PARENTERALS: COMPOUNDING STERILE FORMULATIONS

CHAPTER 9

CHAPTER OUTLINE

• Compounding Sterile Formulations• Special Considerations• Regulatory Oversight

• LVP Solutions• SVP Solutions• Special Solutions• Administration Devices• Laminar Flow Hoods• Biological Safety Cabinets• Clean Rooms

• Aseptic Techniques in Hoods & Cabinets

• Working with Vials• Working with Ampules• Syringes & Needles• Filters• Quality Assurance & Infection

Control• Parenteral Incompatibilities• Units of measurement• Review

SPECIAL REQUIREMENTS OF STERILE FORMULATIONS

• Sterile– NOT a relative term– Free from bacteria and other microorganisms

• No particulate material

• Pyrogen–free

• Stable for its intended use

• Many require physiological pH

• Many require osmotic pressure similar to blood

REGULATORY OVERSIGHT OF STERILE COMPOUNDING

• Compounding is regulated by state boards of pharmacy.

• USP (United States Pharmacopeia – a non-profit organization) has federal authority to set compounding and manufacturing standards. – USP chapters < 1,000 are enforceable by the FDA.

• Some states accept USP standards as the state’s regulations. But some states have different regulations.

REGULATORY OVERSIGHT OF STERILE COMPOUNDING

• Chapter <795> deals with nonsterile compounding.

• Chapter <797> deals with sterile compounding.– CSP – compounded sterile preparation– The intent is to prevent harm and fatality resulting

from microbial contamination excessive bacterial endotoxins large errors in the strength of correct ingredients and the presence of incorrect ingredients.

COMPOUNDING STERILE FORMULATIONS

• Injectables – IV, IM, SC, ID

• Ophthalmic

• Intranasal

• Otic

• Inhalation

TYPES OF STERILE INTRAVENOUS SOLUTIONS – LVPs

• Large-volume parenterals (LVPs) : > 100 ml– Correct electrolyte imbalance– Vehicle for administering other drugs

• Available in plastic bags and glass bottles

• Common LVP solutions: – Dextrose 5% in water– 0.9% NS (sodium chloride) solution– Ringer’s solution– Lactated Ringer’s solution

Ports

Administration port

Medication port

TYPES OF STERILE INTRAVENOUS SOLUTIONS - LVPs

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TYPES OF STERILE INTRAVENOUS SOLUTIONS - SVPs

• Small volume parenterals (SVPs): < 100 ml

– primarily used for delivering medications– ampules, prefilled syringes, single or multidose vials

• Additive - a drug that is added to a parenteral solution

• Admixture - the resulting solution when a drug is added to a parenteral solution

TYPES OF STERILE INTRAVENOUS SOLUTIONS - SVPs

• Ready-to-mix systems – Add-Vantage®

– Add-a-Vial®

– Mini-Bag Plus®

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TOTAL PARENTERAL NUTRITION (TPN) SOLUTIONS

• Nutritional support to patients who are unable to take in adequate nutrients

• Contains macro- and micronutrients– Macronutrients: dextrose and protein– Micronutrients: electrolytes, vitamins, and trace

elements– Lipid emulsion: fatty acids and calories

• Available in 2 or 3 liter sizes

• Administered via the subclavian vein over 8-24 hours

DIALYSIS SOLUTIONS

• Dialysis - the passage of small particles through membranes byosmosis

• Peritoneal dialysis – a solution placed into and emptied from the peritoneal cavity to remove toxic substance from the body– hypertonic– administered several times a day

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IRRIGATION SOLUTIONS

• Sometimes called “splash” solutions

• Container size: > 1,000 ml, designed to empty rapidly

• Surgical irrigation solutions - bathe and moisten body tissue, dressing, or wash instruments

• Urological irrigation solutions - maintain tissue integrity or remove blood to maintain a clear field of visi on

ADMINISTRATION DEVICES – ADMINISTRATIONS SETS

• Flow rate control– clamp on administration set– drip chamber– controller – combination controller/pump– volume control chamber

IV administration set • device used to deliver IV fluids to patients • have many variations.

ADMINISTRATION DEVICES – POSITIVE PRESSURE PUMPS

• Cassette pump– for ambulatory patients

• Syringe pump– very useful in neonatal, infant, and critical care applications

• Peristaltic pump– micro-pulses– uses tubing that is reinforced with silastic insert

• Elastomeric pump– balloon-like reservoir

ADMINISTRATION DEVICES – PIGGYBACKS, HEPARIN LOCKS

• A piggyback is a SVP admixture that is administered through an existing IV line.

– Usually over a short time, from 30 minutes to 1 hour

• Heparin Locks – Used if no primary LVP is available– Heparin is used to fill tubing, preventing blood clots.

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LAMINAR FLOW HOODS (LFH)

• Enclosed work area designed to establish and maintain an ultraclean work area

– Air is pushed through a high efficiency particulate air (HEPA) filter that removes 99.97% of particles > 0.3 µm.

– Air flows over work surface at a uniform velocity (i.e., laminar flow) of 80-100 ft./min.

– USP Chapter <797> requires LFH to be ISO Class 5 environments.• no more than 3,520 particles ≥ 0.5 µm

• Both horizontal and vertical designs

LAMINAR FLOW HOODS (LFH) – HORIZONTAL HOOD

HEPA filter

intake filter

laminar flow viewed from above

blowerair in

air out

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LAMINAR FLOW HOODS (LFH) – VERTICAL HOODS

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BIOLOGICAL SAFETY CABINETS

• Designed differently than laminar flow hoods

• Protects personnel and the environment

• Class II, Type A1 cabinets are recommended for preparing chemotherapy agents.

CLEAN ROOMS

• Sterile compounding must be housed in an area isolated from the main traffic – a clean room.

• Need an ISO Class 7 environment– no more than 352,000 particles ≥ 0.5 µm per cubic meter of

air– have unrestricted air flow– only designated personnel in space

• If the clean room is ISO Class 5 environment, LFH/biological safety cabinets are not required.

ASEPTIC TECHNIQUES

• Sum total of methods and manipulations required to minimize the contamination of CSPs

• Can’t say this loudly enough: Working in a LHF or biological safety cabinet does not, by itself, guarantee the sterility of CSPs. ASEPTIC TECHNIQUES MUST ALSO BE USED.

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PREPARING LHF (AND BIOLOGICAL SAFETY CABINETS)

• Turn the hood “on” at least 30 minutes before use.

• Maintain a designated clean area around the hood.

• Thoroughly clean the hood.– Use the correct cleaning order for the interior

surfaces of the hood.

ASEPTIC TECHNIQUE – COLLECT SUPPLIES

• Gather all the necessary materials for the operation and make sure they are– not expired– free from particulate matter such as dust– and have no leaks -- check by squeezing plastic

solution containers

• Only essential objects and materials necessary for the product preparation should be placed in the LFH.

ASEPTIC TECHNIQUE – GROWING AND HAND WASHING

• All jewelry should be removed from the hands and wrists.

• Put on lint-free garments and barrier clothing. – Note: there is a proper sequence for dressing.

• Wash hands and forearms thoroughly. – use antibacterial soap– work soap under fingernails

• interlace fingers• wash up to elbows

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ASEPTIC TECHNIQUE – WORKING IN A LFH

• Work without interruptions.

• Place nonsterile objects downstream from sterile objects inside the LFH.

• Place larger objects toward the front of the LFH away from the HEPA filter.

• Do not eat, drink, talk, or cough in the LFH.

ASEPTIC TECHNIQUE – WORKING IN A LFH

• Plan a work area at least 3 inches from the back and 6 inches from the front of the LFH.– Make sure nothing obstructs the flow of air from

the HEPA filter over the work area.– Nothing should pass behind a sterile object and

the HEPA filter in a horizontal airflow hood or above a sterile object in a vertical airflow hood.

• Swab with an alcohol wipe all surfaces that require puncture. Use a new wipe with each surface.

WORKING WITH VIALS

• Two types of vials used to make admixtures– for drugs already in a solution– for drugs in a lyophilized powder that must be dissolved

in a dilute to make a solution.

• To withdraw a solution from a vial– Introduce a volume of air into the vial equal to the

volume of solution to be removed .– Draw the solution into a syringe and remove air bubbles.– Remember that the plunger and the tip of the syringe are

sterile and must not be touched.

CORING• Coring is when a needle damages the rubber closure of a

parenteral container causing fragments of the closure to fall into the container and contaminate its contents.

• To prevent coring– Place the vial on a flat surface and position the needle point on

the surface of the closure at about a 45° angle.– Put downward pressure on the needle while gradually bringing

the needle to an upright position (90° angle).Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission

from the publisher.

AMPULES

• An ampule is a single-dose-only drug container.

• Gently tap the top of the ampule to bring the medication to the lower portion of the ampule.

• Clean the neck with an alcohol swab; then grasp the ampule between your thumb and index finger at the neck while keeping the swab still in place.

• Forcefully snap the neck away from you.

AMPULES

• To withdraw solution from an ampule, tilt the ampule to about 20° down and use a filter needle or filter straw to remove the solution.

• Position the needle or straw on the shoulder area of the ampule. Place the beveled edge against the side of the ampule.

SYRINGES AND NEEDLES• Basic parts of a syringe

– barrel - tube that is open at one end and tapers into a hollow tip at the other end

– plunger - piston-type rod with a slightly cone-shaped stopper that passes inside the barrel

– tip - attachment point for a needle

• Common types: Slip-Tip®, Luer-Lock®, and Eccentric tips®.

• Available in sizes from 1 ml to 60 ml.Images copyright Perspective Press and Morton Publishing Company. May not be copied, re-used, reproduced, or re-transmitted without express written permission

from the publisher.

SYRINGES AND NEEDLES• Basic parts of a needle

– hub – at one end of the needle; attaches to the syringe

– shaft – long stem of the syringe– bevel – angled end of the syringe forming a point

• Needles are made of stainless steel or aluminum. – Needle lengths range from 3/8” to > 3 inches. – Needles come in gauges ranging from 27 to 13

(higher the gauge number, the smaller the lumen size).

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FILTERS

• Two types of construction– depth filters – twisting channels through the filter

material– membrane filters – small pores of a uniform size in

filter material

• Found in many types of packaging– round plastic holder– flat plastic holder such as a final filter– inside a needle such as a filter needle

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FILTERS

• Depth filter – filters a solution either pulled into or expelled out of a syringe

– but not both ways with the same filter

• Membrane filters – filters only a solution expelled out of a syringe

QUALITY ASSURANCE (QA) - FACILITIES

• USP Chapter <797> requires every compounding facility has to have a QA program.

• Environmental Quality and Infection Control Plans– certification of ISO class– monitoring of airborne particulates and microbiologicals.– cleaning and sanitizing compounding areas.– hazardous materials regulations.

QUALITY ASSURANCE (QA) – COMPOUNDING OPERATIONS

• Proper preparation of product

• Inspection and final check of product– container integrity and leaks– product cloudiness, particulates, color

• Sharps disposal– Sharps are objects that might puncture or cut the skin

of anyone who handles them.– Containers should be easily identified, leak proof,

puncture proof, and be able to be sealed permanently.

PARENTERAL INCOMPATIBILITIES

• Incompatibilities– drug and drug incompatibility– drug and IV solution incompatibility– drug and parenteral container incompatibility

• Characteristics of incompatibilities– color change– hazy appearance– precipitations– gas evolution– chemical degradation

PARENTERAL INCOMPATIBILITIES – HOW TO MINIMIZE

• Use solutions promptly after preparation.

• Minimize the number of drugs that are added at one time.

• Check references or package inserts if additives

– will result in a very high or very low solution pH

– contain calcium, magnesium, or phosphate salts

– contain acetate or lactate

PARENTERAL INCOMPATIBILITIES – CONTRIBUTING FACTORS

• pH (degradation, precipitation)

• Light (degradation)

• Temperature (stability)

• Dilution (proper concentration may avoid incompatibility)

• Buffer capacity (change pH)

• Time (degradation)

PARENTERAL INCOMPATIBILITIES – CONTRIBUTING FACTORS

• Filters – Inline filters cause 90% reduction in nitroglycerin.

• Solutions – Amphotericin B is not compatible in NS.

• Chemical Complexation– Calcium reduces tetracycline activity.– Needles or filters containing aluminum should not be used

with Cisplatin-AQ.

• Plastics – Some drugs may bind to plastics.– Plasticizers can leach out of plastics – may bind to some

drugs.

UNITS OF MEASUREMENT

• Molarity– A mole is the number of grams numerically equal to the

molecular weight of the drug.

• Osmole– Equal to the molecular weight of the drug divided by the

number of ions formed when a drug dissolves in solution.• Osmole = molecular weight

# of ions

UNITS OF MEASUREMENT

• Equivalent– Equal to the molecular weight of the drug divided by the

valence of the ions formed when a drug dissolves in solution.• Equivalent weight = molecular weight

• Percentage weight per volume (w/v)– Refers to drug’s weight per 100 ml if drug is a solid– Refers to drug’s volume per 100 ml if drug is a liquid.

• Solid: % = weight (gm)

• Liquid: % = volume (ml)

valence

100 ml

100 ml

UNITS OF MEASUREMENT

• International Units (IU)– Drug potency varies between biological sources.• penicillin• insulin• heparin• vitamins