USP 37 [795] Pharm. Comp. Non-Sterile Prep

Potassium Biphthalate, 0.05 m—Dissolve 10.12 g ofKHC8H4O4, previously dried at 110° for 1 hour, in water tomake 1000 mL.

Equimolal Phosphate, 0.05 m—Dissolve 3.53 g ofNa2HPO4 and 3.39 g of KH2PO4, each previously dried at120° for 2 hours, in water to make 1000 mL.

Sodium Tetraborate, 0.01 m—Dissolve 3.80 g ofNa2B4O7 · 10H2O in water to make 1000 mL. Protect fromabsorption of carbon dioxide.

Calcium Hydroxide, saturated at 25°—Shake an excessof calcium hydroxide with water, and decant at 25° beforeuse. Protect from absorption of carbon dioxide.

Because of variations in the nature and operation of theavailable pH meters, it is not practicable to give universallyapplicable directions for the potentiometric determinationsof pH. The general principles to be followed in carrying outthe instructions provided for each instrument by its manu-facturer are set forth in the following paragraphs. Examinethe electrodes and, if present, the salt bridge prior to use. Ifnecessary, replenish the salt bridge solution, and observeother precautions indicated by the instrument or electrodemanufacturer.

To standardize the pH meter, select two Buffer Solutionsfor Standardization whose difference in pH does not exceed4 units and such that the expected pH of the material undertest falls between them. Fill the cell with one of the BufferSolutions for Standardization at the temperature at which thetest material is to be measured. Set the “temperature” con-trol at the temperature of the solution, and adjust the cali-bration control to make the observed pH value identicalwith that tabulated. Rinse the electrodes and cell with sever-al portions of the second Buffer Solution for Standardization,then fill the cell with it, at the same temperature as the ma-terial to be measured. The pH of the second buffer solutionis within ±0.07 pH unit of the tabulated value. If a larger de-viation is noted, examine the electrodes and, if they are faul-ty, replace them. Adjust the “slope” or “temperature” con-trol to make the observed pH value identical with that tabu-lated. Repeat the standardization until both Buffer Solutionsfor Standardization give observed pH values within 0.02 pHunit of the tabulated value without further adjustment ofthe controls. When the system is functioning satisfactorily,rinse the electrodes and cell several times with a few por-tions of the test material, fill the cell with the test material,and read the pH value. Use carbon dioxide-free water (seeWater in the section Reagents, Indicators, and Solutions) forsolution or dilution of test material in pH determinations. Inall pH measurements, allow a sufficient time for stabilization.

Where approximate pH values suffice, indicators and testpapers (see Indicators and Indicator Test Papers, in the sec-tion Reagents, Indicators, and Solutions) may be suitable.

For a discussion of buffers, and for the composition ofstandard buffer solutions called for in compendial tests andassays, see Buffer Solutions in the section Reagents, Indicators,and Solutions.

á795ñ PHARMACEUTICALCOMPOUNDING—NONSTERILE

PREPARATIONS

INTRODUCTION

The purpose of this chapter is to provide compounderswith guidance on applying good compounding practices forthe preparation of nonsterile compounded formulations fordispensing and/or administration to humans or animals.Compounding is an integral part of pharmacy practice andis essential to the provision of healthcare. This chapter andapplicable monographs on formulation help define goodcompounding practices. Furthermore, this chapter providesgeneral information to enhance the compounder's ability inthe compounding facility to extemporaneously compoundpreparations that are of acceptable strength, quality, andpurity. Pharmacists, other healthcare professionals, and oth-ers engaged in the compounding of drug preparationsshould comply with applicable state and federal compound-ing laws, regulations, and guidelines.

DEFINITIONS

ACTIVE PHARMACEUTICAL INGREDIENT (API)—Any substanceor mixture of substances intended to be used in the com-pounding of a drug preparation, thereby becoming the ac-tive ingredient in that preparation and furnishing pharmaco-logical activity or other direct effect in the diagnosis, cure,mitigation, treatment, or prevention of disease in humansand animals or affecting the structure and function of thebody.ADDED SUBSTANCES—Ingredients that are necessary to com-pound a preparation but are not intended or expected tocause a pharmacologic response if administered alone in theamount or concentration contained in a single dose of thecompounded preparation. The term is used synonymouslywith the terms inactive ingredients, excipients, and pharma-ceutical ingredients.BEYOND-USE DATE (BUD)—The date after which a com-pounded preparation should not to be used; determinedfrom the date the preparation is compounded.COMPONENT—Any ingredient used in the compounding of adrug preparation, including any active ingredient or addedsubstance that is used in its preparation.COMPOUNDER—A professional authorized by the appropriatejurisdiction to perform compounding pursuant to a prescrip-tion or medication order by a licensed prescriber.COMPOUNDING—The preparation, mixing, assembling, alter-ing, packaging, and labeling of a drug, drug-delivery device,or device in accordance with a licensed practitioner’s pre-scription, medication order, or initiative based on the practi-tioner/patient/pharmacist/compounder relationship in thecourse of professional practice. Compounding includes thefollowing:

• Preparation of drug dosage forms for both human andanimal patients

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• Preparation of drugs or devices in anticipation of pre-scription drug orders based on routine, regularly ob-served prescribing patterns

• Reconstitution or manipulation of commercial productsthat may require the addition of one or more ingredi-ents

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

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

HAZARDOUS DRUG—Any drug identified by at least one ofthe 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 NationalInstitute for Occupational Safety and Health (NIOSH)publications]

MANUFACTURING—The production, propagation, conversion,or processing of a drug or device, either directly or indirect-ly, by extraction of the drug from substances of natural ori-gin or by means of chemical or biological synthesis. Manu-facturing may also include any packaging or repackaging ofthe substance(s) or labeling or relabeling of containers forresale by pharmacies, practitioners, or other persons.PREPARATION—For the purposes of this chapter, a compoun-ded drug dosage form or dietary supplement or a device towhich a compounder has introduced a drug. This term willbe used to describe compounded formulations; the termproduct will be used to describe manufactured pharmaceuti-cal dosage forms. (For the definitions of official substanceand official products, see General Notices and Requirements.)STABILITY—The extent to which a preparation retains, withinspecified limits and throughout its period of storage anduse, the same properties and characteristics that it possessedat the time of compounding (see Stability Considerations inDispensing Practice á1191ñ, the table Criteria for AcceptableLevels of Stability)VEHICLE—A component for internal or external use that isused as a carrier or diluent in which liquids, semisolids, orsolids are dissolved or suspended. Examples include, but arenot limited to, water, syrups, elixirs, oleaginous liquids, solidand semisolid carriers, and proprietary products.

CATEGORIES OF COMPOUNDING

In the three general categories of nonsterile compound-ing described in this section, different levels of experience,training, and physical facilities are associated with each cate-gory.

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 Preparationsá797ñ for risk levels associated with sterile preparations. Spe-cialty areas such as radiopharmaceuticals require specialtraining and are beyond the scope of this chapter. Com-pounders shall acquire and maintain knowledge and skills inall areas (e.g., dosage form, patient population, and medicalspecialty) for which they compound.

Description of Categories

Simple—Making a preparation that has a United StatesPharmacopeia (USP) compounding monograph or that ap-pears in a peer-reviewed journal article that contains specificquantities of all components, compounding procedure andequipment, and stability data for that formulation with ap-propriate BUDs; or reconstituting or manipulating commer-cial products that may require the addition of one or moreingredients as directed by the manufacturer. Examples in-clude Captopril Oral Solution, Indomethacin Topical Gel, andPotassium Bromide Oral Solution, Veterinary.

Moderate—Making a preparation that requires specialcalculations or procedures (such as calibration of dosageunit mold cavities) to determine quantities of componentsper preparation or per individualized dosage units; or mak-ing a preparation for which stability data for that specificformulation are not available. Examples include MorphineSulfate Suppositories, diphenhydramine hydrochloride troch-es, and mixing two or more manufactured cream productswhen the stability of the mixture is not known.

Complex—Making a preparation that requires specialtraining, environment, facilities, equipment, and proceduresto ensure appropriate therapeutic outcomes. Examples ofpossible complex preparation types include transdermaldosage forms, modified-release preparations, and some in-serts and suppositories for systemic effects.

RESPONSIBILITIES OF THE COMPOUNDER

The compounder is responsible for compounding prepa-rations of acceptable strength, quality, and purity and in ac-cordance with the prescription or medication order. Thecompounder is also responsible for dispensing the finishedpreparation, with appropriate packaging and labeling, andin compliance with the requirements established by the ap-plicable state agencies, state boards of pharmacy, federallaw, and other regulatory agencies where appropriate. Indi-viduals who are engaged in drug or dietary supplementcompounding shall be proficient in compounding andshould continually expand their compounding knowledgeby participating in seminars and/or studying appropriate lit-erature. They shall be knowledgeable about the contents ofthis chapter and should be familiar with PharmaceuticalCompounding—Sterile Preparations á797ñ, PharmaceuticalDosage Forms á1151ñ, Pharmaceutical Calculations in Prescrip-tion Compounding á1160ñ, Quality Assurance in Pharmaceuti-cal Compounding á1163ñ, Prescription Balances and VolumetricApparatus á1176ñ, Stability Considerations in a DispensingPractice á1191ñ, Written Prescription Drug Information—Guide-

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lines á1265ñ, and all applicable compounding laws, guide-lines, and standards.

To ensure the quality of compounded preparations, com-pounders shall adhere to the following general principles(additional information on these general principles is provi-ded in the sections that follow).

General Principles of Compounding

1. Personnel are appropriately trained and are capable ofperforming and qualified to perform their assigned du-ties. Such training should be documented.

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

3. Bulk component containers are labeled with appropri-ate Occupational Safety and Health Administration(OSHA) hazard communication labels (see OSHA.gov),and Material Safety Data Sheets (MSDSs) are availableto compounding personnel for all drugs and chemicalsused in compounding.

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

5. The compounding environment is suitable for its inten-ded purpose; and procedures are implemented to pre-vent cross-contamination, especially when compound-ing with drugs (e.g., hazardous drugs and known aller-gens like penicillin) that require special precautions.

6. Only authorized personnel are allowed in the immedi-ate vicinity of the drug compounding operations.

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

8. Compounding conditions and procedures are adequatefor preventing errors.

9. All aspects of compounding are appropriately docu-mented.

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

COMPOUNDING PROCESS

The compounder is responsible for ensuring that each in-dividual incidence of compounding meets the criteria givenin this section (additional information on these criteria isprovided in the sections that follow).

Criteria When Compounding Each DrugPreparation

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

• the chemical and physical properties of the com-ponents

• dosage form

• therapeutic appropriateness and route of adminis-tration, including local and systemic biological dis-position

• legal limitations, if any2. A Master Formulation Record should be created before

compounding a preparation for the first time. This re-cord shall be followed each time that preparation ismade. In addition, a Compounding Record should becompleted each time a preparation is compounded.

3. Ingredients used in the formulation have their expectedidentity, quality, and purity. If the formulation is for hu-mans, ingredients are not on a list of federally recog-nized drugs or specific drug products that have beenwithdrawn or removed from the market for safety or ef-ficacy reasons (see www.FDA.gov). If the formulation isfor food-producing animals, ingredients are not on alist of components prohibited for use in food-produc-ing animals. Certificates of Analysis, when applicable,and MSDSs have been consulted for all ingredientsused.

4. Compounding is done in an appropriately clean andsanitized area dedicated to this activity (see the sectionCompounding Facilities).

5. Only one preparation is compounded at one time in aspecific workspace.

6. Appropriate compounding equipment has been selec-ted and inspected for cleanliness and correct function-ing and is properly used.

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

8. Personnel engaged in compounding maintain goodhand hygiene and wear clean clothing appropriate tothe type of compounding performed (e.g., hair bon-nets, coats, gowns, gloves, facemasks, shoes, aprons, orother items) as needed for protection of personnelfrom chemical exposures and for prevention of drugcontamination.

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

10. Critical processes (including but not limited to weigh-ing, measuring, and mixing) are verified by the com-pounder to ensure that procedures, when used, willconsistently result in the expected qualities in the fin-ished preparation.

11. The final preparation is assessed using factors such asweight, adequacy of mixing, clarity, odor, color, consis-tency, pH, and analytical testing as appropriate; andthis information is recorded on the Compounding Re-cord (see Chapter á1163ñ).

12. The preparation is packaged as recommended in thePackaging and Drug Preparation Containers section ofthis chapter.

13. The preparation container is labeled according to allapplicable state and federal laws. The labeling shall in-clude the BUD and storage and handling information.The labeling should indicate that “this is a compoun-ded preparation.”

14. The Master Formulation Record and the CompoundingRecord have been reviewed by the compounder to en-

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sure that errors have not occurred in the compoundingprocess and that the preparation is suitable for use.

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

COMPOUNDING FACILITIES

Compounding facilities shall have an adequate space thatis specifically designated for compounding of prescriptions.This space shall provide for the orderly placement of equip-ment and materials to prevent mixups among ingredients,containers, labels, in-process materials, and finished prepa-rations and is designed, arranged, and used to prevent ad-ventitious cross-contamination. Areas used for sterile prepa-rations shall be separated and distinct from the nonsterilecompounding area (see Chapter á797ñ, Environmental Quali-ty and Control).

Potable water shall be supplied for hand and equipmentwashing. This water meets the standards prescribed in theEnvironmental Protection Agency’s National Primary Drink-ing Water Regulations (40 CFR Part 141). Purified Water (seePurified Water monograph) shall be used for compoundingnonsterile drug preparations when formulations indicate theinclusion of water. Purified Water should be used for rinsingequipment and utensils. In those cases when a water is usedto prepare a sterile preparation, follow the appropriate mon-ographs and general chapters (see Water for PharmaceuticalPurposes á1231ñ).

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

The entire compounding and storage area should be welllighted. Heating, ventilation, and air conditioning systemsshall be controlled to avoid decomposition and contamina-tion of chemicals (see the General Notices and Requirements,Preservation, Packaging, Storage, and Labeling, Storage Tem-perature and Humidity; and the manufacturers’ labeled stor-age conditions). Appropriate temperature and humiditymonitoring should be maintained as required for certaincomponents and compounded dosage forms. All compo-nents, equipment, and containers shall be stored off thefloor and in a manner to prevent contamination and permitinspection and cleaning of the compounding and storagearea.

Hazardous drugs shall be stored, prepared, and handledby appropriately trained personnel under conditions thatprotect the healthcare workers and other personne. The fol-lowing are references for the safe handling of antineoplasticand hazardous drugs in healthcare settings:

• OSHA Technical Manual—Section VI: Chapter 2, Con-trolling Occupational Exposure to Hazardous Drugs

• NIOSH Alert: Preventing Occupational Exposure to Anti-neoplastic and Other Hazardous Drugs in Health Care Set-

tings (DHHS (NIOSH) Publication No. 2004-165) andupdates.

Disposal of all hazardous drug wastes shall comply with allapplicable federal and state regulations. All personnel whoperform routine custodial waste removal and cleaning activi-ties in storage and preparation areas for hazardous drugsshall be trained in appropriate procedures to protect them-selves and prevent contamination.

COMPOUNDING EQUIPMENT

The equipment and utensils used for compounding of adrug preparation shall be of appropriate design and capaci-ty. The equipment shall be of suitable composition that thesurfaces that contact components are neither reactive, addi-tive, nor sorptive and therefore will not affect or alter thepurity of the compounded preparations. The types and sizesof equipment depend on the dosage forms and the quanti-ties compounded (see Chapter á1176ñ and equipment man-ufacturers' instruction manuals).

Equipment shall be stored to protect it from contamina-tion and shall be located to facilitate its use, maintenance,and cleaning. Automated, mechanical, electronic, and othertypes of equipment used in compounding or testing ofcompounded preparations shall be routinely inspected, cali-brated as necessary, and checked to ensure proper perform-ance. Immediately before compounding operations, theequipment shall be inspected by the compounder to deter-mine its suitability for use. After use, the equipment shall beappropriately cleaned.

Extra care should be used when cleaning equipment usedin compounding preparations that require special precau-tion (e.g., antibiotics and cytotoxic and other hazardousmaterials). When possible, special equipment should bededicated for such use, or when the same equipment is be-ing used for all drug products, appropriate procedures shallbe in place to allow meticulous cleaning of equipment be-fore use with other drugs. If possible, disposable equipmentshould be used to reduce chances of bioburden and cross-contamination.

COMPONENT SELECTION, HANDLING, ANDSTORAGE

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

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

2. Compounders shall first attempt to use componentsmanufactured in an FDA-registered facility. When com-ponents cannot be obtained from an FDA-registered fa-cility, compounders shall use their professional judg-ment in selecting an acceptable and reliable source andshall establish purity and safety by reasonable means,which should include Certificate of Analysis, manufac-turer reputation, and reliability of source.

3. Official compounded preparations are prepared fromingredients that meet requirements of the compendial

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monograph for those individual ingredients for whichmonographs are provided. These preparations may belabeled USP or NF as appropriate.

4. When components of compendial quality are not ob-tainable, components of high quality such as those thatare chemically pure, analytical reagent grade, or Ameri-can Chemical Society–certified may be used. However,these components should be used cautiously becausethe standards for analytical reagents or AmericanChemical Society–grade materials do not considerwhether any impurity present raises human or animalsafety concerns.

5. For components in containers that have an expirationdate from the manufacturer or distributor, the materialmay be used in compounding before that expirationdate (a) when the material is stored in its original con-tainer under conditions to avoid decomposition of thechemicals (see Chapter á1191ñ and á659ñ Packaging andStorage Requirements, unless other conditions are notedon the label), (b) when there is minimal exposure ofthe remaining material each time material is withdrawnfrom the container, and (c) when any withdrawals fromthe container are performed by those trained in theproper handling of the material. If the component hasbeen transferred to a different container, that containershall be identified with the component name, originalsupplier, lot or control number, transfer date, and expi-ration date and shall provide integrity that is equivalentto or better than that of the original container.

6. For components that do not have expiration dates as-signed by the manufacturer or supplier, the com-pounder shall label the container with the date of re-ceipt and assign a conservative expiration date, not toexceed three years after receipt, to the component (seethe General Notices and Requirements, Preservation,Packaging, Storage, and Labeling, Labeling, ExpirationDate and Beyond-Use Date) based on the nature of thecomponent and its degradation mechanism, the con-tainer in which it is packaged, and the storage condi-tions.

7. If a manufactured drug product is used as the source ofactive ingredient, the drug product shall be manufac-tured in an FDA-registered facility, and the manufactur-er’s product container shall be labeled with a batchcontrol number and expiration date. When compound-ing with manufactured drug products, the compound-er shall consider all ingredients, including excipients,present in the drug product relative to the intendeduse of the compounded preparation and the effect ofmanipulating the drug product on the therapeutic ap-propriateness and stability of the components.

8. If the preparation is intended for use as a dietary or nu-tritional supplement, then the compounder must ad-here to this chapter and must also comply with anyfederal and state requirements. Generally, dietary sup-plements are prepared from ingredients that meet USP,FCC, or NF standards. Where such standards do not ex-ist, substances may be used in dietary supplements ifthey have been shown to have acceptable food-gradequality using other suitable procedures.

9. When a component is derived from ruminant animals(e.g., bovine, caprine, ovine), the supplier shall providewritten assurance that the component is in compliancewith all federal laws governing processing, use, and im-portation requirements for these materials.

10. When compounding for humans, the compoundershould consult the list of components that have beenwithdrawn or removed from the market for safety or ef-ficacy reasons by FDA (see www.FDA.gov). When com-pounding for food-producing animals, the compound-er should consult the list of components prohibited foruse in food-producing animals.

11. All components used in the compounding of prepara-tions must be stored as directed by the manufacturer,or according to USP, NF, or FCC monograph require-ments, in a clean area, and under appropriate tempera-ture and humidity conditions (controlled room temper-ature, refrigerator, or freezer). All components shall bestored off the floor, handled and stored to prevent con-tamination, and rotated so that the oldest stock is usedfirst. All containers shall be properly labeled.

STABILITY CRITERIA AND BEYOND-USEDATING

The BUD is the date after which a compounded prepara-tion shall not be used and is determined from the datewhen the preparation is compounded. Because compoun-ded preparations are intended for administration immedi-ately or following short-term storage, their BUDs are as-signed on the basis of criteria different from those applied toassigning expiration dates to manufactured drug products.

BUDs should be assigned conservatively. When assigninga BUD, compounders shall consult and apply drug-specificand general stability documentation and literature whenavailable 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 prepara-

tion• the container in which it is packaged• the expected storage conditions• the intended duration of therapy (see the General Noti-

ces and Requirements, Preservation, Packaging, Storage,and Labeling, Labeling, Expiration Date and Beyond-UseDate).

When a manufactured product is used as the source ofthe API for a nonsterile compounded preparation, the prod-uct expiration date cannot be used solely to assign a BUDfor the compounded preparation. Instead, the compoundershall refer to the manufacturer for stability information andto the literature for applicable information on stability, com-patibility, and degradation of ingredients; shall consider sta-bility factors in Chapter á1191ñ; and shall use his or hercompounding education and experience. All stability datashall be carefully interpreted in relation to the actual com-pounded formulation.

At all steps in the compounding, dispensing, and storageprocess, the compounder shall observe the compoundeddrug preparation for signs of instability. For more specificdetails of some of the common physical signs of deteriora-

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tion (see Chapter á1191ñ, Observing Products for Evidence ofInstability). However, excessive chemical degradation andother drug concentration loss due to reactions may be invis-ible more often than visible.

General Guidelines for Assigning Beyond-UseDates

In the absence of stability information that is applicable toa specific drug and preparation, the following table presentsmaximum BUDs recommended for (1) nonsterile compoun-ded drug preparations that are packaged in tight, light-re-sistant containers and stored at controlled room tempera-ture, unless otherwise indicated; and for (2) sterile prepara-tions for which a program of sterility testing is in place (seethe General Notices and Requirements, Preservation, Packag-ing, Storage, and Labeling). Drugs or chemicals known to belabile to decomposition will require shorter BUDs.

BUD by Type of Formulationa

For Nonaqueous Formulations—The BUD is not later than the timeremaining until the earliest expiration date of any API or 6 months,whichever is earlier.

For Water-Containing Oral Formulations—The BUD is not later than14 days when stored at controlled cold temperatures.

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

a These maximum BUDs are recommended for nonsterile compoundeddrug preparations in the absence of stability information that is applicableto a specific drug or preparation. The BUD shall not be later than the expi-ration date on the container of any component.

Susceptible preparations should contain suitable antimi-crobial agents to protect against bacteria, yeast, and moldcontamination inadvertently introduced during or after thecompounding process. When antimicrobial preservatives arecontraindicated in such compounded preparations, storageof the preparation at controlled cold temperature is necessa-ry; to ensure proper storage and handling of such com-pounded preparations by the patient or caregiver, appropri-ate patient instruction and consultation is essential. Antimi-crobial preservatives should not be used as a substitute forgood compounding practices.

For information on assigning BUDs when repackagingdrug products for dispensing or administration, see the Gen-eral Notices and Requirements, Preservation, Packaging, Stor-age, and Labeling, Labeling, Expiration Date and Beyond-UseDate, and Packaging and Repackaging—Single-Unit Contain-ers á1136ñ.

Assurance of sterility in a compounded sterile preparationis mandatory. Compounding and packaging of sterile drugs(including ophthalmic preparations) requires strict adher-ence to guidelines presented in Chapter á797ñ and in themanufacturers’ labeling instructions.

PACKAGING AND DRUG PREPARATIONCONTAINERS

The compounder shall ensure that the containers andcontainer closures used in packaging compounded prepara-tions meet USP requirements (see á659ñ Packaging and Stor-age Requirements; Containers—Glass á660ñ; Containers—Plas-

tics á661ñ; Containers—Performance Testing á671ñ; Chapterá1136ñ); and when available, compounding monographs.Compounders are not expected to perform the tests descri-bed in these chapters but should be knowledgeable aboutthe standards described in them. Container suppliers shallsupply, upon request, verification of USP container compli-ance. Containers and container closures intended for thecompounding of sterile preparations must be handled as de-scribed in Chapter á797ñ.

The containers and closures shall be made of suitableclean material in order not to alter the quality, strength, orpurity of the compounded drug preparation. The containerused depends on the physical and chemical properties ofthe compounded preparation. Container–drug interactionshould be considered for substances that have sorptive orleaching properties.

The containers and closures shall be stored off the floor,handled and stored to prevent contamination, and rotatedso that the oldest stock is used first. The containers and con-tainer closures shall be stored in such a way as to permit in-spection and cleaning of the storage area.

COMPOUNDING DOCUMENTATION

Documentation, written or electronic, enables a com-pounder, whenever necessary, to systematically trace, evalu-ate, and replicate the steps included throughout the prepa-ration process of a compounded preparation. All com-pounders who dispense prescriptions must comply with therecord-keeping requirements of their state boards of phar-macy. When the compounder compounds a preparation ac-cording to the manufacturer’s labeling instructions, thenfurther documentation is not required. All other compoun-ded preparations require further documentation as descri-bed in this section.

These records should be retained for the same period oftime that is required for any prescription under state law.The record may be a copy of the prescription in written ormachine-readable form and should include a Master Formu-lation 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 in-gredients

• description of all ingredients and their quantities• compatibility and stability information, including refer-

ences when available• equipment needed to prepare the preparation, when

appropriate• mixing instructions that should include:

1. order of mixing2. mixing temperatures or other environmental con-

trols3. duration of mixing4. other factors pertinent to the replication of the

preparation as compounded

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• sample labeling information, which shall contain, in ad-dition to legally required information:

1. generic name and quantity or concentration ofeach active ingredient

2. assigned BUD3. storage conditions4. prescription or control number, whichever is appli-

cable• 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 prepara-

tion• names and quantities of all components• sources, lot numbers, and expiration dates of compo-

nents• total quantity compounded• name of the person who prepared the preparation,

name of the person who performed the quality controlprocedures, and name of the compounder who ap-proved 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 bythe patient or caregiver

Standard Operating Procedures

All significant procedures performed in the compoundingarea should be covered by written standard operating pro-cedures (SOPs). Procedures should be developed for the fa-cility, equipment, personnel, preparation, packaging, andstorage of compounded preparations to ensure accountabil-ity, accuracy, quality, safety, and uniformity in compound-ing. Implementing SOPs establishes procedural consistencyand also provides a reference for orientation and training ofpersonnel.

Material Safety Data Sheets File

MSDSs shall be readily accessible to all employees work-ing with drug substances or bulk chemicals located on thecompounding facility premises. Employees should be in-structed on how to retrieve and interpret needed informa-tion.

QUALITY CONTROL

The safety, quality, and performance of compoundedpreparations depend on correct ingredients and calcula-tions, accurate and precise measurements, appropriate for-mulation conditions and procedures, and prudent pharma-ceutical judgment. As a final check, the compounder shallreview each procedure in the compounding process. To en-sure accuracy and completeness, the compounder shall ob-serve the finished preparation to ensure that it appears asexpected and shall investigate any discrepancies and takeappropriate corrective action before the prescription is dis-pensed to the patient.

Compounding Controls

1. The Master Formulation Record, the Compounding Re-cord, and associated written procedures shall be fol-lowed in execution of the compounding process. Anydeviation in procedures shall be documented.

2. The compounder shall check and recheck each proce-dure at each stage of the process. If possible, a trainedsecond person should verify each critical step in thecompounding process.

3. The compounder shall have established written proce-dures that describe the tests or examinations conduc-ted on the compounded preparation (e.g., the degreeof weight variation among capsules) to ensure theiruniformity and integrity.

4. Appropriate control procedures shall be established tomonitor the output and to verify the performance ofcompounding processes and equipment that may beresponsible for causing variability in the final compoun-ded preparations.

5. For further guidance on recommended quality controlprocedures, see Chapter á1163ñ.

PATIENT COUNSELING

At the time of dispensing the prescription, the patient orthe patient’s agent shall be counseled about proper use,storage, handling, and disposal of the compounded prepa-ration. The patient or the patient’s agent shall also be in-structed to report any adverse event and to observe and re-port to the compounder any changes in the physical charac-teristics of the compounded preparation (see Chapterá1191ñ, Responsibility of the Pharmacist). The compoundershall investigate and document any reported problem witha compounded preparation and shall take corrective action.

TRAINING

All personnel involved in the compounding, evaluation,packaging, and dispensing of compounded preparationsshall be properly trained for the type of compounding con-ducted. It is the responsibility of the compounder to ensurethat a training program has been implemented and that it isongoing. Compounding personnel should be evaluated atleast annually. Steps in the training procedure include thefollowing:

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• All employees involved in pharmaceutical compound-ing shall read and become familiar with this chapter.They should also be familiar with the contents of theUSP Pharmacists' Pharmacopeia and other relevant pub-lications, including how to read and interpret MSDSs.

• All employees shall read and become familiar with eachof the procedures related to compounding, includingthose involving the facility, equipment, personnel, ac-tual compounding, evaluation, packaging, storage, anddispensing.

• All personnel who compound hazardous drugs shall befully trained in the storage, handling, and disposal ofthese drugs. This training shall occur before preparingor handling hazardous drugs. For information on train-ing for personnel who compound hazardous drugs, seethe references in Compounding Facilities earlier in thischapter.

• All training activities shall be documented. The com-pounder shall meet with employees to review theirwork and answer any questions the employees mayhave concerning compounding procedures.

• The compounder shall demonstrate the procedures forthe employee and shall observe and guide the employ-ee throughout the training process. The employee willthen repeat the procedure without any assistance from,but under the direct supervision of, the compounder.

• When the employee has demonstrated to the com-pounder a verbal and functional knowledge of the pro-cedure, then and only then will the employee be per-mitted to perform the procedure without direct super-vision. However, the compounder should be physicallypresent and shall approve all ingredients and theirquantities and the final preparation.

• When the compounder is satisfied with the employee’sknowledge and proficiency, the compounder will signthe documentation records to show that the employeewas appropriately trained.

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

• The compounder is solely responsible for the finishedpreparation.

COMPOUNDING FOR ANIMAL PATIENTS

A compounder’s responsibility for providing patients withhigh-quality compounded preparations extends beyond thehuman species. All portions of this chapter apply to com-pounded preparations formulated for animal patients. Inten-ded use of any animal patient (e.g., companion, perform-ance, food) shall be determined before compounding forthat patient.

Because humans can consume animal patients as food,care must be taken to prevent drug residues from enteringthe human food chain when compounded preparations areused in animal patients. For this reason, all compounderspreparing formulations for animals shall possess a functionalknowledge of drug regulation and disposition in animal pa-tients. Veterinarians are required by law to provide food-producing animal caregivers with an accurate length of timeto withhold treated animal tissues (e.g., meat, milk, eggs)

from the human food supply. This length of time is referredto as a withdrawal time (WDT) and must also, by law, be in-cluded on the dispensing label of every prescription pre-pared for a food-producing species.

Drug use in any performance animal is strictly regulatedby federal and state governments, in addition to the gov-erning bodies of each of the specific disciplines. Penalties forviolation of these rules may be severe for all contributing tothe violation, including the veterinarian, pharmacist, andcaregiver.

The pharmacist shall be knowledgeable about the individ-ual species’ limitations in physiology and metabolic capacitythat can result in toxicity when certain drugs or excipientsare used in compounded preparations. For this reason, com-pounders making preparations for animals should use, whenpossible, formulations specifically developed for animal pa-tients. If such formulations are not available, the compound-er shall conduct a literature review to determine whether aspecific component of the formula is toxic to the target spe-cies. Extrapolating compounding formulations intended foruse in humans may not be appropriate for animal speciesand may contribute to negative outcomes.

Veterinarians and pharmacists making preparations for an-imal patients should be familiar with all state and federalregulations regarding drug use in animals, including but notlimited to the Food, Drug, and Cosmetic Act; the AnimalDrug Amendment; the Animal Medicinal Drug Use Clarifica-tion Act; and FDA's Compliance Policy Guideline for Com-pounding of Drugs for Use in Animal Patients.

á797ñ PHARMACEUTICALCOMPOUNDING—STERILE

PREPARATIONS

INTRODUCTION

The objective of this chapter is to describe conditions andpractices to prevent harm, including death, to patients thatcould result from (1) microbial contamination (nonsterility),(2) excessive bacterial endotoxins, (3) variability in the in-tended strength of correct ingredients that exceeds eithermonograph limits for official articles (see “official” and “arti-cle” in the General Notices and Requirements) or 10% fornonofficial articles, (4) unintended chemical and physicalcontaminants, and (5) ingredients of inappropriate qualityin compounded sterile preparations (CSPs). ContaminatedCSPs are potentially most hazardous to patients when ad-ministered into body cavities, central nervous and vascularsystems, eyes, and joints, and when used as baths for liveorgans and tissues. When CSPs contain excessive bacterialendotoxins (see Bacterial Endotoxins Test á85ñ), they are po-tentially most hazardous to patients when administered intothe central nervous system.

Despite the extensive attention in this chapter to the pro-vision, maintenance, and evaluation of air quality, the avoid-ance of direct or physical contact contamination is para-

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USP 37 [795] Pharm. Comp. Non-Sterile Prep

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Transcript of USP 37 [795] Pharm. Comp. Non-Sterile Prep