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795 PHARMACEUTICAL COMPOUNDING—NONSTERILE PREPARATIONS

For the purposes of this chapter, the pharmacist or other licensed health care professional responsible for preparing the
compounded preparations is referred to as “compounder”.

Compounding is an integral part of pharmacy practice and is essential to the provision of health care. The purpose of this
chapter and applicable monographs on formulation is to help define what constitutes good compounding practices and to
provide general information to enhance the compounder’s ability in the compounding facility to extemporaneously compound
preparations that are of acceptable strength, quality, and purity.

Compounding is different from manufacturing, which is guided by GMPs (see Good Manufacturing Practices for Bulk
Pharmaceutical Excipients 1078 ). Some of the characteristics or criteria that differentiate compounding from
manufacturing include the existence of specific practitioner–patient–compounder relationships; the quantity of medication
prepared in anticipation of receiving a prescription or a prescription order; and the conditions of sale, which are limited to
specific prescription orders.

The pharmacist’s responsibilities in compounding drug preparations are to dispense the finished preparation in accordance
with a prescription or a prescriber’s order or intent and to dispense those preparations in compliance with the requirements
established by the Boards of Pharmacy and other regulatory agencies. Compounders must be familiar with statutes and
regulations that govern compounding because these requirements vary from state to state.

The compounder is responsible for compounding preparations of acceptable strength, quality, and purity with appropriate
packaging and labeling in accordance with good compounding practices (see Good Compounding Practices 1075 ),
official standards, and relevant scientific data and information. Compounders engaging in compounding should have to
continually expand their compounding knowledge by participating in seminars, studying appropriate literature, and consulting
colleagues.

RESPONSIBILITY OF THE COMPOUNDER

The compounder is responsible for ensuring that the quality is built into the compounded preparations of products, with key
factors including at least the following general principles. (See also Good Compounding Practices 1075 .)

1. Personnel are capable and qualified to perform their assigned duties.

2. Ingredients used in compounding have their expected identity, quality, and purity.

3. Compounded preparations are of acceptable strength, quality, and purity, with appropriate packaging and labeling,
and prepared in accordance with good compounding practices, official standards, and relevant scientific data and

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information.

4. Critical processes are validated to ensure that procedures, when used, will consistently result in the expected
qualities in the finished preparation.

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

6. Appropriate stability evaluation is performed or determined from the literature for establishing reliable beyond-use
dating to ensure that the finished preparations have their expected potency, purity, quality, and characteristics, at
least until the labeled beyond-use date.

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

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

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

COMPOUNDING ENVIRONMENT

Facilities

Areas designated for compounding have adequate space for the orderly placement of equipment and materials to prevent
mixups between ingredients, containers, labels, in-process materials, and finished preparations. The compounding area is
also to be designed, arranged, used, and maintained to prevent adventitious cross-contamination. Areas used for sterile
preparations are to be separated and distinct from the nonsterile compounding area (see Environmental Quality and Control
under Pharmaceutical Compounding—Sterile Preparations 797 ). The entire compounding area is to be well-lighted.
Heating, ventilation, and air conditioning systems are to be controlled to avoid decomposition of chemicals (see Storage
Temperature under Preservation, Packaging, Storage, and Labeling in the General Notices and Requirements and the
manufacturers’ labeled storage conditions). Storage areas provide an environment suitably controlled to ensure quality and
stability of bulk chemicals and finished preparations.

Potable water is to be supplied for hand and equipment washing. This water meets the standards prescribed in the EPA’s
National Primary Drinking Water Regulations (40 CFR Part 141). Purified Water must be used for compounding nonsterile
drug preparations when formulations indicate the inclusion of water. Purified Water must also be used for rinsing equipment
and utensils. In those cases when a water is used to prepare a sterile preparation, Water for Injection, Sterile Water for
Injection, or Bacteriostatic Water for Injection must be used (see Water for Pharmaceutical Purposes 1231 and
Pharmaceutical Compounding—Sterile Preparations 797 ).

Compounding areas are to be maintained in a clean and sanitary condition. Adequate washing facilities are to be provided,
including hot and cold water, soap or detergent, and air driers or single-service towels. Sewage, trash, and other refuse in the
compounding area is to be disposed of in a safe, sanitary, and timely manner. Equipment is to be thoroughly cleaned
promptly after use to avoid cross-contamination of ingredients and preparations. Special precautions are to be taken to clean
equipment and compounding areas meticulously after compounding preparations that contain allergenic ingredients (e.g.,
sulfonamides or penicillins).

Equipment

Equipment is to be of appropriate design and size for compounding and suitable for the intended uses. The types and sizes
of equipment will depend on the dosage forms and the quantities compounded (see Weights and Balances 41 ,
Prescription Balances and Volumetric Apparatus 1176 , and equipment manufacturers’ instruction manuals). All
equipment is to be constructed so that surfaces that contact pharmaceutical components, in-process materials, or finished
preparations are not reactive, additive, or adsorptive to avoid altering the safety, identity, strength, quality, or purity of the
preparation. The use of micropipets, electronic or analytical balances, or triturations or dilutions shall be considered when

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needed quantities are too small to accurately measure with standard equipment required by a state Board of Pharmacy.
Equipment and accessories used in compounding are to be inspected, maintained, cleaned, and validated at appropriate
intervals to ensure the accuracy and reliability of their performance.

STABILITY OF COMPOUNDED PREPARATIONS

“Stability” is defined as 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 the table Criteria for
Acceptable Levels of Stability under Stability Considerations in Dispensing Practice 1191 .

The compounder must avoid formulation ingredients and processing conditions that would result in a potentially toxic or
ineffective preparation. The compounder’s knowledge of the chemical reactions by which drugs degrade provides a means
for establishing conditions under which the rate of degradation is minimized. The factors that influence the stability of
compounded preparations are generally the same as those for manufactured drug products (see Factors Affecting Product
Stability and Responsibility of the Pharmacist under Stability Considerations in Dispensing Practice 1191 ).

Primary Packaging

Compounded preparations should be packaged in containers meeting USP standards (see Containers under Preservation,
Packaging, Storage, and Labeling in the General Notices and Requirements, Containers 661 , and Containers
—Permeation 671 ). The container used depends on the physical and chemical properties of the compounded
preparation. Container–drug interaction is to be considered with substances such as phenolic compounds and sorptive
materials (e.g., polypeptides and proteins).

Sterility

Assurance of sterility in a compounded sterile preparation is mandatory. Compounding and packaging of sterile drugs, such
as ophthalmic solutions, will require strict adherence to guidelines presented in the general test chapter Pharmaceutical
Compounding—Sterile Preparations 797 and in the manufacturers’ labeling instructions.

Stability Criteria and Beyond-Use Dating

The beyond-use date is the date after which a compounded preparation is not to be used and is determined from the date the
preparation is compounded. Because compounded preparations are intended for administration immediately or following
short-term storage, their beyond-use dates may be assigned based on criteria different from those applied to assigning
expiration dates to manufactured drug products.

Compounders are to consult and apply drug-specific and general stability documentation and literature when available, and
are to consider the nature of the drug and its degradation mechanism, the container in which it is packaged, the expected
storage conditions, and the intended duration of therapy when assigning a beyond-use date (see Expiration Date and
Beyond-Use Date under Labeling in the General Notices and Requirements). Beyond-use dates are to be assigned
conservatively. When using manufactured solid dosage forms to prepare a solution or aqueous suspension, the compounder
is also to consider factors such as hydrolysis and the freeze-thaw property of the final preparation before assigning a beyond-
use date. In assigning a beyond-use date for a compounded drug preparation, in addition to using all available stability
information, the compounder is also to use his or her pharmaceutical education and experience.

When a manufactured product is used as the source of active ingredient for a nonsterile compounded preparation, the
product expiration date cannot be used to extrapolate directly a beyond-use date for the compounded preparation. However,
a compounder may refer to the literature or to the manufacturer for stability information. The compounder may also refer to
applicable publications to obtain stability, compatibility, and degradation information on ingredients. All stability data must be
carefully interpreted in relation to the actual compounded formulation.

At all steps in the compounding, dispensing, and storage process, the compounder is to observe the compounded drug
preparation for signs of instability. For more specific details of some of the common physical signs of deterioration, see

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Observing Products for Evidence of Instability under Stability Considerations in Dispensing Practice 1191 . However,
excessive chemical degradation and other drug concentration loss due to reactions may be invisible more often than they are
visible.

In the absence of stability information that is applicable to a specific drug and preparation, the following maximum beyond-
use dates are recommended for nonsterile compounded drug preparations1 that are packaged in tight, light-resistant
containers and stored at controlled room temperature unless otherwise indicated (see Preservation, Packaging, Storage, and
Labeling in the General Notices and Requirements).

For Nonaqueous Liquids and Solid Formulations—

Where the Manufactured Drug Product is the Source of Active Ingredient— The beyond-use date is not later than 25% of the
time remaining until the product’s expiration date or 6 months, whichever is earlier.

Where a USP or NF Substance is the Source of Active Ingredient— The beyond-use date is not later than 6 months.

For Water-Containing Formulations (prepared from ingredients in solid form)— The beyond-use date is not later than 14 days
for liquid preparations when stored at cold temperatures between 2 and 8 (36 and 46 F).

For All Other Formulations— The beyond-use date is not later than the intended duration of therapy or 30 days, whichever is
earlier. These beyond-use date limits may be exceeded when there is supporting valid scientific stability information that is
directly applicable to the specific preparation (i.e., the same drug concentration range, pH, excipients, vehicle, water content,
etc.). See also the beyond-use dating information in the Labeling section under Repackaging Into Single-Unit Containers and
Unit-Dose Containers for Nonsterile Solid and Liquid Dosage Forms under Containers 661 .

Beyond-Use Labeling

Federal law requires that manufactured drug products be labeled with an expiration date. Some state laws may require a
beyond-use date. The label on the container or package of an official compounded preparation must bear a beyond-use date.
Good compounding practice dictates beyond-use labeling for all compounded preparations.

DEFINITIONS

For purposes of this chapter, the following terms shall have these meanings.

PREPARATION is a drug dosage form, a dietary supplement, or a finished device. It is the finished or partially finished
preparation of one or more substances formulated for use on or for the patient or consumer (see General Notices and
Requirements).

OFFICIAL SUBSTANCE includes an active drug entity, a dietary supplement, or a pharmaceutic ingredient (see also NF 23) or a
component of a finished device.

ACTIVE INGREDIENT usually refers to chemicals, substances, or other components of articles intended for use in the diagnosis,
cure, mitigation, treatment, or prevention of diseases in humans or other animals or for use as dietary supplements.

ADDED SUBSTANCES are ingredients that are necessary to prepare the preparation but are not intended or expected to cause
a human pharmacologic response if administered alone in the amount or concentration contained in a single dose of the
compounded preparation. The term added substances is usually used synonymously with the terms inactive ingredients,
excipients, and pharmaceutic ingredients.

INGREDIENT SELECTION

Sources

Official compounded preparations are prepared from ingredients that meet requirements of the compendial monograph for

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those individual ingredients for which monographs are provided.

A USP or an NF grade substance is the preferred source of ingredients for compounding all other preparations. If that is not
available, or when food, cosmetics, or other substances are or must be used, then the use of another high-quality source,
such as analytical reagent (AR), certified American Chemical Society (ACS), or Food Chemicals Codex (FCC) grade, is an
option for professional judgment. For any substance used in compounding not purchased from a registered drug
manufacturer, the compounder must establish purity and safety by reasonable means, which may include lot analysis,
manufacturer reputation, or reliability of source.

A manufactured drug product may be a source of active ingredient. Only manufactured drugs from containers labeled with a
batch control number and a future expiration date are acceptable as a potential source of active ingredients. When
compounding with manufactured drug products, the compounder must consider all ingredients present in the drug product
relative to the intended use of the compounded preparation.

A compounder may not compound a drug preparation that appears on the FDA list of drug products withdrawn or removed
from the market for safety reasons.

Compounding Nondrug Requirements

If the preparation is intended for use as a dietary or nutritional supplement (to supplement the diet) or cosmetic (e.g., to
beautify), then the compounder must adhere to Good Compounding Practices 1075 and to this chapter, and must comply
with any federal and state requirements.

CHECKLIST FOR ACCEPTABLE STRENGTH, QUALITY, AND PURITY

The following questions are to be considered carefully before compounding.

1. Have the physical and chemical properties and medicinal, dietary, and pharmaceutical uses of the drug substances
been reviewed?

2. Are the quantity and quality of each active ingredient identifiable?

3. Will the active ingredients be effectively absorbed, locally or systemically according to the prescribed purpose, from
the preparation and route of administration?

4. Are there added substances (see Definitions), confirmed or potentially present from manufactured products, that
may be expected to cause an allergic reaction, irritation, toxicity, or undesirable organoleptic response from the
patient? Are there added substances (see Definitions), confirmed or potentially present, that may be unfavorable
(e.g., unsuitable pH or inadequate solubility)?

5. Were all calculations and measurements confirmed to ensure that the preparation will be compounded accurately
(see Pharmaceutical Calculations in Prescription Compounding 1160 )?

COMPOUNDED PREPARATIONS

The term compounded preparations includes the terms compounded dosage forms, compounded drugs, and compounded
formulations, and means finished forms that are prepared by or under the direct supervision of a licensed compounder.

When controlled substances are used, check with state and federal authorities concerning their policies. Unless
otherwise indicated or appropriate, compounded preparations are to be prepared to ensure that each preparation shall
contain not less than 90.0% and not more than 110.0% of the theoretically calculated and labeled quantity of active ingredient
per unit weight or volume and not less than 90.0% and not more than 110.0% of the theoretically calculated weight or volume
per unit of the preparation. Compounded preparations include, but are not restricted to, the following pharmaceutical dosage
forms described under Pharmaceutical Dosage Forms 1151 .

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Capsules, Powders, Lozenges, and Tablets

When compounding these dosage forms, the compounder is to prepare an amount of the total formulation sufficient to allow
the prescribed amount or quantity to be accurately dispensed. Selected practices and precautions for compounding these
dosage forms include the following:

reducing solid ingredients to the smallest reasonable particle size;

implementing appropriate checks to ensure that all ingredients are blended to achieve a homogeneous mixture;

monitoring humidity if moisture might cause hydrolysis, dosage form adhesion to containers, or softening or partial
dissolution of capsule shells;

accurately performing weighings to ensure that each unit shall be not less than 90% and not more than 110% of the
theoretically calculated weight for each unit [NOTE—Preparations classified as dietary supplements are required by
the U.S. Food and Drug regulations to be not less than 100% of the declared potency.]; and

packaging dosage units according to container specifications for capsules and tablets of the specific active
ingredient unless specified otherwise in individual monographs (see Containers 661 ).

Emulsions, Solutions, and Suspensions

When compounding these dosage forms, the compounder is to prepare a 2% to 3% excess amount of the total formulation to
allow the prescribed amount to be accurately dispensed. Selected practices and precautions for compounding these dosage
forms include the following.

For single-unit containers, the weight of each filled container, corrected for tare weight, shall be the equivalent of not
less than 100% and not more than 110% of the labeled volume.

Aqueous suspensions are prepared by levigating the powder mixture to a smooth paste with an appropriate wetting
agent. This paste is converted to a free-flowing fluid by adding adequate vehicle. Successive portions of the vehicle
are used to wash the mortar, or other vessel, to transfer the suspension quantitatively to a calibrated dispensing
bottle or graduate. The preparation may be homogenized to ensure a uniform final dispersion.

Reducing solid ingredients to the smallest reasonable particle size.

Solutions shall contain no visible undissolved matter when dispensed. [NOTE—An exception may occur with
supersaturated solutions such as Potassium Iodide Oral Solution.]

Emulsions and suspensions are labeled, “Shake well before using.”

Suppositories

When compounding suppositories, the compounder is to prepare an excess amount of total formulation to allow the
prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms
include the following:

not using ingredients that are caustic or irritating, and thoroughly comminute solids that are abrasive to the mucous
membranes;

selecting a base that allows active ingredients to provide the intended local or systemic therapeutic effect;

reducing solid ingredients to the smallest reasonable particle size; and

weighing a representative number of suppositories to ensure that each is not less than 90% and not more than 110%
of the average weight of all suppositories in the batch.

Creams, Topical Gels, Ointments, and Pastes

When compounding semisolid dosage forms, the compounder is to prepare an excess amount of total formulation to allow

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the prescribed quantity to be accurately dispensed. Selected practices and precautions for compounding these dosage forms
include the following:

not using ingredients that are caustic, irritating, or allergenic to the skin or other application sites unless they are
necessary for a treatment;

selecting a base or vehicle that allows active ingredients to provide the intended local or systemic therapeutic effect;

reducing solid ingredients to the smallest reasonable particle size;

geometrically incorporating the active ingredients with the added substances to achieve a uniform liquid or solid
dispersion in the dosage form; and

observing the uniformity of the dispersion by spreading a thin film of finished formulation on a flat transparent
surface (e.g., clear glass ointment slab).

COMPOUNDING PROCESS

The compounders are to consider using the following steps to minimize error and maximize the prescriber’s intent.

1. Judge the suitability of the prescription to be compounded in terms of its safety and intended use. Determine what
legal limitations, if any, are applicable.

2. Perform necessary calculations to establish the amounts of ingredients needed (see Pharmaceutical Calculations in
Prescription Compounding 1160 ).

3. Identify equipment needed.

4. Don the proper attire and wash hands.

5. Clean the compounding area and needed equipment.

6. Only one prescription should be compounded at one time in a specified compounding area.

7. Assemble all necessary materials to compound the prescription.

8. Compound the preparation following the formulation record or prescription (see Compounding Records and
Documents below), according to the art and science of pharmacy.

9. Assess weight variation, adequacy of mixing, clarity, odor, color, consistency, and pH as appropriate.

10. Annotate the compounding log, and describe the appearance of the formulation.

11. Label the prescription containers to include the following items: a) the name of the preparation; b) the internal
identification number; c) the beyond-use date (see Beyond-Use Labeling); d) the initials of the compounder who
prepared the label; e) any storage requirements; and f) any other statements required by law.

12. Sign and date the prescription affirming that all procedures were carried out to ensure uniformity, identity, strength,
quantity, and purity.

13. Thoroughly and promptly clean all equipment, and store properly.

COMPOUNDING RECORDS AND DOCUMENTS

All compounders who dispense prescriptions must comply with the record keeping requirements of their individual states. If
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. Such compounding documents are to list
the ingredients and the quantity of each in the order of the compounding process.

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The objective of the documentation is to allow another compounder to reproduce the identical prescription at a future date.
The formulation record provides a consistent source document for preparing the preparation (recipe), and the compounding
record documents the actual ingredients in the preparation and the person responsible for the compounding activity. These
records are to 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 that includes a formulation record, a compounding record, and
a Material Safety Data Sheets (MSDS) file.

Formulation Record

The formulation record is a file of individually compounded preparations. This record must list the name, strength, and
dosage form of the preparation compounded, all ingredients and their quantities, equipment needed to prepare the
preparation, when appropriate, and mixing instructions. Mixing instructions should include the order of mixing, mixing
temperatures or other environmental controls, such as the duration of mixing, and other factors pertinent to the replication of
the preparation as compounded. The formulation record must include an assigned beyond-use date, the container used in
dispensing, the storage requirements, and any quality control procedures.

Compounding Record

The compounding record contains documentation of the name and strength of the compounded preparation, the formulation
record reference for the preparation, and the sources and lot numbers of ingredients. The compounding record also includes
information on the total number of dosage units compounded, the name of the person who prepared the preparation and the
name of the compounder who approved the preparation, the date of preparation, the assigned internal identification number
or the prescription number and an assigned beyond-use date, and the prescription number. For all compounded
preparations, results of quality control procedures are to be recorded (e.g., weight range of filled capsules). When
compounding problems occur with preparations prepared according to USP compounding monographs, the compounder
must complete a USP Monograph Experience Reporting Form, and submit the form to USP for evaluation.

MSDS File

MSDS are to be readily accessible to all employees working with drug substances or bulk chemicals located on the
compounding facility premises. Employees are to 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 is to review each procedure in the compounding process. To ensure accuracy and
completeness, the compounder is to observe the finished preparation to ensure that it appears as expected and is to
investigate any discrepancies and take appropriate corrective action before the prescription is dispensed to the patient (see
the Checklist for Acceptable Strength, Quality, and Purity, the appropriate pharmaceutical dosage form under Compounded
Preparations, and the steps under Compounding Process).

VERIFICATION

Compounding procedures that are routinely performed, including batch compounding, shall be completed and verified
according to written procedures. The act of verification of a compounding procedure involves checking to ensure that
calculations, weighing and measuring, order of mixing, and compounding techniques were appropriate and accurately
performed.

PATIENT COUNSELING

The patient or the patient's agent should be counseled about proper use, storage, and evidence of instability in the
compounded preparation at the time of dispensing (see Responsibility of the Pharmacist under Stability Considerations in

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Dispensing Practice 1191 ).

1 For guidelines applicable to dating sterile compounded preparations, see Storage and Beyond-Use Dating under Pharmaceutical Compounding

—Sterile Preparations 797 .

Auxiliary Information— Staff Liaison : Claudia C. Okeke, Ph.D., Associate Director

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