795 PHARMACEUTICAL COMPOUNDINGNONSTERILE PREPARATIONS
For the purposes of this chapter, the pharmacist or other licensed health care professional responsible for preparing the compounded preparations is referred to as compounder.
Compounding is an integral part of pharmacy practice and is essential to the provision of health care. The purpose of this chapter and applicable monographs on formulation is to help define what constitutes good compounding practices and to provide general information to enhance the compounder's ability in the compounding facility to extemporaneously compound preparations that are of acceptable strength, quality, and purity.
Compounding is different from manufacturing, which is guided by GMPs (see Good Manufacturing Practices for Bulk Pharmaceutical Excipients 1078). Some of the characteristics or criteria that differentiate compounding from manufacturing include the existence of specific practitionerpatientcompounder relationships; the quantity of medication prepared in anticipation of receiving a prescription or a prescription order; and the conditions of sale, which are limited to specific prescription orders.
The pharmacist's responsibilities in compounding drug preparations are to dispense the finished preparation in accordance with a prescription or a prescriber's order or intent and to dispense those preparations in compliance with the requirements established by the Boards of Pharmacy and other regulatory agencies. Compounders must be familiar with statutes and regulations that govern compounding because these requirements vary from state to state.
The compounder is responsible for compounding preparations of acceptable strength, quality, and purity with appropriate packaging and labeling in accordance with good compounding practices (see Good Compounding Practices 1075), official standards, and relevant scientific data and information. Compounders engaging in compounding should have to continually expand their compounding knowledge by participating in seminars, studying appropriate literature, and consulting colleagues.
RESPONSIBILITY OF THE COMPOUNDER
The compounder is responsible for ensuring that the quality is built into the compounded preparations of products, with key factors including at least the following general principles. (See also Good Compounding Practices 1075.)
Areas designated for compounding have adequate space for the orderly placement of equipment and materials to prevent mixups between ingredients, containers, labels, in-process materials, and finished preparations. The compounding area is also to be designed, arranged, used, and maintained to prevent adventitious cross-contamination. Areas used for sterile preparations are to be separated and distinct from the nonsterile compounding area (see Environmental Quality and Control under Pharmaceutical CompoundingSterile Preparations 797). The entire compounding area is to be well-lighted. Heating, ventilation, and air conditioning systems are to be controlled to avoid decomposition of chemicals (see Storage Temperature under Preservation, Packaging, Storage, and Labeling in the General Notices and Requirements and the manufacturers' labeled storage conditions). Storage areas provide an environment suitably controlled to ensure quality and stability of bulk chemicals and finished preparations.
Potable water is to be supplied for hand and equipment washing. This water meets the standards prescribed in the EPA's National Primary Drinking Water Regulations (40 CFR Part 141). Purified Water must be used for compounding nonsterile drug preparations when formulations indicate the inclusion of water. Purified Water must also be used for rinsing equipment and utensils. In those cases when a water is used to prepare a sterile preparation, Water for Injection, Sterile Water for Injection, or Bacteriostatic Water for Injection must be used (see Water for Pharmaceutical Purposes 1231 and Pharmaceutical CompoundingSterile Preparations 797).
Compounding areas are to be maintained in a clean and sanitary condition. Adequate washing facilities are to be provided, including hot and cold water, soap or detergent, and air driers or single-service towels. Sewage, trash, and other refuse in the compounding area is to be disposed of in a safe, sanitary, and timely manner. Equipment is to be thoroughly cleaned promptly after use to avoid cross-contamination of ingredients and preparations. Special precautions are to be taken to clean equipment and compounding areas meticulously after compounding preparations that contain allergenic ingredients (e.g., sulfonamides or penicillins).
Equipment is to be of appropriate design and size for compounding and suitable for the intended uses. The types and sizes of equipment will depend on the dosage forms and the quantities compounded (see Weights and Balances 41, Prescription Balances and Volumetric Apparatus 1176, and equipment manufacturers' instruction manuals). All equipment is to be constructed so that surfaces that contact pharmaceutical components, in-process materials, or finished preparations are not reactive, additive, or adsorptive to avoid altering the safety, identity, strength, quality, or purity of the preparation. The use of micropipets, electronic or analytical balances, or triturations or dilutions shall be considered when needed quantities are too small to accurately measure with standard equipment required by a state Board of Pharmacy. Equipment and accessories used in compounding are to be inspected, maintained, cleaned, and validated at appropriate intervals to ensure the accuracy and reliability of their performance.
STABILITY OF COMPOUNDED PREPARATIONS
Stability is defined as 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 the table Criteria for Acceptable Levels of Stability under Stability Considerations in Dispensing Practice 1191.
The compounder must avoid formulation ingredients and processing conditions that would result in a potentially toxic or ineffective preparation. The compounder's knowledge of the chemical reactions by which drugs degrade provides a means for establishing conditions under which the rate of degradation is minimized. The factors that influence the stability of compounded preparations are generally the same as those for manufactured drug products (see Factors Affecting Product Stability and Responsibility of the Pharmacist under Stability Considerations in Dispensing Practice 1191).
Compounded preparations should be packaged in containers meeting USP standards (see Containers under Preservation, Packaging, Storage, and Labeling in the General Notices and Requirements, ContainersPlastics 661, and ContainersPerformance Testing 671). The container used depends on the physical and chemical properties of the compounded preparation. Containerdrug interaction is to be considered with substances such as phenolic compounds and sorptive materials (e.g., polypeptides and proteins).
Assurance of sterility in a compounded sterile preparation is mandatory. Compounding and packaging of sterile drugs, such as ophthalmic solutions, will require strict adherence to guidelines presented in the general test chapter Pharmaceutical CompoundingSterile Preparations 797 and in the manufacturers' labeling instructions.
Stability Criteria and Beyond-Use Dating
The beyond-use date is the date after which a compounded preparation is not to be used and is determined from the date the preparation is compounded. Because compounded preparations are intended for administration immediately or following short-term storage, their beyond-use dates may be assigned based on criteria different from those applied to assigning expiration dates to manufactured drug products.
Compounders are to consult and apply drug-specific and general stability documentation and literature when available, and are to consider the nature of the drug and its degradation mechanism, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy when assigning a beyond-use date (see Expiration Date and Beyond-Use Date under Labeling in the General Notices and Requirements). Beyond-use dates are to be assigned conservatively. When using manufactured solid dosage forms to prepare a solution or aqueous suspension, the compounder is also to consider factors such as hydrolysis and the freeze-thaw property of the final preparation before assigning a beyond-use date. In assigning a beyond-use date for a compounded drug preparation, in addition to using all available stability information, the compounder is also to use his or her pharmaceutical education and experience.
When a manufactured product is used as the source of active ingredient for a nonsterile compounded preparation, the product expiration date cannot be used to extrapolate directly a beyond-use date for the compounded preparation. However, a compounder may refer to the literature or to the manufacturer for stability information. The compounder may also refer to applicable publications to obtain stability, compatibility, and degradation information on ingredients. All stability data must be carefully interpreted in relation to the actual compounded formulation.
At all steps in the compounding, dispensing, and storage process, the compounder is to observe the compounded drug preparation for signs of instability. For more specific details of some of the common physical signs of deterioration, see Observing Products for Evidence of Instability under Stability Considerations in Dispensing Practice 1191. However, excessive chemical degradation and other drug concentration loss due to reactions may be invisible more often than they are visible.
In the absence of stability information that is applicable to a specific drug and preparation, the following maximum beyond-use dates are recommended for nonsterile compounded drug preparations1 that are packaged in tight, light-resistant containers and stored at controlled room temperature unless otherwise indicated (see Preservation, Packaging, Storage, and Labeling in the General Notices and Requirements).
For Nonaqueous Liquids and Solid Formulations
Where the Manufactured Drug Product is the Source of Active Ingredient The beyond-use date is not later than 25% of the time remaining until the product's expiration date or 6 months, whichever is earlier.
Where a USP or NF Substance is the Source of Active Ingredient The beyond-use date is not later than 6 months.
For Water-Containing Formulations (prepared from ingredients in solid form) The beyond-use date is not later than 14 days for liquid preparations when stored at cold temperatures between 2 and 8 (36 and 46 F).
For All Other Formulations The beyond-use date is not later than the intended duration of therapy or 30 days, whichever is earlier. These beyond-use date limits may be exceeded when there is supporting valid scientific stability information that is directly applicable to the specific preparation (i.e., the same drug concentration range, pH, excipients, vehicle, water content, etc.). See also the beyond-use dating information in the Labeling section under Repackaging Into Single-Unit Containers and Unit-Dose Containers for Nonsterile Solid and Liquid Dosage Forms 681.
Federal law requires that manufactured drug products be labeled with an expiration date. Some state laws may require a beyond-use date. The label on the container or package of an official compounded preparation must bear a beyond-use date. Good compounding practice dictates beyond-use labeling for all compounded preparations.
For purposes of this chapter, the following terms shall have these meanings.
preparation is a drug dosage form, a dietary supplement, or a finished device. It is the finished or partially finished preparation of one or more substances formulated for use on or for the patient or consumer (see General Notices and Requirements).
official substance includes an active drug entity, a dietary supplement, or a pharmaceutic ingredient (see also NF 23) or a component of a finished device.
active ingredient usually refers to chemicals, substances, or other components of articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases in humans or other animals or for use as dietary supplements.
added substances are ingredients that are necessary to prepare the preparation but are not intended or expected to cause a human pharmacologic response if administered alone in the amount or concentration contained in a single dose of the compounded preparation. The term added substances is usually used synonymously with the terms inactive ingredients, excipients, and pharmaceutic ingredients.
Official compounded preparations are prepared from ingredients that meet requirements of the compendial monograph for those individual ingredients for which monographs are provided.
A USP or an NF grade substance is the preferred source of ingredients for compounding all other preparations. If that is not available, or when food, cosmetics, or other substances are or must be used, then the use of another high-quality source, such as analytical reagent (AR), certified American Chemical Society (ACS), or Food Chemicals Codex (FCC) grade, is an option for professional judgment. For any substance used in compounding not purchased from a registered drug manufacturer, the compounder must establish purity and safety by reasonable means, which may include lot analysis, manufacturer reputation, or reliability of source.
A manufactured drug product may be a source of active ingredient. Only manufactured drugs from containers labeled with a batch control number and a future expiration date are acceptable as a potential source of active ingredients. When compounding with manufactured drug products, the compounder must consider all ingredients present in the drug product relative to the intended use of the compounded preparation.
A compounder may not compound a drug preparation that appears on the FDA list of drug products withdrawn or removed from the market for safety reasons.
Compounding Nondrug Requirements
If the preparation is intended for use as a dietary or nutritional supplement (to supplement the diet) or cosmetic (e.g., to beautify), then the compounder must adhere to Good Compounding Practices 1075 and to this chapter, and must comply with any federal and state requirements.
CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND PURITY
The following questions are to be considered carefully before compounding.
The term compounded preparations includes the terms compounded dosage forms, compounded drugs, and compounded formulations, and means finished forms that are prepared by or under the direct supervision of a licensed compounder.
When controlled substances are used, check with state and federal authorities concerning their policies. Unless otherwise indicated or appropriate, compounded preparations are to be prepared to ensure that each preparation shall contain not less than 90.0% and not more than 110.0% of the theoretically calculated and labeled quantity of active ingredient per unit weight or volume and not less than 90.0% and not more than 110.0% of the theoretically calculated weight or volume per unit of the preparation. Compounded preparations include, but are not restricted to, the following pharmaceutical dosage forms described under Pharmaceutical Dosage Forms 1151.
Capsules, Powders, Lozenges, and Tablets
When compounding these dosage forms, the compounder is to prepare an amount of the total formulation sufficient to allow the prescribed amount or quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following:
Emulsions, Solutions, and Suspensions
When compounding these dosage forms, the compounder is to prepare a 2% to 3% excess amount of the total formulation to allow the prescribed amount to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following.
When compounding suppositories, the compounder is to prepare an excess amount of total formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following:
Creams, Topical Gels, Ointments, and Pastes
When compounding semisolid dosage forms, the compounder is to prepare an excess amount of total formulation to allow the prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms include the following:
The compounders are to consider using the following steps to minimize error and maximize the prescriber's intent.
COMPOUNDING RECORDS AND DOCUMENTS
All compounders who dispense prescriptions must comply with the record keeping requirements of their individual states. If the compounder compounds a preparation according to the manufacturer's labeling instructions, then further documentation is not required. All other compounded preparations require further documentation. Such compounding documents are to list the ingredients and the quantity of each in the order of the compounding process.
The objective of the documentation is to allow another compounder to reproduce the identical prescription at a future date. The formulation record provides a consistent source document for preparing the preparation (recipe), and the compounding record documents the actual ingredients in the preparation and the person responsible for the compounding activity. These records are to 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 that includes a formulation record, a compounding record, and a Material Safety Data Sheets (MSDS) file.
The formulation record is a file of individually compounded preparations. This record must list the name, strength, and dosage form of the preparation compounded, all ingredients and their quantities, equipment needed to prepare the preparation, when appropriate, and mixing instructions. Mixing instructions should include the order of mixing, mixing temperatures or other environmental controls, such as the duration of mixing, and other factors pertinent to the replication of the preparation as compounded. The formulation record must include an assigned beyond-use date, the container used in dispensing, the storage requirements, and any quality control procedures.
The compounding record contains documentation of the name and strength of the compounded preparation, the formulation record reference for the preparation, and the sources and lot numbers of ingredients. The compounding record also includes information on the total number of dosage units compounded, the name of the person who prepared the preparation and the name of the compounder who approved the preparation, the date of preparation, the assigned internal identification number or the prescription number and an assigned beyond-use date, and the prescription number. For all compounded preparations, results of quality control procedures are to be recorded (e.g., weight range of filled capsules). When compounding problems occur with preparations prepared according to USP compounding monographs, the compounder must complete a USP Monograph Experience Reporting Form, and submit the form to USP for evaluation.
MSDS are to be readily accessible to all employees working with drug substances or bulk chemicals located on the compounding facility premises. Employees are to 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 is to review each procedure in the compounding process. To ensure accuracy and completeness, the compounder is to observe the finished preparation to ensure that it appears as expected and is to investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient (see the Checklist for Acceptable Strength, Quality, and Purity, the appropriate pharmaceutical dosage form under Compounded Preparations, and the steps under Compounding Process).
Compounding procedures that are routinely performed, including batch compounding, shall be completed and verified according to written procedures. The act of verification of a compounding procedure involves checking to ensure that calculations, weighing and measuring, order of mixing, and compounding techniques were appropriate and accurately performed.
The patient or the patient's agent should be counseled about proper use, storage, and evidence of instability in the compounded preparation at the time of dispensing (see Responsibility of the Pharmacist under Stability Considerations in Dispensing Practice 1191).
1 For guidelines applicable to dating sterile compounded preparations, see Storage and Beyond-Use Dating under Pharmaceutical CompoundingSterile Preparations 797.
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