Assigning a Beyond-Use Date

Beyond-use dates are different from expiration dates.  Expiration dates are required on commercially manufactured products and are determined after extensive study of the product's stability. Most expiration dates are given in years for commercial products. Beyond-use dates are used for compounded preparations and are generally in days or months.

The major problem for pharmacists is that the stability of compounded formulations often is not known. Also,

• Many instabilities cannot be detected without the use of analytic equipment. This is in contrast to incompatibilities that can be visually observed.
• It is not possible to use a manufacturer's expiration date and extrapolate or estimate a beyond-use date for a compounded formulation. The compounded formulation probably will not be identical to the manufactured product; it may have a different drug concentration, use different diluents, be a different fill volume, and be packaged in a different container type.

If the compounded formulation is an official monograph in the USP/NF, the beyond-use date given in the monograph can be used provided the procedure in the monograph was followed.

When an official monograph isn't present, a systematic approach to assigning the date can be as follows:

Step 1. Beyond-use dates should be in accordance with the manufacturer’s approved labeling. This means that the product was formulated according to the manufacturer’s directions, or that the formulation contains the same concentration of drug, in the same diluent, in the same packaging, for the same intended period of use, and so on.

Step 2. When this is not possible, a pharmacist ideally consults with the manufacturer to establish a beyond-use date. The USP/NF Section <1206> Sterile Drug Products for Home Use, Storage and Beyond-Use Dating directs that:

"Where possible, the beyond-use date should be in accordance with allowances specified in the approved labeling. However, reliable, published stability information is sometimes lacking for many types of drugs. In these instances, pharmacists should consult with the drug’s manufacturer to establish a beyond-use date. Because of compelling patient-care needs, a pharmacist may be unable to stay within the approved labeling and product guidelines stated in the package insert. For example, a higher concentration of drug may be prescribed; different diluent, container, etc., may be necessary; or the patient may require the HSD for longer periods of time. The pharmacist should communicate the deviations from the package insert to the manufacturer when requesting stability information. Otherwise, the pharmacist should ensure that the manufacturer’s stability information is product specific, that is, the exact strength, diluent, fill volume, and container type (PVC bag, plastic syringe, elastomeric infusion device, etc.) will be used by the pharmacist when preparing the HSD. Pharmacists should obtain a letter from the manufacturer certifying the beyond-use dating period provided."

Step 3. If the manufacturer cannot assist in assigning a beyond-use date, the next step is to obtain published stability information from reference books or the primary literature. Direct extrapolation of the information to the specific compounded formulation requires that the scientific study data utilize the same drug source, the same drug concentration, and the same compounding procedures, stores the formulation in the same container, and has subjected the formulation to the same anticipated environmental variables.

A growing number of reference sources contain stability information, and the pharmacist should have ready access to this material. Some of the more common resources are:

• Trissel’s Stability of Compounded Formulations
• Trissel’s Handbook of Injectable Drugs
• AHFS Drug Information
• United States Pharmacopeia
• Remington: The Science and Practice of Pharmacy
• USP Dispensing Information
• Journal of Pharmaceutical Sciences
• American Journal of Health-System Pharmacy
• International Journal of Pharmaceutical Compounding
• Thompson's A Practical Guide to Contemporary Pharmacy Practice
  

Step 4. Many times the published references do not evaluate exactly the same formulation, or the study did not examine the stability for a long enough period of time. In other words, the evidence is not from a product-specific experiment. In this case, the USP24/NF19 Section <795> gives the following maximum recommended beyond-use dates for nonsterile compounded drug preparations packaged in tight, light-resistant containers when stored at controlled room temperature, unless otherwise noted.

Nonaqueous liquids and solid formulations:

• If the source of the ingredient(s) is a manufactured drug product, the beyond-use date is not later than 25% of the time remaining until the original product’s expiration date, or 6 months, whichever is earlier.
• If the source of the ingredient(s) is a USP or NF substance, the beyond-use date is not later than 6 months.

Water containing formulations:

• When prepared from ingredients in solid form, the beyond-use date should be not later than 14 days when stored at cold temperature.

For all other formulations:

• The beyond-use date is not later than the intended duration of therapy or 30 days, whichever is earlier.

The USP24/NF19 <1206> recommends that written policies and procedures be established for determining and documenting the beyond-use dates assigned to its compounded products. As part of these policies and procedures, additional information that should be included is

• Copies of product specific stability studies based on a stability indicating analytical procedure
  
• Copies of letters from manufacturers certifying the beyond-use dating
• Predictive materials such as publications, charts, and tables
• In-house quality control data collected for compounded formulations