Patient care is in a continual state of change, and pharmacy practice must reinvent itself to keep up with dynamic times. The coronavirus disease 2019 (COVID-19) pandemic has increased the rate of that change and has forced pharmacists and other healthcare professionals to adapt more quickly. Pharmaceutical compounding provides a prime example of the need to stay updated with new evidence and evolving requirements that keep patients and healthcare professionals safe. Compounding is the creation of customized medications for specific patients that should be prepared in an appropriate environment to maintain safety and effectiveness. Pharmacies across the country are looking for new ways to stay ahead of potential contamination, supply shortages, and uncertain times.

Pharmacists are relied on to have expertise in medication compounding and the guidelines that govern compounding practice. U.S. Pharmacopeia General Chapter <795> (USP <795>) addresses extemporaneous compounding of pharmaceuticals and defines what constitutes good compounding practices.1 The complexity of compounding guidance can be difficult for pharmacy staff to adhere to, especially those who do not perform extemporaneous compounding on a routine basis.

This article will summarize USP <795> and nonsterile compounding best practices for the preparation and dispensing of compounded formulations. USP <795> covers the following major elements: categories of compounding; responsibilities of the compounder; criteria when compounding each drug preparation; compounding-facility requirements; component selection, handling, and storage; stability criteria and beyond-use dating; and compounding documentation and quality control.1

Categories of Compounding

USP <795> classifies compounding into three categories: simple, moderate, and complex. Simple compounding means the making of preparations that have USP compounding monographs or other sources of clear data for stability and procedure. Moderate compounding refers to the making of preparations that do not have a specific formulation available and need special calculations or procedures, such as mixing creams, when stability is not known. Complex compounding involves the making of preparations that require special training, equipment, and procedures to ensure therapeutic outcomes, such as modified-release preparations.1

Responsibilities of the Compounder

The compounder has the responsibility for preparing, packaging, labeling, and dispensing the compound in accordance with a valid prescription. The compounder must be knowledgeable about the contents of USP <795> as well as many other compounding laws, guidelines, and standards. Continually staying updated on and expanding one’s knowledge of these topics is becoming exceedingly difficult given the amount of information compounders are responsible for. General principles of compounding include documenting training and qualifications of personnel; ensuring ingredients’ identity, purity, and quality; labeling bulk-component containers according to Occupational Safety and Health Administration (OSHA) standards; providing a suitable compounding environment and maintaining equipment; creating reproducible processes; and investigating and correcting all issues or problems in the compounding process.1

Criteria When Compounding Each Drug Preparation

Compounding criteria are as follows:

• The dose safety and intended use of the preparation or device have been evaluated for suitability.
• A Master Formulation Record should be created and followed each time a compound is made.
• Ingredients used in formulation have the expected identity, quality and purity.
• Compounding is done in an appropriately clean and sanitized area.
• Only one preparation is compounded at one time in a specific workspace.
• Appropriate compounding equipment is used and maintained.
• A reliable beyond-use date (BUD) is established to ensure potency, purity, and quality.
• Personnel wear clothing and personal protective equipment to prevent exposure and drug contamination.
• The preparation is made in accordance with USP <795> and other official standards.
• Processes are verified by the compounder to ensure expected qualities in the finished product.
• Packaging, containers, and closures are made of suitable clean material in order not to alter quality, strength, or purity. Container-drug interactions should be considered.
• Labeling is correct according to state and federal laws.
• The Master Formulation Record and the Compounding Record are reviewed by the compounder to ensure that no errors have occurred.
• The preparation is delivered to the patient or caregiver with appropriate consultation.1

Commercially available compounding kits can help facilitate all of the above criteria to take some of the burden off the compounder. Each kit is packaged to yield one preparation per patient and contains all necessary equipment to compound the product. Packaging each preparation for one-time use helps prevent contamination and produce a reliable BUD. The labeling on each kit should meet state and federal laws, including instructions for use by the pharmacist and proper storage.1 Information for final product labeling is also provided by the kit manufacturer.

Compounding-Facility Requirements

Requirements for facilities designed for nonsterile drug preparation are generally less involved than those for facilities designed for sterile preparation because International Organization for Standardization (ISO) classification and sterile spaces are not necessary. That said, USP <795> still describes in depth the conditions that must be met when compounding in order to ensure purity and safety. Compounding facilities must have space that is designated for compounding medications, and nonsterile and sterile compounding must have distinct and separate areas to avoid cross-contamination. Potable water is adequate for hand and equipment washing, but purified water must be used for compounding nonsterile drug preparations. The areas used for compounding shall be clean, sanitary, and in a good state of repair, and waste should be disposed of in accordance with guidelines. Sinks should be easily accessible, and the plumbing system must be free of defects that could contribute to contamination when compounding. Pharmacy staff should be consulted in the designing of this work area in order to identify equipment, storage, and materials optimal for pharmacy workflow. USP <795> also addresses hazardous drugs until USP <800> becomes official, stating that they are to be stored and handled under conditions that protect healthcare workers according to the OSHA Technical Manual and the National Institute for Occupational Safety and Health Alert, Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings. The requirements help protect staff, the preparation, and ultimately the patient from contamination.1

Component Selection, Handling, and Storage

USP <795> states that a USP, National Formulary (NF), or Food Chemicals Codex (FCC) substance is the recommended source for all compounding ingredients. This ensures that all components meet conditions described in the USP-NF compendium. Compounders should attempt to use components manufactured in FDA-registered facilities. If a component cannot be obtained from an FDA-registered facility, professional judgment should be used in selecting an acceptable and reliable source in order to establish purity and safety. Caution should be used for any component not made in an FDA-registered facility, as it could present safety concerns for the end user. Components are to be stored off the floor in order to prevent contamination and facilitate cleaning. When stored appropriately, a component may be used before its manufacturer-assigned expiration date. If an expiration date is not provided, the compounder should label the product with the date received and assign a conservative date not to exceed 3 years after receipt. This guidance applies to all preparations intended for use as dietary or nutritional supplements. If ingredients are used that have no USP, FCC, or NF standard, food-grade quality ingredients should be used.1

One practice that can help compounders meet the above guidance is the use of compounding kits such as FIRST Kits, which contain bulk drug substances that comply with standards of an applicable USP or NF monograph. Each component of a kit is accompanied by a certificate of analysis from the manufacturer. It is important to look for products that conduct full USP monograph testing. Frequent USP grade tests should be conducted to ensure that the dose, safety, and intended use of each preparation are evaluated fully.

Stability Criteria and Beyond-Use Dating

When a manufacturer provides a product, it performs specific tests to determine expiration dating. The expiration date differs from the BUD, which is the last date a compounded product can be used and is assigned when the preparation is compounded. Compounders shall refer to manufacturers for stability information and to the literature for other applicable information on stability, compatibility, and degradation of ingredients in order to assign BUDs to compounded preparations. In the absence of stability information for a specific drug and preparation, the following parameters for maximum BUDs for different types of formulations may be used: nonaqueous formulations, 6 months; water-containing topical/dermal liquids and semisolids, 30 days; and water-containing oral formulations, 14 days when refrigerated.1

Using commercial compounding kits, such as those produced by Azurity, can help ensure accurate BUDs, as manufacturers have documented stability testing that supports the BUD for each bulk drug substance and for the compounded product. This ensures purity, quality, and characteristics of the finished compound.

Compounding Documentation and Quality Control

Documentation is of the utmost importance in compounding practice. USP <795> advises on specific required documentation to ensure that compounding processes meet the quality intended in the regulation. The Master Formulation Record is the documentation of drug compound recipes and is used in conjunction with the Compounding Record, which is documentation of each instance a compound is prepared. USP <795> states that when the compounder compounds a preparation according to the manufacturer’s labeling instructions, further documentation is not required.1 There are products available that include everything pharmacists need, along with instructions for compounding the components included within the kit, lessening the amount of documentation needed. The quality, safety, and effectiveness of a compound depend on the correctness of all of the above aspects of compounding. Compounders must do a final check to review each procedure in the compounding process. The function of quality management is to prevent problems and establish standard operating procedures for inspecting and approving all final products.

Recommendations for My Peers

In turbulent times such as these that increase the need for quality assurance, many pharmacists look for easier ways to achieve USP <795> compliance. As a pharmacist, a solution that has helped me in my practice is finding products that include everything I need to compound included inside of a kit, making it so easy for pharmacies to meet USP <795> criteria. There are companies out there, such as Azurity Pharmaceuticals, that make products such as this to help make compounding simple and efficient, allowing pharmacists to easily meet their compounding requirements under Section 503A of the Federal Food, Drug, and Cosmetic Act and the USP standards for nonsterile compounded preparations. Products that make compounding easier for us that include all necessary components in a kit enable pharmacists to compound a finished product in accordance with a specific formulation. As healthcare professionals continue to battle the COVID-19 pandemic, the availability of safe, specialized individual preparations is of the utmost importance. To that end, pharmacists should strive to achieve deep knowledge of pharmaceutical compounding and continue to develop ways to ensure purity, safety, and consistency in each compound made for their patients.

REFERENCES

1. U.S. Pharmacopeial Convention. <795> pharmaceutical compounding—nonsterile preparations. Revision Bulletin. January 1, 2014. www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/revisions/gc795.pdf. Accessed November 7, 2020.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.