The need for a quality assurance system is well documented in United States Pharmacopeia (USP) chapters for compounded preparations (see Quality Control under Pharmaceutical Compounding—Nonsterile Preparations 795 and Quality Assurance (QA) Program under Pharmaceutical Compounding—Sterile Preparations 797). A quality assurance program is guided by written procedures that define responsibilities and practices that ensure compounded preparations are produced with quality attributes appropriate to meet the needs of patients and health care professionals. The authority and responsibility for the Quality Assurance program should be clearly defined and implemented and should include at least the following nine separate but integrated components: (1) training; (2) standard operating procedures (SOPs); (3) documentation; (4) verification; (5) testing; (6) cleaning, disinfecting, and safety; (7) containers, packaging, repackaging, labeling, and storage; (8) outsourcing, if used; and (9) responsible personnel.

The definition of compounding for the purpose of this chapter is defined in general test chapter 795.

The safety, quality, and efficacy and/or benefit of compounded preparations depend on correct ingredients and calculations; accurate and precise measurements; appropriate formulation, facilities, equipment, 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.

The water used in all aspects of compounding should meet the requirements of Waters for Pharmaceutical Purposes 1231.

Radiopharmaceuticals and radiolabeled materials have unique characteristics requiring additional quality assurances described in Positron Emission Tomography Drugs for Compounding, Investigational, and Research Uses 823 and the Radiopharmaceuticals as CSPs section under 797.

The responsibilities of the compounder and compounding personnel can be found in chapters 795 and 797.

Personnel involved in nonsterile or sterile compounding require additional, specific training and periodic retraining beyond the training needed for routine dispensing duties. A thorough quality assurance program for compounded preparations requires documentation of both training and skill competency. In addition, the authority and responsibility for the QA program should be clearly defined as implemented. Training for nonsterile compounders should meet or exceed the standards set forth in 795, and personnel training for sterile preparation compounders should meet or exceed the standards set forth in 797.

SOPs for pharmaceutical compounding are documents that describe how to perform routine and expected tasks in the compounding environment, including but not limited to procedures involving:

SOPs are itemized instructions that describe when a task will be performed, how a task will be performed, who will perform the task, why the task is necessary, any limitations in performing the task, and what action to take when unacceptable deviations or discrepancies occur.

SOPs must be reviewed regularly and updated as necessary. Auditing and verifying compliance with established SOPs should be performed periodically. The SOP should be specific to each device and process used in compounding. Properly maintained and implemented SOPs are vital to preparation quality.

The purpose of documentation is to provide a record of all aspects of compounding operations and procedures that are described in this chapter, in 795, and in 797. Information on the compounding record should ideally be entered as the tasks are performed or as testing data is received. Compounding records should be reviewed for accuracy, completeness (as appropriate) and approved by QA personnel, prior to dispensing. Additionally, beyond-use dating and sterility studies, where appropriate, should be documented by reference to at least one of the following:

Verification involves authoritatively signed assurance and documentation that a process, procedure, or piece of equipment is functioning properly and producing the expected results. The act of verification of a compounding procedure involves checking to ensure the calculations, weighing and measuring, order of mixing, and compounding techniques and equipment were appropriate and accurately performed. The quality of ingredients should be verified upon receipt (e.g., Certificate of Analysis, manufacturer's label on commmercial products, etc.). Verification may require outside laboratory testing when in-house capabilities are not adequate. Equipment verification methods are sometimes available from manufacturers of the specific equipment or can be developed in-house. The responsibility for assuring that equipment performance is verified, including work completed by contractors, resides with the compounder.

See Component Selection, Handling, and Storage under 795.

A quality assurance program for compounded preparations should include testing during the compounding process and of the finished compounded preparation, when appropriate, as described in chapters 795 and 797. The compounder should have a basic understanding of pharmaceutical analysis to ensure that valid results are obtained when tests are being conducted, whether they are done in-house or outsourced. Acceptance criteria shall be determined prior to testing. Testing every compounded preparation is neither practical nor officially required, but compounders should conduct visual inspections and know: (1) the importance of testing in the overall quality program in the compounding facility, (2) when to test, (3) what to test, (4) what appropriate method(s) and equipment to use, (5) how to interpret the results, (6) the limits of the test, and (7) specific actions required when a preparation does not meet specifications. Investigative and corrective action should extend to other preparations that may have been associated with the specific failure or discrepancy. Testing may involve one or more quality attributes, and each test will have one or more acceptable procedures, usually with well-defined acceptance criteria.

The goal in testing is to determine accurately the adequacy of the compounding process and the quality of the preparation. Any testing procedure used should have accuracy, reproducibility, and specificity. No single testing procedure is suitable for all drugs or preparations because a number of factors determine the validity and reliability of results.

Compounding professionals have two options for the testing that is required for compounded preparations or their ingredients. Some testing methods can easily be performed at the compounding site, but some may need to be outsourced to a contract laboratory. Some testing methods can be conducted in-house by an individual who possesses a good understanding of pharmaceutical analysis and proper training. See Table 1 for a list of compendial testing methods and USP chapters for reference.

If testing is done at the compounding site, appropriate equipment shall be obtained and qualified either by the manufacturer upon sale or by the compounding professional upon receipt and shall be maintained, calibrated, and used properly. If testing is outsourced, the compounding professional should determine what to outsource, how to select a laboratory, and should develop an ongoing relationship with the laboratories chosen. Contract laboratories shall follow standards set forth in USP general chapters, as appropriate, and preferably should be registered with the U.S. Food and Drug Administration (FDA).

note: In this section the terms “unit” and “dosage unit” are synonymous. To ensure the consistency of dosage units, each unit in a batch should have a uniform weight within a narrow range. Dosage units are defined as dosage forms containing a single dose or a part of a dose in each unit. If multiple dose units are compounded in a batch formulation, the total number of units should not deviate outside of ±10% of the theoretical number of units.

First, zero or tare the balance. During the compounding process intermediate weighing may be necessary to ensure that all substances have been included and weighed accurately.

At the end of the compounding process, for the dosage form and quantity designated, take care to preserve the integrity of each dosage unit during the following assessment procedures. Assume the concentration (weight of drug substance per weight of dosage unit) is uniform. The following are examples of weight assessment.

Microbiological testing for pharmacy compounding includes sterility, endotoxin, preservative effectiveness testing, and microbial limit testing (see 797).

Sterility Testing—Sterility tests may be conducted using commercial kits or by developing and verifying USP sterility testing protocols. Standards and procedures are explained in 71.

Endotoxin Testing—Endotoxin tests may be conducted using commercial kits or by purchasing the components separately. Endotoxin testing may be performed in-house with appropriate training and experience. See 85.

Preservative Effectiveness Testing—Preservative effectiveness testing may be conducted when preparing a frequently compounded formulation that contains a preservative. When such a test is performed, the results shall support the beyond-use-date (BUD) assigned to the compounded preparations. See 51.

Microbial Limit Testing—Microbial limit testing may be conducted to provide an estimate of the number of viable aerobic microorganisms (see 61) or to demonstrate freedom from designated microbial species (see 62).

This section applies to both equipment and facilities (see 795, 797, and Disinfectants and Antiseptics 1072).

For storage, packaging, repackaging, and labeling of compounded preparations and repackaging of manufactured products (when defined as compounding in USP), refer to USP General Notices and Requirements and the following general chapters:

note: This section addresses only the purchasing or selling of compounded preparations from pharmacy to pharmacy, not the outsourcing of analytical testing of compounded preparations.

For pharmacies that prepare outsourced compounded preparations or repackaged commercial products, documentation of beyond-use dating, as defined previously in the Documentation section of this chapter, is required and shall be provided upon request. In addition, documentation of compliance with USP chapters 795 and 797 is required and shall be provided upon request.

For facilities that receive outsourced compounded preparations or repackaged commercial products, documentation shall be on file for all BUDs assigned to those preparations or products.

The responsibility and authority for a quality assurance program should be clearly defined and implemented. Personnel responsible for the quality assurance program should have the education, training, and experience necessary to perform the assigned functions. Quality assurance personnel should assure that documentation, verification, and testing are performed in accordance with written policies and procedures. If deviations from approved policies and procedures occur, it is the responsibility of the quality assurance personnel to investigate and to implement appropriate corrective action. Documentation of any investigations and corrective actions is the responsibility of the quality assurance personnel. Responsible personnel in the quality assurance program are essential in assuring the safety, identity, strength, quality, and purity of compounded drug preparations.

A quality assurance program is necessary to ensure the quality of compounded preparations. A sound quality assurance program includes detailed SOPs, documentation, verification, analytical and microbiological testing as appropriate to particular compounded preparations, and responsible quality assurance personnel. Compounding professionals must determine the types of testing and degree of testing that will be a part of their quality assurance program. They also must decide whether to perform testing in-house or outsource it to a contract laboratory.