Controlled Environment Professionals Serving USP <797> Customers Need to Understand Beyond Use Dating

Controlled environment professionals are responsible for collecting most of the viable air and surface samples in 503A sterile compounding organizations. This means that in the event of a microbial excursion, the sterile compounding organization is most likely going to contact the servicing company for guidance on next steps.

This typically gets handled in two different ways.

1. The servicing company passes the call onto their contract lab, where a microbiologist speaks directly with the customer about what was recovered.
2. The servicing company calls the lab and speaks with a microbiologist about what was recovered and then follows up with the customer.

In either case, the customer usually asks whether they should shorten beyond-use dates (BUDs) based on the number and type of microorganisms recovered. Having worked at a contract lab, this is typically an area where the lab bows out and doesn’t make any recommendations, leaving both scenarios with the servicing company to discuss with the customer. But this does not mean the servicing company should be telling the sterile compounding organization what to assign as a BUD.

It is the sterile compounding organization’s responsibility to determine BUDs and if they are not following the minimum standards of the chapter, they need to apply more conservative dating. However, the servicing company can provide some valuable insight if its personnel are familiar with BUDs, compounding risk levels, and now the new compounding categories.

So, what are BUDs? USP 797 (2021) defines BUD as “either the date, or hour and date, after which a compounded sterile preparation (CSP) must not be used. The BUD is determined from the date and time that preparation of the CSP is initiated.”¹ It does not include administration time. For example, if an IV bag is prepared for a patient with a BUD of 10:00 pm, January 10, 2022, administration to the patient must be started by 10:00 pm, January 10, 2022. Administration does not need to be completed by this time.

Let’s look to USP 797 for the criteria used to determine BUDs. Looking at the current version of the chapter, which became effective in 2008, BUDs are based on compounding risk levels. You probably have a good understanding of the risk levels, since they have been the standard for 14 years. There are essentially 5 risk levels.

Table 1. includes risk level, what defines the risk level, where compounding occurs, and the possible beyond-use dating.

Instead of risk levels, the 2021 version of USP 797 has categories. With the release of the 2019 version of the chapter, we saw 2 compounding categories. Based on the appeals³ received by USP, it was evident they needed to add another compounding category.⁴ The categories are based on where a preparation is compounded, the compounding methods, and if sterility testing will be performed.

Table 2. Compounding Categories According to USP 797 (2021)¹

At this point, you are probably wondering where this is going. After reviewing the tables, you likely noticed that there is beyond-use dating for preparations made in a segregated compounding area (SCA) for both the 2008 and 2021 versions of the chapter. And you’ve probably heard of sterile compounding organizations dropping to 12-hour BUD after an excursion. This is because if they have an excursion in the cleanroom suite, it has sometimes been interpreted that they are essentially compounding in an SCA, because they lost their state of microbial control. This may make sense depending on what and how many organisms were recovered. However, it’s likely an extreme response, especially for first-time excursions and it may not be practical for patient care. So, what are they to do?  How can you help? There is no one-size-fits-all answer, and the actions taken will be excursion specific. But, understanding how BUDs work and being armed with a few basic points will allow you to point them in the right direction.

Points to Remember When Discussing Excursions with Customers Adapted From USP Chapter <1116>⁵

• Aseptic and sterile are not the same. Sterile means having a complete absence of viable microorganisms or organisms. Aseptic processing prevents contamination by the exclusion of microorganisms. Even though it’s called sterile compounding, the goal is a sterile preparation, but the process itself is aseptic. 
• People are present in the sterile compounding environment; therefore, microbial contamination is expected. Staphylococcus, Micrococcus, and Corynebacterium species are going to be recovered from viable air and surface samples at some point in time for every sterile compounding organization. With these types of microorganisms, it’s the number recovered that matters. There is less concern when 11 CFU/m³ are recovered in an ISO Class 7 buffer room than when 60 CFU/m³ are recovered in that same room. Even though both exceed the >10CFU/m³ action level, the investigations and corrective actions will be very different. Keep in mind, based on the 2008 version of the chapter, if a coagulase-positive Staphylococcus species is recovered, regardless of the number, the recovery must be immediately remedied.
• Sample locations below the action level does not guarantee microbial control. For example, consistent recovery of the same microorganism in the buffer room by the PEC, even under the action level, could be a cause for concern. The opposite is also true. Excursions beyond the action levels or the recovery of “highly pathogenic organisms” does not necessarily indicate a loss of control. The best example of this is 1 colony-forming unit (CFU) of mold recovered in the anteroom. Even though this must be investigated based on the 2008 version of USP 797, it does not mean the entire cleanroom suite is unfit for sterile compounding. In both scenarios, trending CFUs recovered, types of microorganisms, and frequency of recovery all aid in the development of a reasonable corrective action plan.

As part of the BUD conversation with your customer, you need to know the history of the sampling location(s) with excursions. If you’re not trending data for them, be sure you refer to the last few reports. Depending on the type and number of microorganisms recovered, having a microbiologist on the call is valuable, especially if the discussion regarding what was recovered has not yet occurred. Table 3. provides some general guidance on BUD adjustments for both first-time excursions and repeat excursions. It will still be up to the sterile compounding organization to decide on the BUDs.

Table 3. General Guidance on BUD Adjustments Associated with Microbial Excursions

This table can be a useful resource, but it must be used in conjunction with current data, past data, and overall facility compliance with USP 797. When in doubt about the best advice to give, recommend that the customer discuss the excursion with an industry subject matter expert or their State Board of Pharmacy inspector.  

Because controlled environment professionals are an integral part of a sterile compounding organization’s viable sampling program, the education of these professionals is essential to good customer service. In many cases, one or two individuals will have the responsibility of aiding their sterile compounding customers through an exceeded action investigation. Having a basic understanding of BUDs will facilitate discussion with customers and ensure the servicing company is providing appropriate guidance.

References

1. United States Pharmacopeial Convention, Inc. <797> Pharmaceutical Compounding—Sterile Preparations. Proposed 2021 version.
2. United States Pharmacopeial Convention, Inc. <797> Pharmaceutical Compounding—Sterile Preparations. 2008 version.
3. United States Pharmacopeial Convention, Inc. Appeals Panel Decisions on USP <795>, <797>, and <825>. March 12, 2020.
4. United States Pharmacopeial Convention, Inc. Compounding Expert Committee Responses to Stakeholder Engagement Themes for the 2021 Proposed Revisions to <797>. September 1, 2021.
5. United States Pharmacopeial Convention, Inc. <1116> Microbiological Control and Monitoring of Aseptic Processing Environments. USP43-NF38.