Overview

_____

“USP 795 encompasses the minimum standard requirements of compounded nonsterile preparations (CNSPs) for both humans and animals.” This chapter breakdown will help provide essential standards and guidelines for preparing CNSPs, to ensure the safety and well-being of patients.

Clean Air Essentials Guideline: As of November 1, 2023, the USP 795 chapter had been revised, featuring updated guidelines and protocols for CNSPs. Explore the downloadable USP 795 comparison chart to discover the specific changes that have been made.

What is Non-sterile Compounding?

_____

Non-sterile Compounding “involves various processes such as combining, admixing, diluting, pooling, reconstituting (other than as specified in the manufacturer’s provided instructions), or making alterations to drug products or bulk drug substances to create a non-sterile preparation.”

*Note: The handling of non-sterile hazardous drugs (HDs) must also meet the compliance standards under Hazardous Drugs - Handling in Healthcare Settings (USP <800>). 

1. Scope

_____

CNSPs subject to the requirements

The types of CNSPs that fall under the guidelines apply to a variety of dosage forms, including, but not limited to:

• Solid Oral Preparations: Solid forms that are taken orally.
• Liquid Oral Preparations: Liquid form for oral consumption.
• Rectal Preparations: Designed for rectal use.
• Vaginal Preparations: For patients who require vaginal applications.
• Topical Preparations: Includes creams, gels, and ointments used on the skin’s surface.
• Nasal and Sinus Preparations for Local Application: Nasal Sprays or nasal irrigation.
• Otic Preparations - With the exception of those used when the eardrum is perforated.

Practices that do not fall under the requirements outlined in this chapter:

• Nonsterile Radiopharmaceuticals: includes requirements that can be found in Radiopharmaceuticals—Preparation, Compounding, Dispensing, and Repackaging <825>.
• Reconstitution: If you properly adhere to the manufacturer's instructions to reconstitute a nonsterile product, you don't need to worry about the guidelines in this chapter.
• Repackaging: Refer to Good Repackaging Practices <1178> for recommendations.
• Splitting Tablets: If you're breaking or cutting a tablet into smaller portions.
• Administration: When preparing a single dose for a single patient with a planned administration window of 4 hours, this practice doesn't fall within the scope of this chapter's guidelines.

*Note: If you require more information on safe practices, such as labelling, be sure to review your facility’s Standard Operating Procedures (SOPs).

Oversight by Designated Individuals

Let's talk about the individuals overseeing the operations within a compounding facility. “The facility must appoint one or more people who can be responsible and accountable for the facility's performance as well as the personnel engaged in preparing Compounded Non-sterile Preparations (CNSPs).

These designated individuals have a range of important responsibilities, which may include but are not limited to:

• Compliance Training: Responsible for supervising the training program to ensure that everyone involved in compounding, handling, and preparing CNSPs is fully knowledgeable of their roles and responsibilities.
• Component Selection: Ensuring the right components are selected during the preparation process.
• Monitoring & Corrective Action: Appointed personnel regularly observe compounding activities. If any practices fall short of the required standards, they take immediate action to course-correct.
• Full SOP Implementation: Ensure that all Standard Operating Procedures (SOPs) are not only in place but also fully implemented. Should problems arise, they are responsible for ensuring that the necessary follow-up actions are carried out.
• Storage Procedures and Documentation: Implement and monitor the handling and storage procedures of CNSPs and their respective components.

To ensure clarity and accountability, the designated person(s) must be clearly identified in the facility's Standard Operating Procedures (SOPs). In cases where a compounding facility has only one person responsible for all compounding activities, that individual automatically assumes the role of the designated person.

2. Personnel Training and Evaluation: Building Competence

_____

Training and competency are key when it comes to the personnel involved in the compounding of CNSPs. All individuals who compound or directly oversee compounding activities must undergo training to demonstrate their knowledge and competency. This helps to ensure they are well-prepared for their roles before working independently.

The development and implementation of a comprehensive training program falls under the responsibility of the appointed designated person(s). This program outlines the necessary training, frequency, and the process for evaluating personnel competency. Its goal is to equip personnel with the essential knowledge and skills to effectively perform their assigned tasks. Those involved in compounding or supervising compounding personnel must complete this training initially, as well as refresh it at a minimum every 12 months. Meanwhile, personnel with roles that include in-process checks, final verification, or dispensing of CNSPs must complete training as mandated by the facility's Standard Operating Procedures (SOPs).

To ensure accountability, the training and competency of personnel must be documented, as explained in Section 14: Documentation. Before personnel can independently compound CNSPs or oversee compounding, they must complete training and demonstrate their knowledge of related nonsterile manipulation tasks. This includes core competencies such as:

• Hand hygiene
• Proper garbing
• Effective cleaning and sanitization
• Safe handling and transportation of components and CNSPs
• Accurate measuring and mixing
• The correct use of equipment and devices for compounding CNSPs
• Proper documentation of the compounding process, including Master Formulation and Compounding Records (Section 7)

The training process involves the following steps:

• A full understanding of the USP <795> chapter requirements.
• Interpreting safety data sheets (SDSs) and, if applicable, certificates of analysis (COA).
• Reading and comprehension of requirements for specific compounding duties.

Training and observation can be conducted by either the designated person(s) or an alternative assigned trainer. Once personnel have been trained and evaluated, they will be expected to repeat the procedures independently under the direct supervision of the designated person(s) or assigned trainer. Full execution of autonomous procedures will be permitted to personnel only after the independent demonstration is successfully completed and documented by the designated person(s) or assigned trainer as outlined in Section 14.

In addition to the initial and annual competency training and outlined evaluations, the designated person(s) or assigned trainer must regularly monitor and observe ongoing compounding activities. If they notice improper practices, they must take immediate action to correct personnel. 

*Note: The facility's SOPs should describe the monitoring and observation procedures related to compounding activities and personnel.

In cases where a compounding facility has only one person in the compounding operation, that person must document their training and competency. Additionally, they must comply with the other requirements outlined in this chapter.

3. Personal Hygiene and Garbing - Maintaining Cleanliness

_____

Maintaining personal hygiene is crucial, especially in the compounding area. Individuals must assess their risk of contamination to either the environment or Compounded Nonsterile Preparations (CNSPs). Conditions like rashes, recent tattoos, oozing sores, conjunctivitis, or active respiratory infections should be reported to the designated person(s). The designated person(s) decides if these individuals should temporarily refrain from working in compounding areas until their conditions have dissipated, or the risk of contamination has been resolved.

Compounding Preparation for Personnel

Compounding personnel should maintain proper hand hygiene and cleanliness based on their compounding tasks. Prior to entry into the compounding area, personnel should remove non-easily cleanable items that could interfere with garbing. At a minimum, this would include:

• Removal of personal outer garments like bandanas, coats, hats, and jackets.
• Removal of all hand, wrist, and exposed jewelry, including piercings that might hinder garbing or hand hygiene (e.g., watches or rings that could damage gloves).
• Removal of earbuds or headphones.

The designated person(s) can allow exceptions as long as they won't compromise the environment or CNSP quality. Any exceptions should be documented.

Hand Hygiene: Keeping Hands Clean

Compounding personnel must abide by proper hand hygiene procedures before entering the compounding area, as outlined in Box 1.

*Note: Using alcohol-based hand rub alone is not appropriate.

Box 1. Stay Clean with Proper Hand Hygiene

	Wash and lather hands with soap and water for a minimum of 30 seconds.
	Dry hands thoroughly with disposable towels or wipes.
	Don gloves.

 

To minimize all possible risks of cross-contamination between CNSPs and other objects, gloves should be properly wiped or replaced prior to starting a different CNSP that involves different components. 

Documenting and Cleaning Frequency

Cleaning and sanitizing activities must be documented daily when compounding takes place. Here's a summary of the minimum cleaning and sanitizing frequencies for various surfaces in nonsterile compounding areas:

• Work surfaces: At the beginning and end of each shift during compounding activities, following spills, and when contamination is known or suspected.
• Floors: Daily during compounding activities, following spills, and when contamination is known or suspected.
• Walls and ceilings: When visibly soiled, following spills, and when contamination is known or suspected.
• Storage shelving: Every 3 months, following spills, and when contamination is known or suspected.

6. Components

_____

The compounding facility should have the following documentation easily accessible to relevant personnel:

• Standard Operating Procedures (SOPs) include components’ selection and inventory control from when they are received until they are used in Compounded Nonsterile Preparations (CNSPs). 
• Safety Data Sheets (SDSs) to personnel who work with components in the facility.
• Personnel should also be trained in both the retrieval and interpretation of information.

Component Selection:

A designated person is responsible for selecting the components used in compounding. 

Active Pharmaceutical Ingredients (APIs) must:

• Adhere to the requirements outlined in the USP–NF monographs
• Include a Certificate of Analysis (COA)
• Be manufactured in FDA-registered facilities (in the U.S.). 

For Components other than APIs:

• Should be accompanied by a COA that verifies compliance with USP–NF monographs

Water:

• Should meet specified quality standards for CNSPs which would include:
• Purified Water, sterile water for irrigation

Following compounding completion, the CNSP must undergo a visual inspection before dispensing.

This inspection helps verify the physical characteristics of the CNSP including color, texture, and uniformity, to ensure it meets standards. The inspection also ensures that the CNSP labeling aligns with the CR, prescription, or medication order. Additionally, it examines the container closure's integrity for any possible issues related to leakage or improper seal.

*Note: Any CNSP with visible defects under P.A.L is promptly rejected, marked as rejected, and segregated from active stock for proper disposal.

9. Labeling: Identifying Information for Safety

_____

Every CNSP must feature clear and compliant labelling to prevent errors during storage, dispensing, and usage. Labelling encompasses all written, printed, or graphic material placed on the immediate container or packaging system. This does not include the outer shipping container.The label on each container of a CNSP must include the following information:

• Internal identification number
• Active ingredient(s): the amount, activity, or concentration
• Storage conditions (if different from room temperature)
• Beyond-use date (BUD)
• Dosage form
• Total quantity/volume (if not evident from the container)

The dispensed CNSP's label should include the following information:

• Route of administration
• Indication of compounding
• Special handling instructions (if applicable)
• Warning statements (if applicable)
• Compounding facility name and contact info for external distribution

Labelling procedures in the facility's SOPs are followed to prevent labelling errors involved with CNSPs.

*Quick Check: The label's conformity is verified against the prescription or medication order, MFR, and CR.

10. Establishing Beyond-Use Dates (BUDs)

_____

Understanding BUD Terminology

Each CNSP label must include the Beyond-Use Date (BUD), signifying the date or date and time until which the preparation remains safe and effective for use. BUDs are expressed in hours, days, or months.

*Note: It's vital to differentiate between BUDs and expiration dates.

*Quick Check* An expiration date relates to the duration during which a conventionally manufactured product, active pharmaceutical ingredient (API), or added substance is expected to meet quality standards and remain suitable for use under prescribed storage conditions. It also dictates when the product should be dispensed or utilized.

Factors Influencing BUD Determination

When determining the BUD for a CNSP, factors affecting its quality require careful consideration, including:

• Chemical and physical stability properties of the API and any added substances in the preparation. 
• (i.e.) Rapid degradation, strength reduction, or the generation of harmful impurities under specific storage conditions can significantly impact the BUD.
• Compatibility of the container closure system with the completed preparation
• Evaluation of potential degradation in the container closure system, which could compromise CNSP integrity.
• Assessment of the risk of microbial proliferation within the CNSP.
• Significant deviations from the essential compounding procedures can influence the formulation's stability.

11. Standard Operating Procedures (SOPs)

_____

Facilities creating CNSPs are mandated to formulate comprehensive SOPs that encompass all compounding procedures. These SOPs should be understood and adhered to by all personnel engaged in compounding, and their oversight falls upon those responsible for these activities.

*Note: One or more designated individual(s) should be assigned the responsibility of ensuring the thorough implementation of the facility's SOPs. This entails addressing any issues, deviations, or errors that come to light through appropriate follow-up measures.

12. Quality Assurance, Recall, Complaints and Adverse Events

_____

Quality Assurance (QA) ensures consistent adherence to quality standards throughout the compounding process, while Quality Control (QC) confirms that specifications are met through testing and documentation before releasing CNSPs. These QA and QC programs should be documented in the facility's SOPs, covering all aspects of CNSP preparation in compliance with this chapter and relevant regulations.

Designated personnel overseeing QA and QC programs are responsible for documenting the following:

• Proper adherence to procedures

• Error prevention, complaint assessment, and corrective actions.

The roles, responsibilities, and training of personnel involved in the QA program are outlined in the SOPs. The QA and QC programs undergo an annual review, with results documented and necessary actions taken.

Recall and Notification

The facility should have procedures to identify the need for recalls, including immediate notification to prescribers if specification failures could potentially harm patients. Unused dispensed CNSPs are recalled, and any remaining pharmacy stock is quarantined. The SOP for recalling dispensed CNSPs outlines procedures for assessing problem severity, identifying affected distribution, identifying patients who received the CNSP, disposal of recalled CNSPs, and documenting the reason for the recall. Recall implementation is documented and reported to relevant regulatory bodies as required by applicable regulations.

Handling Complaints

SOPs for managing complaints should be completed. Complaints related to CNSP quality, labelling, or possible adverse reactions are reviewed by designated personnel to assess potential quality issues.

Complaint records must be easily accessible and aligned with the record requirements outlined in Section 14. CNSPs returned due to complaints are quarantined and disposed of in compliance with applicable regulations.

Reporting Adverse Events

Reporting adverse events potentially related to CNSP quality is carried out in accordance with the facility's SOPs and relevant regulations. If an investigation suggests a quality issue that could impact other patients, the affected patients and prescribers are notified.

13. CNSP Packaging and Transport: Safeguarding and Moving

_____

CNSP Packaging Safety

Facility SOPs must include CNSP packaging. The packaging materials selected should encompass the preservation of the CNSP's physical and chemical stability while also maintaining personnel safety.

Transporting of CNSPs:

For CNSP transport, written SOPs must specify the transportation mode, special handling requirements, and the need for temperature monitoring devices.

14. Documentation: Proof of Compliance

_____

All CNSP preparation facilities, whether written or electronic records, must maintain comprehensive documentation to verify their adherence to the requirements outlined in this chapter. This documentation encompasses several key elements:

• Records related to personnel training, competency assessments, and qualifications, along with any corrective measures taken for identified deficiencies.
• Documentation concerning equipment, including calibration, verification, and maintenance reports.
• Certificate of Analysis (COAs) and records for non-conventionally manufactured components.
• Component receipt documentation.
• Written Standard Operating Procedures (SOPs), Master Formulation Records (MFRs), and Compounding Records (CRs).
• Records of release inspections and testing.
• Detailed accounts of complaints, adverse events, and the steps taken to resolve them.
• Results and actions stemming from investigations.
• Records of cleaning and sanitizing in the designated compounding area.
• Temperature logs.
• Records of accommodations made for personnel involved in CNSP compounding.
• Regular reviews, such as annual assessments of quality assurance (QA) and quality control (QC) programs, as well as yearly checks on chemical hazard and disposal information.

All documentation must conform to relevant laws and regulations, maintain legibility, and be stored in a way that prevents deterioration or loss. Essential Compounding Records (CRs) for a specific CNSP must remain accessible for a minimum of two years post-preparation or in compliance with applicable regulations, whichever period is longer.