sterile compounding and preparations a knowledge

Course Administered By:

J&D Educational Services, Inc

J&D Educational Services PO Box 130909

The Woodlands, Texas 77393-0909 Voice: 1-866-747-5545 Fax: 1-281-298-8335

www.jdeducation.com

STERILE COMPOUNDING AND PREPARATIONS A Knowledge Based Program for Technicians

By

Jeff Blackburn, MBA – Healthcare Administration, C.Ph.T.

ACPE No. 0096-9999-09-020-H04-T

Total number of pharmacy continuing education hours: 6 hours (0.6 CEU’s)

Release Date: 4/6/2009

Expiration Date: 4/6/2012

Course Cost: $19.00 (to be paid at time of testing) Average time to Complete: Approximately Six hours including testing Course Value: Six Contact Hours Reading: 52 Pages

Final Exam: 50 Questions Completion Requirements: Answer 70% of question correctly Complete Evaluation

The Texas Tech University – HSC- School of Pharmacy is accredited by The Accreditation Council For Pharmaceutical Education (ACPE) as a provider of continuing

Pharmaceutical Education.

Sterile Preparations J&D Educational Services

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Course Objectives

1. Discuss the role of the C.Ph.T. in sterile compounding.

2. Review sterile preparation formulations.

3. Describe some of the issues related to large volume parenteral solutions.

4. Describe some of the issues related to small volume parenteral solutions.

5. Discuss the equipment and facilities related to sterile preparations.

6. Review the procedures related to sterile compounding.

7. Discuss the procedure related to proper aseptic technique.

8. Review quality control procedures related to sterile preparations.


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Table of Contents

I. Overview of Sterile Compounding and the Role of the C.Ph.T.

II. Sterile Preparation Formulation

III. Sterile Preparation Facilities and Equipment

IV. Laminar Flow Hoods

V. Perenteral Solutions

a. Large Volume b. Small Volume

VI. Uses for Sterile Compounding

VII. Aseptic Technique

VIII. Policies and Procedures for Compounding Sterile Preparations

IX. Packaging

X. Labeling Sterile Preparation

XI. Storage

XII. Quality Control and Maintaining Integrity


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I. Overview of Sterile Compounding and the Role of the C.Ph.T. When drugs need to be injected, any one of several routes can be used to administer the drug. The most common injectable routes of administration are intravenous (in the vein), intramuscular (in the muscle), and subcutaneous (in the skin). The compounding of sterile preparations is an integral part of any health-system setting. While the majority of perenteral products are prepared using commercially available medications and diluents solutions, pharmacy departments still perform intravenous manufacturing. The reasons for this vary greatly, but can include:

• Special patient populations such as pediatrics, geriatrics, or the terminally ill (pain management). For these patients, the appropriate strengths for certain drugs may not be available.

• Some patients might be allergic to the diluents and preservatives in commercially

available products.

• Some drugs are unstable and require preparation to be dispensed every few days.

• A combination therapy that a prescriber desires, but that is not currently commercially available.

Intravenous Administration Intravenous administration of drugs has advantages over other routes of administration because it provides the fastest route to the bloodstream. There are no barriers like skin or muscle to absorb the drug first, which allow the most rapid onset of action. If someone cannot take medication by mouth because he is unconscious or vomiting, then intravenous administration is the best route. Since the inner lining of a vein is relatively insensitive to pain, drugs that can be irritating if given by another route can be given intravenously as a slow rate without causing pain. Drugs that can be diluted to reduce irritation can be given only intravenously because the tissue and skin around the other routes of administration cannot accommodate large volumes. There are two types of intravenous administration. The first is an intravenous injection in which the prepared medication is drawn up into a syringe and administered immediately. The amount of medication is usually a small volume pushed through an IV line that is already in place on the patient. The second type of administration is an IV infusion. Infusions are given to overcome dehydration, to build up depleted blood volumes, and to serve as an aid for the administration of medications. An infusion allows a larger volume to be given at a constant rate, depending on the drug to be administered. Infusions can be administered continuously or intermittently. Continuous infusions are used to administer larger


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volumes of solutions over several hours at a slow, constant rate. Intermittent infusions are used to administer a relatively small volume over a shorter time at specific intervals. The Role of the Pharmacy Technician The above reasons demonstrate why the need for compounding pharmacists will continue to grow and why the responsibilities and opportunities for pharmacy technicians are also increasing. As pharmacists become part of a multidisciplinary, multi-skilled team to provide quality patient care, they rely more and more on pharmacy technicians. Technicians have now assumed many of the duties that were once performed by the pharmacist. Once such duty is drug preparation, specifically, compounding and intravenous drug preparation. Pharmacy technicians are actively involved in all aspects of pharmaceutical care. The Scope of Pharmacy Practice Project1 found that 26% of technicians’ time is spent in collecting, organizing, and evaluating information. The second most time-consuming functions (21%) involve preparing, dispensing, distributing, and administering medications. Another survey, of Georgia technicians, identified what percentages of hospital technicians prepare certain sterile dosage forms (Table 1 – 1).2 Table 1 -1 Percentage of Pharmacy Technicians Who Participate in Sterile Compounding by Preparation Type Sterile Dosage Form Technician Participation

in Extemporaneous Compounding %

Unit Dose Inj. 60 Large Volume parenteral Admixtures

81

TPNs 57 IV piggybacks 85 Chemotherapy 31 Narcotic infusions 38 Pharmacy technicians who engage in pharmaceutical compounding must expand their compounding knowledge and be trained at a higher skill level to perform the compounding responsibilities of sterile technique properly and safely.

1 Summary of the final report of the Scope of Pharmacy Practice project. Am J Hosp Pharm, 1994;51:2179-82. 2 Anderson RJ. Pharmacy technician survey in the state Georgia. Ga J Hosp Pharm. 1993:7(summer):179.


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Pharmacy technicians must possess the following basic requirements to participate in sterile compounding:

• A working knowledge of the policy and procedure manuals for compounding, dispensing, and delivering sterile products.

• Adequate training and adherence to hygienic and aseptic techniques. • Access to sufficient reference materials about sterile products. • Knowledge and awareness of the proper methods to store, label, and dispose of

drugs and supplies. • Awareness of how to conduct sterile compounding in an area separate from other

activities. • Knowledge of established procedures for assigning beyond-use dates that exceed

the manufacturer labeled expiration dates. The level of difficulty of preparing the compounding prescriptions is determined by the physical properties of the drug being prescribed and the dosage form desired either by the prescriber or patient. In some cases compounding will be a simple two-step process, whereas in others it will require extensive knowledge and many steps to perform. Sterile compounding is an advanced pharmacy technique that requires proper training of technicians, in addition to their general education. This course is not designed to take the place of a formal education either in institutional settings or academic programs. It is merely a review of compounding practices for pharmacy technicians who are currently working in this area of the pharmacy or for technicians who would like to know more about the processes. Like all good continuing education, it is intended to expand your knowledge and reinforce concepts you already know. One point which must always be remembered, the pharmacist maintains control over all pharmacy activities. The ultimate responsibility rests with the licensed pharmacist.


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II. Sterile Preparation Formulations The objective of formulating and compounding sterile preparations is to provide a dosage form of a labeled drug, in the stated potency, that is safe to use if administered properly.3 This section will explore the professional standards and operating procedures that should be followed during formulation and compounding. The components, containers, and closures also are described, as well as the physiologic and physical norms of preparing formulations for parenteral and ophthalmic use. Stability, incompatibility of drugs, sterilization methods, labeling, documentation, and end preparation evaluation is discussed in later sections. Federal Regulations When formulating and compounding sterile preparations, the technician must follow both state laws and Food and Drug Administration (FDA) regulations. State pharmacy practice acts and board of pharmacy regulations cover these activities. The FDA also regulates formulation and compounding under adulteration, misbranding, and new drug provisions of the Federal Food, Drug, and Cosmetic Act (The Act). Adulteration Section 501(a)(2)(B) of the Act states that a drug is adulterated if “the methods used in, or the facilities or controls used for its manufacture, processing, packing or holding do not conform to current good manufacturing practice.”4 Technicians who compound sterile preparations must meet purported norms (what is implied on the label is true). Purported norms include identity and strength of ingredients, quality, and purity. Failure to ensure purported norms renders the preparation adulterated and misbranded. Professional Standards Bulk, or unformulated, drug substances and added substances, or excipients, must be stored in tightly closed containers under temperature, humidity, and lighting conditions that are either indicated by official monographs or approved by suppliers; also the date of receipt in the compounding facility must be clearly and indelibly marked on each package of ingredient. After receipt by the compounding facility, packages of ingredients that lack a supplier’s expiration date cannot be used after on year, unless either appropriate inspection or testing indicates that the ingredient has retained its purity and quality for use in compounded sterile preparations.

3 Turco SJ. Composition. In: Turco SJ, ed. Sterile Dosage Forms, Their Preparation and Clinical Application, 4th ed. Philadelphia, PA: Lea & Febiger; 1994:1127. 4 Food and Drug Administration. Chap 32, Division of Field Regulatory Guidance. Hospital pharmacies status as drug manufacturer, FDA Guide 7132.06. Washington, DC: Oct 1, 1980.


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Written Procedures Any technician who formulates and compounds sterile preparations should develop and comply with the following written procedures. Pharmacies must have a specifically designated and adequate area (space) for the orderly placement of equipment and materials to be used in compounding. Compounding of sterile preparations should be in a separate and distinct area from non-sterile compounding.5 The technician ensures that the sterile components under his supervision meet acceptable criteria of stability and sterility by:6

• Using the oldest stock first and observing expiration dates.

• Storing components under the environmental conditions stated in the individual monographs and/or in the labeling.

• Observing components for evidence of instability. Although chemical

degradation ordinarily cannot be detected by the naked eye, some physical changes not necessarily related to chemical potency, such as change in color and odor, or formation of a precipitate, or clouding of solution, may alert the technician of a stability problem. If a component has undergone a physical change not explained in the labeling, such a preparation is never to be dispensed.

• Observing components for evidence of lack of sterility. The presence of

microbial contamination in sterile components cannot be detected visually, but color change, cloudiness, surface film, or gas formation is sufficient reason to suspect possible contamination. Evidence that the integrity of the seal has been violated should make the component suspect of microbial contamination.

• Properly handling and labeling preparations that are repackaged, diluted, or mixed

with other products.

• Dispensing the proper container with the proper closure.

• Sterile compounding equipment must be appropriate in design, size, and composition so that surfaces contacting components are not reactive, additive, or adsorptive. These surfaces should not alter the required safety, identity, strength, quality, and purity of the components.

5 National Association of Boards of Pharmacy. Good compounding practices applicable to state licensed pharmacies. Model State Pharmacy Act and Model Rules of the National Association of Boards of Pharmacy. http://nabp.net ; accessed September 9, 2003. 6 Standard operating procedure: Certificates of analysis of materials used for pharmaceutical compounding. Internat J Pharma Compound. 2001 (Mar/Apr): 5:147.


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• As a technician, your work must be checked by a licensed pharmacist. Dispensing pharmacist must inspect and approve or reject all formulas, calculations, substances, containers, closures, and in-process materials.

Technicians who compound batches of parenteral preparations must follow a master formula sheet to reproduce preparations that meet all purported norms. Components Components are any ingredient used in compounding, whether or not they appear in the final preparation (intermediate ingredients). Whenever available, commercially sterile components should be used. Commercial ingredients should be made in an FDA approved facility and meet official compendial requirements (contained in a list). If these requirements cannot be met, an alternative substance must be used. Vehicles Vehicles for most liquid sterile preparations have no therapeutic activity or toxicity. Rather, they serve as solvents or mediums for the administration of therapeutically active ingredients. For parenteral preparations, the most common vehicle is water. Vehicles must meet USP (United States Pharmacopeia) requirements. Water for Injection Water for injection is purified by distillation or reverse osmosis and is free of pyrogens (bacterial substance that can produce fever). Sterile water for injection USP is sterilized and packaged in single-dose containers not exceeding 1000 ml. Bacteriostatic water for injection is sterilized and contains one or more bacteriostatic agents in a container no larger than 30 ml. Sterile water for inhalation is sterilized and packaged in single-dose containers that are labeled with the full name. As implied, this component cannot be used to prepare parenterals. Sterile water for irrigation is sterilized and packaged in single-dose containers with no added substances. Although this component may be packaged in containers larger than 1000 ml, it is not intended for parenteral use. Aqueous Isotonic Vehicles Aqueous isotonic vehicles are often used in sterile preparations. A common vehicle is sodium chloride injection, a 0.9% solution (also known as normal saline) that is sterilized and packaged in single-dose containers no larger than 1000 ml. Bacteriostatic sodium chloride injection is a 0.9% sodium chloride injection that contains one or more bacteriostatic agents in a container no larger than 30 ml. Sodium chloride irrigation also is a 0.9% solution; however, it has no preservatives and may be packaged in a container larger than 1000 ml.


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Other isotonic vehicles include Ringer’s injection, dextrose injection 5%, and lactated Ringer’s injection. None of these components is available in containers larger than 1000 ml. Water-Miscible Solvents A water-miscible solvent is a solution that can be thoroughly mixed with water. Several water-miscible solutions are used as a portion of the vehicle in sterile preparations (co-solvents). These solvents, such as ethyl alcohol, liquid polyethylene glycol, and pro-pylene glycol) dissolve drugs with low water solubility. Preparations compounded with these components are usually administered intramuscularly.7 Examples of drugs in co-solvent formulations include some barbiturates, antihistamines, and cardiac glycosides. Nonaqueous Vehicles Nonaqueous vehicles, such as fixed oils, can be used to formulate parenteral preparations, USP specifies that fixed oils must be vegetable in origin and odorless and also have no rancid taste.8 Examples include peanut, cottonseed, corn, and sesame oils. Some vitamins and hormones can only be solubilized in these oils. Also, oil-based parenterals can only be given intramuscularly. Solutes A solute is a component of a solution. In a solution, the dissolving substance is called the solvent, whereas the dissolved substance is called the solute. Solute chemicals dissolved in vehicles should be USP grade or better since their contaminants can:

• Alter solubility and compatibility of other solutes • Cause catalytic chemical reactions • Cause toxicity of patients

Solutes may be active ingredient or added substances. Added substances can increase stability or usefulness if they are harmless in their administered amounts and do not interfere with therapeutic efficacy. Antimicrobial Preservatives If a concentration is considered bacteriostatic (preventing bacteria from growing and multiplying, but not really killing them) a antimicrobial preservative may be added. Some preservatives, however, have innate toxicity within these concentrations and are used mostly in ophthalmics and seldom in injectables. Examples include phenylmercuric nitrate 0.01%, benzalkonium chloride 0.01%, and phenol 0.5%).

7 Avis KE. Levchuk JW. Chapter 41. Parenteral preparations In: Gennaro AR, ed, Remington: the Science and Practice of Pharmacy, 20th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000. p 780-806. 8 United States Pharmacopeial Convention. Chapter 1 Injections. In: United States Pharmacopeia 27th rev./National Formulary 22nd.


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Benzyl alcohol (usually 0.9%) is commonly used in injectables. In oleaginous (oily) preparations, no antimicrobial is highly effective. An antimicrobial agent may be effective in one formula of ingredients but not in another. To select a preservative, an appropriate reference should be consulted and its effectiveness should be verified. USP provides a test for the efficacy of antimicrobial preservatives. pH Buffers Buffering agents stabilize a solution against degradation. Buffering agents are formulated at the lowest concentration needed for stability so that they do not disturb the body’s natural pH. Acid salts such as citrates, acetates, and phosphates are commonly used as buffers. Antioxidants Antioxidants help to prevent oxidation of the component drug. Oxidation is defined as the interaction between oxygen molecules and all the different substances. Technically, however, with the discovery of electrons, oxidation came to be more precisely defined as the loss of at least one electron when two or more substances interact. Those substances may or may not include oxygen. This can work to degrade the drug/drugs with in the solution. The most common antioxidants are the sodium and potassium salts of meta-sulfite and sulfite ions. However, the choice of salt depends on the pH of the system to be stabilized. Metabisulfite is used for low pH values, bisulfite for intermediate pH values, and sulfite for high pH ranges. Chelating Agents Chelating agents enhance the effectiveness of antioxidants. They form complexes with trace amounts of heavy metals, thereby eliminating the catalytic activity of metals during oxidation. The most commonly used chelating agent is edenate sodium. Tonicity Agents The tonicity agents are used to adjust the composition of the formulation to the desired isotonic range. Some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. Solubilizers When performing sterile compounding, technicians must know the solubility characteristics of drug substances, since they must possess some solubility to elicit a therapeutic response. Polyethylene glycols 300 and 400, and propylene glycol, glycerin, and ethyl alcohol frequently are used. However, toxic levels of these solvents must be avoided as well as amounts that make the preparation too viscous (thick or sticky) for parenteral use.


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Emulsifiers Some drugs are minimally soluble in water. Emulsifiers are used to suspend tiny oil globules in water to create an emulsion that contains a uniformed concentration of the active drug throughout the volume of the liquid. One example is a soybean oil and water emulsion manufactured with egg yolk. An example of an active drug is propofol that is dissolved in soybean oil which is emulsified into a concentration. Containers Containers are defined as “that which holds the article and is or may be indirect contact with the articles. The closure is part of the container.”9 All containers for sterile preparations must be sterile, free of both particulate matter and pyrogens. These containers should not interact physically or chemically with formulations to alter their required strength, quality, or purity. Containers must also permit inspection of their contents. Single or Multiple Dose Containers Sterile, single-dose containers are intended for parenteral, inhalation, irrigation, octic, and ophthalmic administration. Examples are prefilled syringes, cartridges, ampuls, and vials (when labeled as single-use). Multiple-dose containers permit withdrawal of successive portions of their contents without changing the strength, quality, or purity of the remaining portions. Sterile, multiple-dose containers may be used for preserved parenterals, ophthalmics, and octics. Glass Glass is the most popular material for sterile preparation containers. USP classifies glass as Type I (borosilicate glass), Type II (soda-lime-treated glass), Type III (soda-lime glass), or NP (soda-lime glass unsuitable for parenteral containers). Different glass types vary in their resistance to attack by water and chemicals. For pharmaceutical containers, glass must meet the USP test for chemical resistance. Because most pharmacy personnel do not have the time or facilities to perform glass chemical interaction studies, they should use only Type I glass to minimize sterile preparation compatibilities. 9 United State Pharmacopeial Convention. General notices and requirements. In: United States Pharmacopeia, 27th.


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Plastic Plastic polymers can be used as sterile preparation containers but present three problems:

1. Permeation of vapors and other molecules in either direction through the container.

2. Leaching of constituents from the plastic into the preparation.

3. Sorption of drug molecules onto the plastic.

Plastics must meet USP specifications for biological reactivity and physiochemicals. Most plastic containers do not permit ready inspection of their contents because they are unclear. Most plastics also melt under heat sterilization. Closures Rubber closures must be rendered sterile, free from pyrogens and surface particles. To meet these specifications, multiple washings and autoclavings are required. An autoclave heats sterilizing solutions above their boiling point to sterilize medical instruments. Closures are made of natural, neoprene, or butyl rubber. Thus, the rubber sealing of a vial or the plug in a syringe is a complex material that can interact with the ingredients of a formula. Rubber closures also are subject to coring. Therefore, you should consult the literature standards when selecting a rubber closure for sterile preparations. Parenteral Formulations Pharmacists and technicians will compound a wide variety of sterile formulations in different settings. These formulations will include products administered by injection, such as:

• Intravenous (IV) – medication is injected directly into the vein • Intramuscular (IM) – medication is injected directly into a large muscle • Subcutaneous (SC) – also know as hypodermic injection; medication is injected

into the tissue under the skin • Intradermal (ID) – medication is injected into the substance of the skin • Intrathecal – medication is injected into the spinal canal • Epidural – medication is injected through a catheter placed in the “epidural

space”, which is the outermost part of the spinal canal. There are also other sterile products, which may be administered by the following routes:

• Inhalation – medication is inhaled through the mouth • Intranasal – medication is inhaled through the nose • Ophthalmic – medication administered through the eye


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Parenteral preparations are classified into six general categories:10

1. Solutions read for injection.

2. Dry, soluble preparations ready to be combined with solvent before use.

3. Suspensions ready for injection.

4. Dry, insoluble preparations ready to be combined with a vehicle before use.

5. Emulsions.

6. Liquid concentrates ready for dilution prior to administration. Most compounded sterile parenteral preparations are aqueous solutions (first category). Other categories usually require the equipment and expertise of a licensed pharmacist. In addition to using appropriate vehicle, solvent, and container, you must ensure that the final aqueous solution maintains the appropriate physiological and physical norms. Large Volume Parenteral Solutions Large-volume parenteral (LVP) solutions are commonly stored in plastic or glass. Solutions for injection must be sterile, and contamination must be prevented by using aseptic techniques. LVP solutions are available in a variety of sizes (250 mL, 500 mL, 1000 mL). Examples of LVP solutions with additives, manufactured in standard concentrations, include:

• Aminophylline • Dopamine • Lidocaine • Nitroglycerin • Potassium

In some cases, the preparation of LVPs by the pharmacist or technician depends on the drug and intended use. The preparation of LVPs in the pharmacy must always follow aseptic technique (discussed later). Common examples of LVPs in use include:

• Dextrose Injection, USP • Dextrose and Sodium Chloride Injection

10 Avis KE, Levchuk JW. Chapter 41. Parenteral preparations. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy, 20th ed. Baltimore, MD: Lippincott Williams & Wilkins: 2000. p. 780-806.


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• Amino Acid Injection • Mannitol Injection, USP • Ringer’s Injection, USP • Lactated Ringer’s Injection, USP • Sodium Chloride Injection, USP

These solutions are usually administered by intravenous infusion to replenish body fluids, electrolytes, or provide nutrition. They are usually administered in volumes of 100 mL to 1 liter amounts (and more) per day by slow intravenous infusion with or without controlled-rate infusion systems. When a patient is being maintained on parenteral fluids for several days, simple solutions providing adequate amounts of water, dextrose, and small amounts of sodium and potassium generally suffice. When patients are unable to take oral nutrition or fluids for several days or weeks, solution of higher caloric content may be used (total parenteral nutrition). These admixtures are very useful for:

• Patients receiving chemotherapy • Anorexic patients • Pediatric patients

Small-Volume Parenteral Solutions Small-volume parenteral (SVP) solutions can be either directly administered to a patient or added to another parenteral formulation. Additive parenteral solutions are called “admixtures.” SVP solutions can be supplied in different forms:

• Prefilled syringes • Glass or plastic vials sealed with a rubber closure • Ampules • Plastic minibags or “piggybacks”

Physiological Norms When injectable solutions are formulated, every effort should be made to mimic the body’s normal serum values for pH and tonicity and to create a pyrogen-free preparation. pH The term pH is used to describe the degree of acidity of a solution. pH values range from 0 to 14, with values below 7 representing greater acidity of the solution, while values above 7 represent less acidity or greater alkalinity. A solution having a pH of 7 is neither acid, nor alkaline; it is considered neutral. Plasma in our body is about 7.4, and solutions should try to stay around that number, pH is another characteristic that cannot be seen, but can be tested after it is prepared. Normal human serum pH, a logarithmic measure of the hydronium ion concentration in solution, is 7.4. Drugs that are acids or bases or their


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salts sometimes must be buffered to a pH near normal (e.g., 3-8) to prevent pain or tissue damage. Tonicity Another characteristic that also cannot be seen is isotonicity. An isotonic solution has the same concentration as red blood cells. Isotonic IV solutions minimize patient discomfort and damage to red blood cells. Stinging caused by either a hypertonic (shrinking of red blood cells) or hypotonic (swelling of red blood cells) solution is not experienced with an isotonic solution. IV solutions should be as close to isotonic as possible. A good reference point to remember is that 0.9 percent sodium chloride injection and 5 percent dextrose injection are both approximately isotonic. Any chemical dissolved in water exerts a certain osmotic pressure, which is the pressure exerted by a solution necessary to prevent osmosis into that solution when it is separated from the pure solvent (i.e., a solute concentration related to the number of dissolved particles per unit volume).11 Blood has an osmotic pressure corresponding to sodium chloride 0.9%; thus, its common name is normal saline. Normal saline is said to be “isosmotic” with blood ad other physiologic fluids. In the medical setting, the term “isotonic” is used synonymously with isosmotic. A solution is isotonic with a living cell if no net gain or loss of water is experienced by the cell and no other change is present when the cell contacts that solution. Very hypotonic (containing a low concentration of solute relative to another solution) IV preparations can cause hemolysis (the destruction or dissolution) of red blood cells. Very hypertonic (contains a high concentration of solute relative to another solution) injections can damage tissue and cause pain on injection. The greater the volume of solution to be injected, the closer the parenteral preparation should be to isotonicity. Pyrogenicity Pyrogens are contaminants that are unacceptable in final compounded sterile preparations. Pyrogens are fever-producing endotoxins from bacteria. As large proteins, pyrogens are not removed by normal sterilization procedures and can exist for years in aqueous solution or dried form. The sources of pyrogens in sterile preparations are:

• Aqueous vehicles • Equipment • Containers and closures • Chemicals used as solutes • Human touch

11 Reich I, Poon CY. Sugita ET. Chap. 18. Tonicity, osmoticity, osmolality and osmolarity. In: Gennaro AR, ed. Remington: The Science and Practice of Pharmacy. 20th ed. Baltimore, MD: Lippincott Williams & Wilkins; 2000. p. 246-62.


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If sterile water for injection is the vehicle, the risk of pyrogens in water is eliminated. Equipment, containers, and closures can be decontaminated by dry heat or by washing or soaking with acids and bases. Touch contamination is most easily prevented with proper aseptic technique (discussed later). Physical Norms Particulates Parenteral solutions must be free of particulate matter – mobile, undissolved solids not intended for sterile preparations. Examples include lint, cellulose12 and cotton fibers, glass, rubber, metals, plastics, undissolved chemicals, rust, diatoms, and dandruff. Sources of particulate matter are:

• Vehicles and solutions • Environment • Containers and closures • Personnel

A careful choice of components, containers, and closures can minimize particulate contamination. Also, filtration can remove particles and bacteria from sterile preparations. Stability Stability of parenteral preparations must be assured so that patients receive the intended dose. Hydrolytic (decomposition of a chemical compound) and oxidative degradations are the most common forms of instability but rarely show as cloudiness or color changes. The rate of hydrolysis13 may be affected by storage temperature or pH of the solution. Oxidation is affected by temperature, pH, exposure to light, oxygen concentration of the solutions, and impurities. Because numerous factors affect the stability of drug molecules, parenterals from bulk chemicals should use a short beyond the use date. The choice of packaging also is important for perenteral drug stability. Impurities Heavy metals (like lead and mercury) are also to be minimized in sterile preparations. Heavy metals can be toxic and can catalyze the degradation of active ingredients and preservatives. Introduction of these impurities is most likely when non-sterile; raw materials are used in compounding. 12 Cellulose is one of many polymers found in nature. Wood, paper and cotton all contain cellulose. 13 Hydrolysis is a chemical reaction during which one or more water molecules are split into hydrogen and hydroxide ions. It is the type of chemical reaction that is used to break down certain polymers, often increasing the strength or pH.


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III. Sterile Preparation Facilities and Equipment

The following equipment is essential for sterile compounding:

• Syringes and needles • Alcohol pads • Large-volume parenteral (LVP) solutions. • Small-volume parenteral (SVP) solutions • Ampules or vials • Laminar airflow hoods • Refrigerators (with thermometers) • Freezers • Sinks with hot and cold water • Automated compounding devices • Disinfectant cleaning solutions • Disposable, lint-free towels or wipes • Disposable gowns, caps, masks, and sterile gloves • Sharp containers • Computer systems • Shelving • Carts • Stainless steel furniture

Laminar Flow Hoods Sterile products should be prepared in Class 100 environments, which can contain no more than 100 particles (a small piece or portion of anything, such as microorganisms) per cubic foot. These particles are 0.5 microns (or larger) in size. Laminar flow hoods are commonly used to achieve a Class 100 environment. Laminar flow hoods are designed to reduce the risk of airborne contamination during the preparation of IV admixtures by providing an ultra-clean environment. The most important part of a laminar flow hood is a high-efficiency, bacteria-retentive filter, commonly called a HEPA (high-efficiency particulate air) filter. Room air is taken into the unit and passed through a pre-filter to remove relatively large contaminants such as dust and lint. The air is then compressed and channeled up behind and through the HEPA filter, where virtually all bacteria are removed. The purified air then flows out over the entire work surface in parallel lines at a uniform velocity. The orientation of the direction of airflow can be horizontal or vertical. Great care must be exercised to prevent cross-contamination from one operation to another, especially with horizontal laminar airflow. Vertical laminar airflow hoods are used to prepare drugs for chemotherapy.


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Vertical Laminar Airflow Hoods With vertical flow, room air enters at the top of the unit and is channeled through the bacteria-retentive filter (which forms the ceiling of the unit) and down vertically across the work surface area. As with the horizontal flow hood, this type of vertical flow hood is not suitable for chemotherapy drugs. Although they protect the drug product from microbial contamination, they do not protect personnel or the environment from the hazards of the drug agents. These laminar flow hoods blow air across the work surface toward the operator and into the work environment. Drug particles or aerosols of these hazardous agents can easily contaminate both workers and the work environment. Biological Safety Cabinets Since horizontal laminar-airflow hoods blow air toward the operator, vertical laminar airflow hoods are preferred when working with hazardous substances. Vertical flow hoods are part of a family of equipment called biohazard cabinets or biological safety cabinets. Three types of biohazard cabinets are available:

1. Class I cabinets have a HEPA filter on their exhaust outlet but not for inward airflow. The protect personnel and the environment but do not prevent contamination of compounded preparations. This class of hoods has no application in compounding sterile preparations.

2. Class II cabinets have HEPA filtered inward air for protection of compounded

preparations and HEPA filtered exhaust air to protect personnel. They are suitable for compounding sterile preparations. Class II cabinets are classified according to how their exhaust air is vented.

a. Type A cabinet:

i. Maintains a minimum calculated average inflow air velocity of 75 ft/min through the work area access opening.

ii. Has HEPA filtered air from a common plenum (some air is exhausted from the cabinet and some is supplied to the work area).

iii. May have air exhausted back into the controlled area. iv. May have positive-pressure-contaminated ducts and plenums.

b. Type B cabinet exhausts some or all air outside the controlled area. These cabinets are further classified as B1, B2, or B3:

i. B1 cabinet: 1. Maintains an average air velocity of 100 ft/min. 2. Has HEPA filtered down flow air composed largely of

uncontaminated, recirculated inflow air? 3. Exhausts most contaminated air to the atmosphere through

a dedicated duct and HEPA filter 4. Has all contaminated ducts and plenums under negative

pressure?


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ii. B2 cabinet, sometimes called a total exhaust cabinet, differs from B1 cabinet in that it:

1. Has all down flow air drawn through a HEPA filter from the controlled area or outside, not recirculated from the cabinet.

2. Exhausts all air to the atmosphere after HEPA filtration, not to recirculation in the cabinet controlled area.

iii. B3 cabinet, sometimes referred to as a convertible cabinet: 1. Has HEPA filtered air that is a portion of the mixed down

flow and inflow air from a common exhaust plenum? 2. Exhausts all air to the atmosphere after HEPA filtration. 3. Can be converted from a Type B to a Type A cabinet if

desired.

3. Class III cabinets are totally enclosed, vented, and gastight units. Operations are conducted through attached rubber gloves, and the cabinet is maintained under negative pressure. These cabinets have limited applications in the preparation of sterile products and are intended for the handling of extremely hazardous substances

A biological safety cabinet functions by having air taken into the unit at the top, where it passes through a prefilter to remove large contaminants. Air then passes through a HEPA filter and is directed down toward the work surface, just as with a vertical laminar flow hood. The filter forms the ceiling of the work area in the biological safety cabinet and removes bacteria to provide ultraclean air. Unlike the mechanism in a vertical laminar flow hood, however, as air approaches the work surface, it is pulled through vents at the front, back, and sides of the unit. A major portion of the contaminated air is recirculated back into the cabinet, and a minor portion is passed through a HEPA filter before being exhausted into the room. As just described, biological safety cabinets are of two basic types A Class II type A, which is what we just described above, represents the minimum recommended environment for preparing chemotherapy agents. Class II, type B biological safety cabinets have greater intake flow velocities and are vented outside the building rather than back into the room. This type of safety cabinet is preferred, but he need to vent the filtered air outside can carry with it a substantial construction cost. It is important that biological safety cabinets run continuously. If turned off for any reason, such as for maintenance or changing the HEPA filter, the biological safety cabinet must be thoroughly cleaned with a detergent, and the exhaust area must be covered with impermeable plastic and sealed to prevent any contaminants from escaping the unit.


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Hood Selection. Vertical laminar airflow hoods are the preferred choice. These cabinets prevent cumulative exposure to potentially toxic medications, especially if the staff routinely compound hazardous preparations for a long time. When sterile preparations are compounded, aerosols can form and be blown toward the operator using a horizontal hood. Long-term exposure to cytotoxic agents as well as other drugs, especially antibiotics, is a great concern. Vertical airflow hoods minimize such exposure. The disadvantage of vertical airflow versus horizontal airflow hoods are expense and ease of use. Class II hoods are more expensive than horizontal hoods and can be very costly to install due to venting requirements. Furthermore, vertical airflow hoods generally are more restrictive and may slow workflow. Laminar Airflow Hood Basics A laminar flow hood has three basic functions. The first is to provide clean air in the working area. This is done by passing room air through a bacteria-retentive filter to provide a continuous flow of clean air in the work area. Second, the constant flow of air out of the laminar flow hood prevents room air from entering the work area. Last, the air flowing out suspends and removes contaminants introduced in the work area by material (such as IV bags, syringes, and drug packaging) or personnel. Thus, the laminar flow hood provides an environment virtually free of airborne contaminants, in which procedures can be safely performed. Laminar flow hoods may be used in the pharmacy to perform the following procedures:

• Preparations of IV admixtures • Preparations of ophthalmic solutions • Reconstitution of powdered drugs • Filling unit dose syringes • Preparation of miscellaneous sterile products.

Laminar flow hoods come in various sized and models. One model, called a console model, sits on the floor. The other common model is called a bench or countertop model, because it sits on top of the counter, and the space underneath it can be used for storage space. Both the console and bench models are available with vertical rather than horizontal airflow. Laminar airflow hoods are usually kept running continuously. If the hood is turned off, it is recommended to run for at least 30 minutes before using the work surface area in order to replace the room air with clean, filtered air. Laminar flow hoods should be inspected and certified every six months to assure that the HEPA filter is intact, unclogged, and has no holes in it. The prefilters in the hoods should be changed monthly.


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It is important for pharmacy technicians to keep their hands within the cleaned area of the hood as much as possible, and to not touch their hair, face, or clothing. Only materials essential for preparing the sterile products should be placed in the laminar airflow workbench or barrier isolator. Cleaning Laminar Airflow Hoods Cleaning the laminar airflow hoods may be done with a non-shedding wipe or sponge dampened with Water for Injection, with or without mild detergent. This should be followed by:

• Seventy percent isopropyl alcohol (or another appropriate disinfecting agent) should be used to clean all interior working surfaces before each use.

• A clean, lint-free cloth should be moved in a side-to-side motion, beginning at the rear and moving toward the front of the LAH.

• The walls of the LAH also must be cleaned from top to bottom with 70 percent isopropyl alcohol.

• This procedure should occur often throughout the compounding period and whenever the work surface becomes dirty.

• Because some materials require water to remove them, these materials may be first cleaned off with water, followed by the alcohol or other disinfecting agent.

• If the LAH has Plexiglas sides, they should be cleaned with warm, soapy water instead of alcohol.

• Spray bottles of alcohol or other disinfecting agents should never be used in the LAH.

• Once it is applied, alcohol should be allowed to air dry. Needles A needle consists of two parts: the shaft and the hub. The shaft is the long, slender stem of the needle that is beveled (diagonal cut) at one end to form a point. The hollow bore of the needle shaft is known as the lumen. At the other end of the needle is the hub, to which a syringe can be attached (Figure 3-1).


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Needle size is designated by length and gauge. The length of a needle is measured in inches from the juncture of the hub and the shaft to the tip of the point. Needle lengths range from ⅜ inch to 3 ½ inch or longer. The gauge of a needle, used to designate the size of the lumen, ranges from 27, the finest, to 13, the largest. The finer the needle, the higher the gauge number will be. In some disposable needles, the gauge is designated by color of the hub. One factor in choosing the needle size is the thickness (viscosity) of the injectable solution. A fine needle with a relatively small lumen may be acceptable for most solutions, but a needle with a larger lumen and a smaller gauge number may be needed for more viscous solutions. Another factor in selecting the proper needle is the nature of the rubber closure to be penetrated. A fine needle with a smaller lumen may be preferred for rubber closures that “core” easily, meaning that part of the rubber closure gets carried into the drug solution when the needle penetrates the rubber closure. Needles are sent from the manufacturer individually packaged in paper and plastic overwraps. Sterility is guaranteed as long as the package remains intact. Therefore, damaged packages should be discarded. The hub of the needles should not be touched when removing the over-wrap.


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A needle shaft usually is metal and is lubricated with a sterile silicone coating for smooth, easy access into rubber closures. Therefore, needles should never be swabbed with alcohol or touched. They should be handled by their protective covers only, and these covers should be left in place until the needles or syringes are used. Used needles should not be recapped, but rather discarded into a sharps container while still attached to the syringe. Filter needles are similar to other needles, except that they have a filter in the hub to catch any particles from an ampule or vial and are used to vent small-volume vials. Syringes The two basic parts of a syringe are the barrel and the plunger (Figure 3-1). The barrel is a tube that is open at one end, tapering into a hollow tip at the other end. The open end is extended radically outward to form a rim, or flange, to prevent the barrel from slipping through the fingers during manipulation. The plunger is a piston-type rod with a slightly cone-shaped tip that passes inside the barrel of the syringe. The other end of the plunger is shaped into a flat knob for easy manipulation. The plunger must be able to move freely throughout the barrel, yet its surface must be so close to the barrel that the fluid cannot pass between, even when under considerable pressure. The tip of the syringe provides the point of attachment for a needle. The tip may be tapered to allow the needle hub to be slipped over it and held on by friction. When this method is used, the needle is reasonably secure, but it may slip off if not properly attached or is considerable pressure is used to inject the solution. Locking devices have been developed to secure the needle more firmly on the tip of the syringe. These devices incorporate a collar with a circular internal groove into which the needle hub is inserted. A half-turn locks the needle in place. This method is especially valuable when pressure is required. Graduation lines on the barrel of the syringe indicate the volume of solution inside. Accurate readings are more easily made if the color of the tip of the plunger is different from that of the syringe itself. Syringes are disposable and have a capacity range of 1 – 60 ml. Graduation lines may be in milliliter, depending on the capacity of the syringe; for example, the larger the capacity of the syringe, the larger is the interval between graduation lines. Special purpose syringes, such as insulin syringes, have graduation lines in both milliliters and insulin units to reflect their intended use. In the selection of an appropriate syringe, as a rule the capacity of the syringe should be the next size larger than the volume to be measured. For example, a 3 ml syringe should be selected to measure a 2.3 ml dose, or a 5 ml syringe to measure a 3.8 ml dose. In this way, the graduation marks on the syringe will be in the smallest possible increments for the dose measured. Syringes should not be filled more than three-quarters of capacity.


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Sterile, disposable syringes are discarded after one use and have the same advantages as disposable needles. Although syringes today are made of plastic because it cost less, glass syringes can still be bought for drugs that are incompatible with plastic. Syringes and needles need to be disposed of in a sharp container. Do not recap needles after they have been used. Some common doses of frequently used or emergency drugs come in prefilled syringes. Prefilled syringes eliminate the need to measure doses, thus saving time. Prefilled syringes are commonly seen in emergency carts or are used in emergency rooms when it is critical to get the medication to the patient as quickly as possible. Most prefilled syringes are supplied in a syringe that does not have a plunger. This is to prevent the drug from accidentally squirting out if pressure were applied to the plunger when being stored or transferred. Vials Injectable medications usually are supplied in vials or ampuls, each requiring different techniques for withdrawal of the medication. A vial is a plastic or glass container with a rubber closure secured to its top by a metal ring. Multidose vials contain preservatives that allow their contents to be used after the rubber stopper is punctured. This stopper usually is protected by a flip-top cap or metal cover, but most caps do not guarantee sterility of the rubber closure. Therefore, all vials should be swabbed with 70% isopropyl alcohol before needle entry and left to dry. The correct technique is several firm strokes in the same direction over the rubber closure, using a clean, unused portion of a swab on each pass. The swabbing is effective in two ways:

• The alcohol acts as a disinfecting agent. • The physical act of swabbing in one direction remove particles from the vial

diaphragm. Bottles or trays of isopropyl alcohol should not be used. Because alcohol may harbor resistant spores, repeated use of non-sterile tray or bottle could promote this problem. Individually packaged swabs are sterile from the manufacturer. When vials are pierced with needles, cores or fragments of the rubber closure can form. To prevent this problem, the needle should be inserted so that the rubber closure is penetrated at the same point with both the tip and heel of the bevel. This noncoring technique is accomplished by first piercing the rubber closure with the bevel tip and then applying lateral (away from the bevel) and downward pressure to insert the needle. Vials are closed-system containers, since air or fluid cannot pass freely in or out of them. Therefore, the volume of fluid to be removed from a vial should be replaced with an equal volume of air to avoid creating a vacuum. But this technique should not be used with drugs that produce gas when they are reconstituted (e.g., ceftazidime).


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If the drug within a vial is in a powered form it must be reconstituted first. The desired volume of the diluent (e.g., sterile water for injection) is injected into the vial. As the diluent is added, an equal volume of air must be removed to prevent a positive pressure from developing inside the vial. This procedure may be accomplished by allowing air to flow into the syringes before removing the needle from the vial. Although most drugs dissolve rapidly when shaken, a technician must be sure that a drug is completely dissolved before proceeding. Ampuls Ampuls are composed entirely of glass. Once an ampul is broken, it becomes an open-system, single-use container. Since air or fluid may now pass freely in and out of them, the volume of fluid removed does not have to be replaced with air. Before an ampul is opened, any solution visible in the top portion (head) should be moved to the bottom (body) by one of the following methods:

• Swirling the ampul in an upright position. • Tapping the head with one’s finger • Inverting the ampul and then quickly swinging it into an upright position.

To open an ampul properly, its neck should be cleansed with an alcohol swab and the swab should be left in place. This swab can prevent accidental cuts to the fingers as well as spraying of glass particles and aerosolized drug. The head of the ampul should be held between the thumb and index finger of one hand, and the body should be held with the thumb and index finger of the other hand. Pressure should be exerted on both thumbs, pushing away from oneself in a quick motion to “snap” the ampul open at the neck. Ampuls should not be opened toward the HEPA filter of the laminar airflow workbench or toward other sterile products within the workbench. Extreme pressure may result in crushing the head between the thumb and index finger. Therefore, if the ampul does not open easily, it should be rotated so that pressure on the neck is at a different angle. To with draw medication from an ampul, it should be tilted and the bevel of the needle placed in the corner space (or shoulder) near the opening. Surface tension should keep the solution from spilling out of the tilted ampul. The syringe plunger is then pulled back to withdraw the solution. The use of a filter needle eliminates glass or paint chips that may have fallen into a solution from being drawn up into the syringe. Sometimes, a medication (e.g., a suspension) may need to be withdrawn from an ampul with a regular needle; a filter needle should then be used to push the drug out of the syringe. In all cases, the same filer needle should not be used for both withdrawing and injecting, since it will mollify the filtering effort.


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IV Bags Plastic bags are used for diluting a solution and are the most common way of administering intravenous medications to patients. Plastic bags are available in many different sizes, with 50, 100, 250, 500, and 1000 ml being the most common. Special bags for compounding parenteral nutrition are available in 2,000 ml and 3,000 ml sizes. Some IV bags are made of PVC (polyvinyl chloride). More expensive than plastic bags, these bags are used for specific drugs (like Taxol) that can adhere to the plastic of the non-PVC IV bags. At the top of the bag is a flat plastic extension with a hole to allow it to be hung on an administration pole. At the other end of the bag are two ports of about the same length. The administration set port has a blue plastic cover that serves to maintain the sterility of the port. The cover is easily removed by pulling on it. Once it is pulled off, the sterile port of the administration set is exposed. Solution will not drip from the plastic bad at this point because a plastic diaphragm about ½ inch inside the port seals in the liquid. The spike of the administration set is inserted into the port, puncturing the inner diaphragm to allow the solution to flow from the flexible plastic bag into the administration set. When the solution has filled the administration set (this process is called “priming” the set), make sure to clamp the administration set so that the solution does not leak out. Once the inner diaphragm is punctured, it is not resealable. The other port is the medication port. It is covered by a protective rubber tip. Medication is added to the solution through the medication port by means of a needle and syringe. The rubber tip is self-sealing, thus preventing solution from leaking when the needle punctures the tip. Approximately ½ inch inside this port is a plastic diaphragm that must be punctured for solution to enter the bag. The inner diaphragm is not self-sealing when punctured by a needle, so the rubber tip must stay attached to the bag. Graduation marks to indicate the volume of solution infused are located on both sides of the front of some plastic bags at 25-100 ml intervals, depending on their capacity. When you place a label on a plastic bag, it does not matter which side of the bag you place the label; however, many institutions place the label on the printed side of the bag, beneath the solution name, and offset slightly to one side so that the graduation marks near the side can still be read. This procedure has the advantage of providing a convenient cross-check between the actual solution and the name appearing on the admixture label. Some IV solutions, such as 5 percent dextrose injection and 0.9 percent sodium chloride injection, are available in minibags, or piggyback bags. These bags typically hold 50 ml or 100 ml of solution and are used to administer drugs intermittently rather than continuously. The plastic bag system is completely closed to air. It does not depend on air to displace the solution as it leaves the bag. The bag collapse as the solution is administered, so a vacuum is not created inside.


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IV. Aseptic Technique

Sterility Sterility is the freedom from bacteria and other microorganisms. Solutions to be injected must be sterile. A product is either sterile or not sterile; products cannot be partially sterile. Sterility cannot be visibly seen, but proper aseptic technique can maintain the sterility of solutions, drugs, and supplies during preparation. While the importance of sterility was first recognized in the late 1800s, the concept of aseptic technique was not described until years later.14 The need to sterilize solutions and equipment became accepted in the 1920s and 1930s.15 Moreover, the development of sterile and pyrogens-free products and their applications continues today. In the late 1960s improperly manufactured and compounded IV solutions caused a rash of complications in patients.16 Following these incidents, the National Coordinating Committee on Large Volume Parenterals (NCLVP) published recommendations for techniques to compounding sterile preparations for pharmacist and other professionals. A training manual for IV admixture personnel, largely intended for pharmacy technicians who prepare sterile products, was first published in 1972. This manual was revised in 1990. The American Society of Health-System Pharmacists (ASHP) published a videotape and study guide on aseptic technique. This combination product was the first comprehensive guide to aseptic technique with practical application to many pharmacy settings. ASHP and the United States Pharmacopeial Convention (USP) publish guidelines regarding aseptic technique and further established practice standards for compounding sterile preparations. ASHP’s Manual for Pharmacy Technicians, third edition also includes a chapter on technician training as it relates to aseptic technique and compounding sterile preparations. Aseptic Technique: Overview Aseptic technique is carrying out a procedure under controlled conditions in a manner that minimizes the chance of contamination. Contamination can be caused by the following factors:

• Environment – controlling the air where the compounding is being performed. • Equipment – all objects that come in contact with the drug(s) must be sterile. • Personnel – touch contamination is the most frequent cause of contamination.

14 Griffenhagan GB. The history of parenteral medication. BullParenter Drug Assoc. 1962; 16:129. 15 Masson AH. The early days of intravenous salin. PharmJ. 1976; 217:571-80. 16 Maki DG, Goldmann DA, Rhame FS. Infection control in intravenous therapy. Ann Intern Med. 1973:79:867-87.


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The preparation of sterile drug compounds requires the utmost diligence to ensure final product integrity and sterility. Sterile products must be prepared with aseptic technique in a class 100 environment containing no more that 100 airborne particles of a size 0.5 micron and larger, per cubic foot of air. As discussed earlier, such an environment exist inside a certified horizontal or vertical laminar flow hood, a class 100 clean room, and a barrier isolator. A barrier isolator is a closed system made up of four solid walls, an air-handling system, and a transfer and interaction compartment.

Aseptic technique refers to the procedures used during preparation that maintains the sterility of pharmaceutical dosage forms. Sterilization is an essential concept in the preparation of sterile pharmaceutical products. Its aim is to provide a product that is safe and that eliminates the possibility of introducing infection. Sterilization is a process used to destroy or eliminate viable microorganisms that may be present in or on a particular product or package. The process requires an overall understanding and control of all parts of the preparation for use of a particular product. Aseptic technique describes the methods used to manipulate sterile products so that they remain sterile. Technique is a separate element in compounding of sterile preparations, independent from equipment and the environment. Proper technique does not eliminate the need for good equipment and a proper environment. Conversely, good equipment and an ideal environment do not change the need for a good technique. Equipment and Environment The laminar airflow hood workbench (LAFW) is considered critical equipment for good aseptic technique. Issues related to handling and compounding of cytotoxic agents and using a biological safety cabinet are not addressed here, because they were discussed in a previous section. The critical principle in the use of LAFWs is that nothing should interrupt the airflow between the high-efficiency particulate air (HEPA) filter and the sterile object. This aseptic compounding space is referred to as the “critical area” and any foreign object can increase turbulence within this area. Contaminants from the foreign object may be blown or carried onto the sterile injection port, needle, or syringe. Large materials placed within the LAFW also can disturb the patterned flow of air from the HEPA filter. This “zone of turbulence” created behind an object could extend outside the workbench, pulling or allowing contaminated room air into the aseptic environment. When laminar airflow is accessible to all sides of an object, the zone of turbulence extends approximately three times the diameter of that object. When airflow is not accessible on all sides (e.g., adjacent to a vertical wall), a zone of turbulence may extend six times the diameter of an object. For these reasons, objects should be at least 6 inches from the sides and front edge of the workbench, without blocking air vents and without obstructing airflow. Hands also should not block airflow.


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The following are general principles for proper operation of LAFWs:

1. All aseptic manipulations should be performed at least 6 inches within the LAFW. This distance prevents reflected contamination from the technician’s body and “back-wash” contamination from turbulent air patterns developing at the LAFW-room air interface.

2. A LAFW should operate continuously. If the LAFW is turned off, it should not

be used for a specified time when reactivated, depending on the manufacturer’s recommendations (e.g., 30 minutes). This downtime allows all room air to be purged from the critical area.

3. Before use, all interior working surfaces of the LAFW should be cleaned with

70% isopropyl alcohol or another disinfecting agent and a clean, lint-free non-shedding cloth. Cleaning should be performed from back to front so that contaminants are moved away from the HEPA filter. Throughout the compounding period, the LAFW should be cleaned often. Some materials are not soluble in alcohol and may initially require water for removal. To avoid damage, Plexiglas sides should be cleaned with warm, soapy water rather than alcohol.

4. Nothing should touch the HEPA filter, including cleaning solution, aspirate from

syringes, and glass from ampuls. Ampuls should not be broken directly toward the filter.

5. A LAFW should be positioned away from excess traffic, doors, air vents, fans,

and air currents capable of introducing contaminants.

6. Hand and wrist jewelry should not be worn; jewelry may introduce bacteria or particles.

7. Actions such as talking and coughing should be directed away from the critical

area, and any unnecessary motion should be avoided to minimize airflow turbulence.

8. Only objects that are essential to compounding sterile preparations should be

placed in the LAFW, no paper, pens, labels, or trays.

9. LAFWs should be tested and certified by qualified personnel every 6 months, whenever the LAFW is moved, and if filter damage is suspected. Tests can certify airflow velocity and HEPA filter integrity.

10. Food and drink should not be permitted within the aseptic preparation area

(controlled or critical area).


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Although the LAFW provides a sterile environment, the strict aseptic technique must be used to ensure the sterility of the final preparation. The two most critical aspects of aseptic technique are proper hand washing and use and manipulation of syringes, needles, vials, and ampuls. Hand Washing Touch is the most common means of contaminating a pharmacy-compounded sterile preparation. Since the fingers harbor bacterial contaminants, hands should be washed properly. For nearly 200 years, cleansing hands with an antiseptic agent has been recommended to prevent transmitting contagious diseases to patients. Hands must be washed properly, by using the correct technique. Proper hand washing depends on running water, a cleansing agent, and friction. The hands, fingernails, wrists, and forearms should be scrubbed under running water, with the fingertips pointing downward. Soap and friction are applied to the hands and wrist. Proper hand washing includes the following steps:

1. Remove all wrings and watches. 2. Stand close to, but not touching, the sink. 3. Turn on the faucet using a foot pedal or a dry sterile towel. Discard the towel. 4. Wet hand, wrists, and forearms under running warm water, and apply liquid

antibacterial soap. 5. For 15 to 30 seconds, scrub the palm of one hand with the fingers of the other

hand, then repeat for the opposite hand. 6. Use a brush and scrub the fingernails and backs and palms of the hands, and then

scrub the wrists and forearms. 7. Hold the hands in a downward position and rinse well. 8. Dry the hands and then the wrists gently with a sterile towel. 9. Use a dry, sterile towel to turn off the faucet if it is not operated by a foot pedal.

Hand-washing agents should be selected based on their ability to kill microorganisms on the hands at the time of washing and also to provide a residual effect. Isopropyl and ethyl alcohol hand rinses, gels, or foams, or a solution of 4% chlorhexidine gluconate are the best agents for reducing resident flora and transient microorganisms. Results vary with isopropyl alcohol products for initial reduction of microorganisms, but these products clearly have little residual effect. Since most alcohol products are solutions, gels, or foams, they serve as hand disinfectants rather than hand-washing agents. Therefore, hand washing with soap before application of these agents sometimes is recommended. However, this additional step might lower compliance with procedures.


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When decontaminating hands with an alcohol-based hand rub, apply product to palm of one hand and rub hands together; covering all surfaces of hands, and fingers, until hands are dry. Follow the manufacturer’s recommendations regarding the volume of product to use. Multiple-use cloth towels of the hanging or roll type are not recommended for use in health-care settings. Hand washing is sometimes incorrectly omitted when gloves are worn, the assumption being that they provide enough hand protection. In fact, microorganisms multiply rapidly inside warm moist gloves and then can leak through them. The Center for Disease Control (CDC) has stated that gloving does not replace hand washing and that hand washing is imperative after gloves are removed.17 Clean Room A clean room is an area that is specially constructed and maintained to reduce the probability of environmental contamination of sterile products during the manufacturing process. Clean rooms must meet the high standards of purity and cleanliness for parenteral compounding products, and must follow USP 797, which is a stringent set of rules and regulations regarding aseptic preparations. USP 797 requires that the surfaces of all floors, wall, ceilings, cabinets, shelving, and work surfaces in the buffer room should be soft and smooth. These surfaces must also be free from crevices or cracks, making them easy to clean and sanitize. Because air is one of the greatest potential sources of contaminants in clean rooms, special attention must be given to air being drawn into clean rooms by the following systems:

• Heating • Ventilation • Air conditioning

Personnel entering the aseptic area should enter only through an airlock. They should be attired in sterile coveralls with sterile hats, masks, goggles, and foot covers. Traffic flow into the room should be minimized and in-and-out movement rigidly restricted during a filling procedure. Clean rooms sometimes have an anteroom that is used for non-aseptic activities related to the clean room operation such as:

• Gowning • Handling stock • Order processing

17 Update: universal precautions for prevention of transmission of human immunodeficiency virus, hepatitis B virus, and other bloodborne pathogens in healthcare settings. MMWR. 1988:37 (June 24): 377-83, 387-8.


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V. Procedures for Compounding of Solutions

A sterile product contains no living microorganisms. The need for sterility is based on the fact that through injection, the major body defense mechanisms are bypassed. In the hospital, a majority of patients will receive a medication that is administered by injection. Examples of ophthalmic preparations that must be sterile include ointments, solutions, and suspensions. Sometimes pharmacy technicians must compound two solutions that are not commercially available. An example is the compounding of two materials that are both liquid in nature. Procedure for Compounding Solutions The procedure for sterile compounding of solutions must be performed in the clean air space by using proper aseptic technique, as follows:

• Prepare all materials needed for the procedures. • Swab the rubber tops of vials with alcohol and wait for them to dry. • Pull the plunger back on the syringe slightly, and then pull the amount needed to

by drawn up. • Insert the needle through the stopper. • Push the air from the syringe into the vial. • Withdraw the desired amount of medication. • Withdraw the needle. • Add the medication into the IV bag. • Gently shake the bag of solution. • Label the product of compounded solution. • Store the product in the refrigerator.

Sterile preparations may be compounded in various final containers, including flexible plastic bags, glass bottles, semi-rigid plastic containers, and syringes, or as the drug vial itself. Flexible plastic bags made of polyvinyl chloride (PVC) or polyolefin are easy to store compared to glass bottles, less likely to break, and do not need to be vented. PVC bags are available in several sizes and solution types. These bags are supplied in plastic over-wraps, which limit fluid loss. Once this over-wrap is removed, the remaining solution should be used as soon as possible. The injection port of a PVC bag, covered by a protective rubber tip, should be positioned toward the HEPA filter when an IV admixture is prepared. This positioning minimizes air turbulence in the critical area. Before compounding, all material should be assembled. Vials, ampuls, and IV solution containers should be inspected for cloudiness, particulate matter, cracks or punctures, expiration dates, and any indications of defects. Only necessary materials should be placed with in the LAFW. Next, all injection surfaces should be disinfected. Drug fluid should be withdrawn from its container in the amount needed, using the syringe size just larger than the volume to


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be injected. To obtain an accurate measurement, air bubbles should be removed by the following method:

1. Pulling back slightly on the plunger to remove any fluid trapped in the needle. 2. Tapping the syringe. 3. Depressing the plunger.

The instillation of drug into a PVC bag requires insertion of a needle into the alcohol-swabbed injection port and injection of the appropriate volume of fluid. The injection port has two diaphragms that must be pierced:

• Outside latex tip. • Plastic diaphragm about ⅜ inch inside the injection port.

To ensure fluid transfer into the IV bag, a needle longer than ⅜ inch should be used. Adding medication to a glass infusion container begins with removal of the protective cap from the IV bottle. A drug additive then is injected through the alcohol-swabbed rubber stopper or latex diaphragm. Needles should be inserted through rubber stoppers using the non-coring technique previously described for vials. Following admixture, a protective seal is placed over the stopper of a glass container before it is removed from the laminar-airflow workbench. If the final sterile preparation is in a syringe, the needle used in compounding should be removed and discarded. The syringe should then be capped with a sterile tip. A small volume of air or overfill may be left in the syringe for priming the needle or tubing before administering the dose. The syringe should be placed in a plastic bag or other container for transport, which minimizes the potential for plunger depression and/or leakage. Once the sterile preparation is compounded, it should be properly labeled and inspected for cores and particulates. All drug and IV solution containers should be checked by a pharmacist to verify that the technician added the proper amount of the correct drug to the correct IV solution and the correct label affixed to the compounded preparation. Compatibility Not all drugs are compatible with each other. The incompatibility may be between two drugs or between a drug and an IV solution. The possibility of an unexpected or undesirable combination is relatively low compared with the number of IV admixtures prepared, but it is always possible. An incompatibility can lead to a patient not receiving the full therapeutic dose of a medication or, even worse, can lead to an adverse reaction. Some incompatibilities, such as a color change or hazy appearance, can be seen. Precipitate can form in the solution, or an evolution of a gas may even be smelled. Be aware that sometimes when drugs are combined and a visible change occurs, it could be expected and harmless. Reading the package insert or checking with the pharmacist can confirm the reason for this change in appearance. Other incompatibilities cannot be


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visually recognized. If two drugs are mixed that are incompatible with each other, one drug can cause the degradation of the other drug. Many factors can affect the compatibility and stability of drugs in IV admixtures. The following list describes each of these factors:

• pH – pH is one of the most common causes of incompatibilities. Combining two drugs that require two different pH values for the final solution can cause one or both drugs to either degrade or precipitate.

• Light – Some drugs will start to break down and lose their therapeutic effect if

exposed to light.

• Dilution – the concentration of a drug in solution may be a factor in its compatibility with other drugs. A problem can be avoided by assuring that the drug in question is properly diluted before it is combined with the other drug.

• Chemical composition – the chemical complexity of one drug can cause a reduced

therapeutic effect of the other drug, because when the two drugs combine, their new chemical combination may initiate adverse events.

• Time – Most drugs start to degrade in a short time after being added to an IV

solution.

• Solutions – Some drugs require a specific solution or diluent to be used for reconstitution and further dilution. Choosing the wrong solution can cause the drug to be broken down more quickly or can cause precipitate to form. Some drugs are packaged with a specific diluent for reconstitution.

• Temperature – Heat increases the rate of most chemical reactions, and since the

degradation of a drug in solution can be considered a chemical reaction, care must be taken to keep admixtures at a stable temperature. Some drugs can remain more stable refrigerated than if they were kept at room temperature. Some drugs, however, should never be refrigerated because a precipitate can form. Not many experts recommend freezing drugs after reconstitution, and sometimes freezing actually reduces the stability of the drug.

• Buffer capacity – this is the ability of a solution to resist change in pH when either

an acidic or alkaline substance is added to the solution. Many drugs contain buffers to increase their stability. IV solutions in general do not have high buffer capacities. So, when a drug with a high buffer capacity is added, the resulting solution will have a pH closest to the drug added.

• Order of Mixing – the order in which drugs are added to the solution may be a

factor in compatibility. Drugs that are concentrated and combined may react to form precipitate, whereas both drugs in diluted solutions may be combined acceptably. This is very important when mixing parenteral nutrition solutions.


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Electrolytes are commonly prescribed with phosphates, and this causes a mixing problem when mixing parenteral solutions if it is not done correctly. To avoid the problem, it is important to mix the solution well after each addition is made and then to add the electrolytes last after the phosphate has been diluted.

• Plastic – some drugs are incompatible with the plastic container that the solution

will be placed in. Polyvinyl chloride (PVC) plastic can leach certain properties of the plastic out of the bad, or the drug may adhere to the bag. It is recommended that one use non-PVC container for these specific drugs.

• Filters – Filters represent a possible problem in effectively administering a drug to

a patient. Filters can cause a reduction in concentration of the drug to be administered.

To minimize incompatibilities, the following guidelines need to be followed whenever possible:

1. Use solutions promptly after preparation in order to ensure administration of the most stable product; drugs tend to degrade in a relatively short time. If a newly made admixture is not immediately used, it should be placed in the refrigerator.

2. Minimize the number of drugs added to a solution. As the number of drugs added

increases, the chance of an incompatibility rises. It becomes increasingly difficult to find information on compatibilities when more than two drugs are added to a solution.

3. Check incompatibility resources to verify which drugs have a very high or very

low pH. Since most drugs are acidic, their combination with a drug having a very high pH is more likely to result in an incompatibility.

The most often used resources for information on incompatibilities are the manufacturer’s drug package inserts. The package inserts have a wealth of information about the drug. The package insert is developed by the manufacturer and approved by the FDA (Food & Drug Administration) when the drug is marketed. The package insert generally is not as great a reference for incompatibilities specifically; however, there are other excellent resources out there, like The American Journal of Health-System Pharmacy frequently has detailed research articles on intravenous incompatibilities. Some very useful reference books are the Handbook of Injectable Drugs and the Facts and Comparisons Book. Many pharmacy departments maintain a file that categorizes drugs to make looking up drug information quicker and easier. Some pharmacy computer systems screen IV admixture incompatibilities as well as drug interactions, alerting the pharmacist or pharmacy technician to these issues when the order is entered, before it is prepared.


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VI. Labeling A properly compounded sterile preparation, must be labeled accurately and completely to facilitate appropriate and safe administration to the patient. Checking the accuracy of the compounded sterile preparation’s label independently against the original physician’s order/prescription and the ingredients used to compound the preparation is an integral part of the pharmacist’s verification process prior to release of the preparation. In addition, the sterile preparation’s primary and auxiliary labels serve as communication tools regarding proper handling, storage, administration, and drug information for the person administering the drug to the correct patient. Therefore, the terminology used on the label should be descriptive but still appropriate to the knowledge of the user with the use of abbreviations minimized. All labels should be legible and affixed to the final container in a manner enabling them to be read both before and while the sterile preparation is being administered. If a container is to be hung, each label must be positioned so that it is right side up during administration. Light-resistant bags, for photosensitive drugs, and other overwraps should not limit the visibility of the label. Small containers may require unique methods of affixing the label. For medium-sized syringes, labels often are “flagged” so that syringe markings are not covered or obstructed. Labels are often “flagged” for compounded sterile preparations dispensed in small vials and ophthalmic bottles. Very small syringes can be sealed in a larger bag or overwrap, which is then labeled. If the syringe might be removed from the bag some time before administration, a second, smaller label on the syringe should give key information (e.g., drug name, concentration, beyond-use date, and route). Based on the sterilization method, e.g., steam; final labeling with all required labeling components may need to occur post-sterilization. The exact information on a label varies based on the preparation type and the patient’s location/setting, not the ASHP or USP compounded sterile preparation risk-levels. Effective 2004, there are official USP required labeling elements for all compounded sterile preparations regardless of where the patient is receiving the preparation.18 General label content is similar, but slight variations exist in addition to the USP standard for patient specific labeling in institutional and home care settings as well as for compounded sterile batch preparations. This chapter will review general labeling guidelines, the USP labeling requirements for sterile preparations, both required and optional patient specific labeling elements as specified by ASHP and JCAHO, batch labeling elements, and additional labeling strategies that can be utilized to help prevent medication errors and facilitate proper disposal of returned preparations to ensure compliance with the Healthcare Insurance Portability and Accountability Act (HIPPA) privacy regulations. 18 Pharmaceutical compounding – Sterile preparations. In: United States pharmacopeia, 27th rev./national formulary, 22nd ed. Rockville, MD: United States Pharmacopeial Convention.


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General Labeling Guidelines In order to ensure proper labeling, the following guidelines should be followed:

• Drug labeling is required if the compounded sterile preparation is not administered immediately or if it is administered by someone other than the person who prepared the medication.

• The label conforms to all applicable federal, state and local laws and regulations.

• Medication labels are typed or electronically printed in a standardized format to

ensure accurate and complete labeling. The label is legible, easily read, and free from erasures and strikeovers.

• The appropriate primary and auxiliary labels are firmly affixed to the container.

• The metric system of measures should be used instead of the apothecary system.

• Numbers, letters, coined names, unofficial synonyms, and prohibited

abbreviations are not used to identify medications with the exception of approved letter or number codes for investigational drugs.

• All medications with illegible or worn labels are properly and safely destroyed.

• A uniform, systematic labeling method is used. One order or drug preparation

batch is filled and labeled at a time.

• During the hours the pharmacy is open, dilutions and labeling are done in a pharmacy. Within the pharmacy, only a pharmacist or authorized pharmacy technician under the direction and supervision of a pharmacist, may label and dispense medications, make labeling changes, or transfer medications to different containers.

UPS Labeling Requirements for Compounded Sterile Preparations With the introduction of the new United States Pharmacopeia’s (USP) Chapter <797>, there exists a minimum labeling standard for compounded sterile preparations that applies to all health care settings, not just health care institutions and pharmacies. The parts of a label are described below; the numbers in parenthesis correspond to information on the label. Names and amounts or concentrations of ingredients The name of each drug, preferably generic, should be clearly shown. This includes the names of all drug products or ingredients added or used to prepare the finished preparation, including admixture solutions and their corresponding volumes. The trade


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drug name or commonly known name of the preparation can be included if it can reduce the potential for error. Although the amount or volume of admixture solution, e.g. dextrose or sodium chloride, usually is unimportant in the patient’s therapy, it may be a consideration in certain clinical settings. The admixture solution itself; however, definitely affects the compounded sterile preparation’s stability and beyond-use dating. Total volume of the preparation Total volume is usually expressed in the metric system, e.g., milliliters (mls) or liters. For IV piggybacks and continuous infusions, this measurement allows tracking the patient’s total fluid intake. If the volume of the admixture solution is not significantly different from the total volume, these measurements are used interchangeably (e.g., antibiotic solutions). For larger volume solutions with multiple additives, the actual or calculated total volume should be used (e.g., TPN solutions). For syringes and vials that are overfilled, both scribed medication dose should be clearly shown on the label. Beyond-use date This date is the last date that the sterile preparation can be used by the patient and should be consistent within each health care setting. Beyond-use dating should be based on known stability information and sterility considerations. The specific beyond-use date of a preparation should be based on published data, appropriate testing, or USP-NF standards. Appropriate route(s) of administration Even though the route of administration may be implied by the dosage form (e.g., IV bag implies IV or intravenous administration unless labeled otherwise), the appropriate route(s) of administration should be placed on the preparation’s label. Especially when a container is used outside of the normal pattern or a dosage form has multiple uses, the route must be clearly stated to prevent medication errors. Often, drugs can be given only be certain routs or the amount/concentration is route specific and, therefore, may be dangerous otherwise. Syringes should be clearly labeled with the intended route of administration (e.g., IV push, pump or gravity, epidural, or Intrathecal, intravitreal, or intramuscular). In some cases, the ramifications of giving a particular drug or dose by an unintended route can be fatal. Patient-controlled analgesia (PCA) containers also should be clearly marked since they may be the same for IV and epidural PCA, but the concentration of drug differs. Storage conditions Storage instructions can be put on the primary label or added as an auxiliary label. Preparations must be stored in accord with the condition stated on the label to ensure the preparation’s sterility and stability. This can include, but is not limited to, whether the preparation should be refrigerated, kept at room temperature, protected from light, or not


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shaken. If the sterile preparation requires refrigeration, it should be separated from food to avoid contaminating the outside of the container. Other information for safe use Other information, including cautionary statements, for the safe use of the preparation can be put on the primary label or added as auxiliary labels. This information should include the initials of the responsible pharmacist who prepared or checked the preparation and complete directions for the proper clinical administration of the compounded sterile preparation, including device specific settings and instructions. In addition, hazardous drugs should have appropriate precautionary labels to facilitate safe handling, use, and disposal.


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VII. Storage and Handling of Sterile Preparations Monitoring the storage conditions in the pharmacy is necessary to ensure that sterile products retain their respective quality attributes. Controlled-temperature storage areas such as refrigerators and freezers should be monitored at least once daily with results documented on a temperature log. This section covers pharmacy’s responsibility for sterile commercial products and compounded preparations beginning when products are first received and continuing through compounding and waste disposal. To ensure both preparation quality and public safety, correct storage and handling procedures are necessary every step of the way. Sterile Components Components are comprised of active and inactive ingredients, intermediate containers (e.g., a syringe used to transfer a drug from one container to another), final containers and closures. A procedure should specify the visual inspection of commercially available drug products, sterile ready-to-use containers, and devices (e.g., syringes and needles) upon receipt in the pharmacy. All items must be free from defects, within the manufacturer’s expiration dating, and suitable for their intended use. USP Storage Conditions Intravenous solutions, sterile commercial product, and sterile supplies should be stored according to manufacturer labeling or USP product monographs to preserve stability of ingredients. Most sterile products are aqueous solutions for which hydrolysis is the most common chemical degradation reaction. In general, the rate of a chemical reaction increases exponentially for each 10° C increase in temperature. Thus, storage of a beta-lactam antibiotic solution for one day at controlled room temperature will have an equivalent hydrolytic effect of approximately 3 to 5 days in cold temperatures. Cold temperatures may cause harm as well, for example refrigeration may cause harm as well, for example refrigeration may cause precipitates and freezing may break an emulsion or denature proteins. Recommended storage conditions are usually stated on a product’s label and may include a specified temperature range or a designated place (e.g., “refrigerate”). Supplemental instruction (e.g., “protect from light”) should also be followed carefully. If a preparation must be protected from light and is in a clear or translucent container enclosed in an opaque outer covering, this covering should not be removed until the contents are to be used. In the absence of specific instructions, a sterile product should be stored at controlled room temperature away from excessive or variable heat, cold, and light, e.g., away from heating pipes and fluorescent lights.


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Clarifying Controlled Room Temperature Since controlled room temperature may range from 15° C to 30° C, such storage may not be adequate for certain temperature-sensitive drugs. Clinically important changes can result from only a 5° C variation in room temperature over the shelf life of a preparation. Alterations in temperature-related drug stability could potentially compromise an interpretation and assignment of beyond-use dates to compound preparations. Therefore, USP has further defined controlled room temperature:

“Controlled room temperature…encompasses the usual…working environment of 20° C to 25° C (68° to 77° F)…that results in a mean kinetic temperature calculated to be not more than 25 degrees; and that allows for excursions between 15 and 30 degrees C (59° and 86° F)…in pharmacies, hospitals, and warehouses.

Monitoring Storage Conditions To ensure that the potency of a sterile commercial product is retained through its expiration date, pharmacy personnel must monitor drug storage areas. Controlled temperature areas like refrigerators, freezers, and incubators should be monitored at least once daily and the results should be documented on a temperature log. A continuous temperature recording device or a thermometer with adequate accuracy and sensitivity may be used if properly calibrated at reasonable intervals. On each day, pharmacy personnel should verify that the recording device is working and that temperatures are within the desired range. The temperature-detecting mechanism should be carefully placed so that it accurately reflects the unit’s temperature. The pharmacy personnel must also monitor conditions that cause temperature fluctuations such as frequent or extended opening of refrigerator doors. Outside the Pharmacy While compounded sterile preparations are within the confines of a clean-room, storage and other handling conditions can be largely controlled. Since sterile preparations must be transported for use in various patient care settings, their handling outside the pharmacy also must be considered. Efforts must focus on the acceptable focus on the acceptability of the sterile preparation for patient use (including stability of ingredients and sterility) and also on the reduction of waste and preparation costs. Key factors to consider include the transfer of sterile preparation form the sterile compounding area, storage conditions during transport and in the storage conditions during transport and in the patient care setting, and methods for return, recycling, and disposal. USP chapter <797> states that pharmacy is responsible for ensuring that compounded sterile preparations maintain their quality until administration to the patient. All personnel (including couriers and other non-pharmacy staff) who package, handle, transport, and store compounded sterile preparations outside the pharmacy must be appropriately trained so that this expectation is met.


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Quality Control

Quality control is the day-to-day assessment of all operations from the receipt of raw materials to the distribution of the finished product. Quality assurance is an oversight function, involving the adjusting of quality-control procedures and systems, with suggestions for changes as needed. Each pharmacy should have written procedures covering the following:

• Handling and storage • Preparing admixtures • Labeling • Transportation of IV fluids to the floors

Personnel involved in the preparation of IV admixtures should be trained and monitored on a regular basis. For quality control, documentation is essential and should include:

• Documentation of training and procedures • Quality control results • Laminar airflow hood certification • Production records • Concentration of all preparations

Quality-control documentation is required by various agencies and organizations.


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Final Exam

Directions: Select the most appropriate answer from the choices given.

1. Which of the following is not an injectable route of administration?

a. Sublingual b. Intravenous c. Intramuscular d. Subcutaneous

2. While the majority of perenteral products are prepared using commercially available medications and diluents, pharmacy departments still perform intravenous manufacturing.

a. True b. False

3. According to the Scope of Pharmacy Practice Project, ___% of a pharmacy technician’s time is spent collecting, organizing, and evaluating information. a. 20% b. 22% c. 26% d. 35%

4. According to the Scope of Pharmacy Practice Project, the second most time consuming function, ___%, involve preparing, dispensing, distributing, and administering medications.

a. 35% b. 21% c. 24% d. 18%

5. Pharmacy technicians must possess which of the following basic requirements to participate in sterile compounding?

a. A working knowledge of the policy and procedures manual for

compounding, dispensing, and delivering sterile products. b. Adequate training and adherence to hygienic and aseptic techniques. c. Knowledge and awareness of the proper methods to store label and

dispose of drugs and supplies. d. All of the above.


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Final Exam

6. The level of difficulty of preparing the compounding prescription is determined by _________________________________.

a. The physical properties of the drug being prescribed. b. The dosage form desired either by the prescriber or patient. c. Both a and b. d. Neither a or b.

7. Sterile compounding is an advanced pharmacy technique that is part of the general education for a pharmacy technician and does not require additional training.

a. True b. False

8. The pharmacist maintains control over all pharmacy activities and the ultimate responsibility rest with him or her.

a. True b. False

9. The objective of formulating and compounding sterile preparations is: a. State laws b. Food and Drug Administration (FDA) regulations c. Both a and b d. Neither a or b

10. Adulteration is: a. When two drugs that are only compatible with another drug are

compounded together. b. When the methods used in, or the facilities or controls used for

manufacturing, processing, packing, or holding do no conform to current good manufacturing practice.

c. Expired drugs d. None of the above.

11. When formulating and compounding sterile preparations, the technician must follow: a. Federal Regulations b. State laws c. Professional standards d. Written procedures e. All of the above.


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Final Exam

12. As a technician, your work must be checked by a licensed pharmacist.

Dispensing pharmacist must inspect and approve or reject all formulas, calculations, substances, containers, closures, and in-process materials.

a. True b. False

13. Technicians who compound batches of parenteral preparations must follow a master formula sheet to reproduce preparations that meet all purported norms.

a. True b. False

14. An ingredient is only considered a component of a compound if it appears in the final preparation.

a. True b. False

15. For parenteral preparations, the most common vehicle is:

a. Water b. Dextrose c. Sodium Chloride d. Lactated ringer’s injection

16. Sodium chloride injection 0.9% solution that is sterilized and packaged in a single-dose container is sold in no larger than ______ml size.

a. 30ml b. 100ml c. 1000ml d. 1500ml

17. All of the following are Water-Miscible Solvents except for: a. Ethyl alcohol b. Liquid polyethylene glycol c. Propylene glycol d. Lactated ringer’s injection


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Final Exam

18. USP specifies that fixed oils must be:

a. Vegetable in origin b. Odorless c. Have no rancid taste d. All of the above.

19. Solutes may be active ingredients or added substances.

a. True b. False

20. An antimicrobial agent may be effective in one formula of ingredients but not in another.

a. True b. False

21. _____________ stabilize a solution against degradation.

a. Solutes b. Antimicrobial agents c. Buffering agents d. Antioxidants

22. ______________ help to prevent oxidation of the component drug.

a. Solutes b. Antimicrobial agents c. Buffering agents d. Antioxidants

23. _________________ enhance the effectiveness of antioxidants.

a. Chelating agents b. Tonicity agents c. Solubilizers d. Emulsifiers


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Final Exam

24. ___________ are used to suspend tiny oil globules in water to create an emulsion that contains a uniformed concentration of the active drug throughout the volume of the liquid.

a. Chelating agents b. Tonicity agents c. Solubilizers d. Emulsifiers

25. The closure is part of the container.

a. True b. False

26. ______________ containers permit withdrawal of successive portions of their contents without changing the strength, quality, or purity of the remaining portions.

a. Single-dose b. Multiple-dose

27. ___________ is the most popular material for sterile preparation containers.

a. Glass b. Plastic

28. ____________ is a parenteral formulation that is injected directly into the vein.

a. Intravenous b. Intramuscular c. Intradermal d. Subcutaneous

29. ___________ is a parenteral formulation that is injected into the substance of the skin.

a. Intravenous b. Intramuscular c. Intradermal d. Subcutaneous


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Final Exam

30. A solution having a pH of 7 is ____________. a. Acid b. Alkalinity c. Neutral d. All of the above.

31. If sterile water for injection is the vehicle in a formulation, the risk of pyrogens in water is eliminated.

a. True b. False

32. Because numerous factors affect the stability of drug molecules, the choice of packaging is not important.

a. True b. False

33. With a Laminar Flow Hood, the orientation of the direction of airflow can be:

a. Horizontal b. Vertical c. Either d. Neither

34. ___________ cabinets are totally enclosed, vented, and gastight units. Operations are conducted through attached rubber gloves, and the cabinet is maintained under negative pressure.

a. Class II b. Class III c. Both a and b d. None of the above

35. If a Laminar Flow Hood is turned off, it is recommended to run for at least ___ minutes before using the work surface area in order to replace the room air with clean filtered air.

a. 10 minutes b. 20 minutes c. 30 minutes d. 40 minutes


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Final Exam

36. Laminar Flow Hoods should be inspected and certified every year.

a. True b. False

37. The finer the needle, the higher the gauge number will be.

a. True b. False

38. In the selection of an appropriate syringe, as a rule the capacity of the syringe should be the next size smaller than the volume to be measured.

a. True b. False

39. All vials should be swabbed with 70% isopropyl alcohol before needle entry and left to dry. The swabbing is effective because:

a. The alcohol acts as a disinfecting agent. b. The physical act of swabbing in one direction remove particles from the

vial diaphragm. c. Both a and b d. None of the above

40. Ampuls are closed-system containers, since air or fluid cannot pass freely in or out of them.

a. True b. False

41. Contamination can be caused by the following factors:

a. Environment b. Equipment c. Personnel d. All of the above

42. When laminar airflow is accessible to all sides of an object, the “zone of turbulence” extends approximately __ times the diameter of that object. a. 3 b. 5 c. 10 d. 12


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Final Exam

43. __________ is the most common means of contaminating a pharmacy-compounded sterile preparation.

a. Air flow b. Expired drugs c. Touch d. Dirt in the clean room

44. When wearing gloves, there is no longer a need for hand washing.

a. True b. False

45. To ensure fluid transfer into the IV bag, a needle longer than ⅜ inch should be used.

a. True b. False

46. The order in which drugs are added to the solution may be a factor in compatibility.

a. True b. False

47. Drug labeling is required if: a. The compounded sterile preparation is not administered immediately b. If it is administered by someone other than the person who prepared the

medication. c. Both a and b d. None of the above. e.

48. Certain dosage forms do not need the route of administration on the label because it is implied.

a. True b. False


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Final Exam

49. Controlled-temperature storage areas such as refrigerators and freezers should be monitored at least:

a. Daily b. Weekly c. Monthly d. Annually

50. Each pharmacy should have written procedures covering: a. Handling and storage b. Preparing admixtures c. Labeling d. All of the above

sterile compounding and preparations a knowledge

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