suppository and Troche molds made of plastic areslowly replacing the older heavy metal molds. The moldsmay also serve as part of the dispensing package. Cautionmust be observed since these molds are available in dif-ferent sizes, unlike many of the metal molds which werereasonably standardized at 2 mL each.

Weight sets (Brass, $75) usually contain both apothe-cary and metric weights for use with prescriptionbalances. The metric system is now the only official sys-tem in the U.S.P. XXIII.

Advanced Nonsterile Product CompoundingEquipment

Balances (electronic) ($850 to $2500) are available toweigh quantities as low as 1 mg. These electronic bal-ances are useful in compounding pharmacies to weighsmall quantities of drugs very accurately and with a rela-tively low investment. They are easy to use, clean andcalibrate. The cost of a balance is generally proportionalto the lowest weight that can be measured.

Dry baths are alternatives to hot plates and are replac-ing water baths in many laboratories. A dry bath isessentially a heated chamber that can be filled with sand,salt or aluminum blocks designed to hold various sizes ofglassware. For example, a beaker can be “wiggled” intothe sand after the sand has equilibrated to the desiredtemperature for heating a preparation. These dry bathsare easy to use and clean and are virtually maintenance-free.

Blenders (Cabinet top and hand held, $50-$300) areindispensable in the preparation of many products.Kitchen blenders are excellent for preparing solutions,suspensions, emulsions and even gels (if done properly).They are available in the standard kitchen size of about 28ounces and in laboratory sizes with vessels ranging from12 mL to about 4,000 mL. Hand-held blenders are excel-lent for preparing lotions, creams and other semisolidand liquid preparations. They are available as single,dual and variable speed.

Carts (plastic/metal-$50-300) are items of equipmentor furniture that can be very useful in compounding.They can serve to move supplies from one area to anoth-er as well as provide working surfaces when necessary.

Choppers/Grinders ($30) and Coffee Grinders ($15-25) are available in kitchen departments in large stores aswell as in gourmet shops. They can be used for particlesize reduction and even for blending small quantities ofpowders.

Crimper, hand operated ($250) is used to attach alu-minum tamper-evident safety caps on containers ofprepared products. This is a very convenient system forpackaging products where evidence of the package hav-ing been opened is desired and is similar to the seals usedfor injectables.

Dispensing pumps, (variable speed, $1500-2000) areinvaluable when the same volume of a liquid has to bemeasured and dispensed repeatedly. They are especiallyuseful in packaging finished products into containers.

Pipet bulbs ($10) can be used to aid in pipetting andeliminate many of the dangers associated with pipettingby mouth. There are numerous styles of these bulbswhich may be used not only with measuring pipets butalso with transfer pipets for moving small quantities ofliquids from one vessel to another.

Fat/oil separators ($10) can be used to obtain a foam-free liquid from an ingredient that has a foam on topwhich makes it difficult to measure. The spout originatesat the bottom of the container so the liquid, not the foam,is dispensed. These are often referred to as “gravy sepa-rators”.

Food Processors ($200) capable of slicing, grating,chopping, pureeing, mixing and kneading, dependingupon the various blades that are available, have manyapplications, including the preparation of ointments andpastes.

Heat guns (variable heat, $50-65) can be used whenheat is required in a situation where a hot plate is incon-venient. A heat gun can be used to direct the heat to a

specific area where it is needed, as in sealing plastic dosecontainers. It can also be used to apply gentle heat tobeakers of liquids, etc.

Homogenizers (Hand operated, $375) are available forassistance in the preparation of fine emulsions. They areeasily disassembled for cleaning and work with as littleas 60 mL. of liquid.

Lead Sticks (Flexible) are convenient for wrappingaround beakers, flasks, and other pieces of equipment toprevent them from falling over. The sticks are made ofsoft lead with colorful plastic coatings and are availablein many diameters and lengths. They easily may beshaped or formed to fit around almost any piece of labo-ratory glassware or equipment.

Light boxes are excellent aids to determining the com-pleteness of solution when dissolving solids and fordetecting precipitants when working with materials thatmay be incompatible or near the limit of solubility. A sim-ilar piece of equipment can be made by painting a pieceof Masonite one-half black and one-half white, using“flat” paints. When this board is hung on a wall with afluorescent light immediately above it, the dark and lightbackgrounds may be used to help determine the presenceof particles in a solution.

Orbital mixers ($300) can be used to mix a large num-ber of beakers, bottles, flasks, etc. simultaneously. Thecontainers are fixed in place on a platform that moves ina circular or orbital motion. These are very widely usedin laboratories and can be used to advantage in com-pounding pharmacies where a large number ofcontainers need to be mixed simultaneously.

Mixer (professional or kitchen, $350-450) can be usedfor beating, mixing, whipping and kneading with flatbeaters, dough hooks and wire whips. They can be usedfor the preparation of products ranging from liquids,including emulsions, to ointments.

pH Meters ($50-2000) are now commonplace in com-pounding pharmacies. pH is critical for drug solubilityand stability. Many products must be buffered, or the pHadjusted to a certain range that requires a greater degreeof accuracy today than that provided by pH indicatorpapers.

Pipettors (micropipettors-variable sizes 5-200 µL, 200-1000 µL, $175 each) are excellent for measuring smallvolumes of liquids accurately. They eliminate the need toprepare aliquots of drugs where only a very small quan-tity is required. Variable micropipettors are available sothe investment can be kept to a minimum. For example,one micropipettor can be used for 200 to 1000 uL andanother one for 5 to 200 uL. Multiple channel micropipet-tors are available for use where up to 12 channels must bedelivered simultaneously; for example, when 0.5 mL isbeing placed in small vials/ampules and a large quantityare being prepared.

Powder blenders ($2000-4000) enable pharmacists toblend powders in a dust free environment and protect theoperator from powder dust. These blenders mechanical-ly blend in enclosed plastic bags without allowing any ofthe powder to escape into the environment.

Sealers, bag or suppository ($115) are convenient forsealing plastic bags or certain suppository molds.

Sealers, tube ($800) are widely used for packaginglarge numbers of ointments, creams, or gels in plastictubes. They are easy to use and provide reproducibleresults attractively packaged.

Tablet press (single punch, $550) is an easy-to-usemethod of preparing individual tablets. A blend of the

active drug and excipients can be weighed and placed inthe die, the handle lowered, and a tablet produced bycompression.

Tea/spice balls ($5-15) can be used to contain a flavor-ing ingredient while immersing it in a liquid until thedesired strength is obtained.

Thermometers with alarm ($60) can be used to pro-vide an audible indication when a refrigerator or ovengets out of a preset temperature range. These are mostoften used on freezers and refrigerators, especially ultra-freezers.

Tool sets, cooks’ ($50) have some useful implementsfor compounding, often including a pasta fork, turner,solid spoon, ladle, server and a skimmer; complete witha hanging rack.

Ultrasonic cleaners, ($175-1000) are useful for cleaningitems but are also very useful for accelerating the disso-lution of slowly dissolving drugs.

Water system (high quality, various prices) may berequired if the Pharmacy is involved in preparing a largequantity of products requiring different grades of water.

Workbench protector sheets of plastic, rubber orabsorbable paper are often convenient for defining awork area for a specific project. They can be cleaned ordisposed of when finished.

General and Advanced Sterile ProductCompounding Equipment

Many of the items listed in the categories of sterileproduct compounding and advanced sterile productcompounding can be placed into one of four general cat-egories. The first group includes those items that are usedfor the preparation of sterile products: ampule openers,impulse sealers, vacuum pumps, sterile filtration equip-ment, sterile spatulas and spoons. Second is a list of itemsfor quality control, including an anemometer, particlecounter, particulate testing equipment, pyrogen testmaterials and sterility test equipment. The third area isthat of product storage and delivery, including suchitems as a refrigerator, cooler/heater for automobile, icereplacement gel, and an ultra-freezer. Fourth, we includethose items used for maintenance of the clean room envi-ronment, such as apparel for personnel, cleaningmaterials, and HEPA filters.

SUMMARYTo invest or not to invest? This is an age-old question

concerning business opportunities, both professional andvocational. Some pharmacists hesitate to invest hundredsor thousands of dollars in equipment necessary tobecome involved in compounding pharmacy. There is noquestion that taking the time and using the professionaland scientific expertise of the Pharmacist in preparingspecific dosage forms and strengths to meet the individ-ual needs of patients is financially worthwhile. A firststep includes informing local Physicians of the availabili-ty of compounding services to meet the needs of theirpatients and practice. This brief introduction often hasresulted in new opportunities for professional activities.In times of shrinking fees and margins and increaseddemands on pharmacists time for patient counseling,investments in time-saving technologies should be con-sidered, as should additional services to meet thedemands of the marketplace for individualized patientcare through compounded prescriptions.

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SecundumArtem

VOLUME 13 NUMBER 4


INTRODUCTION

What is USP Chapter <795>? Why should com-pounders be familiar with it? Where did it come from?From where did it derive its authority? Do I have tofollow it? What happens if I don’t? Is it really impor-tant? What if I have never had a problem before……doI still need to comply with its standards? Who estab-lishes these standards? Are they “set in stone” or dothey change over time? What is the relationshipbetween the USP and the U.S. government? What isthe relationship between the USP and the Food andDrug Administration? Do the USP standards reallycontribute to patient safety?

All these are valid questions that deserve an answer.As we travel from looking at where the pharmacopeiascame from and from where they derive their authority,we will look at how the USP-NF shapes pharmacycompounding and the pharmaceutical industry today.

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GOALS AND OBJECTIVESGoal: The goal of this article is to provide information on the historical development and practical implementation

of USP Chapter <795> Pharmaceutical Compounding-Nonsterile Preparations.

Objectives: After reading and studying the article, the reader will be able to:1. Discuss the history and development of the USP-NF and the USP-Pharmacists’ Pharmacopeia.2. List the five questions that should be considered concerning each compounded prescription.3. Discuss the difference between a “product” and a “preparation” as well as the difference between an “expiration date”

and a “beyond use date”.4. Discuss the various sections of USP Chapter <795> and their application.5. List the two basic reasons or intent for developing USP Chapter <795>.

USP Chapter <795>Pharmaceutical Compounding - Nonsterile Preparations

Loyd V. Allen, Jr., Ph.D., R.Ph., Professor Emeritus, University of Oklahoma, HSC College of Pharmacy, Oklahoma City, OK 73190

Two things to keep in mind regarding the USP andthese chapters; the intent is to protect both the patientAND the pharmacist. Protection of the patient isaddressed when these standards are followed and thepharmacist when any adverse event might occur wherepatient harm and/or litigation results.

BACKGROUND

Pharmaceutical compounding is the history of pharmacy,spanning the past 5,000 years, until the early to mid1900s when the pharmaceutical industry came intobeing. There are many recorded writings of formulasand methods of treating disease in pharmacy historybooks. The standards for uniformity and quality inpharmacy compounding started back in 1580 in Bergamo,Italy, where the term “pharmacopoeia” was first used inconnection with a local book of drug standards. Manypharmacopeias were developed on local, city and

7. Which of the following is NOT on the checklist for acceptable strength, quality and purity?A. Have the physical and chemical properties and medicinal, dietary, and

pharmaceutical uses of the drug substances been reviewed?B. Are the quantity and quality of each active ingredient identifiable?C. Will the active ingredients be effectively absorbed, locally or system-

ically according to the prescribed purpose, from the preparation and route of administration?

D. Has the bioavailability of the compounded preparation been demonstrated?E. Were all calculations and measurements confirmed to ensure

that the preparation will be compounded accurately?8. The purposes of the thirteen steps in the Compounding Process are to:

I. minimize errorsII. maximize the prescribers’ intent for the patientIII. provide shortcuts in compoundingA. I onlyB. III onlyC. I and II onlyD. II and III onlyE. I, II and III.

9. Which of the following records is where the information concerning the ingredients used in compounding a prescription, such as the man-ufacturer, lot numbers, expiration dates of chemicals, are recorded?A. formulation recordB. compounding recordC. material safety data sheetD. certificate of analysisE. none of the above

10. The purpose of the compounding standards of the USP are to:I. ensure third party reimbursementII. enhance patient safetyIII. protect the pharmacistA. I onlyB. III onlyC. I and II onlyD. II and III onlyE. I, II and III.

11. My practice setting is: a. Community-based c. Hospital-basedb. Managed care-based d. Consultant and other

12. The quality of the information presented in this article was:a. Excellent b. Good c. Fair d. Poor

13. The test questions correspond well with the information presented.a. Yes b. No

14. Approximately how long did it take you to read the Secundum Artem article AND respond to the test questions? ______________________________________________________________

15. What topics would you like to see in future issues of Secundum Artem? ______________________________________________________________

1. The first U.S. Pharmacopeia was established in 1820 by a group of:A. pharmacists.B. physicians.C. government agents.D. state boards.E. physicians and dentists.

2. Today, the USP/NF standards are applicable to:I. pharmaceutical companiesII. compounding pharmaciesIII. health food/nutrition storesA. I onlyB. III onlyC. I and II onlyD. II and III onlyE. I, II and III.

3. The USP began to reorient its activities to include pharmacy compounding again in:A. 1965B. 1970C. 1975D. 1980E. 1985

4. The terminology applied to compounded prescriptions and the date after which they should not be used are:A. products, expiration dateB. products, beyond use dateC. preparations, expiration dateD. preparations, beyond use dateE. none of the above

5. The ultimate responsibility for compliance with all the USP/NF standards for compounding rest with the:

A. prescribing physicianB. ownerC. compounderD. technicianE. all the above

6. If no valid data is available for an aqueous, oral compounded sus-pension, the beyond use date to be applied is:A. 24 hours at room temperatureB. 72 hours at refrigerated temperatureC. 1 week at room temperatureD. 2 weeks at refrigerated temperatureE. 6 months at refrigerated temperature

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ACPE No. 748-000-05-001-H01

Please print address clearly below ORaffix an address label here if available

Name_____________________________________________________________________________________________________Home Address _____________________________________________________________________________________________

City______________________________________________State______________ Zip___________________________________

Primary State Licensure _____________________________________________________________________________________

License No._________________________________________________________________________________________________

Home Phone ( )_________________________________ Bus. Phone ( ) ____________________________________

Email Address:_____________________________________________________________________________________________

Please circle the most appropriate answer for each of the following questions. There is only ONE correct answer per question.

VERIFICATION

Verification, not validation, is what is required. Ver-ification involves checking to ensure that all theprocesses were appropriate and accurately per-formed. Validation is much more involved andtime-consuming.

PATIENT COUNSELINGAs with any prescription, patient counseling isimportant. It is especially important with com-pounded preparations where the beyond-use datemay be rather short. Patients should be counseledabout use, storage and evidence of instability (visu-al changes, odor, etc.).

SUMMARY

There is no question that the standards of the USPserve to enhance patient safety and also protect thepharmacist. There are many general chapters in theUSP that either directly or indirectly affect pharma-cy compounding. The primary chapters are <795>Pharmaceutical Compounding-Nonsterile Prepara-tions, <797> Pharmaceutical CompoundingCompounding-Sterile Preparations, <1075> GoodCompounding Practices, and <1160> Pharmaceuti-cal Calculations in Prescription Compounding.

In the next issue, we will discuss the rationalebehind and the practical application of USP <797>.

REFERENCES

1.Allen Jr LV, Popovich NG, Ansel HC. Ansel’sPharmaceutical Dosage Forms and Drug DeliverySystems, 8th Ed. Baltimore MD, Lippincott,Williams & Wilkins, 2005, pp 7-12.

2.U.S. Pharmacopoeial Convention, Inc. USP-Phar-macists’ Pharmacopeia, Rockville MD, U.S.Pharmacopeial Convention, Inc., 2005, pp 408-413.

Copies of the individual USP Chapter <795>Pharmaceutical Compounding-Nonsteri le Preparations or the new USP-Pharmacists’ Pharmacopeia , can be obtained onl ine atwww.usp.org or by calling 1-800-227-8772.

COMPOUNDING RECORDS AND DOCUMENTS

Formulation Record, Compounding Record,MSDS FileState boards of pharmacy have record keepingrequirements that must be met. The following arepractical for quality purposes and to enable anothercompounder to duplicate the preparation when pre-pared at a later time.

The formulation record generally will be either onthe computer system, or may be an individual newprescription or request. This is where the processstarts. The formulation record can be used to pre-pare the documentation for the compoundingrecord.

The compounding record contains the sources and lotnumbers of the ingredients, calculations, processesused, results of any testing done, an assignedbeyond-use date, identification numbers, name ofthe compounder, quantity of the preparation com-pounded and other pertinent information. It containsall relevant information related to the actual com-pounding of the specific prescription. It is used forchecking the final preparation for accuracy.

Material Safety Data Sheets (MSDSs) may be eitherhard copy or accessible electronically. They areneeded for all drug substances or bulk chemicalslocated in the compounding pharmacy. If commer-cial products are used, the package insert can servethis purpose.

QUALITY CONTROL

All the paperwork from the first step to the finalpreparation should be reviewed along with observ-ing the finished preparation.

Standard Operating Procedures (SOPs) are docu-ments that describe how to perform routine tasks inthe environment of formulation development, pur-chasing, compounding, testing, maintenance,materials handling, quality assurance and dispens-ing. They contain step-by-step instructions toperform tasks reliably and consistently; includinghow a task will be performed, who will do the task,who is responsible, why it will be performed andany limits associated with the task.

Date__________________________

the USP purchased the NF and in 1980 the first com-bined USP-NF was published and continuallypublished the book every 5 years. In 2002, annual revi-sions were implemented. Today the USP-NF ispublished on an annual basis. 1

There was a change in the USP during the early-mid1900s as the pharmaceutical industry began to growand assume a major role in providing pharmaceuticalsto the public. The USP changed its format from an ori-entation towards compounded pharmaceuticals tomanufactured pharmaceuticals. This change continuedthroughout the 1900s and early into the 2000s. Also,during the 1800s and 1900s, the State Boards of Phar-macy enforced the standards of the USP and NF inpharmacies at the state level. However, as compound-ing diminished, the state boards did not necessarilyrequire USP or NF volumes actually be in the requiredlibrary of the pharmacies.

However, in the 1970s, there was a resurgence of phar-macy compounding and in 1985, the USP Conventionpassed two resolutions urging the USP to becomeactive again in promoting standards for pharmacycompounding. This was followed with convention res-olutions in 1990, 1995 and again in 2000.

In 1993, there was the formation of the Expert Adviso-ry Panel and the Review Panel on PharmacyCompounding Practices by the USP. The Expert Advi-sory Panel is divided into two groups; one to work ongeneral chapters and the other to work on compound-ing monographs. In 1996, the USP published thechapter Pharmacy Compounding Practices <1161> toprovide guidance to pharmacists and other compound-ing professionals on proper compounding practicesand techniques.

When Congress enacted the FDA Modernization Act of1997 (FDAMA97) that referred to pharmacy com-pounding, the FDA formed an internal FDA SteeringCommittee and an external FDA Compounding Advi-sory Committee to aid in implementing thecompounding provisions of FDAMA97. SinceFDAMA97 referred to USP and the enforceability of itscontents, it was deemed necessary to renumber <1161>Pharmacy Compounding Practices from an informa-tional chapter (numbered >1000), to <795> anenforceable chapter (numbered <1000) and ultimatelyits name was changed to Pharmaceutical Compound-ing-Nonsterile Preparations. It became official inJanuary 2000 and remains so today.

national levels in Europe. Some of the best known werethe London, Edinburgh and Dublin Pharmacopeiaswhich were official until 1864, when they were com-bined and replaced by the well-known BritishPharmacopeia.1

The U.S. Pharmacopeia (USP) was established in Janu-ary 1820 by a group of physicians from the United Statesat the first Pharmacopeial convention. The objective ofthe USP was to establish uniform standards for themedications they prescribed. In December 1820, theypublished the first U.S. Pharmacopeia. Following this,the USP convention met every 10 years and produced arevision to the book; pharmacists were invited to join in1850. 1

The USP is an independent organization where deci-sions about standards are made by the many volunteersserving on various expert committees. There are twocommittees that address compounding; one for nonster-ile and one for sterile activities. Each committee consistsof 10 to 12 volunteers from pharmacy practice, acade-mia and related support companies. The expertcommittees meet with sufficient frequency to accom-plish their goals (usually one to three times per year)and conduct much of their business via telephone, e-mails, etc. Each committee has a staff liaison at USPthat is responsible for working with the committees.

The USP was mentioned as a “standard” in the DrugImportation Act of 1848 and the USP and NF were bothestablished as official compendia for the United Statesin the Pure Food and Drug Act of 1906. Its’ status con-tinues today. In 1938, the Food and DrugAdministration (FDA) was born, having originally beenthe US Department of Agriculture Bureau of Chemistry,then the Food, Drug and Insecticide Administration andfinally the FDA. The FDA can enforce the standardsestablished by the USP for the pharmaceutical industryor the standards it develops. The USP is independentand has no relationship with either the federal govern-ment or the FDA. It is unique because otherpharmacopoeias throughout the world are prepared bythe government of the country, but not the USP. 1

The National Formulary (NF) was first published in 1888by the American Pharmaceutical Association, listingstandardized formulas including the ingredients andtheir quantities required for compounding purposes. 1

In 1940, the USP changed from the 10-year to a 5-yearmeeting cycle to adapt more rapidly to change. In 1975

In the mid-1990s, those involved with the USP phar-macy compounding activities saw the need to reorientpart of the USP-NF back to pharmacy. It was evidentthat the regular USP-NF had grown so much and wasso entrenched in the pharmaceutical industry, but yetmuch of it still applied to pharmacy practice. It wasthen that the idea of a separate compendium was born.In July 2005, the long-awaited USP-Pharmacists’ Phar-macopoeia was published, containing official andauthorized information for pharmacists.

TAKE A TOUR THROUGH <795>2

Walking through USP <795>, the first thing that is dis-cussed is the responsibility of the compounder (whichcovers pharmacists, physicians, etc.). One has to havea facility in which to practice that meets certain mini-mum standards as well as equipment. One must alsoknow about the stability of the compounded prepara-tions and what kind of beyond-use date can be placedon the preparations. The next item concerns the selec-tion of ingredients and their quality. There is achecklist that should be considered before compound-ing and then a discussion of procedures for differentdosage forms. The compounding process is discussedas well as necessary records and documentation. Thechapter concludes with short discussions on qualitycontrol, verification and patient counseling.

Before we look at some details, let’s go over some ter-minology. We have “manufactured products” and“compounded preparations”; this distinguishesbetween the output of the pharmaceutical companies(products) and the pharmacies (preparations). Phar-macists compound “preparations”; the pharmaceuticalindustry manufactures “products”. Also, productshave “expiration dates” that are determined throughextensive laboratory experimentation, statistical analy-sis, etc. Compounded preparations have “beyond-usedates” which are conservative reasonable estimates.

Let’s briefly review the intent and/or emphasis of thevarious sections of <795>.

RESPONSIBILITY OF THE COMPOUNDER

The buck stops here! The primary emphasis on theresponsibility of the compounder centers around assur-ance of quality in the areas of personnel, ingredients,finished preparations, processes, environment, stabili-ty, consistency, error-prevention and documentation.

FACILITY AND EQUIPMENT

Facilities and EquipmentThe primary requirement here is adequate and appropri-ate space. These requirements are similar to thosemandated by the state boards of pharmacy.

Equipment must simply be appropriate in design and sizeand suitable for the purpose for which it is used. It shouldnot interact or interfere with the compounded preparationor process. It must be properly maintained, used, calibrat-ed and cleaned.

STABILITY OF COMPOUNDED PREPARATIONS

Primary Packaging, Stability Criteria and Beyond-UseDating, Beyond-Use LabelingThe beyond-use date is the responsibility of the com-pounder and is determined from the time ofcompounding, not the time of dispensing. Compounderscan consult appropriate literature, manufacturers andwork with analytical laboratories to determine an appro-priate beyond-use date. In the event there is no dataavailable, the chapter provides guidelines that can beused, as follows: 2

● Solids and non-aqueous liquids prepared from com-mercially available dosage forms - 25% of the remaining expiration date of the commercial product, or 6 months, whichever is earlier.

● Solids and non-aqueous liquids prepared from bulk ingredients - up to 6 months.

● Water-containing formulations (prepared from ingre-dients in solid form) - up to 14 days when stored in arefrigerator.

● All other formulations - up to 30 days or the intended duration of therapy, whichever is earlier.

DEFINITIONS

The purpose of this section is merely to provide a defini-tion for some terms used in the chapter.

INGREDIENT SELECTION

SourcesFirst and foremost, USP and NF grade ingredients shouldbe used. If an item is not monographed in the USP or NF,

then the pharmacist must select a reasonable high-quality grade ingredient from a reliable source.Certificates of analysis can be useful in establishingquality of the ingredients used, both active andexcipients. Items not to be compounded are those onthe FDA negative list. However, one must read thenegative list very carefully because in some cases, itis not all dosage forms of an active drug, but just aspecific dosage form that is on the list and otherdosage forms can be prepared.

CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY AND PURITY

A series of five questions are presented for consider-ation concerning each and every compoundedpreparation. While some of these questions are secondnature, some may require some thought and eveninvestigation, such as those related to local or sys-temic absorption. These questions are as follows: 2

1. Have the physical and chemical properties and medicinal, dietary, and pharmaceutical uses ofthe drug substances been reviewed?

2. Are the quantity and quality of each active ingre-dient identifiable?

3. Will the active ingredients be effectively absorbed, locally or systemically according to the prescribed purpose, from the preparation and route of administration?

4. Are there added substances, confirmed or poten-tially present from manufactured products, that may be expected to cause an allergic reaction, irritation, toxicity, or undesirable organoleptic response from the patient? Are there added sub-stances, confirmed or potentially present, that may be unfavorable (e.g., unsuitable pH or inad-equate solubility)?

5. Were all calculations and measurements con-firmed to ensure that the preparation will be compounded accurately?

COMPOUNDED PREPARATIONSQuality suggestions, clinical considerations andtechnical procedural hints are provided for solid, liq-uid and semisolid dosage forms.

COMPOUNDING PROCESS

Thirteen steps are presented to minimize error andmaximize the prescriber’s intent for the patient.These should all be covered in the standard operatingprocedures of the pharmacy and are good practicestandards to follow. The steps are as follows: 2

1. Judge the suitability of the prescription to be compounded in terms of its safety and intendeduse. Determine what legal limitations, if any, are applicable.

2. Perform necessary calculations to establish the amounts of ingredients needed.

3. Identify equipment needed.

4. Wear the proper attire and wash hands.

5. Clean the compounding area and neededequipment.

6. Only one prescription should be compounded at one time in a specified compounding area.

7. Assemble all necessary materials to compound the prescription.

8. Compound the preparation following the for-mulation record or prescription, according to the art and science of pharmacy.

9. Assess weight variation, adequacy of mixing, clarity, odor, color, consistency and pH as appropriate.

10. Annotate the compounding log, and describe the appearance of the formulation.

11. Label the prescription containers to include the following items:

a) The name of the preparationb) The internal identification number c) The beyond-use dated) The initials of the compounder who

prepared the label e) Any storage requirementsf) Any other statements required by law.

12. Sign and date the prescription affirming that all procedures were carried out to ensure unifor-mity, identity, strength, quantity, and purity.

13. Thoroughly and promptly clean all equipment, and store properly.




























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COMPOUNDING PROCESS












































DEFINITIONS













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SecundumArtem

VOLUME 13 NUMBER 4


INTRODUCTION












BACKGROUND
























ACPE No. 748-000-05-001-H01



City______________________________________________State______________ Zip___________________________________


License No._________________________________________________________________________________________________


Email Address:_____________________________________________________________________________________________


VERIFICATION



SUMMARY


REFERENCES









QUALITY CONTROL



Date__________________________

SecundumArtem

VOLUME 13 NUMBER 4


INTRODUCTION












BACKGROUND
























ACPE No. 748-000-05-001-H01



City______________________________________________State______________ Zip___________________________________


License No._________________________________________________________________________________________________


Email Address:_____________________________________________________________________________________________


VERIFICATION



SUMMARY


In the next issue, we will discuss the rationalebehind and the practical application of USP <797>.

REFERENCES









QUALITY CONTROL



Date__________________________

SecundumArtem

VOLUME 4 NUMBER 6


General “Good Compounding Practices” for Nonsterile Products

INTRODUCTIONPharmacists are the only health profrssionals formal-

ly trained in the art and science of compoundingmedications. Consequently, they are expected to pos-sess the knowledge and skills necessary to compoundextemporaneous preparations. The percentage of com-pounded prescriptions represented 11% of allprescriptions dispensed in 1994 (Drug Topics, July 10,1995), which is a great increase over the 1970s and 1980s.It is evident that the need for individualized drug ther-apy for patients has been realized and is resulting inpatient-specific prescriptions and the compounding ofmedications that are not commercially available.

Accompanying this increase in compounded pre-scriptions is the need for Good Compounding Practicesto guide the compounding activities of pharmacists andpharmacist-supervised personnel. The purpose of thisedition of Secundum Artem is to provide some generalguidelines as Good Compounding Practices forNonsterile Products. Many states have modified andadopted state-specific Good Compounding Practicesdeveloped by the National Association of Boards ofPharmacy (NABP). Further pharmacists engaged in thecompounding of drugs must operate in conformancewith applicable state law regulating the practice of phar-macy.

Compounding is an integral part of pharmacy prac-tice and is essential to the provision of health care.Compounding can be simple, such as the addition of aliquid to a manufactured drug powder; or complex,such as the preparation of a multicomponent parenteralnutrition solution. Compounding basicaliy differs frommanufacturing in that compounding involves a specificpractitioner-patient-pharmacist relationship, a relative-ly small quantity of medication prepared, and theconditions of sale (specific prescription order).

The pharmacist is responsible for compoundingpreparations of acceptable strength, quality, and puritywith appropriate packaging and labeling in accordancewith good pharmacy practices, official standards andcurrent scientific principles. Pharmacists should expandtheir compounding knowledge continually throughparticipation in seminars, literature study, and consulta-tion with colleagues.

A few general guidelines should be mentionedbefore beginning the specific detailed discussion.

Loyd V. Allen, Jr., Ph.D., R.Ph., Professor Emeritus,University of Oklahoma, HSC College of Pharmacy,Oklahoma City, OK 73190.

• Pharmacists may compound, in reasonable quantities,drug products that are commercially available in the marketplace based upon the existence of a pharma-cist/patient/prescriber relationship and the presenta-tion of a valid prescription.

• Pharmacists may compound over-the-counter medica-tions in commercially-available dosage forms or in alternative dosage forms to accommodate patient needs.

• Pharmacists may compound drugs in limited quanti-ties prior to receiving a valid prescription based on a history of receiving valid prescriptions that have beengenerated solely within an established pharmacist/patient/prescriber relationship, and pro-vided that they maintain the prescriptions on file for all such products dispensed at the pharmacy.

• Pharmacists should not offer compounded medica-tions to other pharmacies for resale; however, a prac-titioner may obtain compounded medication to administer to patients but it should be labeled with the following: “For Office Use Only”, date compounded, “beyond-use” date, and name, strength and quan-tity of active ingredients.

• Compounding pharmacists/pharmacists may adver-tise or otherwise promote the fact that they provide prescription compounding services. (Currently, phar-macists should not solicit business by promoting the compounding of a specific drug product).

Other activities related to compounding and communi-cations are involved; in general, the pharmacist may:

1. Present the fact that prescription and over-the-countercompounding services are provided. These services may be, but are not limited to: chemicals, devices, and alternative dosage forms.

2. Provide drug searches on specific chemicals in differ-ent dosage forms, strengths, bases, etc., to accommodate physicians’ specific needs.

3. Provide follow-up information as a result of a practi-tioner’s request of information regarding a compounded medication.

4. Have discussions with practitioners regarding a particular dosage form when discussing services with a health care provider.

One of the greatest services a compounding pharmacistprovides is problem-solving for the patient and physician.

Compounding is an integral part

of pharmacy practice and is

essential to the provision of

health care.

One of the greatest services a

compounding pharmacists

provides is problem-solving

for the patient and physician.

DEFINITIONSCompounding is the preparation, mixing, assembling, packaging, and/or

labeling of a drug or device as the result of a practitioner’s prescription drugorder or initiative based on the practitioner/patient/ pharmacist relationship inthe course of professional practice, or for the purpose of, or as an incident to,research, teaching, or chemical analysis and not for sale or dispensing.Compounding also includes the preparation of drugs or devices in anticipationof prescription drug orders based on routine, regularly observed prescribingpatterns.

Manufacturing is the production, preparation, propagation, conversionand/or processing of a drug or device, either directly or indirectly, by extrac-tion from substances of natural origin or independently by means of chemicalor biological synthesis, and includes any packaging or repackaging of the sub-stance(s) or labeling or relabeling of its container, and the promotion andmarketing of such drugs or devices. Manufacturing also includes the prepara-tion and promotion of commercially available products from bulk compoundsfor resale by pharmacies, practitioners, or other persons.

FACILITY Pharmacies engaging in compounding should have a designated area with

adequate space for the orderly placement of equipment and materials to beused to compound medications. The compounding area for sterile drug prod-ucts should be separate and distinct from the area used for the compounding ordispensing of non-sterile drug products. The area(s) used for the compoundingof drugs should be maintained in a good state of repair and in a clean and san-itary condition. It should be free of infestation by insects, rodents, and othervermin.

The compounding area should be free of dust-collecting overhangs such asceiling pipes, hanging light fixtures, and ledges. The actual work area should belevel, smooth, impervious, free of cracks and crevices, and non-shedding.Surfaces should be cleaned at the beginning and completion of each com-pounding operation. The entire compounding area should be cleaned daily orweekly but not during the process of compounding. Prior to each compound-ing activity, pharmacies engaged in occasional compounding should preparean area adequate for the safe and orderly compounding of the prescriptionsreceived.

Bulk drugs and other materials used in the compounding of drugs must bestored in adequately labeled containers in a clean, dry area or under properrefrigeration as required. Drugs should be removed from cartons and boxesbefore being stored in the compounding area.

Adequate lighting and ventilation should be provided in all drug com-pounding areas. Potable water should be supplied under continuous positivepressure in a plumbing system free of defects that could contribute contamina-tion to any compounded drug product. Adequate washing facilities, other thanrestrooms, must be easily accessible to the compounding area(s) of the phar-macy. These facilities should include, but not be limited to, hot and cold water,soap or detergent and air-dryers or single-source towels. Trash should be heldand disposed of in a timely and sanitary manner. Sewage, trash, and otherrefuse in and from the pharmacy and immediate drug compounding area(s)should be disposed of in a safe and sanitary manner.

PERSONNELThe pharmacist has the responsibility and authority to inspect and approve

or reject all components, drug product containers, closures, in-process materi-als, labeling; and the authority to prepare and review all compounding recordsto assure that no errors have occurred in the compounding process. The phar-macist is also responsible for the proper maintenance, cleanliness, and use of allequipment used in prescription and compounding practice.

Pharmacists should possess education, training, and proficiency properlyand safely to perform compounding duties at the level with which they areinvolved. All pharmacists who engage in compounding of drugs should be pro-ficient in the art and science of compounding and should maintain proficiencythrough current awareness and continuing education.

Personnel engaged in the compounding of drugs should wear clean clothingappropriate to the operation being performed. Protective apparel, such ascoats/jackets, aprons, or hand or arm coverings, should be worn as necessaryto protect drug products from contamination. A clean laboratory jacket gener-ally is considered appropriate attire for nonsterile compounding procedures.Work with hazardous materials, such as chemotherapeutic agents, may requirethe use of goggles, gloves, masks/respirators, double gowns, foot covers, andthe availability of showers and eyewash stations.

Only personnel authorized by the pharmacist-in-charge should be in the immediate vicinity of the drug compounding operation. Any person with anapparent illness or open lesion(s) that may adversely affect the safety or quali-

ty of a drug product being compounded should be excluded from direct contactwith components, drug product containers, closures, in-process materials, anddrug products until the condition is corrected or determined by competentmedical personnel to not jeopardize the safety or quality of the product(s) beingcompounded. All personnel who assist the pharmacist in compounding proce-dures should be instructed to report to the pharmacist any health condition thatmay have an adverse effect on drug products.

Instruction for compounding pharmacists should include, but not be limitedto, the following:

1. Proper use of compounding equipment such as balances and measuring devices, including guidelines for selecting proper measuring devices, limitations of weighing equipment and measuring apparatus, and the importance of accuracy in measuring.

2. Pharmaceutical techniques needed for preparing compounded dosage forms (i.e., comminution, trituration, levigation, pulverization by intervention, and geometric dilution).

3. Properties of dosage forms to be compounded and related factors such as stability, storage considerations, and handling procedures.

4. Literature regarding stability, solubility, and other physicochemical properties of the ingredients.

5. Handling of nonhazardous and hazardous material in the work area, including protective measures for avoiding exposure, emergencyprocedures to follow in the event of exposure, and the location of Material Safety Data Sheets (MSDSs) in the facility.

6. Use and interpretation of chemical and pharmaceutical symbols and abbreviations in medication orders and in product formulation directions.

7. Pharmaceutical calculations review.

EQUIPMENTThe pharmacist is responsible for the equipment in the compounding

process. A suggested equipment list was published in Secundum Artem (Volume4, Number 3). Equipment used in the compounding of drug products shouldbe of appropriate design, adequate size, and suitably located to facilitate oper-ations for the dosage forms to be prepared. It should be of a neutral andimpervious composition so that components, in-process materials, or drugproducts will not react with, add to, or be absorbed by it in such a way that thesafety, identity, strength, quality, or purity of the drug product is alteredbeyond the desired composition.

Equipment and utensils used for compounding should be cleaned and sani-tized immediately prior to use to prevent contamination that would alter thesafety, identity, strength, quality, or purity of the drug product beyond thedesired results. Clean equipment and utensils must be protected from contam-ination prior to use. Immediately prior to compounding operations, allequipment must be inspected by the pharmacist and determined to be suitablefor use.

If drug products which require special precautions to prevent contaminationare involved in a compounding process, appropriate precautions must be takento prevent cross-contamination. These include dedication of equipment for theoperations or meticulous cleaning of the contaminated equipment.

Automatic, mechanical, or electronic equipment, or other types of equip-ment or related systems that will perform a function satisfactorily may be usedin the compounding of drug products. If such equipment is used, it should beroutinely inspected, calibrated or checked to assure proper performance. Themaintenance of the equipment should be documented.

Balances:In addition to Class A torsion balances, many compounding pharmacies also

have electronic balances, most with a capacity of about 300 g and a sensitivityof about 1 mg. Balances should be situated in areas of low humidity and placedon flat, nonvibrating surfaces away from vents, fans, and other currents of mov-ing air. The performance of the balances should be checked at least monthly andthe performance documented.

Measuring Equipment: In addition to the customary measuring equipment consisting of graduated

cylinders, pipets, calibrated syringes, etc., it is becoming more commonplace touse micropipets for measuring very small quantities of liquids. Micropipetsshould be checked frequently to determine their accuracy in the volume of liq-uid delivered. This can be accomplished easily by weighing the volume ofPurified Water delivered onto a tared receptacle on a balance. Their perfor-mance should be documented. Ordinarily, two or three pipets can cover therange of about 10 µL to about 5 mL.

INGREDIENT SELECTION Pharmacists should receive, store, and use drug substances for compound-

ing that meet official compendial requirements.If this is not possible, then pharmacists shoulduse professional judgment to procure alterna-tives, such as analytical reagent (AR), or certifiedAmerican Chemical Society (ACS) grades. If adesired substance is not an official preparation orsubstance, additional information, such as a cer-tificate of analysis, should be obtained by thepharmacist to ensure its suitability by compari-son with general USP/NF standards. It is theresponsibility of the pharmacist to select the“most appropriate” quality of chemical for com-pounding. USP/NF would be the first choice; if itis not available, descend the list of purity gradesusing professional judgment and discretion tochoose the appropriate source.

Chemicals should be stored according to themanufacturers’ directions or the USP/NF mono-graphs, generally in tight, light-resistantcontainers at room temperature. Temperaturerequirements for storage of substances aredetailed in the USP/NF. The temperatures of thestorage areas, including refrigerators and freez-ers, should be monitored and recorded at leastmonthly. Flammable or hazardous productsshould be stored appropriately in safety storagecabinets and containers which are available frommany laboratory suppliers.

THE COMPOUNDING PROCESS Questions to be considered prior to com-

pounding a prescription include the following: 1. What are the physical and chemical pro-

perties and medicinal and pharmaceutical uses of the drug substance?

2. Is the quantity and quality of each active ingredient identifiable?

3. Will the preparation and route of adminis-tration, provide adequate absorption, either locally or systematically, according to the purpose of the prescription?

4. Are any excipients present from any source (manufactured products) that may be expected to cause an allergic reaction, irritation, toxicity, or an undesirable organoleptic response from the patient?

5. For orally administered products, are the active ingredients stable in the normal gas-tric pH range or are they subject to extensive hepatic first-pass metabolism?

The compounding process may include thefollowing steps:

1. Judging the suitability of the prescription in terms of its safety and intended use and the dose for the patient.

2. Performing the calculations to determine the quantities of the ingredients needed.

3. Selecting the proper equipment and making sure it is clean.

4. Donning the proper attire and washing hands.

5. Cleaning the compounding area and the equipment, if necessary.

6. Assembling all the necessary materials/ ingredients to compound and package the prescription.

7. Compounding the prescription according to the Formulary record or the prescription, according to the art and science of pharmacy.

8. Checking, as indicated, the weight variation, adequacy of mixing, clarity, odor, color, consistency and pH.

9. Entering the information in the compounding log.

10. Labeling the prescription. 11. Signing and dating the prescription, affirming

that all the indicated procedures were carried out to ensure uniformity, identity, strength, quality, and purity.

12. Cleaning and storing all equipment. 13. Cleaning the compounding area.

Continuous Quality Improvement:The pharmacist reviews each step in the com-

pounding procedure to assure accuracy, andcompleteness before dispensing the prescription tothe patient. The steps to be reviewed include a (1)preparatory step (2) final check, and (3) sign off bythe pharmacist. A pharmacist may also use profes-sional judgment and discretion to completeanalytical testing of the dissolution rates and concen-trations of compounded medications.

The preparatory step includes, but is not limited to: 1. Appropriate ingredients, adjuvants, and

equipment selected for the specific preparation.

2. Correct calculations. 3. Accurately performed measurements using

properly functioning equipment. 4. Appropriate formulation for the intended use

and stability limits of the preparation.

The compounding step includes, but is not limited to:

1. Accurately following and documenting proce-dures and techniques used in preparing the product.

2. Obtaining a reasonably esthetic product and ensuring content uniformity.

The final check includes verifying that: 1. The calculated yield is consistent with the

actual yield. 2. The tolerance for individual dose weight vari-

ation has been met by a sampling technique when appropriate (i.e., capsule weight).

3. The physical characteristics (clarity, color, odor, etc.) of the preparation are consistent with those predicted for the preparation.

4. Physical tests were performed when appropri-ate and the preparation meets those test limits.

5. The preparation is suitably labeled and the contents have been verified with the prescription order. All legal requirements have been imprinted on the label and in the compounding record.

6. The preparation is suitably packaged for patient use and a container has been selected which will protect the preparation from undueenvironmental exposure at least until the “discard after” date.

7. There is documentation as listed in the section entitled “Records and Reports”.

8. Patient or caregiver has been adequately informed about ways to identify obvious evidence of instability in the compounded preparation.

9. The preparation is labeled with explicit stor-age and administration instructions.

Analytical testing may include:1. Additional tests, assays, or visual observa-

tions of samples of the preparation to assure the content, stability, pH, etc.

2. The pharmacist may use an analytical testing laboratory to perform testing of certain processes or products that are compounded. This does not include each and every pre-scription that is compounded by that process,

but testing of “samples” that have been com-pounded.

PACKAGING AND STORAGE The pharmacist should inspect and approve all

components, drug product containers, closures,labeling, and any other materials involved in thecompounding process. Materials used in the com-pounding of drugs should be handled and stored ina manner consistent with contamination avoidanceand prevention. These materials should be stored offthe floor, preferably on shelves in a clean environ-ment.

Compounded preparations should be packagedin containers meeting USP standards. The containeremployed depends on the physical and chemicalproperties of the compounded preparation and theintended use of the product.

Materials used should not be reactive, additive, orabsorptive so as to alter the safety, identity, strength,quality, or purity of the compounded drug beyondthe specifications for an acceptable product.Materials, ingredients and supplies should be rotat-ed to use the oldest stock first. Packagingspecifications as described in the current edition ofthe USP/NF should be consulted and followed. If noexpiration date is provided on the chemical/materi-als used, a system of monitoring should be provided,such as placing the date of receipt of the materials onthe label of the container.

To help maintain potency, materials used forpackaging should not interact physically or chemi-cally with the product. Container characteristics ofconcern include inertness, visibility, strength, rigidi-ty, moisture protection, ease of reclosure, andeconomy of packaging. Plastic containers haveincreased in popularity and use because they are lessexpensive and lighter in weight than glass. Onlyplastic containers meeting USP/NF standardsshould be used.

Labeling should be done according to state andfederal regulations. Usually, this includes the gener-ic or chemical name of the active ingredients, thestrength or quantity, pharmacy lot number, beyond-use date and any special storage requirements. Whena commercial drug product has been used as a sourceof the drug, only the generic name of the drug prod-uct should be used on the label, not the proprietaryname. Inactive ingredients and vehicles should alsobe listed on the label. The use of specialty “coined”names or short names for convenience should be dis-couraged. This can cause difficulty in emergencyrooms in case of an overdose, accidental poisoning,or for health professionals treating the patient whorequire knowledge of the patient’s medication. Whenpreparing batch quantities of products, a lot numbershould be assigned and should be placed on thelabels. If extra labels are prepared but not used, theyshould be destroyed.

CONTROLSThe pharmacist should review all compounding

records for accuracy and conduct in-process andfinal checks to assure that errors have not occurred inthe compounding process. Written procedures forcompounding of drugs should be available and fol-lowed to ensure the identity, strength, quality, andpurity of the finished product. Such proceduresshould include a listing of the ingredients, quantities,order of mixing/preparation and a detailed descrip-tion of the compounding process. The equipmentand utensils should be listed as well as the contain-er/closure packaging system. Informationconcerning stability and compatibility should beincluded, as well as any documentation related to theproduct.

Ingredients should be weighed, measured, or subdivided accurately asindicated. These operations should be checked and rechecked by the com-pounding pharmacist at each step in the compounding process to ensurethat the correct weight or measure is obtained.

Written procedures (Standard Operating Procedures, SOPs) should beavailable describing tests or examinations to be conducted on the finishedproduct. The tests could include physical examination, pH determina-tions, weight, volume, etc. These procedures are established to monitorthe output of the compounding pharmacy and to validate the perfor-mance of those compounding processes that may cause variability in thecompleted drug product.

LABELING OF EXCESS PRODUCTS If excess product is prepared or if quantities of product are prepared in

anticipation of prescriptions within a reasonable time, written proceduresshould be available for the proper labeling of the excess product. Includedshould be the complete list of ingredients, preparation date, the assignedexpiration date, appropriate testing/published data, and control num-bers. The product should be stored and inventoried to help ensure itsstrength, quality, and purity. At the completion of the compoundingprocess, the excess product should be examined once more for correctlabeling and contents.

STABILITY, EXPIRATION, AND BEYOND-USE DATING The USP/NF defines “stability” as the “extent to which a dosage form

retains, within specified limits and throughout its period of storage anduse, the same properties and characteristics that it possessed at the time ofits preparation”. There are five types of stability described in the USP/NF:chemical, physical, microbiological, therapeutic, and toxicological. Anumber of factors influence stability, including the properties of eachingredient, environmental factors (temperature, light humidity, air), par-ticle size, pH, properties of water and other solvent used, nature of thecontainer and the presence of other substances resulting from contamina-tion or purposeful mixing of ingredients.

“Discard after” dating is a period determined during which a com-pounded product may be usable after dispensing. This period should bebased on available stability information and seasonable patient needswith respect to the intended drug therapy. When a commercial drugproduct is used as a source of active ingredient, its expiration date oftencan be used as a factor to determine “discard after” dating. When deter-mining “discard after” dating, a pharmacist may consider:

1. The nature of the drug and its degradation kinetics. 2. The container in which it is packaged. 3. The expected storage conditions to which the preparation may be

exposed. 4. The expected length of therapy. 5. The expiration date of similar commercial products for guidance, if

the active ingredient is a USP or NF product. 6. Published literature. 7. The manufacturer, if no inforrnation is available.

The beyond-use date assigned to a specific product should be based upon the following:

1. Physical and chemical properties of the ingredients. 2. Use of preservatives and/or stabilizers. 3. Dosage form prepared. 4. Storage conditions. 5. Scientific, laboratory or reference data.

The assignment of a beyond-use date is a very difficult activity. All theavailable stability information should be consulted and a conservativeestimate made for the product. General guidelines that may be consideredare as follows:

1. When a manufactured commercial product is used as the source of the active ingredient, the beyond-use date should be no more than 25% of the manufacturer’s remaining expiration date or six months,whichever is less.

2. When a USP or NF pure chemical is used, no more than six months, for dry products.

*ln cases that do not fail within the guidelines above, use 30 days or the intended period of therapy, whichever is less.

The compounding pharmacist must avoid formulation ingredients andconditions that could result in a subpotent product, leading to poor clini-cal results. A knowledge of the chemical reactions by which drugsdegrade often provides a means of establishing conditions under which

the rate of degradation is minimized. At all steps in the compounding,dispensing and storage process, the pharmacist should observe the com-pounded drug preparation for signs of instability.

All compounded products should be observed periodically for signs ofphysical instability, including observations for microbiological and fungalcontamination for all products that do not have preservatives in their for-mulas. If large quantities of any one product are legitimately prepared, itmay be advisable to conduct potency and stability assays on the productto provide the compounding pharmacist with the assurance of productpotency to the assigned beyond-use date.

RECORDS AND REPORTS Pharmacists should maintain at least four sets of records for com-

pounding.

Formulation Record (Master Control Record): The formulation record provides a consistent source document for

preparing the formulation, a “recipe”, and the compounding record doc-uments the actual ingredients in the preparation and the personresponsible for the compounding activity.

The formulation record is a recipe file. It lists the name, strength, andthe dosage form of the preparation, the ingredients and their quantities,calculations regarding dilutions/aliquots, equipment needed to preparethe preparation and mixing instructions. Mixing instructions include theorder of mixing and any other environmental conditions that should bemonitored, such as the temperature, duration of mixing, etc. An assigned“beyond-use” time, dispensing container, storage requirements and anyquality control procedures must be included. When formulas originatefrom published articles, copies of these should be duplicated and attachedto or filed with the written procedures. Computerized records are appro-priate. Records should be in sufficient detail that preparations can beduplicated.

Compounding Record: The compounding record contains the name and strength of the com-

pounded preparation, the formulation record reference for thepreparation and the sources and lot numbers of the ingredients used inthe preparation. It also must include information such as the total numberof dosage units compounded, the name of the person preparing the prod-uct, the name of the pharmacist approving the preparation, the date ofpreparation, the assigned internal identification number, an assignedbeyond-use date, and the prescription number. The results of the qualitycontrol procedures should also be recorded, i.e., weight range of filledcapsules.

A summary of example contents of compounding records for two dif-ferent situations follows: A. Compounding records for products prepared in anticipation of orders:

1. Date of preparation. 2. Facility lot number. 3. Manufacturers’ lot numbers and expiration date of all components

or source if no number is available. 4. Complete formula, including complete methodology and necessary

equipment. 5. Signature or initials of the pharmacists or supportive personnel per-

forming the compounding function. 6. Signature or initials of the pharmacist- supervisor. 7. Package size and the number of units prepared. 8. Documentation of the Quality Control procedures used. 9. Criteria used to establish the “beyond-use” date.

B. Compounding records for products prepared on individual prescription:1. Date of preparation. 2. Complete formula. 3. Signature of pharmacist or supportive person performing the

compounding function. 4. Signature or initials of the pharmacist responsible for supervising

the supportive personnel and conducting in-process and final checks of the compounded products if supportive personnel perform the compounding function.

5. Quantity in units of the finished products or grams of raw materials.

6. The package size and the number of units prepared. 7. Documentation of performance of quality control procedures. These

are not necessarily required if two or more commercially available oral liquids are mixed, or the products are intended for external use.

Equipment-Maintenance Records: Equipment-maintenance records include documentation of checks of

balances, refrigerators, freezers, mixers, and all equipment. Equipmentfiles should be organized and routinely updated. Calibration checkrecords should be maintained documenting the performance of the equip-ment. Refrigerator and freezer thermometers should be checked anddocumented routinely. Temperatures should be recorded on a regularbasis to document the performance of these pieces of equipment.

Ingredient Records: Records of ingredients purchased should include certificates of purity

or certificates of analysis for chemicals and Material Safety Data Sheets(MSDSs). There should be an MSDS file for any bulk drug or chemicalsubstance located in the pharmacy. MSDSs should be requested from thechemical supplier and kept on file in the pharmacy. Employees should beinstructed as to the location of the file and its format.

Records and reports should be retained for the period of time indicat-ed in state laws and regulations for the retention of prescription files. Allrecords and reports should be readily available in the pharmacy forauthorized inspection during the retention period. These records shouldbe retained as original hard copy, true copies such as photocopies, micro-film, microfiche, or other accurate reproduction of the original records.Computerized records also can be utilized.

PATIENT COUNSELING Compounded prescriptions provide an excellent opportunity for

patient counseling and to explain to the patient that this particular pre-scription has been prepared especially for him/her. If further steps arerequired prior to administration, this should be explained in detail to thepatient, as well as the other items on which patients routinely are coun-seled.

REFERENCE LIBRARY Compounding pharmacists must have ready access to reference mate-

rials on all aspects of compounding. This may involve on-site books,reprints, journals, etc. as well as telephone access to information from acompounding or drug information center. Computer access also is accept-able.

A suggested minimal library includes at least the following items: Remington’s Practice of Pharmacy Secundum Artem Pharmaceutical Dosage Forms and Drug Delivery Systems (Allen, Popovich,

Ansel) Pharmaceutical Calculations (Stoklosa, Ansel) Handbook of Pharmaceutical Excipients American Hospital Formulary Service: Drug Information Martindale’s The Extra PharmacopoeiaThe Merck Index USP PHARMACIST’ PHARMACOPEIAUSP-DI

Specific reference to the following USP Reference monographs: <41> Weights and Balances <661> Containers <671> Containers — Permeation <795> Pharmaceutical Compounding - nonsterile preparations<797> Pharmaceutical Compounding - sterile preparations<1176> Prescription Balances and Volumetric Apparatus <1191> Stability Considerations in Dispensing practice Compounding monographs as they are published in the USP/NF.

Information contained herein is a general guide. Pharmacists shouldconsult applicable state laws and regulations for specific requirements oftheir respective practice settings.


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Documents

Drug Distribution and Control: Preparation and Handling … Compounding Set 1.pdf · · 2016-08-20ASHP Technical Assistance Bulletin on! Compounding Nonsterile Products in Pharmacies!!!