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By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development
On June 1, 2019, the United States Pharmacopeial Convention published revisions to the compounding Chapters <795> and <797> in the United States Pharmacopeia and National Formulary, which were set to become official on December 1. These revisions affect the beyond-use date (BUD) that can be applied to compounded formulations, among other standards. On September 23, USP announced they were postponing the official dates of the revised chapters due to pending appeals to certain revisions of both chapters. With the revised chapters becoming official at some point in the near future, our Formulation Development department is hard at work planning updates to all of our formulas to be compliant with the new USP standards. We will complete these updates within our formulation database when we are notified of the new official date and contents of the Chapters <795> and <797>, and they will go into effect in our database on the day that they become official. Therefore, it will be important for PCCA members to download the latest versions of PCCA formulas after the date that the new chapters become official (which has not been announced yet), as there will be changes that should be noted and documented for master formulas.
Even with the delay in these standards, we wanted to announce what these future changes will look like. Below is a summary of the formula changes based on the latest version of USP Chapter <795> as it is written currently. We will make further changes as needed based on the appeals outcome, and we will announce those changes as well. Since USP Chapter <800> will become official on December 1, I have also highlighted a formula change that we have already implemented for PCCA formulas that contain an ingredient designated as a hazardous drug by the National Institute for Occupational Safety and Health. In the second part of this article, I summarize the formula changes we are planning to make based on the latest version of USP <797> as it is currently written.
Changes Related to USP <795> Updated BUDs Section 10.3 in the revised USP Chapter <795> sets parameters to consider when establishing BUDs for compounded nonsterile preparations (CNSPs). It states, “BUDs for CNSPs should be established conservatively to ensure that the preparation maintains its required characteristics to minimize the risk of contamination or degradation.” Following the guidelines shown below, we will update the BUDs of all PCCA formulas for CNSPs (excluding FormulaPlus™ formulas, which have extended BUDs compliant with USP <795>). We will also update the storage requirements listed in the formulas to comply with the chapter.
USP <795> established the BUDs listed below based on a CNSP’s ability to maintain chemical and physical stability and suppress microbial growth. The BUDs require packaging the CNSPs in tight, light-resistant containers. USP determined the BUDs by assessing the susceptibility to microbial contamination and the potential for active ingredient degradation in a CNSP through its water activity (Aw). Reduced water activity greatly assists in active ingredient stability and the prevention of microbial growth. Therefore, USP considers preparations with water activity above 0.6 (Aw > 0.6) to be aqueous and preparations with water activity equal to or less than 0.6 (Aw ≤ 0.6) to be nonaqueous (anhydrous). As a reminder, the BUDs below were established in USP <795> as it is currently written, and they may change depending on the outcome of the pending appeals.
Maximum Default BUDs in the New USP <795>
USP Chapter <795> has also provided ways to extend BUDs beyond those listed above. If the United States Pharmacopeia and National Formulary has a compounded preparation monograph for the CNSP, the BUD must not exceed the one specified in the monograph. PCCA has quite a few of these formulas documented for our members review within our formulation database. They are cross-referenced and searchable by “USP monograph.”
Another means of extending a BUD up to a maximum of 180 days is by conducting a stability study using a stability-indicating assay for the active ingredient(s), the CNSP as a whole, and the type of container-closure that will be used. Additionally, Chapter <795> states that an FDA-registered laboratory should perform an antimicrobial effectiveness test (covered in USP Chapter <51>) when extending the BUD of a CNSP. In other words, the stability study must include assays for each of the individual active ingredients within the specific compounded formula and in the specific container noted, plus USP <51> testing.
This is where PCCA’s FormulaPlus program is so valuable: We have done all of this testing for PCCA members and have published over 135 nonsterile FormulaPlus formulas with extended BUDs. Many of these are bracketed formulas that allow compounders to use the data for a broad range of active ingredient concentrations and many formula options. FormulaPlus formulas are denoted in our database with the “BUD Study” designation and the FormulaPlus Symbol. PCCA members can view the FormulaPlus master list for the complete list of FormulaPlus-studied formulas.
Adding Physical Description Sections 7.1 and 7.2 in the revised USP Chapter <795> list requirements for master formulation records and for compounding records. One of the noted items to document is the physical description for the final CNSP. We are adding this description to our formulations to help our members with these requirements. We will add physical descriptions to the majority of our existing formulas, and these will be included in all PCCA formulas in the future.
Changes Related to USP <800> To help PCCA members comply with the requirements established in USP General Chapter <800>, we have added a note to all PCCA formulas that use an ingredient designated as a hazardous drug by the National Institute for Occupational Safety and Health. The note indicates that one or more ingredients in the formula is designated as a hazardous drug, and it also states that USP <800> provides guidelines for handling such substances. If PCCA members with Clinical Services access have questions about any of these changes, they can contact our Clinical Services department.
Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, received her pharmacy degree from Mercer University in Atlanta, Georgia, in 1995. She currently is involved with and oversees the development and implementation of new formulas at PCCA. She had more than six years of compounding experience with pharmacies in Georgia and Florida prior to joining the PCCA staff in 2004. Her areas of interest include women’s health, veterinary and pain management compounding.
A version of this article previously appeared in PCCA’s members-only magazine, the Apothagram. PCCA members can find a more detailed description of these formula changes in the Fall 2019 issue.
Reference United States Pharmacopeial Convention. (2019). General chapter <795> pharmaceutical compounding — Nonsterile preparations. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.