Compounding slides :(

what is compounding?

creation of a pharmaceutical preparation (drug) by a licensed pharmacist to meet the unique needs of an individual patient when a commercially available drug does not meet those needs

what is nonsterile compounding?

combining, admixing, diluting, pooling, reconstituting other than as provided in the manufacturer’s labeling, or otherwise altering a drug product or bulk drug substance to create a nonsterile preparation

which USP is nonsterile?

795

Examples of nonsterile compounds

capsules or powders, oral liquid medications (suspensions, solutions), topical medications (ointments, lotions, gels, medication sticks), rectal medications, otic medications (ear drops)

what is sterile compounding

combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug product or bulk drug substance to create a sterile medication

which USP is for sterile compounding

797

why do we need sterile medications?

when route of medication administration bypasses the body’s natural defense mechanisms

examples of sterile compounds

IV medications, fluids and nutrition; epidural, intrathecal medications, ophthalmic medications (eye drops, eye ointments), inhaled medications.

why do we compound?

drug or dosage form is not commercially available, dose unavailable, or formulation is inappropriate for patient.

T/F: it is legal to compound a preparation because it is cheaper than the commercially available product

FALSE

what are some risks with compounding

compounded drugs are not FDA-approved and therefore do not have the same safety, quality, and effectiveness requirements as FDA-approved drugs; increased risk when compounders engage in large-scale, non-patient specific compounding and distribution

which compounding center had a fungal meningitis outbreak due to contaminated methylprednisolone epidurals

New England Compounding Center (NECC)

what did the 2012 fungal meningitis outbreak lead to compounding wise?

new legal safeguards, Drug Quality and Security Act (2013) amended the Federal Food, Drug, and Cosmetic Act (FD&C). 503A and 503B of the FD&C address human drug compounding and prevents compounding pharmacies from functioning like drug manufacturers.

what is 503A

addresses the conditions in which a licensed pharmacist may compound a drug product in a state licensed pharmacy or a federal facility (compounded drug is for an identified patient; drugs are distributed pursuant to a valid patient-specific prescription; drugs compounded in advance of receiving prescriptions are only in limited quantities; must keep batching record)

T/F: 503A pharmacies are exempt from current good manufacturing practices (CGMP)

TRUE

rules for outpatient (community) 503A pharmacies?

patient receives a prescription for the compounded product

rules for inpatient (healthcare facility) 503A pharmacies?

order is placed in the patient’s health record/chart for the compounded drug product

what is 503B

established a new, voluntary category of compounders known as outsourcing facilities; may distribute compounded drugs pursuant to a patient-specific prescription OR in response to an order from a healthcare provider such as a hospital, that is not for an identified individual patient (e.g. for office stock).

T/F: 503B outsourcing pharmacies are subject to CGMP requirements

True

how are 503B outsourcing facilities different from 503A pharmacies?

compounding for long-term inventory and sale; elect to register with the FDA as an outsourcing facility; subject to different laws, inspections, and industrial regulations (CGMP); beyond the scope of typical hospital or community practice.

what is a preparation?

a compounded drug dosage form to which a compounder has introduced a drug (Ex: aspirin powder paper prepared in your pharmacy from tablets)

what is a product?

a manufactured pharmaceutical dosage form (ex: aspirin from Bayer)

Errors in pharmacy compounding:

lack of knowledge of accepted standards, inadequate training, disregard of published guidelines for environmental controls or compounding procedures, mathematical errors in calculating amounts of ingredient, weighing/measuring errors, improper ingredient selection, compounding procedural errors.

how to be accurate in compounding

practice techniques (quiet, focused environment; calculations-write down steps with units, independent colleague checks; weighing/measuring-self “triple-check,” colleague verification; awareness of unusual quantities), drug information skills

safety in compounding

adherence to federal and state rules and regulations; adherence to applicable USP chapters

powder definition

mixtures of dry finely divided drugs and/or chemicals that may be intended for internal or external use; solid dosage form that may be comprised of only the active drug or a mixture of the active drug and other ingredients

nonsterile preparations where the final dosage form is a powder

bulk powders and divided powers

nonsterile preparations made with powders, but the final dosage form is not a powder

capsules, suspensions, solutions, ointments

Sources of powders for nonsterile preparations

bulk powders, crushed tablets, opened capsules

T/F: the weight of powder does not always equal the weight of the active pharmaceutical ingredient (API)

true

what is a certificate of analysis

document produced by manufacturers with results of laboratory testing verifying the product conforms to requirements (USP); required by USP for all APIs used in compounding; when compounding with powders must review assay (potency) and take this into consideration when calculating

T/F: when compounding you can ignore the water content in powders because it is usually negliglible

False (often, but not always, negligible)

compounded powders for dispensing

divided powders and bulk powders

what are divided powders

powder papers/chartulae/charts; single doses of powdered API individually wrapped in paper/cellophane/foil packets; more accurate dosages than bulk powders; patient-specific label should indicate quantity of active ingredients contained in one dose

what are bulk powders

medications are not potent and can be dosed accurately and safely using general measuring devices (teaspoon, cup); labeled for concentration of active ingredients contained in the product (%w/w, mg of drug per gram of product, etc.)

Advantages of powder dosage forms

tailored doses; easily administered to patients who cannot swallow tablets or capsules; drugs most stable in solid form; undesirable taste less noticeable in powder form; rapid onset (disintegration not required); external or internal use

if particle sizes are not uniform in powders what can happen?

the powder will segregate according to the different particle sizes which can lead to inaccurate dosing

importantance of uniform particle size

results in uniform dissolution rate, uniform sedimentation rate, and minimizes stratification when powders are stored/transported

what does comminution mean

the process of reducing the particle size of a powder

ways to reduce the particle size of a powder

trituration, pulverization by intervention, and levigation

what is trituration

mix thoroughly, make homogenous; continuous rubbing or grinding of powder in a mortar with a pestle; use for hard, fracturable powders

what is pulverization by intervention

uses an intervening solvent (alcohol, acetone) to dissolve the powder, then the dissolved powder is mixed in a mortar or spread on an ointment slab to enhance the evaporation of the solvent; The solvent evaporates, and the powder will recrystallize out of solution as fine particles. Used with hard crystalline powders that do not dissolve easily.

what is levigation

reduces particle size by triturating in a mortar or spatulating on an ointment slab with a small amount of liquid solvent in which the solid is not soluble (usually mineral oil or glycerin- the levigating agent or wetting agent); often used when compounding powders into ointments or suspensions

goal of blending powders

create a homogenous mixture!

how can blending of powders be accomplished?

homogenizers, ointment mills, grinders

what is geometric dilution

used when blending two or more ingredients of different quantities; method of mixing ingredients to ensure that ingredients are evenly distributed; smaller volume ingredient (active drug) is mixed with an equal volume of the other ingredient (diluent); that mixture is then mixed with an equal volume of the larger ingredient; repeated until the mixture is complete

what are glass mortars good for?

best used for liquids and for compounds that are oily or can stain

what are wedgewood mortars for?

rough surface for grinding dry crystalline and hard powders

what are porcelain mortars for?

the smooth surface is preferred for blending powders and pulverizing gummy consistencies

safety PPE when compounding nonsterile preparations

gloves must be worn, gown, hair covers, shoe coves, and face masks should be worn

safety precautions for powders

containment ventilated enclosure (CVE) aka powder containment hoods; protect the compounder from airborne particles; not required compounding facility to determine if/when used; consider when powder poses a respiratory or allergenic risk; this is different than the considerations for compounding with hazardous drugs (USP 800)

beyond use date for other nonaqueous dosage forms

180 days

storage temperatures for other nonaqueous dosage forms

refrigerated or room temperature

what is USP

A nonprofit scientific organization founded in 1820. A standard-setting organization NOT a regulatory or enforcement agency! Published the USP Compounding Compendium

USP 795

“Pharmaceutical compounding-nonsterile preparations", standards for compounding nonsterile medications to ensure patient benefit and reduce risks such as contamination, infection, or incorrect dosing. Not a “guideline,” must follow entire standard to be compliant

nonsterile compounding is:

combining, diluting, pooling, or other methods of mixing products and components; also includes reconstituting products other than the way specifically listed in the manufacturer’s labeling (also includes compounding kits)

Nonsterile compounding is not:

prepackaging items, splitting tablets, reconstituting according to manufacturer’s labeling

what is a designated person

the person responsible for overseeing all aspects of compounding at a facility - does not need to be a pharmacist

compounding documentation:

documentation enables a compounder to systemically trace, evaluate, and replicate the steps included throughout the preparation process of a compounded preparation; must comply with state boards of pharmacy

what compounding documentation is needed?

master formulation record and compounding record; should also have standard operating procedures (SOPs)

what is the master formulation record

the recipe for the CNSP - REQUIRED FOR ALL COMPOUNDS

what needs to be included in a master formulation record (MFR)

name, strength or activity, dosage form; container-closure system; complete instructions for preparing the CNSP, including equipment, supplies, and a description of the compounding steps; physical description of the final CNSP; assigned BUD and storage requirements (with reference), calculations as needed to determine and verify quantities of components and strength of API; labeling requirements; quality control procedures; other information needed to describe the process and ensure repeatability.

what is a compounding record

a record of ingredients used to make a CNSP; required for all compounds; the MFR and the CR can be separate or combined documents

what must the compounding record contain

name, strength or activity, and dosage form of the CNSP; master formulation record reference for the CNSP; calculations performed to determine and verify quantities and/or concentrations of components if appropriate; name, vender or manufacturer, lot number, and expiration date of each component; weight or measurement of each component; date and time of preparation; assigned internal lot number; total quantity compounded; physical description of the final CNSP; assigned BUD and storage requirements; results of quality control procedures; and method to identify the individuals involved in the compounding process and verifying the final CNSP

what is are BUDs

the date/time after which a compounded nonsterile preparation (CNSP) may not be stored or transported

BUD for Non preserved aqueous dosage forms

14 days

BUD for preserved aqueous dosage forms

35 days

BUD for oral nonaqueous liquids

90 days

storage for nonpreserved aqueous dosage forms

refrigerated

storage for preserved aqueous dosage forms

refrigerated or room temperature

storage for oral nonaqueous liquids

refrigerated or room temperature

what MUST the label contain

assigned internal lot number, active components (amount/activity/concentration), dosage form, amount/volume in the container, storage temp if not room temperature, and BUD

what should a label include but it’s not required

name/address/contact info of compounding pharmacy if CNSP will be sent outside the facility where it was compounded, route of administration, indication, special handling, and warning statements

what are capsules

solid oral dosage forms, unit doses of drugs enclosed within soluble shells of gelatin, may be clear or colored, and can be filled with dry powder, liquids, or gels.

advantages of capsules

can mask unpleasant taste/smell//appearance of API, uncompressed powders dissolve and absorb more quickly (than tablets), variety of administration routes (oral, inhalation, rectal), can be formulated to delay drug release, may be easier to swallow than tablets

disadvantages of capsules

can be tampered with, humidity/moisture concerns (aqueous liquids dissolve moisture shell, cannot use with hygroscopic/deliquescent materials)

how many capsule sizes for human use?

eight sizes

T/F: as capsule size number increase, the capsule size/content capacity decreases

True

how to select capsule size

trial and error; rule of 7s

how to find capsule size via rule of 7s

convert capsule content to grains, subtract grains from “7,” round to the nearest whole number, try this capsule size

what is the optimum capsule size

#2 or #3

most often used method to fill capsules

"punch” method

quality control for capsules

polish capsules as needed to remove fingerprints or excess powders; visually inspect for uniformity in appearance/color, uniform fill, and that it is tightly closed and locked.

capsule storage

dispense in plastic or glass vials; if stored in high humidity capsules will absorb moisture, become malformed or misshapen; if stored in low humidity capsules can become dry, brittle, and crack

examples of primary literature

clinical research studies and reports (ex: original research published in scientific refereed journal articles)

examples of secondary literature

summarizes and synthesizes primary literature (ex: books, literature review articles)

examples of tertiary literature

summaries or condensed versions of materials with references to primary or secondary sources (ex: textbook, handbook, database)

what information are we looking for when doing nonsterile compounding

compounding formulas, solubility/compatibility, standards; federal/state laws

where do we look for information regarding nonsterile compounding

databases, websites, journals, texts, and unpublished data

which option is an easy first step to locate a compounding formula or find out if it is commercially available

databases

what information do websites give us for compounding

general compounding support - contain original material as well as links to other websites; evidence-based compounding formulas (most appear in tertiary references); regulatory standards (federal and state laws)

what information do we get from journals

primary literature publications of evidence-based compounding formulas as well as other articles (reviews, etc.) relevant to pharmacy compounding topics

what information do we get from texts

less frequently used but may use for solubility or compatibility data when established compounding formulas are not available

what can unpublished data show tell us?

internal studies/validation

liquid dosage forms

encompasses many formulations such as: suspensions, solutions (syrups, tinctures, elixirs, spirits, oral, otic, ophthalmic, nasal), emulsions (oil-in-water, water-in-oil)

T/F: liquid dosage forms should be calculated and compounded only for the prescribed quantity (no extras)

True!

advantages of oral liquid dosage forms

can accommodate precise, nonstandard dosing; easy to administer (oral admin, enteral feeding tubes)

disadvantages of oral liquid dosage forms

drug often less stable in liquid form; shorter BUD; difficult to mask unpleasant smells or tastes; specific storage conditions; safety (measuring devices, measuring abilities, variability in standard concentrations)

Safety issues with suspensions

Many medications may have compounding formulas available for multiple different final concentrations; important when compounding medications to ensure patient is getting the intended concentration (and dose) especially at transitions of car, changing pharmacies, and changing prescribers

what is ASHP Standardize4Safety

a national, interprofessional effort to standardize medication concentrations to reduced errors, especially during transitions of care - includes standard concentrations for IV infusions, compounded oral liquid medications, IV intermittent medications, PCAs, and epidurals