Using Hospital Laboratory Services to Perform Quality-control Testing on Compounded Preparations
Ronald F. Donnelly, MSc (Chem), BSc (Pharm)
Product Development Pharmacist
Department of Pharmaceutical Services
The Ottawa Hospital
The successful preparation of both sterile and nonsterile compounded preparations that are elegant in appearance is only part of the equation when providing acceptable pharmaceutical preparations. Another important factor is ensuring that the potency of the preparation is correct. To ensure this, several end-preparation assessments and tests must be undertaken. If properly validated, the services of the institution's laboratory may be utilized to perform some of the testing to help assist the hospital pharmacist.
End-preparation assessment and testing are a requirement of the United States Pharmacopeia (USP) Chapter <797> and should be done when a batch-size of compounded sterile preparation (CSP) is 25 units or greater or when the CSP is in the high-risk category. The assessment and testing requirements can be broken down into two categories, 1) required and 2) recommended. Physical inspection, compounding accuracy, sterility testing, and bacterial-endotoxin testing are required, and it is recommended that potency/purity testing, particulate testing, and pH also be performed. For nonsterile preparations, USP <795> recommends the following checks be performed:
- Adequacy of mixing
- Analytical testing where appropriate
A brief discussion of the tests that could possibly be performed by a hospital laboratory will follow. It is the combination of all these components that helps to ensure that a safe, elegant, and effective preparation is compounded.
CSP can be tested for particulate matter (both quantity and size) using either a light obscuration particle counter, if available, or the membrane microscope particle-count method. Information for these two test methods can be found in USP Chapter <1788> Methods for the Determination of Particulate Matter in Injections and Ophthalmic Solutions. A light obscuration particulate counter is a very specialized piece of equipment and not many hospital laboratories would have one, but a standard microscope using an ocular micrometer and set at ×100 magnification could be used to quantify the particles in the 10-mcm and 25-mcm range. The ocular micrometer is calibrated using a certified stage micrometer.
A pH meter that has been calibrated with at least two certified buffers that bracket the anticipated pH can be used to measure the pH of the solution.
Since most hospital laboratories can perform osmolality testing on serum and urine samples using freezing point depression, this method could be used for pharmaceutical preparations. Most laboratories use certified standards that are run throughout the day as part of their quality-control (QC) program.
To measure the specific gravity of urine samples, the lab may use a refractometer and certified standards. This same instrument could be used to determine the specific gravity of some preparations.
Some hospital hematology areas are equipped to determine the viscosity of serum or plasma using automated or semi-automated viscometers. The laboratory QC standards can be used to verify the method is working correctly.
CSP samples could be sent to the microbiology section of the laboratory to test for sterility, while nonsterile preparations could be sent to monitor for mold growth. If the preparations contain known preservatives, then the procedure will have to be validated to ensure that the preservatives do not cause false-negative results. The common methods of inactivating the preservatives are through dilution or inactivating the agent. If no preservatives are present, then the preparations will have to be tested for growth inhibition of the test organisms under the previously validated test conditions.
The biochemistry section of most hospital laboratories measures the levels of many common drugs and electrolytes found in body fluids. Some of the common methods used are:
- Ion-selective electrodes
- High-performance liquid chromatography (HPLC)
- Gas chromatography (GC)
Immunoassay methods are usually used for the determination of drug levels, ion-selective electrodes for assaying electrolytes, HPLC for drugs, and GC for drugs and organic solvents. Strength testing could also be used to verify the adequacy of mixing powders.
There are several points that need to be checked off before these assay methods can be used as part of the QC-testing program and the results can be considered accurate. All the methods need to be validated as to the specificity for the target compound. The immunoassay methods use antibodies (both monoclonal and polyclonal) to form complexes that may not be specific to the target drug and may cross-react with other drugs that have similar chemical structure. The manufacturers of the test kits can often provide information to this regard, but they may not have information regarding the cross-reactivity with impurities or degradation preparations. This process would have to be performed as part of the validation to ensure the specificity of the method. Also, this method may require a certain matrix to work properly, as the methods were developed for use with body-fluid samples. One way to determine the matrix effect and validate the accuracy of the method would be to prepare solutions in various diluents (i.e., distilled water, D5W, NS) and determine if the correct results are being achieved. Similar matrix problems also may occur with the ion-selective electrode methods, and the above diluent technique could help to overcome them as well.
HPLC and GC methods must also be validated for specificity, especially when the test sample may have excipients in it (e.g., suspensions, capsules). To achieve this, blank samples containing everything except the target compound are usually analyzed for interfering peaks. If no peaks are eluted at the same time as the compound under investigation and analysis of a reference sample gives the same retention time, then the method could be deemed specific for the chemical. Occasionally with GC, the analytes must be derivatized to optimize the assay method so specificity validation would require the blanks and reference samples to go through the same steps.
With all of these assay methods, there are a couple of drawbacks. First the range of detection can sometimes be mcg/mL or even ng/mL, so large dilutions are often required to bring the test samples down to these values. Also, sometimes the range is very narrow so the Coefficient of Variance (%) becomes more of a factor.
Using Strength Methods for Stability Testing
In addition, these strength methods may be used for stability studies, but further validation is required to prove each method is stability indicating. Forced-degradation samples can be used to accomplish this so that the method accurately measures only the active ingredients, without interference from degradation products, excipients, or any other potential impurities.
Using a hospital laboratory can be a viable option when looking at ways to expand your QC program, for both CSP and nonsterile preparations, as long as the methods are validated. It can help reduce the cost of purchasing and maintaining your own equipment by utilizing existing resources and avoiding duplication of the QC testing of the equipment. You can also tap into the expertise available in the laboratory. Using a hospital laboratory can help you to achieve your goal of meeting the compounding standards and providing an accurate preparation.