1163 QUALITY ASSURANCE IN PHARMACEUTICAL COMPOUNDING
The need for a quality assurance system is well documented in United States Pharmacopeia (USP) chapters for compounded preparations (see Quality Control under Pharmaceutical CompoundingNonsterile Preparations 795 and Quality Assurance (QA) Program under Pharmaceutical CompoundingSterile 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 Radiopharmaceuticals for Positron Emission TomographyCompounding 823 and the Radiopharmaceuticals as CSPs section under 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.
STANDARD OPERATING PROCEDURES
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.
Table 1. U.S. Pharmacopeia Chapters for Selected Quality Testing Methods and Procedures
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).
Selection of a Testing Method One general consideration in testing procedure selection is the type of information needed, such as quantitative (strength, concentration), semiquantitative (where a tolerance level is involved, as in endotoxin levels), or qualitative (presence/absence testing, including substance identification, sterility). Another consideration involves the physical and chemical characteristics of the analyte, including solubility, partition coefficient, dissociation constant (pKa), volatility, binding, and the quantity present. The testing method selected also depends upon factors such as sample handling/preparation/purification requirements; type of data needed; and accuracy, reproducibility, and specificity required.
The degree of quantitative measurement and specificity must be considered in the verification process. The typical analytical characteristics used in method verification include accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and ruggedness. Generally, the greater the level of accuracy, precision, or specificity required, the more sophisticated and expensive the testing methods needed. The methods used are also governed by the types of instrumentation available and the standards available for comparison.
Pharmaceutical analysis decisions include procedure selection, obtaining a representative sample (the number of preparation units selected to adequately represent the entire formulation, e.g., 10 randomly selected capsules from a preparation of 100 capsules), storage/shipping of the sample, sample preparation for analysis, the actual analysis, data acquisition, data treatment, and interpretation.
The compounding professional is responsible for implementing a program using selected testing methods for the preparations compounded in the facility. USP chapters on spectroscopy and chromatography methods are referenced in Table 1. Examples of general and microbiological testing methods are discussed later in this chapter. Examples of selected testing methods for bulk substances and various dosage forms (see Pharmaceutical Dosage Forms 1151) are shown in Table 2.
Sampling Requirements Before collecting samples for testing, compounding professionals should consider the following factors:
Storage Requirements Storage requirements for samples must be specified, including type of container, temperature, humidity, and light protection (see General Notices and Requirements and the Containers, Packaging, Repackaging, Labeling, and Storage section in this chapter).
The effect(s) that any substance has on the compounded preparation that may interfere or alter the results must be known beforehand. When sending a preparation to a contract laboratory, the compounder should provide the complete written formulation so that the laboratory can quickly determine if there may be any interfering substances present.
Data Interpretation Requirements The collection of raw data from the testing process must be completed accurately. One must ensure that appropriate and valid descriptive statistics (e.g., mean, standard deviation) are used to analyze the data and that the operating parameters of the analytical instruments are well-established. Reference values, if available, should be provided with the analytical results. A description of the analytical controls used by the laboratory is important for documentation, as is the source of reference standards used to establish standard curves.
Personnel Requirements and Considerations If testing is done in-house, personnel involved in this activity must be appropriately trained and evaluated with documentation of the training and evaluation. If testing is outsourced, the compounder must be assured of the credentials, proper training, and continuing competency activities of the personnel in the contract laboratory.
Table 2. Selected Compendial Testing Methods for Bulk Substances and Various Dosage Forms
PHYSICAL TESTING OF DOSAGE UNITS
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.
Other Solids (Including Tablets, Suppositories, Inserts, and Lozenges)
Semi-Solids (Including Creams, Gels, and Ointments)
Additional Quality Assurance Checks Before Packaging Semi-Solids
Visually inspect the preparation for foreign materials and expected appearance.
Measure pH, when applicable.
Microbiological testing for pharmacy compounding includes sterility, endotoxin, preservative effectiveness testing, and microbial limit testing (see 797).
Sterility TestingSterility tests may be conducted using commercial kits or by developing and verifying USP sterility testing protocols. Standards and procedures are explained in 71.
Endotoxin TestingEndotoxin 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 TestingPreservative 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.
CLEANING, DISINFECTING, AND SAFETY
This section applies to both equipment and facilities (see 795, 797, and Disinfectants and Antiseptics 1072).
CONTAINERS, PACKAGING, REPACKAGING, LABELING, AND STORAGE
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.
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USP35NF30 Page 795Pharmacopeial Forum: Volume No. 36(1) Page 247