While the terms beyond-use date (BUD) and expiration date may sound interchangeable, they are not the same. Both BUDs and expiration dates provide information about the duration of a medication’s usability, but there are key differences between the two that can play an important role in patient outcomes and purchasing decisions.
The Importance of Drug Stability
Drug stability refers to a drug product retaining its key properties—including active ingredient strength as noted on its label and sterility, if applicable—within a set tolerance range, from its time of preparation until it reaches its BUD or expiration date.
Stability depends on a variety of factors including the type of drug and its degradation rate, drug dosage, preservatives used, container integrity, the likelihood of any level of contamination occurring during manufacturing, and storage conditions.
Unstable veterinary medications can pose multiple problems including:
- Degradation of the active ingredient.
- An increased concentration of the active ingredient.
- Drug contamination during distribution or storage as a result of impaired packaging integrity.
- Changes in the drug’s bioavailability, altering the rate and amount of medication absorbed by the patient.
- Development of toxic byproducts due to the breakdown of one or more of the drug’s components.
Beyond-Use Date vs. Expiration Date
To avoid the health risks and other issues resulting from the use of unstable veterinary medications, practitioners and pet owners alike rely on the date provided on a medication’s label, the BUD or the expiration date, to inform them of how long a medication will remain stable and can be safely used. BUDs and expiration dates differ considerably though in terms of the quality of information they provide, so it’s helpful to understand the differences between them.
503A Compounding Pharmacies – Beyond-Use Date
Traditional compounding pharmacies, also referred to as 503A pharmacies, modify medications to fill individual, patient-specific prescriptions. Medication alterations can include combining two or more drugs together, dosage modifications, adding flavorings palpable to the patient, and other changes as needed for the patient. 503A pharmacies label their products with a BUD, not an expiration date.
503A pharmacies determine BUDs in compliance with the requirements set by the United States Pharmacopeia (USP). BUDs are calculated based on the date of compounding, and USP Chapter <795> defines the BUD for non-sterile products as the date beyond which the non-sterile compound should not be used, and USP Chapter <797> states the BUD for sterile compounds as the time or date beyond which a sterile compound may not be administered, stored, or transported. BUDs are typically short, often spanning only a few days or months.
In an ideal situation, BUDs are assigned based on testing conducted by the 503A pharmacy; however, under USP guidelines, these pharmacies are not required to conduct stability testing, and many 503A pharmacies lack the resources to support a rigorous testing program for the small batch sizes they produce. This presents a problem because many instabilities can only be identified using analytic equipment.
Even in compounding pharmacies that do conduct their own testing, it is often limited to strength-over-time testing. With this type of analysis, unwanted chemicals that may have developed due to drug degradation, preservatives, and other substances are not separated from the active ingredient during testing, so the results are not a reliable indicator of stability.
In place of stability testing, 503A compounding pharmacies often rely the following to establish the BUD:
- Manufacturer recommendations
- Published clinical literature
- Limits set by the USP
However, variances in formulation, container/closure system, and storage conditions between the medication the compounding pharmacy is altering and the reference drug that has undergone stability testing can result in an inaccurate BUD. A lack of proven stability at the time of compounding and throughout the medication’s use are the tradeoffs that often come with the highly customized, patient-specific prescriptions available through 503A pharmacies.
Overall, it’s important to keep in mind that a compounded medication’s BUD:
- Often represents a compounding pharmacy’s educated guess as to how long a veterinary medication will remain stable.
- Usually is not verified through testing.
- Has an accuracy level that will vary depending on the pharmacy’s processes and the quality of training it provides its staff.
As a result, researching and verifying a 503A compounding pharmacy’s reputation is key in situations where a needed medication cannot be sourced from a commercial drug manufacturer or a 503B outsourcing facility.
503B Outsourcing Facilities – Expiration Date Advantage
Unlike 503A compounding pharmacies, 503B outsourcing facilities such as Epicur, which manufacture larger batches of compounded veterinary medications customized to clinic and hospital needs, are allowed to assign expiration dates to their compounded products.
An expiration date indicates when the strength and/or safety of a medication can no longer be guaranteed by the manufacturer. In contrast with BUDs, expiration dates can be assigned only after extensive product stability testing. 503B outsourcing facilities must have a thorough stability testing program in place that complies with the Food and Drug Administration’s (FDA) cGMP regulations (21 CFR Parts 210 and 211), and typically adheres to the International Council for Harmonisation (ICH) guideline Q1A(R2), as recommended by the FDA. The purpose of stability testing, as noted by the ICH, is to determine “how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity and light.”
Some of the most important tests conducted are:
- Long-term and accelerated testing – The compounded drug is studied for 12 months under expected storage conditions (long-term) and for six months in conditions that exceed the recommended limits for temperature and humidity (accelerated). The results are used to determine shelf-life and recommended storage conditions.
- Stress testing – Includes exposing the compounded drug to temperatures and humidity extremes that exceed those used in accelerated testing to assess the degradation products, or impurities, that develop.
- Container closure integrity testing – The compounded product is assessed to ensure it remains stable and sterile, if applicable, in its intended packaging.
As a result of the extensive stability testing conducted, there are several benefits to procuring manufactured veterinary medications from a 503B drug manufacturer:
- Every product line undergoes stability testing, increasing confidence that the drug will remain stable through its expiration date and is safe to use. Any changes to a product line, including formulation or container, requires new stability studies to be performed.
- Factors that could impact the effectiveness of the medication, such as impurities resulting from the material of the container, are addressed and eliminated during stability testing, improving treatment effectiveness and patient outcomes.
- Expiration dates often extend beyond the timeframe of a BUD, making it easier for clinics and hospitals to have customized medications on hand to meet patient needs.
A veterinary medication’s stability is critical to ensuring its safety, quality, and efficacy and plays an important role in safeguarding patient well-being.
Are you confidently prescribing the best medication for your patients?