Beyond-Use Dates, Part 2
I would like to begin this second issue of the Science and Technology Newsletter with a quote from Richard Penna.
The sciences are what support pharmacy's expertise in drug distribution and drug use. Recent history leads one to question whether we in the profession, and some in pharmaceutical education, recognize and appreciate the contribution that the pharmaceutical sciences have made and continue to make to the pharmacy profession and health care. The pharmaceutical sciences are what make us unique. They provide us the special value that we bring to the bedside. No other health professional is capable of bringing to the pharmacotherapeutic decision-making table such concepts as pH, particle size, partition coefficient, protein binding, structure-activity relationships, economics, and epidemiology. The pharmaceutical sciences, combined with pharmacy's infrastructure, including pharmaceutical education, are what make the pharmacist an indispensable participant on the health care team." (Penna R. Am J Pharm Educ 1997; 61(Spring):103).
In the first issue, we discussed drug stability, degradation, rates of degradation, reaction order, the Arrhenius Equation, and the Q10 method of calculating shelf life estimates. Determining beyond-use dates and evaluating stability studies is a responsibility of pharmacists involved in all areas of nonsterile and sterile compounding.
Determining Beyond-Use Dates
Beyond-use dates (BUDs) and expiration dates are not the same and, as presented in last month's issue of this newsletter, they are assigned on different criteria.
Expiration dates are assigned by the manufacturer of a product and indicate when a product has lost sufficient strength that it is outside acceptable limits established for the product. At this point, that product should not be dispensed or used. The expiration date stated on a label of that product is usually valid until the last day of the stated expiry month. Expiration dates for the chemical and physical stability of manufactured sterile products are similarly determined from results of rigorous analytical, stability, and performance testing, and they are specific for a particular formulation in its container and at stated exposure conditions of illumination and temperature.
BUDs are assigned by pharmacists. If compounding is from commercially manufactured products, compounding personnel can consult the manufacturer of the particular product ingredients used for compounding, or appropriate literature sources for advice on assigning BUDs based on chemical and physical stability parameters. When compounded preparations (CPs) lack information in the manufacturer labeling, appropriate literature sources or by direct testing evidence, BUDs are assigned as described in accordance with USP <795> and <797>. When assigning a BUD, the compounding personnel should consider the nature of the drug and its degradation mechanism and its congeners, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy. Stability information must be carefully interpreted in relation to the actual compounded formulation and conditions for storage and use. Predictions based on other evidence in the literature, such as charts, and tables results in theoretical BUDs which should act as reasonable estimates.
These estimates introduce 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 CPs' characteristics (e.g., composition, concentration of ingredients, fill volume, container type, material) and the characteristics of the products from which stability data or information is to be extrapolated. Compounded sterile preparations (CSPs) with ingredients that have narrow therapeutic windows should be evaluated carefully so that safe BUDs are used. The greater the doubt of the accuracy of theoretically predicted beyond-use dating, the greater the need to determine dating periods experimentally. Where such is not available, care should be used to designate a BUD. Theoretically predicted BUD periods should be carefully considered for CSPs prepared from nonsterile bulk active ingredients having high therapeutic activity or toxic degradation components, especially where these CSPs are expected to be compounded routinely. When CSPs will be distributed to and administered in residential locations other than healthcare facilities, the effect of potentially uncontrolled and unmonitored temperature conditions should be carefully considered when assigning BUDs. It must be ascertained that CSPs must not be exposed to warm temperatures unless the compounding facility provides adequate evidence to justify stability of CSPs during such exposure.
It should be recognized that the correct evidence of stability for predicting beyond-use dating can be obtained only through preparation-specific experimental studies. Quantitative stability-indicating assays such as high-performance liquid chromatographic (HPLC) assays and other analytical methods are appropriate for most CPs. There are a number of qualified analytical methods which will be suitable depending on the chemical composition of the CPs. Examples include CPs with a narrow therapeutic index, where close monitoring or dose titration is required to ensure therapeutic effectiveness and to avoid toxicity. The analytical method used must be drug specific, and estimates on BUD are used if results are supported by only marginal evidence or where a significant margin of safety cannot be verified for the proposed BUD period. In short, BUD periods established from product-specific data acquired from the appropriate instrumental analyses are clearly more reliable than those predicted theoretically. To ensure consistent practices in determining and assigning BUDs, the compounding facility should have written policies and procedures governing the determination of the BUDs for all CPs. These policies should be made available to all compounding personnel, and procedures should be in place to ascertain that these personnel have been trained in processes for determining BUDs.
Why Must BUDs be Carefully Determined?
When attempting to predict a theoretical BUD, a compounded or an admixed preparation should be considered as a unique system that has physical and chemical properties and stability characteristics that differ from its components because of the multi-step preparation process. 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 SVI's 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 preparation. This is why the BUD assigned has to be carefully determined or extrapolated. Preparation-specific, experimentally determined stability data evaluation protocols are preferable to published stability information. Compounding personnel should consult stability references to understand the appropriate parameters that must be considered when initiating or evaluating a preparation-specific stability study.
Compounding personnel who assign BUDs to CPs theoretically must critically interpret and evaluate the most appropriate available information sources to determine a conservative and safe BUD. The standard operating procedure manual of the compounding facility and each specific CP formula record must describe and discuss the general basis used to assign the BUD and storage conditions.
What is the BUD for Proprietary Bag and Vial Systems?
The sterility storage and stability BUD times for attached and "activated" container pairs of drug products for intravascular administration (e.g., ADD-Vantage, Mini Bag Plus) depends on instructions indicated by the manufacturer. The word "activated" is defined as allowing contact of the previously separated diluent and drug contents and thereby create a mixture or preparation. The manufacturers' instructions for handling and storing ADD-Vantage, Mini Bag Plus, Add A Vial, Add-Ease products, and any others should be adhered to.
Monitoring Controlled Storage Areas
To ensure that product potency is retained through the manufacturer's labeled expiration date, compounding personnel should monitor and document the drug storage areas within the compounding facility.
Next month we will look at examples of published stability studies and their interpretation as well as some examples of compounded preparations for sterile and nonsterile preparations and how to assign their BUDs.
Loyd V. Allen, Jr., Ph.D., R.Ph.