THE PCCA BLOG

USP Chapter 795-Related Changes to Formulations

Wed, 28 Jun 2023 11:00:00 GMT

by Melissa Merrell Rhoads, PharmD, PCCA Director of Formulations

The revised USP Chapter 795 will become official on November 1, 2023. This chapter describes the full guidelines for pharmaceutical compounding of nonsterile preparations (CNSPs). Specifically looking at the revisions related to the beyond-use date (BUD), we will be updating all PCCA formulas for compliance.

USP states the BUDs presented “are based on the ability of the CNSP to maintain chemical and physical stability and to suppress microbial growth.” The dosage forms are described as aqueous and nonaqueous based on water activity (a_wor Aw). An aqueous preparation is one that has an a_w ≥ 0.6 (e.g., emulsions, gels, creams, solutions, sprays or suspensions). Nonaqueous dosage forms have an a_w < 0.6 and are separated into two categories: “nonaqueous oral liquid” and “other nonaqueous dosage forms” (e.g., capsules, tablets, granules, powders, nonaqueous topicals, suppositories, and troches or lozenges).

Below are the revised BUDs and notes that will be added to all nonsterile formulas.

Non-preserved aqueous (PF) – 14 days refrigerated

Note: According to USP guidelines, “in the absence of a USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a non-preserved aqueous dosage form with a water activity (Aw) of >/= 0.6 is 14 days stored in a refrigerator, unless such storage affects the physical or chemical properties of the CNSP.

For more information, refer to current USP Chapter 795.

Preserved aqueous – 35 days

Note: According to USP guidelines, “in the absence of a USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a preserved aqueous dosage form with a water activity (Aw) of >/= 0.6 is 35 days.

For more information, refer to current USP Chapter 795.

Nonaqueous (anhydrous) oral liquid – 90 days

Note: According to USP guidelines, “in the absence of a USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a nonaqueous oral liquid dosage form with a water activity (Aw) of < 0.6 is 90 days.

For more information, refer to current USP Chapter 795.

Nonaqueous (anhydrous) excluding nonaqueous oral liquids – 180 days

Note: According to USP guidelines, “in the absence of a USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a compounded CNSP that is a nonaqueous dosage form (excluding nonaqueous oral liquids) with a water activity (Aw) of < 0.6 is 180 days.

For more information, refer to current USP Chapter 795.

Additional notes are also being added to the formulas to bring awareness to some of the guidelines that the USP Chapter 795 now requires during the compounding process. The notes below are not all encompassing of the chapter requirements, so we recommend that you become familiar with the chapter and that you are in compliance with all requirements.

Component evaluation before use

Note: USP Chapter 795 states guidelines regarding “component evaluation before use.” “Compounding personnel must visually re-inspect all components to detect any container breakage, looseness of the cap or closure, or deviation from the expected appearance or texture of the contents that might have occurred during storage.”

Visual inspection

Note: USP Chapter 795 states guidelines regarding “visual inspection.” After the completion of compounding, the preparation must be visually inspected to determine whether the physical appearance is as expected. The inspection must also include visual inspection of container closure integrity.

Establishing and extending BUD

Note: USP Chapter 795 sets forth parameters to consider when establishing a BUD and 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.” Stability testing may be performed by a FDA-registered laboratory using a stability-indicating assay to extend the BUD.  An antimicrobial effectiveness test (see USP Chapter 51) must also be performed by a FDA-registered laboratory when extending the BUD of an aqueous CNSP.

PCCA Members with clinical services may contact our Clinical Services Team for additional information on PCCA Formulas and other compounding concerns.

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

USP 795: Revisions & Impacts, Part 2

Wed, 15 Feb 2023 13:30:23 GMT

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

If you missed Part 1 of our USP 795: Revisions & Impacts, it can be found here.

Beyond Use Dates

The concept of water activity receives significant discussion in the revisions to 795. Water activity is a measure of the water that is unbound and freely available to participate in chemical, biochemical or physicochemical reactions, or provides an environment that supports microbial growth. Compounded preparations with a water activity less than 0.6 are considered anhydrous with extended BUDs because they are less likely to allow degradation of API or microbial growth. Discussions on water activity were expanded in 795 revisions and examples of the water activity of various dosage forms were added to the chapter (USP 1112 also discusses water activity).

The maximum potential BUDs that can be assigned to compounded nonsterile preparations without additional stability testing has changed. Nonaqueous topicals, suppositories and troches are now preparations that allow up to 180-day expanded BUDs. Nonaqueous oral preparations can be assigned up to a 90-day BUD. Aqueous dosage forms are separated based on whether or not they have a preservative: non-preserved aqueous dosage forms may be given up to a 14-day BUD when stored at refrigerated temperature; preserved aqueous dosage forms may be given up to a 35-day BUD at room temperature or under refrigeration.

BUDs may extend up to 180 days with a stability study (published or unpublished) using a stability-indicating assay for the API(s), CNSP and type(s) of container closure used. If the BUD of an aqueous preparation is extended, the formulation must also be tested for the performance of the preservative, known as antimicrobial effectiveness testing, according to USP Chapter 51. Revisions to Chapter 795 also permit use of bracketing for stability studies and antimicrobial effectiveness testing. Bracketing is performing tests on a low concentration and a high concentration of API(s). If the formulation passes the tests at both concentrations, the data can be applied to all strengths that fall between the two that were tested.

PCCA has developed over 200 FormulaPlus^™ formulas tested with stability-indicating assays and USP 51 antimicrobial effectiveness (when applicable) for extended BUDs. Some of these are bracketed formulations to help PCCA members address the variety of strengths prescribed by practitioners. FormulaPlus^™ formulas meet all requirements in USP 795 revisions.

THE DESIGNATED PERSON(S)

Responsibility for the performance of the compounding operation created a new role, called the “designated person(s) (DP),” which holds one or more people responsible and accountable for the performance and operation of the facility and personnel preparing CNSPs. The DP(s) is tasked with over 20 areas of responsibility. Note a pharmacy can have one or several persons as the designated person(s), hence the “(s).” These responsibilities can therefore be divided among team members who are appropriate for each responsibility. A few DP(s) key responsibilities are training, documentation and quality control/assurance. While training was discussed above, it is imperative to highlight documentation, including:

Personnel training, competency assessments and qualification records, with corrective actions for any failures
Equipment records (e.g., calibration, verification and maintenance reports)
Certificates of analysis and all documentation required for components not conventionally manufactured
Receipt of components
Standard operating procedures, master formulation records and compounding records
Release-inspection and testing records
Information related to complaints and adverse events, including corrective actions taken
Results of investigations and corrective actions
Records of cleaning and sanitizing the designated compounding area
Temperature logs
Accommodations to personnel compounding CNSPs
Any required routine review (e.g., yearly review of quality assurance and quality control programs, yearly review of chemical hazard and disposal information)

USP 795 references USP 1163 on quality assurance, which can be a helpful resource in developing the required formal written quality assurance and quality control program. This program should establish a system of:

Adherence to procedures
Prevention and detection of errors and other quality problems
Evaluation of complaints and adverse events
Appropriate investigations and corrective actions, such as:

Determining when recalls must be initiated, including procedures to immediately notify the prescriber of a failure of specifications with the potential to cause patient harm (e.g., strength, purity or other quality attributes)
Determining the distribution of any affected CNSP, including other affected lots, and the date and quantity of distribution
Identifying patients who received the CNSP
Recalling any unused dispensed stock and quarantining any remaining stock
Disposing of the recalled CNSP and documentation

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.

Look for USP 797: Revisions & Impacts, Part 1 Blog, on March 1.

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

Modular Compounding Cleanroom 101

Wed, 18 Jan 2023 18:26:42 GMT

by Matt Martin, PharmD, BCSCP, PCCA Director of Clinical Services and Mike DeLisio, PCCA North American Sales Director

If you're thinking of integrating compounding services into your pharmacy, are new to compounding or are a seasoned professional who’s looking to expand, it's important to know regulatory standards are changing the compounding environment. Modular cleanrooms are a great way to implement or expand existing cleanrooms and address the ever-evolving compounding pharmacy regulations and standards.

Advantages of choosing a modular compounding cleanroom include:

Lower costs
Greater customization & flexibility
Can be built adjacent to existing walls within pharmacy lab
Shorter build time
Easier to clean and maintain pressure
Reduces risk of insanitary conditions related to appropriate materials of construction
Less “down” time
Easier to supply air and exhaust air if required
Fewer disruptions for pharmacy & customers

What is a modular cleanroom?

Generally speaking, a modular cleanroom provides a dedicated space for compounding medicines within an enclosed environment. Its purpose is to help prevent compounded medications from potential contaminants and protect compounders from potentially harmful chemicals (hazardous materials) when appropriate controls are included in the design of the room. As such, a compounding cleanroom requires a well-sealed area using non-porous, powder coated materials that won’t harbor chemicals or microbes.

Modular cleanrooms are built using prefabricated materials. Given the increased regulatory focus on maintaining sanitary conditions in cleanroom environments, materials used in prefabricated constructions must be able to sustain routine exposure to harsh cleaning, sanitizing, decontaminating, or sporicidal solutions, which can easily degrade walls, doors, ceilings, and floors when they are not made from suitable materials.

Careful consideration should also be given to the cleanroom’s design, which directly impacts staff efficiency and efficacy of meeting cleaning standards. For example, walls, floors and ceilings designed with rounded or coved corners are much easier to clean than those with angular corners. Ceilings designed with a T-grid system with removable vinyl coated panels are easily sanitized and help safeguard against hidden microbes and other potential contaminants.

The type of compounding performed by your pharmacy will determine the types and levels of controls needed in the cleanroom:

A cleanroom used to compound non-sterile preparations (CNSP, USP 795) require the fewest controls;
A cleanroom used for CNSP using hazardous materials (USP 795 + USP 800) increases controls;
A cleanroom used to compound sterile preparations (CSP, USP 797) adds significant controls;
A cleanroom used for CSP using hazardous materials (USP 797 + USP 800) need maximum controls.

Additional Considerations

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

USP 795 revisions define minimum schedules for cleaning and sanitizing nonsterile compounding area surfaces. Cleaning and sanitizing procedures also changed in Chapter 797 revisions, including environmental monitoring and cleaning processes for specific categories of compounded sterile preparations. The FDA also focuses on the quality of the compounding environment for both CNSPs and CSPs in their guidance, Insanitary Conditions at Compounding Facilities .

Cleanroom Providers

Given regulatory oversight and complexities, it’s vital to partner with an experienced and reputable cleanroom provider with:

Knowledge of regulatory & compounding industry standards
Recommendations to improve pharmacy workflow & minimize patient inconvenience
Experience in modular compound cleanroom installation for type(s) of compounding
Guidance and support throughout the build process
1. Immediate notification of delays in cleanroom construction materials or build time
2. Previous customer experience (i.e., testimonials, peer organizations, peer collaboration)
3. Foremen and installation crews familiar with all wall-system components & trained from A to Z to install modular compounding cleanrooms

Initial Steps

Decide type(s) of compounding service(s) your pharmacy will offer (including lab expansion)
Become familiar with USP Minimum Standards
1. USP 795 sets minimum standards for non-sterile compounded preparations
2. USP 797 sets minimum standards for sterile compounded preparations
3. USP 800 sets minimum standards for compounding preparations with hazardous materials
Contact your state board of pharmacy to learn state board requirements
Become familiar with FDA guidance

Helpful Resources

PCCA partnered with ISO 9001 certified Nicos to deliver seamless cleanroom design with expert support that exceed USP minimum standards. Learn more here.

Look for our forthcoming four-part Blog series on USP 795, 797 and 800 Revisions & Impacts, scheduled to begin February 13.

For those looking for USP implementation training, we partnered with the Alliance for Pharmacy Compounding (APC) to provide courses on quality, compliance and regulatory requirements.

PCCA offers additional resources to our members, including eLearning Compounding Training and multiple online webinars and training sessions . Members with Clinical Services may also contact our Clinical Services team for help with formulas and other compounding concerns.

The Top 5 Blog Posts of 2019

Wed, 11 Dec 2019 16:29:00 GMT

By PCCA

And just like that, The PCCA Blog is closing its first full calendar year in the world. Between January and November of 2019, we published 71 blog posts and attracted tens of thousands of readers just like you, many of whom have subscribed as well. Thank you to all of our readers and subscribers for making it a wonderful year. We’re grateful to be able to produce content that professionals in the pharmacy compounding industry find valuable. Below are some of our top-performing posts of the year, reflecting some of the biggest changes that our area of health care is experiencing along with the ever-present need for research-based clinical information.

1. Notable Changes in the New USP <795>
Even though implementation of the new USP General Chapter <795> has been delayed due to appeals, it is still crucial to have a full and nuanced understanding of it. In this post, PCCA Clinical Compounding Pharmacist Matt Martin, PharmD, addresses notable changes to the new USP guidelines and provides some considerations for implementation.

2. An Innovative Option for Hirsutism: Topical Metformin
Clinically, hirsutism “refers to women with excess growth of stiff, pigmented hair (known as ‘terminal hair’) in a male pattern,” explains PCCA Clinical Compounding Pharmacist Sara Hover, RPh, FAARM. But she has exciting news about a potential option for women with hirsutism as well.

3. Oral vs. Topical Estrogen: What the Literature Is Showing about Health Risk
Compounded bioidentical hormone replacement therapy (BHRT) is an important treatment option for women around the world. Colleagues and patients alike come to experts like Pamela Smith, Nat Jones and Sara Hover for guidance. In this two-part post, they cover this all-too-important topic in the BHRT conversation, showing what current literature says about the usage of oral vs. topical estrogen.

4. Upcoming Changes to PCCA Formulas per the New USP <795>, <797> and <800>
The new and revised USP chapters affect many aspects of compounding, including formulas. In this post, PCCA Director of Formulation Development Melissa Merrell Rhoads, PharmD, details the updates we’re planning to make to our formulas based on the new USP guidelines. Pro tip: Look at the types of updates we’re going to make to our formulas as a guide for changes you should consider in your own.

5. Notable Changes in the New USP <797>
The new USP General Chapter <797> implementation is delayed because of appeals just like USP <795>, and that gives compounders more time to become familiar with it. Let Dylan Herr, RA/QA Development Manager at Eagle, help with that. She understands that this version makes significant revisions to the old one, and in this post, she provides you with an overview of those changes and strategies for implementing them.

We’re hard at work planning more content for 2020 that we hope will help you serve patients and grow your business, so keep an eye on The PCCA Blog. If you like what you see, consider subscribing. We’ll send you email notifications when we publish new posts. And if you’re already a subscriber, sit back and relax. We’ll be in touch.

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

Wed, 06 Nov 2019 14:52:00 GMT

By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development

As I wrote in the first part of this article, 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. However, USP later announced that they would postpone that official date because of pending appeals to certain parts of the revised chapters. The revisions in USP <795> and <797> affect the beyond-use date (BUD) that can be applied to compounded formulations, among other standards.

Even though the date when the revised chapters become official is postponed, our Formulation Development department is working on updates to 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.

Therefore, 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 <797> 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.

Changes Related to USP <797>
Sterilization Procedures
Section 10 of the revised USP Chapter <797> discusses sterilization and depyrogenation for compounded sterile preparations (CSPs). The method of sterilization plays a role in establishing the BUD for CSPs. The chapter establishes two categories for CSPs: aseptically processed, which are sterilized by filtration, and terminally sterilized, which are sterilized by steam heat (autoclaving) or dry heat. We will update PCCA formulas to reflect these compounding processes and provide specific instructions to render the preparations sterile.

BUDs
Section 14 of USP Chapter <797> discusses the parameters for establishing BUDs for CSPs. Table 11 of the chapter covers the parameters in detail, but the BUDs are based primarily on factors that affect the achievement and maintenance of sterility (risk of microbial contamination). The chapter assumes that CSPs will remain chemically and physically stable within the container-closure systems used. Chapter <797> does not provide specific direction on chemical stability, but requires that compounders consider the chemical and physical properties of the drug and/or its formulation as well as the compatibility of the container-closure system with the finished preparation. Since establishing a BUD per these new guidelines depends on multiple factors, our sterile formulas (outside of FormulaPlus formulas) will no longer assign a specific BUD, but will rather provide the relevant guidelines for compounders to determine the maximum BUD they will be able to assign based on whether sterility testing was performed and passed and the temperature at which the preparation will be stored.

According to USP Chapter <797>, a multiple-dose CSP must additionally pass antimicrobial effectiveness testing in accordance with USP Chapter <51>. After the multiple-dose CSP is dispensed, and upon initially entering or puncturing the container for the first time, “the multiple-dose container must not be used for longer than the assigned BUD or 28 days if supported by antimicrobial effectiveness testing results (see <51>) on the CSP, whichever is shorter.” As an alternative, compounders may dispense the preparation in smaller, sealed, single-use, sterilized and depyrogenated container-closure systems.

According to the new guidelines as they are currently written in USP Chapter <797>, there are no means to extend a BUD beyond the dates listed in Table 11. However, PCCA’s data on our sterile FormulaPlus formulas is still a valuable resource. Since USP <797> does not address chemical stability, these studied formulas provide documented chemical stability and therefore ensure the chemical and physical stability of the preparation. We have 12 sterile FormulaPlus formulas, and several are bracketed studies allowing for a broad range of active ingredient concentrations. PCCA members can view these in the FormulaPlus master list.

Given the significant changes in pharmacy compounding recently, it is as important as ever to ensure that compounders comply with the latest standards. We hope that the updates we will make to our formulas when the new USP <795> and <797> become official — as well as the change we’ve implemented for compliance with USP <800> — will help them do just that. 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 <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.

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.

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 <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.

THE PCCA BLOG

USP Chapter 795-Related Changes to Formulations

Non-preserved aqueous (PF) – 14 days refrigerated

Preserved aqueous – 35 days

Nonaqueous (anhydrous) oral liquid – 90 days

Nonaqueous (anhydrous) excluding nonaqueous oral liquids – 180 days

Component evaluation before use

Establishing and extending BUD

USP 795: Revisions & Impacts, Part 2

Beyond Use Dates

THE DESIGNATED PERSON(S)

Modular Compounding Cleanroom 101

What is a modular cleanroom?

Additional Considerations

Cleanroom Providers

Initial Steps

Helpful Resources

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

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

Notable Changes in the New USP <795>

References