USP 797 beyond use dating: Collaboration in sterile compounding revisions
The BUD as defined in USP <797> is “The date, or hour and the date, after which a CSP must not be used, stored, or transported. The date is determined from the date and time the preparation is compounded.” The BUD reflects the time of compounding and by when the CSP must be used or administration began. The BUD is not the same as the manufacturer's assigned expiration date. The BUD does not include administration time.
How is a USP 797 BUD determined?
In USP <797> (2023), the primary criteria for establishing the BUD shifts from the complexity of the preparation to the environment where it is compounded, in recognition that these conditions have the greatest potential for introducing contamination to the final dose. Additional considerations include stability, sterility, starting components, processing techniques, and storage containers and conditions.
Compounding environment
Where the CSP is prepared should be the first consideration for determining the BUD. The less controlled the environment, the greater the risk of contamination, and thus, the shorter the BUD. An example is a segregated compounding area designated for compounding within the pharmacy. The more controls, such as positive pressure and air exchanges in a cleanroom suite, the longer the potential BUD.
Stability and sterility
Stability incorporates not only the chemical stability of the active ingredient, but also the chemical and physical properties of the excipient, vehicle, and the integrity of the container closure system. For the default BUDs in the revised chapters, stability is assumed, and additional testing is not expected, though a shorter BUD must be assigned if the physical and chemical stability is less than the limit stated in the Chapter. For Category 3 CSPs, stability-indicating analytical method testing is required to ensure the active ingredient remains stable over the extended BUD.
Sterility means the absence of viable organisms. Many factors influence the stability of the final CSP, including the compounding environment and personnel, as well as the quality measures in use, such as environmental monitoring, garbing compliance, and training. Additional testing to validate sterility is required for Category 3 CSPs and any CSP that starts from nonsterile components.
It is important to distinguish stability and sterility when establishing a BUD. Just because a CSP may be stable for a defined period does not guarantee its sterility during that same time. In general, apply the shorter date or time to ensure the CSP is both stable and safe for the patient.
Compounding and processing techniques
CSPs are prepared via aseptic processing or terminal sterilization. Most preparations are aseptically processed CSPs, meaning simple manipulation of sterile components via an aseptic technique. CSPs may also be prepared via aseptic processing from non-sterile starting ingredients, followed by sterilization by filtration to reduce the risk of contaminants. Terminal sterilization applies steam, dry heat, or irradiation to sealed (finished) containers to achieve sterility and may include verified testing to provide reasonable assurance of sterility. Terminal sterilization allows for longer BUDs because it uses a confirmed procedure to provide reasonable assurance that a CSP will be free of contaminants.
Starting components
Most CSPs begin as sterile powders or liquids, which then require reconstitution and/or further dilution to provide the finished dosage form. However, some CSPs begin as non-sterile components, such as active pharmaceutical ingredients (API) or bulk powders. These non-sterile ingredients must be sterilized during the preparation process, as well as pass USP <71> Sterility Testing and USP <85> Bacterial Endotoxin Testing.
Storage environment
In general, microbes prefer room temperature (20-25⁰C) or warmer to grow and thrive. Longer BUDs are allowed when CSPs are stored under refrigeration or freezing because lower temperatures usually inhibit or slow microbial growth. Be sure to confirm the CSP is stable under various conditions if indicated.
Additional environmental controls
Additional environmental controls, such as the use of sterile garb and more frequent cleaning and monitoring, help minimize the risk of microbial contamination, allowing for extended BUDs.
Key themes in beyond use date USP 797 revisions
The criteria described above factor into the BUD assigned to each category of compounding. The following tables summarize the considerations and resulting BUD for each category.
