RxPrep 2022 Course Book - Sterile Preparations PDF

RxPREP 2022 COURSE BOOK APPLYING PRODUCT AND AUXILIARY LABELS The labeling of all compounded products must include the BUD and storage and handling information. There should be a label indicating that it is a compounded product. All hazardous drugs {HDs) should be labeled appropriately. Certain for...

RxPREP 2022 COURSE BOOK APPLYING PRODUCT AND AUXILIARY LABELS The labeling of all compounded products must include the BUD and storage and handling information. There should be a label indicating that it is a compounded product. All hazardous drugs {HDs) should be labeled appropriately. Certain formulations may need additional auxiliary labels {see below). Topical products: Emulsions, suspensions: t~ \ SHAKE WELL r Suppositories'. some troches, REFRIGERATE some suspens10ns: lLJ r PATIENT COUNSELING The pharmacist must counsel the patient or caregiver about the proper use of a compounded product, with similar information as required for prescription drugs. ADRs resulting from a compounded product should be reported I RxPREP ©2021, ©2 02 2 to the pharmacy, and the pharmacist will need to record the ADR in the compounding record. The patient's profile should include the ADR. Depending on the reaction, further action may be necessary. • .•• STERILE PREPARATIONS PHYSIOCHEMICAL CONSIDERATIONS Human blood and body tissues have an osmotic pressure {number of particles in solution) equivalent to 0.9% sodium chloride {which is considered isotonic). Most sterile preparations, including intravenous {IV) solutions and ophthalmic products should be isotonic to human blood and contain a similar number of particles in solution (i.e., osmolarity) of -285 mOsm/L. This prevents fluid transfer across biological semipermeable membranes. Osmolarity and isotonicity are discussed later in this chapter and in the Calculations II chapter. • • The pH of sterile preparations should be close to neutral {pH of 7); blood is slightly alkaline at a pH of 7.35 - 7.45. Non-PVC bags should be used for IV medications that have leaching or sorption issues {see the Intravenous Medication Principles chapter). The IV tubing must be sterile and nonpyrogenic. COMMON PRODUCTS USED IN STERILE COMPOUNDING AMPULES AND VIALS Ampules: ampules are small, sealed glass containers with a long neck that contain liquid medication. The ampule is broken by snapping the neck at the narrowest part The glass is weaker in that area and will snap off. This can introduce glass particles into the drug solution. A filter needle or filter straw will be required to remove the glass. Vials that contain liquids: a volume of drug from the vial is drawn up in a syringe, which can then be added to an IV bag. The compounder will inject a volume of air equal to the volume of drug that is withdrawn to equalize the pressure. A different process if used for hazardous drugs due to risk of exposure of the personnel (discussed later in the chapter). Vials that contain lyophlllzed or freeze-dried powder. the powder needs to be reconstituted by adding sterile water for injection. bacteriostatic water for injection or a diluent supplied by the manufacturer. Drugs may be commercially available as powders because they are unstable as a solution. The image to the right shows a vial of lyophilized powder before and after reconstitution. @ Labels courtesy of i!ll '©RxPrep, Inc. Q shamrock iol,els 281 17 I CO MPOUNDIN G Ill : D OC UMENTATI O N & PREPA RATI O N IV BAGS ,----- Small volume parenteral (SVP): SVPs are IV bags or syringes that contain a LARGE VOLUME PARENTERAL WITHIVPB small volume (100 ml or less) of fluid. SVPs can contain plain fluid, such as NS or DSW, that can be sent to the patient care area for floor stock or labeled for a specific patient. SVPs can also contain a drug with or without a diluent. These can be compounded in the pharmacy or come in ready-to-use containers from the manufacturer (see section below). The SVPs are often "piggybacked" onto a large volume parenteral (LVP). These are called IV piggybacks (IVPBs); see figure. This reduces the need to have multiple lines running into the patient. The drugs will mix together in the tubing so they must be compatible in the IV line. Large volume parenteral (LVP): LVPs are IV containers that contain more than 100 ml. 1 liter bags are commonly used to provide fluids, and are available in a variety of formulations: NS, ½NS, DSW, DS½NS, DSNS, lactated ringers (LR) and others used less commonly, including D10NS, D2.S½NS, D5 1/,NS, DS¼NS. Parenteral nutrition (PN) for adults is prepared as a LVP. m-6 IVPB LVP CJ,eck SccondJiry Adrnln~lr• Uon Set V•l110 - Prlmory Admln~tratlon si,_t r- 0 , L READY-TO-USE STERILE MEDICATIONS Ready-to-use medications (RTUs): are available as prepared IV bags or prefilled syringes. The pharmacy staff opens the outer container and applies the patient label. These do not have a CSP risk level, as they are not compounded. The expiration date is provided by the manufacturer, and is on the packaging. Ready-to-use vial/bag systems (ADD-Vantage, Mlnlba1 Plus, others): vials and bags are supplied together. The vial can be attached to the bags at the bedside by the nurse for immediate use. If the vial is attached in the pharmacy cleanroom (in an ISO 5 hood inside an ISO 7 buffer room; see the Compounding I chapter), it can be saved for an extended period of time as indicated by the manufacturer on the packaging. Each of the proprietary bag and vial systems are different in design, but all involve an activation step of releasing IV fluid into the drug vial and then returning the reconstituted drug back into the bag. WORKFLOW FOR CSP PREPARATION Pharmacist reviews the order. Gather and inspect all materials. Clean hood. Place only needed items in the hood. Prepare CSPs with aseptic technique. Properly dispose of syringes and needles into the sharps container (see the Medication Safety & Quality Improvement chapter). Visually inspect all finished CSPs. If high-risk, complete terminal sterilization (discussed later in this chapter). HOW TO SET UP ITEMS IN THE STERILE HOOD Space requirements for sterile compounding are discussed in detail in the Compounding I chapter; refer there for information on ISO air ratings, laminar airflow hood requirements and more. Only required items can be placed in the hood. No paper, pens, labels, calculators or trays. All work must be done within the sterile hood at least six inches from the front to prevent the hood air (ISO s) and buffer room air (ISO 7) from mingling. Place all items in the sterile hood side-by-side. Items should not be closer than six inches from the back of the hood. Nothing should be between the sterile object and the HEPA filter in a horizontal airflow hood or above a sterile object in a vertical airflow hood. Do not tear open components. Open along the seal within the hood. Do not touch the syringe tip or plunger, even with gloved hands. 282 RxPREP 2022 COURSE BOOK HOW TO TRANSFER SOLUTIONS AND INJECT INTO IV BAGS For greatest accuracy, use the smallest syringe that can hold the desired amount of solution. The syringe should not be larger than twice the volume to be measured. Powders are reconstituted by introducing a diluent such as sterile water for injection, bacteriostatic water for injection (which is sterile) or a diluent provided by the manufacturer. In some cases, dilution is done with saline or dextrose solution. Swab the rubber top of the vial (or ampule neck) with 70% IPA, and wait for it to air-dry; do not blow on or wave over it to dry faster. Prior to withdrawing any liquid from a vial, inject a volume of air equal to the volume of fluid to be removed. Exception: do not in ject air prior to removing hazardous drugs from vials. The negative-pressure technique (described in the next section) or a closed-system transfer device (CSTD) should be used. As part of their mechanism, CSTDs equalize the pressure in the vial which eliminates the need to inject air. Puncture the rubber top of the vial with the needle, bevel !!E_ and at a 45-degree angle. Then bring the syringe and needle straight up to a 90-degree angle while penetrating the stopper. Depress the plunger of the syringe, emptying the air into the vial. Invert the vial with the attached syringe. Draw up the amount of liquid required. Withdraw the needle from the vial. In the case of a multi-dose vial, the rubber cap will close, sealing the contents of the vial. The volume of solution drawn into a syringe is measured at the point of contact between the rubber piston and the side of the syringe barrel. Coring occurs when a small piece of rubber from the stopper is aspirated into the needle, and is put into the solution in the vial. The rubber piece can get injected into a patient. Look for small cored pieces floating near the top of the solution during the visual inspection of the CSP. If the medication is in a glass ampule, open the ampule by snapping the neck away from you. Tilt the ampule, then withdraw the fluid using a filter straw or filter needle to remove any glass particles that may have fallen into the ampule. The needle must be changed before injecting the syringe contents into an IV bag to avoid introducing glass or particles into the bag. A standard needle could be used to withdraw the drug from the ampule, as long as it is then replaced with a filter device before the drug is pushed out of the syringe. I RxPREP ©2021, ©2022 Negative-Pressure Technique Air should not be injected into a vial containing a HD. Positive pressure can cause the HD to spray out around the needle, contaminating the workspace and endangering personnel. Instead, the negative-p1•essu.r e techniqu e should be used. First, pull the plunger back to fill the syringe with a volume of air equal to the volume of drug to be removed. Insert the needle into the vial, invert the vial and pull on the plunger. This will create a vacuum that pulls the drug out of the vial and into the syringe. This should be done in small increments, pausing to allow the air to move out of the syringe and into the vial, until the desired volume of drug has been drawn up. VISUAL INSPECTION The supervising pharmacist should verify that the correct volume of product is in the syringe before compounding continues. This is the safest method because the pharmacist can see the actual volu me in the syringe. The "syringe pullback method" is when the pharmacist verifies the volume in an empty syringe after the compounding is done; the technician "pulls-back" the plunger of the syringe to the volume of product that was added into the IV admixture and places the empty syringe next to the vial. This method relies on memory and is not recommended. Finished CSPs are visually inspected immediately after preparation, against a dark background, for particulates, cored pieces, precipitates and cloudiness. The container should be lightly squeezed to check for leakage. TERMINAL STERILIZATION Terminal sterilization is required for high-risk CSPs (discussed on the next page). Terminal sterilization methods include steam sterilization (with an autoclave), dry-heat sterilization (depyrogenation), gas sterilization, ionizing radiation and unidirectional aseptic processing. Do not use heat on heat-sensitive drugs (e.g., proteins, including hormones and insulin). Bubble-Point Test and Filter Integrity CSPs that are heat-labile (e.g., hormones, insulin, other proteins) can be sterilized with filtration using a 0.22-micron filter. The filter will remove microorganisms larger than 0.22 microns, including bacteria, viruses, yeast and fungi. If filtering is used, the bubble-point test must be performed. This test uses pressure to force liquid to "bubble" out of the filter to test the filter integrity. 283 17 I COMPOUNDING Ill: DOCUMENTATION & PREPARATION LABEL REQUIREMENTS The labels of CSPs must have the names and amounts or concentrations of ingredients, the total volume, the BUD, the route of administration, the storage requirements and other information for safe use. All hazardous preparations must have a label that reads "Chemotherapy- dispose of properly" or something similar. Typically, the sterile additives (i.e., drugs) come in solution and are ready to be withdrawn from the vial and used. The additives are injected into a sterile diluent contained in an IV bag, or drawn up into a sterile syringe. Low-risk sterile drugs have the lowest contamination risk, and the longest BUD. MEDIUM-RISK STERILE COMPOUNDING Auxiliary labels should be placed on CSPs that require special handling (e.g., if a filter or light protection is required, or if the CSP should not be refrigerated). High-alert medications (defined by ISMP) are drugs that have a high risk of causing significant patient harm when used incorrectly. Appropriate auxiliary labels such as "Contains Potassium" or "Warning: Paralyzing Agent" should be used. PVROGEN (BACTERIAL ENDOTOXIN) TESTING Endotoxins are produced by both Gram-positive and Gramnegative bacteria and fungi. Endotoxins from Gram-negative bacteria are more potent and represent a serious threat to patient safety. Pyrogens can come from using equipment (such as glassware and utensils) washed wit h tap water. To avoid this issue, glassware and utensils should be rinsed with sterile water and depyrogenated using dry-heat (steam) sterilization with an autoclave. Certain CSPs must be tested for endotoxins. The reagent for the bacterial endotoxins test (BET) is called the Limulus Ameb •yt y at (LAL). OR :'J'J Kiri// M/ayshev, winnievinzence/Shutterstock.com The contamination risk increases each time the bag is entered (i.e., with a syringe, to place in an additive). If more than 3 sterile components are needed (including the diluent), the CSP is medium-risk. Parenteral nutrition preparations require many additives (see image below) including dextrose, lipids, amino acids, multivitamins, minerals, electrolytes and other sterile ingredients. A compounded parenteral nutrition would be medium-risk. Another type of mediumrisk compounding is making a batch of drugs; for example, preparing ten IV bags of cefazolin in 50 mL DSW for the ten total knee arthroplasty surgeries scheduled that day. STERILE PREPARATION AND RISK USP categorizes CSPs by the ~isk of contamination, which is based on the compounding area, ingredients and equipment used, and the complexity of the preparation. A sterile product that is contaminated with microorganisms or any other type of contaminant can cause severe illness and death. The risk levels are low, medium and high. Categorization into these three levels assumes that compounding is done in a cleanroom (i.e., an ISO 5 PEC contained within an ISO 7 SEC). Low-risk and medium-risk CSPs are commonly prepared by pharmacy staff. There are two other special categories: low with less than 12-hour BUD and immediate-use. These risk levels are used to determine an appropriate BUD. LOW-RISK STERILE COMPOUNDING The majority of sterile compounds prepared by pharmacists are low-risk. Low-risk sterile compounding uses 1 to 3 components (including the diluent) that are supplied as sterile from the manufacturer. 284 HIGH-RISK STERILE COMPOUNDING High-risk sterile compounding is not common in most practice settings. High-risk sterile compounding uses non-sterile ingredients and equipment, including some of the equipment that is normally used for non-sterile compounding. Consequently, the end product will need to be sterilized prior to use. High-risk sterile drugs have the highest contamination risk, and the shortest BUD, with the exception of immediate-use CSPs. These are CSPs prepared in emergency situations in which there is inadequate time to prepare the CSP aseptically, such as during a code blue. Immediate-use CSPs have the shortest BUD. RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 Ce11tain high-risk CSPs and CSPs intended for use beyond the recommended BUD must have sterility testing. The sterility testing should use either tryptic soy broth (TSB) or fluid thioglycollate medium (ITM), and include bacterial endotoxin (pyrogen) testing prior to use. AREA REQUIREMENTS• RISK LEVEL CHARACTERISTICS EXAMPLES INSIDE A CLEAN ROOM s; 3 sterile ingredients (includfng diluent) Low I No more than 2 entries into any 1 sterile container or device Reconstituting a single-dose vial - ' - ' of antibiotic with sterile water and transferring it to a normal saline IV bag. Limited to transferring, measuring and mixing manipulations Medium ISO 5 PEC ISO 7 buffer area ISO 7 ante area (HD) ISO 8 ante area (non-HD) High > 3 sterile ingredients OR Preparing parenteral nutrition. Multiple doses of a sterile product withdrawn from the same vial to make several CSPs of the same product (a batch) Complex aseptic manipulations Using a multi-dose vial of antibiotic and transferring single-doses to several normal saline IV bags for multiple patients. This process is called batch preparation. ---+-- • Non-sterile ingredients ----- Non-sterile equipment Using a non-sterile bulk drug powder or non-sterile equipment to a make a preparation that will be termlnally sterilized. Sterile components were held outside of ISO 5 air for more than 1 hour. ISO 5 PEC in an SCA ISO 5 C-PEC in a C-SCA Oean, uncluttered, functionally separate area Low-risk CSPs with 12-hr or less BUD See characteristics for low-risk Reconstituting a single-dose vial of antibiotic and transferring to a small IV bag in a CAI in an SCA in a satellite pharmacy (not in a cleanroom). Immediate-use Only intended for emergency administration Providing stat IV drug administration in a medical setting or ambulance. Must be for administration within 1 hour • Requirements are discussed in detail in the Compounding I chapter. DETERMINING THE BEYOND-USE DATE BASED ON CSP RISK LEVEL The BUD is the date or time after which the CSP should not be used. The BUD is determined by USP 797 standards and the stability/expiration date of the individual ingredients, whichever is shorter. The higher the CSP risk level, the shorter the BUD, and the colder the storage temperature, the longer the BUD. Sterility testing can be done to see if a longer BUD is possible. CSP RISK LEVEL ROOM TEMP BUD REFRIGERATED BUD Low 48 hours 14 days 30 hours 9 days 24 hours 3 days --Medium High Low-risk CSP prepared in an ISO 5 PEC or C-PEC in an SCA or 1 12 hours C-SCA (not in a cleanroom) Immediate-use 1 hour Foo. NIA FROZEN BUD 45 days -- NIA NIA ----285 17 I COMPOUNDING Ill: DOCUMENTATION & PREPARATION BUDs for Single-Dose Containers (SDC) and Multi-Dose Containers (MDC) The BUDs in this table are for the vials, bags, bottles, syringes and ampules that contain the drugs, electrolytes and other items that are being put into the CSPs. For example, a single-dose 1 g vial of vancomycin, once opened, can be used for up to 6 hours if the vial was opened in and remains in the PEC, which has ISO 5 air. DOSE BUD SOC - vial, bag, bottle, syringe 1 hour from the time of puncture or opening Outside an ISO 5 environment SOC - vial, bag, bottle, syringe Up to 6 hours from the time of puncture or opening Inside an ISO 5 environment Any unused contents left in the ampule cannot be stored and must be discarded SOC - ampule Inside or outside an ISO 5 environment MDC -- I Inside or outside an ISO 5 environment I Up to 28 days from the time of puncture or opening, unless otherwise specified by the manufacturer CSP QUALITY ASSURANCE Every facility that prepares CSPs must have a quality assurance (QA) plan that evaluates, corrects and improves the quality processes. The plan should minimally include: Personnel training and assessment Environmental monitoring Equipment calibration and maintenance Each part of the QA plan must be documented and the follow-up actions identified must have assigned personnel responsible for each item, with expected dates of completion. If a problem has been identified or a medication error or safety issue has occurred, a root cause analysis should be started as soon as possible, discussed in the Medication Safety & Quality Improvement chapter. A failure mode and effects analysis of new techniques can help to identify problems with new procedures in advance. Standard Operating Procedures (SOPs), described earlier, should be developed, followed and periodically reviewed to determine if revisions are needed. RECALLS When high-risk level CSPs are dispensed before receiving the results of their sterility tests, there must be a written procedure requiring daily observation of the incubating test specimens and immediate recall of the dispensed CSPs if there is evidence of microbial growth. All patients and physicians who received the recalled CSPs are notified of the potential risk. If sterility test results come back positive, there should be an investigation of aseptic technique, environmental control and other sterility assurance measures to determine the source of contamination and improve the methods or processes. Recalls apply to both sterile and non-sterile preparations and are discussed further in RxPrep's MPJE Course. CLASS DESCRIPTION Class I A situation in which there is a reasonable probability that the use or exposure will cause serious adverse health consequences or death. For example, microbial growth is observed in an intrathecal injection. Recall Class II Recall Class Ill Recall 286 A situation in which use or exposure can cause temporary or reversible adverse health consequences or where the probability of harm is remote. For example, ketorolac injections have been recalled in 2010 and 2015 due to the possibility of particles in the vials. A situation in which use or exposure is not likely to cause adverse health consequences. For example, the coloring on tablets may have been applied inconsistently. RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 OSMOLARITY AND INTRAVENOUS DRUGS OSMOLARITY AND TONICITY Osmolarity and tonicity are related terms; both are used to express the solute concentration in solution. Osmolarity includes all solutes and tonicity includes only the solutes that do not cross the vasculature (i.e., the biological membrane). Osmolarity in Intravenous Formulations Saline concentrations greater than 0.9% are referred to as hypertonic. Hypertonic saline injections, given erroneously, can be fatal. Hypertonic saline (commonly 3% or 23.4%) is used for various indications in the acute care setting, such as treating hyponatremia (3%) and for use in preparing parenteral nutrition (23.4%). When hypertonic saline is administered into a peripheral vein, the high concentration of solutes relative to the concentration in the blood will cause water to move out of the 1·ed blood cells (RBCs) in an attempt to dilute the solute concentration. This will cause the RBCs to become shriveled and dysfunctional. To avoid adverse outcomes, hypertonic saline is often restricted to the pharmacy and only dispensed for administration in areas of the hospital where safety can be monitored (e.g., a critical care unit). The osmolarity of an IV formulation can impact its administration. The highest osmolarity acceptable for peripheral IV administration is -900 mOsmol/L. Solutions with higher osmolarity should be administered via a central line (i.e., not by peripheral administration) to avoid damaging the vein (i.e., phlebitis). The central line delivers intravenous medications and fluids into a larger blood volume, which quickly dilutes the solution. When a preparation has lower osmolarity than blood (i.e., it is hypotonic), the RBCs will absorb fluid. This can cause hemolysis (i.e., the RBCs will burst), which can be fatal. In general, ½NS (0.45%), which has an osmolarity of 154 mOsm/L, is the lowest osmolarity of saline that should be administered intravenously alone. Lower concentrations of saline, such as ¼NS (0.225%) can be administered if combined with other fluids, such as 5% dextrose, which will increase the total osmolarity of the fluid. RESISTING CHANGES IN pH WITH BUFFER SYSTEMS As stated earlier, the blood has a slightly alkaline pH of 7.35 - 7.45. Tissues and cells (e.g. the nose, eyes, skin) are very sensitive to changes in pH (defined as the number of protons in solution). The body uses the carbonic acid-bicarbonate buffer system to resist changes in pH in both directions: When the pH rises, the blood becomes more basic. Hydrogen ions (protons) will be released from carbonic acid, which causes the pH of the blood to lower. The blood becomes more acidic. When the pH falls, the blood becomes more acidic. Hydrogen ions get picked up (more bicarbonate binds with protons), which causes the pH of the blood to rise. The blood becomes more basic. The above scenario is referring to the carbonic acidbicarbonate buffer system. There are two other buffer systems that resist changes in pH; the phosphate buffer system and the protein buffer system. Preparations that are administered in sensitive tissue (e.g., eye drops, injections) must be formulated to keep the pH within a narrow range to avoid damaging the tissue and causing pain. In addition to providing acceptable formulations for patient care, the pH will be an important consideration to provide stability for the drug in the solution. Similar to human blood, compounding preparations that require a narrow pH range will need a buffer system that can resist changes in pH. Buffer systems, similar to the buffer systems in the body, consist of an acid and its salt. For example, acetic acid is used with sodium acetate, its salt, in a common buffer system: Acetic acid serves as the proton donor to decrease the pH. Sodium acetate serves as the proton acceptor, to increase the pH. In the Calculations IV chapter, the Henderson-Hasselbalch equation was used to calculate the pH of a solution when the molar (M) concentrations of the buffer components were provided. A variation of the Henderson-Hasselbalch can be used to determine the amount of buffer required. 287