Understanding the Beyond-Use Date (BUD) for Compounded Drugs

During storage, the potency of all medications decreases, and the potential for dangerous microbial growth increases over time. To prevent these changes from jeopardizing a patient’s health, drug manufacturers and compounding pharmacies assign dates beyond which medications should be discarded. Depending on the type of medication, either a beyond-use date (BUD) or an expiration date will be assigned. There are important differences between the two and various factors that compounding pharmacies must consider when providing a BUD for a compounded drug.

Beyond-use date vs. expiration date

FDA-approved medications are assigned an expiration date by their manufacturer based on rigorous tests to determine the stability of an active pharmaceutical ingredient (API). The results of these tests are then evaluated and verified by the FDA. In contrast to commercial medications, compounded drugs are produced on an as-needed basis to meet a specific patient’s needs. Due to  the manipulations they undergo, compounded drugs are not FDA-approved and therefore do not have an FDA-verified expiration date. Instead, they have a beyond-use date (BUD) that specifies the date on which they should no longer be used and should be discarded. This date is assigned by the compounding pharmacy (according to USP guidelines) when it creates the compounded medication. One of the key reasons for the differences between a BUD and an expiration date is that because of the changes they undergo, compounded formulations are different from their FDA-approved counterparts—whether it be a different dosage form, varied strength, or additional or omission of ingredients (i.e, allergens, dyes, preservatives). The changes a compounding pharmacy makes to address a specific patient’s needs may affect the drug’s stability. Thus, a BUD must be assigned to each individual formulation based on the alterations that have been made and a variety of other factors, as discussed below.

BUD and expiration date

Changes in compounded drugs during storage

Despite their differences, both expiration dates and BUDs are meant to minimize patient risks associated with changes that drugs may undergo during storage. These changes are unique to each drug and are affected by everything from excipients added during compounding, to the storage container and temperature. 

These changes include chemical degradation and microbial growth that affect the potency and safety of compounded drugs. The two main reactions responsible for the degradation of drugs, hydrolysis and oxidation, respectively occur when water and oxygen in the air react with one or more components in a formulation. Refrigeration or freezing can slow down these reactions, but this may also increase the moisture content due to a higher relative humidity at lower temperatures. Compounds such as excipients (diluents, solubilizers, absorption promoters, etc.) can also potentially interact with the API and change its solubility, activity, or potency.1 

Microbial contamination and proliferation is one of the main safety concerns for compounded drugs, whose risk increases with the storage length. A contributor to microbial proliferation is cross-contamination that occurs when providers use the same multi-dose container when administering medications (typically non-sterile drugs) to patients in their office. For example, a physician may use the same jar of a topical formulation on several different patients, applying the topical with a new tongue depressor every time. Each time the jar is opened, the chance for microbial infiltration increases. This can be prevented by packaging non-sterile medications in airless pumps that protect from bacterial infiltration by blocking air from entering the container after a medication has been dispensed. For sterile medications, puncture rules should be followed, as will be discussed in the next section.

Due to the risk of microbial proliferation increasing over time and because the API may gradually degrade and lose its potency, medications are no longer considered safe to administer past their BUD and should be discarded. In order to assign a BUD, compounding pharmacists must have an understanding of the above factors that may affect the potency and safety of a compounded drug.

Assigning a BUD 

Both the FDA and United States Pharmacopeial Convention (USP) have provided guidance for selecting a beyond-use date. As mentioned earlier, although the FDA does not directly regulate BUDs for compounded formulations, it does provide draft guidance that recommends that if the compounded medication uses an FDA-approved drug that provides a specific storage condition and timeframe, the BUD should not exceed this range.2 For example, if the compounded medication uses an FDA-approved drug that is stable for seven days when refrigerated, then the compounded drug should not be assigned a BUD that exceeds this timeframe. In the absence of specific stability or sterility testing for compounded formulations, the BUD should not exceed established expiration or retest-by dates for any of its individual components. In other words, the most conservative BUD should prevail to err on the side of caution and ensure patient safety. Compounded drugs often contain several additional ingredients that are not present in FDA-approved drugs, and these individual ingredients may have expiration dates that are shorter than those for the FDA-approved drug. Because of this, BUDs are typically shorter than the expiration dates for commercially-available drugs.

The USP also provides guidance for compounded medications in chapters <795> and <797>, which apply to non-sterile and sterile non-hazardous compounding, respectively.3 USP chapters <800> and <825> provide guidance for hazardous compounding and radiopharmaceuticals, respectively. Under these guidelines, there are four categories for compounded drugs: immediate use and Category 1, 2, and 3. 

Immediate-use compounded formulations should be administered to a patient within 4 hours of compounding and the remainder discarded. This type of compounding occurs on-site in care facilities such as hospitals. 

Category 1 compounded drugs are assigned a BUD of 12 hours at room temperature or ≤ 24 hours when refrigerated.

Category 2 compounded drugs have a more complex method of BUD assignment that depends on how the drug was compounded (aseptically processed or terminally sterilized), whether sterility tests were performed, and the storage temperature. Performing sterility tests and storing at a lower temperature can be used to extend the BUD following USP guidelines.

Category 3 compounded drugs require much stricter testing and preparation conditions than Category 2. In addition to sterility tests, they must also pass stability tests in accordance with a validated procedure to ensure that the API has not degraded and does not contain impurities. USP also requires Category 3 compounded formulations to be packaged and stored in exactly the same type of container as specified in the study from which the stability data were derived. 

The number of doses in a container for an injectable medication also affects when a drug must be discarded. The FDA distinguishes three different scenarios for injectables and biological drugs, depending on the number of doses within a container and the number of target patients: single-dose, multiple-dose, and single-patient-use containers. Once punctured, single-patient-use and multiple-dose containers should not be used for longer than the assigned BUD or 28 days—whichever is earlier—to minimize the likelihood of microbial contamination. To avoid confusion at the clinic, providers are recommended to write the puncture date on the container.

BUD puncture rule example: Let’s assume the originally assigned BUD was 45 days, and the container was initially punctured 5 days after compounding was completed. Under the 28 day puncture rule, even though there are 40 days remaining on the original BUD, the remainder of the medication should be administered no later than 28 days after the initial puncture. The rest of the medication should be discarded after this date. 

BUD for nutritional IV therapy

Nutritional IV therapy is useful for patients with conditions that may affect the ingestion or absorption of nutrients. To ensure safety during the compounding of sterile medications and more specifically, nutritional IV therapy formulations, a sterile ISO Class 5 laminar flow hood is recommended. Our HEPA-filtered airflow ISO Class 5 Laminar flow hoods preserve a uniform airflow, prevent sample contamination, and create a particulate-free work area. Once formulated, we assign a BUD based on USP <797> guidance, which states that if a compounded single-dose container is entered or punctured outside of a sterile environment, it should be used within one hour of puncture. Regardless of the assigned BUD, any remaining dose must be discarded after the BUD is reached. 

Why choose VLS Pharmacy and New Drug Loft

VLS Pharmacy considers many factors when assigning a BUD, including the storage conditions, the expiration date of any FDA-approved APIs, and the presence of any excipients we add. As a 503A pharmacy specializing in sterile and non-sterile compounding, we will support you and your patients by creating safe, individualized, and effective pharmaceutical therapies. All formulations are compounded with high-quality pharmaceutical-grade APIs sourced directly from PCCA, the leader of superior-quality APIs because they test each lot against the certificate of analysis (C of A), USP, EP, NF, FCC, ACS, and PCCA standards. We assign our BUDs by relying on our considerable expertise and following USP <797> sterile compounding standards and USP <795> non-sterile guidelines, as well as USP <800> guidelines for hazardous drugs. Although we are not bound by CGMP regulations, we still perform CGMP-type testing on our sterile medications to ensure patient safety and the stability and efficacy of our medications.

For men and women at any age, feeling healthy, confident, and comfortable is of the utmost importance. Your patients’ needs will change with each life stage. As such, they require an adaptive and personalized treatment plan. By working with a trusted compounding pharmacy like VLS Pharmacy and New Drug Loft, you are expanding the possibilities for successful and sustainable care.

 

Reach out to our team to learn about best practices and to partner with our experts on custom compounded medications for your patients. All medications from VLS Pharmacy and New Drug Loft are prepared in a lab that follows safety and quality standards per our status as a 503A pharmacy.

 

References

  1. Akers MJ. Excipient–Drug Interactions in Parenteral Formulations. J Pharm Sci. 2002;91(11):2283-2300. doi:10.1002/JPS.10154
  2. Kiester M, Capt R. Stability/BUDs: Science and Guidance: Part I.
  3. USP Compounding Standards and Beyond-Use Dates (BUDs). Published online 2019. Accessed November 9, 2022. https://www.usp.org/sites/default/files/usp/document/our-work/compounding/usp-bud-factsheet.pdf

 


 

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