Implementing new regulations is rarely a painless process. Even with extensive preparation, applying new rules to complex pharmacy processes almost always raises some thorny issues. With the changes to USP <797>, common concerns include: When does the beyond-use date (BUD) clock start ticking? Should infusion time (also known as hang time) be incorporated into the BUD? What is the impact of BUD on tubing changes? Incorrect answers to these questions can lead to unnecessary waste, patient care disruptions, and frequent exchanging of bags, which increases the risk of error and contamination.

To correctly answer these questions, it is important to define the terms used in the regulations including their source, which ultimately determines the applicability to practice. Consider terms addressing when a product can be used and when it must be discarded, such as BUD or infusion time. Because BUD is defined within USP <797>, a standard for compounding of sterile preparations, it only applies through compounding and up to the time of administration, at which point the standard no longer applies.

A misunderstanding of such technicalities can lead to inappropriate interpretation of the terms, especially when communicating across different professions (eg, from pharmacy to nursing). For example, pharmacy compounders generally communicate the BUD of a CSP on its final label, and if the label identifies this as an expiration date, it could lead to confusion and inappropriate actions by administering practitioners. Thus, it is imperative that pharmacy personnel have a clear understanding of use times of CSPs and their components.

Compounding vs Preparation

In USP <797>, sterile compounding is defined as “the process of combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug product or bulk drug substance to create a sterile preparation.”1 This is a slightly different definition than the FDA’s: “the process of combining, mixing, or altering ingredients to create a medication tailored to the needs of an individual patient.”2 Most state regulations include a definition of compounding, which may rely on the USP or FDA definition or use state-specific wording. Removal of a sterile product or preparation and placement into a different container is often termed repackaging, but is actually compounding since the drug, diluent, containers, and closure system must all comply with the USP <797> standard.3

USP <797> includes a section on “preparation per approved labeling” that highlights the activity of preparing a conventionally manufactured sterile product in accordance with the directions in the approved labeling, which is outside the scope of USP <797> if certain conditions are met (see FIGURE 1). However, detailed instruction in the package insert must include information for the diluent, the resulting strength, the container closure system, and the storage time (see FIGURE 2). Additionally, this applies only when preparing a single dose for a single patient. Unfortunately, apart from some newer agents, few package inserts include all the required information.

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Defining Expiry of CSPs

There are significant nuances among the various terms used to define the expiry of a product (see TABLE 1). Further, most health systems limit their compounding to USP <797> Category 1 and 2 using aseptic processing without performing sterility testing, which limits the BUD by storage condition (see TABLE 2).

BUDs must incorporate the stability of the drug, diluent, container, and closure system as well as the maximum BUD permitted by <797>, which is primarily limited by sterility assurance. A more conservative BUD may need to be assigned based on the limits from <797>, in-use time listed in product labeling, or specific situations that may be addressed in organizational policies.

The allowable BUDs for proprietary vial and bag systems differ from other CSPs since these point-of-care systems are FDA-approved or cleared devices. It is important for compounders to review the approved labeling of the specific system to ensure the drug meets the requirements for use with the system (eg, vial septum diameter) and the appropriate beyond-use date if storing drugs docked for future activation. USP <797> differentiates that practice (which is considered compounding) from the situations where a nurse or other clinician attaches and activates the vial/bag for immediate administration (which is not considered compounding). Some manufacturers have performed additional studies on the stability of drugs using the system after activation and before administration. Note that the allowance for storing the attached (but not activated) units is based on the docking manipulation performed under ISO class 5 using aseptic technique. This may be accomplished in a primary engineering control either in a buffer room of a cleanroom suite or in a segregated compounding area. In either case, the proprietary bag and vial system manufacturer’s BUD listed in the product labeling may be used.

CSP Components

Sterile compounding encompasses a variety of dosage forms, including base solutions (LVPs, SVPs, irrigations), vials (single-dose, multiple-dose, pharmacy bulk packages, imaging bulk packages), and others such as ophthalmics. For compounders, it is key to recognize the manufacturer’s intended use of the dosage form and appropriate routes of administration as outlined in the approved labeling.

Approved labeling may indicate a specific BUD or in-use time once the vial or package is opened or the contents are accessed. Further, the approved labeling may indicate a BUD or in-use time once the contents are further diluted and/or added to a final CSP.

• Large Volume Parenteral (LVP): Sterile solutions intended for administration in relatively large volumes, more than 100 mL.
• Small Volume Parenteral (SVP): Sterile solutions intended for intravenous administration in smaller volumes, 100 mL or less.
• Irrigations: Sterile solutions designed for various types of irrigation, including wound, eye, or bladder irrigation. They are not suitable for parenteral routes of administration as they are formulated with a different level of sterility assurance than parenteral solutions using less stringent sterilization or filtration processes and may contain small particulate matter, which is generally acceptable for their intended external or local use.
• Single-Dose Vial (SDV): Containers that are intended to supply a single dose of medication and are meant for one-time use. They generally do not contain preservatives.
• Multiple-Dose Vial (MDV): Containers designed to hold multiple doses of a medication. They may have a rubber stopper that is designed to be pierced multiple times for withdrawal of doses. They generally contain preservatives.
• Pharmacy Bulk Package (PBP): Containers that hold a large quantity of drug intended for further compounding or repackaging. They are not intended for direct patient use and should only be used for compounding purposes.
• Imaging Bulk Package (IBP): Containers that hold a large quantity of contrast agents for use in medical imaging procedures, such as CT scans or MRIs.

Defining In-Use Time

It is notable that the term in-use time is not used within USP <797>; however, it frequently appears in FDA guidance documents and in conventionally manufactured drug products’ approved labeling. The FDA defines in-use time as “the maximum amount of time that can be allowed to elapse between penetration of a container-closure system containing a sterile drug product, or after a lyophilized drug product has been reconstituted, and before patient administration.”⁵ Despite the FDA’s definition, manufacturers often describe this time period inconsistently, as they may or may not include storage after dilution or administration in their usage.

Therefore, whenever assessing an in-use time for a conventionally manufactured drug product, it is prudent to determine the context in which the term is being applied (see TABLE 3).

In-use time can be confusing as it may refer only to the storage of a penetrated single-dose vial (A), a compounded sterile preparation (B), or administration time (C). However, manufacturers may also specify a combination of these time periods (A+B or A+B+C). It is important to recognize the context and application of the given use time based on the activity and follow appropriate actions if the in-use time is reached prior to applicable additional actions (eg, the start of administration).

Defining the BUD’s End Point

Think of the BUD as a storage time: from the point the CSP mixing begins until the point when administration to the patient begins. With the onset of administration, the BUD no longer applies, and the health system policy must establish the allowance for infusion time.

There is no nationally accepted length of allowable infusion time for most IV fluids. The Center for Disease Control and Prevention (CDC)’s Guidelines for the Prevention of Intravascular Catheter-Related Infections, 2011 provides some information concerning replacing IV administration sets but has no recommendations on the infusion time for the majority of IV fluids.⁶ The Infusion Therapy Standards of Practice, 8th edition, 2021 from the Infusion Nurses Society (INS) provides additional detail and uses the CDC recommendations as the basis for their standards.⁷ However, they also do not detail specific guidance for infusion time.

CDC recommendations are categorized based on existing scientific data, theoretical rationale, applicability, and economic impact. CDC has a standard method of listing recommendations, and their guidance regarding IV tubing changes (note: not infusion time) includes those in Category 1A, Category 1B, and unresolved issues.6

• Category 1A Recommendations: strongly recommended for implementation and strongly supported by well-designed experimental, clinical, or epidemiologic studies
• Category 1B Recommendations: strongly recommended for implementation and supported by some experimental, clinical, or epidemiologic studies and a strong theoretical rationale; or an accepted practice (eg, aseptic technique) supported by limited evidence
• Unresolved Issue: for which evidence is insufficient or no consensus regarding efficacy exists

The previous version of the CDC document (from 2002) contained an appendix summarizing recommendations, including limited information on infusion time of IV solutions.8 Though no longer included in the current document, it does serve to provide some guidance for policy development.

Recommendations from the CDC and the INS include:6,7

• Manufacturers’ recommendations should be followed for specific medications
• Parenteral nutrition (with or without fat) infusion time should not exceed 24 hours
• Fat emulsion infusion time should not exceed 24 hours
  • Note: The INS standards limit fat emulsion hang time to 12 hours
• Propofol infusion time should not exceed the manufacturer’s recommendations (which vary based on manufacturer) and should be changed at the same time as the tubing
• Tubing changes are listed in the CDC recommendations:
  • In patients NOT receiving blood, blood products, or fat emulsions, replace administration sets that are continuously used, including secondary sets and add-on devices, no more frequently than at 96-hour intervals but at least every 7 days. This is a Category 1A recommendation.
  • Replace tubing used to administer blood, blood products, or fat emulsion within 24 hours of initiating the infusion. This is a Category 1B recommendation.
  • Replace tubing used to administer propofol infusions every 6 or 12 hours, when the vial is changed, per the manufacturer’s recommendations. This is a Category 1A recommendation.

Clarifying Expiry on the Label

Expiration date and time is commonly entered on pharmacy labels, but confusion exists: Is that the time by which the IV must be started? If the expiry occurs during the time the infusion bag is hanging, must it be removed? The organization should establish common wording to address all situations encountered.

Misleading Terms:

• Expires
• Use by
• Administer by

Improved Terms:

• Start administration by
• Spike by

For certain short-stability CSPs that are infused over long periods of time (ie, continuous infusions), there may be situations wherein the product reaches its expiration during the infusion time. In this uncommon situation, the container would need to be discarded and replaced with a new infusion. In such a scenario, the pharmacy compounder may consider compounding and dispensing smaller aliquots of the medication to prevent this from occurring. Further, these medications should include proper labeling to differentiate the expiration date from a BUD, and to clarify what actions are needed when the time is reached. This may not apply to CSPs that are administered over short time frames only (ie, intermittent infusions).

Applying the Definitions

Each of the terms reviewed herein may be seen as a timeline or spectrum from the moment a vial is penetrated, through compounding, and through administration. Fentanyl citrate for infusion is an excellent example that ties these terms together (see FIGURE 3).

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Fentanyl is supplied as a 2,500 mcg/50 mL single-dose vial.⁹ The package insert of the fentanyl vial does not specify an in-use time of the vial once penetrated; therefore, a 12-hour room temperature discard time can be applied following USP <797>. This time frame identifies that compounding must be initiated within this 12-hour period, or any remnants in the vial must be discarded. A stability-indicating method study demonstrates that diluting fentanyl citrate 2,500 mcg in 250 mL of 0.9% sodium chloride for injection has a 93-day controlled room temperature stability when stored in polyolefin bags.¹⁰ Following USP <797> Category 2 conditions, using all sterile starting components and not performing a sterility test allows a maximum BUD of 4 days at controlled room temperature. This time frame identifies the storage of the CSP and when administration must begin, or the CSP must be discarded. Once administration starts, the infusion time may be up to a maximum of 96 hours to allow the medication to infuse, or when a line change occurs, or the when the limits of the organizational policy are reached. If the administration is not complete when this time period is reached, the bag should be replaced and discarded.

Conclusion

It is key to develop an organizational policy that takes a holistic, interdisciplinary approach to establishing appropriate medication dating requirements from compounding through manipulation, administration, and the ultimate wasting of any remaining product. To begin, a health system committee should review national recommendations (such as those from the CDC and INS) against the procedures performed in the organization. The organization should address the tubing change guidance in the CDC recommendations and determine if the IV infusion time should match or differ from the tubing change time policy. Finally, the organization should identify a list of short-stability CSPs, which may require custom use-times and/or specific labeling that differs from other CSPs.

It is common for organizations to establish different allowances for infusion time based on the level of infection risk:

• In emergencies (eg, in the field, during a code, etc)
• For immediate use (outside of ISO Class 5 primary engineering controls)
• Pharmacy compounded (under USP <797> compliant conditions)
• Manufacturers’ plain or premixed solutions (with no additions to the fluid)

Many organizations establish a policy to change continuous infusion CSPs prepared and started in emergency situations as soon as possible after the patient is stabilized, or for those prepared under the immediate use provision of USP <797> within 24 hours. While these approaches are not required, if they are utilized, each should be clearly outlined in policy and operationalized appropriately. Some organizations permit longer infusion times for manufactured (plain and premixed) IVs than they do for pharmacy prepared sterile preparations (ie, 96 hours). Conversely, some organizations may elect to require shorter infusion times be applied to all applicable products or preparations (eg, 24 hours). See FIGURE 4 for an example of a policy statement that can be used to address allowable infusion times for an organization.

Kevin Hansen, PharmD, MS, BCSCP, is the pharmacy director, 503B program at Premier Inc. He earned his doctor of pharmacy degree from LECOM, completed a PGY1/PGY2/MS health-system pharmacy administration and leadership residency program at the University of North Carolina Medical Center, and is a board certified sterile compounding pharmacist.

Patricia C. Kienle, RPh, MPA, BCSCP, FASHP, is the director of accreditation and medication safety for Cardinal Health. She received her pharmacy degree from the Philadelphia College of Pharmacy and Science and a master’s in public administration from Marywood University in Scranton, Pennsylvania.

References

1. United States Pharmacopeial Convention. USP General Chapter <797> Pharmaceutical Compounding—Sterile Preparations. www.usp.org/compounding/general-chapter-79. Accessed November 28, 2023.
2. US Food & Drug Administration. Compounding and the FDA: Questions and Answers. www.fda.gov/media/90978/download. Updated June 29, 2022. Accessed November 28, 2023.
3. US Food and Drug Administration. Repackaging of Certain Human Drug Products by Pharmacies and Outsourcing Facilities. www.fda.gov/media/90978/download. Published January 2017. Accessed November 29, 2023.
4. Daptomycin [package insert]. Lexington, MA: Cubist Pharmaceuticals; 2011.
5. US Food and Drug Administration. Information for Health Care Facilities and Providers on “in-use time” | COVID-19. www.fda.gov/drugs/coronavirus-covid-19-drugs/information-health-care-facilities-and-providers-use-time-covid-19. Updated August 4, 2020. Accessed November 29, 2023.
6. Centers for Disease Control and Prevention. Guidelines for the Prevention of Intravascular Catheter-Related Infections, 2011. www.cdc.gov/infectioncontrol/pdf/guidelines/bsi-guidelines-H.pdf. Updated October 2017. Accessed November 29, 2023.
7. Gorski LA, et al. Infusion Therapy Standards of Practice. 2021;44(4).
8. Morbidity and Mortality Weekly Report (MMWR). Erratum: Vol. 51, No. RR-10. www.cdc.gov/mmwr/preview/mmwrhtml/mm5132a9.htm. Published August 15, 2002. Accessed November 29, 2023.
9. Fentanyl [package insert]. Lake Forest, IL: Hospira, Inc.; 2016.
10. Donnell RF. Stability of Fentanyl Citrate in Polyolefin Bags. Int J Pharm Compd. 2016;20(6):514-516.