Upon completion of this exercise, you should be able to:
Garfinkle, B., Henley, M. Sterilization, Chapter 84, pp. 1463-1464, 1478-1479, 1482-1485; Avis, K.E., Levchuk, J.W. Parenteral Preparations, Chapter 87, pp. 1524-1533; and Turco, S.J. Intravenous Admixtures, Chapter 88, pp. 1549-1562, all in Remington's, 19th Ed.
The USP 24/NF19 Section <1206> Sterile Drug Products for Home Use and ASHP Technical Assistance Bulletin on Quality Assurance for Pharmacy-Prepared Sterile Products define three Risk Levels of Sterile Compounding. These Risk Levels might be summarized as follows:
Risk Levels and Associated Risks in Sterile Compounding
|Low Risk||· product is compounded with commercially available
· compounding involves few aseptic manipulations
·"closed system" transfers are used
|High Risk, Category I||· prepared from commercially prepared compounds|
· closed system pooling of sterile drug products
· complex, numerous manipulations over a long period of time
· multiday infusion via a portable pump or reservoir
|High Risk, Category II||· prepared from nonsterile drug substance|
· "open systems"
Examples of these categories are shown below:
Comparison of USP Section <1206> and ASHP Technical Assistance Bulletin Categories
USP Section <1206>
ASHP Technical Assistance Bulletin
|Low Risk Category
Sterile drug products transferred from vials or ampules into sterile final containers with syringe and needle
Sterile drug products transferred into sterile elastomeric infusion containers with aid of mechanical pump and appropriate sterile transfer device, with or without subsequent addition of sterile drug products with sterile syringe and needle
Sterile nutritional solutions combining dextrose injection and amino acid injection via gravity transfer into sterile empty containers, with or without addition of sterile drugs to final container with sterile syringe and needle
|Risk Level I
Single patient admixtures
Single patient ophthalmics with preservatives
Single patient syringes without preservatives used in 28 hours
Batch prefilled syringes with preservatives
|High Risk Category I
Sterile nutritional solutions compounded with automated compounder, involving repeated attachment of fluid containers to proximal openings of compounder tubing set and of empty final containers to distal opening
Additive transfers into filled final container from individual drug products containers or from pooled additive solution
Ambulatory pump reservoirs prepared by adding more than one drug product, with evacuation of air from reservoir prior to dispensing
Ambulatory pump reservoirs prepared for multiday (ambient temperature) administration
|Risk Level 2
TPNs for administration after 7 days
Injections for use in portable pump or reservoir
Batch reconstituted antibiotics without preservatives
Batch prefilled syringes without preservatives
|High Risk Category II
Injectable morphine solutions prepared from nonsterile morphine substance and suitable vehicles
Sterile nutritional solutions prepared from nonsterile ingredients, with initial mixing in non-sealed or nonsterile reservoir
|Risk Level 3
Alum bladder irrigations
Morphine injections made from powder or tablets
TPNs made from dry amino acids
Autoclaved IV solutions
TPNs sterilized by final filtration
GENERAL COMMENTS ABOUT ASEPTIC TECHNIQUES
Guidelines recommend that Low Risk Level compounding be done in a Class 100 laminar flow hood. The High Risk categories require that a laminar flow hood be located in a Class 100,000 (Category 1) or 10,000 (Category 2) controlled area. In any of these cases, however, working in a laminar flow hood is not sufficient to ensure sterility. The hood does not provide sterility - just an ultraclean work area.
Products will be placed in the hood for assembly or compounding that are either sterilized before hand or will be sterilized by filtration while in the hood. Personnel carrying out these procedures must use techniques to minimize the potential contamination (microorganisms, particulate material, pyrogens) possible during these manipulations. Aseptic technique can be defined as the sum total of methods and manipulations required to minimize the contamination of sterile compounded formulations.
The following are considered minimum requirements for good aseptic technique:
Aseptically Transferring Drug From a Vial
There are two types of parenteral vials that are used in making admixtures: (1) a vial that already has the drug in solution, and (2) a vial that requires a lyophilized powder be dissolved in a diluent to make a solution. In either case, a needle will be used to penetrate the rubber closure on the vial.
To prevent coring, use the following technique:
If the drug is already in solution, then the aseptic transfer technique is as follows:
If the drug is a lyophilized powder in a vial, it will need to be reconstituted before it can be withdrawn. First, determine the correct volume of suitable diluent to use. This information will be in the drug product information. Then the following steps can be followed:
Aseptically Transferring Drug From an Glass Ampule
Ampules have a colored stripe around the neck if they are pre-scored to indicate the neck has been weakened by the manufacturer to facilitate opening. Some ampules are not pre-scored by the manufacturer, and the neck must first be weakened (scored) with a fine file. The ampule is always broken open at the neck.
To open an ampule:
To transfer the drug solution from an opened ampule:
Aseptically Adding Drug Solution to Large Volume Parenterals and Small Volume Parenterals
Generally, LVP solutions are used as primary or continuous infusion solutions by administering them at a slow infusion rate. Drug additives can then be introduced directly into LVP with a syringe and needle. Drug additives can also be introduced into LVP at the Y-connection of the administration set. Drug additives are also put in minibags and used as a piggyback on the LVP.
All of these scenarios require a syringe and needle to transfer the drug additive solution into a plastic bag or administration set injection port. The needle must be at least ½ inch long and not less than 19 gauge to ensure that the inner diaphragm of the port will be penetrated and that the protective rubber cover will reseal.
To transfer a drug additive to a LVP or SVP container or an administration set with a needle and syringe:
Discarded gloves, needles, syringes, ampules, vials, and prefilled syringes used in preparing sterile formulations pose a source of contamination and should be disposed of properly. Receptacles that are leakproof, puncture proof, sealable, and easily identifiable should be used. Needles and syringes should be placed in "sharps" containers. They should not be clipped or recapped in order to prevent aerosolization or accidental needle sticks. Excess solutions should be returned to their original vial, an empty vial, or some other suitable closed container.
Inspections and End Product Evaluations
Preparations in flexible containers should be squeezed to ensure the absence of unintended holes and slits. Glass bottles should be examined for cracks and leaking stoppers.
Visual inspection will show two of the six characteristics of parenteral solutions: (1) particulate material and (2) stability if such stability is physically characterized by precipitation or crystallization. The presence (or absence) of particulate material is best determined when the parenteral is held against an illuminated light/dark background.
Formulation properties should be known before hand and documented on the formulation record. The compounded product should be compared to these standards.
The pharmacist should also verify that the product was accurately prepared with respect to:
During compounding, volumes of additives in syringes should be examined to confirm accurate measurements. The volumes of solutions remaining in vials and ampules should be determined to compare to the theoretical volumes required to make the formulation. A mass balance of materials should be evident. Also additive containers and syringes should be available (not discarded in the trash) until the product checks are completed.
Formulations should be subjected to quality control tests as outlined in the formulation records and compounding records. These are generally the physical tests that can be conducted within the pharmacy and may involve weight variation, specific gravity, pH, filtration membrane integrity, etc.
Formulations that are not distributed promptly should be inspected again before leaving the pharmacy. The purpose of the pre-distribution inspection is to check for defects such as precipitation, cloudiness, and leakage which may have developed during storage.
Admixture labeling must clearly document base vehicle (solution) and added components as well as information about the patient. The following two labels may serve as guides.
Patient Name:__________________ Location: ______________ Order #:_______________________
School of Pharmacy University of North Carolina Chapel Hill, NC
COMPATIBILITY AND STABILITY
The National Coordinating Committee on Large Volume Parenterals (NCCLVP) defines instability as "a phenomenon which occurs when an LVP or LVP drug product (IV admixture) is modified due to storage conditions (e.g. time, light, temperature, sorption). An unsuitable product may be formed.
Incompatibility is defined as "a phenomenon which occurs when on drug is mixed with others and produces an unsuitable product by some physiochemical means. The new product is unsuitable for administration because the "active" drug has been modified (e.g., increase in toxicity), or because some physical change (e.g., solubility) has occurred.
If the stability or incompatibility of a given formulation is not known, the pharmacist should concern the following factors to anticipate the likelihood of these problems.
Chemical and Physical Properties of the Admixture
Fortunately, each of the structural functional groups can undergo only a limited number of possible reactions. The most significant among them seems to be hydrolysis (as in the case of esters, amides, and lactams) and oxidation (of catechols, phenols, and unsaturated compounds) as well as precipitation of weak electrolytes or neutral, hydrophobic compounds. These reaction and their rates may be pH dependent.
A product may be stable or soluble only at a pH that is not physiologically safe. When added to an infusion, a change in pH could take place and the chance for precipitation or accelerated chemical degradation increases. For example, Potassium Penicillin G contains a citrate buffer, and the injection is buffered at pH 6.5 when reconstituted. The solution is stable for 24 hours at such pH; however, it loses activity much faster at a lower pH.
In general, the following intravenous fluids are NOT recommended for any drug admixture. These infusions are unstable by nature and drug admixtures could trigger adverse reactions such as coagulation, coalescence or gas evolution, therefore rendering the IV infusion potentially hazardous, if not fatal.
You should recall that the solubility of a weak acid or base may depend on pH: amines (dobutamine, dopamine, epinephrine, morphine) are basic and are generally soluble in acid media, whereas carboxylic and other acids (penicillins, cephalosporins, 5-fluorouracil) are generally soluble in basic media. Making the former basic or the latter acidic could induce precipitation.
Common LVP and Their pHs
|D5 Lactated Ringer's||5.1|
Nonelectrolytes in Solution
Generally, nonelectrolyte or neutral drugs (such as digoxin, phenytoin, and the benzodiazepines) are dissolved in a nonaqueous or a cosolvent vehicle due to their poor solubility in water. If the drug is placed in an aqueous environment, it may form a precipitate, with concomitant loss of drug activity and/or danger to the patient. The solvents used in nonaqueous parenteral products are usually listed on the product's label. Hence, if the drug is dissolved in a water miscible solvent and one administers it slowly, dilution of the vehicle results in cosolvent fractions that maintain the drug in solution. If a cosolvent system must be used, the fraction of cosolvent in the initial stock solution should be as high as possible, to decrease the probability of precipitation upon administration.
Non-polar, sparingly soluble drugs stored in plastic containers tend to partition into the plastic container wall. A classical example is nitroglycerin. Nitroglycerin has low water solubility, approximately 0.1%, which suggests that it has high non-polar solubility. Indeed, if nitroglycerin in aqueous solution is placed in a polyvinylchloride IV bag (non-polar medium) or is delivered through a polyvinylchloride IV set, there is little doubt that with time the drug will be lost by adsorption to the plastic. This seems to be true also for vitamin A acetate, warfarin, methohexital, terbutaline, lorazepam, and insulin. Since the dosing of nitroglycerin is critical, it should be dispensed in glass IV bottles and infused with a special, non-adsorbing infusion set.
Interaction with Antioxidants
Several parenteral products contain sulfites to prevent oxidative degradation. Sulfites, however, may chemically react with other drugs. For example, fluorouracil and thiamine hydrochloride react with bisulfites which can lead to inactive products. Fortunately, when such incompatibilities are discovered, they often find their way into the literature for the benefit of others.
With the increased use of large volume parenterals as electrolyte and nutritional supplements, an unlimited number of potential incompatibilities could result. In general monovalent cations are usually compatible. However, divalent cations like calcium and magnesium can be troublesome in the presence of bicarbonate, citrate, and phosphate, reacting to form insoluble complexes. When bicarbonate reacts, it will decompose to release CO2 gas, which can have devastating clinical effects. Calcium also forms complexes with tetracyclines resulting in an inactivated product.
Many injections have special storage requirements such as protect from light (PFL) or refrigeration. Using these solutions in intravenous fluids may produce conditions not favorable to the drug's stability. Light sensitive drugs, when administered through an infusion, should be covered with aluminum foil, or other opaque materials, during administration to reduce photodecomposition.
|Fluorouracil (5-FU)||Vitamin B Complex|
SPECIAL CONSIDERATIONS AND PRECAUTIONS
Certain pharmaceutical preparations require special precautions in their preparation to minimize product contamination or environmental hazards. The following information may serve as a helpful guideline for a few of these classes of drugs.
Parenteral Nutrition Solutions
Because of their high risk for bacterial growth and their vast potential for drug incompatibilities, these products require special attention. Strict adherence to aseptic technique and frequent sterility testing are essential. Whenever feasible, it is desirable to maintain a separate hood for nutrition solutions to avoid cross contamination with other medicinal agents.
Cytotoxic Agents (Cancer Chemotherapy Agents)
These agents present an environmental hazard. It is now known that prolonged exposure to these agents may lead to the development of cancers. For this reason special precautions must be taken to minimize the exposure of pharmacy personnel to these agents. These agents should be prepared in a shielded vertical flow hood, so that materials are not blown into the operators face. When possible it is best to have the responsibility for preparing these agents rotated among pharmacy personnel to minimize any one individual's exposure. It is desirable that pregnant women be exempted from preparation of these agents.
These agents also represent an environmental hazard and must be handled carefully. In addition to adhering to the guidelines set forth for cytotoxic agents, one may further reduce his exposure to these agents by working with them in protective lead vial shields. Special storage and disposal of these agents is required.
Due to the allerginicity of the penicillins, it is desirable to work with them in a shielded vertical flow hood to avoid environmental contamination. When working with any of the antibiotics, it is important to remember that prolonged exposure may lead to infections of exposed areas by nonsusceptible bacteria and fungi. It is recommended that anyone who must prepare large numbers of antibiotic doses wash their hands frequently to avoid infections of the hands and nail beds.