Extending Beyond Use Dates for Compounded Preparations
Dr. Qiang Liu, Research and Development Laboratory Supervisor
A beyond use date (BUD) is the date after which a compounded preparation shall not be used. The BUD is determined from the date the preparation is compounded. This date should be based on drug-specific, scientifically valid studies when possible. Things to consider when assigning BUD include:
- The drug and its degradation mechanism
- The dosage form and its components
- The potential for microbial proliferation
- The container in which the preparation is packaged
- The expected storage conditions
- The intended duration of therapy
USP <797> describes four methods for assigning a beyond use date:
- Product labeling
- Commercial product manufacturer consultation
- Appropriate literature
- Direct testing
Beyond use dating must be carefully interpreted with respect to the actual compounded formulation and conditions for storage and use. Predictions based on literature are considered theoretical beyond-use dates as the published data introduces varying degrees of assumptions with a likelihood of error or inaccuracy. Pharmacists using literature to assign a beyond use date must look for the exact drug formula, storage conditions, and container/closure to reduce the likelihood of errors. State and federal regulations also require pharmacists to have written justification for a beyond use date assignment.
The only truly valid beyond use date is obtained through product-specific studies supported by scientific data. These direct testing studies use stability indicating methods (SIM) to ensure therapeutic effectiveness of compounded drug products.
A SIM is a reliable, meaningful, and specific analytical procedure that accurately and precisely measures active pharmaceutical ingredients (API) by separating the API from its degradation products and excipients. A SIM must be validated for the exact formulation being tested. High performance liquid chromatograph (HPLC) is one of the most commonly used techniques for examining the chemical stability of compounded product, but not all HPLC tests are stability indicating. A forced degradation study must be performed on the compounded drug product and not inferred from testing on only the API.
Testing the concentration of the drug is just one component of a stability study. Testing should include evaluation of the physical, chemical, and microbiological properties of the product. Common tests in a stability study include:
- Assay (Stability Indicating Method)
- Sterility – USP <71> (sterile preparations)
- Endotoxin – USP <85> (sterile preparations)
- pH – USP <791>
- Visual Inspection (Appearance)
- Particulate Matter – USP <788> / <789> (all sterile solutions for IV injection or ophthalmic)
- Preservative Effectiveness – USP <51> (preparations containing an antimicrobial preservative)
- Preservative Quantification – (preparations containing an antimicrobial preservative)
- Microbial Limits – USP <61> (nonsterile preparations)
- Absence of Specified Organisms – USP <62> (nonsterile preparations)
Additional tests for biological products BUD include:
- Protein content – USP <1057>
- Potency or activity – such ELISA assay
- Product related impurity including protein aggregates, size and charge variants
Please contact ARL (800) 393-1595 or firstname.lastname@example.org with questions.