795 PHARMACEUTICAL COMPOUNDINGNONSTERILE PREPARATIONS
The purpose of this chapter is to provide compounders with guidance on applying good compounding practices for the preparation of nonsterile compounded formulations for dispensing and/or administration to humans or animals. Compounding is an integral part of pharmacy practice and is essential to the provision of healthcare. This chapter and applicable monographs on formulation help define good compounding practices. Furthermore, this chapter provides general information to enhance the compounder's ability in the compounding facility to extemporaneously compound preparations that are of acceptable strength, quality, and purity. Pharmacists, other healthcare professionals, and others engaged in the compounding of drug preparations should comply with applicable state and federal compounding laws, regulations, and guidelines.
Active Pharmaceutical Ingredient (API) Any substance or mixture of substances intended to be used in the compounding of a drug preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and animals or affecting the structure and function of the body.
Added Substances Ingredients that are necessary to compound a preparation but are not intended or expected to cause a pharmacologic response if administered alone in the amount or concentration contained in a single dose of the compounded preparation. The term is used synonymously with the terms inactive ingredients, excipients, and pharmaceutical ingredients.
Beyond-Use Date (BUD) The date after which a compounded preparation should not to be used; determined from the date the preparation is compounded.
Component Any ingredient used in the compounding of a drug preparation, including any active ingredient or added substance that is used in its preparation.
Compounder A professional authorized by the appropriate jurisdiction to perform compounding pursuant to a prescription or medication order by a licensed prescriber.
Compounding The preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioners prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. Compounding includes the following:
Hazardous Drug Any drug identified by at least one of the following six criteria:
Manufacturing The production, propagation, conversion, or processing of a drug or device, either directly or indirectly, by extraction of the drug from substances of natural origin or by means of chemical or biological synthesis. Manufacturing may also include any packaging or repackaging of the substance(s) or labeling or relabeling of containers for resale by pharmacies, practitioners, or other persons.
Preparation For the purposes of this chapter, a compounded drug dosage form or dietary supplement or a device to which a compounder has introduced a drug. This term will be used to describe compounded formulations; the term product will be used to describe manufactured pharmaceutical dosage forms. (For the definitions of official substance and official products, see General Notices and Requirements.)
Stability The extent to which a preparation retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding (see Stability Considerations in Dispensing Practice 1191, the table Criteria for Acceptable Levels of Stability)
Vehicle A component for internal or external use that is used as a carrier or diluent in which liquids, semisolids, or solids are dissolved or suspended. Examples include, but are not limited to, water, syrups, elixirs, oleaginous liquids, solid and semisolid carriers, and proprietary products.
CATEGORIES OF COMPOUNDING
In the three general categories of nonsterile compounding described in this section, different levels of experience, training, and physical facilities are associated with each category.
Criteria used to determine overall classification include:
See Pharmaceutical CompoundingSterile Preparations 797 for risk levels associated with sterile preparations. Specialty areas such as radiopharmaceuticals require special training and are beyond the scope of this chapter. Compounders shall acquire and maintain knowledge and skills in all areas (e.g., dosage form, patient population, and medical specialty) for which they compound.
Description of Categories
Simple Making a preparation that has a United States Pharmacopeia (USP) compounding monograph or that appears in a peer-reviewed journal article that contains specific quantities of all components, compounding procedure and equipment, and stability data for that formulation with appropriate BUDs; or reconstituting or manipulating commercial products that may require the addition of one or more ingredients as directed by the manufacturer. Examples include Captopril Oral Solution, Indomethacin Topical Gel, and Potassium Bromide Oral Solution, Veterinary.
Moderate Making a preparation that requires special calculations or procedures (such as calibration of dosage unit mold cavities) to determine quantities of components per preparation or per individualized dosage units; or making a preparation for which stability data for that specific formulation are not available. Examples include Morphine Sulfate Suppositories, diphenhydramine hydrochloride troches, and mixing two or more manufactured cream products when the stability of the mixture is not known.
Complex Making a preparation that requires special training, environment, facilities, equipment, and procedures to ensure appropriate therapeutic outcomes. Examples of possible complex preparation types include transdermal dosage forms, modified-release preparations, and some inserts and suppositories for systemic effects.
RESPONSIBILITIES OF THE COMPOUNDER
The compounder is responsible for compounding preparations of acceptable strength, quality, and purity and in accordance with the prescription or medication order. The compounder is also responsible for dispensing the finished preparation, with appropriate packaging and labeling, and in compliance with the requirements established by the applicable state agencies, state boards of pharmacy, federal law, and other regulatory agencies where appropriate. Individuals who are engaged in drug or dietary supplement compounding shall be proficient in compounding and should continually expand their compounding knowledge by participating in seminars and/or studying appropriate literature. They shall be knowledgeable about the contents of this chapter and should be familiar with Pharmaceutical CompoundingSterile Preparations 797, Pharmaceutical Dosage Forms 1151, Pharmaceutical Calculations in Prescription Compounding 1160, Quality Assurance in Pharmaceutical Compounding 1163, Prescription Balances and Volumetric Apparatus 1176, Stability Considerations in a Dispensing Practice 1191, Written Prescription Drug InformationGuidelines 1265, and all applicable compounding laws, guidelines, and standards.
To ensure the quality of compounded preparations, compounders shall adhere to the following general principles (additional information on these general principles is provided in the sections that follow).
General Principles of Compounding
The compounder is responsible for ensuring that each individual incidence of compounding meets the criteria given in this section (additional information on these criteria is provided in the sections that follow).
Criteria When Compounding Each Drug Preparation
Compounding facilities shall have an adequate space that is specifically designated for compounding of prescriptions. This space shall provide for the orderly placement of equipment and materials to prevent mixups among ingredients, containers, labels, in-process materials, and finished preparations and is designed, arranged, and used to prevent adventitious cross-contamination. Areas used for sterile preparations shall be separated and distinct from the nonsterile compounding area (see Chapter 797, Environmental Quality and Control).
Potable water shall be supplied for hand and equipment washing. This water meets the standards prescribed in the Environmental Protection Agencys National Primary Drinking Water Regulations (40 CFR Part 141). Purified Water (see Purified Water monograph) shall be used for compounding nonsterile drug preparations when formulations indicate the inclusion of water. Purified Water should be used for rinsing equipment and utensils. In those cases when a water is used to prepare a sterile preparation, follow the appropriate monographs and general chapters (see Water for Pharmaceutical Purposes 1231).
The plumbing system shall be free of defects that could contribute to contamination of any compounded preparation. Adequate hand and equipment washing facilities shall be easily accessible to the compounding areas. Such facilities shall include, but are not limited to, hot and cold water, soap or detergent, and an air-drier or single-use towels. The areas used for compounding shall be maintained in clean, orderly, and sanitary conditions and shall be maintained in a good state of repair. Waste shall be held and disposed of in a sanitary and timely manner and in accordance with local, state, and federal guidelines.
The entire compounding and storage area should be well lighted. Heating, ventilation, and air conditioning systems shall be controlled to avoid decomposition and contamination of chemicals (see the General Notices and Requirements, Preservation, Packaging, Storage, and Labeling, Storage Temperature and Humidity; and the manufacturers labeled storage conditions). Appropriate temperature and humidity monitoring should be maintained as required for certain components and compounded dosage forms. All components, equipment, and containers shall be stored off the floor and in a manner to prevent contamination and permit inspection and cleaning of the compounding and storage area.
Hazardous drugs shall be stored, prepared, and handled by appropriately trained personnel under conditions that protect the healthcare workers and other personne. The following are references for the safe handling of antineoplastic and hazardous drugs in healthcare settings:
Disposal of all hazardous drug wastes shall comply with all applicable federal and state regulations. All personnel who perform routine custodial waste removal and cleaning activities in storage and preparation areas for hazardous drugs shall be trained in appropriate procedures to protect themselves and prevent contamination.
The equipment and utensils used for compounding of a drug preparation shall be of appropriate design and capacity. The equipment shall be of suitable composition that the surfaces that contact components are neither reactive, additive, nor sorptive and therefore will not affect or alter the purity of the compounded preparations. The types and sizes of equipment depend on the dosage forms and the quantities compounded (see Chapter 1176 and equipment manufacturers' instruction manuals).
Equipment shall be stored to protect it from contamination and shall be located to facilitate its use, maintenance, and cleaning. Automated, mechanical, electronic, and other types of equipment used in compounding or testing of compounded preparations shall be routinely inspected, calibrated as necessary, and checked to ensure proper performance. Immediately before compounding operations, the equipment shall be inspected by the compounder to determine its suitability for use. After use, the equipment shall be appropriately cleaned.
Extra care should be used when cleaning equipment used in compounding preparations that require special precaution (e.g., antibiotics and cytotoxic and other hazardous materials). When possible, special equipment should be dedicated for such use, or when the same equipment is being used for all drug products, appropriate procedures shall be in place to allow meticulous cleaning of equipment before use with other drugs. If possible, disposable equipment should be used to reduce chances of bioburden and cross-contamination.
COMPONENT SELECTION, HANDLING, AND STORAGE
The following guidelines shall be followed when selecting, handling, and storing components for compounded preparations.
STABILITY CRITERIA AND BEYOND-USE DATING
The BUD is the date after which a compounded preparation shall not be used and is determined from the date when the preparation is compounded. Because compounded preparations are intended for administration immediately or following short-term storage, their BUDs are assigned on the basis of criteria different from those applied to assigning expiration dates to manufactured drug products.
BUDs should be assigned conservatively. When assigning a BUD, compounders shall consult and apply drug-specific and general stability documentation and literature when available and should consider:
When a manufactured product is used as the source of the API for a nonsterile compounded preparation, the product expiration date cannot be used solely to assign a BUD for the compounded preparation. Instead, the compounder shall refer to the manufacturer for stability information and to the literature for applicable information on stability, compatibility, and degradation of ingredients; shall consider stability factors in Chapter 1191; and shall use his or her compounding education and experience. All stability data shall be carefully interpreted in relation to the actual compounded formulation.
At all steps in the compounding, dispensing, and storage process, the compounder shall observe the compounded drug preparation for signs of instability. For more specific details of some of the common physical signs of deterioration (see Chapter 1191, Observing Products for Evidence of Instability). However, excessive chemical degradation and other drug concentration loss due to reactions may be invisible more often than visible.
General Guidelines for Assigning Beyond-Use Dates
In the absence of stability information that is applicable to a specific drug and preparation, the following table presents maximum BUDs recommended for (1) nonsterile compounded drug preparations that are packaged in tight, light-resistant containers and stored at controlled room temperature, unless otherwise indicated; and for (2) sterile preparations for which a program of sterility testing is in place (see the General Notices and Requirements, Preservation, Packaging, Storage, and Labeling). Drugs or chemicals known to be labile to decomposition will require shorter BUDs.
Susceptible preparations should contain suitable antimicrobial agents to protect against bacteria, yeast, and mold contamination inadvertently introduced during or after the compounding process. When antimicrobial preservatives are contraindicated in such compounded preparations, storage of the preparation at controlled cold temperature is necessary; to ensure proper storage and handling of such compounded preparations by the patient or caregiver, appropriate patient instruction and consultation is essential. Antimicrobial preservatives should not be used as a substitute for good compounding practices.
For information on assigning BUDs when repackaging drug products for dispensing or administration, see the General Notices and Requirements, Preservation, Packaging, Storage, and Labeling, Labeling, Expiration Date and Beyond-Use Date; Repackaging into Single-Unit Containers and Unit-Dose Containers for Nonsterile Solid and Liquid Dosage Forms 681, and PackagingUnit-of-Use 1136.
Assurance of sterility in a compounded sterile preparation is mandatory. Compounding and packaging of sterile drugs (including ophthalmic preparations) requires strict adherence to guidelines presented in Chapter 797 and in the manufacturers labeling instructions.
PACKAGING AND DRUG PREPARATION CONTAINERS
The compounder shall ensure that the containers and container closures used in packaging compounded preparations meet USP requirements (see the General Notices and Requirements, Preservation, Packaging, Storage, and Labeling, Containers; ContainersGlass 660; ContainersPlastics 661; ContainersPerformance Testing 671; Chapter 681; Chapter 1136; Packaging PracticeRepackaging a Single Solid Oral Drug Product into a Unit-Dose Container 1146); and when available, compounding monographs. Compounders are not expected to perform the tests described in these chapters but should be knowledgeable about the standards described in them. Container suppliers shall supply, upon request, verification of USP container compliance. Containers and container closures intended for the compounding of sterile preparations must be handled as described in Chapter 797.
The containers and closures shall be made of suitable clean material in order not to alter the quality, strength, or purity of the compounded drug preparation. The container used depends on the physical and chemical properties of the compounded preparation. Containerdrug interaction should be considered for substances that have sorptive or leaching properties.
The containers and closures shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. The containers and container closures shall be stored in such a way as to permit inspection and cleaning of the storage area.
Documentation, written or electronic, enables a compounder, whenever necessary, to systematically trace, evaluate, and replicate the steps included throughout the preparation process of a compounded preparation. All compounders who dispense prescriptions must comply with the record-keeping requirements of their state boards of pharmacy. When the compounder compounds a preparation according to the manufacturers labeling instructions, then further documentation is not required. All other compounded preparations require further documentation as described in this section.
These records should be retained for the same period of time that is required for any prescription under state law. The record may be a copy of the prescription in written or machine-readable form and should include a Master Formulation Record and a Compounding Record.
Master Formulation Record
This record shall include:
The Compounding Record shall contain:
Standard Operating Procedures
All significant procedures performed in the compounding area should be covered by written standard operating procedures (SOPs). Procedures should be developed for the facility, equipment, personnel, preparation, packaging, and storage of compounded preparations to ensure accountability, accuracy, quality, safety, and uniformity in compounding. Implementing SOPs establishes procedural consistency and also provides a reference for orientation and training of personnel.
Material Safety Data Sheets File
MSDSs shall be readily accessible to all employees working with drug substances or bulk chemicals located on the compounding facility premises. Employees should be instructed on how to retrieve and interpret needed information.
The safety, quality, and performance of compounded preparations depend on correct ingredients and calculations, accurate and precise measurements, appropriate formulation conditions and procedures, and prudent pharmaceutical judgment. As a final check, the compounder shall review each procedure in the compounding process. To ensure accuracy and completeness, the compounder shall observe the finished preparation to ensure that it appears as expected and shall investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient.
At the time of dispensing the prescription, the patient or the patients agent shall be counseled about proper use, storage, handling, and disposal of the compounded preparation. The patient or the patients agent shall also be instructed to report any adverse event and to observe and report to the compounder any changes in the physical characteristics of the compounded preparation (see Chapter 1191, Responsibility of the Pharmacist). The compounder shall investigate and document any reported problem with a compounded preparation and shall take corrective action.
All personnel involved in the compounding, evaluation, packaging, and dispensing of compounded preparations shall be properly trained for the type of compounding conducted. It is the responsibility of the compounder to ensure that a training program has been implemented and that it is ongoing. Compounding personnel should be evaluated at least annually. Steps in the training procedure include the following:
COMPOUNDING FOR ANIMAL PATIENTS
A compounders responsibility for providing patients with high-quality compounded preparations extends beyond the human species. All portions of this chapter apply to compounded preparations formulated for animal patients. Intended use of any animal patient (e.g., companion, performance, food) shall be determined before compounding for that patient.
Because humans can consume animal patients as food, care must be taken to prevent drug residues from entering the human food chain when compounded preparations are used in animal patients. For this reason, all compounders preparing formulations for animals shall possess a functional knowledge of drug regulation and disposition in animal patients. Veterinarians are required by law to provide food-producing animal caregivers with an accurate length of time to withhold treated animal tissues (e.g., meat, milk, eggs) from the human food supply. This length of time is referred to as a withdrawal time (WDT) and must also, by law, be included on the dispensing label of every prescription prepared for a food-producing species.
Drug use in any performance animal is strictly regulated by federal and state governments, in addition to the governing bodies of each of the specific disciplines. Penalties for violation of these rules may be severe for all contributing to the violation, including the veterinarian, pharmacist, and caregiver.
The pharmacist shall be knowledgeable about the individual species limitations in physiology and metabolic capacity that can result in toxicity when certain drugs or excipients are used in compounded preparations. For this reason, compounders making preparations for animals should use, when possible, formulations specifically developed for animal patients. If such formulations are not available, the compounder shall conduct a literature review to determine whether a specific component of the formula is toxic to the target species. Extrapolating compounding formulations intended for use in humans may not be appropriate for animal species and may contribute to negative outcomes.
Veterinarians and pharmacists making preparations for animal patients should be familiar with all state and federal regulations regarding drug use in animals, including but not limited to the Food, Drug, and Cosmetic Act; the Animal Drug Amendment; the Animal Medicinal Drug Use Clarification Act; and FDA's Compliance Policy Guideline for Compounding of Drugs for Use in Animal Patients.