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1075 GOOD COMPOUNDING PRACTICES
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The purpose of this chapter is to provide compounders with guidance on applying good compounding practices for the preparation of compounded formulations for dispensing and/or administration to humans or animals. This chapter is intended to provide information as a supplement to other relevant chapters. The following discussion is applicable to those engaged in compounding preparations in all pharmacies.USP29 It is expected that pharmacists or compounders engaged in the compounding of drugs will compound in conformance with applicable state and federal compounding laws, regulations, or guidelines.
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APPLICABLE DEFINITIONS
Compounding (see Pharmaceutical Compounding—Nonsterile Preparations 795)—Compounding involves the preparation, mixing, assembling, packaging, and labeling of a drug or device in accordance with a licensed practitioner's prescription of medication orderUSP29 under an initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. Compounding includes the following:
  1. Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns.
  2. Reconstitution or manipulationUSP29 of commercial products that may require the addition of oneUSP29 or more ingredients as a result of a licensed practitioner's prescription drug order.
  3. Preparation of drugs or devices for the purposes of, or as an incident to, research, teaching, or chemical analysis.
Categories of Compounding— The categories of compounding are intended to provide an understanding among compounders when different forms of preparations are compounded. It is to be understood that there are levels of training associated with each category. In the categories of compounding described below, certain criteria were used to determine the overall classification.
Category 1 Nonsterile—Simple
Generally, the mixing of two or more
commercial products
Category 2 Nonsterile—Complex
Generally, compounding with the bulk
drug substances or when calculations
are required.
Category 3 Sterile—Risk Level 1
(See Low-Risk Level in USP general
chapter 797)
Category 4 Sterile—Risk Level II
(See Medium-Risk Level in USP general
chapter 797)
Category 5 Sterile—Risk Level III
(See High-Risk Level in USP general
chapter 797)
Category 6 Radiopharmaceuticals
Preparation of radiopharmaceuticals
Category 7 Veterinary
Preparation of veterinary pharmaceu-
ticals
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Manufacturing— Manufacturing involves 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 also includes (1) any packaging or repackaging of the substance(s) or labeling or relabeling of containers for the promotion and marketing of such drugs or devices; (2) any preparation of a drug or device that is given or sold for resale by pharmacies, practitioners, or other persons; (3) the distribution of inordinate amounts of compounded preparations or the copying of commercially available drug products; and (4) the preparation of any quantity of a drug product without a licensed prescriber/patient/licensed pharmacist/compounder relationship.
Component— A component is any ingredient used in the compounding of a drug product, including any that are used in its preparation, but may not appear on the labeling of such a product. (See Pharmaceutical Compounding—Nonsterile Preparations 795 for additional definitions.)
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Compounder— A compounder is a professional authorized by the state to perform compoundingUSP29 pursuant to a prescription order by a licensed prescriber.
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RESPONSIBILITIES OF THE COMPOUNDER
  1. Compounders who are engaged in drug compounding or nutriceutical compounding shall be proficient in compounding and should continually expand their compounding knowledge by participating in seminars and/or studying appropriate literature.
  2. A compounder mustUSP29 be familiar with all of the details of Pharmaceutical Compounding—Nonsterile Preparations 795, Pharmaceutical Compounding—Sterile Preparations 797, Pharmaceutical Calculations in Prescription Compounding 1160,USP29 and other applicable state or federal compounding guidelines or laws. In addition, the compounder mustUSP29 be responsible for the following:
    • certifying all prescription orders;
    • approving or rejecting all components, drug product containers, closures, in-process materials, and labeling;
    • preparing and reviewing all compounding records to assure that errors have not occurred in the compounding process;
    • assuring the proper maintenance, cleanliness, and use of all equipment used in a prescription compounding practice;
    • assuring that only authorized personnel shallUSP29 be in the immediate vicinity of the drug compounding operations;
    • assuring that the drug product and components of drug products are not on the list of federally recognized drug products that have been withdrawn or removed from the market for public health reasons.
  3. The compounder mustUSP29 ensure that personnel engaged in compounding wear clean clothing appropriate to the type of compounding performed, e.g., coats, gowns, gloves, masks, shoes, aprons, or other items as needed for protection of personnel from chemical exposures and for prevention of drug contamination.
  4. The compounder mustUSP29 implement procedures to prevent cross-contamination when compounding with drugs (e.g., penicillins) that require special precaution to prevent cross-contamination.
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TRAINING
All personnel involved in the compounding, evaluation, packaging, and dispensing of compounded preparations shall be properly trained for the type of compounding conducted. All training activities will be covered by appropriate standard operating procedures (SOPs) and documentation.
All compounders and all personnel involved in compounding must be well trained and must participate in current, relevant training programs. It is the responsibility of the compounderUSP29 to ensure that a training program has been implemented and that it is ongoing. Standards of USP29 practice require that all employees be adequately trained in their job functions and that all of the training is properly documented. Steps in the training procedure will include the following:
  1. All employees involved in pharmaceutical compounding shall read and become familiar with Pharmaceutical Compounding—Nonsterile Preparations 795, Pharmaceutical Compounding—Sterile Preparations 797, and Pharmaceutical Calculations in Prescription Compounding 1160.
  2. All employees shall read and become familiar with each of the procedures related to compounding, including those involving the facility, equipment, personnel, actual compounding, evaluation, packaging, storage, and dispensing.
  3. The compounder shall meet with employees to review their work and answer any questions the employees may have concerning SOPs.
  4. The compounder shall demonstrate the procedures for the employee, and will observe and guide the employee throughout the training process.USP29 The employee will then repeat the procedure without any assistance from, but under the directUSP29 supervision of, the compounder.USP29
  5. When the employee has demonstrated to the compounder a verbal and functional knowledge of the procedure, then and only then, will the employee be permitted to perform the procedure without directUSP29 supervision. However, the compounder should be physically present and should check off the final preparation.USP29
  6. When the compounder is satisfied with the employee’s knowledge and proficiency, the compounder will sign off on the documentation records to show that the employee was appropriately trained.USP29
  7. The compounder shall continually monitor the work of the employee and assure that the employee's calculations and work are accurate and adequately performed. The compounder is completely responsible for the finished preparation. The compounder willUSP29 answer any questions the employee may have concerning the SOPs.
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PROCEDURES AND DOCUMENTATION
All significant procedures performed in the compounding area will be covered by SOPs and will be documented.
Procedures should be developed for the facility, equipment, personnel, preparation, packaging, and storage of compounded preparations to ensure accountability, accuracy, quality, safety (including access to Material Safety Data Sheets), and uniformity in compounding.USP29 Implementing SOPs establishes procedural consistency and also provides a reference for orientation and training of personnel.
Documentation enables a compounder,USP29 whenever necessary, to systematically trace, evaluate, and replicate the steps included throughout the preparation process of a compounded preparation.USP29
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DRUG COMPOUNDING FACILITIES
  1. Compounding facilities shall have an adequate space that is specifically designated for compounding of prescriptions. This area may include a space for the storage of equipment and materials.
  2. Sterile compounded preparations shall be compounded in accordance with the provisions in Pharmaceutical Compounding—Sterile Preparations 797, and aseptic processes shall be conducted in an area separate and distinct from the area used for the compounding of nonsterile products.
  3. The areas used for compounding shall be maintained in clean, orderly, and sanitary conditions.
  4. The areas for drug compounding shall be maintained in a good state of repair. The plumbing system shall be free of defects that could contribute to contamination of any compounded product. Adequate washing facilities shall be easily accessible to the compounding areas. Such facilities shall include, but not be limited to, hot and cold water, soap or detergent, and an air-drier or single-use towels.
  5. Potable water shall be supplied under continuous positive pressure.
  6. The area for compounding shall have adequate lighting and ventilation.
  7. The area for compounding shall be free of infestation by insects, rodents, and other vermin. Trash shall be held and disposed of in a sanitary and timely manner.
  8. Sewage and other refuse in the area of compounding shall be disposed of in a safe and sanitary manner.
  9. Bulk drugs and other chemicals or materials used in the compounding of drugs must be stored as directed by the manufacturer, or according to USP monograph requirements, in a clean, dry area, under appropriate temperature conditions (controlled room temperature, refrigerator, or freezer).USP29 The bulk chemicals shall be stored in a manner such that they are protected from contamination. All containers shall be properly labeled.
  10. If parenteral products are compounded, the compounder shall refer to Pharmaceutical Compounding—Sterile Preparations 797, and Injections 1 for compounding technique applications.
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DRUG COMPOUNDING EQUIPMENT
  1. The equipment or utensils used for compounding of a drug preparationUSP29 shall be of appropriate design and capacity. The equipment shouldUSP29 be stored in such a manner as to protect it from contamination, and shall be located in such a place as to facilitate operations for its use, maintenance, and cleaning.
  2. USP29 The equipment shouldUSP29 be of suitable composition such that the surfaces that contact components are neither reactive, additive, nor absorptive and therefore will not affect or alter the purity of the compounded preparations.
  3. Automated, mechanical, electronic, and other types of equipment used in compounding or testing of compounded preparations shouldUSP29 be routinely inspected, calibrated as necessary, and checked to ensure proper performance.
  4. Immediately prior to initiation of compounding operations, the equipment shall be inspected by the compounder to determine its suitability for use.
  5. After use, the equipment should be appropriately cleaned. Extra care should be used when cleaning equipment used in compounding preparations requiring special precaution,USP29 e.g., antibiotics, cytotoxins, cancer drugs, and other hazardous materials. USP29 If possible, special equipment may be dedicated for such use or if the same equipment is being used for all drug products, appropriate procedures must be in place to allow meticulous cleaning of equipment prior to use with other drugs.
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COMPONENT SELECTION REQUIREMENTS
  1. The compounder mustUSP29 first attempt to use USP–NF drug substances manufactured in an FDA-registered facility.
  2. The compounder shall also first attempt to use inactive components manufactured in an FDA-registered facility.
  3. If components are not obtainable from an FDA-registered facility or if the FDA and/or the providing company cannot document FDA registration, compounders shall use their professional judgment in first receiving, storing, or using the components that meet official compendial requirements or are provided by another high quality source.
  4. If components of compendial quality are not obtainable, components of high quality such as those that are chemically pure, analytical reagent grade, American Chemical Society-certified, or Food Chemicals Codex grade may be used.
  5. When a component is not obtained from an official compendial source or is not obtainable from the sources mentioned above, the component may be obtained from a source deemed acceptable and reliable in the professional judgment of the compounder.
  6. When a component is derived from ruminant animals (e.g., bovine, caprine, ovine) the supplier shall provide written assurance that these animals were born, raised, andUSP29 slaughtered in countries where bovine spongiform encephalopathy (BSE) and scrapie are known not to exist.
  7. The compounder shall not use components that are listed by FDA to be withdrawn from the market for public health reasons.
  8. Components shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first.
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PACKAGING AND DRUG PREPARATIONUSP29 CONTAINERS
  1. The compounder shall ensure that the containers and container closures used in packaging the compounded preparations meet the requirements under Containers 661 and Containers—Permeation 671. The compounder shall obtain written records from the supplier to show that the containers meet USP requirements.
  2. Containers and container closures intended for compounding of sterile preparations and nonsterile preparations must be handled, sterilized (if appropriate), and stored as described in Pharmaceutical Compounding—Sterile Preparations 797 and Pharmaceutical Compounding—Nonsterile Preparations 795. The use of commercially available presterilized containers is encouraged for sterile preparations.USP29
  3. The containers and closures shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest USP29 stock is used first.
  4. The containers and container closures shall be stored in such a way as to permit inspection and cleaning of the work area.
  5. The containers and container closures shall be made of clean materials that are neither reactive, additive, nor absorptive.
  6. The containers and closures shall be of suitable material so as not to alter the quality, strength, or purity of the compounded drug.
  7. The compounder shall ensure that the containers and container closures selected to dispense the finished compounded prescription, whether sterile or nonsterile or radiopharmaceutical, meet the criteria in sections (a)–(f) above.
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COMPOUNDING CONTROLS
  1. The compounder shouldUSP29 ensure that there are written procedures for the compounding of drug products to assure that the finished products have the identity, strength, quality, and purity that they purport to have. These procedures should be available in either written form or electronically stored with printable documentation.USP29
  2. The compounder shall establish procedures that include a description of (1) components, their amounts, the order of component additives, and the compounding process; (2) the required equipment and utensils; and (3) the drug product container and closure system.USP29
  3. The written procedures described above shall be followed in execution of the compounding process.
  4. The compounder shall accurately weigh, measure, and subdivide as appropriate.
  5. The compounder shall check and recheck each procedure at each stage of the process to ensure that each weight or measure is correct as stated in the written compounding procedures.
  6. If a component is transferred from the original container to another container (e.g., a powder is taken from the original container, weighed, placed in a container, and stored in that other container), the new container shall be identified with the component name, weight or measure, the lot or control number, the expiration or beyond-use date, and the transfer date.
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  7. The compounder shouldUSP29 have established written procedures that will describe the tests or examinations to be conducted on the preparationUSP29 compounded (e.g., the degree of weight variation among capsules) to assure uniformity and integrity of compounded drug preparations.USP29
  8. Appropriate control procedures shouldUSP29 be established to monitor the output and to validate the performance of those compounding processes that may be responsible for causing variability in the final compounded preparations. Factors that may cause variability include (1) capsule weight variation; (2) adequacy of mixing to assure uniformity and homogeneity; and (3) clarity, completeness, or pH of solutions.
  9. Appropriate written procedures shouldUSP29 be designed to prevent microbiological contamination of compounded drug preparationsUSP29 purporting to be sterile, and these procedures shall be followed. Such procedures shall include validation of sterilization processes (see Pharmaceutical Compounding—Sterile Preparations 797).
  10. The compounder shouldUSP29 establish appropriate beyond-use dates determined either from available USP–NF monographs, appropriate testing, or from peer-reviewed literature.
  11. The compounder shouldUSP29 adopt appropriate storage requirements as provided in Preservation, Packaging, Storage, and Labeling under General Notices and Requirements.
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LABELING
  1. The compounder's preparation label should contain information required by state and federal law and accepted standards of practice. [NOTES—(a) The compounder shall use the established name or distinct common name (cannot use the trademarked name of a manufactured product). (b) The compounder cannot indicate that the compounded product is therapeutically equivalent to a manufactured product. (c) The label should state that this is a compounded preparation. (d) The compounder shall not use an NDC number assigned to another product.]USP29
  2. The compounder shall label any excess compounded products so as to reference them to the formula used, the assigned control number, and beyond-use date based on the compounder's appropriate testing, published data, or USP–NF standards.
  3. Preparations compoundedUSP29 in anticipation of a prescription prior to receiving a valid prescription should not be prepared in an inordinate amount. A regularly used amount should be prepared on the basis of a history of prescriptions filled by the pharmacy. These preparations shouldUSP29 be labeled or documentation referenced with the following:
    1. A complete list of ingredients or preparation name and reference or established name or distinct common name
    2. Dosage form
    3. Strength
    4. Preparation date
    5. Name and address of compounder
    6. Inactive ingredients
    7. Batch or lot number
    8. Assigned beyond-use date, based on published data, or appropriate testing, or USP–NF standards.
      Storage conditions for these preparations shouldUSP29 be dictated by their composition and sterility, e.g., stored in a clean, dry place under appropriate temperature conditions (controlled room temperature, refrigerator, or freezer.)USP29
  4. The compounder shouldUSP29 examine the preparationUSP29 for correct labeling after completion of the compounding process.
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RECORDS AND REPORTS
  1. The compounder shall maintain records, including but not limited to, the hard copy of the prescription to indicate that the prescription is compounded, and to provide formulation records and compounding records.USP29
  2. The compounder shall keep adequate records of controlled drug substances (scheduled drugs) used in compounding.
  3. All records of all compounded preparationsUSP29 shall be kept for a period of time as set forth in the federal andUSP29 state laws or regulations. Such records shall be readily available for authorized inspection.
  4. The compounding records shall include the manufacturer and lot number of all ingredients.
    5. USP29
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COMPOUNDING FOR A PRESCRIBER'S OFFICE USE
  1. Compounders may prepare compounded drug preparationsUSP29 for a prescriber's office use only where permitted by federal and state requirements.USP29
  2. An order by the prescriber indicating the formula and quantity ordered may be filled in the compounder's facility.
  3. Where compounding for office use is permitted, theUSP29 compounder shall compound the preparation for the soleUSP29 purpose of administration by or for the prescriber.
  4. A record of the compounding process shall be maintained.
  5. A label mustUSP29 be generated and a number may be assigned.
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COMPOUNDING VETERINARIAN PRODUCTS
  1. Compounders shall compound prescriptions for animals on the basis of prescription orders.
  2. These prescriptions shall be handled and filled according to the guideline available for compounding of veterinarian products.USP29
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COMPOUNDING PHARMACY GENERATED PRODUCTS
  1. Compounders may prepare compounded drug products that can be sold without a prescription.
  2. Pharmacy generated products (PGP) shall be compounded using the same procedures as those for prescription drug products detailed in this chapter.
  3. Additional labeling sufficient for patient use will be required to meet the individual State Board of Pharmacy and federal requirements. [NOTE—PGPs are clearly different from drugs defined in section 201 (g) of the Federal Food, Drug, and Cosmetic Act.]
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Auxiliary Information— Staff Liaison : Claudia C. Okeke, Ph.D., Associate Director
Expert Committee : (CRX05) Compounding Pharmacy05
USP29–NF24 Page 2903
Pharmacopeial Forum : Volume No. 31(1) Page 101
Phone Number : 1-301-816-8243