In accordance with the March 2020 decision by USP to remand the 2019 revisions of General Chapters <795> Pharmaceutical Compounding – Nonsterile Preparations and <797> Pharmaceutical Compounding – Sterile Preparations, the USP is committed to gathering stakeholder feedback and proceeding in a transparent manner as the expert committees evaluate the course of action.The primary subjects driving the appeals and decisions regard the changes in the default beyond use dates (BUDs) and criteria for extended BUDs for both nonsterile and sterile compounds. The goals of stakeholder engagement are to include a broad range of perspectives on the topics and to gather additional information to facilitate further discovery and discussion.
To that end, USP convened several stakeholder meetings in the last several months. The first meeting, held on July 28, 2020 with invited panelists, solicited opinions on the key strengths of the revised chapters, as well as areas needing further clarity or which prove to be particularly challenging. Feedback gathered at this meeting also informed the topics for a BUD forum held on September 15, 2020.
In the midst of these decisions and stakeholder meetings, a new cycle of the compounding Expert Committees (EC) began their term in Summer 2020. This marks the third EC to discuss revisions to the sterile compounding chapter, indicating the difficulty in moving changes forward in a manner that will satisfy the goals of the USP and affected stakeholders.
During the September 15, 2020 forum, members of the past and current ECs, as well as the FDA compounding liaison and several invited guests representing various sectors of the compounding community participated in a live Q & A session. In addition, over 1400 constituents joined the call and had the opportunity to provide feedback via an online chat function.
- How is a BUD determined? – During both the <795> and <797> sessions, the EC members provided background on the rationale for changes to the BUD framework. Protecting the patient is the primary objective of both compounding chapters.
- In Chapter 795, there are 14 subchapters referenced within the chapter, half of which reference BUD. Using water activity (further described in USP <1112>) as the basis for the framework puts more emphasis on reducing the risk based on likelihood for microbial growth in the final product. However other aspects of stability and compatibility should be considered as well.
- In Chapter 797, the criteria for BUDs shifts from the complexity of the preparation to the environment where it is compounded, in recognition that these conditions have the greatest potential for introducing microbial risk to the final product.
- Several compounding stakeholders discussed the desire to extend BUDs in in the interest of patient care and access, yet acknowledged the challenge and investment to comply with the criteria for doing so.
- Stability vs Sterility – For both compounded non-sterile preparations (CNSPs) and compounded sterile preparations (CSPs), the proposed revisions to the BUD framework are based on these two key concepts.
- Stability incorporates not only the chemical stability of the active ingredient, but also the chemical and physical properties of the excipient, vehicle and the integrity of the container closure system. Multiple guidance documents exist for conducting stability studies. For the default BUDs in the revised chapters, stability is assumed, and additional testing is not expected.
- Sterility encompasses the compounding environment and personnel, as well as the quality measures in use such as environmental monitoring, garbing compliance and training.
- Throughout both sessions, multiple references were made to FDA comments to USP which emphasized that the FDA’s primary concern is regarding the sterility of a compounded product. In addition, introducing stability studies to assign and extend BUDs may have an inadvertent but adverse impact on the sterility of the product and ultimately increase risk to the patient.
- Adding these dimensions further complicated the BUD issue and led to discussions on the ability of individual compounding sites to replicate all conditions of a stability study and the implications to sterility.
- One size does not fit all – While there is already a delineation of two groups of compounders i.e. 503A and 503B, General Chapters 795 and 797 may only meet the needs of part of the 503A compounding community. I suspect that the revised BUDs actually are adequate for most compounders. But for those pharmacies wishing to extend BUDs, or for veterinary applications, perhaps separate guidance should be developed. Asked, but not discussed, was the issue of shortened BUDs for CSPs in restricted airway barrier systems (RABS).
- Clear as mud – At times, even the experts were discussing, agreeing and disagreeing. This revealed great insight into the open dialogue the experts engage in when determining these standards. However, if the experts are confused, how much more challenged is the typical pharmacy leader or inspector to understand and correctly interpret the regulations?
- “Science and compliance working together is the perfect balance,” according to Tom Kupiec, a stakeholder from ARL BioPharma. This sentiment resonated with many participants. The compounding community desires clear evidence for the standards, and a clear path on how to do what is expected. This can be especially challenging when regulatory bodies also struggle to interpret the standards. The regulatory community also desires clear guidance or criteria for sterility testing parameters for those wishing to extend BUDs. While forums like this provide an opportunity to learn and participate in the process, ultimately it appears compounders and regulators are still in limbo as we await further guidance from the Expert Committees.
- Continue to follow the current versions of the USP chapters, all available for download:
- 2014 <795> Pharmaceutical Compounding – Nonsterile Preparations
- 2008 <797> Pharmaceutical Compounding – Sterile Preparations
- 2019 <825> Radiopharmaceuticals – becomes official December 1, 2020
- <800> Handling Hazardous Drugs in Healthcare Settings – Refer to state regulatory groups and accreditation guidance as some are already enforcing these standards.
- Note the June 26, 2020 USP Revision Bulletin published to clarify the term “antineoplastic” for the purpose of Chapter 800.
- Review references and subchapters within <795> and <797> and educate yourself on criteria for extending BUDs if this is something your pharmacy does or is considering. It is unlikely for BUDs to simply stay as they are, so it is best to be prepared.
- Subscribe to USP to receive updates on the next forum or opportunity to comment. Participation is educational if not enlightening!