THE PCCA BLOG

USP Chapter 800: Managing HD Spills

Wed, 02 Oct 2024 21:27:53 GMT

by Celeste Zizzamia, PharmD, BCSCP, PCCA Clinical Compounding Pharmacist

The United States Pharmacopeia (USP) General Chapter 800 addresses the handling of hazardous drugs (HDs) to minimize the risk of exposure to patients, health care workers and the environment. It became compendially applicable in November 2023. USP 800 contains some key elements that specifically apply to employee safety and HD containment. Section 16, for example, discusses managing HD spills and retaining spill kits on site. This article addresses HD spills that occur in a compounding pharmacy; however, it can be adapted for handling of non-HD chemical spills as well.

Spill Control

Team members involved in HD spill cleanup must be properly trained in spill management and the use of appropriate personal protective equipment (PPE), including respirators. Team members qualified in spill control must be available whenever HDs are handled in the pharmacy. Spills must be contained and cleaned immediately by qualified personnel.

Standard operating procedures (SOPs) that address spill management must also be in place. SOPs should include:

How to document HD spills
Personnel responsible for spill management
Prevention of spills
Cleanup of spills
Evaluation of personnel exposed during spills
Size and scope of spills, including capacity of spill kits
PPE (including respirators) and cleanup materials for handling spills
Location of spill kits

Spill Kits

Management and effective cleanup of HD spills require access to appropriate spill kits. Spill kits can be purchased from various vendors; however, it is often easier to make one by using PPE and cleaning materials already onsite. Doing so will allow your pharmacy staff to use properly fitted PPE and familiar cleanup materials.

Prepackaged spill kits often do not contain the correct sizes of PPE required by team members, nor do they have the correct N95 respirators that properly fit staff. Many prepackaged spill kits do not contain deactivating, decontaminating, cleaning and disinfectant cleaners (DDCD), nor do they contain the appropriate number of cleaners for containing a spill. In addition, your staff may not be familiar with the DDCD agents included in the spill kit and, therefore, may require additional training during a spill occurrence.

Creating a spill kit with materials already available in the pharmacy may make it easier, safer and less stressful for your staff to manage an HD spill, especially if HD spills seldom occur. Each spill kit should contain at least:

2 HD gowns
2 pairs of shoe covers
2 pairs of ATSM D6978 appropriately sized gloves
Fit tested N95 respirator (or other appropriate respirator as determined by size and scope of kit)
Low-lint absorbent materials/pads/wipes that may otherwise be used during routine cleaning procedures DDCD cleaner
Sign to notify of HD spill in the area
Container for disposal of HD waste
Eye protection (Please note: Goggles or a full facepiece respirator must be used as eye protection. Eyeglasses or safety glasses with side shields will not adequately protect eyes.)
Disposable scoop and/or shovel for container fragments

PPE sizes can be customized to the specific employees involved in spill management or based on the largest team member’s size.

The spill kit should be stored in a puncture-resistant container or bucket with a cover, so if broken glass or hard plastic fragments are within HD substance spills, all can go into the container for disposal. The container should be clearly labeled as a spill kit on the outside and placed in an easily identified area so all team members know where it’s located. At a minimum, spill kits should be located in areas where chemicals are received and prepared. Spill kits should also be labeled with the item of shortest expiration date on the outside of the kits; that item should be replaced as needed prior to expiration.

Spill Drills

When a liquid or powder HD spill occurs, staff members may feel stressed and unsure of how to handle the spill due to infrequent occurrences.

It’s recommended that staff routinely practice and understand how to handle a spill to reduce stress and potential confusion. Recommendations include:

Spill drills conducted frequently with staff responsible for management of spills
- Create mock HD spill using an inert substance:
  - Baby powder can be used to represent a powder spill
  - Water colored with food color can stand in for a liquid spill
  - Glow powder can be used to show a spill and see if any residue is left behind after following the procedures outlined in the spill kit
- Use spill kit contents to clean up spill
- Documentation of spill drills as part of training
Laminated instructions inside spill kit
- List of “how to” instructions contained within the spill kit
- One team member will clean the spill while another team member calls out step-by-step instructions to guide the cleanup of the spill
Disposal of spill contents
- Disposal of contents of spill contained in bag labeled for hazardous disposal
- Check with your waste disposal company on HD spill disposal procedures
  - Usually disposed of in same manner as other HDs

While USP 800 may not be enforceable in all states, it is important to note that federal agencies, such as the Occupational Safety and Health Administration (OSHA), the National Institute for Occupational Safety and Health (NIOSH) and the FDA, are involved in protecting compounding pharmacy staff from potential exposure to HDs.

Additional information regarding USP 800 is available in the blog: USP 800: Is It Enforceable?

Members with clinical services access may contact our Clinical Services team for help with spill kits and other compounding questions.

References

United States Pharmacopeia. Online Subscription Required.
OSHA. Controlling Occupational Exposure to Hazardous Drugs. Accessed September 2024 at https://www.osha.gov/hazardous-drugs/controlling-occex#resources

These statements are provided for educational purposes only. They have not been evaluated by the Food and Drug Administration, and are not to be interpreted as a promise, guarantee or claim of therapeutic efficacy or safety. The information contained herein is not intended to replace or substitute for conventional medical care or encourage its abandonment.

Nonsterile Pharmacy Training: Mastering the Role of the Designated Person

Wed, 24 Jul 2024 20:43:54 GMT

Revisions to USP 795, which went into effect November 1, 2023, introduce a new position for compounders: the Designated Person. This person or group of persons are responsible for creating and overseeing training, reviewing compounding staff competencies and maintaining training records for all compounding staff members. In this blog, we review the key responsibilities of the Designated Person for training standards and explore solutions that may help drive greater efficiencies in your compounding pharmacy’s training program.

by Jerra Banwarth, RPh, FAPC, PCCA Director of Online Education

Key Responsibilities of the Designated Person

As the guardian of pharmacy training, competency testing and recordkeeping, the Designated Person must:

Develop Training Programs: Create, implement and maintain a comprehensive training program that aligns with USP 795 requirements, including detailed, engaging and effective training materials.
Ensure Core Competencies: Competency isn't just about experience; it's about demonstrable skills. The Designated Person must ensure that all personnel involved in compounding are competent in their tasks, which involves annual assessments and practical evaluations of required competencies which are documented and tracked yearly.
Document and Track Training: Accurately record all staff training activities, completion rates and competency assessments; manage and track records; and make appropriate updates to training materials.
Implement Standard Operating Procedures (SOPs): Ensure staff members read, understand and adhere to the facility’s SOPs. This includes keeping the documents current and relevant to the pharmacy's daily operations on an annual basis.
Create Quality Assurance & Control with Corrective Actions: The designated person must create and manage a quality assurance and quality control program. Any deviation from those established standards will require immediate attention. The Designated Person must investigate, document and implement corrective actions for any out-of-specification events, ensuring continuous quality improvement.

Streamline Nonsterile Pharmacy Training Responsibilities with eLearning

We developed the PCCA eLearning Compounding Training & Learning Management System to simplify training and provide management efficiencies to ensure compounding pharmacies retain compliance.

Comprehensive eLearning Platform: Our eLearning platform delivers ready-made, interactive and USP-compliant training courses that cater to different learning styles (auditory, visual and tactile), enabling retention of information.
Customizable Competency Assessments: The competency assessment templates are customizable to fit specific procedures and equipment used in your pharmacy, saving significant time while ensuring assessments are relevant, consistent and comprehensive.
Automated Tracking and Documentation: The eLearning Management System included with the platform automates tracking and documentation of training and competency assessments. Expiration alerts serve as reminders for annual training and assessments while easy access to documents streamlines administrative processes.
Integration of SOPs: Integrating your facility’s SOPs into the Learning Management System can ensure that staff are not only reading but also understanding and applying these procedures. Interactive and scenario-based lessons make SOPs more relatable and easier to remember, helping staff understand and apply procedures.
Continuous Updates: Ongoing updates ensure training content remains current with industry changes, helping to maintain compliance and the overall quality of compounded products.

The role of the Designated Person is undeniably challenging, but with the right tools and solutions, it becomes manageable and even rewarding. By leveraging PCCA’s comprehensive eLearning Compounding Training & Learning Management System, the Designated Person can effectively implement and sustain robust training programs. This ensures compliance with USP 795 and fosters a culture of excellence and continuous improvement within your compounding pharmacy.

Click to learn more about how our eLearning Compounding Training & Learning Management System can help your pharmacy and request a free demo!

PCCA members with clinical services access may contact our Clinical Services team for help with USP 795 compliance and other compounding concerns.

USP 800: Is It Enforceable?

Wed, 10 Jan 2024 22:42:05 GMT

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

Sections of the United States Pharmacopeia (USP) that don’t get enough attention are the General Notices. USP General Notices describe how the USP works. For example, this particular notice has shaped the applicability of USP 800:

“Applicable general chapters” means general chapters numbered below 1000 or above 2000 that are made applicable to an article through reference in General Notices, a monograph, or another applicable general chapter numbered below 1000.¹

Until recently, USP 800 was an official chapter within USP but wasn’t considered “compendially applicable” because it wasn’t referenced in the General Notices, a monograph or another applicable general chapter numbered below 1000. However, on November 1, 2023, revisions to USP Chapter 795 and Chapter 797 became official. USP 795 and 797 are applicable general chapters that reference USP 800, which make USP 800 compendially applicable and potentially enforceable.

To determine if USP 800 is enforceable in your practice, you need to know which state or states your pharmacy is licensed in and know the related state board of pharmacy requirements. In my review of state regulations, more than 30 states have language generally requiring compliance with USP when compounding. This general language would require compliance with USP 795, 797 and 800.

Alternatively, some states are not allowed to adopt items by reference in their regulations. In other words, some states cannot simply say, “Follow USP,” but are required to write their own regulations. Some of those states write regulations that closely mirror USP chapters, but those state regulations may differ from USP. A few states have requirements that are more stringent than USP 795, 797 and 800. Other states are still considering USP 800 and will make their decisions at some point in the future. Several states have also delayed enforcement of USP 795, 797 and 800 for one to two years.

A few resources may help you understand where your state board of pharmacy is on these topics, such as state board of pharmacy websites, newsletters and the “law book” of each state. Calling a state board of pharmacy or inspectors for information — notably with mixed results — may produce a productive result. Another resource available to members of the Alliance for Pharmacy Compounding (APC) is their Compilation of State-Adopted USP 795, 797 and 800 Rules. Please note that use of this resource requires APC membership.

If you’ve researched the potential enforcement of USP 800 where your pharmacy is licensed and found that it’s not currently being enforced, you may think that nothing needs to be done when compounding hazardous drugs. However, the FDA does.

The FDA releases its thoughts on a variety of topics through what they call guidance documents. The preface in the agency’s Guidance for Industry, Insanitary Conditions at Compounding Facilities states:

This guidance represents the current thinking of the Food and Drug Administration (FDA or the Agency) on this topic. It does not create any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the title page.

The guidance initially says that it’s not binding on the FDA or the public — which might make you think it’s not important — to the contrary, that guidance is a critical resource for understanding FDA’s thoughts and expectations during the agency’s inspections of compounding facilities, independent of whether or not any particular USP chapters are enforced by the state board of pharmacy. The guidance specifically calls out the handling of hazardous drugs, including sensitizing or highly potent drugs:

Handling bulk drug substances or drug products that are hazardous, sensitizing, or highly potent (e.g., hormones) with inadequate controls to prevent cross-contamination. This includes:

inadequate dedication, segregation, and containment (e.g., a powder-containment hood) of a suite, room, or piece of equipment based on risk;
inadequate cleaning of rooms, work surfaces, and equipment (e.g., utensils), including spills;
inadequate segregation of HVAC systems (as appropriate for the operation); and
inadequate control over the movement of personnel and materials.

Other federal agencies, including the Occupational Safety and Health Administration (OSHA) and the National Institute for Occupational Safety and Health (NIOSH), are involved in protecting compounding pharmacy staff from potential exposure to hazardous drugs.

USP 800 may or may not be enforced by your board or boards of pharmacy, despite being an official chapter that is now compendially applicable within the USP. Regardless of a board of pharmacy’s position, the FDA, OSHA and NIOSH are interested in preventing the potential for cross-contamination of hazardous, sensitizing and highly potent drugs on patients and compounding pharmacy staff.

The FDA rarely, if ever, references a USP chapter in inspection reports for compounding pharmacies. The state’s position on USP 800 does not affect the FDA’s approach to preventing insanitary conditions from existing in compounding facilities. Nor does the state’s position affect OSHA regulations.

Members with clinical services access may contact our Clinical Services team for help with compounding sterile and nonsterile formulations in compliance with USP Chapters 795, 797, 800 and the FDA’s Insanitary Conditions Guidance, as well as other compounding concerns.

References

United States Pharmacopeia. Online Subscription Required.

USP Chapters 795- and 797-Related Changes to PCCA Formulations

Wed, 01 Nov 2023 17:51:51 GMT

USP Chapters 795- and 797-Related Changes to PCCA Formulations

by Melissa Merrell Rhoads, PharmD, PCCA Director of Formulations

USP Chapter 795

USP Chapter 795 describes the full guidelines for pharmaceutical compounding of nonsterile preparations (CNSPs). Specifically looking at the revisions related to BUDs, 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 (aw or Aw). An aqueous preparation is one that has an aw ≥ 0.6 (e.g., emulsions, gels, creams, solutions, sprays or suspensions). Nonaqueous dosage forms have an aw of < 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).

The following shows the revised BUDs and Notes that were added to all PCCA nonsterile formulas.

Non-preserved aqueous (PF) – 14 days refrigerated

Note: According to USP guidelines, “in the absence of an 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.*

Preserved aqueous – 35 days

Note: According to USP guidelines, “in the absence of an 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.*

Nonaqueous (anhydrous) oral liquid – 90 days

Note: According to USP guidelines, “in the absence of an 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.*

Nonaqueous (anhydrous) excluding nonaqueous oral liquids – 180 days

Note: According to USP guidelines, “in the absence of an 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 were added to bring awareness to new requirements of USP Chapter 795 during the compounding process. Examples of the notes include visually inspecting all components prior to use and visually inspecting the final preparation, including the container closure integrity. The Notes are not all encompassing. We recommend you become familiar with USP Chapter 795 to ensure compliance with all requirements.

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 an 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 an FDA-registered laboratory when extending the BUD of an aqueous CNSP.

USP Chapter 797

USP Chapter 797 describes the minimum standards to follow for the preparation of compounded sterile preparations (CSPs) for human and animal drugs. If adopted by your state board of pharmacy, you must meet the requirements of USP 797 to ensure the sterility of CSPs, which include but are not limited to injections, irrigations (for internal body cavities), ophthalmics and inhalations.

Notable changes in the PCCA sterile formulas for USP 797 appear as updates in the compounding procedures and Notes, as well as BUD revisions.

Sterilization and depyrogenation procedures described in Section 10 of USP 797 state, “The sterilization method used must sterilize the CSP without degrading its physical and chemical stability or the packaging integrity. The primary means of sterilizing compounded preparations are: terminal sterilization, which includes dry heat or autoclave, and filtration.” Note: USP 797 requires pre-filtering solutions through a 1.2-micron filter to remove potential particulate matter prior to sterilizing the preparation through autoclave or dry heat.

FILTRATION

Sterilization Procedure for Aqueous Solutions

Filter the solution through a sterile and depyrogenated filter (appropriate for pharmaceutical use) with a nominal pore size of 0.22 micron (PCCA #35-1156) or smaller into an appropriate sterilized and depyrogenated container-closure system. According to USP guidelines, a bubble point test must be performed on the used filter to ensure integrity of that filter. Refer to product specifications for the required minimum pressure.

Sterilization Procedure for Oil or Alcohol Solutions

Filter the solution through a sterile and depyrogenated Teflon® filter (appropriate for pharmaceutical use) with a nominal pore size of 0.2 micron (PCCA #35-2720) or smaller into an appropriate sterilized and depyrogenated container-closure system. According to USP guidelines, a bubble point test must be performed on the used filter to ensure integrity of that filter. Refer to product specifications for the required minimum pressure.

AUTOCLAVE

Sterilization Procedure for Solutions

Filter the solution through a sterile and depyrogenated filter (appropriate for pharmaceutical use) with a nominal pore size of not larger than 1.2 micron (PCCA #35-5755) for removal of potential particulate matter into an appropriate sterilized and depyrogenated container-closure system.

Crimp and seal the serum bottle. Autoclave the preparation until the contents within the vial have reached 121°C, 15 psi for the length of time necessary to render the preparation sterile.

The duration of this process can vary between 20 to 60 minutes, depending on preparation volume and load configuration. This process must be verified and documented with each sterilization run or load through the use of Sterilization Integrators, Steam (PCCA #35-3848) and SporeView® Steam Biological Indicators (PCCA #35-3634) per USP guidelines. Refer to USP 1229, Sterilization of Compendial Articles, for more information.

Sterilization Procedure for Suspensions

When autoclaving compounded suspensions, the initial filter step is removed. After the autoclave process, it is important to provide constant agitation while the preparation is cooling to prevent clumping of the suspension.

DRY HEAT/CONVECTION

Sterilization Procedure for Solutions

Crimp and seal the serum bottle. Dry heat the oil solution in a convection oven until the contents of the vial have reached a temperature of 160°C or higher for a sufficient time to render the preparation sterile.

The duration of time for this process can vary and will depend upon preparation volume and load configuration. Per USP guidelines, this process must be verified and documented with each sterilization run or load through the use of SporeView® Culture Set Biological Indicators (PCCA #35-3632) and temperature monitoring. Refer to USP 1229, Sterilization of Compendial Articles, for more information. Remove from oven immediately and allow to cool to room temperature.

Sterilization Procedure for Suspensions

For dry-heat sterilizing compounded oil suspensions, remove the initial filter step. After the dry-heat process, provide constant agitation while the preparation is cooling to prevent clumping of the suspension.

MULTIPLE DOSE COMPOUNDED PREPARATIONS

USP 797 requires preserved multiple-dose CSPs: a multiple dose CSP must be prepared as a Category 2 or Category 3 CSP. An aqueous multiple-dose CSP must pass antimicrobial effectiveness testing per USP 51 Antimicrobial Effectiveness Testing (AET) standards. After a multiple-dose CSP (aqueous or nonaqueous) is dispensed and upon initially entering or puncturing the container on first use, the preparation’s BUD is 28 days or less.

BEYOND-USE DATES (BUDS)

We do not list specific BUDs on our sterile formulations due to several parameters for consideration when establishing BUDs. As a guide, we include the following Note on all PCCA sterile formulations:

Note: USP Chapter 797 sets forth parameters to consider when establishing BUDs, stating, “BUDs for CSPs should be established conservatively to ensure that the drug maintains its required characteristics (i.e., stability and sterility) until its BUD.” According to USP Chapter 797, “BUDs for CSPs must be established in accordance with Table 12 for Category 1 CSPs, Table 13 for Category 2 CSPs and Table 14 for Category 3 CSPs. One day is equivalent to 24 hours. The BUD limits in these tables are based on the risk of microbial contamination or not achieving and maintaining sterility despite implementation of the requirements in this Chapter. The CSP formulation must remain chemically and physically stable, and its packaging must maintain its integrity for the duration of the BUD.”

Extending the BUD of a sterile preparation per current USP Chapter 797 requires sterility testing for each batch in compliance with USP Chapter 71, including method suitability. Alternative sterility testing methods may be used per USP 797 if they are verified to be at least as effective and reliable as those described in USP 71. Other necessary data may include published or unpublished stability studies utilizing stability-indicating methods, endotoxin testing, container-closure integrity, antimicrobial effectiveness testing (where relevant), potency testing after compounding, as well as other relevant release checks, testing and documentation.

Members with clinical services access may contact our Clinical Services team for help with compounding sterile and non-sterile formulations in compliance with USP Chapters 795 and 797, as well as other compounding concerns.

Versions of this Blog originally appeared in PCCA’s members-only magazine, the Apothagram, as well as in separate Blog posts.

Modular Compounding Cleanroom 101

Wed, 11 Oct 2023 15:48:05 GMT

Modular Compounding Cleanroom 101: Why would your pharmacy need one?

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 operational costs
Greater customization & flexibility
Can be built adjacent to existing walls within pharmacy lab
Shorter build time
Easier to clean and maintain press53tg45lated 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
- Immediate notification of delays in cleanroom construction materials or build time
- Previous customer experience (i.e., testimonials, peer organizations, peer collaboration)
- 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.

Watch our free webinar — Preparing for USP Compliance: What You Need & Need to Know — to learn how pending USP updates may impact cleanrooms in your state and pharmacy, as well as other relevant information.

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

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.

How to Determine API Calculations in Pharmacy Compounding

Tue, 18 Apr 2023 17:19:07 GMT

By Matt Martin, PharmD, PCCA Clinical Services Manager, and Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development

We prepared this article to guide compounding pharmacies on how to review USP monographs related to an active ingredient as well as its certificate of analysis (COA) to determine the appropriate amount of chemical to use in compounding a desired medication. It will provide considerations for pharmacies as they develop their standard operating procedures (SOPs) for their compounding practices. We will review the process of evaluating a chemical and use examples to illustrate each step. It should be noted that the examples are based on PCCA chemicals and that there can be differences in the chemicals from other vendors that may result in them having different specifications on their COAs.

In pharmacy compounding, it is necessary to understand how the strength of medications is expressed and which calculations are needed to determine the amount of any active pharmaceutical ingredient (API) in a compounded medication. In order to accomplish this, the pharmacy should have a process detailed in an SOP. Below are the general steps that the SOP should address followed by examples of applying these steps to specific chemicals.

In determining the applicability of the data from the COA of the chemical:

Evaluate how the strength of the compounded preparation is going to be expressed
Evaluate if the assay as well as water and/or solvent content (loss on drying) from the COA will need to be applied
Evaluate if other conversions, such as a base/salt calculation or molecular weight “fixed factor” calculation, will be needed

1. Evaluate how the strength of the compounded preparation is going to be expressed.

One of the best resources for understanding how the strength of drug products is expressed is the United States Pharmacopeia (USP). It sets standards for chemical quality and contains both chemical and drug product monographs that detail what the assay for those products is measuring in terms of the molecular formula of the drug. This is very helpful when determining the calculations that apply to any specific API. Reviewing the USP chemical monograph and the drug product monograph will allow you to determine if the API strength is expressed as the free base, salt form, esterified form, hydrated form, anhydrous form, etc. Compounders should therefore strongly consider having access to the full USP to be able to use both the chemical and drug product monographs. Access to the full USP is available at uspnf.com.

While the USP monographs cover most drug products and APIs, not all drug products and APIs have an official USP monograph. When a USP drug product monograph is not available, it may be necessary to review the package insert(s) of drug products to gain an understanding of how the strength of a drug product is expressed.

Different scenarios exist, one of them being a situation when no calculation is necessary. Here is an example:

Example of No Calculation Needed: Morphine Sulfate Pentahydrate

One good example is morphine sulfate pentahydrate. Here is the USP chemical monograph definition: “Morphine Sulfate contains not less than 98.0 percent and not more than 102.0 percent of (C₁₇H₁₉NO ₃)₂ · H₂SO₄, calculated on the anhydrous basis.”¹ This reveals that the assay of the chemical morphine sulfate pentahydrate is measuring the morphine sulfate content and not the morphine sulfate pentahydrate content of the chemical.

However, the USP drug product monograph provides this definition: “ Morphine Sulfate Injection is a sterile solution of Morphine Sulfate in Water for Injection. It contains NLT 90.0% and NMT 110.0% of the labeled amount of morphine sulfate pentahydrate [(C ₁₇H₁₉NO₃)₂ · H₂ SO₄ · 5H₂O] ”² (emphasis added).

This example shows that while the chemical assay measures the anhydrous morphine sulfate content of the chemical, the drug is dosed on the amount of morphine sulfate pentahydrate. Therefore, no calculation is required when compounding with morphine sulfate pentahydrate. For this reason, we have the following note on all the PCCA morphine sulfate formulas: “Dosing of Morphine Sulfate is based on the amount of Morphine Sulfate Pentahydrate therefore no calculation is required.”

2. Evaluate if the assay as well as water and/or solvent content (loss on drying) from the COA will need to be applied.

Once you know how the strength of a drug product is expressed, you can examine the API that you have and determine what calculations may need to be performed. These calculations may include accounting for the assay as well as the water and/or solvent content (loss on drying), or the use of a fixed conversion factor based on your pharmacy’s SOP.

It is important to note that there is no uniform set of calculations that can be applied to all chemicals equally. Each set of calculation considerations is specific to a particular chemical. The assay as well as the water and/or solvent content, or loss on drying, are specific to each lot number of the API and can be found on each lot’s COA.

The assay of the chemical is a measure of the potency of that lot of chemical. When a chemical assay is performed, it may be tested as it is in the container you receive, which would be the “as-is basis.” According to the General Notices of USP, “All calculations in the compendia assume an ‘as-is’ basis unless otherwise specified.”³ In the case of an assay done on the as-is basis, only the assay would be needed for calculations as opposed to the assay and water content or loss on drying.

The alternatives to “as-is” are when the assay is performed on the “anhydrous basis” or on the “dried basis.” When the assay is performed on either the anhydrous basis or on the dried basis, the chemical is exposed to conditions (such as a chemical-specific heating process) that cause any water or a volatile substance, such as a solvent involved in the manufacturing process of the chemical, to be driven out of the chemical prior to the assay being performed. When water alone is being driven out of the chemical, this will be reflected on the COA as “water” or “water determination.” When the substance being driven out is water and/or another volatile substance, this will be reflected on the COA as “loss on drying” or “LOD.” The specifics of these tests are discussed in their respective USP chapters, USP <921> Water Determination and USP <721> Loss on Drying. Using the assay and/or the water or loss on drying from the COA is one part of assuring the appropriate potency of the compounded medication.

Let’s review an example using naltrexone for evaluating the COA to calculate the appropriate amount of naltrexone HCl USP dihydrate versus anhydrous naltrexone HCl USP:

Example of Using COA to Calculate API Amount: Naltrexone HCl

Here is the naltrexone HCl USP chemical monograph definition: “Naltrexone Hydrochloride contains NLT 98.0% and NMT 102.0% of naltrexone hydrochloride (C20H23NO4 · HCl), calculated on the anhydrous, solvent-free basis.”4

The naltrexone HCl USP drug product monograph provides this definition: “Naltrexone Hydrochloride Tablets contain NLT 90.0% and NMT 110.0% of the labeled amount of naltrexone hydrochloride (C20H23NO 4 · HCl).”5

The USP naltrexone HCl chemical monograph and the naltrexone HCl tablet drug product monograph both measure the amount of naltrexone HCl. The naltrexone HCl USP chemical monograph measures the naltrexone HCl on the anhydrous and solvent-free basis. Therefore, you need to use the COA to calculate either the amount of naltrexone HCl anhydrous or dihydrate or anhydrous naltrexone HCl in compounded formulations.

Naltrexone Hydrochloride USP Anhydrous may have a limit of total solvents up to 5% (and up to 11% for the Dihydrate form) and an assay of 98 – 102% calculated on the anhydrous and solvent-free basis. It is important that you obtain a Certificate of Analysis for your specific lot number to verify the percentage of limit of total solvents and assay (on the anhydrous and solvent-free basis).

The following is an example calculation based on Lot #C200577 with a limit of total solvents of 0.4% and an assay of 100.3% on the anhydrous and solvent-free basis.

Naltrexone Hydrochloride 1.5 mg per capsule is required in this formula. The limit of total solvents is 0.4% for this lot. Thus, 100% minus 0.4% yields 99.6% of anhydrous and solvent-free Naltrexone Hydrochloride. Divide 1.5 mg per capsule by 99.6% equals 1.506 mg per capsule of Naltrexone Hydrochloride (anhydrous and solvent-free). Since the assay is 100.3% on the anhydrous and solvent-free basis, the required amount of Naltrexone Hydrochloride USP Anhydrous will be 1.506 mg per capsule divided by 100.3% which is 1.501 mg per capsule, or 0.15 Gm for each 100 capsules.

Naltrexone HCl USP dihydrate may be used and calculated in the same manner. The difference is the variable amount of total solvent content between the anhydrous version (may be up to 5%) and the dihydrate version (may be up to 11%). Again, it is important that you obtain a COA for your specific lot number to verify the percentage of solvent content and the assay (on the anhydrous and solvent-free basis) for either chemical used.

3. Evaluate if other conversions, such as a base/salt calculation or molecular weight “fixed factor” calculation, will be needed.

A base/salt conversion or other calculations may also be necessary to determine how much API you will need to use in a given formulation. Sometimes, using the COA to calculate the amount may consistently produce very similar results as a “fixed conversion factor” based on a molecular weight ratio. USP does not have specific guidance on the issue of using the COA versus the use of a “fixed factor” when deemed appropriate. Policies involving the decision to choose either the COA or a fixed factor should be clearly delineated in the pharmacy’s SOP, and the accompanying rationale should be explained. The most accurate method is always the use of the lot-specific COA. Each pharmacy must determine what is an acceptable cutoff if following the practice of using a fixed factor.

An example of using a fixed conversion factor based on molecular weight ratio is estradiol. Amlodipine besylate and prazosin HCl provide good illustrations of base/salt conversion as well. We present these examples below:

Example of Fixed Conversion Factor: Estradiol

The estradiol USP drug product monographs discuss how the strengths of these products are expressed: “Estradiol Tablets contain not less than 90.0 percent and not more than 115.0 percent of the labeled amount ofC₁₈H₂₄O₂.” ⁶ “Estradiol Vaginal Cream contains NLT 90.0% and NMT 110.0% of the labeled amount of estradiol (C₁₈H₂₄O₂) in a suitable cream base.”⁷

The estradiol USP chemical monograph states, “Estradiol contains not less than 97.0 percent and not more than 103.0 percent of C₁₈H ₂₄O₂, calculated on the anhydrous basis.”⁸

When you compare the USP drug product monographs to the chemical monograph, you can note that these monographs are all measuring the chemical in the same form: C₁₈H₂₄O₂. Thus, the data from the COA will apply. In the case of estradiol, the assay is measured on the anhydrous basis, so the water content from the COA will also need to be used in the calculations.

Let’s say that 0.1 Gm of estradiol is needed for a compounded formulation and that the COA for your lot of estradiol USP has an assay of 99.7% and a water content of 3.1%. The first step will be to work with the water content. The water content will be subtracted from 100% and then converted to a decimal. The amount calculated in the previous step will be divided by this decimal.

100% – 3.1% = 96.9%

96.9%/100% = 0.969

0.1 Gm/0.969 = 0.1032 Gm

The next step will be to use the assay, but it will need to be converted from a percentage to a decimal. This is done by dividing the percentage by 100%.

Assay 99.7%/100% = 0.997

The amount of (anhydrous) API needed is then divided by this decimal.

0.1032 Gm/0.997 = 0.1035 Gm

In order to have 0.1 Gm of estradiol for the formulation, it will require 0.1035 Gm of this lot number of estradiol USP.

However, upon reviewing numerous COAs for estradiol USP, you will see that application of the assay and water content will consistently require approximately 3% more API be used in each formulation. For this reason, some pharmacies choose to employ a fixed factor of 1.033 for estradiol formulations as opposed to the specifics of the COA for each lot due to this consistency. In this case, a formulation that requires 0.1 Gm of estradiol would be calculated as 0.1033 Gm of any lot of estradiol hemihydrate USP. PCCA’s formulations also use this fixed conversion factor and have the following note listed on all formulas:

“Estradiol 1 milligram is equivalent to Estradiol Hemihydrate USP 1.033 milligrams. This fixed conversion factor is based on the ratio of the molecular weight of Estradiol Hemihydrate to the Estradiol base. (You may calculate the amount of Estradiol to be used in the formulation by using the assay and water content from the C of A for your specific lot. However, do not calculate using BOTH the fixed conversion and the C of A assay & water content.) You should follow your standard operating procedure for appropriately calculating these amounts for your formulations. ”

If you consider that the difference in this example between using the COA and the fixed conversion factor was 0.0002 Gm, this is a difference of 0.2% in the final formulation. Each pharmacy must determine what is acceptable if following this practice. It is important to note that you should not calculate using both the fixed conversion and the COA assay and water content.

As another example, some pharmacies, and PCCA formulations, also use a fixed conversion factor for lidocaine HCl monohydrate. Here is the fixed conversion factor: Lidocaine HCl monohydrate 1 mg is equivalent to lidocaine HCl 0.938 mg.

Example of Base/Salt Conversion: Amlodipine Besylate

What many would call “amlodipine tablets” are found in the USP drug product monographs as “amlodipine besylate tablets.” Based on the name of the USP drug product monograph, one might believe that these tablets express their strength as the amount of amlodipine besylate. However, upon review of the amlodipine besylate tablet monograph’s definition section, one finds: “Amlodipine Besylate Tablets contain NLT 90% and NMT 110% of the labeled amount of amlodipine (C₂₀H₂₅ClN₂O ₅).”⁹ The drug product monograph shows that these tablets express their strength as the amount of amlodipine instead of the amount of amlodipine besylate. This is an important distinction when comparing it to the bulk API used to compound amlodipine oral suspension or capsules. The bulk API is amlodipine besylate (C₂₀H₂₅ ClN₂O₅ · C₆H₆O₃S), which is a salt form of amlodipine. In order to determine the amount of amlodipine besylate that is equivalent to amlodipine, we will have to employ a base/salt conversion.

A base/salt conversion is a ratio of the molecular weight of the salt form of the chemical to the molecular weight of the base form of the chemical, or vice versa. The molecular weight of amlodipine besylate (the salt form) is 567 Gm/mole. The molecular weight of amlodipine (the free base form) is 409 Gm/mole. The ratio of the molecular weights of amlodipine besylate to amlodipine is 567/409, or 1.39. This means that for every gram of amlodipine needed, the formulation will require 1.39 Gm of amlodipine besylate.

PCCA amlodipine formulations therefore use this fixed base/salt conversion: Amlodipine 1 mg is equivalent to amlodipine besylate 1.39 mg. Therefore, an amlodipine 1 mg/mL oral suspension would require 1.39 mg/mL amlodipine besylate, or 0.139 Gm for a 100 mL preparation.

Example of Base/Salt Conversion: Prazosin HCl

An example of a base/salt conversion that must also take the COA into consideration is prazosin HCl polyhydrate. The prazosin HCl USP chemical monograph provides this definition: “Prazosin Hydrochloride contains NLT 97.0% and NMT 103.0% of prazosin hydrochloride (C₁₉H ₂₁N₅O₄ · HCl), calculated on the anhydrous basis.”¹⁰

The prazosin HCl USP drug product monograph provides this definition: “Prazosin Hydrochloride Capsules contain an amount of prazosin hydrochloride (C₁₉H₂₁N₅O₄ · HCl) equivalent to NLT 90.0% and NMT 110.0% of the labeled amount of prazosin (C₁₉H₂₁N₅O₄).” ¹¹

The chemical monograph reveals that the assay is measuring the prazosin HCl (salt form) content; however, the drug product monograph shows the strength as prazosin (free base). In the prazosin formulas developed at PCCA, we document multiple steps of calculation to obtain the correct amount of prazosin HCl USP polyhydrate to be used in a prazosin compound: First, a salt conversion from prazosin to prazosin HCl must be done. Second, the percentage of water content may vary lot to lot from 8–15% for prazosin HCl USP polyhydrate. Third, the assay of prazosin hydrochloride USP (on the anhydrous basis) may also vary lot to lot between 97–103%

All of these need to be taken into account. As always, it is important that you obtain a COA for your specific lot number to verify the percentage of water content and the assay (on the anhydrous basis).

The following is an example calculation with a water content of 11.7% and an assay of 99.3% on the anhydrous basis.

Let’s assume prazosin 1 mg/mL is required in a suspension formula. Prazosin 1 mg is equivalent to prazosin HCl 1.095 mg. Multiplying 1 mg by 1.095 equals prazosin HCl 1.095 mg/mL that is required in this formula. The water content is 11.7%; thus, 100% minus 11.7% yields 88.3% of anhydrous prazosin HCl. Dividing 1.095 mg by 88.3% equals prazosin hydrochloride anhydrous 1.24 mg/mL.

Since the assay is 99.3% on the anhydrous basis, the required amount of prazosin HCl USP polyhydrate will be 1.24 mg/mL divided by 99.3%, which is 1.249 mg/mL, or 0.1249 Gm for every 100 mL of suspension.

As stated above, the processes and examples described in this article provide considerations for you as you develop your SOPs for your compounding practice. These examples demonstrate the need to evaluate the application of calculations to each drug individually. In addition, reviewing the USP chemical and drug product monographs when they are available provide clarity as to how the data should be applied in each case. Using these resources should help you determine the applicability of the chemical’s COA and how to accurately calculate the appropriate amount of API to use for the needed dose. Our Clinical Services department is available to work with PCCA members on these calculations and other formulation needs they may have.

Matt Martin, PharmD, is the Clinical Services Manager 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.

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.

References

1. United States Pharmacopeial Convention. (2020). Morphine sulfate. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

2. United States Pharmacopeial Convention. (2020). Morphine sulfate injection. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

3. United States Pharmacopeial Convention. (2020). General notices and requirements. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

4. United States Pharmacopeial Convention. (2020). Naltrexone hydrochloride. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

5. United States Pharmacopeial Convention. (2020). Naltrexone hydrochloride tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

6. United States Pharmacopeial Convention. (2020). Estradiol tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

7. United States Pharmacopeial Convention. (2020). Estradiol vaginal cream. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

8. United States Pharmacopeial Convention. (2020). Estradiol. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

9. United States Pharmacopeial Convention. (2020). Amlodipine besylate tablets. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

10. United States Pharmacopeial Convention. (2020). Prazosin hydrochloride. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

11. United States Pharmacopeial Convention. (2020). Prazosin hydrochloride capsules. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

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

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?

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.

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.

Proposed Changes to USP 795

Tue, 02 Nov 2021 13:37:00 GMT

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

This article ws updated on January 14,2022.

On September 1, 2021, the United States Pharmacopeia (USP) prepublished their latest proposed revisions to General Chapter 795, Pharmaceutical Compounding — Nonsterile Preparations. These proposed changes are not in effect now and have several steps to go before they will become official. The most important next step in the process is the comment deadline for this chapter, which is March 17, 2022. Pharmacies and other stakeholders that wish to submit comments about improvements to the proposed changes will need to do so by that date.

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

Training

In the proposed changes to USP 795, there are some themes that stand out when compared to the current version of the chapter. There is a significant expansion and emphasis on training, including knowledge in and demonstration of core competencies. It is important to highlight that training includes not only the ability to read and understand the concepts, but also for the trainee to demonstrate both their knowledge and their ability to perform the tasks. The training and demonstration of knowledge and ability must also be documented. The core competencies listed in the proposed revisions are:

Hand hygiene
Garbing
Cleaning and sanitizing
Handling and transporting components and compounded nonsterile preparations (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:

Reading and understanding the chapter as well as other applicable standards and relevant literature (such as USP Chapters 7, 51, 659, 800, 1112, 1163, 1178 and 1231, all of which are referenced in USP 795)
Understanding and interpreting safety data sheets (SDSs) and, if applicable, certificates of analysis (COA)
Reading and understanding procedures related to the staff member’s compounding duties

It is significant that hand hygiene, garbing, cleaning and sanitizing are cited as core competencies for nonsterile compounding. While some may consider garbing and personal protective equipment (PPE) as items there to protect the compounder from drugs and chemicals they work with, the garbing process and PPE are also significant tools in reducing the potential contamination that people can produce through shedding of skin and bacteria throughout the workday. In other words, properly donned PPE protects the compounder from chemicals and protects the chemicals (and CNSPs) from the compounder.

Cleaning and Sanitizing

Table 1 of the proposed changes to USP 795 also defines minimum schedules for cleaning and sanitizing nonsterile compounding areas. While this chapter is addressing nonsterile compounding, it is also important to consider that USP has multiple chapters on microbial limits for nonsterile preparations, including USP 61 and USP 62. These chapters look at total microbial contamination limits and specific objectionable microorganisms that should not be in nonsterile compounds. The FDA has also been focused on the quality of the environment in which nonsterile preparations are compounded through their guidance document Insanitary Conditions at Compounding Facilities and has been explicit in stating that insanitary conditions are a focus for their inspections of compounding facilities. I’ve written more about the FDA Insanitary Conditions guidance on The PCCA Blog as well.

Beyond-Use Dates

Beyond-use dates (BUDs) are always of significant interest to compounders because they affect patient care opportunities. In considering BUDs, it is common to consider the chemical and physical properties of the active pharmaceutical ingredient (API) in the formulation. However, the proposed chapter increases focus on the container closure system that will be used for the final formulation. Compounders are expected to consider the potential of the container closure to interact with the CNSP, visually inspect the integrity of the container closure prior to releasing the CNSP and consider the possibility of the container closure degrading over the BUD of the preparation. 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 for the compounded preparation.

The concept of water activity was introduced in the last proposed revisions to Chapter 795 and has been further highlighted in these latest proposed revisions. Water activity is the water that is unbound and freely available to participate in chemical, biochemical or physicochemical reactions or provide an environment that can support microbial growth. Compounded preparations with a water activity less than 0.6 are considered anhydrous and are provided longer default BUDs because they are less likely to allow degradation of the active ingredient or allow microbial growth. The discussion on water activity has been expanded in the proposed revisions, and examples of the water activity of various dosage forms have been added to the chapter as opposed to only referencing USP 1112, which is the chapter on water activity.

Also on The PCCA Blog: Why Water Activity Matters in Pharmacy Compounding

The maximum BUDs that can be assigned to compounded nonsterile preparations without additional stability data remain fairly similar to the former proposed revisions, but with a few key updates. Nonaqueous topicals, suppositories and troches are now preparations that can have up to a 180-day default BUD. Nonaqueous oral preparations still have a 90-day maximum default BUD. Aqueous dosage forms remain separated based on whether or not they have a preservative: Non-preserved aqueous dosage forms can have up to a 14-day BUD when stored at refrigerated temperature, and preserved aqueous dosage forms can have up to a 35-day BUD at room temperature or under refrigeration.

BUDs of preparations can be extended up to 180 days with a stability study (published or unpublished) using a stability-indicating analytical method for the API(s), CNSP and type of container closure that will be used. If the BUD of an aqueous preparation is being extended beyond the default BUD offered by the proposed revisions, the formulation must also be tested for the performance of the preservative, known as antimicrobial effectiveness testing, according to USP Chapter 51.

The proposed revisions to Chapter 795 also permit the use of bracketing for both stability studies and antimicrobial effectiveness testing. Bracketing is performing the tests on a low concentration and a high concentration of the active ingredient(s) in the formulation. If the formulation passes the tests at both concentrations, then the data can be applied to all strengths of the formulations between the two that were tested.

As a side note, PCCA has developed over 175 FormulaPlus^™ formulations that have been tested with stability-indicating assays and USP 51 antimicrobial effectiveness testing when appropriate to provide extended BUDs. Some of these are bracketed formulations to help PCCA members address the variety of strengths that are prescribed by practitioners. These formulations therefore meet all of the current and proposed guidelines in USP 795.

The Designated Person(s)

Responsibility for the performance of the compounding operation is another new theme in the proposed revisions to Chapter 795. A new role within USP chapters is called the “designated person(s).” The designated person(s) is one or more individuals assigned to be responsible and accountable for the performance and operation of the facility and personnel for the preparation of CNSPs. Specifically, the designated person(s) is tasked with over 20 areas of responsibility in the proposed revisions. It is important to note that a pharmacy can have one designated person or several, hence the “(s)” at the end of “person(s).” These responsibilities can therefore be divided among members of the team who are appropriate for each responsibility. A few of the key responsibilities of the designated person(s) are training, documentation, and quality control and quality assurance. While I discussed training above, it is imperative to highlight the need for documentation. The proposed revisions call out a variety of areas for documentation, including:

Personnel training, competency assessments and qualification records, including 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)

The proposed revisions make reference to 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, which should include 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 have received the CNSP
- Recalling any unused dispensed stock and quarantining any stock remaining
- Disposing of the recalled CNSP and documentation thereof

What Comes Next

After the March 17, 2022, comment deadline, the USP Compounding Expert Committee will have to review the comments and determine if further changes to the proposed chapter will be made. The USP Expert Committee does not have a defined time period for reviewing the comments submitted, which is one reason that a future implementation date cannot be precisely predicted. If the USP Compounding Expert Committee moves to implement the revisions to USP 795, they would provide a six-month implementation window before the chapter becomes official, which is also when it would become enforceable in most states. The new USP Chapter 795 will also be significant for USP Chapter 800, Hazardous Drugs — Handling in Healthcare Settings. When the new USP Chapter 795 becomes official, it will also make USP Chapter 800 “compendially applicable” in USP terms, meaning that it will also become enforceable in many states. For more information on this chapter, visit the PCCA USP 800 webpage.

Pharmacies and other stakeholders can find the proposed changes to USP 795 on USP’s website as well as a link to submit comments on the proposed changes . PCCA also 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.

USP–NF and U.S. Pharmacist Featuring Proprietary PCCA Bases

Wed, 21 Apr 2021 13:54:23 GMT

By Maria Carvalho, PharmD, MRPharmS, PhD, Manager of PCCA Science

United States Pharmacopeia 43 – National Formulary 38

The United States Pharmacopeia (USP) was created over 200 years ago and, combined with the National Formulary (NF), is now the global leader in setting standards that help ensure quality and safety in medicines. It includes monographs for substances, products and compounded preparations. Monographs for compounded preparations describe formulas (ingredients and quantities), specific directions to correctly compound the particular preparation, packaging and storage information, labelling information, pH, beyond-use dates based on stability studies, and detailed assays (in the majority of monographs). The USP Compounding Compendium is a separate publication that includes sections from USP–NF that are relevant specifically for the practice of compounding.¹

The latest versions of the USP (43^rd edition) and NF (38^th edition), as well as the corresponding USP Compounding Compendium, have recognized the importance of several proprietary PCCA bases by including a total of five monographs in their official texts that use them as vehicles. The PCCA bases perform consistently with formulations for patients needing extended stability data, and these monographs provide further validation of the versatility of our bases in compounded formulations. This USP–NF recognition is of great value for compounding pharmacists in the U.S. and worldwide who demand the highest quality standards for their compounded formulations. The same rigorous testing used for USP Compounded Preparation Monographs is performed on all of our FormulaPlus^™ formulas, which are available to PCCA members with Clinical Services support.

The PCCA bases featured in the official compendia are in the table below.

*USP–NF* Compounded Preparation Monographs with PCCA Bases ¹
Monograph	Proprietary PCCA Base	Page Number(s)
Clindamycin Hydrochloride Compounded Oral Solution	SuspendIt^® (PCCA #30-4825)	481
Doxycycline Compounded Oral Suspension, Veterinary	Fixed Oil Suspension Vehicle (PCCA #30-4316)	495–497
Estriol Compounded Vaginal Cream	Emollient Cream^™ (PCCA #30-3168)	499–500
Ondansetron Compounded Topical Gel	Lipoderm^® (PCCA #30-3338)	539
Phenytoin Compounded Topical Gel	Spira-Wash^® Gel (PCCA #30-4678)	547–548

U.S. Pharmacist

U.S. Pharmacist is a monthly journal dedicated to providing pharmacists with peer-reviewed clinical articles relevant to the full spectrum of pharmacy-practice settings. The journal includes an open-access column on pharmacy compounding written by contributing editor Loyd V. Allen, Jr., PhD, RPh. Proprietary PCCA bases have been featured in this column as well, namely VersaBase^® Cream (PCCA #30-3641), Lipoderm (PCCA #30-3338) and PracaSil^®-Plus (PCCA #30-4655) (see table below). The most recent publication, dated January 19, 2021, discusses a formula with baclofen, clonidine HCl, gabapentin and ketamine in Lipoderm. Lipoderm is described in this publication as “an elegant alternative to traditional Pluronic Lecithin Organogels (PLOs), having a smooth and creamy feel rather than the tacky feel of PLOs. It contains a proprietary liposomal component that may increase the permeation of a variety of actives. Lipoderm is a stable system that does not separate upon refrigeration and has great resiliency in the presence of ionic substances.”² These independent formulas also provide further validation of the versatility of our bases in compounded formulations.

Compounding Formulas with PCCA Bases Published in U.S. Pharmacist
Publication Date	Formula	Issue
September 15, 2017	Progesterone 50 mg/Gm in VersaBase Cream	U.S. Pharmacist vol. 42, iss. 9, p. 47–48
November 20, 2018	Sertraline 4 mg/0.1 mL in Lipoderm	U.S. Pharmacist vol. 43, iss. 11, p. 47–48
October 16, 2019	Clotrimazole 2%, Ibuprofen 2%, Metronidazole 2%, Nifedipine 0.2%, and Dexpanthenol 3% in PracaSil-Plus	U.S. Pharmacist vol. 44, iss. 10, 48–CV
January 19, 2021	Baclofen 2%, Clonidine HCl 0.2%, Gabapentin 10%, and Ketamine HCl 5% in Lipoderm	US Pharmacist vol. 46, iss. 1, p. 44-45

For more information on the science behind PCCA’s proprietary bases, please consult the corresponding technical reports at pccarx.com/science. PCCA members can also contact us at PCCAScience@pccarx.com.

Maria Carvalho, PharmD, MRPharmS, PhD, is the Manager of PCCA Science. She is a certified pharmacist in Portugal and the United Kingdom with a PhD in pharmaceutical compounding from the University College of London (UCL). Maria has worked in community pharmacy, hospital pharmacy and the pharmaceutical industry in Europe and the United States. She was a teaching assistant at the UCL School of Pharmacy (UK) and an invited teacher at the University Fernando Pessoa (Portugal). Maria has authored and co-authored many scientific publications, including the book Compounding Practices in Europe (ISBN-10:149236925X).

References

1. United States Pharmacopeial Convention. (2020). United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

2. Allen, L. V., Jr. (2021). Baclofen 2%, clonidine HCl 0.2%, gabapentin 10%, and ketamine HCl 5% in Lipoderm. U.S. Pharmacist, 46 (1), 44–45. https://www.uspharmacist.com/article/baclofen-2-clonidine-hcl-02-gabapentin-10-and-ketamine-hcl-5-in-lipoderm

Choosing the Appropriate Antimicrobial Preservative for Compounded Medication

Tue, 16 Mar 2021 20:15:42 GMT

By Melissa Merrell Rhoads, PharmD, PCCA Director of Formulation Development, and Suki Pramar, PhD, PCCA Compounding Consultant

Pharmacies add antimicrobial preservatives to water-containing (aqueous) compounded medications to protect them from microbial growth. This in turn protects patients from potential exposure to microbial contamination. It should go without saying that this is an incredibly important part of pharmacy compounding, so we have written this article to help pharmacies develop criteria for preservative selection for their aqueous compounded preparations. However, this article is not exhaustive, and pharmacies must look at all aspects of the preparation, including pH, other included ingredients and the dispensing device along with the properties of the desired preservative to determine the appropriate selection during formulation development. Ultimately, the only definitive proof that a preservative is appropriate for a given preparation is through USP <51> antimicrobial effectiveness testing.

Potential Contaminants in Common Aqueous Dosage Forms

USP Chapter <1112>, Application of Water Activity Determination to Nonsterile Pharmaceutical Products, lists some common aqueous dosage forms along with the greatest potential contaminant for consideration. We have listed a few below, but any water-containing compounded preparation with a water activity above 0.6 should be considered for appropriate preservation to protect the preparation from microbial growth.Preparations with a w ater activity below 0.6 are considered anhydrous.

Potential Contaminants in Common Aqueous Dosage Forms ¹
Dosage Form	Water Activity (Aw)	Greatest Potential Contaminants
Nasal	0.99	Gram-negative bacteria
Shampoo	0.99	Gram-negative bacteria
Topical cream	0.97	Gram-positive bacteria
Oral liquid	0.90	Gram-positive bacteria and fungi
Oral suspension	0.87	Fungi

General Considerations for Using Preservatives

USP Chapters <1151> and <51> provide general guidance on the use of preservatives. USP Chapter <1151>, Pharmaceutical Dosage Forms, suggests that preservatives should be added to most water-containing compounded preparations and states, “Acceptance criteria for preservative content in multidose products should be established. They are based on the levels of antimicrobial preservative necessary to maintain the product’s microbiological quality at all stages throughout its proposed usage and shelf life (see Antimicrobial Effectiveness Testing <51>).” ²

Regarding nonsterile compounds, USP Chapter <51>, Antimicrobial Effectiveness Testing, states, “Nonsterile dosage forms may have preservatives added to protect them from growth of microorganisms inadvertently introduced during or subsequent to the manufacturing process.” For sterile compounds, USP Chapter <51> says, “In the case of sterile articles packaged in multiple-dose containers, antimicrobial preservatives are added to inhibit the growth of microorganisms that may be introduced from repeatedly withdrawing individual doses. One or more antimicrobial preservative(s) are expected in all sterile multidose units.” ³

However, there are certain situations when a preservative may not be necessary, such as those listed below, but this should be evaluated on a case-by-case basis.

When the preparation will be used immediately
When no water is present or the water available for chemical or microbial activity is very low (that is, when the preparation is anhydrous)
When the pH of the preparation is less than 3 or greater than 9
When component ingredients included in the formulation have antimicrobial properties (such as ethyl alcohol in concentrations greater than 10%)

Here are important considerations for selecting a preservative to use in an aqueous compounded preparation:

Dosage form and route of administration: oral, topical, nasal, ophthalmic, injection, etc.
pH of the final preparation
Solubility of the preservative within the formulation
Compatibility with ingredients in the formulation

Commonly Used Preservatives in Compounded Medications

Preservatives are grouped into categories that include antibacterials or antifungals as well as some others. While they are grouped according to their primary activity, the majority of them may be active against both bacteria and fungi. Below are some of the most commonly used preservatives in compounded formulations. Please note that the antimicrobial activity of preservatives may be affected by other excipients in a formula, such as ionic surfactants, or certain types of plastic used in dispensing containers.

Antibacterial Agents

Antibacterial agents are active against Gram-positive and/or Gram-negative microorganisms.

Benzyl alcohol
- Bactericidal at 1-2%
- Most effective at pH less than 5; minimal activity at pH 8 and above
- Incompatible with methylcellulose
- Polysorbates may reduce its activity
- Water soluble
Benzalkonium chloride
- Most-used concentration is 0.01%
- Most effective at pH range of 4–10
- Should not be used orally because it is a gastrointestinal irritant
- For ophthalmics, its bactericidal properties are improved by the addition of 0.1% EDTA
Imidurea (imidazolidinyl urea)
- Commonly used in topical formulations at a concentration of 0.03–0.5%
- Most effective pH range of 3–9
Chlorobutanol
- Commonly used in ophthalmic and parenteral preparations at a concentration of 0.5%
- Should be used in solutions buffered at pH 5–5.5
- Carboxymethylcellulose and polysorbates may reduce antimicrobial activity
- Methylcellulose does not interact with it
Phenol
- Primarily used in parenteral formulations and some topical preparations at a concentration of 0.15–1%
- Optimal activity in acidic solutions

Antifungal Agents

Sodium benzoate
- Effective concentration 0.1–0.3%
- Most effective in acidic solutions of pH 2–5; ineffective at a pH above 5
- Effectiveness may be reduced by polysorbates
- Water soluble
- This is the preservative used in PCCA’s SuspendIt® (PCCA #30-4825), so it is important to check the pH of your compounded preparation to ensure adequate preservation
Potassium sorbate
- Effective concentration 0.1–0.2%
- Ineffective at a pH above 6
- Water soluble
Methylparaben and propylparaben
- Methylparaben effective concentration 0.05–0.25%/>
- Propylparaben effective concentration 0.02–0.04%
- Most effective when used in combination; the majority of PCCA’s formulas use a combination (PCCA members, see PCCA Formula #1686 Preserved Water (Parabens) (USP <51> Study))
- Most effective over a broad pH range of 4–8
- Parabens are FDA approved for use in oral, topical, rectal, vaginal, urethral, ophthalmic, nasal, inhalation, irrigation and parenteral products, but irritation has been reported with the use of parabens in ophthalmic preparations
- Parabens are not compatible with Methocel (Hydroxypropyl Methylcellulose), Methylcellulose, Hydroxypropyl cellulose (HPC) and Hydroxyethyl cellulose (HEC), leading to compromised preservative effectiveness.

Other Potential Antimicrobial Agents

Other agents that are used as solvents or vehicles at certain concentrations may be self-preserving.

Ethyl alcohol
- While a common guideline is 10% or more ethyl alcohol can be a preservative, the concentration required for preservation is based on the amount of “free water” within the preparation
Glycerin
- Can be a preservative at concentrations of 50% and higher
Propylene glycol
- May be effective at a concentration of 10% and above; however, it may require up to 30% concentration to inhibit the growth of certain molds

We have listed commonly used preservatives per dosage form/route of administration below. This is only a general guide for educational purposes, and again, you must look at all aspects of the preparation, including pH, other included ingredients and the dispensing device along with the properties of the desired preservative to determine the appropriate selection for formulation development. Ultimately, the only definitive proof that a preservative is appropriate for a given preparation is through USP <51> antimicrobial effectiveness testing.

Commonly Used Preservatives by Dosage Form
Dosage Form/Route of Administration	Preservative & Commonly Used Concentration
Oral*	Methylparaben 0.05% + propylparaben 0.025%
	Sodium benzoate 0.2–0.5%
	Potassium sorbate 0.2%
Topical*	Methylparaben 0.05% + propylparaben 0.025%
	Benzalkonium chloride 0.01%
	Ethyl alcohol > 10%
	Propylene glycol > 10%
Nasal	Benzalkonium chloride 0.01%
	Methylparaben 0.05% + propylparaben 0.025%
Ophthalmic	Chlorobutanol 0.5%
	Benzalkonium chloride 0.01% + EDTA 0.1%
Injection	Benzyl alcohol 1–2%
	Methylparaben 0.05% + propylparaben 0.025%
	Benzalkonium chloride 0.01% + EDTA 0.1%

* Premade, proprietary PCCA bases contain preservatives, which should be evaluated based on your final preparation to ensure preservation. But as with all formulations, the only definitive proof of preservation is through USP <51> antimicrobial effectiveness testing.

PCCA members can also access our preservative chart (PCCA Document #97579) for a list of criteria on potential preservatives for formulations.

References

United States Pharmacopeial Convention. (2020). General chapter <1112> application of water activity determination to nonsterile pharmaceutical products. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/
United States Pharmacopeial Convention. (2020). General chapter <1151> pharmaceutical dosage forms. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/
United States Pharmacopeial Convention. (2020). General chapter <51> antimicrobial effectiveness testing. In United States pharmacopeia and national formulary (USP 43rd ed. & NF 38th ed.). https://www.uspnf.com/

Additional Works Consulted

Lester, D. E. (2018). A practical guide to contemporary pharmacy practice and compounding (4th ed.). Wolters Kluwer.

Sheskey, P. J., Hancock, B. C., Moss, G. P., & Goldfarb, D. J. (Eds.). (2020). Handbook of pharmaceutical excipients (9th ed.). Pharmaceutical Press.

Suki Pramar, PhD, is a compounding consultant at PCCA. She earned her PhD in pharmaceutics from the University of Houston in 1991, and she joined PCCA’s staff in 1999. Suki was appointed to the American Pharmacists Association’s Compounding Pharmacy Task Force in 2016.

8 Academic, Peer-Reviewed Stability Studies on SuspendIt®

Wed, 28 Oct 2020 12:47:36 GMT

By Maria Carvalho, PharmD, MRPharmS, PhD, Manager of PCCA Science

Compounding pharmacists often need to prepare palatable, uniform, stable oral liquids, particularly for pediatric patients. Issues with taste-masking; solubility; and physical, chemical and microbiological stability must be considered when preparing these customized oral liquid medications. In order to ensure optimal formulations and enhanced compliance for each unique patient, PCCA developed SuspendIt , a contemporary suspending vehicle that offers convenience and dosing flexibility for compounded medications. SuspendIt has special thixotropic properties that allow it to thicken when standing in order to minimize the settling of particles and become thinner when shaken so the medication can be accurately administered. It is also sugar-free, paraben-free, dye-free and gluten-free.

PCCA members with Clinical Services have access to over 150 standardized formulas for SuspendIt oral liquids, many with beyond-use-dates (BUDs) superior to those pre-established by the United States Pharmacopeia (USP). Stability testing is particularly important for oral liquids, but this is a costly and time-consuming process that requires physical, chemical and microbiological expertise. For this reason, PCCA partnered with the College of Pharmacy at Xavier University of Louisiana (XULA) for the development of academic, peer-reviewed stability studies on SuspendIt. Supported by governmental grants from the National Institutes of Health and the U.S. Department of Health and Human Services, and financial sponsorship from PCCA, researchers at XULA have already published a total of eight validated stability studies in the International Journal of Pharmaceutical Compounding (IJPC). The initial studies evaluated the physical and chemical stability of a SuspendIt formula for a standard drug concentration (e.g., clindamycin hydrochloride 10 mg/mL) at three temperature conditions (5° C, 25° C and 40° C). The later studies evaluated the stability of a bracketed drug concentration (e.g., ursodiol 50–100 mg/mL) at two temperature conditions (5° C and 25° C). These allow compounders to use a single formula to create a number of compounds with extended BUDs as long as the active ingredient in each compound is within the range of strengths listed in the formula. IJPC recognized the quality of these academic studies by adopting some of the SuspendIt formulas as official IJPC formulas.

Learn more about our standardized oral liquid formulations here on The PCCA Blog: “ The Importance of Standardized Formulations for Patient Safety .”

The high quality of these studies has been recognized further by USP, which adopted three of these academic studies as official monographs: “Clindamycin Hydrochloride Compounded Oral Solution,” official as of August 1, 2019, as well as the spironolactone and ursodiol studies, which are not yet official. Furthermore, USP gave its Silver Award in 2018 and Golden Award in 2019 to Dr. Yashoda Pramar, the lead researcher for these studies at XULA. These awards recognize the contribution of new monographs as part of USP’s Donor Recognition Program. Academic institutions like XULA are recognized for their unbiased, state-of-the-art research, and PCCA is very proud of this ongoing partnership.

Below are brief summaries of the published, peer-reviewed stability studies of compounded medications with SuspendIt that researchers at the XULA College of Pharmacy have conducted.

1. “Stability of Clindamycin Hydrochloride in PCCA Base SuspendIt”

This study was initially published in the September/October 2016 issue of IJPC , and the formula was subsequently recognized as an official formula in the January/February 2017 issue of IJPC . The formula was also adopted as an official USP Compounded Preparation Monograph, “Clindamycin Hydrochloride Compounded Oral Solution,” on August 1, 2019. It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded clindamycin hydrochloride 10 mg/mL oral suspension in SuspendIt.

2. “Stability of Spironolactone Oral Suspension in PCCA Base, SuspendIt”

This study was initially published in the July/August 2017 issue of IJPC , and the formula was subsequently recognized as an official formula in the November/December 2017 issue of IJPC and the March/April 2018 issue of IJPC . The formula has also been accepted as a USP Compounded Preparation Monograph, but it is not official yet. It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded spironolactone 5 mg/mL oral suspension in Suspendit.

3. “Physicochemical Stability of an Oral Suspension of Trimethoprim 20 mg/mL in Combination with Sulfadiazine 200 mg/mL in PCCA Base, SuspendIt”

This study was initially published in the September/October 2017 issue of IJPC , and the formula was subsequently recognized as an official formula in the May/June 2018 issue of IJPC . It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded trimethoprim 20 mg/mL and sulfadiazine 200 mg/mL oral suspension in SuspendIt.

4. “Stability of Compounded Ursodiol Suspensions in PCCA Base, SuspendIt”

This study was published in the January/February 2019 issue of IJPC . The formula has also been accepted as a USP Compounded Preparation Monograph, but it is not official yet. It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded ursodiol 50–100 mg/mL oral suspensions in SuspendIt.

This stability study was also presented by lead XULA researcher Dr. Yashoda Pramar at the 2018 APhA (American Pharmacists Association) Annual Meeting & Exposition in Nashville, Tennessee, as a poster presentation (Figure 1).

Figure 1. Scientific poster presented by XULA researchers at the 2018 APhA Annual Meeting & Exposition.

5. “Physicochemical Stability of Compounded Naltrexone Hydrochloride Solutions in PCCA Base, SuspendIt”

This study was published in the March/April 2019 issue of IJPC . It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded naltrexone hydrochloride 0.5–5 mg/mL oral solutions in SuspendIt.

This stability study was also presented by lead XULA researcher Dr. Yashoda Pramar at the 2019 APhA Annual Meeting & Exposition in Seattle, Washington, as an oral presentation.

6. “Physicochemical Stability of Compounded Amlodipine Besylate Suspensions in PCCA Base, SuspendIt ”

This study was published in the November/December 2019 issue of IJPC . It establishes BUDs of 90 days at refrigerated temperature and 7 days at room temperature for the studied formulation of compounded amlodipine besylate 0.5–10 mg/mL oral suspensions in SuspendIt.

7. “Physicochemical Stability of Compounded Allopurinol Suspensions in PCCA Base, SuspendIt”

This study was published in the September/October 2020 issue of IJPC . It establishes a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded allopurinol 10–20 mg/mL oral suspensions in SuspendIt.

8. “Physicochemical and Microbiological Stability of Compounded Metronidazole Suspensions in PCCA Base, SuspendIt”

This study will be published in a future issue of IJPC. It will establish a BUD of 180 days at refrigerated and room temperatures for the studied formulation of compounded metronidazole 25–50 mg/mL oral suspensions in SuspendIt.

PCCA members with Clinical Services access can find PCCA compounded oral suspension formulas that correspond to the ones above in our formula database.

Maria Carvalho, PharmD, MRPharmS, PhD, is the Manager of PCCA Science. She is a certified pharmacist in Portugal and the United Kingdom with a PhD in pharmaceutical compounding from the University College of London (UCL). Maria has worked in community pharmacy, hospital pharmacy and the pharmaceutical industry in Europe and the United States. She was a teaching assistant at the UCL School of Pharmacy (UK) and an invited teacher at the University Fernando Pessoa (Portugal). Maria has authored and co-authored many scientific publications, including the book: Compounding Practices in Europe (ISBN-10:149236925X).

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.

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.

New Releases on PCCA Play — August 2019

Wed, 21 Aug 2019 14:34:00 GMT

By PCCA

PCCA Play is our educational media library exclusively for members. It offers tens of thousands of dollars’ worth of educational content available on desktop, tablet or smartphone. PCCA members can also access premium content through a subscription or a la carte rental.

PCCA Play includes everything from main-stage presentations at our live events to our recorded webinars, bringing PCCA members the information they need, when and where they need it.

Now Free
Here is a video that is now free on PCCA Play.

Quality and USP <800> Implementation
This video is a combination of two presentations from the 2017 PCCA Quality Symposium. In part one, Ross Caputo, PhD, Eagle President, covers essential quality assurance elements for compounding pharmacies. In part two, Jerra Banwarth, RPh, FIACP, PCCA Education and Training Manager, discusses USP <800> risk assessment steps in detail.

New Release (at a Great Price)
This new release on PCCA Play is available for just $95.00.

USP <797> — Is Your Pharmacy Ready?
PCCA Clinical Compounding Pharmacist Matt Martin, PharmD, and Eagle Vice President of Operations Megan Jeffrey Liotta, MS, share detailed information about how the revisions to USP General Chapter <797> may affect personnel qualifications, facilities and documentation in compounding pharmacies.

Members, stay tuned to PCCA Play: We’ll release our latest webinar recording on the revised USP <795> soon!

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.

Recommendations for Navigating USP <800>

Wed, 29 May 2019 19:03:00 GMT

By Matt Martin, PharmD, PCCA Clinical Compounding Pharmacist

Are you done remodeling for USP <800>? Have you started? What is your board of pharmacy’s stance on it? What about other states you’re licensed in? How about the FDA’s take on USP <800>? How many times have you read the chapter? Do you have a full and nuanced understanding of it? Do you have questions about what it means to be compliant with various parts of the chapter? Have you selected the equipment you will need? Are you certain that the contractors you are working with have the appropriate knowledge of working with health care facilities and can build out or remodel your facility to the appropriate specifications? Do you have appropriate personal protective equipment lined up?

Is your pulse racing or sweat forming on your forehead as you read this list of questions? Let’s start with some basics.

Know Your Regulators

USP General Chapter <800> is scheduled to become official in the United States Pharmacopeia on December 1, 2019, along with substantially revised versions of General Chapters <795> and <797>. It is a busy year for changes to the guidelines provided by USP.

When USP chapters under <1000> become official, they can be enforced, but this is up to each regulatory entity that would have a role in enforcement. The United States Pharmacopeial Convention is not a regulatory body and does not enforce USP chapters. However, state boards of pharmacy are regulators and may enforce USP chapters. The state boards are making a range of choices about USP <800>, from rejecting it, to enforcing parts of it, to adopting all of it and expecting full compliance by December 1, 2019. If you don’t know what your state is doing, call your board of pharmacy and ask. You may also be able to reach out to your state’s pharmacists association to see what it knows about USP <800> enforcement in your state.

“The state boards are making a range of choices about USP <800>, from rejecting it, to enforcing parts of it, to adopting all of it and expecting full compliance by December 1, 2019.”

Beyond the boards of pharmacy, there are questions about what the FDA may do in regards to their inspections of pharmacies once USP <800> becomes official. As of the date of this publication, the FDA has not taken any official position on USP <800> and how they may use it in their inspections of pharmacies.

Read It, and Read It, and Read It

If you haven’t been reading up on USP <800>, you’re behind, but there’s no time like the present, so go get your copy from USP and start reading. You can access it for free . Seriously, after you’re done with this article, go get the chapter and read it several times. As you do, make sure to highlight the words “should” and “shall” in the document. When it comes to USP chapters, a “should” is a recommendation and a “shall” is a requirement.

Once you’ve been through it several times, you will likely have questions. USP has a webpage dedicated to frequently asked questions (FAQs) about this chapter. PCCA also has resources on our dedicated USP <800> page. PCCA members with Clinical Services access can also send their questions to the Clinical Services team here at PCCA so that we can discuss them.

“When it comes to USP chapters, a ‘should’ is a recommendation and a ‘shall’ is a requirement.”

Interpreting the Chapter

USP <800> defines hazardous drugs (HDs) as those on the NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016 . The NIOSH list divides hazardous drugs into different groups based on their classification.

One of the questions that has been raised at various conferences is whether or not USP <800> allows you to perform a risk assessment for NIOSH Group 2 and 3 APIs, and whether this excludes them from being required to be compounded in a negative pressure room. This is based on question 18 from the USP’s Chapter <800> FAQ. The question is, “Can the reconstitution, mixing, and diluting of Group 2 and 3 HDs on the NIOSH list be performed under an assessment of risk?” The answer USP provides is, “Yes. The reconstitution, mixing, and dilution of dosage forms of Group 2 and 3 HDs may be considered under an assessment of risk.”¹

Some take this to mean that they do not have to compound drugs in Groups 2 and 3 in a negative pressure room. However, I would note that when USP <800> discusses an “API,” it is referring to raw materials or chemicals used as active ingredients. Box 1 on page 2 of the chapter states that “any HD API” or “any antineoplastic requiring HD manipulation” on the NIOSH list must follow the requirements of USP <800>.² Based on this, all hazardous drug chemicals must follow the requirements of USP <800>, including the manipulation within a negative pressure room. Therefore, the statements as written do not allow an assessment of risk for Group 2 and 3 active pharmaceutical ingredients because the chapter states explicitly that “any HD API” on the NIOSH list must follow the requirements of USP <800>.

“Box 1 on page 2 of the chapter states that ‘any HD API’ or ‘any antineoplastic requiring HD manipulation’ on the NIOSH list must follow the requirements of USP <800>.²”

Start with the Right Plan

Pharmacies working with contractors in their area are finding wide variance in the proposals they are being provided to build “appropriate” facilities. The only thing worse than remodeling or building a facility is the opportunity to do it a second time if it isn’t done right the first time. This will likely prove even more costly than doing it correctly at first.

This is why Eagle has two engineers on staff who have been working with pharmacies ranging from a review of their build-out plans all the way up to managing their entire remodel or construction project. Would you like to have an experienced engineer talk about your plans directly with your chosen contractor? Jeff Gloyer and Chris Trotter are engineers at Eagle and can be a part of your team to help get your facility ready for USP <800> compliance. I would highly recommend using the services of these engineers. Eagle has also made this offering customizable on an hourly basis, so you can consult their engineers as much as you need without committing to a required minimum number of hours. Much the same as we would advocate for patients and prescribers to use pharmacists as the medication experts, I would encourage you to use the engineers at Eagle in the design of your remodel or new construction.

“The only thing worse than remodeling or building a facility is the opportunity to do it a second time if it isn’t done right the first time.”

As you work on your journey to USP <800> compliance, PCCA and Eagle stand ready to help you answer your questions, select appropriate equipment and PPE, and partner with you to aid in the design and execution of your remodel or new construction. PCCA members with Clinical Services access can call our Clinical Services team at 800.331.2498, and any compounding pharmacy can contact Eagle at 800.745.8916.

PCCA offers compounding pharmacies exclusive access to customizable, world-class cleanrooms by Nicos Group. For more information about Nicos cleanrooms, contact us 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.

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

References

1. United States Pharmacopeial Convention. (2017). FAQs: <800> hazardous drugs—Handling in healthcare settings. Retrieved from http://www.usp.org/frequently-asked-questions/hazardous-drugs-handling-healthcare-settings

2. United States Pharmacopeial Convention. (2017). <800> hazardous drugs—Handling in healthcare settings. Retrieved from http://www.usp.org/usp-chapter-800-download

Why PCCA Chose Nicos, and Why You Should Too

Thu, 09 May 2019 18:32:00 GMT

Part of building the world’s best support network for compounding pharmacies is finding the right people to partner with. For us at PCCA, we wanted to find a cleanroom provider that we and our customers could trust. That is why we chose to partner with the Nicos Group. When it was time to renovate our chemical repackaging facility at PCCA, after careful deliberation, we chose Nicos. We believed Nicos would build a repacking area that met FDA regulations.

They did not disappoint.

In short, we trust Nicos to deliver a beginning to end cleanroom solution for your pharmacy. We know from personal experience that you can too.

That trust makes the compounding world a better, more reliable place for compounders and their patients.

Having a cleanroom that meets the upcoming USP <800> facility requirements is essential to the long-term success of compounding pharmacies in states that adopt the guidelines. That means being informed when considering what kind of cleanroom to build, but USP <800> can get dense and confusing when it comes to design elements and layout. To address that potential issue, Eagle’s own Jeffery Gloyer wrote an article that details crucial considerations you need to know when it comes to cleanroom design. After reading Jeffery’s article, head over to our USP <800> education page to get even more answers you’re looking for. No matter your comfortability with USP <800>, you can take comfort in this — with a Nicos Group cleanroom, you will have a facility that meets all your regulatory needs.

Not only does Nicos deliver customizable, world-class cleanrooms with high quality finishes applied to all surfaces as well as fully flush and coved joints for quick and effective cleaning, they help you through the entire process, providing:

Complete project management, including design, construction, support and installation
Detailed engineering documentation
Factory-trained installation crews led by professional engineers

Partners join hands when they see that working together can build better solutions for the clients they serve. We’re proud to be partners with the Nicos Group. Not only because they provide an excellent service and product, but because they are invested in empowering pharmacies with the very best cleanroom technology in the world.

THE PCCA BLOG

USP Chapter 800: Managing HD Spills

Spill Control

Spill Kits

Spill Drills

References

Nonsterile Pharmacy Training: Mastering the Role of the Designated Person

Key Responsibilities of the Designated Person

Streamline Nonsterile Pharmacy Training Responsibilities with eLearning

USP 800: Is It Enforceable?

References

USP Chapters 795- and 797-Related Changes to PCCA Formulations

USP Chapters 795- and 797-Related Changes to PCCA Formulations

USP Chapter 795

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

Establishing and extending BUD

USP Chapter 797

FILTRATION

Sterilization Procedure for Aqueous Solutions

Sterilization Procedure for Oil or Alcohol Solutions

AUTOCLAVE

Sterilization Procedure for Solutions

Sterilization Procedure for Suspensions

DRY HEAT/CONVECTION

Sterilization Procedure for Solutions

Sterilization Procedure for Suspensions

MULTIPLE DOSE COMPOUNDED PREPARATIONS

BEYOND-USE DATES (BUDS)

Modular Compounding Cleanroom 101

Modular Compounding Cleanroom 101: Why would your pharmacy need one?

What is a modular cleanroom?

Additional Considerations

Cleanroom Providers

Initial Steps

Helpful Resources

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

How to Determine API Calculations in Pharmacy Compounding

Modular Compounding Cleanroom 101

What is a modular cleanroom?

Additional Considerations

Cleanroom Providers

Initial Steps

Helpful Resources

Related Blog Posts:

Proposed Changes to USP 797

Beyond-Use Dates

Endotoxin Testing

Garbing Practices

Environmental Monitoring

Cleaning and Sanitizing

Next Steps in the Process

Proposed Changes to USP 795

Training

Cleaning and Sanitizing

Beyond-Use Dates

The Designated Person(s)

What Comes Next

USP–NF and U.S. Pharmacist Featuring Proprietary PCCA Bases

Choosing the Appropriate Antimicrobial Preservative for Compounded Medication

8 Academic, Peer-Reviewed Stability Studies on SuspendIt®

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)

New Releases on PCCA Play — August 2019

Notable Changes in the New USP <797>

Notable Changes in the New USP <795>

References

Recommendations for Navigating USP <800>

Why PCCA Chose Nicos, and Why You Should Too