Beyond-Use Dating for Sterile Compounding


June 2021 - Vol.18 No. 6 - Page #8

Q&A with Lee Murdaugh, BS Pharm, PhD

Director of Accreditation and Medication Safety

Cardinal Health

 

Beyond-use dating can be a key component to waste reduction efforts in the pharmacy, yet it must be applied carefully and strategically to ensure patient safety. Determining the beyond-use date (BUD) for compounded sterile preparations (CSPs) can seem complex—given the many factors that need to be accounted for, including stability, sterility, and storage. However, through a combination of compliant testing, well-crafted standard operating procedures (SOPs), and thorough documentation, it is possible to adopt best practices that demystify and streamline the BUD process.

Pharmacy Purchasing and Products: What are some of the factors that impact the assignment of BUDs?

Lee Murdaugh: There are a wide variety of factors that can impact BUD determinations for CSPs including, but not limited to:

  • The compounding environment, such as ISO Class 5 primary engineering control (PEC) in a cleanroom suite, ISO Class 5 PEC in a segregated compounding area, or a non-controlled environment for immediate use
  • Stability and compatibility of all components of a CSP including drugs, containers or devices, and closure systems
  • Initial quality of the ingredients and devices used (ie, sterile vs non-sterile)
  • Complexity of preparation (eg, number and types of manipulations, preparation time, equipment used)
  • Aseptic processing and sterilization method (eg, aseptic preparation using filtration, terminal sterilization via autoclaving)
  • Storage conditions (eg, temperature, duration)
  • Use of a USP monograph for a specific formulation

PP&P: What evidence-based data is available to aid in BUD decisions?

Murdaugh: Various evidence-based resources are available to assist in determining BUDs, several of which are specifically dedicated to determining the stability of a CSP. Information from manufacturers of the ingredients (eg, package insert or other written documentation), compendial references (eg, ASHP’s Handbook of Injectable Drugs, King’s Guide to Parenteral Admixtures, Bing/Nowobiliski-Vasilios’s Extended Stability for Parenteral Drugs), as well as peer-reviewed studies using appropriate stability-indicating testing methods, may all be used to establish stability information. However, when using information from these sources, it is important to ensure that you are using the same type and concentration of ingredients (including diluents and IV fluids), container and closure systems, and storage conditions as noted in the source.

Nonetheless, stability alone does not determine a BUD. Both stability and sterility must be considered. The BUD is determined by the shorter of the stability dating or sterility dating (ie, the maximum BUDs in USP <797> or direct sterility testing of each batch compounded).

PP&P: What is the best way to utilize sterility, potency, and endotoxin testing?

Murdaugh: In addition to stability testing, sterility, potency, and endotoxin test results also serve to support BUD determinations. In fact, there are several scenarios in which <797> mandates these tests be performed.

Sterility Testing

Under USP <797>, sterility testing must be performed for the following high-risk level preparations (eg, those compounded using non-sterile components):

  • Batches of more than 25 identical preparations
  • Multiple dose vials for administration to multiple patients
  • Preparations exposed to temperatures from 2°C to 8°C for more than 12 hours before sterilization
  • Preparations exposed to temperatures greater than 8°C for more than 6 hours before sterilization

In addition, if BUDs are used that exceed those specified in USP <797>, sterility testing must be performed, regardless of the risk level of the preparation (ie, low-, medium-, high-risk). Testing must be performed for each group of preparations compounded following the requirements in USP <71> Sterility Tests.

Endotoxin Testing

USP <797> requires that endotoxin testing be performed for the following high-risk level preparations (eg, those compounded using non-sterile components), excluding ophthalmic and inhalation preparations:

  • Batches of more than 25 identical preparations
  • Multiple dose vials for administration to multiple patients
  • Preparations exposed to temperatures of 2°C to 8°C for more than 12 hours before sterilization
  • Preparations exposed to temperatures greater than 8°C for more than 6 hours before sterilization

Testing must be performed for each group of preparations compounded and meet the requirements in USP <85> Bacterial Endotoxins Test.

Potency Testing

Potency testing is used to determine the concentration (strength) of the active ingredients in a preparation. This testing should be performed for non-sterile to sterile CSPs to establish the concentration of the active pharmaceutical ingredients (API) for the compounding formulation. If the type of the API or manufacturer of the API is changed, the test should be performed again to verify the concentration of the API in the compounding formulation.

PP&P: What SOPs are recommended for quality control testing?

Murdaugh: SOPs for quality control tests should be customized to the specific type of testing being performed. Nonetheless, each SOP should include the following:

  • What to test
  • When to test
  • Where testing is performed (ie, environmental conditions)
  • Testing method and procedures
  • Equipment, devices, supplies, and other components needed
  • Selection of sample size and number of samples to be collected
  • Sample collection, preparation, and purification requirements
  • Storage and transport of samples for analysis including container type, temperature, humidity, and light protection
  • Acceptance criteria for the type of preparation(s) tested
  • Actions required when specifications are not met, or deviations occur
  • Required documentation
  • Training, competency evaluation, and qualifications of personnel performing the test, including laboratory personnel

PP&P: How do you interpret the results of these additional tests?

Murdaugh: Results must meet the acceptance criteria for the test as specified in applicable general chapters, monographs, or General Notices found in the United States Pharmacopeia-National Formulary (USP-NF). Use appropriate statistics (eg, mean, standard deviation) in data analysis and reference values if reference standards are used in testing.

PP&P: How do you document these practices?

Murdaugh: Documentation of testing is a crucial element of any compounding process, yet all too often it does not receive sufficient attention. Consider that easily accessible, thorough documentation will facilitate consistent compounding processes and provide crucial information to aid in evaluation of any problems with the preparation. Recommended documentation should include:

  • Written policies and procedures for the determination of BUDs
  • References to support the assigned BUDs
  • Master formulation records that contain the essential information needed to compound the preparation, including:
    • Name, strength, dosage form of preparation
    • Identities and amounts of all ingredients
    • Type and size of container and closure system(s)
    • Complete instructions for preparing the CSP including equipment, supplies, a description of compounding steps, and any special precautions
    • Physical description of the final CSP
    • BUD and storage requirements
    • Reference source to support the stability of the CSP
    • Quality control testing and procedures
    • Other information needed to describe the compounding process and ensure repeatability (eg, adjusting pH/tonicity, sterilization method)
  • Documentation of in-process and end-point monitoring, checks, and testing
  • Compounding records
  • Information on the quality testing methodologies used
  • Information supporting the quality of the components used (eg, certificate of analysis)
  • Results of quality testing

PP&P: What additional issues have the potential to impact BUD assignments?

Murdaugh: Depending on your location, some state boards of pharmacy and departments of health have more stringent requirements regarding compounding sterile preparations, which encompass the assignment of BUDs and required quality control testing. It is important to be aware of and follow state requirements, especially if such requirements are more stringent than USP standards.

In April 2020, USP developed interim operational guidance for sterile compounding to address the challenges presented by the public health emergency due to the COVID-19 pandemic, such as shortages of essential medications and supplies. The guidance includes BUDs that may be used, provided that re-use of personal protective equipment follows the USP Response to Shortages of Garb and Personal Protective Equipment (PPE) for Low and Medium-Risk Sterile Compounding During COVID-19 Pandemic, that the compounding complies with all other requirements in the current USP <797>, and considerations are given to increased frequency of personnel monitoring and surface sampling. The details can be found in the guidance document, Operational Considerations for Sterile Compounding During COVID-19 Pandemic, at www.usp.org/compounding.

Before adopting this policy, verify with your state pharmacy board and other regulatory agencies (eg, departments of health) that the use of these guidance recommendations is allowed in your state. Furthermore, note that the recommendations in the USP interim guidance document are not USP standards and are intended for use only during the designated public health emergency period. When the emergency is lifted, regulatory bodies and accreditation organizations will expect BUDs to be assigned as required in the current official version of USP <797> (2008).

Ultimately, the assignment of BUDs should always follow a conservative path in order to minimize risks to patient safety.


Lee Murdaugh, BS Pharm, PhD, is director of accreditation and medication safety for Cardinal Health. She is the author and editor of the American Society of Health-System Pharmacists (ASHP) publication Competence Assessment Tools for Health-System Pharmacies and co-author of Assuring Continuous Compliance with Joint Commission Standards: A Pharmacy Guide.

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