Midterm Concepts(No math)

What is compounding?

The 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 Non sterile 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

Types of non sterile compounds

• Capsules or powders

• Oral liquid medications

  • this includes: Suspensions, solutions

• Topical medications

  • this includes: 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

Why do we need sterile medications?

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

Type of sterile medications

• Intravenous (IV) medications, fluids, nutrition

• Epidural, intrathecal medications

• Subcutaneous, intramuscular medications

• Ophthalmic medications (eye drops, eye ointments)

• Inhaled medications

Reasons for compounding

Drug or dosage form not commercially available

• Example: Oral liquid dosage form needed, specialized topical formulation, suppositories

Dose unavailable

• Example: the patient may need a very low or very high dose that isn’t produced by pharmaceutical companies, requiring a compounded version

Formulation inappropriate for patient

• Example: patient who is Ketogenic cant have certain additives in their medications or if someone has allergies to the additives in the pharmaceutical compound

What is Section 503A

Addresses the conditions in which a licensed pharmacist may compound a drug product in a state licensed pharmacy or a federal facility

• The compounded drug is for an identified individual patient

• Drugs are distributed pursuant to a valid patient-specific prescription

• Drugs compounded in advance of receiving prescriptions are compounded only in limited quantities

503A pharmacies are exempt from Current Good Manufacturing Practices (CGMP)

State-licensed physicians and pharmacists who compound under section 503A of the Federal Food, Drug, and Cosmetic Act (FD&C Act) may only compound drug product using bulk drug substances that

1. Comply with an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph if one exists, and the USP chapter on pharmacy compounding

2. Are components of FDA-approved drug products if an applicable USP or NF monograph does not exist

3. Appear on FDA’s list of bulk drug substances that can be used in compounding (the 503A bulks list) if such a monograph does not exist and the substance is not a component of an FDA-approved drug product.

• In addition, bulk drug substances must be accompanied by a valid certificate of analysis and must have been manufactured by an establishment registered with FDA under section 510 of the FD&C Act

What are 503A pharmacies?

Outpatient (community)

• Patient receives a prescription for the compounded product

Inpatient (healthcare facility)

• Order is placed in the patient's health record/chart for the compounded drug product

What are 503B legal requirements?

Established outsourcing facilities

• Subject to CGMP requirements

• May distribute compounded drugs pursuant to a patient-specific prescription OR in response to an order from a health care provider, such as a hospital, that is not for an identified individual patient (e.g., for office stock)

Comparison between 503 A vs 503 B facilities

What is a preparation?

A compounded drug dosage form to which a compounder has introduced a drug

• Example: Aspirin powder paper prepared in your pharmacy from tablets

What is a product?

Manufactured pharmaceutical dosage forms

• Example: Aspirin tablets from Bayer

What is a powder?

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

What nonsterile preparations where powder is the final dosage form dispensed to the patient

• Bulk Powders

• Divided Powders

What nonsterile preparations where powders are used to prepare a different final dosage form dispensed to the patient

• Capsules

• Suspensions

• Solutions

• Ointments

Sources of powders for nonsterile preparations

Bulk powders

Crushed tablets
Opened capsules

T/F: When compounding with powders, the weight of powder always equal the weight of the active pharmaceutical ingredient (API)

False; May be pure powder OR a powder containing active ingredient + excipients

• Even pure powder may not be 100% potent

  • you need to see Certificate of Analysis

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 (United States Pharmacopeia) for all APIs used in compounding

• When compounding with powders, must review assay (potency) and take this into consideration when calculating

• you may also need to consider water content

  • Often, but not always, negligible

What are the characteristics of a divided powder?

• uses Powder papers/chartulae/charts

• Single doses of powdered API individually wrapped in paper/cellophane/foil packets

  • More accurate dosage than bulk powders

• Patient-specific label should indicate quantity of active ingredient(s) contained in one dose

What are the characteristics of a bulk powder?

• Medications are not potent and can be dosed accurately and safely using general measuring devices (teaspoon, cup)

• Labeled for concentration of active ingredient(s) contained in the product (%w/w, mg of drug per gram of product, etc.)

Advantages of powders

• 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

What is important about powder particle size distribution?

Good powder formulation has uniform particle size distribution

• If particle sizes are not uniform, the powder will segregate according to the different particle sizes= Inaccurate dosing

Uniform particle size allows for

• uniform dissolution rate

• Uniform sedimentation rate

• Minimizes stratification when powders are stored/transported

What is Comminution?

the process of reducing the particle size of a powder

What are the three methods of comminution?

• Trituration

• Pulverization by intervention

• Levigation

Trituration characteristics

•Mix thoroughly, make homogenous

•Continuous rubbing or grinding of powder in a mortar with a pestle.

Used for hard, fracturable powder

Pulverization by Intervention characteristics

•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

Levigation characteristics

•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

What is blending?

Goal: Create a homogenous mixture

• Can be accomplished manually or with electric mixing equipment

  • via Homogenizers, ointment mills, grinders

• we use geometric dilution to achieve this goal

What is Geometric Dilution?

Method of mixing ingredients to ensure that ingredients are evenly distributed.

• The 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 mixture is complete

When would you use a glass mortar?

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

When would you use a Wedgewood mortar?

Rough surface for grinding dry crystalline and hard powders

When would you use a Porcelain mortar?

Smooth surface, preferred for blending powders and pulverizing gummy consistencies

What are the USP 797 standards for non sterile preparations

PPE per USP <795> when compounding nonsterile preparations

• Gloves MUST be worn

• Gown, hair covers, shoe covers, face masks SHOULD be worn

• Containment ventilated enclosures are not required but should be considered if powder poses respiratory or allergenic risk

Beyond use date definition

is the date or time after which a compounded sterile preparation (CSP) or compounded nonsterile preparation (CNSP) may not be stored or transported.

• Calculated from the time of compoundin

BUD for powders

180 days

CNSPs with a stability study using a stability-indicating analytical method for the components may have a BUD up to

180 days

What is USP?

A standard-setting organization, not a regulatory or enforcement agency

• Publishes the USP Compounding Compendium

  • USP <795>; USP <797>; USP <800

What is USP 795?

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

• When performing nonsterile compounding, compliance with chapter <795> is required

What is non sterile compounding according to USP 795?

• combining, diluting, pooling, or other methods of mixing products and components

• reconstituting products other than the way specifically listed in the manufacturer’s labeling

• Also includes compounding kits

According to USP 795, 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

• Developing and implementing policies and procedures

• Overseeing compliance with <795> and other applicable laws, regulations, and standards

• Ensuring competency of personnel

• Ensuring environmental control of the facilities used for storing and compounding CNSPs

Does not need to be a pharmacist

garb and hand hygiene in patients according to 795

Garb:

• Latex-free, powder-free gloves must be worn when compounding

Hand hygiene prior to compounding:

• Wash hands and forearms with soap and water for at least 30 seconds

Components of a compounded nonsterile preparation (CNSP):

API, water, other ingredients

Active Pharmaceutical Ingredient (API)

any substance or mixture of substances intended to be used in the compounding of a preparation, thereby becoming the active ingredient in that preparation and furnishing pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease in humans or animals or affecting the structure and function of the body

USP 795 documentation

• Must comply with state boards of pharmacy

• Retained for the same period that is required for any prescription under state law

• Should include Master Formulation Record and a Compounding Record

• Should also have standard operating procedures (SOPs)

What is the master formulation record?

The Recipe” for the CNSP; Required for all compounds

• It is prepared before the actual compounding process and is used as a standard guide for consistent preparation

• Ensures consistency and reproducibility for each batch of a compound

What is the compounding record?

A record of ingredients used to make a CNSP

• Required for all compounds

• preparation of a specific instance of the compound

• Usually done during or after the actual compounding process. It records all the specifics of a particular batch

• Provides traceability for each batch made and ensures that all steps were followed according to the MFR.

Note: The MFR and the CR can be separate or combined documents

A label when dispensed according to USP 795 must have

• Assigned internal lot number

• Active components (amount/activity/concentration)

• Dosage form

• Amount/volume in the container

• Storage temp (if not room temp)

• Beyond-use date

Labeling can also include in 795…(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 that the preparation is compounded

Special handling

Warning statements

What are capsules?

• Solid oral dosage form

• Unit doses of drugs enclosed within soluble shells of gelatin

• May be clear or colored

• Can be filled with dry powders, liquids or gels

Capsule advantages and disadvantages

What is capsule size

Eight sizes of capsules available for human use

• As capsule size number increases, capsule size/content capacity decrease

Ways to select a capsule size

• Capsule manufacturers will provide guidelines based on powder density

  • May also provide capacity of five common drugs for that size capsule

• Trial and error

• Rule of 7s—>Golden standard

  • Convert capsule content to grains

  • Subtract grains from “7”

  • Round to nearest whole number

  • Try this capsule size first

How to fill capsules?

For hand filling, pharmacists most often use “punch” method

• Ingredients are triturated to the same particle size, then mixed using geometric dilution

• Powder is placed on paper or ointment slab and smoothed with spatula to height approximately half the length of the capsule body

The base of the capsule is held vertically, and the open end is repeatedly pushed or “punched” into the powder until the capsule is filled; the cap is then replaced to close the capsule

Calculate and prepare ingredients for one extra dose

Quality control for capsules

± 5% standard pharmaceutical accuracy

• e.g., capsule compounded to weigh 400 mg

  • (0.05) * 400 mg = 20 mg

    • acceptable capsule weight on check 380 mg-420 mg

capsule storage

Areas of high humidity=capsules will absorb moisture, become malformed or misshapen

Areas of low humidity=capsules can become dry, brittle, and crack

• need Dispense in plastic or glass vials

capsules BUD

180 days

What do databases provide

An easy “first step” to locate a compounding formula

• May not be all-inclusive, but a good place to start

• Can also be a resource for what is commercially available; is it necessary compound or can you order the product

What do websites provide in compounding?

• General compounding support

  • Contain original material as well as links to other websites, compounding formulas, stability information, general education and training

• Evidence-based compounding formulas

• Regulatory standards; federal and state laws

What do journals provide in compouding?

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

What are texts used for in compounding?

Less frequently used, may have access to electronic versions

May use for solubility or compatibility data when established compounding formulas are not available.

Types of liquid dosage forms

• Suspensions

• Solutions

  • Syrups, tinctures, elixirs, spirits

  • Oral, otic, ophthalmic, nasal

• Emulsions

  • Oil-in-water

  • Water-in-oil

How are doses prescribed in liquid aq forms?

Dose is prescribed/ordered as a measurement of volume

• ml, tsp, tbsp, oz

Advantages and Disadvantages of liquid dosage forms

What are suspensions?

Liquid preparations that consist of solid particles dispersed throughout a liquid phase in which the particles are not soluble

• Can be oral, topical, injectable (sterile compounding)

• May be compounded from bulk powder, or commercially available tablets or capsules

Advantages and Disadvantages of Suspensions

Properties of suspensions

• Fine, uniform-sized particles

• Uniform dispersion of the particles in the liquid vehicle

• Slow settling of particles

• Ease of redispersion when the compounded product is shaken

To IMPROVE properties of suspension:

• Decrease particle size/diameter

• Decrease the DIFFERENCE in the density between solid and liquid

• Increase the viscosity of the suspending liquid

To increase Increase the density of the liquid

use Sucrose, glycerin, sorbitol

To Increase the viscosity of the liquid

use Viscosity-inducing agent along with Acacia, methylcellulose, etc.

To allow for Ease of redispersion

use flocculating agents-electrolytes→ structure of particles held by weak bonds that easily break apart when suspension is shaken

• Used in commercially manufactured suspensions; suspending vehicles (oral-plus, etc.) are flocculating systems

BUDs for oral non-aqueous liquids

90 days

BUD for preserved aqueous dosage forms

35 days