DDS Lecture 2 Content

Compounding

Compounding

• preparation, mixing, assembling, altering, packaging, and labeling of a drug, drug-delivery device, or device in accordance with a licensed practitioner’s prescription, medication order, or initiative based on the practitioner/patient/pharmacist/compounder relationship in the course of professional practice

• reconstitution or manipulation of commercial products that may require the addition of one or more ingredients as a result of a licensed practitioner’s prescription

• preparation of drugs or devices for purposes of research, teaching, chemical analysis

Compounding Category 1

• Nonsterile-Simple

• Mixing of 2+ commercial products

Compounding Category 2

• Nonsterile-Complex

• compounding with bulk drug substances

• when calculations required

Compounding Category 3

• Sterile- risk level I

• low-level risk in USP 797

Compounding Category 4

• sterile- risk level II

• medium risk in USP 797

Compounding Category 5

• sterile-risk level III

• high risk in USP 797

Compounding Category 6

radiopharmaceuticals

Compounding category 7

veterinary pharmaceuticals

Manufacturing

• production, propagation, conversion, or processing of drug or device, either directly or indirectly, by extraction of the drug from substances of natural origin or by means of chemical or biological synthesis

• any packaging/repackaging of substances or labeling/relabeling of containers for promotion and marketing of drugs/devices

• any preparation of drug or device that is given or sold for resale by pharmacies, practitioners, etc

• distribution of inordinate amounts of compounded preparations or the copying of commercially available drug products

• preparation of any quantity of a drug product without a licensed prescriber/patient/licensed pharmacist/compounder relationship

Current Good Compounding Practices are formed by…

• US Pharmacopiea-National Formulary

• Food and Drug Modernization Act of 1997

• National Association of Boards of Pharmacy

Responsibilities of Compounder

• shall be proficient in compounding

• should continually expand compounding knowledge (seminars, studying literature)

• must be familiar with USP 795, 797, 1160, other state/federal compounding guidelines/laws

• ensure compounding personnel wear appropriate, clean clothing to protect and prevent contamination

• implement procedures to prevent cross-contamination

• certify all prescription orders

• approve/reject all components, containers, closures, in-process materials, labeling

• prepare and review all records to assure errors haven’t occurred

• assure proper maintenance, cleanliness, use of equipment

• assure only authorized personnel be in immediate vicinity of compounding operation

• assure that drug product and components are not on list of federally recognized drug products that have been withdrawn/removed from market

Compounder Training

• must be well-trained

• participate in current, relevant training programs

• all training activities covered by appropriate standard operating procedures and documentation

Standard Operating Procedures

• SOPs

• developed for facility, equipment, personnel, preparation, packaging, storage

• ensures accountability, accuracy, quality, safety, and uniformity in compounding

• includes access to material safety data sheets

Documentation

enables compounder to systematically trace, evaluate, and replicate steps included throughout preparation process of a compounded preparation

Compounding Facility requirements

• adequate space specifically designated for compounding

• Aseptic processes conducted in separate/distinct area from area used for nonsterile compounding

• maintained in clean, orderly, sanitary conditions

• maintained in good state of repair

  • defect-free plumbing

  • adequate, easily accessible washing facilities with hot and cold water, soap/detergent, air-dryer or single-use towels

• Potable water supplied under continuous positive pressure

• have adequate lighting and ventilation

• free of infestation

• trash held and disposed of in sanitary and timely manner

• sewage/refuse disposed safely and sanitarily

• bulk drugs/chemicals/materials must be stored as directed by manufacturer or according to USP monograph

  • clean, dry area under appropriate temperature conditions

  • protected from contamination

• all containers properly labeled

Compounding Equipment Requirements

• of appropriate design and capacity

• stored to protect from contamination and facilitate operations for use, maintenance, and cleaning

• suitable composition so surfaces that contact components are not reactive, additive, or absorptive (won’t affect purity of compounded preparations)

• routinely inspected, calibrated, checked (for automated, mechanical, electronic)

• inspected to determine suitability for use before compounding

• appropriately cleaned after use

Component Selection Requirements

1. Attempt to use USP-NF drugs and inactive components manufactured in FDA-registered facility

2. If not available, use professional judgement in receiving storing, or using components that meet official compendial requirements or provided by high quality source

3. If components of compendial quality are not obtainable, components of high quality may be used (chemically pure, analytical reagent grade, American Chemical society-certified, Food Chemicals Codex)

4. If not obtainable from sources in 1-3, component may be obtained from acceptable and reliable source based on professional judgement

5. When component derived from ruminant animals (bovine, caprine, ovine), supplier shall provide written assurance that animals were born/raised/slaughtered where bovine spongiform encephalopathy (BSE) and scrapie known not to exist

6. Shall not use components listed by FDA to be withdrawn from market for public health

7. Components should be stored off floor, handled/stored to prevent contamination, rotated so oldest stock used first

Food and Drug Modernization Act of 1997

• ensures patients have access to individualized drug therapy

• compounding provisions

• result of many pharmacy organizations working together

National Association of Boards of Pharmacy

• developed good compounding practices applicable to state-licensed pharmacies

• 8 recommendations

Standards for packaging contained in

• current good manufacturing practice

• US pharmacopeia

• FDA’s guideline for submitting documentation for packaging for human drugs and biologics

Why is packaging important for drugs?

• A drug product may become useless or hazardous if it reacts with packaging materials or decomposes because of improper storage

• outward appearance of the prescription drug package is often the only tangible basis for the patient’s judgement of a pharmacist’s care and skill

Container

that which holds the article

Immediate container

that which is in direct contact with the article at all times

Closure

Part of the container

Tight Container

• protects contents from contamination by extraneous liquids, solids, or vapors, from loss of article, from efflorescence, deliquescence, or evaporation under ordinary conditions

• capable of tight re-closure

Reversible Child-Resistant caps

• flips from snap-off to child resistant

• easy snap-off pop caps

• child resistant safety caps

What are pharmacy vials made of?

light resistant polypropylene

Well-closed container

protects contents from extraneous solids and from loss of article under ordinary conditions

Light-resistant container

• protects contents from effects of light by virtue of properties of material or coating

• clear/colorless/translucent container may be made light-resistant by means of opaque covering (must have label saying cover is needed until time for use)

Hermetic container

impervious to air or any other gas under ordinary conditions

Tamper-resistant containers

containers that are so sealed that the contents cannot be used without obvious destruction of seal

Single dose container

• holds a quantity of drug intended as a single dose and, when opened, cannot be resealed with assurance that sterility has been maintained

• injectable products

• ex. fusion-sealed ampuls and prefilled syringes and cartridges

Multiple-dose container

• hermetic container that permits withdrawal of successive portions of the contents without changing the strength or endangering the quality or purity of the remaining portion

• injectable products

• commonly called vials

Single unit container

• designed to hold a quantity of drug intended for administration as a single dose promptly after the container is opened

• termed unit dose package

• tablets, capsules, oral liquids

Multiple Unit container

• containers contain more than a single unit or dose of the medication

• tablets, capsules, oral liquids

Packaging Materials

• paper

• plastic-coated

• foil-coated

• metal

• glass

• plastic

Glass

• inert

• provides visibility and stability

• FDA approved

• can block actinic rays

  • amber: 98%

  • green: 59%

  • blue: 41%

  • clear:38%

Potential problems with plastic containers

• permeation (can allow vapor/gas into container)

• leaching (movement of container into contents)

• sorption (binding of molecules to polymers): adsorption, absorption

• chemical reactions

• alteration of properties

Nitroglycerin stability and loss

• stability at 25 Celsius for 62 days

• Glass, screw-cap vial: 4% loss

• plastic, snap-cap vial: 29.3% loss

Types of Plastics

• polyethylene

• polypropylene

• polyvinyl chloride

• polystyrene

• polycarbonate

Polyethylene

• widely used

• good water barrier

• poor oxygen barrier

• not too clear

• odors, flavors, and gases permeate

• mainly used for granules and powders

Polyethylene Pails

• vacuum tight: use with granulars, fine powders

• tamper-evidence with use of cable ties

• lid includes neoprene gasket for moisture resistance

• molded, high-density polyethylene

• FDA compliant

Polypropylene

• very popular

• excellent barrier to water, gases

• not too clear

• pharmacy vials are made of light-resistant polypropylene

Polyvinyl Chloride

• clear, rigid

• good oxygen barrier

• permeable to water

• yellows when exposed to heat or UV light

• used for parenteral solutions

Polystyrene

• rigid

• crystal clear

• used for solid dosage forms

Polycarbonate

• clear, transparent

• rigid

• possible replacement for glass

• expensive

Vial usage

tablets, capsules

Rx bottle, Rx oval usage

liquids

Wide mouth bottle usage

bulk powders, tablets, capsules, viscous liquids

Dropper bottles

ophthalmics, otics, nasal solutions, oral solutions with small dosages

Applicator bottle usage

topical medications

ointment jar usage

ointments/creams/gels (jar)

collapsible tube usage

ointments/creams/gels (tube)

sifter top usage

powders

Hinged-lid box usage

suppositories, powder papers (h)

Slide boxes

suppositories and powder papers (s)

Child-Resistant container

• significantly difficult for children under 5 to open or to obtain a harmful amount of its contents within reasonable time

• not difficult for “normal adults” to use properly

Child-resistant and adult-senior use packages

• reduce accidental poisonings

• patient care institutions exempt

Compliance Packaging

• meant to increase compliance, assist patients in taking meds on schedule

• educational techniques

• reminder aids

• compliance packages

• devices

Labeling

• label on container as well as other written, printed, or graphic matter upon immediate container of article or in package/wrapper in which it is enclosed, except outer shipping container

• complete list of ingredients or preparation name and reference, established name, or distinct common name

• dosage form

• strength

Labeling for Parenteral/Topical preparations

• contains names for all added substances

• parenteral: amounts

Labeling for Vitamin Products

• metric units

• may contain USP units

Labeling for electrolytes

• milli-equivalents

• weights

Labeling for special capsules/tablets

• chewable?

• enteric coated?

Manufacturer’s Label

• FDA approved for prescription drugs

• controlled by FDA

Prescription label

• controlled by state board of pharmacy

• must also meet federal requirements (FDA, DEA)

OTC Labeling

• standard format

• “drug facts” box

• standardized headings and subheadings

• standard order of presentation and style

• simpler language that is more easily understood by consumer

Storage

• conditions must be included in label

• ensure stability for intended shelf life

• include: expiration and beyond use dating, temperatures, reasonings to protect from freezing

• consider: temperature, humidity, gases, light

High Temperature effects on drug

• increases rate of chemical reactions

• may cause:

  • sublimation (solid)

  • solvent loss (liquid)

  • chemical decomposition of dyes (color fading)

  • phase separation (emulsion)

  • increased sedimentation (suspension)

  • increased disintegration times (tablet)

Low temperature effect on drugs

• crystal formation in solutions

• phase separation (emulsion)

• increased sedimentation (suspensions)

• cracking of sugar-coated tablets

“Freezer” temperature

-25 degrees C to -10 degrees C

“Cold” temperatureRe

Not exceeding 8 degrees C

“Refrigerator” temperature

2 degrees C to 8 degrees C

“Cool” temperautre

8-15 degrees C

“Room” temp

prevailing temperature

“warm” temp

30-40 degrees C

“excessive heat” temp

above 40 degrees C

Controlled room temperature

• 20-25 degrees C

• maintained thermostatically

• allows for excursions between 15-30 C that are experienced in pharmacies, hospitals, warehouses

Reasonings to protect drug from freezing

• risk of container breakage

• loss of strength/potency

• risk of destructive alteration of dosage form

When no specific storage instructions are given…

• protect from moisture, freezing, and excessive heat

• store at room temp or cool, dry place

Transportation considerations

• stability

• packing

• temperature

• humidity

• time

• shipping schedules (generally, don’t order on friday)

Records and Reports

• compounder shall maintain records (hard copy of prescription, formulation records, compounding records)

• records of controlled drug substances used

• all records of compounded preparations kept for period of time as set forth in federal and state laws

• records shall include manufacturer and lot number of all ingredients

When compounding for a prescriber’s office use…

• only where permitted by federal and state requirements

• order by prescriber indicating formula and quantity ordered may be filled in compounder’s facility

• compound for sole purpose of administration by or for prescriber

• record of compounding process shall be maintained

• label must be generated, number may be assigned

When compounding Veterinary Products…

• shall compound on basis of prescription orders

• prescriptions shall be handled and filled according to available guidelines

Compounded dosage forms

• oral capsules and liquids

• transdermals

• lollipops

• troches

• tablet triturates

• sublingual drops

• rapid dissolve tablets

• suppositories

• enemas

• rectal rockets

• effervescent powders

• nasal and otic preparations

• topical creams, ointments, gels, powders, sprays

• oral adhesives, mouthwashes, rinses

• sterile products (inhalation solution, injections, ophathalmics, total parenteral nutrition)

pH considerations in formulation process

• one of most important factors

• affect solubility and stability

• effect of pH on solubility: critical in formulation of liquid dosage forms

• solubility of weak acid/base is often pH dependent (most drugs are weak acids/bases)

Solubility and pH

• total quantity of monoprotic weak acid (HA) in solution at a specific pH is the sum of the concentrations of both the free acid and salt (A-) forms

• if excess drug is present, the quantity of free acid in solution is maximized and constant because of its saturation solubility

• as pH of solution increases, the quantity of drug in solution increases because the water-soluble ionizable salt is formed

HA < - > H⁺ + A^-

^{Ka= dissociation constant}

Saturation Solubility and pH

• certain pH level where total solubility of drug solution is saturated with responect to both salt and acid forms of drug (pHmax)

• solution can be saturated with respect to salt at higher pH, but not with respect to acid

• solution can be saturated with respect to acid at lower pH, but not to salt

used to calculate total quantity of drug that can be maintained in solution at a selected pH when below pHmax

Sa = saturation solubility of free acid

S’a= saturation solubility of salt

used to calculate total quantity of drug that can be maintained in solution at selected pH when above pHmax

Sa = saturation solubility of free acid

S’a= saturation solubility of salt

A pharmacist prepares a 3% solution of an antibiotic as an ophthalmic solution and dispenses it to a patient. A few days later, the patient returns the eye drops to the pharmacist because the product contains a precipitate. The pharmacist, checking the pH of the solution and finding it to be 6, reasons that the problem may be pH related. The physicochemical information of interest on the antibiotic includes the following:

Molecular weight	285 (salt) 263 (free acid)
3% solution of the drug	0.1053-M solution
Acid form solubility (S<sub>a</sub>)	3.1 mg/mL (0.0118 M)
K<sub>a</sub>	5.86 × 10<sup>−6</sup>

At pH=6, there is only 0.0809 M solution, not 0.1053 M solution prepared; drug had precipitated out of solution at that pH

Partition Coefficient

• measure of molecule’s lipophilic character

• distribution of a solute added to a mixture of two immiscible liquids between the two phases at constant temperature

• depends on drug concentration only if drug molecules have tendency to associate in solution

• high P= lipophilic

• low p= hydrophilic

Applications of Partition Coefficient

• extraction of crude drugs

• recovery of antibiotics from fermentation broth

• recovery of biotechnology-derived drugs from bacterial cultures

• extraction of drugs from biologic fluids for therapeutic drug monitoring

• absorption of drugs from dosage forms (ointments, suppositories, transdermals)

• study of distribution of flavoring oil between oil and water phases of emulsions

pKa/ Dissociation Constant

• determined by potentiometric titration

Dissociation of drugs

• extent of dissociation or ionization is highly dependent on pH

• in formulation, vehicle is often adjusted to certain pH to obtain certain ionization level for solubility/stability

• in pharmacokinetic area, extent of ionization of drug has strong effect on extent of absorption, distribution, elimination

Hydrates

• water present in molecule

• more chemical must be weighed to obtain actual active drug

Dexamethasone

less than 0.5% weight water

Dexamethasone acetate

• one molecule of water of hydration

• 3.5-4.5% water

• anhydrous form: less than 0.4% water

Dexamethasone sodium phosphate

up to 16% water and alcohol

Lidocaine hydrochloride

• monohydrate or anhydrous form

• water content between 5-7%