Parenteral Nutrition PDF

**Parenteral Nutrition** Parenteral nutrition (PN) is the process of providing nutrition to individuals that are unable to receive nutritional intake via the gastrointestinal tract. This is a complex process that could result in harm to patients if not performed in a safe manner by trained individu...

**Parenteral Nutrition** Parenteral nutrition (PN) is the process of providing nutrition to individuals that are unable to receive nutritional intake via the gastrointestinal tract. This is a complex process that could result in harm to patients if not performed in a safe manner by trained individuals. This section will discuss procedures for safely compounding parenteral nutrition. First let's discuss the different types of parenteral nutrition compounding. Depending on the compounding facility a commercially available multichambered parenteral nutrition bags may be utilized, or they may compound custom PN bags. Facilities may also compound PN as a 2-in-1 formulation or a 3-in-1 formulation. - 3-in-1 emulsion: mixture of crystalline amino acids, dextrose, and oil-in-water lipid emulsion (also known as Total Nutrient Admixture or TNA) - 2-in-1 solution: mixture of crystalline amino acids and dextrose - In this setup an oil-in-water lipid emulsion is infused separately to the patient Irregardless of the formulation used, facilities and compounding personnel must be aware of the potential stability and compatibility concerns when compounding parenteral nutrition. The American Society of Parenteral and Enteral Nutrition Parenteral Nutrition Safety Committee defines stability and compatibility in this way (2022): - *Stability -- maintenance of chemical integrity of active ingredient(s) or the physical integrity of the dosage form or system over time in a specific environment.* - *Instability -- irreversible decomposition and/or degradation of active ingredients or dosage form due to pH, temperature, light, oxygen, solvents, and/or reactants* - *Compatibility -* *uneventful physical and chemical coexistence of two or more components once combined* - *Incompatibility - change in color, pH, osmolality, or formation of a precipitate that alters the admixture* PN should not be used as a vehicle for non-nutrient medications without supporting data as this increases the risks of instability and incompatibility. Compatibility Incompatibilities within a PN admixture can limit therapeutic effect or increase risk of adverse effects. Physical precipitates can occur in an admixture if not dosed or compounded correctly. There are a variety of potential causes of incompatibility. One major factor that is controllable by the compounder is the order of mixing during PN compounding. Calcium and phosphate containing products may precipitate (formation of solid material) if there is too high of concentrations of these products within the PN or if they are injected into the final bag too closely in sequence. Calcium and phosphate salts have improved solubility when there is an increase in separation between the two additives. Stability Total nutrition admixtures (3-in-1 admixtures) contain and oil-in-water lipid emulsion. A variety of factors can cause instability of the lipid emulsion which can lead to oiling out (cracking) or coalescence. These conditions cause the TNA to be unsafe for use. - Coalescence: appears as presence of yellow-brown oil droplets at or near the TNA surface - Oiling out: yellow-brown liquid at the surface Final concentrations of amino acids, dextrose, and lipids can impact the stability of PN. ASPEN guidelines recommend that a TNA maintain final concentration of amino acids \> 4%, dextrose \> 10%, and lipids \> 2% for stability. The compounder must inspect the final products for any signs of instability or incompatibility prior to dispensing the PN. Any irregularities should be reported to the designated pharmacist. All PN bags should be dispensed with a filter for use during administration. This filter helps to prevent any potential precipitate from reaching the patient that was either not caught during the verification or was not visible due to the white appearance of the TNA. A 1.2‐μm filter is recommended for use with all PN both 2-in-1 and 3-in-1 formulations. Multichambered PN (MCB-PN) Many smaller facilities choose to utilize multichambered PN for their patient needs due to the need for minimal compounding. This offers healthcare facilities an option for parenteral nutrition if they do not have a USP 797 compliant sterile compounding facility or if they are unable to outsource this need. The MCB-PN are available as both two-chamber and three chamber bags that must be activated prior to administration by breaking the seal between the individual chambers to allow the contents to mix. Safety considerations when using MCB-PN must still be considered. - These bags may not be recognized as PN which could lead to inappropriate use. - Failing to activate the bag properly the bags prior to use. - Allowing the MCB-PN to hang greater than 24 hours increasing the risk of infection for the patient. - Failing to account for stability of the MCB-PN when introducing additives - Failing to add essential components (multivitamins and trace elements). - Administering a two-chamber MCB-PN without lipids leading to essential fatty acid deficiency. - Errors in transitions of care. - For at-home PN, failure to provide adequate patient or caregiver education. Two Chamber Three Chamber Nourish to flourish  Custom PN Custom PN can be compounded either utilizing an automated compounding device or by use of gravity compounding. Gravity compounding is a manual method that relies on gravity to transfer large fluid volumes from the original container to the final PN container. This method is no longer commonly utilized due to the labor-intensive nature of the process and the increased risks of contamination of final products due to multiple manipulations. The use of technology has streamlined this process with an automated compounding device. Automated compounding devices utilize a fluid pump technology and software that controls the compounder pump. This setup provides a higher level of accuracy than that which is achievable through manual processes. It also has built in safeguard such as barcode scanning, alerts for situations that could result in inaccurate dosages being delivered (empty source containers or occluded tubing), alerts for formulations issues, and recommendations to ensure a compatible final product. The compounding facility should follow these general considerations for use: - Only properly trained and competent personnel should be permitted to use the automated compounding device. - The compounder should not be utilized for any other purpose than for PN without approval from the designated pharmacist. - The automated compounded devices must be used according to the manufacturer recommendations and tubing change recommendations should be followed. - The sequence of additives in the compounding device should not be altered from the established format. References 1. Boullata JI, Mirtallo JM, Sacks GS, et al. ASPEN Parenteral Nutrition Safety Committee. Parenteral nutrition compatibility and stability: a comprehensive review. *J Parenter Enter Nutr*. 2022;46(2):273‐299. doi:10.1002/jpen.2306 23. 2. Boullata JI, Holcombe B, Sacks G, et al. Parenteral Nutrition Safety Committee, American Society for Parenteral and Enteral Nutrition. Standardized competencies for parenteral nutrition order review and parenteral nutrition preparation, including compounding: the ASPEN model. *Nutr Clin Pract*. 2016;31(4):548‐555. 3. ASHP Guidelines on the Safe Use of Automated Compounding Devices for the Preparation of Parenteral Nutrition Admixtures. Developed through the ASHP council on professional affairs and approved by the ASHP board of directors on April 27, 2000. *AM J Health-Syst Pharm.* 2022; 79: 730-735. doi:10.1093/ajhp/zxac004. 4. Mirtallo JM, Ayers P, Boullata J, et al. ASPEN Lipid Injectable Emulsion Safety Recommendations, Part 1: Background and Adult Considerations. *Nutr Clin Pract*. 2020;35(5):769-782. [doi:10.1002/ncp.10496](https://doi.org/10.1002/ncp.10496). 5. Mays A, Ayers, P, Monczka J, et al. Safety in parenteral nutrion compounding. *Nutr Clin Pract.* 2023;38:1253-1263. doi: 10.1002/ncp.11064. **Assessment Questions** **Specialized Compounded Sterile Preparations** *Epidural and Intrathecal Admixtures* Compounded sterile preparations administered via the epidural and intrathecal routes are considered high risk admixtures due to the high-risk nature of the route of administration. Due to this the Institute of Safe Medication Practices recommends that all intrathecal and epidural admixtures undergo a preproduction visual confirmation of the amount of each ingredient (prior to addition to the final container). Proxy methods of verification such as the syringe pull-back method of verification should not be used in the preparation of epidural and intrathecal admixtures. All epidural and intrathecal admixtures should also be preservative free. Multiple-dose vials contain a small amount of a preservative agent, added to retard the growth of bacteria or other organisms that may inadvertently contaminate a product. These preservatives are neurotoxic when injected intrathecally and epidurally. Because of their toxicity, solutions with preservatives should not be used for epidural or intrathecal dosage forms. *Ophthalmic Admixtures* Compounding of ophthalmic admixtures is similar to that of IV preparations, but present additional concerns. The following are important factors to consider in preparing an ophthalmic preparation. - Sterility - pH, buffering - inherent toxicity of the drug - need for a preservative - solubility - stability in an appropriate vehicle - tonicity - viscosity - packaging and storage of the finished product. Ophthalmic admixtures must be sterile just as IV admixtures must be sterile. All the aseptic principles discussed previously also apply to compounding of ophthalmic admixtures. Ophthalmic admixtures prepared from a sterile powder or in a glass ampule should be filtered through a 5-micron filter to remove potential particulate matter. Any ophthalmic products requiring sterilization must use a validated method. The most common method is use of a 0.22-micron filter to filter into a sterile final container. Preservative-free products should be used as some preservatives are known to be toxic to internal structures of the eye. References American Society of Hospital Pharmacists. ASHP technical assistance bulletin on pharmacy-prepared ophthalmic products. *Am J Hosp Pharm*. 1993; 50:1462--3. *Medication Cassettes* There are a variety of brands of medication cassettes and pump systems that can be utilized to continuously deliver a medication infusion either to a targeted site or into the patient's circulatory system. These cassettes and pumps are commonly compounded in compounding facilities. Filling of medication cassette instructions: - Open the medication cassette and inspect to ensure it is not damaged - Attached a luer-lock syringe containing the desired medication to the end of the cassette line - Tilt the cassette to a 70-degree angle and fill - When 75% full clamp the line and tap the cassette to gather the air at the top near the outlet point. - Open the clamp and withdraw the air - Hold the syringe with the tip down and finish filling the reservoir - Clamp the line and disconnect the syringe - Cap line with a sterile cap It is important with medication cassettes to remove all the air from the reservoir. For other types of pump systems it is important to follow the manufacturer's instructions for filling of these pumps. CADD Medication Cassette Reservoirs \| Medline Industries, Inc. *Irrigations* Irrigation fluids are used to irrigate a variety of wounds and internal body cavities. Because many of these body cavities are not normally open to the external environment the irrigation fluids must be sterile and comply with all aseptic principles. Unlike IV admixtures, irrigations are commonly mixed into sterile irrigation bottles.  **Assessment Questions** **Hazardous drugs** To understand sterile compounding of hazardous drugs, compounding personnel must be knowledgeable regarding published information on USP 800 Hazardous Drugs -- Handling in Healthcare Settings and the NIOSH List of Hazardous Drugs in Healthcare Settings. [USP 800]: Describes the practices and standards for the safe handling of Hazardous Drugs (HD). Handling HDs includes, but is not limited to, the receipt, storage, compounding, dispensing, administration, and disposal of sterile and nonsterile **products and preparations.** [NIOSH List of Hazardous Drugs in Healthcare Setting]: assists employers in providing safe and healthy workplaces by identifying drugs approved by the FDA that have intrinsic properties that meet the NIOSH definition of a hazardous drug. NIOSH defines a hazardous drug as a drug that is: 1. Approved for use in humans by the FDA 2. Not regulated by the US Nuclear Regulatory Commission; and, 3. Either: a. Manufacturer Special Handling Information (MSHI) included in the prescribing information b. Identified as carcinogenic hazard, developmental hazard, reproductive hazard, genotoxic hazard, or other health hazard exhibiting one or more of the following toxicity criteria in humans, animal models, or in vitro systems i. carcinogenicity ii. developmental toxicity iii. reproductive toxicity iv. genotoxicity v. organ toxicity at low dose; or, vi. structure and toxicity profile that mimics existing drugs meeting any of these previous toxicity types ***Hazardous Drug Classifications (Classified by NIOSH)*** **The 2016 NIOSH list of hazardous drugs classified hazardous drugs by these categories:** - **[Table 1: Antineoplastic]: These are Cytotoxic products AKA Chemotherapy. Products that inhibit or prevent the growth and spread of tumors or malignant cells. (Example: Cytarabine)** - **[Table 2: Non-Antineoplastic]: Drugs that meet one or more of the NIOSH criteria for a hazardous drug, including those with the manufacturer's safe-handling guidance. (Example: Fosphenytoin)** - **[Reproductive-Risk]: Non- Antineoplastics that primarily have adverse reproductive effects. (Example: Valproate Sodium)** **The draft of the 2020 NIOSH List of Hazardous Drugs in Healthcare Settings made these changes to the categories:** - **Table 1 no longer contains just antineoplastic drugs. This table now includes drugs that contain manufacturers safe handling instructions (MSHI) in the package insert, are known to be a human carcinogen, or classified as "carinogenic" or "probably carcinogenic".** - **Tabe 2 medications meet the NISOH definition of a hazardous drug but do not meet the criteria for inclusion in table 1. This table now also includes developmental and/or reproductive hazards.** - **There is no longer a table 3 for reproductive risk as these are included in table 2.** **The *NIOSH List of Hazardous Drugs in Healthcare Settings, 2023* is still under development.** Required Work Practices for Compounding Hazardous Drugs - Unnecessary items should be left out of the PEC - All HD preparations should be compounded on an absorbent, plastic-backed mat (chemo mat). - The mat should be changed immediately if a spill occurs and regularly during use and should be discarded at the end of the daily compounding activity. - Transport bags should not be placed inside the PEC during compounding to prevent contamination. - Waste and sharps containers within the PEC should be decontaminated prior to removing from the PEC. **Importance of PPE** Routes of unintentional entry of HDs into the body include dermal and mucosal absorption, inhalation, injection, and ingestion (e.g., contaminated foodstuffs, spills, or mouth contact with contaminated hands). In addition to unintentional exposure during the compounding process, containers of HDs have been shown to be contaminated upon receipt. Both clinical and nonclinical personnel may be exposed to HDs when they handle HDs or touch contaminated surfaces. Each compounding facility should establish PPE standard operating procedures for all steps of the process handling of hazardous drugs. PPE requirements during sterile compounding were discussed previously. Priming of Administration Set (also known as tubing) When compounding hazardous medications, the administration tubing is primed in the pharmacy prior to adding any medication to the bag. This means that fluid from the IV bag is allowed to flow through the tubing to remove all the air from the tubing. This is to ensure the final dose is ready for administration and to prevent hazardous substance exposure to the individual administering the dose. Process for priming of tubing: 1. Remove the tab from the infusion port. 2. Remove the cap from the tubing spike. 3. Push and twist the tubing spike into the infusion port. 4. Hang the IV bag. 5. Gently squeeze the drip chamber to fill it halfway. 6. Slowly allow open the clamp by turning it. 7. The fluid will drain through tubing removing air. Once all air is eliminated clamp the tubing shut. Closed System Drug-Transfer Devices (CSTD) NIOSH defines a Closed System Drug-Transfer Device as a "drug transfer device that mechanically prohibits the transfer of environmental contaminants into the system and the escape of the hazardous drug or vapor concentrations outside the system." These devices achieve this by one of two means: - Physical barrier - Air-cleaning technology The intent of these devices is to prevent personnel exposure to hazardous substances. NIOSH recommends that these devices are used be used during compounding of hazardous products all the way through the process of administration of these products. The components involved with the CSTD will depend upon the brand utilized within the compounding facility. These are some of the components utilized with CSTD: - Drug vial adaptors - IV bag/line adaptor - Syringe adaptors or syringe units - Administration sets - Spike adaptors Process for use of CSTD 1. CSTD administration set or a spike adaptor with regular administration set is attached to the final container and primed prior to addition of hazardous medication. 2. A CSTD line adaptor is placed at the end of the tubing 3. The vial adaptors are attached to the top of the medication vials. 4. A CSTD syringe unit or syringe adaptor is used to attach to the vial adaptors and draw up the desired dose. 5. The syringe then attaches to the CSTD administration set or spike adaptor to inject the medication into the final container. 6. An IV-line adaptor is sent with the final dose for the individual administering the dose to attach to the patient's IV line (this ensure it is a closed system during administration as well). If a CSTD is not utilized during compounding the compounder should utilize negative pressure technique to prevent exposure to hazardous substances. When utilizing negative pressure technique there is either no air injected into the vial prior to withdrawing liquid or less air is injected than the solution that is being withdrawn. When utilizing this technique, no more air than 75% of the volume you plan to withdraw should be injected into the vial. Spill Kit A spill kit must always be available in areas where hazardous drugs are being handled. Personnel must be properly trained in use of the spill kit and proper use of PPE and respirators when cleaning up spills. Any spill must be contained and cleaned immediately and disposed of as a hazardous waste. References 1. NIOSH (2004). NIOSH Alert: preventing occupational exposures to antineoplastic and other hazardous drugs in health care settings. *DHHS (NIOSH) Publication*, 2004-165. 2. NIOSH (2016). NIOSH list of antineoplastic and other hazardous drugs in healthcare settings*,* 2016*. DHHS (NIOSH) Publication,* 2016- 138.   3. NIOSH (2020). NIOSH List of Hazardous Drugs in Healthcare Settings, 2020. *NIOSH Docket Number 233-C, CDC-2020-0046.* 4. Need Reference for USP 800 **Assessment Questions** **Sterile Preparations from Non-Sterile Components** Compounding with sterile starting ingredients relies on aseptic processing to ensure that the final product is sterile. This means the starting components are sterile and that processing of these components is completed in a controlled environment in a manner that prevent contamination. Unlike with aseptic processing this section is going to discuss requirements if the starting ingredients are not sterile. This includes discussion of requirements of the supplies and components during the process as well as the depyrogenation and sterilization requirements. *Supplies* Supplies (e.g., beakers, utensils, filters, needles, and syringes) must be non-reactive, non-sorptive, sterile, and depyrogenated. *Components* Component Selection Conventionally manufactured products should be used when available and appropriate for the intended CSP. Components that are to be used must: - Comply with criteria in the USP-NF, if one exists - Have documentation or a certificate of analysis (COA) including the specifications and test results that show the API meets expected quality standards - Be manufactured by an FDA-registered facility or comply with the laws and regulations of the applicable regulatory jurisdiction if outside the US Components labeled with the following statements must not be used for compounding of CSPs: - Not for pharmaceutical use - Not for injectable use - Not for human use - Equivalent statements to these A COA or other documentation must also be accompanied by each lot of sterile, depyrogenated containers received showing they meet established specifications. If sterilization and depyrogenation is being performed on site, the efficacy of the process must be established and documented. Component Receipt and Evaluation Every lot of a component received must be inspected for damage, evidence of deterioration, or other quality issues. Any component not passing initial inspection must be promptly rejected, segregated, and clearly labeled. Other lots of that component from that vendor must also be examined to determine if the same defect is present. If the received component does not contain an expiration date, the date of receipt must be clearly marked on the container. These products must be assigned a conservative expiration date, not to exceed 1 year from receipt. Prior to use all component must be reinspected to ensure there are no quality issues present at that time and that they have been stored under correct conditions. To make this determination the following information should be used: - Prescription or medication order - Compounding record - Master formulation record - Vendor labels - COAs - Product labeling - Labeling of CSPs - Documentation of the compounding facility's storage conditions and practices The same rejection process applies when reinspecting components prior to use as it did with inspection upon initial receipt. Storage of Components Components should be stored under conditions consistent with the manufacturer specifications (temperature, humidity, lighting). The temperature in the storage area must be monitored at least once daily or by continuous temperature recording device. Temperature recording devices must be verified for accuracy annually or as specified by manufacturer. *Presterilization Procedures* For facilities that are preparing category 2 or 3 CSPs from nonsterile starting components, presterilization procedures must be completed in an ISO Class 8 or better environment. This includes weighing, measuring, or other means of manipulating the components. These procedures must be performed in single-use containment glove bags. Containment ventilated enclosures (CVEs), BSCs, or CACIs to minimize risk of airborne contamination. If using CVEs, BSCs, or CACIs, these devices must be certified every 6 months. These procedures must not adversely affect the SEC air quality as demonstrated during certification under dynamic operating conditions. *Sterilization methods* Sterilization utilizes either a physical or chemical process to kill or remove all types of microorganisms. The method used for sterilization will depend upon the properties of both the CSP and the final container utilized. The most common method utilized for sterilization is filtration. The following must be considered when selecting an appropriate method of sterilization: - Terminal sterilization is the preferred method unless the specific CSP or final container cannot tolerate terminal sterilization - Steam sterilization is not an option if moisture, pressure, or temperatures would degrade the CSP or if there is insufficient moisture to sterilize the CSP within the final, sealed, final container. - Filtration may not be an option for some CSPs *Filtration* Filtration is not considered terminal sterilization because following filtration the liquid must be transferred into the final container closure system aseptically. Filters are single-use, sterile, depyrogenated devices and must not be re-sterilized or reused. These filters must be certified by the manufacturer to retain 10^7^ microorganisms of a strain of Brevundimonas diminuta per square centimeter of upstream filter surface area under conditions similar to those in which the CSPs will be filtered. The same filter should not be used in both directions. Syringe sizes smaller than 10 ml should be used with caution with disc filters. These syringes can produce pressures higher than the bubble point of the filter. A syringe size of 20 ml is recommended. Filter selection depends upon the following criteria: - Rating for human use (filters stating "for laboratory use only" or similar statement should not be used) - Pore size - Compatibility with solution being filtered - Characteristics of the solution to be filtered Pore Size The pore size in the filter determines the size of the particles retained within the filter membrane. A filter is considered to be sterilizing if it has a nominal pore size of 0.2 or 0.22 micron or smaller. This means that the membrane will retain any particulates and precipitates larger than 0.2 or 0.22 micron. Solution Compatibility There are two common compatibility issues with filters: - Sorption -- drug binds to the filter - Leaching -- solution extracts substances utilized in the manufacture of the filter which results in the final product having unintended components Filters can not be assumed to be chemically and physically compatible with the solution to be sterilized. The manufacturer's technical data sheets should be referenced to ensure they are safe for use. When referencing the data sheets the compounder must ensure they are compatible at the same pressure and temperature conditions used during the compounding process. Larger sized particles may also be physically incompatible with the filter. Larger molecular weight drugs such as proteins could have their structure altered by the shear stress of the filter rendering them inactive. Solution Compatibility Solution compatibility characteristics to consider include: - Volume to be filtered; and, - Particulate load Volume When determining the proper filter to be used the compounder needs to ensure the volume is less than the maximum allowable by that filter. Replacing a filter during the compounding process adds an additional opportunity for contamination and should be avoided. Particulate Load While most solutions compounded in a controlled environment have a low particulate load, compounds containing insoluble or impure components may not. If a high particulate load is anticipated a prefilter should be utilized. This is to ensure that the filter does not become clogged during the compounding process. The prefilters are 5 or 1.2 micron in size and are placed upstream of the 0.2-micron filter to decrease the particulate load on that filter. Need for a prefilter may indicate an inappropriate formulation and should be assessed and modified if necessary. Filter Integrity Performing a filter integrity test following use of a filter is required by USP 797 to ensure that the filter remained intact throughout the sterilization process. The test utilized to check the filter integrity is called a bubble point test. If multiple filters are used during the sterilization process the bubble point test must be completed on each filter. Bubble Point Test Procedure - Filter media is wetted with an appropriate fluid (typically water for hydrophilic membranes) - Pressure is applied to the upstream side of the filter while tubing downstream is submerged in water. Start at 80% of the expected bubble point pressure and slowly increase. - The bubble point is the pressure at which bubbles can be seen exiting the submerged tubing at a rapid and continuous rate. Failure of the test necessitates that the solution be discarded, or after investigating the cause of the failure and selection of an appropriate filter, re-sterilized. This should not occur more than one additional time. If failure occurs it is important to confirm that the filter is physically and chemically compatible with the solution. *Steam Sterilization* Steam sterilization is considered a terminal sterilization process because it is used to sterilize the product and final container. This method of sterilization is not an option if moisture, pressure, or the temperature would degrade the CSP. Steam sterilization uses an autoclave with moist heat at 121 degrees Celsius under a pressure of 15 PSI for 20 to 60 minutes depending on the CSP. This is the preferred method for use sterilizing aqueous solutions and suspensions. The CSP must be placed in the autoclave to allow steam to reach the CSPs without entrapment of air such as flat, stainless-steel trays with low sides or ventilated bottoms. CSPs must be wrapped for steam sterilization in low-lint protective fabric or paper or seal in envelopes that permit steam penetration and are designed to minimize risk of post-sterilization contamination. Immediately prior filling containers for steam sterilization they must be passed through a filter with a pore size of not larger than 1.2-micron for removal of particulate matter. Sealed containers must be able to generate steam internally. Stoppered and crimped empty vials must contain a small amount of sterile water to generate steam. The sterilization method utilized should be validated and documented to ensure the that the survival of the most resistant microorganisms is no greater than 10^-6^. Sterilization methods utilized, validation, and monitoring of sterilization must be documented. These sterilization conditions must be documented: - Temperature - Pressure - Chamber loading configuration - Number of articles sterilized It is critical that the steam autoclave is properly maintained, and the effectiveness verified with appropriate measures to ensure the device is functioning properly. *Dry Heat Sterilization* Dry Heat Sterilization is used for materials that may be damaged by moist hear or are not penetrable by moist heat. There are both forced-air and static-air dry heat sterilizers. This is a time-consuming method of sterilization due to the slow rate of heat penetration and microbial killing. They require higher temperatures and longer exposure times that by using steam. These sterilizers use a dry heat using the following protocols: - 170 degrees Celsius for 60 minutes - 160 degrees Celsius for 120 minutes - 150 degrees Celsius for 150 minutes Documentation of this sterilization method must include: - Duration - Temperature - Load configuration - Number of articles sterilized The effectiveness of the dry heat sterilization must be verified and documented with each sterilization run or load. *Depyrogenation* Dry heat depyrogenation is important to reduce endotoxins present. A solution can be sterile but still be pyrogenic due to the presence of endotoxins. Endotoxins are released upon cell lysis and are pyrogenic when they enter the bloodstream. Endotoxins are difficult to remove from solutions and most of the focus to control this is through indirect means such as controlling the number of endotoxins present in starting materials. For this reason, dry heat depyrogenation is commonly used on glassware, metal, and other thermostable containers and components to render them pyrogen free. Depyrogenation requires more heat than sterilization and typically operate at a range of 170 -400 degrees Celsius. Typically, 250 degrees Celsius for 30 minutes is used for depyrogenation. The effectiveness of dry heat depyrogenation cycle must be established initially and verified annually. If changes are made to the depyrogenation cycle the effectiveness must be re-established. Items that are not thermostable must be depyrogenated by multiple rinses with sterile, nonpyrogenic water and then thoroughly drained or dried immediately before use in compounding. References Forrey, R. A., Amerine L. B., Yaniv A. W. (2024). *Compounding Sterile Preparations, 5^th^ Edition.* American Society of Health Systems Pharmacists, Inc. doi: 10.37573/9781585286492 **Assessment Questions** Visual Inspection All CSPs must be visually inspected at the completion of compounding. Any product found to be of unacceptable quality must be promptly labeled as rejected and segregated to prevent use. The visual inspection must include inspection of: - The product to ensure it is free of visible particulates or other foreign matter, discoloration, or other defects. Changes in color or turbidity of the product may indicate stability or sterility concerns. - Label to ensure the CSP and its labeling match the prescription or medication order - Container closure to ensure it is free of leaks, cracks, or improper seals CSPs that are not immediately dispensed following compounding must also be inspected the day of dispensing. This inspection must include visual inspection for defects such as precipitation, cloudiness, or leakage which developed during storage. The rejection process is the same as the rejection process immediately following compounding. **Sterility, Potency, and Endotoxin Testing** *Sterility Testing Requirements* - Category 1 CSPs -- not required - Category 2 CSPs -- only required if extended expiration dating is desired - Category 3 CSPs -- required The tables below show the difference in allowable beyond use dating with and without sterility testing. Category 2 CSPs Maximum Beyond Use Dating **Without** Sterility Testing Room Temperature Refrigerator Freezer -------------------------------------------------------------- ------------------ -------------- --------- Aseptically processed with one or more nonsterile components 1 day 4 days 45 days Aseptically processed with only sterile components 4 days 10 days 45 days Terminally Sterilized 14 days 28 days 45 days Category 2 CSPs Maximum Beyond Use Dating **With** Sterility Testing Room Temperature Refrigerator Freezer -------------------------------- ------------------ -------------- --------- All aseptically processed CSPs 30 day 45 days 60 days Terminally Sterilized 45 days 60 days 90 days Sterility testing is a destructive process and only tests a small portion of the CSPs compounded. Testing will only detect contamination present in the individual products tested. Other CSPs that are not tested could still be contaminated. The volume of a product to be tested depends upon the volume within the CSP. Total volume of the CSP and the amount to be tested is listed below. - Less than 1 ml: full volume must be tested - 1 ml -- 40 ml: half of the volume is tested - 40 ml -- 100 ml: 20 ml is tested - Greater than 100 ml: 10% of the volume is tested, minimum of 20 ml The number of CSPS to undergo testing depends upon the number of items being compounded. - Batches up to 100 units: 10 % of the products (minimum of 4 products) - Batches 100-500: 10 units tested - Batches \>500 units: 2% tested (up to 20 units) - Large volume parenteral: 2% of the units (up to 10 units) There is an exception to these requirements for pharmacies that are not outsourcing facilities registered with the FDA (503A pharmacy). - Batches 1-39: 10% rounded to a whole number (no minimum of 4) Batches undergoing sterility testing should be quarantined until results are available. If released prior to results the facility must have a mechanism to recall the products. *Interpreting Sterility Testing* Failure of sterility testing is evident by the growth of microorganisms. The cause of the failure should be investigated including the identification of the organism. The sterile testing procedure, compounding facility, process, and personnel should all be evaluated as potential causes. If the source is identified it must be corrected and the facility must determine if this source could also impact other compounded CSPs. The investigation and corrective action must be documented. *Endotoxin Testing Requirements* - Category 1 CSPs - do not require endotoxin testing. - Category 2 CSPs (compounded using one or more nonsterile ingredients and **not** **assigned** an extended BUD as listed in the previous section) - should undergo bacterial endotoxin testing. - Category 2 CSPs (compounded using one or more nonsterile ingredients and **assigned** an extended BUD as listed in the previous section) - must undergo bacterial endotoxin testing. - Category 3 CSPs (compounded from one or more nonsterile components) - must undergo endotoxin testing *Interpreting Endotoxin Testing* If available, the bacterial endotoxin limits in an official USP-NF monograph or other CSP formula source should be utilized. Results of endotoxin testing should be compared to these limits to determine if the CSP may be dispensed. *Potency and Stability Testing* Potency testing compares the amount of active drug present within CSP to the desired amount. This is completed to ensure that the product is within acceptable limits. This is commonly used when compounding recipes utilize bulk ingredients. Stability testing can also be evaluated over time to ensure the product retains its initial chemical, physical, and therapeutic characteristics. These studies can evaluate the degradation of the product over time. *Interpreting Potency and Stability Testing* Potency testing acceptable limit is generally accepted as plus or minus 10% of the labeled strength. Potency testing alone cannot be used to determine the stability of a CSP over time. **Assessment Questions**