Extemporaneous Compunding

FPGEE Preparation Basem Sayed May 26 , 2013

Essential guidance for compounding Guidance

The United States Pharmacopeia (USP) leads the practice of pharmacy compounding through several guidelines described in general USP Chapters (Not necessary to remember the number of chapters).

The USP expects that pharmacists engaged in compounding will do so in accordance with state and federal compounding laws as well as U.S. Food and Drug Administration (FDA) regulations and guidelines.

 Definition of Compounding The USP defines compounding as the preparation, mixing, assembling, packaging, and labeling of a drug or device in accordance with a licensed practitioner's prescription of medication under an initiative based on the practitionerpatient-pharmacist relationship in the course of professional practice. Compounding includes Preparation of drugs or devices in anticipation of prescription drug orders based on routine, regularly observed prescribing patterns. Reconstitution or manipulation of commercial products that may require the addition of one or more ingredients because of a licensed practitioner's prescription drug order Preparation of drugs or devices for the purposes of, or as an incident to, research, teaching, or chemical analysis

 Who is the compounder? Accordingly, the USP defines compounders as pharmacists who are "engaged in drug compounding or nutriceutical compounding" who should be proficient in compounding and should continually expand their compounding knowledge by participating in seminars or studying appropriate literature such as
USP Chapter 795, "Pharmaceutical Compounding-Nonsterile Preparations"; Chapter 797, "Pharmaceutical Compounding-Sterile Preparations"; Chapter 1160, "Pharmaceutical Calculations in Prescription Compounding"; other applicable state and federal compounding guidelines and laws.

 Responsibilities of the compounder Certifying all prescription orders and approving or rejecting all components, drug product containers, closures, in-process materials, and labeling Preparing and reviewing all compounding records to ensure that errors have not occurred in the compounding process Ensuring the proper maintenance, cleanliness, and use of all equipment used in a prescription compounding practice Ensuring that only authorized personnel are in the immediate vicinity of the drug-compounding operations Ensuring that the drug product and components of drug products are not on the list of federally recognized drug products that have been withdrawn from the market or removed from the market for public health reasons.

 Ensuring that personnel engaged in compounding wear clean clothing appropriate to the type of compounding performed (e.g., coats, gowns, gloves, masks, shoes, aprons, and other items, as needed for protection of personnel from chemical exposures and for prevention of drug contamination) Implementing procedures to prevent cross contamination when compounding with drugs (e.g., penicillins) that require special precaution to prevent cross-contamination

USP categories of compounding

The USP has designated seven categories of compounding: Category 1: Nonsterile-Simple (generally, the mixing of two or more commercial products) Category 2: Nonsterile-Complex (generally, compounding with bulk drug substances or compounding that requires calculations) Category 3: Sterile-Risk Level I Category 4: Sterile-Risk Level II Category 5: Sterile-Risk Level III Category6: Radiopharmaceuticals
o preparation of radiopharmaceuticals

Category 7: Veterinary: pharmaceuticals

Preparation

of

veterinary

 FDA Policies The agency will initiate enforcement actions if a compounding pharmacy engages in any of the following acts: Compounding drugs in anticipation of receiving prescriptions, except in very limited quantities, in relation to the drug compounded. Compounding drugs that were withdrawn or removed from the market for safety reasons Compounding finished drugs from bulk active ingredients that are not components of FDA-approved drugs that were approved under an investigational new drug application Receiving, storing, or using drug substances without obtaining written assurance from the supplier that each lot of the drug has been made in an FDA-registered facility

 Receiving, storing, or using drug components not guaranteed to meet official compendia requirements. Using commercial-scale manufacturing or testing equipment for compounding drug products. Compounding drugs for third parties who resell to individual patients or offering compounded drug products at wholesale to other state-licensed persons or commercial entities for resale. Compounding drug products that are commercially available in the marketplace or that are copies of commercially approved FDA drug products. Failing to operate in conformance with applicable state laws regulating the practice of pharmacy

FDA Regulatory Actions

The FDA-initiated regulatory actions include issuance of a warning letter, seizure, injunction, and prosecution.

 The term extemporaneous prescriptions includes compounded dosage forms, compounded drugs, and compounded formulations that are prepared by or under the direct supervision of a licensed pharmacist. The USP states that compounded preparations must contain not less than 90% and not more than110% of the theoretically calculated and labeled quantity of active ingredients.

Types of extemporaneous preparations

On the basis of their physical appearance, extemporaneous preparations are divided into solids, semi solids, and liquids. Solids Solids typically include capsules, powders, and lozenges. In preparing these dosage forms, the pharmacist generally must pay attention to reducing solid ingredients to the smallest reasonable particle size and must ensure that all ingredients are blended together to achieve a homogeneous mixture. During processing, the pharmacist has to monitor humidity to avoid hydrolysis, dosage form adhesion to containers, and softening of capsule shells. Prior to packaging, the pharmacist has to accurately weigh each individual capsule, powder, or lozenge and properly package each dosage unit in the proper container.

 Semisolid dosage forms Semisolid dosage forms include: suppositories, creams, topical gels, ointments, and pastes. When compounding any of these dosage forms, the pharmacist has to prepare an excess amount of the total formulation to allow the prescribed quantity to be accurately dispensed. The pharmacist is also advised to pay attention to the following: not using ingredients that are caustic or irritating and thoroughly comminuting solids that are abrasive to the mucous membranes, selecting a base that allows active ingredients to provide the intended local or systemic therapeutic effect, and reducing solid ingredients to the smallest reasonable particle. size prior to mixing with semisolid base.

 The pharmacist has to geometrically incorporate the active ingredients with the added substances to achieve an acceptable uniformity of the dispersion by spreading a thin film of finished formulation on a flat transparent surface (e.g., clear glass ointment slab).

 Liquids Liquid dosage forms include emulsions, solutions, and suspensions. When compounding these dosage forms, the pharmacist has to prepare a 2-3% excess amount of the total formulation to allow the prescribed amount to be accurately dispensed. The pharmacist has to adhere to certain rules. For single-unit containers, the weight of each filled container, corrected for tare weight, must be the equivalent of not less than 100% and not more than 110% of the labeled volume.

Preparation of liquids
Aqueous suspensions 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 and to transfer the suspension quantitatively to a calibrated dispensing bottle or graduate. The preparation may be homogenized to ensure a uniform final dispersion, and solid ingredients should be reduced to the smallest reasonable particle size. Solutions should contain no visible undissolved matter when dispensed.

Auxillary lablel
Emulsions and suspensionsare labeled "Shake well before using." Other labels such as refrigerate, handled carefully

Beyond use date

The beyond-use date is the date after which a compounded preparation is not to be used. It is determined from the date the preparation is compounded. the following maximum beyond-use dates are recommended for non sterile compounded drugs: Nonaqueous liquids and solid formulations. 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.

 Water-containing formulations. The beyond-use date is not later than 14 days for liquid preparations when stored at cold temperature between 2C and 8C. All other formulations. The beyond-use date is not later than the intended duration of therapy or 30 days.

liquid Preparations

Parenteral preparations
Parenteral preparations include standard injections (i.e., intravenous, intramuscular, intradermal, subcutaneous, intrathecal, epidural); parenteral admixtures; and parenteral nutrition. The following ingredients are used to prepare parenteral formulations: Solvents
o such as water is the main solvent. o Cosolvents, such as ethyl alcohol, glycerin, Polyethylene glycol (PEG), and propylene glycol, are secondary solvents.

Buffers are used to adjust the pH of the solution for solubility and stability reasons
o (phosphate, citrate, acetate, etc.).

 Preservatives are used to prevent bacterial growth in the preparations

(benzalkonium chloride 0.01%, benzyl alcohol1-2%, thimerosal 0.01%).

Antioxidants are used to enhance stability

(ascorbic acid 0.01-0.5%, sodium bisulfate 0.1-1%, sodium metabisulfate 0.1-1%).

Surfactants are used to increase the solubility of the drug (Tween 80 0.1-0.5%, Span 80 0.05-0.25% ). Complexation and chelating agents such as EDTA (ethylenediaminetetraacetic acid) 0.01-0.075% are used to improve stability.

Solutions and Suspensions

Solutions Liquid preparations containing one or more drug substances dispersed in a suitable solvent or a mixture of miscible solvents. Suspensions Liquid preparations containing one or more drug substances dispersed in a solvent such as water; however, the drug is insoluble in the solvent.

 Oral solutions additives Solubilization agents (surfactants) to improve the solubility of the drug in water or, in the case of suspensions, wetting agents (surfactants) to improve the dispersing ability of the solid drug in the aqueous phase. These surfactants have hydrophilic and hydrophobic groups. The most common surfactant is Tween 80. Buffers
Buffers used are hydrochloric acid, citric acid, acetic acid, and sodium phosphate.

Viscosity-increasing agents are used in suspensions to reduce sedimentation rate of solid particles. These agents are polymers such as hydroxymethyl or propyl cellulose. Sweetening agents such as sucrose, aspartame, sorbitol, and cherry syrup are used to add flavor to solutions and suspensions.

Solid Preparations

Capsules
Capsules are the most widely used solid dosage form in pharmaceutical compounding. The powder content (drug plus lactose) is usually enclosed in a hard gelatin body that is sealed off by a hard gelatin cap. Lactose is the main excipient used to prepare capsules. The pharmacist mixes the drug (mixed geometrically with lactose) before hand-filling each capsule. Colors can be added to capsules to ensure proper mixing. If the prescription asks for 50 or more capsules, a Jaansun machine can be used to prepare the capsules.

 Suppositories Suppositories are solid dosage forms used to administer medicine through the rectum, vagina, or urethra. After insertion, they soften or melt by body temperature. Several bases are used with suppositories: oil soluble bases such as cocoa butter; hydrogenated vegetable oils derived from triglycerides such as Fattibase, Wecobee, and Witepsol water-soluble bases such as PEG 300, 400, 1450, 3350, 6000, and 8000.

Semisolid and Topical Preparations

 Ointments and creams Ointments and creams are semisolid topical preparations. Ointments have no water Ointments are made of oleaginous bases such petrolatum, absorption bases such as petrolatum with lanolin, or water-soluble bases such as PEG ointments. Creams are oil-in-water or water in-oil emulsions. Ointments and creams contain waxes and other fatty materials. creams contain water up to 50% or more. Surfactants are added to creams to emulsify the oil or water.
The most used surfactants are Tween 80, Span 80, and sodium lauryl sulfate.

Ointments and creams are prepared by heating the waxes on a hot plate and mixing with other ingredient

 Gels Gels are classified as two-phase systems: ( 1) a polymer that forms a three-dimensional network of particles or solvated macromolecules of the dispersed phase (2) an aqueous or an alcoholic solvent. Polymers used to prepare gels are bentonite, gelatin, tragacanth, alginic acid, carboxymethylcellulose sodium, colloidal silicon dioxide, methylcellulose, poly vinyl alcohol, carbomer, and poloxamer (Pluronic).