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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
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
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