usp 36 - pharmaceutical compounding preparations

USP 36 Physical Tests / ⟨795⟩ Pharmaceutical Compounding—Nonsterile Preparations 355

To standardize the pH meter, select two Buffer Solutions logical activity or other direct effect in the diagnosis, cure,for Standardization whose difference in pH does not exceed mitigation, treatment, or prevention of disease in humans4 units and such that the expected pH of the material under and animals or affecting the structure and function of thetest falls between them. Fill the cell with one of the Buffer body.Solutions for Standardization at the temperature at which the ADDED SUBSTANCES—Ingredients that are necessary to com-test material is to be measured. Set the “temperature” con- pound a preparation but are not intended or expected totrol at the temperature of the solution, and adjust the cali- cause a pharmacologic response if administered alone in thebration control to make the observed pH value identical amount or concentration contained in a single dose of thewith that tabulated. Rinse the electrodes and cell with sev- compounded preparation. The term is used synonymouslyeral portions of the second Buffer Solution for Standardiza- with the terms inactive ingredients, excipients, and pharma-tion, then fill the cell with it, at the same temperature as the ceutical ingredients.material to be measured. The pH of the second buffer solu- BEYOND-USE DATE (BUD)—The date after which a com-tion is within ±0.07 pH unit of the tabulated value. If a pounded preparation should not to be used; determinedlarger deviation is noted, examine the electrodes and, if from the date the preparation is compounded.they are faulty, replace them. Adjust the “slope” or “tem-

COMPONENT—Any ingredient used in the compounding of aperature” control to make the observed pH value identicaldrug preparation, including any active ingredient or addedwith that tabulated. Repeat the standardization until bothsubstance that is used in its preparation.Buffer Solutions for Standardization give observed pH valuesCOMPOUNDER—A professional authorized by the appropriatewithin 0.02 pH unit of the tabulated value without furtherjurisdiction to perform compounding pursuant to a prescrip-adjustment of the controls. When the system is functioningtion or medication order by a licensed prescriber.satisfactorily, rinse the electrodes and cell several times with

a few portions of the test material, fill the cell with the test COMPOUNDING—The preparation, mixing, assembling, alter-material, and read the pH value. Use carbon dioxide-free ing, packaging, and labeling of a drug, drug-delivery device,water (see Water in the section Reagents, Indicators, and So- or device in accordance with a licensed practitioner’s pre-lutions) for solution or dilution of test material in pH deter- scription, medication order, or initiative based on the practi-minations. In all pH measurements, allow a sufficient time tioner/patient/pharmacist/compounder relationship in thefor stabilization. course of professional practice. Compounding includes the

Where approximate pH values suffice, indicators and test following:papers (see Indicators and Indicator Test Papers, in the sec- • Preparation of drug dosage forms for both human andtion Reagents, Indicators, and Solutions) may be suitable. animal patients

For a discussion of buffers, and for the composition of • Preparation of drugs or devices in anticipation of pre-standard buffer solutions called for in compendial tests and scription drug orders based on routine, regularly ob-assays, see Buffer Solutions in the section Reagents, Indicators, served prescribing patternsand Solutions. • Reconstitution or manipulation of commercial products

that may require the addition of one or moreingredients

• Preparation of drugs or devices for the purposes of, oras an incident to, research (clinical or academic),teaching, or chemical analysis

• Preparation of drugs and devices for prescriber’s officeuse where permitted by federal and state law⟨795⟩ PHARMACEUTICAL

HAZARDOUS DRUG—Any drug identified by at least one of theCOMPOUNDING—NONSTERILE following six criteria:• CarcinogenicityPREPARATIONS • 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

INTRODUCTION structure or toxicity [for examples see current Na-tional Institute for Occupational Safety and Health

The purpose of this chapter is to provide compounders (NIOSH) publications]with guidance on applying good compounding practices for MANUFACTURING—The production, propagation, conversion,the preparation of nonsterile compounded formulations for or processing of a drug or device, either directly or indi-dispensing and/or administration to humans or animals. rectly, by extraction of the drug from substances of naturalCompounding is an integral part of pharmacy practice and origin or by means of chemical or biological synthesis. Man-is essential to the provision of healthcare. This chapter and ufacturing may also include any packaging or repackagingapplicable monographs on formulation help define good of the substance(s) or labeling or relabeling of containers forcompounding practices. Furthermore, this chapter provides resale by pharmacies, practitioners, or other persons.general information to enhance the compounder’s ability in PREPARATION—For the purposes of this chapter, a com-the compounding facility to extemporaneously compound pounded drug dosage form or dietary supplement or a de-preparations that are of acceptable strength, quality, and vice to which a compounder has introduced a drug. Thispurity. Pharmacists, other healthcare professionals, and term will be used to describe compounded formulations;others engaged in the compounding of drug preparations the term product will be used to describe manufacturedshould comply with applicable state and federal compound- pharmaceutical dosage forms. (For the definitions of officialing laws, regulations, and guidelines. substance and official products, see General Notices and Re-

quirements.)STABILITY—The extent to which a preparation retains, withinDEFINITIONSspecified limits and throughout its period of storage anduse, the same properties and characteristics that it possessedACTIVE PHARMACEUTICAL INGREDIENT (API)—Any substance orat the time of compounding (see Stability Considerations inmixture of substances intended to be used in the com-Dispensing Practice ⟨1191⟩, the table Criteria for Acceptablepounding of a drug preparation, thereby becoming the ac-Levels of Stability)tive ingredient in that preparation and furnishing pharmaco-

Official from May 1, 2013Copyright (c) 2013 The United States Pharmacopeial Convention. All rights reserved.

Accessed from 121.243.116.38 by Shasun on Mon Apr 08 10:57:28 EDT 2013

356 ⟨795⟩ Pharmaceutical Compounding—Nonsterile Preparations / Physical Tests USP 36

VEHICLE—A component for internal or external use that is of this chapter and should be familiar with Pharmaceuticalused as a carrier or diluent in which liquids, semisolids, or Compounding—Sterile Preparations ⟨797⟩, Pharmaceutical Dos-solids are dissolved or suspended. Examples include, but are age Forms ⟨1151⟩, Pharmaceutical Calculations in Prescriptionnot limited to, water, syrups, elixirs, oleaginous liquids, solid Compounding ⟨1160⟩, Quality Assurance in Pharmaceuticaland semisolid carriers, and proprietary products. Compounding ⟨1163⟩, Prescription Balances and Volumetric Ap-

paratus ⟨1176⟩, Stability Considerations in a Dispensing Prac-tice ⟨1191⟩, Written Prescription Drug Information—Guidelines

CATEGORIES OF COMPOUNDING ⟨1265⟩, and all applicable compounding laws, guidelines,and standards.

In the three general categories of nonsterile compounding To ensure the quality of compounded preparations, com-described in this section, different levels of experience, train- pounders shall adhere to the following general principlesing, and physical facilities are associated with each category. (additional information on these general principles is pro-

Criteria used to determine overall classification include: vided in the sections that follow).• degree of difficulty or complexity of the compounding

processGeneral Principles of Compounding• stability information and warnings

• packaging and storage requirements1. Personnel are appropriately trained and are capable of• dosage forms

performing and qualified to perform their assigned• complexity of calculationsduties. Such training should be documented.• local versus systemic biological disposition

2. Compounding ingredients of the appropriate identity,• level of risk to the compounderpurity, and quality are purchased from reliable• potential for risk of harm to the patientsources and are properly stored according to manu-See Pharmaceutical Compounding—Sterile Preparationsfacturer specifications or USP standards.⟨797⟩ for risk levels associated with sterile preparations.

3. Bulk component containers are labeled with appropri-Specialty areas such as radiopharmaceuticals require specialate Occupational Safety and Health Administrationtraining and are beyond the scope of this chapter. Com-(OSHA) hazard communication labels (see OSHA.pounders shall acquire and maintain knowledge and skills ingov), and Material Safety Data Sheets (MSDSs) areall areas (e.g., dosage form, patient population, and medicalavailable to compounding personnel for all drugs andspecialty) for which they compound.chemicals used in compounding.

4. All equipment used in compounding is clean, prop-Description of Categories erly maintained, and used appropriately.

5. The compounding environment is suitable for its in-Simple—Making a preparation that has a United States tended purpose; and procedures are implemented to

Pharmacopeia (USP) compounding monograph or that ap- prevent cross-contamination, especially when com-pears in a peer-reviewed journal article that contains specific pounding with drugs (e.g., hazardous drugs andquantities of all components, compounding procedure and known allergens like penicillin) that require specialequipment, and stability data for that formulation with ap- precautions.propriate BUDs; or reconstituting or manipulating commer- 6. Only authorized personnel are allowed in the immedi-cial products that may require the addition of one or more ate vicinity of the drug compounding operations.ingredients as directed by the manufacturer. Examples in- 7. There is assurance that processes are always carriedclude Captopril Oral Solution, Indomethacin Topical Gel, and out as intended or specified and are reproducible.Potassium Bromide Oral Solution, Veterinary. 8. Compounding conditions and procedures are ade-

quate for preventing errors.Moderate—Making a preparation that requires special9. All aspects of compounding are appropriatelycalculations or procedures (such as calibration of dosage

documented.unit mold cavities) to determine quantities of components10. Adequate procedures and records exist for investigat-per preparation or per individualized dosage units; or mak-

ing and correcting failures or problems in compound-ing a preparation for which stability data for that specificing, testing, or the preparation itself.formulation are not available. Examples include Morphine

Sulfate Suppositories, diphenhydramine hydrochloridetroches, and mixing two or more manufactured cream COMPOUNDING PROCESSproducts when the stability of the mixture is not known.

Complex—Making a preparation that requires special The compounder is responsible for ensuring that each in-training, environment, facilities, equipment, and procedures dividual incidence of compounding meets the criteria givento ensure appropriate therapeutic outcomes. Examples of in this section (additional information on these criteria ispossible complex preparation types include transdermal dos- provided in the sections that follow).age forms, modified-release preparations, and some insertsand suppositories for systemic effects.

Criteria When Compounding Each DrugPreparationRESPONSIBILITIES OF THE COMPOUNDER

1. The dose, safety, and intended use of the preparationThe compounder is responsible for compounding prepara- or device has been evaluated for suitability in terms

tions of acceptable strength, quality, and purity and in ac- of:cordance with the prescription or medication order. The • the chemical and physical properties of thecompounder is also responsible for dispensing the finished componentspreparation, with appropriate packaging and labeling, and • dosage formin compliance with the requirements established by the ap- • therapeutic appropriateness and route of adminis-plicable state agencies, state boards of pharmacy, federal tration, including local and systemic biologicallaw, and other regulatory agencies where appropriate. Indi- dispositionviduals who are engaged in drug or dietary supplement • legal limitations, if anycompounding shall be proficient in compounding and 2. A Master Formulation Record should be createdshould continually expand their compounding knowledge before compounding a preparation for the first time.by participating in seminars and/or studying appropriate This record shall be followed each time that prepara-literature. They shall be knowledgeable about the contents tion is made. In addition, a Compounding Record




should be completed each time a preparation is com- Potable water shall be supplied for hand and equipmentpounded. washing. This water meets the standards prescribed in the

3. Ingredients used in the formulation have their ex- Environmental Protection Agency’s National Primary Drink-pected identity, quality, and purity. If the formulation ing Water Regulations (40 CFR Part 141). Purified Water (seeis for humans, ingredients are not on a list of feder- Purified Water monograph) shall be used for compoundingally recognized drugs or specific drug products that nonsterile drug preparations when formulations indicate thehave been withdrawn or removed from the market inclusion of water. Purified Water should be used for rinsingfor safety or efficacy reasons (see www.FDA.gov). If equipment and utensils. In those cases when a water is usedthe formulation is for food-producing animals, ingre- to prepare a sterile preparation, follow the appropriate mon-dients are not on a list of components prohibited for ographs and general chapters (see Water for Pharmaceuticaluse in food-producing animals. Certificates of Analy- Purposes ⟨1231⟩).sis, when applicable, and MSDSs have been consulted The plumbing system shall be free of defects that couldfor all ingredients used. contribute to contamination of any compounded prepara-

4. Compounding is done in an appropriately clean and tion. Adequate hand and equipment washing facilities shallsanitized area dedicated to this activity (see the sec- be easily accessible to the compounding areas. Such facili-tion Compounding Facilities). ties shall include, but are not limited to, hot and cold water,

5. Only one preparation is compounded at one time in soap or detergent, and an air-drier or single-use towels.a specific workspace. The areas used for compounding shall be maintained in

6. Appropriate compounding equipment has been se- clean, orderly, and sanitary conditions and shall be main-lected and inspected for cleanliness and correct func- tained in a good state of repair. Waste shall be held andtioning and is properly used. disposed of in a sanitary and timely manner and in accor-

7. A reliable BUD is established to ensure that the fin- dance with local, state, and federal guidelines.ished preparation has its accepted potency, purity, The entire compounding and storage area should be wellquality, and characteristics, at least until the labeled lighted. Heating, ventilation, and air conditioning systemsBUD. shall be controlled to avoid decomposition and contamina-

8. Personnel engaged in compounding maintain good tion of chemicals (see the General Notices and Requirements,hand hygiene and wear clean clothing appropriate to Preservation, Packaging, Storage, and Labeling, Storage Tem-the type of compounding performed (e.g., hair bon- perature and Humidity; and the manufacturers’ labeled stor-nets, coats, gowns, gloves, facemasks, shoes, aprons, age conditions). Appropriate temperature and humidityor other items) as needed for protection of personnel monitoring should be maintained as required for certainfrom chemical exposures and for prevention of drug components and compounded dosage forms. All compo-contamination. nents, equipment, and containers shall be stored off the

9. The preparation is made in accordance with this floor and in a manner to prevent contamination and permitchapter, other official standards referenced in this inspection and cleaning of the compounding and storagechapter, and relevant scientific data and information. area.

10. Critical processes (including but not limited to weigh- Hazardous drugs shall be stored, prepared, and handleding, measuring, and mixing) are verified by the com- by appropriately trained personnel under conditions thatpounder to ensure that procedures, when used, will protect the healthcare workers and other personne. The fol-consistently result in the expected qualities in the fin- lowing are references for the safe handling of antineoplasticished preparation. and hazardous drugs in healthcare settings:

11. The final preparation is assessed using factors such as • OSHA Technical Manual—Section VI: Chapter 2, Con-weight, adequacy of mixing, clarity, odor, color, con- trolling Occupational Exposure to Hazardous Drugssistency, pH, and analytical testing as appropriate; • NIOSH Alert: Preventing Occupational Exposure to Antine-and this information is recorded on the Compound- oplastic and Other Hazardous Drugs in Health Care Set-ing Record (see Chapter ⟨1163⟩). tings (DHHS (NIOSH) Publication No. 2004-165) and

12. The preparation is packaged as recommended in the updates.Packaging and Drug Preparation Containers section of Disposal of all hazardous drug wastes shall comply with allthis chapter. applicable federal and state regulations. All personnel who

13. The preparation container is labeled according to all perform routine custodial waste removal and cleaning activi-applicable state and federal laws. The labeling shall ties in storage and preparation areas for hazardous drugsinclude the BUD and storage and handling informa- shall be trained in appropriate procedures to protect them-tion. The labeling should indicate that “this is a com- selves and prevent contamination.pounded preparation.”

14. The Master Formulation Record and the Compound-COMPOUNDING EQUIPMENTing Record have been reviewed by the compounder

to ensure that errors have not occurred in the com-The equipment and utensils used for compounding of apounding process and that the preparation is suitable

drug preparation shall be of appropriate design and capac-for use.ity. The equipment shall be of suitable composition that15. The preparation is delivered to the patient orthe surfaces that contact components are neither reactive,caregiver with the appropriate consultation.additive, nor sorptive and therefore will not affect or alterthe purity of the compounded preparations. The types and

COMPOUNDING FACILITIES sizes of equipment depend on the dosage forms and thequantities compounded (see Chapter ⟨1176⟩ and equipment

Compounding facilities shall have an adequate space that manufacturers’ instruction manuals).is specifically designated for compounding of prescriptions. Equipment shall be stored to protect it from contamina-This space shall provide for the orderly placement of equip- tion and shall be located to facilitate its use, maintenance,ment and materials to prevent mixups among ingredients, and cleaning. Automated, mechanical, electronic, and othercontainers, labels, in-process materials, and finished prepara- types of equipment used in compounding or testing oftions and is designed, arranged, and used to prevent adven- compounded preparations shall be routinely inspected, cali-titious cross-contamination. Areas used for sterile prepara- brated as necessary, and checked to ensure proper perfor-tions shall be separated and distinct from the nonsterile mance. Immediately before compounding operations, thecompounding area (see Chapter ⟨797⟩, Environmental Qual- equipment shall be inspected by the compounder to deter-ity and Control). mine its suitability for use. After use, the equipment shall

be appropriately cleaned.




Extra care should be used when cleaning equipment 7. If a manufactured drug product is used as the sourceused in compounding preparations that require special pre- of active ingredient, the drug product shall be manu-caution (e.g., antibiotics and cytotoxic and other hazardous factured in an FDA-registered facility, and the manu-materials). When possible, special equipment should be facturer’s product container shall be labeled with adedicated for such use, or when the same equipment is be- batch control number and expiration date. Whening used for all drug products, appropriate procedures shall compounding with manufactured drug products, thebe in place to allow meticulous cleaning of equipment compounder shall consider all ingredients, includingbefore use with other drugs. If possible, disposable equip- excipients, present in the drug product relative to thement should be used to reduce chances of bioburden and intended use of the compounded preparation andcross-contamination. the effect of manipulating the drug product on the

therapeutic appropriateness and stability of thecomponents.

COMPONENT SELECTION, HANDLING, AND 8. If the preparation is intended for use as a dietary orSTORAGE nutritional supplement, then the compounder must

adhere to this chapter and must also comply withThe following guidelines shall be followed when selecting, any federal and state requirements. Generally, dietary

handling, and storing components for compounded supplements are prepared from ingredients that meetpreparations. USP, FCC, or NF standards. Where such standards do

1. A United States Pharmacopeia (USP), National Formu- not exist, substances may be used in dietary supple-lary (NF), or Food Chemicals Codex (FCC) substance is ments if they have been shown to have acceptablethe recommended source of ingredients for com- food-grade quality using other suitable procedures.pounding all preparations. 9. When a component is derived from ruminant animals

2. Compounders shall first attempt to use components (e.g., bovine, caprine, ovine), the supplier shall pro-manufactured in an FDA-registered facility. When vide written assurance that the component is in com-components cannot be obtained from an FDA-regis- pliance with all federal laws governing processing,tered facility, compounders shall use their professional use, and importation requirements for thesejudgment in selecting an acceptable and reliable materials.source and shall establish purity and safety by reason- 10. When compounding for humans, the compounderable means, which should include Certificate of Anal- should consult the list of components that have beenysis, manufacturer reputation, and reliability of withdrawn or removed from the market for safety orsource. efficacy reasons by FDA (see www.FDA.gov). When

3. Official compounded preparations are prepared from compounding for food-producing animals, the com-ingredients that meet requirements of the compounder should consult the list of components pro-pendial monograph for those individual ingredients hibited for use in food-producing animals.for which monographs are provided. These prepara- 11. All components used in the compounding of prepara-tions may be labeled USP or NF as appropriate. tions must be stored as directed by the manufacturer,

4. When components of compendial quality are not ob- or according to USP, NF, or FCC monograph require-tainable, components of high quality such as those ments, in a clean area, and under appropriate tem-that are chemically pure, analytical reagent grade, or perature and humidity conditions (controlled roomAmerican Chemical Society–certified may be used. temperature, refrigerator, or freezer). All componentsHowever, these components should be used cau- shall be stored off the floor, handled and stored totiously because the standards for analytical reagents prevent contamination, and rotated so that the oldestor American Chemical Society–grade materials do not stock is used first. All containers shall be properlyconsider whether any impurity present raises human labeled.or animal safety concerns.

5. For components in containers that have an expirationSTABILITY CRITERIA AND BEYOND-USEdate from the manufacturer or distributor, the mate-

rial may be used in compounding before that expira- DATINGtion date (a) when the material is stored in its origi-nal container under conditions to avoid The BUD is the date after which a compounded prepara-decomposition of the chemicals (see Chapter ⟨1191⟩ tion shall not be used and is determined from the dateand ⟨659⟩ Packaging and Storage Requirements, unless when the preparation is compounded. Because com-other conditions are noted on the label), (b) when pounded preparations are intended for administration im-there is minimal exposure of the remaining material mediately or following short-term storage, their BUDs areeach time material is withdrawn from the container, assigned on the basis of criteria different from those appliedand (c) when any withdrawals from the container are to assigning expiration dates to manufactured drugperformed by those trained in the proper handling of products.the material. If the component has been transferred BUDs should be assigned conservatively. When assigningto a different container, that container shall be identi- a BUD, compounders shall consult and apply drug-specificfied with the component name, original supplier, lot and general stability documentation and literature whenor control number, transfer date, and expiration date available and should consider:and shall provide integrity that is equivalent to or • the nature of the drug and its degradation mechanismbetter than that of the original container. • the dosage form and its components

6. For components that do not have expiration dates • the potential for microbial proliferation in theassigned by the manufacturer or supplier, the com- preparationpounder shall label the container with the date of • the container in which it is packagedreceipt and assign a conservative expiration date, not • the expected storage conditionsto exceed three years after receipt, to the component • the intended duration of therapy (see the General No-(see the General Notices and Requirements, Preserva- tices and Requirements, Preservation, Packaging, Stor-tion, Packaging, Storage, and Labeling, Labeling, Expira- age, and Labeling, Labeling, Expiration Date and Be-tion Date and Beyond-Use Date) based on the nature yond-Use Date).of the component and its degradation mechanism, When a manufactured product is used as the source ofthe container in which it is packaged, and the stor- the API for a nonsterile compounded preparation, the prod-age conditions. uct 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 PACKAGING AND DRUG PREPARATIONto the literature for applicable information on stability, com- CONTAINERSpatibility, and degradation of ingredients; shall consider sta-bility factors in Chapter ⟨1191⟩; and shall use his or her The compounder shall ensure that the containers andcompounding education and experience. All stability data container closures used in packaging compounded prepara-shall be carefully interpreted in relation to the actual com- tions meet USP requirements (see ⟨659⟩ Packaging and Stor-pounded formulation. age Requirements; Containers—Glass ⟨660⟩; Containers—Plas-At all steps in the compounding, dispensing, and storage tics ⟨661⟩; Containers—Performance Testing ⟨671⟩; Chapterprocess, the compounder shall observe the compounded ⟨1136⟩); and when available, compounding monographs.drug preparation for signs of instability. For more specific Compounders are not expected to perform the tests de-details of some of the common physical signs of deteriora- scribed in these chapters but should be knowledgeabletion (see Chapter ⟨1191⟩, Observing Products for Evidence of about the standards described in them. Container suppliersInstability). However, excessive chemical degradation and shall supply, upon request, verification of USP containerother drug concentration loss due to reactions may be invis- compliance. Containers and container closures intended forible more often than visible. the compounding of sterile preparations must be handled as

described in Chapter ⟨797⟩.The containers and closures shall be made of suitableGeneral Guidelines for Assigning Beyond-Use

clean material in order not to alter the quality, strength, orDatespurity of the compounded drug preparation. The containerused depends on the physical and chemical properties ofIn the absence of stability information that is applicable tothe compounded preparation. Container–drug interactiona specific drug and preparation, the following table presentsshould be considered for substances that have sorptive ormaximum BUDs recommended for (1) nonsterile com-leaching properties.pounded drug preparations that are packaged in tight,

The containers and closures shall be stored off the floor,light-resistant containers and stored at controlled room tem-handled and stored to prevent contamination, and rotatedperature, unless otherwise indicated; and for (2) sterile prep-so that the oldest stock is used first. The containers andarations for which a program of sterility testing is in placecontainer closures shall be stored in such a way as to permit(see the General Notices and Requirements, Preservation, Pack-inspection and cleaning of the storage area.aging, Storage, and Labeling). Drugs or chemicals known to

be labile to decomposition will require shorter BUDs.COMPOUNDING DOCUMENTATION

BUD by Type of Formulationa

Documentation, written or electronic, enables a com-For Nonaqueous Formulations—The BUD is not later than the timepounder, whenever necessary, to systematically trace, evalu-remaining until the earliest expiration date of any API or 6 months,ate, and replicate the steps included throughout the prepa-whichever is earlier.ration process of a compounded preparation. AllFor Water-Containing Oral Formulations—The BUD is not latercompounders who dispense prescriptions must comply withthan 14 days when stored at controlled cold temperatures.the record-keeping requirements of their state boards ofFor Water-Containing Topical/Dermal and Mucosal Liquid andpharmacy. When the compounder compounds a prepara-Semisolid Formulations—The BUD is not later than 30 days.tion according to the manufacturer’s labeling instructions,

a These maximum BUDs are recommended for nonsterile com- then further documentation is not required. All other com-pounded drug preparations in the absence of stability information pounded preparations require further documentation as de-that is applicable to a specific drug or preparation. The BUD shall not scribed in this section.be later than the expiration date on the container of any compo- These records should be retained for the same period ofnent. 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 Formu-Susceptible preparations should contain suitable antimi-lation Record and a Compounding Record.crobial agents to protect against bacteria, yeast, and mold

contamination inadvertently introduced during or after thecompounding process. When antimicrobial preservatives are Master Formulation Recordcontraindicated in such compounded preparations, storageof the preparation at controlled cold temperature is neces- This record shall include:sary; to ensure proper storage and handling of such com- • official or assigned name, strength, and dosage form ofpounded preparations by the patient or caregiver, appropri- the preparationate patient instruction and consultation is essential. • calculations needed to determine and verify quantitiesAntimicrobial preservatives should not be used as a substi- of components and doses of active pharmaceuticaltute for good compounding practices. ingredients

For information on assigning BUDs when repackaging • description of all ingredients and their quantitiesdrug products for dispensing or administration, see the Gen- • compatibility and stability information, including refer-eral Notices and Requirements, Preservation, Packaging, Stor- ences when availableage, and Labeling, Labeling, Expiration Date and Beyond-Use • equipment needed to prepare the preparation, whenDate, and Packaging and Repackaging—Single-Unit Containers appropriate⟨1136⟩. • mixing instructions that should include:

Assurance of sterility in a compounded sterile preparation 1. order of mixingis mandatory. Compounding and packaging of sterile drugs 2. mixing temperatures or other environmental(including ophthalmic preparations) requires strict adher- controlsence to guidelines presented in Chapter ⟨797⟩ and in the 3. duration of mixingmanufacturers’ labeling instructions. 4. other factors pertinent to the replication of the

preparation as compounded• sample labeling information, which shall contain, in ad-

dition to legally required information:1. generic name and quantity or concentration of

each active ingredient2. assigned BUD




3. storage conditions4. prescription or control number, whichever is Compounding Controls

applicable• container used in dispensing 1. The Master Formulation Record, the Compounding• packaging and storage requirements Record, and associated written procedures shall be• description of final preparation followed in execution of the compounding process.• quality control procedures and expected results Any deviation in procedures shall be documented.

2. The compounder shall check and recheck each proce-dure at each stage of the process. If possible, aCompounding Recordtrained second person should verify each critical stepin the compounding process.The Compounding Record shall contain:

3. The compounder shall have established written proce-• official or assigned name, strength, and dosage of thedures that describe the tests or examinations con-preparationducted on the compounded preparation (e.g., the• Master Formulation Record reference for thedegree of weight variation among capsules) to ensurepreparationtheir uniformity and integrity.• names and quantities of all components

4. Appropriate control procedures shall be established to• sources, lot numbers, and expiration dates ofmonitor the output and to verify the performance ofcomponentscompounding processes and equipment that may be• total quantity compoundedresponsible for causing variability in the final com-• name of the person who prepared the preparation,pounded preparations.name of the person who performed the quality con-

5. For further guidance on recommended quality controltrol procedures, and name of the compounder whoprocedures, see Chapter ⟨1163⟩.approved the preparation

• date of preparation• assigned control or prescription number PATIENT COUNSELING• assigned BUD• duplicate label as described in the Master Formulation At the time of dispensing the prescription, the patient orRecord the patient’s agent shall be counseled about proper use,• description of final preparation storage, handling, and disposal of the compounded prepa-• results of quality control procedures (e.g., weight range ration. The patient or the patient’s agent shall also be in-of filled capsules, pH of aqueous liquids) structed to report any adverse event and to observe and• documentation of any quality control issues and any report to the compounder any changes in the physical char-adverse reactions or preparation problems reported acteristics of the compounded preparation (see Chapterby the patient or caregiver ⟨1191⟩, Responsibility of the Pharmacist). The compounder

shall investigate and document any reported problem with aStandard Operating Procedures compounded preparation and shall take corrective action.

All significant procedures performed in the compoundingTRAININGarea should be covered by written standard operating pro-

cedures (SOPs). Procedures should be developed for the fa-All personnel involved in the compounding, evaluation,cility, equipment, personnel, preparation, packaging, and

packaging, and dispensing of compounded preparationsstorage of compounded preparations to ensure accountabil-shall be properly trained for the type of compounding con-ity, accuracy, quality, safety, and uniformity in compound-ducted. It is the responsibility of the compounder to ensureing. Implementing SOPs establishes procedural consistencythat a training program has been implemented and that it isand also provides a reference for orientation and training ofongoing. Compounding personnel should be evaluated atpersonnel.least annually. Steps in the training procedure include thefollowing:

Material Safety Data Sheets File • All employees involved in pharmaceutical compoundingshall read and become familiar with this chapter.

MSDSs shall be readily accessible to all employees work- They should also be familiar with the contents of theing with drug substances or bulk chemicals located on the USP Pharmacists’ Pharmacopeia and other relevantcompounding facility premises. Employees should be in- publications, including how to read and interpretstructed on how to retrieve and interpret needed MSDSs.information. • All employees shall read and become familiar with each

of the procedures related to compounding, includingthose involving the facility, equipment, personnel, ac-QUALITY CONTROL tual compounding, evaluation, packaging, storage,and dispensing.The safety, quality, and performance of compounded • All personnel who compound hazardous drugs shall bepreparations depend on correct ingredients and calculations, fully trained in the storage, handling, and disposal ofaccurate and precise measurements, appropriate formulation these drugs. This training shall occur before preparingconditions and procedures, and prudent pharmaceutical or handling hazardous drugs. For information onjudgment. As a final check, the compounder shall review training for personnel who compound hazardouseach procedure in the compounding process. To ensure ac- drugs, see the references in Compounding Facilitiescuracy and completeness, the compounder shall observe the earlier in this chapter.finished preparation to ensure that it appears as expected • All training activities shall be documented. The com-and shall investigate any discrepancies and take appropriate pounder shall meet with employees to review theircorrective action before the prescription is dispensed to the work and answer any questions the employees maypatient. have concerning compounding procedures.

• The compounder shall demonstrate the procedures forthe employee and shall observe and guide the em-ployee throughout the training process. The em-ployee will then repeat the procedure without any



USP 36 Physical Tests / ⟨797⟩ Pharmaceutical Compounding—Sterile 361

assistance from, but under the direct supervision of, tion Act; and FDA’s Compliance Policy Guideline for Com-the compounder. pounding of Drugs for Use in Animal Patients.

• When the employee has demonstrated to the com-pounder a verbal and functional knowledge of theprocedure, then and only then will the employee bepermitted to perform the procedure without directsupervision. However, the compounder should bephysically present and shall approve all ingredientsand their quantities and the final preparation. ⟨797⟩ PHARMACEUTICAL

• When the compounder is satisfied with the employee’sknowledge and proficiency, the compounder will sign COMPOUNDING—STERILEthe documentation records to show that the em-ployee was appropriately trained. PREPARATIONS

• The compounder shall continually monitor the work ofthe employee and ensure that the employee’s calcula-tions and work are accurate and adequatelyperformed.

• The compounder is solely responsible for the finished INTRODUCTIONpreparation.

The objective of this chapter is to describe conditions andpractices to prevent harm, including death, to patients thatCOMPOUNDING FOR ANIMAL PATIENTScould result from (1) microbial contamination (nonsterility),(2) excessive bacterial endotoxins, (3) variability in the in-A compounder’s responsibility for providing patients withtended strength of correct ingredients that exceeds eitherhigh-quality compounded preparations extends beyond themonograph limits for official articles (see “official” and “arti-human species. All portions of this chapter apply to com-cle” in the General Notices and Requirements) or 10% forpounded preparations formulated for animal patients. In-nonofficial articles, (4) unintended chemical and physicaltended use of any animal patient (e.g., companion, perfor-contaminants, and (5) ingredients of inappropriate quality inmance, food) shall be determined before compounding forcompounded sterile preparations (CSPs). Contaminatedthat patient.CSPs are potentially most hazardous to patients when ad-Because humans can consume animal patients as food,ministered into body cavities, central nervous and vascularcare must be taken to prevent drug residues from enteringsystems, eyes, and joints, and when used as baths for livethe human food chain when compounded preparations areorgans and tissues. When CSPs contain excessive bacterialused in animal patients. For this reason, all compoundersendotoxins (see Bacterial Endotoxins Test ⟨85⟩), they are po-preparing formulations for animals shall possess a functionaltentially most hazardous to patients when administered intoknowledge of drug regulation and disposition in animal pa-the central nervous system.tients. Veterinarians are required by law to provide food-

Despite the extensive attention in this chapter to the pro-producing animal caregivers with an accurate length of timevision, maintenance, and evaluation of air quality, the avoid-to withhold treated animal tissues (e.g., meat, milk, eggs)ance of direct or physical contact contamination is para-from the human food supply. This length of time is referredmount. It is generally acknowledged that direct or physicalto as a withdrawal time (WDT) and must also, by law, becontact of critical sites of CSPs with contaminants, especiallyincluded on the dispensing label of every prescription pre-microbial sources, poses the greatest probability of risk topared for a food-producing species.patients. Therefore, compounding personnel must be metic-Drug use in any performance animal is strictly regulatedulously conscientious in precluding contact contamination ofby federal and state governments, in addition to the gov-CSPs both within and outside ISO Class 5 (see Table 1) ar-erning bodies of each of the specific disciplines. Penalties foreas.violation of these rules may be severe for all contributing to

To achieve the above five conditions and practices, thisthe violation, including the veterinarian, pharmacist, andchapter provides minimum practice and quality standardscaregiver.for CSPs of drugs and nutrients based on current scientificThe pharmacist shall be knowledgeable about the individ-information and best sterile compounding practices. The useual species’ limitations in physiology and metabolic capacityof technologies, techniques, materials, and procedures otherthat can result in toxicity when certain drugs or excipientsthan those described in this chapter is not prohibited soare used in compounded preparations. For this reason, com-long as they have been proven to be equivalent or superiorpounders making preparations for animals should use, whenwith statistical significance to those described herein. Thepossible, formulations specifically developed for animal pa-standards in this chapter do not pertain to the clinical ad-tients. If such formulations are not available, the com-ministration of CSPs to patients via application, implantation,pounder shall conduct a literature review to determineinfusion, inhalation, injection, insertion, instillation, and irri-whether a specific component of the formula is toxic to thegation, which are the routes of administration. Four specifictarget species. Extrapolating compounding formulations in-categories of CSPs are described in this chapter: low-risktended for use in humans may not be appropriate forlevel, medium-risk level, and high-risk level, and immediateanimal species and may contribute to negative outcomes.use. Sterile compounding differs from nonsterile compound-Veterinarians and pharmacists making preparations foring (see Pharmaceutical Compounding—Nonsterile Prepara-animal patients should be familiar with all state and federaltions ⟨795⟩ and Good Compounding Practices ⟨1075⟩) prima-regulations regarding drug use in animals, including but notrily by requiring the maintenance of sterility whenlimited to the Food, Drug, and Cosmetic Act; the Animalcompounding exclusively with sterile ingredients and com-Drug Amendment; the Animal Medicinal Drug Use Clarifica-ponents (i.e., with immediate-use CSPs, low-risk level CSPs,and medium-risk level CSPs) and the achievement of sterilitywhen compounding with nonsterile ingredients and compo-nents (i.e., with high-risk level CSPs). Some differences be-tween standards for sterile compounding in this chapter andthose for nonsterile compounding in Pharmaceutical Com-pounding—Nonsterile Preparations ⟨795⟩ include, but are notlimited to, ISO-classified air environments (see Table 1); per-sonnel garbing and gloving; personnel training and testing



usp 36 - pharmaceutical compounding preparations

Documents