Beyond-use Date: Establishment and Maintenance
With the introduction of United States Pharmacopeia (USP) Chapters <795> and <797>, the long-standing concept of drug stability (beyond-use dates and expiration dates) came to the forefront of pharmacy compounding practice. This includes the issue of increased waste and the cost associated with it. Many facilities opined that this would cause irreparable harm to both the care of the patient and the fiscal well-being of the institution. One of the first issues dealt with was the terminology. The familiar "Expiration Date" terminology was replaced with "Beyond-use Date" (BUD). Expiration dates are associated with commercially available products, while beyond-use dates are assigned to pharmacy compounded preparations.
BUDs are defined by USP Chapter <797> as the date or time after which a compounded sterile preparation (CSP) shall not be administered, stored, or transported, and by USP Chapter <795> as the date after which a compounded preparation should not be used; determined from the date the preparation is compounded. BUDs are best assigned on the basis of direct testing or extrapolation from reliable literature sources and other documentation (see Stability Criteria and Beyond-Use Dating under Pharmaceutical Compounding-Nonsterile Preparations <795>) or, if not available using the default dates provided in the chapters. The pre-administration storage duration and temperature limits specified apply in the absence of direct sterility testing results that justify different limits for specific CSPs.
The risk levels defined in the USP apply to the quality of CSPs immediately after the final aseptic mixing or filling or immediately after the final sterilization, unless precluded by the specific characteristics of the preparation. Upon subsequent storage and shipping of freshly finished CSPs, an increase in the risks of chemical degradation of ingredients, contamination from physical damage to packaging, and permeability of plastic and elastomeric packaging is expected. In such cases, compounding personnel are responsible for considering the potential additional risks to the integrity of CSPs when assigning BUDs. The pre-administration storage duration and temperature limits specified apply in the absence of direct sterility testing results that justify different limits for specific CSPs.
The direct "end preparation sterility testing" must test for both microbial and fungal contamination. Once the testing is completed, then it is possible to use stability information that is already published and all the parameters match (e.g., fluid, concentration, storage conditions) and has been verified by high-performance liquid chromatography (HPLC) testing. The alternative method is to develop in-house stability data/information through previously vetted processes.
Stability can be determined only by a stability-indicating method (SIM). A SIM can determine both stability and potency. A SIM is a quantitative analytical procedure used to identify the amount of the active pharmaceutical ingredient (API) and the reduction in that amount due to degradation. The U.S. Food and Drug Administration (FDA) defines SIM as a validated analytical procedure that accurately and precisely measures active ingredients (drug substance or drug product) free from potential interferences like degradation products, process impurities, excipients, or other potential impurities. The FDA recommends that all assay procedures for stability studies be stability indicating. During stability studies, HPLC testing is used routinely to separate and quantitate the medication of interest.
There are three components necessary for implementing an SIM:
1. Sample generation
2. Method development
3. Method validation
Sample generation is the easiest to accomplish whereas method development and validation are more difficult but achievable if given the necessary information. In order to understand this, one must first understand some of the terminology that is used.
Potency testing, also known as quantitative tests, are designed to determine how much of the active drug is in the sample. Stability testing is also concerned with potency. Methods of determining potency may or may not be stability indicating. Employing the proper method to determine potency or stability is the key to understanding the difference between potency testing and stability testing. Degradation testing is the gold standard of SIM. Degradation testing can cost as much as $20,000 or more. Because of the cost, it is usually only done in a full-blown stability study. An alternative method has been to perform potency-over-time studies. Due to the expense, one independent laboratory may allow several hospitals within the same system to band together to decrease the initial cost of degradation studies. In potency-over-time studies, data points are identified based on the desired length of time that the preparation will be stored before use and the ability of the data points to establish a comprehensive picture of the degradation/stability processes ongoing in the samples.
Standards of Practice for Extension of Beyond-use Date
Stability-indicating testing is used when extending the BUD longer then the USP defaults for preparations not commercially available and/or for preparations whose method of use suggests the need for a narrow therapeutic window, including epidurals, intrathecals, clinically-indicated high-risk medications, etc.
Examples are provided below of sample data points for particular medications. Note that these time points use data points past the desired length of time of the BUD to establish a trailing trend to validate the strength of the previous time points.
Establishment of a One-week Beyond-use Date
A series of seven time points with multiple tests establishing the initial interaction should be used for testing to establish a BUD of one week (initial or time zero, days 1, 2, 4, 6, 7, and 8).
Establishment of a One-month Beyond-use Date
A series of about six time points with multiple tests establishing the initial interaction should be used for testing to establish a BUD of one month (initial or time zero, days 4, 7, 14, 21, 28, and 35).
Establishment of a Three-month Beyond-use Date
A series of about nine time points with multiple tests establishing the initial interaction should be used for testing to establish a BUD of three months (initial or time zero, weeks 1, 2, 4, 6, 8, and months 3, 4, and 6).
Establishment of a Six-month Beyond-use Date
A series of about fourteen time points with multiple tests establishing the initial interaction should be used for testing to establish a BUD of six months (initial or time zero, weeks 1, 2, 4, 6, 8, and months 3, 4, 5, 6, 7, 8, 10, and 12).
Establishment of a Beyond-use Date with Same Drug - Different Container or Changed but Similar Process
When a drug who's BUD has been established in a specific container or with a specific process has changed, it is appropriate to use the knowledge derived in the initial study to establish the BUD, using lesser numbers of time points by eliminating some of the more frequent intermediate time points. (i.e.; 6 month - initial or time zero, weeks 4, 8, and months 3, 6, 8, 10, and 12).
Maintenance of a Beyond-use Date after Initial Establishment
Each year, there should be a series of tests to establish the continued efficacy of the BUD for each preparation. A one-month retest should have three time points (initial or time zero, months 1 and 2). A three-month retest should have four time points (initial or time zero, months 1, 3, and 4). A six-month retest should have five time points (initial or time zero, months 1, 4, 6, and 8).
BUD extension can only be done if end point sterility testing is done on compounded sterile preparations. It is not for everyone, and can only be accomplished by using an analytical approach. Pharmacists should have the unique skill set to accomplish and maintain these processes.
- Swartz M, Krull I. Developing and validating stability-indicating methods. ChromatographyOnline.com. June 1, 2005. Web. 01 June 2012.
- Latta K. Beyond-use dating. Message to the author. June 4, 2010. E-mail.
Richard Osteen, DPh
Manager: Narcotics, Sterile, and Nonsterile Compounding
Vanderbilt University Medical Center