Nonsterile Pharmaceutical Compounding · USP Chapter 795 • Chapter 795 provides estimates for beyond-use dating: – Refrigerated aqueous solutions = 14 days – Solids and nonaqueous

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Chapter 8

Nonsterile Pharmaceutical Compounding


The Need for Compounding

• Before large-scale pharmaceutical manufacturing, pharmacists compounded most prescriptions.

• Compounding is still necessary, but most chain pharmacies do not have the time, space, or expertise for compounding.

• A growing number of independent pharmacies are specializing in compounding service.


Terms to Remember

compounding the process of preparing a prescribed medication for an individual patient from bulk ingredients created by a pharmacist in order to treat a specified medical condition according to a prescription by a licensed prescriber


The Need for Compounding

• Sterile compounding • Nonsterile compounding


Sterile Compounding

• Includes preparation of injectable medications

• Done mostly in hospital pharmacies • Requires special

– Equipment – Workspaces – Expertise


Terms to Remember

sterile compounding the preparation of a parenteral product in the hospital, home healthcare, nuclear, or community pharmacy setting; an example is an intravenous antibiotic


Terms to Remember

nonsterile compounding the preparation of a medication, in an appropriate quantity and dosage form, from several pharmaceutical ingredients in response to a prescription written by a physician, such as tablets, capsules, ointments, or creams; sometimes referred to as extemporaneous compounding


Nonsterile Compounding • There are many examples of nonsterile

compounding preparations: – Solutions and suspensions – Ointments and creams – Suppositories and capsules

• Many dermatologists and gynecologists prefer to individualize prescriptions for their patients.

• Pharmacists also compound prescriptions from dentists and veterinarians.


Nonsterile Compounding

Why compound? – If prescription calls for a smaller dose

than is commercially available – If a patient requires alternative dosage

form • Cannot swallow pills • Oral medication may harm stomach • May be allergic to preservatives or colorings



• Solution – liquid dosage form – Active ingredient (solute) dissolved in a

solution (solvent), which may be water-based or alcohol-based

• Suspension – active ingredient not dissolved but dispersed – Has a tendency to settle – Suspending agent prevents settling

Safety Note



Regardless of their apparent stability, all suspensions should be dispensed with an auxiliary label reading “Shake Well.”



• Ointments – water-in-oil emulsions – Occlusive – Greasy – Not water washable

• Creams – oil-in-water emulsions – Nonocclusive – Nongreasy – Water washable



• Powder is a finely divided admixture of drugs and/or chemicals.

• Powders range in size from very coarse (No. 8) to very fine (No. 80).

• Dispensing of medicines in powder from is very rare.



• Suppository – solid dosage form for insertion into body orifice – Rectum – Vagina – Urethra

• Consists of active ingredient(s) in a base such as – Cocoa butter – Hydrogenated vegetable oil – Glycerinated gelatin



Suppositories are prepared by – Melting base material – Adding active

ingredient(s) – Pouring into a mold – Chilling to solidify

the suppository



• Capsules – solid dosage form with medicinal preparation inside a gelatin shell

• Medicinal preparation may be – Powder – Granules – Liquid

• Compounding for capsules may be necessary to provide an unusual dosage form.


Nonsterile Compounding • Capsule shells consist of a body and

cap and are made of – Gelatin – Sugar – Water

• Available in standard sizes



Commercially available synthetic hormones come in fixed doses for

– Hormone replacement therapy (HRT) – Estrogen replacement therapy (ERT)


Terms to Remember

hormone replacement therapy (HRT) therapy consisting of some combination of estrogen, progestin (female), and androgen (male) hormones

estrogen replacement therapy (ERT) treatment consisting of some combination of female hormones


Nonsterile Compounding • Physician may want to individualize these

hormones instead. • Bio-identical hormones can be

compounded to meet individual needs. • Dosing can be based on clinical

observations or lab analysis of serum or saliva.

• Hormones can be compounded as a gel or cream formulation.


Laws, Regulations, and Standards for Compounding

• Compounding pharmacies must be licensed.

• Federal and state laws and national standards guide safety practices.

• Compounding pharmacies must follow good compounding practices (see Table 8.2).




Terms to Remember

good compounding practices (GCP) USP standards in many areas of practice to ensure high-quality compounded preparations

anticipatory compounding preparing excess product (besides an individual compound prescription) in reasonable quantities; these preparations must be labeled with lot numbers



• USP Chapter 795 • Accreditation of compounding

pharmacies • Certification of pharmacy technicians


USP Chapter 795

• US Pharmacopeia developed standards for nonsterile compounding (Chapter 795): – Enhances patient safety – Protects pharmacists from law suits

• FDA elects to use and enforce USP standards.


Terms to Remember manufactured products

products prepared off-site by a manufacturer

compounded preparation a patient-specific medication prepared on-site by the technician, under the direct supervision of the pharmacist, from individual ingredients


USP Chapter 795 • Contains policies and procedures for

– Quality control, including quality of source ingredients

– Verification – Patient counseling

• Quality control also includes – Training of personnel – Maintaining stability and consistency of finished

product – Preventing errors – Documenting expiration dates


USP Chapter 795

• Material Safety Data Sheet must be filed for all stored ingredients.

• Contains information on – Hazards and flammability – Procedures for treating accidental

ingestion or exposure


Terms to Remember

Material Safety Data Sheet (MSDS) contains important information on hazards and flammability of chemicals used in compounding and procedure for treatment of accidental ingestion or exposure


USP Chapter 795

• Compounded products have beyond-use dating, which is initiated at the time of compounding, not at the time of dispensing.

• Product stability must be documented.


Terms to Remember beyond-use dating

the documentation of the date after which a compounded preparation expires and should no longer be used

stability the extent to which a compounded product retains the same physical and chemical properties and characteristics it possessed at the time of preparation


USP Chapter 795

• Chapter 795 provides estimates for beyond-use dating: – Refrigerated aqueous solutions = 14 days – Solids and nonaqueous solutions = 6 months or

less – All other formulations = 30 days

• When manufactured or bulk materials are used, take the earlier of these: – 25% of the remaining expiration date – 6 months


USP Chapter 795

• Technician should always have pharmacist check beyond-use dating.

• Beyond-use dating for sterile preparations is stricter: – It may be as little as 24 to 72 hours. – Both stability and sterility must be

documented.


Accreditation of Compounding Pharmacies

• Many compounding pharmacies seek national accreditation: – Protects patients – Protects businesses from legal challenges – Differentiates their practices from those of other

pharmacies • Pharmacy Compounding Accrediting Board

(PCAB) is responsible for accrediting pharmacies.


Accreditation of Compounding Pharmacies

• To be accredited, pharmacy must agree to follow all specified standards

• Must follow continuous quality improvement (CQI) process, including – Periodic spot-checks of technicians’

work – Random selection of product to be

analyzed at an outside lab


Terms to Remember

Pharmacy Compounding Accrediting Board (PCAB)

an organization that provides quality standards for a compounding pharmacy through voluntary accreditation

continuous quality improvement (CQI) a process of written procedures designed to identify problems and recommend solutions


Certification of Pharmacy Technicians

• Pharmacy technicians must pass a broad national certification exam.

• They must also complete minicertifications and laboratory training.

• All compounding tasks must be supervised and checked by the pharmacist.


Documentation of Nonsterile Compounding

• The master control record • The compounding log • Calculations in the compounding

pharmacy


The Master Control Record

• The master control record is the recipe for making the compounded prescription.

• It is prepared by the pharmacist or provided by a compounding service.


Terms to Remember

master control record a recipe for a compound preparation that lists the name, strength, dosage form, ingredients and their quantities, mixing instructions, and beyond-use dating


The Master Control Record

Master control record lists – Drug’s name – Strength – Dosage form – Ingredients and quantities – Mixing instructions – Recommended beyond-use dating – Storage and labeling requirements


The Compounding Log • Generated for each prescription • Pharmacist uses it to complete the

initial calculations and document them • Copy of the log

(called the prescription record) is filed and used for refills


Terms to Remember

compounding log a printout of the prescription for a specific patient, including the amounts or weights of all ingredients and instructions for compounding; used by the technician to prepare a compounded medication for a patient


Terms to Remember

prescription record a computer-generated version of the compounding log that documents the compounding recipe for a specific prescription and patient


The Compounding Log

Compounding log lists – All ingredients of the compounded preparation – Manufacturer – Wholesaler source – Assigned lot number – NDC number – Expiration date for each ingredient – Quantity made – Date of compounding – Initials of pharmacist and compounding technician


Calculations in the Compounding Pharmacy

• Technician in a compounding pharmacy should have – Knowledge of mathematical conversions – Aptitude for performing calculations

• Pharmacist is legally responsible for all calculations made by technicians

• Good practice to double-check pharmacist’s calculations and those in the master control record


Equipment • Weights and Balances • Pharmaceutical Weights • Forceps and Spatulas • Compounding Slab • Mortar and Pestle • Graduate Cylinders, Pipettes, and

Beakers • Other Equipment


Weights and Balances

Class III prescription balance • Two-pan balance • Used weigh small amounts

(120 g or less) • Sensitivity requirement around

+/– 6 mg • Uses pharmaceutical weights to

offset ingredient weight

Technician must become familiar with weights and balances



• Counterbalance – Two-pan balance – Used for larger weights (up to 5 kg) – Sensitivity requirement in the range of

+/- 100 mg – Used for bulk materials, not for

compounding • Ingredients and weights should be

placed on weighing paper


Terms to Remember

Class III prescription balance a two-pan balance used to weigh material (120 g or less) with a sensitivity rating of +/–6 mg; also known as a Class A balance

counterbalance a two-pan balance used for weighing material up to 5 kg with a sensitivity rating of +/–100 mg


Terms to Remember

weighing paper a special paper that is placed on a weighing balance pan to avoid contact between pharmaceutical ingredients and the balance tray; also called powder paper



Digital electronic balance – Single pan – Easier to operate than two-pan balance – More accurate – Much more

expensive than two-pan balances ($2,500 or more)


Terms to Remember

digital electronic analytical balance a single-pan balance that is more accurate than Class III balances or counterbalances; has capacity of 100 g and sensitivity as low as +/–1 mg


Pharmaceutical Weights

• Used with two-pan balances to offset ingredient weight

• Made of polished brass with noncorrosive coating

• Set usually contains both metric and apothecary weights


Terms to Remember

pharmaceutical weights measures of various sizes made of polished brass, often used with a two-pan Class III prescription balance; available in both metric and apothecary weights


Forceps and Spatulas • Forceps are used for grasping small

objects. • Forceps are used with pharmaceutical

weights to avoid transferring moisture or oil from hands, which can change weight and cause measurement errors.


Forceps and Spatulas • Spatulas are used for various tasks:

– Transferring solid ingredients to weighing pans – Preparing ointments and creams – Removing material from mortar and pestle

• Spatulas can be made of – Stainless steel – Plastic – Hard rubber

(useful for corrosive materials)


Terms to Remember

forceps an instrument used to pick up small objects, such as pharmacy weights

spatula a stainless steel, plastic, or hard rubber instrument used for transferring or mixing solid pharmaceutical ingredients


Compounding Slab

• Plate is made of ground glass: – Flat, hard, nonabsorbent surface – Used for mixing compounds

• Disposable, nonabsorbent parchment paper can be used instead.


Mortar and Pestle

• Used for grinding and mixing ingredients • Can be made of glass, porcelain, or

Wedgwood – Coarse-grained porcelain or Wedgwood best

for pulverizing materials

– Smooth glass sets best for mixing liquids and semisolids


Terms to Remember

compounding slab a flat, hard, nonabsorbent surface used for mixing compounds; also known as an ointment slab

mortar and pestle equipment used for mixing and grinding pharmaceutical ingredients


Graduate Cylinders, Pipettes, and Beakers

• A Graduate cylinder is a flask used for measuring liquids:

– Can be glass or polypropylene – Can be conical (wide top, narrow base)

or cylindrical • Conical graduates are calibrated in both

metric and apothecary units. • Cylindrical graduates are calibrated in metric

units and are more accurate.





Beakers are used to measure larger volumes of liquids:

– Not as accurate as graduate cylinders – Used when precision is not required



A pipette is a long, thin, hollow tube: – Calibrated – Used to measure and

transfer liquid volumes less than 1.5 mL

– Sometimes suction device used to draw up liquid


Terms to Remember

graduate cylinder a flask used for measuring liquids

pipette a long, thin, calibrated hollow tube used for measuring liquids less than 1.5 mL


Other Equipment

• Freezers and refrigerators – for storing ingredients and final products

• Container hood, masks, and gowns – for protection when working with powders

• Tablet press – for combining tablet ingredients

• Capsule machine – for making larger quantities of capsules


Other Equipment

Sterile preparations require additional equipment and space:

– Autoclave to sterilize instruments – Incubator to culture products – Clean room environment


Techniques

• Attire and preparation requirements • Technique for weighing

pharmaceutical ingredients • Calculating percentage of error • Technique for measuring liquid

volumes • Techniques for mixing compounded

drugs


Attire and Preparation Requirements

• Minimum requirements for nonsterile compounding – Hairnet – Long lab coat – Gloves

• And for hazardous chemicals – Eye goggles – Mask – Double gowning – Eyewash station


Attire and Preparation Requirements

USP Chapter 795 also specifies the following:

– All personnel must wash hands before and after each compounding procedure.

– Disposable gloves must be discarded after each procedure.

– No food items should be stored or consumed in the staging area.


Technique for Weighing Pharmaceutical Ingredients

• Accurately weighing ingredients is one of the most important parts of compounding.

• The electronic balance is the preferred piece of equipment.



• Must be perfectly level (front to back and side to side)

• Should be warmed up and calibrated each day prior to use

• Should be locked when not in use • Must be cleaned after each use



• Class III prescription balance is sufficient for occasional compounding.

• Pharmacist must check all measurements done by technician.


Calculating Percentage of Error

• Error in measurement is expected in nonsterile compounding.

• Allowances are made for a certain percentage of error.

• Most balances are marked with their degree of accuracy.

• Percentage of error is calculated as (amount of error / quantity desired) x 100


Terms to Remember

percentage of error the acceptable range of variation above and below the target measurement; used in compounding and manufacturing


Technique for Measuring Liquid Volumes

• Always select the measuring device that yields the most accurate volume.

• Use the smallest device that holds the required volume.

• Measure the liquid at eye level. • Read the level at the bottom of the

meniscus.


Terms to Remember

meniscus the moon-shaped or concave appearance of a liquid in a graduate cylinder used in measurement

Safety Note


Technique for Measuring Liquid Volumes

Always measure liquids on a solid, level surface at eye level.


Techniques for Mixing Compounded Drugs

• Technician should first gather these items: – Master control record – Ingredients – Equipment – Mixing directions

• Adequate and uninterrupted time must be provided.

• Best mixing technique should be retrieved from the master control record or from the pharmacist.



• Comminution is the act of reducing a substance to small, fine particles.

• Blending is the act of combining two substances.

• Trituration involves rubbing or grinding a substance to create fine particles: – Generally done with mortar and pestle – Rapid motion with minimal pressure produces

best results


Terms to Remember

comminution the act of reducing a substance to small, fine particles, including trituration, levigation, pulverization, spatulation, sifting, and tumbling

blending the act of combining two substances


Terms to Remember

trituration the process of rubbing, grinding, or pulverizing a substance to create fine particles, generally by means of a mortar and pestle



• Levigation is used when reducing particle size for use in ointments.

• A paste is formed with the solid and a levigating agent: – Castor oil – Mineral oil

• The paste is then triturated with a mortar and pestle.


Terms to Remember

levigation a process usually used to reduce the particle size of a solid during the preparation of an ointment



• Pulverization by intervention reduces particle size with the use of a volatile solvent: – Camphor – Alcohol – Iodine – Ether

• The solvent is then permitted to evaporate.


Terms to Remember

pulverization the process of reducing particle size, especially by using a solvent



• Spatulation uses a spatula to combine and mix

• Sifting is used to blend powders • Tumbling involves placing powders

into a container and shaking


Terms to Remember

spatulation a process used to blend ingredients, often used in the preparation of creams and ointments

sifting a process used to blend powders through the use of a sieve

tumbling a process used to combine powders by placing them in a bag or container and shaking it



• Most ointments and creams are prepared with manual incorporation of materials.

• In some cases, dry ingredients must be triturated to avoid a gritty appearance.



• Powders can be combined using one of the following techniques: – Spatulation – Trituration – Sifting – Tumbling – Levigation

• A diluent powder may be necessary for pediatric doses.


Terms to Remember

diluent powder Mixing an inactive ingredient that is added to the active drug in compounding a tablet or capsule


Techniques for Compounded Drugs

• Hand-filling capsules can be done with the punch method.

• The body of the capsule is punched into a cake of powder until it is full.


Terms to Remember

punch method a method for filling capsules in which the body of a capsule is repeatedly punched into a cake of medication until the capsule is full



• Mortar and pestle can be used to mix more than one drug.

• Geometric dilution method begins by adding the most potent drug.

• An equal amount of the next most potent drug is added and mixed.

• Each successive addition should equal the amount in the mortar.


Terms to Remember

geometric dilution method the gradual combining of drugs using a mortar and pestle


The Compounding Process

• USP Chapter 795 lists fourteen steps for compounding a nonsterile preparation.

• These steps, or something similar, should be included in the pharmacy’s procedure manual.

Safety Note



Compounding should never be rushed.



1. The pharmacist judges the suitability of the prescription to be compounded in terms of safety and intended use.

2. The pharmacist retrieves and reviews the master control record in the computer.

(See Table 8.6)



3. The pharmacist prints out a compounding record or log sheet for the technician to make the nonsterile preparation.

4. A medication container label is typed or created by the computer software using information in the compounding log.

(See Table 8.6)



5. The pharmacist performs all necessary mathematical calculations and identifies the necessary equipment for the technician; the technician double-checks all calculations.

6. The pharmacy technician uses appropriate protective clothing and handwashing technique.

(See Table 8.6)



7. The technician gathers all necessary active and inactive ingredients, as well as prepares and calibrates any necessary equipment.

8. The technician weighs and adds all ingredients for the preparation, initials each step, and adds documentation to the compounding record.

(See Table 8.6)



9. The technician labels and stores the medication in a suitable container.

10. The pharmacist reviews the compounding record and medication container label and assesses the pharmaceutical elegance of the preparation

(See Table 8.6)



11. The technician prepares a medication container label, affixing it to the proper container.

12. The pharmacist signs and dates the compounding record and/or prescription, files the records, and places the compounded preparation in a storage bin for patient pickup.

(See Table 8.6)



13. The technician cleans all equipment thoroughly and promptly, reshelves all active and inactive ingredients, and properly labels and stores any excess preparation.

14. The pharmacist counsels the patient at the time of pickup.

(See Table 8.6)



• Selecting medication containers • Labeling and cleanup • Final check by the pharmacist • Patient counseling by the pharmacist • Reimbursement


Selecting Medication Containers

• Technician should choose best container to extend beyond-use dating as much as possible.

• Amber-colored vials protect product from light.

• Oral syringes are calibrated for dispensing creams and gels.

• New TopiClick container dispenses a measured amount of medication.


Labeling and Cleanup

After compounding – Prescription must be labeled with all required

information. – Prescription balance should be locked and

covered. – Equipment and work area should be thoroughly

cleaned. – Ingredients should be properly stored. – Expired or discarded product should be sealed

and placed in a biohazard container.


Final Check by the Pharmacist

Pharmacist is legally responsible for checking the final product:

– Master control record – Mathematical calculations – Weight measurements – Container label


Final Check by the Pharmacist

Pharmacist also checks the pharmaceutical elegance of the product:

– Adequacy of mixing – Odor – Color – Consistency – pH balance


Terms to Remember

pharmaceutical elegance the physical appearance of the final compound preparation


Patient Counseling by the Pharmacist

• Pharmacist must offer counseling to all patients regarding compounded preparations.

• Pharmacist should ensure that the patient knows – How to take the medication – How to properly store the medication – The beyond-use or expiration date of the

medication


Reimbursement

• Insurance generally does not cover compounded preparations.

• The cost to the patient is based on time and experience of staff, not on the cost of the ingredients.

• Some insurance companies will accept a Universal Claim Form from the pharmacy and reimburse the patient later.


Reference Sources for the Compounding Pharmacy

• Remington: The Science and Practice of Pharmacy

• Secundum Artem: Current and Practical Compounding Information for the Pharmacist (www.paddocklabs.com)



Professional Compounding Centers of America (PCCA)

– National and regional educational and certification seminars

– Pharmacy software – Marketing and business consultations



United States Pharmacopeia (USP) – Monographs for 120 compounded

preparations – Guidelines and standards for safe

preparation, packaging, and storing

Nonsterile Pharmaceutical Compounding · USP Chapter 795 • Chapter 795 provides estimates for beyond-use dating: – Refrigerated aqueous solutions = 14 days – Solids and nonaqueous

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