THE PCCA BLOG

Partnerships Between 503A Pharmacies and 503B Outsourcing Facilities

Wed, 27 Nov 2024 15:31:09 GMT

by Bruno Onwukwe, PharmD Candidate, PCCA Clinical Services Intern, and Celeste Zizzamia, PharmD, BCSCP, PCCA Clinical Compounding Pharmacist

Sections of the FDA’s Drug Quality and Security Act (DQSA) distinguish compounding pharmacies (503A) from outsourcing facilities (503B). Due to several factors, many of which are related to drug shortages and the USP 797/USP 800 updates, 503A pharmacies are considering partnering with 503B entities for compounded sterile preparations and/or hazardous materials. We’ll discuss the differences between 503A pharmacies and 503B outsourcing facilities, review Section 503B and summarize how to effectively evaluate 503B compounding pharmacies for a potential partnership.

Key Differences

A 503A designated pharmacy may compound drugs only for an individual patient with a prescription from a qualified provider. In addition, 503A pharmacies are regulated by a state board of pharmacy, which may follow standards set by the United States Pharmacopeia (USP). In contrast, a 503B outsourcing facility does not require a prescription but must adhere to the FDA’s Current Good Manufacturing Practice (CGMP) regulations. Additional differences between 503A and 503B pharmacies related to compounding sterile and/or hazardous materials include:

Description	503A	503B
Standards	USP 797	CGMP
Regulatory Body	State Board of Pharmacy	FDA
Prescription Requirement	Yes	No
Office-Use Compounding	No	Yes
Max Batch Size	250	N/A
Release Testing	BUD Dependent	Yes
Beyond-Use Date	≤180¹	Stability Study Dependent
Interstate Distribution Limit	<5%	N/A

1. For a compounded sterile product (CSP) that has been terminally sterilized, stored frozen, passed sterility and all applicable tests for Category 3.

The 503A pharmacies that compound sterile preparations and/or hazardous materials can benefit from partnering with 503B outsourcing facilities. Forming a partnership may allow the 503A pharmacy to potentially mitigate risks, reduce operational costs, provide expanded services and improve customer satisfaction.

USP chapters 797 and 800 outline the minimum standards for sterile compounding and compounding hazardous materials. Although currently not adopted by all states, 503A pharmacies should consider implementing the USP standards as best practices in patient care and safety — even if doing so may pose challenges. USP updates include increased environmental monitoring, cleaning and disinfecting, garbing requirements, media-fill testing, personnel training, safety and more.

Wholesale Prohibitions for 503B

Section 503B(a)(8) of DQSA discusses the restrictions on wholesaling for outsourcing facilities. Compounded preparations must not be sold or transferred by an entity other than the outsourcing facility that compounded the product — wholesale distributors, pharmaceutical repackagers and relabelers, marketing firms and websites cannot participate in the sale and transfer of compounded preparations. Section 503B(a)(8) does not, however, prohibit the administration of a compounded product in a healthcare setting, nor its dispensing under a prescription.

The FDA Draft Guidance, which determines standard industry practice, clarified in June 2023 that a 503B outsourcing facility may sell its compounded products to a 503A pharmacy. Therefore, 503A state-licensed pharmacies or federal facilities may dispense compounded products in partnership with outsourcing facilities, opening the possibility of increased partnership between the two entities.

Evaluation Criteria for 503B Partnership

Many factors should be taken into consideration when deciding to partner with a 503B outsourcing facility, including:

Appropriate Licensures and Registrations — Investigate whether the 503B facility has appropriate licensure and registration within the states you intend to operate in.
Compliance with Prohibition on Wholesaling — 503As cannot buy from brokers and must directly purchase compounded products from their 503B partner. 503As, however, may use group purchasing organizations (GPOs) to negotiate contract pricing.
Quality Customer Service — Ensure the 503B facility provides reliable information for inventory, processing and shipping.
Regulatory History — Review their track record of FDA Form 483s, FMD-145s, warning letters, product recalls and other events that may call into question their conditions.

In addition, 503B outsourcing facilities must comply with CGMPs to ensure that safe, quality compounds are prepared and dispensed to patients. Some facilities have not been FDA inspected; however, evaluating the facility’s systems will help to discern CGMP compliance. An evaluation should include:

Audits
Facility Certification
Environmental Monitoring Data
Cleaning and Disinfection Program
Quality Unit
Quality Control
Standard Operating Procedures
Investigations
Personnel Training
Validation Activities
Supplier Qualification Program
Master and Batch Production Records
Equipment
Container-Closure Systems
Laboratory Controls (Method Suitability/Validation/Stability Studies)

Many 503A pharmacies that compound sterile preparations and whose state boards of pharmacy implemented USP 797 updates face a pivotal crossroad. Collaboration with a 503B outsourcing facility may pave the way toward a partnership which can increase efficiencies and free up time for pharmacists and technicians to focus efforts in different areas of patient care activities.

More information about FDA-registered outsourcing facilities can be found at https://www.fda.gov/drugs/human-drug-compounding/registered-outsourcing-facilities.

References

FDA. Prohibition on Wholesaling Under Section 503B of the Federal Food, Drug, and Cosmetic Act. Guidance Document. June 2023. Accessed January 2024 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/prohibition-wholesaling-under-section-503b-federal-food-drug-and-cosmetic-act
FDA. Current Good Manufacturing Practice – Guidance for Human Drug Compounding Outsourcing Facilities Under Section 503B of the FD&C Act. Guidance for Industry. Draft Guidance. January 2020. Accessed January 2024 at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/current-good-manufacturing-practice-guidance-human-drug-compounding-outsourcing-facilities-under
FDA. 21 CFR Part 21 – Current Good Manufacturing Practice for Finished Pharmaceuticals. Accessed January 2024 at https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C/part-211
USP <797> Pharmaceutical Compounding – Sterile Preparations. 01 May 2024. Accessed January 2024 at https://doi.usp.org/USPNF/USPNF_M99925_08_01.html

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.

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

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.

Modular Compounding Cleanroom 101

Wed, 18 Jan 2023 18:26:42 GMT

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

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

Advantages of choosing a modular compounding cleanroom include:

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

What is a modular cleanroom?

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

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

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

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

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

Additional Considerations

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

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

Cleanroom Providers

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

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

Initial Steps

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

Helpful Resources

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

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

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

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

THE PCCA BLOG

Partnerships Between 503A Pharmacies and 503B Outsourcing Facilities

Key Differences

Wholesale Prohibitions for 503B

Evaluation Criteria for 503B Partnership

References

USP Chapter 800: Managing HD Spills

Spill Control

Spill Kits

Spill Drills

References

USP 800: Is It Enforceable?

References

Modular Compounding Cleanroom 101

What is a modular cleanroom?

Additional Considerations

Cleanroom Providers

Initial Steps

Helpful Resources

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