36E77619R0017-025.pdf

BRIEFING

795 Pharmaceutical Compounding—Nonsterile Preparations, USP 41 page 6546. This proposed chapter revision is posted online at www.uspnf.com/notices/general-chapter-795-proposed-revisions with line numbers. Submit comments using the electronic submission form at https://usp.az1.qualtrics.com/jfe/form/SV_aWexhZowjRBbKnP.

The Compounding Expert Committee proposes to revise this chapter to improve clarity, respond to stakeholder input, and align with Hazardous Drugs—Handling in Healthcare Settings 800 . Major proposed revisions to the chapter include:

1. Reorganization of the existing chapter to improve clarity and place key procedural information in boxes for easy reference.

2. Expanded guidance for assigning beyond-use dates (BUD) for compounded nonsterile preparations (CNSP) in the absence of stability information.

3. Removal of specific information on handling of hazardous drugs and addition of references to 800 .

Additionally, minor editorial changes have been made to update this chapter to current USP style.

(CMP: J. Sun.)

Correspondence Number—C199364

795 PHARMACEUTICAL

COMPOUNDING—NONSTERILE

PREPARATIONS

Add the following:

▪1. INTRODUCTION AND SCOPE

1.1 Scope

2. PERSONNEL QUALIFICATIONS—TRAINING, EVALUATION, AND

REQUALIFICATION

3. PERSONAL HYGIENE AND GARBING

3.1 Personnel Preparation

3.2 Hand Hygiene

3.3 Garb and Glove Requirements

4. BUILDINGS AND FACILITIES

5. CLEANING AND SANITIZING

6. EQUIPMENT AND COMPONENTS

6.1 Equipment

6.2 Components

7. SOPs AND MASTER FORMULATION AND COMPOUNDING RECORDS

7.1 Creating and Following SOPs

7.2 Creating Master Formulation Records

7.3 Creating Compounding Records

8. RELEASE TESTING

9. LABELING

10. ESTABLISHING BEYOND-USE DATES

10.1 Terminology

10.2 Parameters to Consider in Establishing a BUD

10.3 Establishing a BUD for a CNSP

11. QUALITY ASSURANCE AND QUALITY CONTROL

12. CNSP HANDLING, PACKAGING, STORAGE, AND TRANSPORT

12.1 Handling of CNSPs

12.2 Packaging of CNSPs

12.3 Storing CNSPs within the Compounding Facility

12.4 Shipping and Transporting CNSPs

13. COMPLAINT HANDLING AND ADVERSE EVENT REPORTING

13.1 Complaint Handling

13.2 Adverse Event Reporting

14. DOCUMENTATION

GLOSSARY

APPENDIX

▪1S (USP42)

Change to read:

INTRODUCTION

The purpose of this chapter is to provide compounders with guidance on applying good compounding practices for the preparation of nonsterile compounded formulations for dispensing and/or administration to humans or animals. Compounding is an integral part of pharmacy practice and is essential to the provision of healthcare. This chapter and applicable monographs on formulation help define good compounding practices.

Furthermore, this chapter provides general information to enhance the compounder's ability in the compounding facility to extemporaneously compound preparations that are of acceptable strength, quality, and purity.

Pharmacists, other healthcare professionals, and others engaged in the compounding of drug preparations should comply with applicable state and federal compounding laws, regulations, and guidelines.

CATEGORIES OF COMPOUNDING

In the three general categories of nonsterile compounding described in this section, different levels of experience, training, and physical facilities are associated with each category.

Criteria used to determine overall classification include:

degree of difficulty or complexity of the compounding process stability information and warnings packaging and storage requirements dosage forms complexity of calculations local versus systemic biological disposition level of risk to the compounder potential for risk of harm to the patient.

See Pharmaceutical Compounding—Sterile Preparations 797 for risk levels associated with sterile preparations. Specialty areas such as radiopharmaceuticals require special training and are beyond the scope of this chapter. Compounders shall acquire and maintain knowledge and skills in all areas (e.g., dosage form, patient population, and medical specialty) for which they compound.

Description of Categories

SIMPLE

Making a preparation that has a United States Pharmacopeia (USP) compounding monograph or that appears in a peer-reviewed journal article that contains specific quantities of all components, compounding procedure and equipment, and stability data for that formulation with appropriate BUDs; or reconstituting or manipulating commercial products that may require the addition of one or more ingredients as directed by the manufacturer. Examples include Captopril Oral Solution, Indomethacin Topical Gel, and Potassium Bromide Oral Solution, Veterinary.

MODERATE

Making a preparation that requires special calculations or procedures (such as calibration of dosage unit mold cavities) to determine quantities of components per preparation or per individualized dosage units; or making a preparation for which stability data for that specific formulation are not available. Examples include Morphine Sulfate Suppositories, diphenhydramine hydrochloride troches, and mixing two or more manufactured cream products when the stability of the mixture is not known.

COMPLEX

Making a preparation that requires special training, environment, facilities, equipment, and procedures to ensure appropriate therapeutic outcomes.

Examples of possible complex preparation types include transdermal dosage forms, modified-release preparations, and some inserts and suppositories for systemic effects.

RESPONSIBILITIES OF THE COMPOUNDER

The compounder is responsible for compounding preparations of acceptable strength, quality, and purity and in accordance with the prescription or medication order. The compounder is also responsible for dispensing the finished preparation, with appropriate packaging and labeling, and in compliance with the requirements established by the applicable state agencies, state boards of pharmacy, federal law, and other regulatory agencies where appropriate. Individuals who are engaged in drug or dietary supplement compounding shall be proficient in compounding and should continually expand their compounding knowledge by participating in seminars and/or studying appropriate literature. They shall be knowledgeable about the contents of this chapter and should be familiar with 797 , Pharmaceutical Dosage Forms 1151 , Pharmaceutical Calculations in

Pharmacy Practice 1160 , Quality Assurance in Pharmaceutical Compounding 1163 , Prescription Balances and Volumetric Apparatus Used in Compounding 1176 , 1191 , Written Prescription Drug Information— Guidelines 1265 , and all applicable compounding laws, guidelines, and standards.

To ensure the quality of compounded preparations, compounders shall adhere to the following general principles (additional information on these general principles is provided in the sections that follow).

General Principles of Compounding

1. Personnel are appropriately trained and are capable of performing and qualified to perform their assigned duties. Such training should be documented.

2. Compounding ingredients of the appropriate identity, purity, and quality are purchased from reliable sources and are properly stored according to manufacturer specifications or USP standards.

3. Bulk component containers are labeled with appropriate Occupational Safety and Health Administration (OSHA) hazard communication labels (see www.OSHA.gov), and Material Safety Data Sheets (MSDSs) are available to compounding personnel for all drugs and chemicals used in compounding.

4. All equipment used in compounding is clean, properly maintained, and used appropriately.

5. The compounding environment is suitable for its intended purpose;

and procedures are implemented to prevent cross-contamination, especially when compounding with drugs (e.g., hazardous drugs and known allergens like penicillin) that require special precautions.

6. Only authorized personnel are allowed in the immediate vicinity of the drug compounding operations.

7. There is assurance that processes are always carried out as intended or specified and are reproducible.

8. Compounding conditions and procedures are adequate for preventing errors.

9. All aspects of compounding are appropriately documented.

10. Adequate procedures and records exist for investigating and correcting failures or problems in compounding, testing, or the preparation itself.

COMPOUNDING PROCESS

The compounder is responsible for ensuring that each individual incidence of compounding meets the criteria given in this section (additional information on these criteria is provided in the sections that follow).

Criteria When Compounding Each Drug Preparation

1. The dose, safety, and intended use of the preparation or device has been evaluated for suitability in terms of:

the chemical and physical properties of the components dosage form therapeutic appropriateness and route of administration, including local and systemic biological disposition legal limitations, if any.

2. A Master Formulation Record should be created before compounding a preparation for the first time. This record shall be followed each time that preparation is made. In addition, a Compounding Record should be completed each time a preparation is compounded.

3. Ingredients used in the formulation have their expected identity, quality, and purity. If the formulation is for humans, ingredients are not on a list of federally recognized drugs or specific drug products that have been withdrawn or removed from the market for safety or efficacy reasons (see www.FDA.gov). If the formulation is for food-producing animals, ingredients are not on a list of components prohibited for use in food-producing animals. Certificates of Analysis, when applicable, and MSDSs have been consulted for all ingredients used.

4. Compounding is done in an appropriately clean and sanitized area dedicated to this activity (see the section Compounding Facilities).

5. Only one preparation is compounded at one time in a specific workspace.

6. Appropriate compounding equipment has been selected and inspected for cleanliness and correct functioning and is properly used.

7. A reliable BUD is established to ensure that the finished preparation has its accepted potency, purity, quality, and characteristics, at least until the labeled BUD.

8. Personnel engaged in compounding maintain good hand hygiene and wear clean clothing appropriate to the type of compounding performed (e.g., hair bonnets, coats, gowns, gloves, facemasks, shoes, aprons, or other items) as needed for protection of personnel from chemical exposures and for prevention of drug contamination.

9. The preparation is made in accordance with this chapter, other official standards referenced in this chapter, and relevant scientific data and information.

10. Critical processes (including but not limited to weighing, measuring, and mixing) are verified by the compounder to ensure that procedures, when used, will consistently result in the expected qualities in the finished preparation.

11. The final preparation is assessed using factors such as weight, adequacy of mixing, clarity, odor, color, consistency, pH, and analytical testing as appropriate; and this information is recorded on the Compounding Record (see 1163 ).

12. The preparation is packaged as recommended in the Packaging and Drug Preparation Containers section of this chapter.

13. The preparation container is labeled according to all applicable state and federal laws. The labeling shall include the BUD and storage and handling information. The labeling should indicate that “this is a compounded preparation.”

14. The Master Formulation Record and the Compounding Record have been reviewed by the compounder to ensure that errors have not occurred in the compounding process and that the preparation is suitable for use.

15. The preparation is delivered to the patient or caregiver with the appropriate consultation.

COMPOUNDING FACILITIES

Compounding facilities shall have an adequate space that is specifically designated for compounding of prescriptions. This space shall provide for the orderly placement of equipment and materials to prevent mixups among ingredients, containers, labels, in-process materials, and finished preparations and is designed, arranged, and used to prevent adventitious cross-contamination. Areas used for sterile preparations shall be separated and distinct from the nonsterile compounding area (see Pharmaceutical Compounding—Sterile Preparations 797 , Environmental Quality and Control).

Potable water shall be supplied for hand and equipment washing. This water meets the standards prescribed in the Environmental Protection Agency’s National Primary Drinking Water Regulations (40 CFR Part 141).

Purified Water (see Purified Water monograph) shall be used for compounding nonsterile drug preparations when formulations indicate the inclusion of water. Purified Water should be used for rinsing equipment and utensils. In those cases when a water is used to prepare a sterile preparation, follow the appropriate monographs and general chapters (see Water for Pharmaceutical Purposes 1231 ).

The plumbing system shall be free of defects that could contribute to contamination of any compounded preparation. Adequate hand and equipment washing facilities shall be easily accessible to the compounding areas. Such facilities shall include, but are not limited to, hot and cold water, soap or detergent, and an air-drier or single-use towels. The areas used for compounding shall be maintained in clean, orderly, and sanitary conditions and shall be maintained in a good state of repair. Waste shall be held and disposed of in a sanitary and timely manner and in accordance with local, state, and federal guidelines.

The entire compounding and storage area should be well lighted. Heating, ventilation, and air conditioning systems shall be controlled to avoid decomposition and contamination of chemicals (see Packaging and Storage Requirements 659 and the manufacturers’ labeled storage conditions).

Appropriate temperature and humidity monitoring should be maintained as required for certain components and compounded dosage forms. All components, equipment, and containers shall be stored off the floor and in a manner to prevent contamination and permit inspection and cleaning of the compounding and storage area.

Hazardous drugs shall be stored, prepared, and handled by appropriately trained personnel under conditions that protect the healthcare workers and other personnel. The following are references for the safe handling of antineoplastic and hazardous drugs in healthcare settings:

OSHA Technical Manual—Section VI: Chapter 2, Controlling Occupational Exposure to Hazardous Drugs

NIOSH Alert: Preventing Occupational Exposure to Antineoplastic and Other Hazardous Drugs in Health Care Settings[DHHS (NIOSH) Publication No. 2004-165] and updates.

Disposal of all hazardous drug wastes shall comply with all applicable federal and state regulations. All personnel who perform routine custodial waste removal and cleaning activities in storage and preparation areas for hazardous drugs shall be trained in appropriate procedures to protect themselves and prevent contamination.

COMPOUNDING EQUIPMENT

The equipment and utensils used for compounding of a drug preparation shall be of appropriate design and capacity. The equipment shall be of suitable composition that the surfaces that contact components are neither reactive, additive, nor sorptive and therefore will not affect or alter the purity of the compounded preparations. The types and sizes of equipment depend on the dosage forms and the quantities compounded (see 1176 and equipment manufacturers' instruction manuals).

Equipment shall be stored to protect it from contamination and shall be located to facilitate its use, maintenance, and cleaning. Automated, mechanical, electronic, and other types of equipment used in compounding or testing of compounded preparations shall be routinely inspected, calibrated as necessary, and checked to ensure proper performance.

Immediately before compounding operations, the equipment shall be inspected by the compounder to determine its suitability for use. After use, the equipment shall be appropriately cleaned.

Extra care should be used when cleaning equipment used in compounding preparations that require special precaution (e.g., antibiotics and cytotoxic and other hazardous materials). When possible, special equipment should be dedicated for such use, or when the same equipment is being used for all drug products, appropriate procedures shall be in place to allow meticulous cleaning of equipment before use with other drugs. If possible, disposable equipment should be used to reduce chances of bioburden and cross-contamination.

COMPONENT SELECTION, HANDLING, AND STORAGE

The following guidelines shall be followed when selecting, handling, and storing components for compounded preparations.

1. A United States Pharmacopeia (USP), National Formulary (NF), or Food Chemicals Codex (FCC) substance is the recommended source of ingredients for compounding all preparations.

2. Compounders shall first attempt to use components manufactured in an FDA-registered facility. When components cannot be obtained from an FDA-registered facility, compounders shall use their professional judgment in selecting an acceptable and reliable source and shall establish purity and safety by reasonable means, which should include Certificate of Analysis, manufacturer reputation, and reliability of source.

3. Official compounded preparations are prepared from ingredients that meet requirements of the compendial monograph for those individual ingredients for which monographs are provided. These preparations may be labeled USP or NF as appropriate.

4. When components of compendial quality are not obtainable, components of high quality such as those that are chemically pure, analytical reagent grade, or American Chemical Society–certified may be used. However, these components should be used cautiously because the standards for analytical reagents or American Chemical Society–grade materials do not consider whether any impurity present raises human or animal safety concerns.

5. For components in containers that have an expiration date from the manufacturer or distributor, the material may be used in compounding before that expiration date (a) when the material is stored in its original container under conditions to avoid decomposition of the chemicals (see 1191 and 659 , unless other conditions are noted on the label), (b) when there is minimal exposure of the remaining material each time material is withdrawn from the container, and (c) when any withdrawals from the container are performed by those trained in the proper handling of the material. If the component has been transferred to a different container, that container shall be identified with the component name, original supplier, lot or control number, transfer date, and expiration date and shall provide integrity that is equivalent to or better than that of the original container.

6. For components that do not have expiration dates assigned by the manufacturer or supplier, the compounder shall label the container with the date of receipt and assign a conservative expiration date, not to exceed three years after receipt, to the component (see

•Labeling 7 , Expiration Date and Beyond-Use Date)• (CN 1-May-2018) based on the nature of the component and its degradation mechanism, the container in which it is packaged, and the storage conditions.

7. If a manufactured drug product is used as the source of active ingredient, the drug product shall be manufactured in an FDA-registered facility, and the manufacturer’s product container shall be labeled with a batch control number and expiration date. When compounding with manufactured drug products, the compounder shall consider all ingredients, including excipients, present in the drug product relative to the intended use of the compounded preparation and the effect of manipulating the drug product on the therapeutic appropriateness and stability of the components.

8. If the preparation is intended for use as a dietary or nutritional supplement, then the compounder must adhere to this chapter and must also comply with any federal and state requirements. Generally, dietary supplements are prepared from ingredients that meet USP, FCC, or NF standards. Where such standards do not exist, substances may be used in dietary supplements if they have been shown to have acceptable food-grade quality using other suitable procedures.

9. When a component is derived from ruminant animals (e.g., bovine, caprine, ovine), the supplier shall provide written assurance that the component is in compliance with all federal laws governing processing, use, and importation requirements for these materials.

10. When compounding for humans, the compounder should consult the list of components that have been withdrawn or removed from the market for safety or efficacy reasons by FDA (see www.FDA.gov).

When compounding for food-producing animals, the compounder should consult the list of components prohibited for use in food-producing animals.

11. All components used in the compounding of preparations must be stored as directed by the manufacturer, or according to USP, NF, or FCC monograph requirements, in a clean area, and under appropriate temperature and humidity conditions (controlled room temperature, refrigerator, or freezer). All components shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. All containers shall be properly labeled.

STABILITY CRITERIA AND BEYOND-USE DATING

The BUD is the date after which a compounded preparation shall not be used and is determined from the date when the preparation is compounded.

Because compounded preparations are intended for administration immediately or following short-term storage, their BUDs are assigned on the basis of criteria different from those applied to assigning expiration dates to manufactured drug products.

BUDs should be assigned conservatively. When assigning a BUD, compounders shall consult and apply drug-specific and general stability documentation and literature when available and should consider:

the nature of the drug and its degradation mechanism the dosage form and its components the potential for microbial proliferation in the preparation the container in which it is packaged the expected storage conditions the intended duration of therapy (see •Labeling 7 , Expiration Date and Beyond-Use Date.)• (CN 1-May-2018)

When a manufactured product is used as the source of the API for a nonsterile compounded preparation, the product expiration date cannot be used solely to assign a BUD for the compounded preparation. Instead, the compounder shall refer to the manufacturer for stability information and to the literature for applicable information on stability, compatibility, and degradation of ingredients; shall consider stability factors in 1191 ; and shall use his or her compounding education and experience. All stability data shall be carefully interpreted in relation to the actual compounded formulation.

At all steps in the compounding, dispensing, and storage process, the compounder shall observe the compounded drug preparation for signs of instability. For more specific details of some of the common physical signs of deterioration (see 1191 , Observing Products for Evidence of Instability).

However, excessive chemical degradation and other drug concentration loss due to reactions may be invisible more often than visible.

General Guidelines for Assigning Beyond-Use Dates In the absence of stability information that is applicable to a specific drug and preparation, the following table presents maximum BUDs recommended for nonsterile compounded drug preparations that are packaged in tight, light-resistant containers and stored at controlled room temperature, unless otherwise indicated (see 659 ). Drugs or chemicals known to be labile to decomposition will require shorter BUDs.

BUD by Type of Formulationa For Nonaqueous Formulations—The BUD is not later than the time remaining until the earliest expiration date of any API or 6 months, whichever

BUD by Type of Formulationa is earlier.

For Water-Containing Oral Formulations—The BUD is not later than 14 days when stored at controlled cold temperatures.

For Water-Containing Topical/Dermal and Mucosal Liquid and Semisolid Formulations—The BUD is not later than 30 days.

a These maximum BUDs are recommended for nonsterile compounded drug preparations in the absence of stability information that is applicable to a specific drug or preparation. The BUD shall not be later than the expiration date on the container of any component.

Susceptible preparations should contain suitable antimicrobial agents to protect against bacteria, yeast, and mold contamination inadvertently introduced during or after the compounding process. When antimicrobial preservatives are contraindicated in such compounded preparations, storage of the preparation at controlled cold temperature is necessary; to ensure proper storage and handling of such compounded preparations by the patient or caregiver, appropriate patient instruction and consultation is essential. Antimicrobial preservatives should not be used as a substitute for good compounding practices.

For information on assigning BUDs when repackaging drug products for dispensing or administration, see General Notices and Requirements, Preservation, Packaging, Storage, and Labeling, Labeling, Expiration Date and Beyond-Use Date, and Packaging and Repackaging—Single-Unit Containers 1136 .

Assurance of sterility in a compounded sterile preparation is mandatory.

Compounding and packaging of sterile drugs (including ophthalmic preparations) requires strict adherence to guidelines presented in 797 and in the manufacturers' labeling instructions.

PACKAGING AND DRUG PREPARATION CONTAINERS

The compounder shall ensure that the containers and container closures used in packaging compounded preparations meet USP requirements (see 659 ; Containers—Glass 660 ; Plastic Packaging Systems and their

Materials of Construction 661 ; Plastic Materials of Construction 661.1 ;

Plastic Packaging Systems for Pharmaceutical Use 661.2 ; Containers— Performance Testing 671 ; 1136 ); and when available, compounding monographs. Compounders are not expected to perform the tests described in these chapters but should be knowledgeable about the standards described in them. Container suppliers shall supply, upon request, verification of USP container compliance. Containers and container closures intended for the compounding of sterile preparations must be handled as described in 797 .

The containers and closures shall be made of suitable clean material in order not to alter the quality, strength, or purity of the compounded drug preparation. The container used depends on the physical and chemical properties of the compounded preparation. Container–drug interaction should be considered for substances that have sorptive or leaching properties.

The containers and closures shall be stored off the floor, handled and stored to prevent contamination, and rotated so that the oldest stock is used first. The containers and container closures shall be stored in such a way as to permit inspection and cleaning of the storage area.

COMPOUNDING DOCUMENTATION

Documentation, written or electronic, enables a compounder, whenever necessary, to systematically trace, evaluate, and replicate the steps included throughout the preparation process of a compounded preparation. All compounders who dispense prescriptions must comply with the record-keeping requirements of their state boards of pharmacy. When the compounder compounds a preparation according to the manufacturer's labeling instructions, then further documentation is not required. All other compounded preparations require further documentation as described in this section.

These records should be retained for the same period of time that is required for any prescription under state law. The record may be a copy of the prescription in written or machine-readable form and should include a Master Formulation Record and a Compounding Record.

Master Formulation Record This record shall include:

official or assigned name, strength, and dosage form of the preparation calculations needed to determine and verify quantities of components and doses of active pharmaceutical ingredients description of all ingredients and their quantities compatibility and stability information, including references when available equipment needed to prepare the preparation, when appropriate mixing instructions that should include:

1. order of mixing

2. mixing temperatures or other environmental controls

3. duration of mixing

4. other factors pertinent to the replication of the preparation as compounded.

sample labeling information, which shall contain, in addition to legally required information:

1. generic name and quantity or concentration of each active ingredient

2. assigned BUD

3. storage conditions

4. prescription or control number, whichever is applicable.

container used in dispensing packaging and storage requirements description of final preparation quality control procedures and expected results.

Compounding Record The Compounding Record shall contain:

official or assigned name, strength, and dosage of the preparation Master Formulation Record reference for the preparation names and quantities of all components sources, lot numbers, and expiration dates of components total quantity compounded name of the person who prepared the preparation, name of the person who performed the quality control procedures, and name of the compounder who approved the preparation date of preparation assigned control or prescription number assigned BUD duplicate label as described in the Master Formulation Record description of final preparation results of quality control procedures (e.g., weight range of filled capsules, pH of aqueous liquids) documentation of any quality control issues and any adverse reactions or preparation problems reported by the patient or caregiver.

Standard Operating Procedures All significant procedures performed in the compounding area should be covered by written standard operating procedures (SOPs). Procedures should be developed for the facility, equipment, personnel, preparation, packaging, and storage of compounded preparations to ensure accountability, accuracy, quality, safety, and uniformity in compounding.

Implementing SOPs establishes procedural consistency and also provides a reference for orientation and training of personnel.

Material Safety Data Sheets File MSDSs shall be readily accessible to all employees working with drug substances or bulk chemicals located on the compounding facility premises.

Employees should be instructed on how to retrieve and interpret needed information.

QUALITY CONTROL

The safety, quality, and performance of compounded preparations depend on correct ingredients and calculations, accurate and precise measurements, appropriate formulation conditions and procedures, and prudent pharmaceutical judgment. As a final check, the compounder shall review each procedure in the compounding process. To ensure accuracy and completeness, the compounder shall observe the finished preparation to ensure that it appears as expected and shall investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient.

Compounding Controls

1. The Master Formulation Record, the Compounding Record, and associated written procedures shall be followed in execution of the compounding process. Any deviation in procedures shall be documented.

2. The compounder shall check and recheck each procedure at each stage of the process. If possible, a trained second person should verify each critical step in the compounding process.

3. The compounder shall have established written procedures that describe the tests or examinations conducted on the compounded preparation (e.g., the degree of weight variation among capsules) to ensure their uniformity and integrity.

4. Appropriate control procedures shall be established to monitor the output and to verify the performance of compounding processes and equipment that may be responsible for causing variability in the final compounded preparations.

5. For further guidance on recommended quality control procedures, see 1163 .

PATIENT COUNSELING

At the time of dispensing the prescription, the patient or the patient's agent shall be counseled about proper use, storage, handling, and disposal of the compounded preparation. The patient or the patient’s agent shall also be instructed to report any adverse event and to observe and report to the compounder any changes in the physical characteristics of the compounded preparation (see 1191 , Responsibility of Pharmacists). The compounder shall investigate and document any reported problem with a compounded preparation and shall take corrective action.

TRAINING

All personnel involved in the compounding, evaluation, packaging, and dispensing of compounded preparations shall be properly trained for the type of compounding conducted. It is the responsibility of the compounder to ensure that a training program has been implemented and that it is ongoing.

Compounding personnel should be evaluated at least annually. Steps in the training procedure include the following:

All employees involved in pharmaceutical compounding shall read and become familiar with this chapter. They should also be familiar with the contents of the USP Pharmacists' Pharmacopeia and other relevant publications, including how to read and interpret MSDSs.

All employees shall read and become familiar with each of the procedures related to compounding, including those involving the facility, equipment, personnel, actual compounding, evaluation, packaging, storage, and dispensing.

All personnel who compound hazardous drugs shall be fully trained in the storage, handling, and disposal of these drugs. This training shall occur before preparing or handling hazardous drugs. For information on training for personnel who compound hazardous drugs, see the references in Compounding Facilities earlier in this chapter.

All training activities shall be documented. The compounder shall meet with employees to review their work and answer any questions the employees may have concerning compounding procedures.

The compounder shall demonstrate the procedures for the employee and shall observe and guide the employee throughout the training process. The employee will then repeat the procedure without any assistance from, but under the direct supervision of, the compounder.

When the employee has demonstrated to the compounder a verbal and functional knowledge of the procedure, then and only then will the employee be permitted to perform the procedure without direct supervision. However, the compounder should be physically present and shall approve all ingredients and their quantities and the final preparation.

When the compounder is satisfied with the employee’s knowledge and proficiency, the compounder will sign the documentation records to show that the employee was appropriately trained.

The compounder shall continually monitor the work of the employee and ensure that the employee's calculations and work are accurate and adequately performed.

The compounder is solely responsible for the finished preparation.

COMPOUNDING FOR ANIMAL PATIENTS

A compounder's responsibility for providing patients with high-quality compounded preparations extends beyond the human species. All portions of this chapter apply to compounded preparations formulated for animal patients. Intended use of any animal patient (e.g., companion, performance, food) shall be determined before compounding for that patient.

Because humans can consume animal patients as food, care must be taken to prevent drug residues from entering the human food chain when compounded preparations are used in animal patients. For this reason, all compounders preparing formulations for animals shall possess a functional knowledge of drug regulation and disposition in animal patients.

Veterinarians are required by law to provide food-producing animal caregivers with an accurate length of time to withhold treated animal tissues (e.g., meat, milk, eggs) from the human food supply. This length of time is referred to as a withdrawal time (WDT) and must also, by law, be included on the dispensing label of every prescription prepared for a food-producing species.

Drug use in any performance animal is strictly regulated by federal and state governments, in addition to the governing bodies of each of the specific disciplines. Penalties for violation of these rules may be severe for all contributing to the violation, including the veterinarian, pharmacist, and caregiver.

The pharmacist shall be knowledgeable about the individual species' limitations in physiology and metabolic capacity that can result in toxicity when certain drugs or excipients are used in compounded preparations. For this reason, compounders making preparations for animals should use, when possible, formulations specifically developed for animal patients. If such formulations are not available, the compounder shall conduct a literature review to determine whether a specific component of the formula is toxic to the target species. Extrapolating compounding formulations intended for use in humans may not be appropriate for animal species and may contribute to negative outcomes.

Veterinarians and pharmacists making preparations for animal patients should be familiar with all state and federal regulations regarding drug use in animals, including but not limited to the Food, Drug, and Cosmetic Act; the

Animal Drug Amendment; the Animal Medicinal Drug Use Clarification Act;

and FDA's Compliance Policy Guideline for Compounding of Drugs for Use in Animal Patients.

GLOSSARY

Active Pharmaceutical Ingredient (API): Any substance or mixture of substances intended to be used in the compounding of a drug preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans and animals or affecting the structure and function of the body.

Added Substances: Ingredients that are necessary to compound a preparation but are not intended or expected to cause a pharmacologic response if administered alone in the amount or concentration contained in a single dose of the compounded preparation. The term is used synonymously with the terms inactive ingredients, excipients, and pharmaceutical ingredients.

Beyond-Use Date (BUD): The date after which a compounded preparation shall not be used; determined from the date the preparation is compounded.

Component: Any ingredient used in the compounding of a drug preparation, including any active ingredient or added substance that is used in its preparation.

Compounder: A professional authorized by the appropriate jurisdiction to perform compounding pursuant to a prescription or medication order by a licensed prescriber.

Compounding: The preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioner's prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice. Compounding includes the following:

Preparation of drug dosage forms for both human and animal patients Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns Reconstitution or manipulation of commercial products that may require the addition of one or more ingredients Preparation of drugs or devices for the purposes of, or as an incident to, research (clinical or academic), teaching, or chemical analysis

Preparation of drugs and devices for prescriber's office use where permitted by federal and state law.

Hazardous Drug: Any drug identified by at least one of the following six criteria:

Carcinogenicity Teratogenicity or developmental toxicity Reproductive toxicity in humans Organ toxicity at low doses in humans or animals Genotoxicity New drugs that mimic existing hazardous drugs in structure or toxicity

[for examples see current National Institute for Occupational Safety and Health (NIOSH) publications].

Manufacturing: The production, propagation, conversion, or processing of a drug or device, either directly or indirectly, by extraction of the drug from substances of natural origin or by means of chemical or biological synthesis.

Manufacturing may also include any packaging or repackaging of the substance(s) or labeling or relabeling of containers for resale by pharmacies, practitioners, or other persons.

Preparation: For the purposes of this chapter, a compounded drug dosage form or dietary supplement or a device to which a compounder has introduced a drug. This term will be used to describe compounded formulations; the term product will be used to describe manufactured pharmaceutical dosage forms. (For the definitions of official substance and official products, see General Notices and Requirements.)

Stability: The extent to which a preparation retains, within specified limits and throughout its period of storage and use, the same properties and characteristics that it possessed at the time of compounding (see Stability Considerations in Dispensing Practice 1191 , the table Criteria for Acceptable Levels of Stability).

Vehicle: A component for internal or external use that is used as a carrier or diluent in which liquids, semisolids, or solids are dissolved or suspended.

Examples include, but are not limited to, water, syrups, elixirs, oleaginous liquids, solid and semisolid carriers, and proprietary products.

▪1. INTRODUCTION AND SCOPE 1

This chapter describes the minimum standards to be followed when 2 preparing compounded nonsterile preparations (CNSPs) for humans and 3 animals. For purposes of this chapter, nonsterile compounding is defined as 4 combining, admixing, diluting, pooling, reconstituting other than as provided 5 in the manufacturer package insert, or otherwise altering a drug or bulk drug 6 substance to create a nonsterile medication. Reconstituting a conventionally 7 manufactured nonsterile product in accordance with the directions contained 8 in the approved labeling provided by the product’s manufacturer is not 9 considered compounding as long as the product is prepared for an individual 10 patient and not stored for future use. 11

1.1 Scope 12

COMPOUNDED NONSTERILE PREPARATIONS AFFECTED 13

CNSPs that may be affected by this chapter include but are not limited to 14 the following dosage forms: 15

Solid oral preparations 16 Liquid oral preparations 17 Rectal preparations 18 Vaginal preparations 19 Topical preparations (i.e., creams, gels, irrigations for non-internal and 20 non-surgical body cavities) 21 Nasal and sinus preparations intended for local application 22 Otic preparations 23

HANDLING OF HAZARDOUS DRUGS 24

Compounding of nonsterile hazardous drugs must also comply with 25 Hazardous Drugs—Handling in Healthcare Settings 800 . 26

AFFECTED PERSONNEL AND SETTINGS 27

This chapter applies to all persons who prepare CNSPs and all places where 28 CNSPs are prepared. This includes but is not limited to pharmacists, 29 technicians, physicians, veterinarians, dentists, naturopaths, chiropractors, 30 and nurses, in all places including but not limited to pharmacies, hospitals 31 and other healthcare institutions, patient treatment sites, and physicians’ or 32 veterinarians’ practice sites. 33 The compounding facility’s leadership and all personnel involved in 34 preparing, storing, packaging, and transporting CNSPs are responsible for 1) 35 ensuring that the applicable practices and quality standards in this chapter 36 are continually and consistently applied to their operations, and 2) 37 proactively identifying and remedying potential problems within their 38 operations. Personnel engaged in the compounding of CNSPs must also 39 comply with applicable laws and regulations of the regulatory jurisdiction. 40 The compounding facility must designate one or more individuals (i.e., the 41 designated person) to be responsible and accountable for the performance 42 and operation of the facility and personnel in the preparation of CNSPs. The 43 responsibilities of the designated person include but are not limited to: 44

Developing and implementing a training program 45 Routinely monitoring and observing compounding activities and taking 46 immediate corrective action if deficient practices are observed 47 Demonstrating the procedures for personnel and observing and 48 guiding personnel throughout the training process 49 Evaluating whether individuals with certain conditions, such as rashes 50 or respiratory illnesses, will be allowed to work in compounding areas 51 before their conditions are resolved because these conditions carry 52 the risk of contaminating the environment and CNSPs 53

Ensuring that standard operating procedures (SOPs) are fully 54 implemented. The designated person must ensure that follow-up is 55 carried out if problems, deviations, or errors are identified 56

Establishing, monitoring, and documenting procedures for the handling 57 and storage of CNSPs and/or components of CNSPs 58

If the compounding facility has only one person responsible for all the 59 compounding in the facility, then that person will become the designate. 60

2. PERSONNEL QUALIFICATIONS—TRAINING, EVALUATION, AND 62

REQUALIFICATION 63

All personnel involved in the preparation and handling of CNSPs must be 64 trained, must demonstrate competency, and must undergo annual refresher 65 training. Training and competency of personnel must be documented as 66 described in 14. Documentation. 67 The designated person must develop a written training program that 68 describes the required training, the frequency of training, and the process 69 for evaluating the competency of personnel involved in nonsterile 70 compounding and handling of CNSPs. This program must equip personnel 71 with knowledge and training in the required skills necessary to perform their 72 assigned tasks. 73 In addition to the initial and annual competency training and evaluation 74 described in this section, the designated person should routinely monitor and 75 observe compounding activities and must take immediate corrective action if 76 deficient practices are observed. SOPs must describe procedures for the 77 monitoring and observing of compounding activities and personnel. 78 Before independently beginning to prepare CNSPs, personnel must 79 complete training and be able to demonstrate proficiency in the theoretical 80 principles and hands-on skills of nonsterile manipulations for the type of 81 compounding they will be performing. Proficiency must be demonstrated in 82 at least the following core competencies: 83

Hand hygiene 84 Garbing 85

Cleaning and sanitizing 86 Component selection, handling, and transport 87 Performing calculations 88 Measuring and mixing 89 Use of equipment 90 Documentation of the compounding process (e.g., Master Formulation 91

Records and Compounding Records) 92

Steps in the training procedure must include the following: 93

Read and understand this chapter 94 Have access to USP compounding monographs, other applicable 95 general chapters, and other relevant literature 96 Understand and interpret Certificates of Analysis (COAs) and Safety 97

Data Sheets (SDS) 98 Read and understand procedures related to their compounding duties, 99 including those regarding the facility, equipment, personnel, garbing, 100 actual compounding processes, evaluation, packaging, storage, 101 transport, and dispensing 102

Additionally, the designated person must demonstrate the procedures for 103 personnel, and must observe and guide personnel throughout the training 104 process. The personnel will then be expected to repeat the procedures 105 independently, but under the direct supervision of the designated person. An 106 employee will be permitted to perform the procedure without direct 107 supervision only after independently demonstrating understanding and 108 competency to the designated person. Upon completion of the training 109 program, the designated person must document that the employee has been 110 trained and successfully completed competency assessments (see 14. 111 Documentation). 112 If the facility has only one person in the compounding operation, that 113 person must document that they have obtained appropriate training outside 114 of the facility and demonstrated competency, and they must comply with the 115 other requirements of this chapter. 116

3. PERSONAL HYGIENE AND GARBING 118

Compounding personnel must maintain personal hygiene. Individuals that 119 may have a higher risk of contaminating the CNSP and the environment 120 (e.g., due to rashes, sunburn, recent tattoos or oozing sores, conjunctivitis, 121 active respiratory infection) must report these conditions to the designated 122 person. The designated person must evaluate whether these individuals will 123 be allowed to work in compounding areas before their conditions are 124 resolved because of the risk of contaminating the environment and CNSPs. 125

3.1 Personnel Preparation 126

Personnel engaged in compounding must maintain hand hygiene and wear 127 clean clothing required for the type of compounding performed. 128 Before entering a designated compounding area, compounding staff must 129 remove any items that are not easily cleanable and that might interfere with 130 garbing. At a minimum, personnel must: 131

Remove personal outer garments (e.g., bandanas, coats, hats, jackets, 132 scarves, sweaters, vests) 133

Remove all hand, wrist, and other exposed jewelry or piercing that can 134 interfere with the effectiveness of the garb or hand hygiene (e.g., 135 watches,…