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By Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist
The content below was based on an earlier proposed version of USP General Chapter 795. However, USP has since released a newer version of the chapter. To see our most current content about the new version of the chapter, please read our blog post Proposed Changes to USP 795.
The philosopher Heraclitus is credited with the saying, “The only constant is change.” This is true for the practice of pharmacy compounding, with the latest addition being new guidelines for both sterile and nonsterile compounding from the United States Pharmacopeia. USP published new versions of General Chapters <795> and <797> on June 1, 2019, which you can download for free here. The chapters are not enforceable until they become official within USP on December 1, 2019. Boards of pharmacy may require compliance with these chapters as early as December, so the time is now to read, reread, and then read these chapters again. Reading USP chapters requires paying special attention to the words “should,” “shall” and “must.” “Shall” and “must” are requirements for compliance with the chapter, while “should” is a recommendation. A number of topics are prescriptive in telling you how to comply, but there are aspects of the chapter that are left up to you to determine what is appropriate based on the compounding done in your practice.
In this post, I am going to review some of the notable aspects of the new USP <795>, which addresses compounded non-sterile preparations (CNSPs), and consider some aspects of implementation. I will also look at some of the resources that PCCA has developed to help compounders with this transition. However, this article is not a substitute for reading the chapter and implementing it in your pharmacy practice as applicable.
Notable Changes
“The strength of the compound must stay within this accepted variability from the time it is prepared through the end of its beyond-use date (BUD).”
In the Scope of the new <795>, USP clarifies that nasal sprays and nasal irrigations are considered nonsterile preparations.1 This has been a discussion point for many pharmacists and their respective Boards of Pharmacy. Due to the wording of the current <797>, many boards of pharmacy have viewed nasal irrigations as sterile preparations, and USP has now clarified their position.
Under Personnel and Settings Affected, USP requires that the facility designates a person or group of people who are “responsible and accountable for the performance and operation of the facility and personnel for the preparation of CNSPs.”1 A portion of the designated person’s responsibility will be focused on training, and they will have to ensure that all compounders demonstrate core proficiencies as listed in the chapter. Training will have to include observation of the trainee to ensure that they can adequately perform the procedures before being allowed to proceed independently. The new <795> requires that gloves be worn during compounding and then requires that the facility document the additional garbing requirements and the frequency of changing the garb “as needed for the protection of personnel from chemical exposures and for prevention of preparation contamination and must be appropriate for the type of compounding performed.”1 People involved in the compounding process are a significant source of potential contamination due to shedding skin particles that may carry bacteria, and the garb chosen should work toward limiting these potential contaminants. While Chapter <800> has been written to address the handling of hazardous drugs, compounders need appropriate garb, containment and documented procedures to prevent exposure to drugs whether they are considered hazardous or not. PCCA offers a wide range of personal protective equipment from Kimberly-Clark® for you to evaluate based on what is appropriate for your practice.
“While Chapter <800> has been written to address the handling of hazardous drugs, compounders need appropriate garb, containment and documented procedures to prevent exposure to drugs whether they are considered hazardous or not.”
The new <795> requires the compounder to make a documented assessment of what is appropriate for manipulating components that could generate airborne chemical particles. Based on your assessment, you may need to work with active ingredients, excipients and other components in a “closed system processing device” (e.g., containment ventilated enclosure (CVE), biological safety cabinet (BSC), single-use containment glove bags).1 In short, you will need to document your decisions and justify them whether or not you use a powder containment hood or another closed system to prevent exposure to chemical particles. PCCA offers CVEs from Nuaire®, including single and double HEPA filter units that come in a range of widths from three feet to six feet that you may consider for both USP <795> and USP <800> compliance.
The new <795> also focuses more on cleaning and disinfecting the designated compounding area or lab and work surfaces, noting that “if compounding is not performed daily, cleaning and sanitizing must be completed before initiating compounding.”1 The agents you use for cleaning and sanitizing are left as professional decisions based on what you are compounding with. However, “if cleaning and sanitizing are performed as separate steps, cleaning must be performed first.”1 Conventional soaps and detergents intended for use at home may leave residues behind, which could be considered contaminants in the final preparation, so compounders should consider lab-grade detergents designed to not leave these residues behind.
Changes Specific to BUDs
Maximum Default BUDs in the New USP <795>
“Water activity in general is the water that is freely available within a substance and is not chemically bound to any other ingredient.”
In the current <795>, aqueous preparations are divided between oral and topical. In the new system, aqueous preparations are no longer divided by route of administration, but rather by whether or not they have a preservative. Refrigeration is key in unpreserved preparations to prevent or reduce microbial growth. One resource for preservative information that you may consider is the Handbook of Pharmaceutical Excipients by Paul J. Sheskey, Walter G. Cook, and others.
In the current <795>, all nonaqueous formulations are treated equally, allowing up to a 180 day BUD. The new <795>, however, splits nonaqueous formulations into solid dosage forms (capsules, tablets, granules, powders) and other nonaqueous formulations that have a Aw of less than or equal to 0.6, such as suppositories, ointments, fixed oils, or waxes.
If you would like a nonsterile formulation to have a BUD that goes beyond these defaults, you have two options. You can see if USP has a formulation monograph for the particular preparation and follow that formulation exactly while documenting that you have met all specifications of the monograph. While USP formulation monographs exist for some medications, many are not addressed. If there is not a USP formulation monograph, you will need a stability study with a stability-indicating assay that includes the specific container-closure used for the formulation. A stability-indicating assay goes beyond potency-over-time testing, exposes the compound to forced degradation and has to be able to detect any break-down product separately from the active ingredient. Aqueous preparations are also required to have a preservative for BUD extension and be tested to pass USP <51> antimicrobial effectiveness testing. The USP <51> antimicrobial effectiveness testing information can come from a published study and is specific to the container-closure testing used in the study.
“Aqueous preparations are also required to have a preservative for BUD extension and be tested to pass USP <51> antimicrobial effectiveness testing.”
Testing a formulation with a single active ingredient to meet these new standards for BUD extension can cost in excess of $10,000. PCCA has developed and is continuing to develop a robust collection of FormulaPlus™ formulations to meet the needs of prescribers, pharmacists and patients. These preparations have been tested with stability-indicating assays, and almost all of them have completed USP <51> antimicrobial testing. The remainder will have this testing completed by December when this chapter becomes official.
FormulaPlus formulations that are tested for one strength can only be used to compound that particular strength with the extended BUD. However, PCCA has also created a number of bracketed FormulaPlus formulations that have been tested at two different strengths with a stability-indicating assay. When a bracketed formula exists, this data can support the BUD extension of the formulation at any strength between the two tested strengths. The approach of bracketing data has been discussed in FDA guidance since at least 2003.2
It is important to note that when applying the data from these formulations, you must follow them exactly, including the same container-closure, and you must use PCCA chemicals. USP specifically states in two separate instances that just because a chemical is labeled USP or NF grade, it does not mean that two chemicals are exactly the same. In General Notices section 4.1, USP states that “because monographs may not provide standards for all relevant characteristics, some official substances may conform to the USP or NF standard but differ with regard to nonstandardized properties that are relevant to their use in specific preparations. To assure substitutability in such instances, users may wish to ascertain functional equivalence or determine such characteristics before use.”3
“USP specifically states in two separate instances that just because a chemical is labeled USP or NF grade, it does not mean that two chemicals are exactly the same.”
In General Chapter <1059>, USP states that “excipients used in drug products typically are manufactured and supplied in compliance with compendial standards. However, the effects of excipient properties on the critical quality attributes (CQAs) of a drug product are unique for each formulation and process and may depend on properties of excipients that are not evaluated in USP or NF monographs.”4
These statements illustrate why any variations to FormulaPlus formulations, including substitution with a non-PCCA chemical or non-PCCA base, may affect physical integrity, solubility or organoleptic properties, or may result in potency or content uniformity issues. Therefore, this type of substitution causes the assigned BUD to be invalid.
While these are some highlights from the new USP <795>, there are numerous additional considerations from the chapter, including quality control and quality assurance. If you are looking for additional resources for implementing USP <795>, consider reading the additional USP chapters referenced throughout <795>. If PCCA members with Clinical Services access have questions about this chapter as you navigate decisions for your practice, please call our clinical compounding pharmacists at 800.331.2498.
Matt Martin, PharmD, is a Clinical Compounding Pharmacist at PCCA. He joined the PCCA Clinical Services department in September 2014. Matt graduated from Morehead State University with a BS in Chemistry in 2002, and received his PharmD from the University of Kentucky College of Pharmacy in 2006. Prior to joining the PCCA team, Matt worked in compounding pharmacy for more than eight years, and has experience with both sterile and non-sterile preparations.