THE PCCA BLOG

USP 795: Revisions & Impacts, Part 1

Mon, 06 Feb 2023 14:33:14 GMT

by Matt Martin, PharmD, BCSCP, PCCA Director of Clinical Services

On November 1, 2022, the United States Pharmacopeia (USP) published revisions to General Chapter 795, Pharmaceutical Compounding — Nonsterile Preparations (CNSPs), which becomes official and possibly enforceable in your state on November 1, 2023. The date also triggers potential enforcement of USP 800, which addresses CNSPs using hazardous drugs.

For access to USP 795 revisions, USP offers two purchase options: the USP Compounding Compendium or the full USP-NF. Purchase of the USP Compounding Compendium grants access to more than 40 USP General Chapters, including 795, 797 and 800. Although purchase of the full USP-NF costs more, access includes USP chemical and product monographs, which are useful in determining how to use data from certificates of analysis.

USP 795 Revisions

USP offers a number of tools, including:

USP 795 FAQs
USP 795 Commentary
USP 795 Open Forum Presentation presented and recorded on November 8, 2022
USP 795 Open Forum Slides presented on November 8, 2022
Adding Flavor to Conventionally Manufactured Nonsterile Products

Training

Revisions to USP 795 emphasize certain subtopics: specifically, a significant expansion and emphasis on training, including knowledge in and demonstration of core competencies. A trainee must show their ability to read and understand concepts and demonstrate their knowledge and ability to perform tasks, with documentation of all trainings and demonstrations.

Core competencies include:

Hand hygiene
Garbing
Cleaning and sanitizing
Handling and transporting components and CNSPs
Measuring and mixing
Proper use of equipment and devices selected to compound CNSPs
Documentation of the compounding process (described in Section 7 of the chapter, Master Formulation and Compounding Records)

In addition, training must include:

Ability to understand USP 795 requirements
Ability to understand and interpret safety data sheets (SDSs) and, if applicable, certificates of analysis (COAs)
Read and understand procedures related to their compounding duties

Hand hygiene, garbing, cleaning and sanitizing are cited as significant core competencies for nonsterile compounding. While some may consider the purpose of garbing and personal protective equipment (PPE) is to protect compounders, the garbing process and PPE are significant tools that reduce skin cells shed and the microbes they can carry from potentially contaminating the compounded medication. In other words, properly donned PPE protects the compounder from chemicals and protects the compounded medication from potential contamination.

Cleaning and Sanitizing

Table 1 in the USP 795 revisions define minimum schedules for cleaning and sanitizing nonsterile compounding area surfaces. USP has multiple chapters on microbial limits for nonsterile preparations, including USP 61 and USP 62. These chapters contain total microbial contamination limits and specific objectionable microorganisms prohibited in nonsterile compounds. The FDA also focuses on the quality of the compounding environment for CNSPs in their guidance, Insanitary Conditions at Compounding Facilities.

Beyond-Use Dates

Beyond-use dates (BUDs) are always of significant interest to compounders because they affect patient care opportunities. When considering BUDs, it is common to look at the chemical and physical properties of an active pharmaceutical ingredient (API). The revisions to USP 795 also focus on the container closure system used for final formulations, including how the container closure may interact with CNSP API(s). Visually inspecting the integrity of the container closure after packaging and prior to release, as well as considering the possible container closure degradation over time, are all valuable. The integrity of the container closure is important because an improperly sealed, cracked or degraded container closure can potentially lead to microbial contamination or a loss of potency.

PCCA offers resources to help pharmacies navigate the changing compounding standards and regulatory environment, including our blog on FDA Insanitary Conditions and limited USP training courses at eLearning Compounding Training.

PCCA offers additional resources to our members, including all courses offered in our eLearning Compounding Training, multiple online webinars and training sessions and, for members with Clinical Services, Speakers Bureau to guide, assist and educate compounding pharmacy staff. Members with Clinical Services may also contact our Clinical Services team for help with formulas and other compounding concerns.

Part 2 of USP 795: Revisions & Impacts can be found here.

The complete version of this article originally appeared in PCCA’s members-only magazine, the Apothagram.

Proposed Changes to USP 797

Wed, 03 Nov 2021 14:16:00 GMT

By Matt Martin, PharmD, BCSCP, PCCA Director of Clinical Services

This article was updated on January 19, 2022.

On September 1, 2021, the United States Pharmacopeia (USP) prepublished their latest proposed revisions to General Chapter 797, Pharmaceutical Compounding — Sterile Preparations. These proposed changes are not in effect now and have several steps to go through before they will become official. The most important next step is the comment deadline for this chapter, which is March 17, 2022. If pharmacies and other stakeholders would like to submit comments about improvements to the proposed changes, they will need to do so by that date.

USP has held two open forums on the proposed revisions, which were opportunities for them to present information about the proposed revisions and their process along with allowing the attendees to ask questions about the proposed revisions. Now is the time for compounding pharmacies to consider how changes to the chapter may affect their practices, patients and procedures to prepare for submitting their comments on anything that they feel should be improved in the proposed revisions.

The most significant proposed revision to USP 797 is the inclusion of Category 3 compounded sterile preparations (CSPs) in addition to the Category 1 and 2 CSPs that were in the previously proposed revision to Chapter 797 in 2019. The addition of the third category involves many other changes in how pharmacies compounding CSPs must operate as well, which I have outlined below.

Beyond-Use Dates

When USP released the previous version of the revised Chapter 797 in 2019, there were two categories of CSPs. In the proposed version released in 2021, these two categories are still present with the same BUDs from the 2019 version. Category 1 CSPs are compounded under the least controlled environmental conditions and therefore are assigned a BUD of 12 hours or less at controlled room temperature or 24 hours or less when refrigerated and meeting the additional requirements for Category 1 CSPs. Category 2 CSPs require more environmental controls and testing than Category 1 CSPs and may be assigned a BUD of greater than 12 hours at controlled room temperature or more than 24 hours if refrigerated, but not exceeding the limits established in Table 11 of the proposed revisions. Please see Table 11 in the proposed revisions to review these BUDs.

In 2019, compounders took notice of the fact that there was not a way to extend the BUDs of Category 1 or 2 compounds. The 2021 proposed version of USP 797, however, has added Category 3 sterile preparations, which can have longer BUDs compared to those for Category 1 and Category 2 sterile preparations that were described originally in the 2019 proposed revisions. Category 3 BUDs are found in Table 12 of the proposed Chapter 797 (below).

TABLE 12: BUD LIMITS FOR CATEGORY 3 CSPs
Compounding Method	Controlled Room Temp. (20 – 25^oC)	Refrigerated (2 – 8^oC)	Freezer (-25 – -10^oC)
Aseptically processed, sterility tested, and passing all applicable test for Category 3 CSPs	60 days	90 days	120 days
Terminally sterilized, sterility tested, and passing all applicable tests for Category 3 CSPS	90 days	120 days	180 days

In order to use these BUDs, the Category 3 sterile preparations have a number of additional requirements beyond Category 2 preparations. The BUD of a Category 3 sterile preparation must be supported by a stability-indicating assay that is validated according to USP 1225, Validation of Compendial Procedures. The sterile preparation relying on this stability study for its extended BUD must be made using the same ingredients and procedures as the study. In addition, the Category 3 sterile preparation must be packaged in a container closure that is composed of the same materials as that used in the study.

Category 3 sterile preparations that are injections or ophthalmic solutions must pass the appropriate particulate matter test once for each formulation. Injections have to pass testing according to USP 788, Particulate Matter in Injections, while ophthalmic solutions have to pass testing according to USP 789, Particulate Matter in Ophthalmic Solutions. Additionally, the container closure systems used for injections and ophthalmic solutions must pass testing according to USP 1207, Package Integrity Evaluation — Sterile Products, for each formulation.

Endotoxin Testing

Category 1 sterile preparations do not require endotoxin testing. Category 2 sterile injectable preparations compounded from one or more nonsterile components and assigned a BUD that requires sterility testing must also be tested for endotoxin content complying with USP 85, Bacterial Endotoxins. If a Category 2 sterile preparation is compounded from one or more nonsterile components but is assigned a BUD that does not require sterility testing, it is not required to have endotoxin testing, although the proposed revisions suggest that it should be tested. Category 3 sterile injectable preparations compounded from one or more nonsterile components must be tested for endotoxin content in accordance with USP 85.

Garbing Practices

Beyond the data and testing supporting the formulation, there are additional requirements for the compounder and others who enter the classified area where Category 3 sterile preparations are compounded. Anyone entering the classified areas used for compounding Category 3 sterile preparations must adhere to stricter garbing practices:

Compounders are not allowed any exposed skin in the buffer room (e.g., face and neck must be covered).
All low-lint garb must be sterile.
Once a compounder leaves a classified area, disposable garbing items must be discarded, and laundered garb must not be reused without being laundered and resterilized with a validated cycle.

Environmental Monitoring

Personnel compounding Category 3 sterile preparations are required to perform media fills with glove fingertip sampling and surface sampling of the direct compounding area at least every three months, compared to at least every six months for those compounding Category 1 or 2 sterile preparations.

Pharmacies compounding Category 3 sterile preparations have more frequent monitoring requirements. Viable air sampling using an impaction device must be completed for each classified area monthly for facilities preparing Category 3 sterile preparations, compared to every six months for facilities preparing Category 1 or 2 preparations. This is a notable change because the 2019 proposed revisions to Chapter 797 required monthly viable air sampling for facilities compounding Category 2 sterile preparations.

Surface sampling is required weekly for Category 3 sterile preparations and also must be performed with each batch of a Category 3 sterile preparation. By contrast, when preparing Category 1 or Category 2 preparations, surface sampling is required on a monthly basis. Surface sampling must be done in all classified areas and pass-throughs. The sampling has to include:

The interior of the primary engineering control (PEC), which is typically a laminar airflow workstation, as well as the equipment contained in it
Staging or work area(s) near the PEC
Frequently touched surfaces

Pharmacies must also conduct viable air sampling and surface sampling:

When new facilities and equipment are certified
After any facilities or equipment are serviced (see Section 4, Facilities and Engineering Controls)
When any problems are identified (e.g., microbial growth in sterility tests of preparations)
When problematic trends are identified (e.g., failed fingertip and thumb sampling results, failed media fill testing, or repeated air or surface contamination)
When changes are made to the facility or processes that could impact the compounding environment (e.g., change in cleaning agents)

Pharmacies must conduct total airborne particle count testing in all classified areas during dynamic operating conditions at least every six months for all categories of sterile preparations as well.

Cleaning and Sanitizing

Cleaning in the proposed Chapter 797 has received some additional considerations. Pharmacies must clean surfaces prior to disinfecting them, unless they use EPA-registered (or equivalent) one-step disinfectant cleaners that clean and disinfect at the same time. However, the disinfectant must have sporicidal properties, so it’s important to confirm that the disinfectant or one-step disinfectant cleaner is sporicidal. After cleaning and disinfecting, pharmacies must apply sterile 70% isopropyl alcohol to remove any residues.

One significant difference exists in the frequency of sporicidal application between Category 1 and 2 preparations and Category 3 preparations. When pharmacies prepare Category 3 sterile preparations, they must apply a sporicidal agent to the PEC, the equipment in the PEC, work surfaces outside the PEC, equipment outside the PEC, pass-throughs and floors at least weekly. Compounding Category 1 and 2 preparations, on the other hand, require application of a sporicidal agent to all of these areas on a monthly basis.

Along with these changes, the process for cleaning the PEC has received more detailed directions. Compounders must:

Remove visible particles or residue from the equipment and interior surfaces of the PEC with an appropriate solution using sterile, low-lint wipes
Apply a sterile cleaning agent followed by a sterile disinfecting agent (or an appropriate one-step disinfectant cleaner as described above) to equipment and interior surfaces of the PEC using sterile, low-lint wipes
Ensure the cleaning and disinfecting agents are in contact with surfaces for the time specified by the manufacturer
Apply sterile 70% isopropyl alcohol to equipment and all interior surfaces in the PEC using sterile, low-lint wipes
Allow the surfaces and equipment to dry before beginning compounding processes

Next Steps in the Process

After the March 17, 2022, comment deadline, the USP Compounding Expert Committee will to review all submitted comments and determine if they will need to make further changes to the proposed chapter. The committee does not have a defined time period for reviewing the comments submitted, so it’s no possible to accurately predict a future implementation date for the chapter. If the USP Compounding Expert Committee moves to implement the revisions to USP 797, they will provide a six-month implementation window before the chapter becomes official, which would also be when it would become enforceable in most states. The new USP Chapter 797 will also be significant for USP Chapter 800, Hazardous Drugs — Handling in Healthcare Settings, because when the new Chapter 797 becomes official, it will also make Chapter 800 “compendially applicable.” In USP terms, this means that it will also become enforceable in many states. For more information about this chapter, visit the PCCA USP 800 webpage.

Pharmacies and other stakeholders can find the proposed changes to USP 797 on USP’s website along with a link to submit comments on the proposed revisions . PCCA has a wide variety of resources available to help pharmacies navigate the changing compounding standards and regulatory environment. PCCA members can reach out to us today if they would like to see how we can help them move forward in their practices.

Matt Martin, PharmD, BCSCP, is the Director of Clinical Services 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 pharmacy compounding for more than eight years and has experience with both sterile and nonsterile preparations.

Upcoming Changes to PCCA Formulas per the New USP <795>, <797> and <800> (Part One)

Mon, 04 Nov 2019 15:26:00 GMT

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>

Non-preserved aqueous dosage forms: 14 days in refrigerator
Preserved aqueous dosage forms: 35 days at controlled room temperature or in refrigerator
Nonaqueous dosage forms: 90 days at controlled room temperature or in refrigerator
Solid dosage forms: 180 days at controlled room temperature or in refrigerator

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.

Notable Changes in the New USP <797>

Wed, 24 Jul 2019 19:11:27 GMT

By Dylan Herr, Eagle RA/QA Development Manager

The content below was based on an earlier proposed version of USP General Chapter 797. 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 797.

On June 1, 2019, a revised version of USP General Chapter <797> was published. The revised chapter will become official in the United States Pharmacopeia on December 1, 2019, along with a revised version of General Chapter <795>, which addresses nonsterile compounding, and the new General Chapter <800>, which addresses hazardous drugs.

The revised USP <797> differs significantly from the current version. Many of the changes in the revised chapter will be relatively simple for pharmacies to address through small procedural updates and personnel training, such as the requirement for different incubation times and temperatures for growth media, or the requirement that incubators are not stored in classified areas. Other changes, however, will be significantly more challenging for some pharmacies to implement. The most significant changes, which I will focus on in this article, are changes in how beyond-use dates (BUDs) are assigned and in testing requirements.

Beyond-Use Dating Requirements
The new USP <797> defines three different classifications of compounded sterile preparations (CSPs): immediate use, Category 1 and Category 2. The differences between each CSP classification are largely related to the environment in which the CSP was prepared, the resulting level of risk of microbial contamination and the BUD that can be assigned.

Immediate use CSPs are not subject to the requirements outlined in USP <797>, as this classification addresses the preparation of sterile compounds for direct and immediate administration to a patient within four hours. They must be prepared in accordance with written procedures to ensure good aseptic practice, must require no more than three different sterile starting components, and must be discarded if administration does not begin within four hours of preparation.

All CSPs that are not immediate use fall into the classification of Category 1 or Category 2 based on the environment in which they are prepared. Category 1 CSPs are compounded in an ISO 5 primary engineering control (such as a laminar-airflow workstation) that is located in a segregated compounding area. Category 2 CSPs are compounded in an ISO 5 primary engineering control that is located in an ISO 7 buffer area. While the facility design and control requirements for Category 1 CSPs are not as stringent as those for Category 2 CSPs, the chapter states that “the requirements that are not specifically described as applicable to Category 1 or Category 2, such as training, competency testing, and personal hygiene for personnel, are applicable to the compounding of all CSPs.”¹ It is therefore important for pharmacies only compounding Category 1 CSPs to employ quality systems that are nearly as robust as those in pharmacies compounding Category 2 CSPs.

“It is therefore important for pharmacies only compounding Category 1 CSPs to employ quality systems that are nearly as robust as those in pharmacies compounding Category 2 CSPs.”

Besides compounding environment, the primary difference between Category 1 and Category 2 CSPs is the maximum allowable BUD that can be assigned to these preparations. The maximum permitted BUD for a Category 1 CSP is 12 hours when the preparation is stored at a controlled room temperature (20–25° C), or 24 hours when it is stored under refrigerated conditions (2–8° C).

The maximum permitted BUD for a Category 2 CSP, as outlined in Table 11 of the chapter, is dependent on whether:

The CPS was aseptically prepared or terminally sterilized
The CPS was subjected to and passed sterility testing
The CPS was prepared from sterile or nonsterile starting components
The CPS will be stored at room temperature, refrigerated or frozen

The revised chapter allows longer BUDs for CSPs that are terminally sterilized, have passed sterility testing, are prepared from sterile starting components and are stored under colder conditions, as these factors help to minimize the risk of microbial contamination or proliferation in finished CSPs.

As an example of how the processing and storage conditions affect the allowable BUD, consider a CSP that is prepared from nonsterile starting components and is stored under refrigerated conditions. If this CSP is sterilized via filtration and is not tested for sterility, the maximum allowable BUD is four days. If sterility testing is performed and passed, the maximum permitted BUD increases to 45 days. If this same CSP was terminally sterilized instead of filter sterilized, it would be allowed a 28 day BUD without sterility testing, or a 60 day BUD if it passes a sterility test.

Another significant change with respect to assigning BUDs is the removal of language that discusses methods of extending BUDs for sterile preparations compounded in an ISO 5 primary engineering control located in an ISO 7 buffer area. While the current USP Chapter <797> allows compounders to use stability studies or relevant scientific literature to extend BUDs for these preparations, the revised chapter does not provide any means of extending BUDs beyond those outlined in Table 11. This is also contrary to the revised Chapter <795>, which allows for extended BUDs on nonsterile preparations if appropriate stability studies are conducted. USP addresses this with question 69 on their Chapter <797> frequently asked questions webpage. The question is, “Can the BUD of Category 2 CSPs be extended beyond those in Table 11. BUDs for Category 2 CSPs?” The answer USP provides is, “The chapter states that BUDs for Category 2 CSPs must be established in accordance with Table 11. However, if there is a compounded preparation monograph for a particular CSP formulation, that BUD may be assigned if the CSP is prepared according to the monograph and all monograph requirements are met.”²

“While the current USP Chapter <797> allows compounders to use stability studies or relevant scientific literature to extend BUDs for [Category 2 CSPs], the revised chapter does not provide any means of extending BUDs beyond those outlined in Table 11.”

Shorter BUDs may result in increased patient costs and operational challenges, so many compounders may try to maximize the allowable BUD by terminally sterilizing or freezing all of the CSPs they prepare. However, they should exercise caution when taking this approach. The revised chapter advises compounders to take into account the physical and chemical stability of CSPs and their components prior to freezing or refrigerating them, as not all CSPs will be compatible with colder conditions. The chapter also requires the compounder to ensure that the container-closure system used to package frozen CSPs is able to withstand the stress of being frozen and thawed. Finally, CSPs that have been thawed are not permitted to be re-frozen. The chapter also points out that while CSPs may be kept under multiple storage conditions prior to use, the BUD is not cumulative. To illustrate this, the chapter provides the following example: “An aseptically processed CSP prepared from one or more nonsterile starting component(s) cannot be stored for 45 days in a freezer, then 4 days refrigerated, and then 1 day at controlled temperature for a total of 50 days.”¹

Additionally, while CSPs that are terminally sterilized are permitted a longer BUD, compounders must define and validate their terminal sterilization cycles. The revised chapter requires that pharmacies prepare detailed standard operating procedures that address sterilization cycle factors such as temperature, pressure, allowable loading conditions, and the use of biological indicators or endotoxin challenge vials. Prior to terminally sterilizing a CSP, the compounder must first demonstrate the effectiveness of the sterilization cycle through use of biological indicators, temperature sensing devices and other physiochemical confirmation methods. The compounder must ensure that the contents of the sterilizer — and not just the equipment itself — reaches the required temperature for sterilization for the duration of time required to achieve an appropriate level of sterility assurance. Lastly, temperature-sensing devices, such as calibrated data or chart recorders, must be used along with appropriate biological indicators to verify that the cycle performs within specification.

“The revised chapter requires that pharmacies prepare detailed standard operating procedures that address sterilization cycle factors such as temperature, pressure, allowable loading conditions, and the use of biological indicators or endotoxin challenge vials.”

Testing Requirements
The revised USP <797> removes the current chapter’s requirement that all batches of CSPs in quantity of 25 units or more must be tested for sterility. Instead, Category 2 CSPs must be tested for sterility if they are assigned a BUD that requires sterility testing per Table 11. The chapter requires that CSPs are tested for sterility using either the compendial method outlined in USP Chapter <71> or a validated alternative method. The chapter also requires that a method suitability test, also described in USP <71>, is conducted to demonstrate that the sterility test is capable of detecting microbial contamination. One of the challenges of the USP Chapter <71> sterility testing method is the 14–18 day incubation time that the method requires. For a Category 2 CSP stored at controlled room temperature, the product will lose up to half of its shelf-life before the sterility test results are available. Fortunately, Eagle is able to offer compounders sterility test results within two business days using our ScanRDI® rapid sterility testing, a method that has been validated as a suitable alternative according to USP Chapter <1223>.

A helpful change in the new chapter is the addition of provisions for small batches of CSPs with regards to required sample sizes for sterility testing. Under the current chapter, the number of units to be tested for sterility is based on Table 3 of USP <71>. For batches smaller than 40 units, four containers must be tested for sterility. The new chapter, however, allows compounders to test 10% of the batch size — rounded up to the next whole number — for batches that are under 40 units. As an example, for a batch size of 15 containers, the compounder must only test two units for sterility, as opposed to the four that would be required under USP <71>.

“The new chapter, however, allows compounders to test 10% of the batch size — rounded up to the next whole number — for batches that are under 40 units.”

The revised chapter also recommends that nearly all injectable Category 2 CSPs are tested for bacterial endotoxins. However, the chapter states that Category 2 injectable CSPs that are assigned a BUD based on sterility testing must be tested for bacterial endotoxins. It also states that Category 2 injectable CSPs that are prepared from nonsterile components should be tested for bacterial endotoxins, even if they are assigned a BUD that does not require sterility testing. (Keep in mind that a “must” is a requirement, but a “should” is a recommendation.)

Lastly, the revised chapter addresses the testing of multiple-dose CSPs. All multiple-dose CSPs are required to be prepared as Category 2 CSPs, and therefore may not be prepared in a segregated compounding area. Additionally, the chapter requires that compounders conduct USP General Chapter <51> antimicrobial effectiveness testing at least once for each formulation in the container-closure system in which it will be dispensed. For formulations with a range of different strengths, compounders may apply a bracketing approach by testing the highest and lowest strength of the formulation so long as the concentration of inactive ingredients, including the preservative, does not change. It does allow compounders to rely on antimicrobial effectiveness testing documented in peer-reviewed literature sources as long as the formulation, preservative and container-closure system are identical to those used in the peer-reviewed study.

“All multiple-dose CSPs are required to be prepared as Category 2 CSPs, and therefore may not be prepared in a segregated compounding area.”

This article is not intended to be an exhaustive examination of the changes to USP <797>. We at Eagle recommend that all compounding pharmacies read and re-read the revised chapter well in advance of December 1, 2019, when it becomes official, in order to become familiar with all changes that may affect their practices. The revised chapter is available for free on USP's website. Additionally, Eagle’s expert consultants can assist pharmacies by performing a comprehensive assessment of their existing practices and procedures to identify gaps between current operations and the requirements of the new chapter, and to help identify appropriate actions to take. If you have any questions about the revised chapter, please contact Eagle Client Care at 800.745.8916 for further assistance.

Dylan Herr joined the Eagle team in 2017. Before that, she worked for five years as the practice manager and compliance officer of a 503A compounding pharmacy. In this role, Dylan led the development and implementation of quality systems and standard operating procedures in addition to managing daily operations of the home infusion practice. Dylan also led the pharmacy through NABP, BOP and FDA inspections, and helped it achieve ACHC and PCAB® accreditation. Her formal education includes a bachelor’s degree in anthropology from Dartmouth College.

References

1. United States Pharmacopeial Convention. (2019). General chapter <797> pharmaceutical compounding — Sterile preparations. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
2. United States Pharmacopeial Convention. (2019). FAQs: <797> pharmaceutical compounding — Sterile preparations. Retrieved from https://www.usp.org/frequently-asked-questions/pharmaceutical-compounding-sterile-preparations

Notable Changes in the New USP <795>

Wed, 17 Jul 2019 15:30:36 GMT

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 introduction of the new Chapter <795> reintroduces the definition of what it means to have variability in strength. While many have considered this a standard of practice for nonsterile preparations, it wasn’t defined in the current version of the chapter. Acceptable variability in strength in the new <795> is described as being within +/- 10% of the labeled strength.¹ It is important to consider how each step of the compounding process affects the final potency and to have standard operating procedures addressing the use of certificates of analysis, base/salt conversions, minimum accurately weighable quantity for your balance, specificity in mixing instructions and many other factors. 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). If testing of a formulation results in a potency on the low end of this range, then compounders should consider if the full BUD can still apply and what data they have to support their decision.

“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

BUDs of compounded preparations are a critical consideration when developing a formulation to meet patient needs and can be a significant factor in the cost of therapy for the patient. The new <795> makes substantial changes to BUDs; defines criteria for BUD extension; and brings attention to preservatives, antimicrobial effectiveness and water activity. Table 3 in the new <795> provides the new maximum default beyond-use dates.

Maximum Default BUDs in the New USP <795>

Non-preserved aqueous dosage forms: 14 days in refrigerator
Preserved aqueous dosage forms: 35 days at controlled room temperature or in refrigerator
Nonaqueous dosage forms: 90 days at controlled room temperature or in refrigerator
Solid dosage forms: 180 days at controlled room temperature or in refrigerator

Aqueous preparations are defined as those that have a water activity (Aw) greater than 0.6. The percentage of water in a substance is not the same as the water activity of the substance. Water activity in general is the water that is freely available within a substance and is not chemically bound to any other ingredient. Microorganisms can use this freely available water to proliferate within the compounded preparation, and it also has the potential to degrade the active ingredient. You can read more about water activity in USP <1112>. You can also read our blog post about water activity.

“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.

References

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.
U.S. Food & Drug Administration. (2003). Guidance for industry: Q1D bracketing and matrixing designs for stability testing of new drug substances and products. Retrieved from https://www.fda.gov/media/71720/download
General notices and requirements. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.
United States Pharmacopeial Convention. (2019). General chapter <1059> excipient performance. In United States pharmacopeia and national formulary (USP 42nd ed. & NF 37th ed.). Rockville, MD: United States Pharmacopeial Convention, Inc.