Editorial: Beyond-Use Dates
I would like to take this editorial to explain a little about Beyond-Use Dates (BUDs), as many questions keep coming up about them and why they may be different from one resource to another.
According to USP General Chapter <795> Pharmaceutical Compounding-Nonsterile Preparations, the Beyond-Use Date is the date after which a compounded preparation is not to be used. This date is determined from the date the preparation is compounded and is assigned differently than Expiration Dates, which are assigned by manufacturers after extensive stability studies of the product-package combinations.
USP Chapter <795> provides dating for compounded nonsterile preparations AND for compounded sterile preparations if sterility testing IS done, in the absence of appropriate reliable stability data from other sources (peer-reviewed studies, specific stability studies, etc.). After all, the primary difference between sterile and nonsterile preparations is "sterility"; all other factors are basically the same.
In looking at page 410 of the USP-Pharmacists Pharmacopeia, Column 2, Paragraph 2, it states, "In the absence of stability information that is applicable to a specific drug and preparation, the following maximum beyond-use dates are recommended for nonsterile compounded drug preparations that are packaged in tight, light-resistant containers and stored at controlled room temperature unless otherwise indicated." The section then goes on to describe the different categories of preparations and recommended BUDs.
USP Chapter <797>, Pharmaceutical Compounding - Sterile Preparations, on pages 416 of the USP-Pharmacists Pharmacopeia under Low-Risk Conditions, item 4, Medium-Risk conditions, Item 5, and High-Risk Conditions, Item 5, "��..in the absence of passing a sterility test, the storage periods cannot exceed the following time periods:�." and it goes on to describe the relatively short BUDs that can be used if sterility testing IS NOT done. On page 424 under Determining Beyond-Use Dates, it states in the first paragraph "Beyond-use dates for Compounded Sterile Preparations (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 Compounding-Nonsterile Preparations <795>." As one can tell, these two chapters, <795> and <797> are interrelated. In other words, if sterility testing IS done, then the BUDs defer to <795>.
The latter half of the section entitled "For All Other Formulations", page 410, column 2, states "These beyond-use date limits may be exceeded when there is supporting valid scientific stability information that is directly applicable to the specific preparation (i.e., the same drug concentration range, pH, excipients, vehicle, water content, etc.)." This provides some latitude for compounding but any variation needs to be reasonable and justifiable. In other words, what is a "reasonable drug concentration range"? What is a reasonable pH variation (keep in mind that for each unit of pH change, there is a ten-fold change in hydrogen ion concentration)? The decision to be made is up to the compounding pharmacists but must be reasonable and justifiable. It sounds like "pharmaceutics" may be important here...
With this provided information, what are some general statements that can be made?
- It is the responsibility of the compounding pharmacist to assign a BUD to all compounded preparations.
- When compounding sterile preparations and sterility testing IS NOT done, the BUDs in <797> apply that are described under the sections of Low-, Medium- and High-Risk categories.
- When compounding sterile preparations and sterility testing IS done, the BUDs in <795> apply.
- Compounding pharmacies should have a Standard Operating Procedure describing how BUDs are determined in their facility.
- There should be justification for every BUD that is assigned that varies from the default recommendations in <795> and <797>.
- In the absence of stability studies or other reliable data specific to the formulation being compounded, the default BUDs in <795> can be used.
- If compounding using a formulation that has been commercially available, that formulation has been extensively evaluated and a BUD up to six months could be used for nonsterile preparations and for sterile preparations if sterility testing IS done (Exercise caution if the sterile preparation is aqueous-based to ensure and confirm sterility).
- If compounding an official compounding formula in the USP-NF or the USP-Pharmacists Pharmacopeia, the BUD listed with the formula can be used if the formula is followed. The BUDs in the official monographs have been obtained from stability studies.
- To extend a BUD in the absence of data, consider dispensing the preparation as a dry solid pre-measured, either in a container or in capsules, to be later reconstituted or mixed with a substance prior to taking.
- Six months is generally the maximum accepted BUD for compounded preparations. The FDA considers anything with a BUD greater than six months as not really meeting the individual physician-patient-pharmacist triad relationship and being a part of extemporaneous compounding, i.e., compounding based upon an individual prescription for an individual patient.
Note: At IJPC, we are going through all the formulas we have posted on CompoundingToday.com and updating all the BUD information. It will be a continuous process to incorporate all the new stability studies as they are published.
Loyd V. Allen, Jr., Ph.D., R.Ph
Editor-in-Chief |
