Beyond-use dates for compounded preparations are usually assigned based on professional experience, which should include careful interpretation of appropriate information sources for the same or similar formulations (see Stability Criteria and Beyond-Use Dating
in the general test chapter Pharmaceutical CompoundingNonsterile Preparations 795
). Beyond-use dates for CSPs are rarely based on preparation-specific chemical assay results, which are used with the Arrhenius equation to determine expiration dates (see General Notices and Requirements
) for manufactured products. The majority of CSPs are aqueous solutions in which hydrolysis of dissolved ingredients is the most common chemical degradation reaction. The extent of hydrolysis and other heat-catalyzed degradation reactions at any particular time point in the life of a CSP represents the thermodynamic sum of exposure temperatures and durations. Such lifetime stability exposure is represented in the mean kinetic temperature calculation (see Pharmaceutical Calculations in Prescription Compounding 1160
). Drug hydrolysis rates increase exponentially with arithmetic temperature increase; thus, exposure of a beta-lactam antibiotic solution for one day at controlled room temperature (see General Notices and Requirements
) will have an equivalent effect on the extent of hydrolysis of approximately 3 to 5 days in cold temperatures (see General Notices and Requirements
Personnel who prepare, dispense, and administer CSPs must store them strictly in accordance with the conditions stated on the label of ingredient products and finished CSPs. When CSPs are known to have been exposed to temperatures warmer than the warmest labeled limit, but not exceeding 40
(see General Notices and Requirements
) for more than 4 hours, such CSPs should be discarded, unless appropriate documentation or direct assay data confirms their continued stability.
Determining Beyond-Use Dates
When CSPs deviate from conditions in the approved labeling of manufactured products contained in CSPs, compounding personnel may consult the manufacturer of particular products for advice on assigning beyond-use dates based on chemical and physical stability parameters. Beyond-use dates for CSPs that are prepared strictly in accordance with manufacturers' product labeling must be those specified in that labeling, or from appropriate literature sources or direct testing. Beyond-use dates for CSPs that lack justification from either appropriate literature sources or by direct testing evidence must be assigned as described in the section Stability Criteria and Beyond-Use Dating
in the general test chapter Pharmaceutical CompoundingNonsterile Preparations 795
In addition, the pharmacist may refer to applicable publications to obtain relevant stability, compatibility, and degradation information regarding the drug or its congeners. When assigning a beyond-use date, pharmacists should consult and apply drug-specific and general stability documentation and literature where available, and they should consider the nature of drug and its degradation mechanism, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy (see Expiration Date and Beyond-Use Date under Labeling in the General Notices and Requirements). Stability information must be carefully interpreted in relation to the actual compounded formulation and conditions for storage and use. Predictions based on other evidence, such as publications, charts, tables, and so forth would result in theoretical beyond-use dates. Theoretically predicted beyond-use dating introduces varying degrees of assumptions, and hence a likelihood of error or at least inaccuracy. The degree of error or inaccuracy would be dependent on the extent of differences between the CSP's characteristics (such as composition, concentration of ingredients, fill volume, or container type and material) and the characteristics of the products from which stability data or information are to be extrapolated. The greater the doubt of the accuracy of theoretically predicted beyond-use dating, the greater the need to determine dating periods experimentally. Theoretically predicted beyond-use dating periods should be carefully considered for CSPs prepared from nonsterile bulk active ingredients having therapeutic activity, especially where these CSPs are expected to be compounded routinely. When CSPs will be distributed to and administered in residential locations other than health care facilities, the effect of potentially uncontrolled and unmonitored temperature conditions must be considered when assigning beyond-use dates. It must be ascertained that CSPs will not be exposed to warm temperatures (see General Notices and Requirements) unless the compounding facility has evidence to justify stability of CSPs during such exposure.
It should be recognized that the truly valid evidence of stability for predicting beyond-use dating can be obtained only through product-specific experimental studies. Semi-quantitative procedures, such as thin-layer chromatography (TLC), may be acceptable for many CSPs. However, quantitative stability-indicating assays, such as high performance liquid chromatographic (HPLC) assays, would be more appropriate for certain CSPs. Examples include CSPs with a narrow therapeutic index, where close monitoring or dose titration is required to ensure therapeutic effectiveness and to avoid toxicity; where a theoretically established beyond-use dating period is supported by only marginal evidence; or where a significant margin of safety cannot be verified for the proposed beyond-use dating period. In short, because beyond-use dating periods established from product-specific data acquired from the appropriate instrumental analyses are clearly more reliable than those predicted theoretically, the former approach is strongly urged to support dating periods exceeding 30 days.
To ensure consistent practices in determining and assigning beyond-use dates, the pharmacy should have written policies and procedures governing the determination of the beyond-use dates for all compounded products. When attempting to predict a theoretical beyond-use date, a compounded or an admixed product should be considered as a unique system that has physical and chemical properties and stability characteristics that differ from its components. For example, antioxidant, buffering, or antimicrobial properties of a sterile vial for injection (SVI) might be lost upon its dilution, with the potential of seriously compromising the chemical stability of the SVIs active ingredient or the physical or microbiological stability of the SVI formulation in general. Thus, the properties stabilized in the SVI formulation usually cannot be expected to be carried over to the compounded or admixed product. Product-specific, experimentally determined stability data evaluation protocols are preferable to published stability information. Pharmacists should consult the general information chapter
under Pharmaceutical Stability 1150
for the appropriate stability parameters to be considered when initiating or evaluating a product-specific stability study.
Compounding personnel who assign beyond-use dates to CSPs when lacking direct chemical assay results must critically interpret and evaluate the most appropriate available information sources to decide a conservative and safe beyond-use date. The standard operating procedures manual of the compounding facility and each specific CSP formula record must describe the general basis used to assign the beyond-use date and storage conditions.
If multiple-dose parenteral medication vials (MDVs) are used, refrigerate the MDVs after they are opened unless otherwise specified by the manufacturer. Discard the MDVs when empty, when suspected or visible contamination occurs, or when the manufacturer's stated expiration date is reached, provided the manufacturers storage conditions have been adhered to. Expiration dating not specifically referenced in the package insert should not exceed 30 days once the vial has been opened.
Monitoring Controlled Storage Areas
To ensure that product potency is retained through the manufacturer's labeled expiration date, pharmacists must monitor the drug storage areas within the pharmacy. Controlled temperature storage areas in the pharmacy (refrigerators, 2
; and incubators, 30
; etc.) should be monitored at least once daily and the results documented on a temperature log. Additionally, pharmacy personnel should note the storage temperature when placing the product into or removing the product from the storage unit in order to monitor any temperature aberrations. Suitable temperature recording devices may include a calibrated continuous recording device or an NBS calibrated thermometer that has adequate accuracy and sensitivity for the intended purpose and should be properly calibrated at suitable intervals. If the pharmacy uses a continuous temperature recording device, pharmacy personnel should verify at least once daily that the recording device itself is functioning properly.
The temperature sensing mechanisms should be suitably placed in the controlled temperature storage space to reflect accurately its true temperature. In addition, the pharmacy should adhere to appropriate procedures of all controlled storage spaces to ensure that such spaces are not subject to significantly prolonged temperature fluctuations as may occur, for example, by leaving a refrigerator door open too long.