1163 QUALITY ASSURANCE IN PHARMACEUTICAL COMPOUNDING
A quality assurance program is a system of steps and actions taken to ensure the maintenance of proper standards in compounded preparations. The need for a quality assurance system is well documented in USP chapters (see Compounding Controls under Good Compounding Practices 1075; Quality Control and Verification under Pharmaceutical CompoundingNonsterile Preparations 795; and The Quality Assurance Program under Pharmaceutical CompoundingSterile Preparations 797). A quality assurance program for compounding should include at least four separate but integrated components: (1) Standard Operating Procedures, (2) Documentation, (3) Verification, and (4) Testing.
STANDARD OPERATING PROCEDURES
Standard Operating Procedures (SOPs) for pharmaceutical compounding are documents that describe how to perform routine and expected tasks in the compounding environment, including formulation development, purchasing, compounding, testing, maintenance, training, materials handling and storage, quality assurance, labeling, beyond-use dating, cleaning, safety, and dispensing. SOPs are itemized instructions that describe how a task will be performed, who will do it, why it is done, any limits, and what to do if a deviation occurs.
SOPs must be reviewed regularly and updated as necessary. The SOP should be specific to each device, process, and decision used in compounding. Properly maintained and implemented SOPs should result in quality preparations and fewer compounding errors.
The purpose of the documentation is to provide a permanent record of all aspects of each compounding operation. Two essential compounding documents, the formulation record and the compounding record, are described in Pharmaceutical CompoundingNonsterile Preparations 795. The compounding record is completed and reviewed for accuracy during the compounding process for the preparation being made.
In addition, many SOPs require specific cross-referenced data collection forms (e.g., air temperature and humidity records and balance maintenance and calibration records). Data collection forms required by SOPs are completed during routine tasks directed by the SOPs and may provide fill-in-the blank spaces for data, including logbook entries, data printouts, and reports.
Verification involves assurance and documentation that a process, procedure, or piece of equipment is functioning properly and producing the expected results. Pharmaceutical CompoundingNonsterile Preparations 795 states: 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. 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.
TESTING OF FINISHED COMPOUNDED PREPARATIONS
A quality assurance program should include testing of finished compounded preparations. It is important for the compounder to 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. While it is not practical to test every compounded preparation, it is incumbent on the compounder to 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 method(s) to use, (5) how to interpret the results, (6) the limits of the test, and (7) what to do if the preparations listed do not meet specifications. Investigative and corrective action should extend to other preparations that may have been associated with the specific failure or discrepancy.
The goal in testing is to produce results as accurately, efficiently, and quickly as possible. Any testing method used should have accuracy, speed, reproducibility, and specificity. No single testing method is suited for all drugs. There are a number of factors that determine the validity and reliability of results.
Compounding facilities have two options when testing is required. Some testing methods can easily be performed in-house, but some may need to be outsourced to a contract laboratory. Relatively basic testing methods that can be conducted in-house with proper training and a modest investment in instrumentation include weight and volumetric measurements, pH, density/specific gravity, refractive index, and UV and visible spectroscopy (see Weights and Balances 41, Volumetric Apparatus 31, Prescription Balances and Volumetric Apparatus 1176, pH 791, Specific Gravity 841, Refractive Index 831, and Spectrophotometry and Light-Scattering 851). Testing methods often outsourced to a contract laboratory include chromatography (high-pressure liquid chromatography (HPLC) and gas chromatography (GC), see Chromatography 621), mass spectroscopy (MS) (see Mass Spectrometry 736), hyphenated methods (HPLC-MS and GC-MS), UV and visible spectroscopy (see Spectrophotometry and Light-Scattering 851), and other sophisticated methods.
If testing is done in-house, appropriate equipment must be obtained, verified either by the manufacturer or by the compounder upon purchase, maintained, calibrated, and used properly. If testing is outsourced, the compounder needs to determine what to outsource and how to select a laboratory, and should develop ongoing relationships with the laboratories chosen. Contract laboratories should follow USP general chapter standards, as appropriate.
Selection of a Testing Method One general consideration in testing method selection is the type of information that is needed, such as quantitative (potency, concentration), semiquantitative (where a tolerance level is involved, as in endotoxin levels), or qualitative (presence/absence type of 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 degree of quantitative measurement and specificity must be considered in the validation process. The typical analytical characteristics used in method validation include accuracy, precision, specificity, detection limit, quantitation limit, linearity, range, and ruggedness (see Validation of Compendial Procedures 1225). 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 not only method selection but also administrative and economic factors, obtaining a representative sample, storage/shipping of the sample, sample preparation for analysis, the actual analysis, data acquisition, data treatment, and interpretation.
Factors Involved in Method Selection The testing method selected depends upon a number of factors, including sample requirements, sample handling/preparation/purification requirements, type of data needed, and levels of specificity and accuracy required.
Sampling Requirements Prior to collecting samples for testing, the following factors should be considered: the number of samples needed, appropriate methods of obtaining representative samples, the physical state of the samples (solid, liquid, or gas), the type of container required for collection and storage, and possible shipping requirements or restrictions. Storage requirements for samples must be specified, such as type of container, temperature, humidity, and light protection (see General Notices and Requirements).
The effect of any substances in the formulation 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 formulation so the laboratory can quickly determine if there may be any interfering substances.
Controlled drug substances, dangerous or hazardous chemicals, flammable or caustic substances, and refrigerated or frozen preparations require special handling during shipping.
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 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 well as 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. It is preferable that the contract laboratory be registered with the Food and Drug Administration (FDA). Also, it may be advantageous if the contract laboratory performs testing for pharmaceutical companies.
Testing Methods Testing methods can be generally divided into physical testing methods, methods that interact with electromagnetic radiation, conductometric techniques, immunoassay methods, separation techniques, and others.
Classification of Analytical Methods
Nonspecific methods include melting, freezing and boiling points, density, refractive index, polarimetry, UV/visible spectroscopy, and pH. Methods that are somewhat more specific include IR spectroscopy, mass spectroscopy, ion selective electrodes, immunoassay methods, and chromatographic methods (HPLC and GC). Suggested testing methods for different dosage forms are shown in Table 1. It is the responsibility of the compounder to implement a program using selected methods for the preparations compounded in the facility.
Table 1. Suggested Analytical Methods for Various Dosage Forms, Depending Upon the Active Drug
Methods that can be routinely used for testing incoming bulk materials, whether active or excipients, include melting, freezing and boiling points, density, refractive index, UV/Visible spectroscopy, IR spectroscopy, polarimetry, pH, and the separation methods. Final preparations may generally require a method such as HPLC or GC.
Microbiological testing for pharmacy compounding includes sterility, endotoxin, and microbial limit testing. Preservative effectiveness may also be considered.
Sterility Testing Sterility tests can be conducted using commercial kits or by developing and validating USP sterility testing protocols, which are more detailed than the commercial sterility-testing kits. Standards and procedures are explained in Sterility Tests 71.
Endotoxin Testing Endotoxin tests can be conducted using commercially available kits or by purchasing the components separately. Endotoxin testing endpoints can be difficult to interpret and in-house testing should only be done after obtaining training and experience. See Bacterial Endotoxins Test 85.
A sound quality assurance program is important in a compounding pharmacy. It includes detailed SOPs, documentation, verification, and analytical and microbiological testing as appropriate. Analytical and microbiological testing will no doubt become a more important part of pharmaceutical compounding as the public and regulatory agencies demand more documentation on the quality of compounded preparations. Compounders must decide on the types of testing and degree of testing that will be a part of their quality assurance program. A decision must also be made on whether to do testing in-house or outsource it to a contract laboratory. It may be practical for larger compounding facilities to have their own analytical and/or microbiological testing laboratory, analytical chemist, or microbiologist to provide rapid turnaround of testing results.
Analytical and microbiological testing should only be performed by those who are trained and experienced, and who can demonstrate validated performance of their operations.
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USP32NF27 Page 684Pharmacopeial Forum: Volume No. 32(5) Page 1517