CSPs compounded under all of the following conditions are at a low risk of contamination.

1. The CSPs are compounded with aseptic manipulations entirely within ISO Class 5 (see Table 1) or better air quality using only sterile ingredients, products, components, and devices.
2. The compounding involves only transfer, measuring, and mixing manipulations with closed or sealed packaging systems that are performed promptly and attentively.
3. Manipulations are limited to aseptically opening ampuls, penetrating sterile stoppers on vials with sterile needles and syringes, and transferring sterile liquids in sterile syringes to sterile administration devices and packages of other sterile products.
4. For a low-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 48 hours at controlled room temperature (see General Notices and Requirements), for not more than 14 days at a cold temperature (see General Notices and Requirements), and for 45 days in solid frozen state at –20 or colder.

1. Single transfers of sterile dosage forms from ampuls, bottles, bags, and vials using sterile syringes with sterile needles, other administration devices, and other sterile containers. The contents of ampuls require sterile filtration to remove any glass particles.
2. Manually measuring and mixing no more than three manufactured products to compound drug admixtures and nutritional solutions.

1. Routine disinfection and air quality testing of the direct compounding environment to minimize microbial surface contamination and maintain ISO Class 5 air quality (see Table 1).
2. Visual confirmation that compounding personnel are properly donning and wearing appropriate items and types of protective garments and goggles.
3. Review of all orders and packages of ingredients to assure the correct identity and amounts of ingredients were compounded.
4. Visual inspection of CSPs to ensure the absence of particulate matter in solutions, the absence of leakage from vials and bags, and the accuracy and thoroughness of labeling.

When CSPs are compounded aseptically under Low-Risk Conditions, and one or more of the following conditions exists, such CSPs are at a medium risk of contamination.

1. Multiple individual or small doses of sterile products are combined or pooled to prepare a CSP that will be administered either to multiple patients or to one patient on multiple occasions.
2. The compounding process includes complex aseptic manipulations other than the single-volume transfer.
3. The compounding process requires unusually long duration, such as that required to complete dissolution or homogeneous mixing.
4. The sterile CSPs do not contain broad-spectrum bacteriostatic substances, and they are administered over several days (e.g., an externally worn or implanted infusion device).
5. For a medium-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 30 hours at controlled room temperature (see General Notices and Requirements), for not more than 7 days at a cold temperature (see General Notices and Requirements), and for 45 days in solid frozen state at –20 or colder.

1. Compounding of total parenteral nutrition fluids using manual or automated devices during which there are multiple injections, detachments, and attachments of nutrient source products to the device or machine to deliver all nutritional components to a final sterile container.
2. Filling of reservoirs of injection and infusion devices with multiple sterile drug products and evacuation of air from those reservoirs before the filled device is dispensed.
3. Filling of reservoirs of injection and infusion devices with volumes of sterile drug solutions that will be administered over several days at ambient temperatures between 25 and 40.
4. Transfer of volumes from multiple ampuls or vials into a single, final sterile container or product.

CSPs compounded under any of the following conditions are either contaminated or at a high risk to become contaminated with infectious microorganisms.

1. Nonsterile ingredients, including manufactured products for routes of administration—other than those listed under c. in the Introduction—are incorporated or a nonsterile device is employed before terminal sterilization.
2. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to ISO Class 5 (see Table 1). This includes storage in environments inferior to ISO Class 5 of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives.
3. Nonsterile preparations are exposed for at least 6 hours before being sterilized.
4. It is assumed, and not verified by examination of labeling and documentation from suppliers or by direct determination, that the chemical purity and content strength of ingredients meet their original or compendial specifications in unopened or in opened packages of bulk ingredients (see Ingredient Selection under Pharmaceutical Compounding—Nonsterile Preparations 795).
5. For a high-risk preparation, in the absence of passing a sterility test, the storage periods cannot exceed the following time periods: before administration, the CSPs are properly stored and are exposed for not more than 24 hours at controlled room temperature (see General Notices and Requirements), for not more than 3 days at a cold temperature (see General Notices and Requirements), and for 45 days in solid frozen state at –20 or colder.

1. Dissolving nonsterile bulk drug and nutrient powders to make solutions, which will be terminally sterilized.
2. Sterile ingredients, components, devices, and mixtures are exposed to air quality inferior to ISO Class 5 (see Table 1). This includes storage in environments inferior to ISO Class 5 of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives.
3. Measuring and mixing sterile ingredients in nonsterile devices before sterilization is performed.
4. Assuming, without appropriate evidence or direct determination, that packages of bulk ingredients contain at least 95% by weight of their active chemical moiety and have not been contaminated or adulterated between uses.

1. Dissolve 3 g of nonsterile commercially available Soybean–Casein Digest Medium in 100 mL of nonbacteriostatic water to make a 3% solution.
2. Draw 25 mL of the medium into each of three 30-mL sterile syringes. Transfer 5 mL from each syringe into separate sterile 10-mL vials. These vials are the controls, and they generate exponential microbial growth, indicated by visible turbidity upon incubation.
3. Under aseptic conditions and using aseptic techniques, affix a sterile 0.2-µm porosity filter unit and a 20-gauge needle to each syringe. Inject the next 10 mL from each syringe into three separate 10-mL sterile vials. Repeat the process into three more vials. Label all vials, affix sterile adhesive seals to the closure of the nine vials, and incubate them at 25 to 35. Inspect for microbial growth over 14 days as described in the Personnel Training and Evaluation in Aseptic Manipulation Skills section.

The licensed health care professionals who supervise compounding are responsible for determining that the selected sterilization method (see Methods of Sterilization under Sterilization and Sterility Assurance of Compendial Articles 1211) both sterilizes and maintains the strength, purity, quality, and packaging integrity of CSPs. The selected sterilization process is expected from experience and appropriate information sources—and, preferably, verified wherever possible—to achieve sterility in the particular CSPs. General guidelines for matching CSPs and components to appropriate sterilization methods include the following:

STERILIZATION BY FILTRATION

STEAM STERILIZATION

Commercially available sterile fluid culture media, such as Soybean–Casein Digest Medium (see Sterility Tests 71), shall be able to promote exponential colonization of bacteria that are most likely to be transmitted to CSPs from the compounding personnel and environment. Media-filled vials are incubated at 25 to 35 for 14 days. Failure is indicated by visible turbidity in the medium on or before 14 days.

The degree of exposure of the product during processing will be affected by the length of time of exposure, the size of the critical site exposed, and the nature of the critical site.

A critical site is any opening providing a direct pathway between a sterile product and the environment or any surface coming in direct contact with the product and the environment. The risk of such a site picking up contamination from the environment increases with time of exposure. Therefore, the processing plan and the intent of the operator should give due consideration to organization, efficiency, and speed in order to keep such exposure time to a minimum. For example, an ampul should not be opened unnecessarily in advance of use.

The size of the critical site affects the risk of contamination entering the product: the greater the exposed area, the greater the risk. An open vial or bottle exposes to contamination a critical site of much larger area than the tip of a 26-gauge needle. Therefore, the risk of contamination when entering an open vial or bottle is much greater than during the momentary exposure of a needle tip.

The nature of a critical site also affects the risk of contamination. The relatively rough, permeable surface of an elastomeric closure retains microorganisms and other contaminants, after swabbing with an alcohol pad, more readily than does the smooth glass surface of the neck of an ampul. Therefore, the surface disinfection can be expected to be more effective for an ampul.

Once the ampul is open, the critical site of exposure is greatly increased, creating a pathway with the potential for introduction of glass, fiber, and dust into the fluid contained in the ampul.

The prevention or elimination of airborne particles must be given high priority. Airborne contaminants are much more likely to reach critical sites than contaminants that are adhering to the floor or other surfaces below the work level. Further, particles that are relatively large or of high density settle from the airspace more quickly and thus can be removed from the vicinity of critical sites.

In general, sterile product preparation facilities utilize laminar airflow workbenches (LAFWs) to provide an adequate critical site environment. A discussion of the necessary facilities and proper procedures for preparing sterile products using LAFWs in clean rooms is presented below. The use of alternative systems in clean rooms that have been verified to achieve the same or better level of environmental quality as that achieved by properly operated LAFWs may also be utilized. An emerging alternative technology utilizes barrier isolator systems to minimize the extent of personnel contact and interaction, to separate the external environment from the critical site, and to provide an ISO Class 5 environment (see Table 1 for preparing CSPs. A well-designed positive pressure barrier isolator, supported by adequate procedures for its maintenance, monitoring, and control, may offer an acceptable alternative to the use of conventional LAFWs in clean rooms for aseptic processing. An example of the arrangement of a clean-room floor plan for low- and medium-risk level CSPs is illustrated in the first drawing in Figure 1. The second drawing in Figure 1 depicts an appropriate multicompartment clean-room floor plan for high-risk level CSPs.

Fig. 1

Engineering controls reduce the potential for airborne contamination in workspaces by limiting the amount and size of contaminants in the CSP processing environment. Primary engineering controls are used and generally include horizontal flow clean benches, vertical flow clean benches, biological safety cabinets, and barrier isolators. Primary environmental control must provide at least ISO Class 5 quality of air (see Table 1) to which sterile ingredients and components of CSPs are directly exposed. Secondary engineering controls generally provide a buffer zone or buffer room as a core for the location of the workbenches or isolators.

Table 1. International Organization of Standardization (ISO) Classification of Particulate Matter in Room Air [Limits are in particles 0.5 µm and larger per cubic meter (current ISO) and cubic feet (former Federal Standard No. 209E, FS209E).]*

Airflow through high-efficiency particulate air (HEPA) filters is unidirectional or columnar, and because of the pore size of the filter the “first air” at the face of the filter is, for the purposes of aseptic compounding, free from airborne particulate contamination. Barrier isolators provide a suitable environment by restricting any ambient air from the work chamber. These systems are not as sensitive to external environments as the HEPA-filtered unidirectional airflow units.

Several aspects of barrier isolation and filtered unidirectional airflow in work environment must be understood and practiced in the compounding process. Policies and procedures for maintaining and working in the prescribed conditions for aseptic processing must be prepared, updated, maintained, and implemented and are determined by the scope and risk levels of the activities undertaken in the SP compounding operation.

In general, the CSP work environment is designed to have the cleanest work surfaces (horizontal or vertical clean benches, biological safety cabinets, or isolators) located in a buffer area, which is preceded by an anteroom that provides a clean area for donning personnel barriers, such as hair covers, gloves, gowns, or full clean-room attire. The class limit of the buffer or core room has to be demonstrably better than that of ambient air to reduce the risk of contaminants being blown, dragged, or otherwise introduced into the filtered unidirectional airflow environment. For example, strong air currents from opened doors, personnel traffic, or air streams from the heating, ventilating, and air-conditioning systems can easily disrupt the unidirectional, columnar airflow in the open-faced workbenches. The operators may also introduce disruptions in flow by their own movements and by the placement of objects onto the work surface.

Buffer or clean-room areas in which LAFWs are located are to provide at least ISO Class 8 air quality (see Table 1). Measuring, weighing, mixing, and other manipulations of nonsterile in-process CSPs are also performed in air quality of at least ISO Class 8 (see Table 1). Appropriate air conditioning and humidity controls must be in place for the buffer area.

The contamination reduction conditions and procedures in this section include LAFWs being located within buffer or clean-room areas that maintain at least an ISO Class 8 (see Table 1). It is preferred, but not necessary, to locate barrier isolators within such a buffer air quality area. The frequency and amount of personnel access to buffer air quality areas is restricted to minimize contaminants, while allowing delivery of essential materials for CSPs. Food, drinks, and materials exposed in patient care and treatment areas must never be introduced into areas where components and ingredients for CSPs are present.

In an area near, but physically isolated from the buffer room area—the anteroom area—supplies, such as needles, syringes, ampuls, bags, vials of parenteral fluids, and packages of transfer tubing sets for large-volume fluids are uncartoned and disinfected.

Hand sanitizing and gowning activities also occur in the anteroom area adjacent to the buffer area. Faucet handles are designed to be hands-free. Before processing CSPs, hands are resanitized after donning all appropriate garb, except for gloves. A demarcation line or barrier identifies the separation of the buffer area from the anteroom area. Compounding personnel must be capable of accessing the buffer area without use of their hands. Anteroom areas adjacent to buffer areas are intended to minimize the introduction of contaminants into buffer areas.

The cleaning, sanitizing, and organizing of the direct and contiguous compounding areas (DCCA) is the responsibility of trained operators (pharmacists and technicians) following written procedures and is performed at the beginning of each shift. Before compounding is performed, all items are removed from the DCCA and all surfaces are cleaned of loose material and residue from spills, followed by an application of a residue-free sanitizing agent2 that is left on for a time sufficient to exert its antimicrobial effect.

Work surfaces near the DCCA in the buffer or clean area are cleaned in a similar manner, including counter tops and supply carts. Storage shelving is emptied of all supplies and then cleaned and sanitized at least weekly, using approved agents.

Floors in the buffer or clean area are cleaned by mopping once daily when no aseptic operations are in progress. Mopping may be performed by trained and supervised custodial personnel using approved agents described in the written procedures. Only approved cleaning and sanitizing agents are used with careful consideration of compatibilities, effectiveness, and inappropriate or toxic residues. Their schedules of use and methods of application are in accord with written procedures. All cleaning tools, such as wipers, sponges, and mops, are nonshedding and dedicated to use in the buffer or clean area. Floor mops may be used in both the buffer or clean area and anteroom area, but only in that order. Most wipers are discarded after one use. If cleaning tools are reused, their cleanliness is maintained by thorough rinsing and sanitization after use and by storing in a clean environment between uses. Trash is collected in suitable plastic bags and removed with minimal agitation.

In the anteroom area, supplies and equipment removed from shipping cartons are wiped with a sanitizing agent, such as sterile 70% isopropyl alcohol (IPA)3 , which is checked periodically for contamination. Alternatively, if supplies are planned to be received in sealed pouches, the pouches can be removed as the supplies are introduced into the buffer or clean area without the need to sanitize the individual supply items. No shipping or other external cartons may be taken into the buffer or clean area. Cleaning and sanitizing of the anteroom area is performed at least weekly by trained and supervised custodial personnel, in accordance with written procedures. However, floors are cleaned and sanitized daily, always proceeding from the buffer or clean area to the anteroom area. Storage shelving is emptied of all supplies and cleaned and sanitized at planned intervals, preferably monthly.

These cleaning and sanitizing procedures apply to both low-risk and high-risk operations.

Personnel are critical keys to the maintenance of asepsis when carrying out their assigned responsibilities. They must be thoroughly trained in aseptic techniques and be highly motivated to maintain these standards each time they prepare a sterile product.

Prior to entering the buffer or clean area, operators should remove outer lab jackets or the like, makeup, and jewelry and should thoroughly scrub hands and arms to the elbow. After drying hands and arms they should properly don clean, nonshedding uniform components, including hair covers, shoe covers, knee-length coats or coveralls, and appropriate protective gloves, in that order. The coats should fit snugly at the wrists and be zipped or snapped closed in the front. Shoe covers should be donned so that feet then touch the floor only on the clean side of the bench or other demarcation. Face masks should be donned just before beginning activities in the DCCA to minimize airborne contaminants from coughing, sneezing, and talking.

When preparing CSPs in a vertical flow LAFW with a transparent shield between the face of the operator and sterile components, or when using an isolator, wearing a face mask is optional, but head and facial hair must be covered.

Appropriate powder-free protective gloves are sterile or, if nonsterile, are sanitized with an appropriate antimicrobial cleaner such as 70% alcohol before use. Protective gloves are put on as the last uniform component. When nonsterile gloves, chosen for their chemically protective composition, are used, they are disinfected with sterile 70% isopropyl alcohol or an antimicrobial agent that is allowed to evaporate before beginning compounding procedures. Sterile and sanitized gloves do not remain sterile and clean during compounding activities because they come in contact with nonsterile surfaces and air. Therefore, compounding personnel must be trained to avoid touching sterile surfaces of packages, transfer devices, and components within ISO Class 5 or superior environments (see Table 1). During protracted compounding activities, personnel should intermittently resanitize their gloves with sterile 70% isopropyl alcohol.

Proper scrubbing and gowning immediately prior to entry into the buffer or clean area is required of all personnel, without exception. Should the operator find it necessary to leave the room, the coat may be carefully removed at the entrance and hung inside out for redonning upon re-entry, but only during the same shift. However, hair covers, masks, shoe covers, and gloves should be discarded and new ones donned prior to re-entry.

For high-risk operations, it is especially critical to minimize the risk of contamination on lab coats, coveralls, and other garb to be worn in the buffer or clean area. Preferably, fresh clean garb should be donned upon each entry into the buffer or clean area to avoid liberating contaminants from previously worn garb. Alternatively, garb that has been worn may be removed with the intention of regarbing for re-entry into the buffer or clean area and stored during the interim under proper control and protection in the anteroom area. Garb worn or taken outside the confines of the anteroom area cannot be worn in the buffer or clean area.

Dispersion of particles from body surfaces, such as from skin rashes, sunburn, or cosmetics, increases the risk of contamination of critical sites and must be appropriately controlled or minimized. If severe, the operator must be excluded from the buffer or clean area until the condition is remedied, especially for high-risk operations.

The pharmacy should have written, properly approved standard operating procedures (SOPs) designed to ensure the quality of the environment in which a CSP is prepared. The following procedures are recommended:

In addition to the evaluation and verification of personnel aseptic techniques and of the adequacy of compounding processes and procedures (see Personnel Training and Evaluation in Aseptic Manipulation Skills section), assessment and verification of the adequacy of the sterile compounding environment is essential, especially for preparing high-risk preparations. Evaluation of environmental quality is performed by measuring both the total number of particles and the number of viable microorganisms in the controlled air environments of the compounding area.

Certification that each LAFW and barrier isolator is functioning properly and meets the air quality requirement of ISO Class 5 (refer to Clean Rooms and Barrier Isolators and Table 1 in the Environmental Quality and Control section) is performed by a qualified operator(s) using current, state-of-the-art electronic air sampling at least every six months and whenever the LAFW or barrier isolator is relocated. Similarly, the air quality of the buffer or clean area and anteroom area is evaluated by a qualified operator(s) for conformance to ISO Class 7 and ISO Class 8 requirements, as appropriate, at least every six months and when renovations occur. These records are maintained and reviewed by the supervising pharmacist or other designated employee.

Evaluation of airborne microorganisms in the controlled air environments (LAFW, barrier isolators, buffer or clean area, and anteroom area) is performed by properly trained individuals using suitable electric air samplers or by exposing sterile nutrient agar plates for a suitable time frame. For either approach, the air sampling is performed at locations judged by compounding personnel to be the most prone to contamination during compounding activities: this includes zones of air backwash turbulence within LAFWs and other areas where air backwash turbulence may enter the compounding area. Such evaluations are performed as a regular and ongoing process at least monthly for sterile compounding areas used for low- and medium-risk preparations and at least weekly for areas used for high-risk preparations.

For electric air samplers that actively collect volumes of air for evaluation, the instructions for verification and use of these devices must be followed. When using the passive exposure of sterile nutrient agar settling plates, the covers are removed and the media is exposed for a period usually lasting 1 hour or longer to collect viable microorganisms as they fall from the environment. At the end of the designated exposure period, the plates are recovered and incubated at a temperature and for a time period conducive to multiplication of microorganisms on the nutrient agar—usually at 30 to 35 for a minimum of 48 hours. The number of discrete colonies of microorganisms are then counted and reported as colony forming units (cfu). This provides a measurement of the level of microbial contamination in the air within the tested environment.

The greatest value of viable microorganism monitored in the air of the compounding environment is realized when normal baseline cfu counts are determined over a period of time. Determining the baseline cfu counts permits identification of a trend toward increasing microbial cfu counts. A sufficiently increasing trend in cfu counts over time must prompt a re-evaluation of the adequacy of cleaning procedures, operational procedures, and air filtration efficiency within the sterile compounding location. Action may be warranted when an increasing trend to 50% above the baseline for areas used for high- and medium- risk preparations or to 100% above baseline for areas used for low-risk preparations is found.

A written plan and schedule for the environmental monitoring procedures for airborne microorganisms must be established and followed. The plan must be adequate to evaluate the various controlled air environment areas (LAFW, barrier isolator, buffer or clean area, and anteroom area) of the sterile compounding facility. All compounding personnel are trained in and educated about the importance of this environmental monitoring process. For sterile compounding areas used for low- and medium-risk preparations, a minimum of monthly evaluation is appropriate. For sterile compounding areas used for high-risk preparations, at least weekly evaluation is appropriate.

Critical operations are carried out by appropriately trained and qualified personnel in a DCCA using proper aseptic techniques described in a written procedure (see Suggested Standard Operating Procedures). Aseptic technique is equally applicable to the preparation of sterile sensitizing and chemotoxic agents. However, it is essential to recognize that additional precautions must be utilized to protect the personnel and the compounding environment from the potential adverse effects of these chemotoxic products. The minimum requirements for this process include the following: working and verified vertical laminar airflow work bench, barrier isolator, or other environmental containment and control device with biohazard control capabilities; the protective capabilities of gowns, masks, bouffants, and gloves; sprayback and spill control techniques and equipment; the use specialized compounding devices and equipment; and proper disposal.

Compounding personnel ascertain that ingredients for CSPs are of the correct identity and appropriate quality using the following information: vendors' labels, labeling, certificates of analysis, direct chemical analysis, and knowledge of compounding facility storage conditions.

STERILE INGREDIENTS and COMPONENTS

NONSTERILE INGREDIENTS and COMPONENTS

It is necessary that equipment, apparatus, and devices used to compound a CSP are consistently capable of operating properly and within acceptable tolerance limits. Written procedures outlining required equipment calibration, annual maintenance, monitoring for proper function, controlled procedures for use of the equipment and specified time frames for these activities are established and followed. Routine maintenance and time intervals are also outlined in these written procedures. Results from the equipment calibration, annual maintenance reports, and routine maintenance are kept on file for the lifetime of the equipment. Personnel is prepared through an appropriate combination of specific training and experience to operate or manipulate any piece of equipment, apparatus, or device they may use when preparing CSPs. Training includes gaining the ability to determine whether any item of equipment is operating properly or is malfunctioning.

The accuracy of an ACD can be determined in various ways to ensure that the correct quantities of nutrients, electrolytes, or other nutritional components are delivered to the final infusion container. Initially, the ACD is tested for its volume and weight accuracy. For volume accuracy, a suitable volume of Sterile Water for Injection, which represents a typical additive volume (e.g., 40 mL for small-volume range of 1 to 100 mL; or 300 mL for large-volume range of 100 to 1000 mL), is programmed into the ACD and delivered to the appropriate volumetric container. The pharmacist then consults Volumetric Apparatus 31 for appropriate parameters to assess the volumetric performance of the ACD. For gravimetric accuracy, the balance used in conjunction with the ACD is tested using various weight sizes that represent the amounts typically used to deliver the various additives. The pharmacist consults Weights and Balances 41 for acceptable tolerances of the weights used. In addition, the same volume of Sterile Water for Injection used to assess volumetric accuracy is then weighed on the balance used in conjunction with the ACD. For example, if 40 mL of water was used in the volumetric assessment, its corresponding weight should be about 40 g (assuming the relative density of water is 1.0). In addition, during the use of the ACD, certain additives, such as potassium chloride (corrected for density differences) can also be tested in the same manner as an in-process test.

Finally, additional tests of accuracy may be employed that determine the content of certain ingredients in the final volume of the parenteral nutrition admixture. Generally, pharmacy departments do not have the capability to routinely perform chemical analyses such as analyses of dextrose or electrolyte concentrations. Consequently, hospital or institutional laboratories may be called upon to perform these quality assurance tests. However, the methods in such laboratories are often designed for biological, not pharmaceutical, systems. Thus, their testing procedures must be verified to meet the USP requirements stated in the individual monograph for the component being tested. For example, under Dextrose Injection, the following is stated: It contains not less than 95.0 percent and not more than 105.0 percent of the labeled amount of C6H12O6·H2O. The hospital or institutional chemistry laboratories have to validate their methods to apply to this range and correct for their typical measurement of anhydrous dextrose versus dextrose monohydrate. Similar ranges and issues exist, for example, for injections of calcium gluconate, magnesium sulfate, potassium chloride, and so forth. The critical point is the use of USP references and possible laboratory procedural differences.

The intermediate precision of the ACD can be determined on the basis of the day-to-day variations in performance of the accuracy measures. Thus, the pharmacist must keep a daily record of the above-described accuracy assessments and review the results over time. This review must occur at least at weekly intervals to avoid potentially clinically significant cumulative errors over time. This is especially true for additives with a narrow therapeutic index, such as potassium chloride.

Finished CSPs are individually inspected in accordance with written procedures after compounding. If not distributed promptly, these products are individually inspected just prior to leaving the storage area. Those products that are not immediately distributed are stored in an appropriate location as described in the written procedures. Immediately after compounding and as a condition of release, each product unit, where possible, should be inspected against lighted white or black background or both for evidence of visible particulates or other foreign matter. Pre-release inspection also includes container–closure integrity and any other apparent visual defect. Products with observed defects should be immediately discarded or marked and segregated from acceptable products in a manner that prevents their administration. When products are not distributed promptly after preparation, a predistribution inspection is conducted to ensure that a CSP with defects, such as precipitation, cloudiness, and leakage, which may develop between the time of release and the time of distribution, is not released.

Written procedures for double-checking compounding accuracy must be followed for every CSP during preparation and immediately prior to release. The double check system should meet state regulations and include label accuracy and accuracy of the addition of all drug products or ingredients used to prepare the finished product and their volumes or quantities. The used additive containers and, for those additives for which the entire container was not expended, the syringes used to measure the additive, should be quarantined with the final products until the final product check is completed. Compounding personnel must visually confirm that ingredients measured in syringes match the written order being compounded. Preferably, a person other than the compounder can verify that correct volumes of correct ingredients were measured to make each CSP. For example, compounding personnel would pull the syringe plunger back to the volume measured.

When practical, confirm accuracy of measurements by weighing a volume of the measured fluid, then calculating that volume by dividing the weight by the accurate value of the density, or specific gravity, of the measured fluid. Correct density or specific gravity values programmed in automated compounding devices, which measure by weight using the quotient of the programmed volume divided by the density or specific gravity, must be confirmed to be accurate before and after delivering volumes of the liquids assigned to each channel or port. These volume accuracy checks and the following additional safety and accuracy checks in this section must be included in the standard operating procedures manual of the CSP facility.

All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25 identical individual single-dose packages (such as ampuls, bags, syringes, vials), or in multiple dose vials for administration to multiple patients, or exposed longer than 12 hours at 2 to 8 and longer than 6 hours at warmer than 8 before they are sterilized must be tested to ensure that they are sterile (see Sterility Tests 71) before they are dispensed or administered. The Membrane Filtration method is the method of choice where feasible (e.g., components are compatible with the membrane). A method not described in the USP may be used if verification results demonstrate that the alternative is at least as effective and reliable as the USP Membrane Filtration method or the USP Direct Inoculation of the Culture Medium method where the membrane filtration method is not feasible.

In such a case, a written procedure requiring daily observation of the media and requiring an immediate recall if there is any evidence of microbial growth must be available. In addition, the patient and the physician of the patient to whom a potentially contaminated CSP was administered is notified of the potential risk. Positive sterility test results should prompt a rapid and systematic investigation of aseptic technique, environmental control, and other sterility assurance controls to identify sources of contamination and correct problems in the methods or processes.

All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25 identical individual single-dose packages (such as ampuls, bags, syringes, vials), or in multiple dose vials for administration to multiple patients, or exposed longer than 12 hours at 2 to 8 and longer than 6 hours at warmer than 8 before they are sterilized must be tested to ensure that they do not contain excessive bacterial endotoxins (see Bacterial Endotoxins Test 85). In the absence of a bacterial endotoxins limit in the official monograph or other CSP formula source, the CSP must not exceed the amount of USP Endotoxin Units (EU per hour per kg of body weight or m2 of body surface area) specified in the above chapter for the appropriate route of administration.

Compounding facilities must have at least the following written procedures for verifying the correct identity and quality of CSPs before they are dispensed and administered:

To inhibit microbial growth from undetected contamination, finished CSPs that will not be immediately dispensed and administered must be refrigerated at 2 to 8, unless their chemical and physical stability are known to be adversely affected by cold temperatures. When CSPs are filled into patient-worn infusion devices that are likely to attain temperatures exceeding 30 for more than 24 hours, the chemical and physical stability at such temperatures and durations must be confirmed from either appropriate literature sources or direct testing.

When CSPs deviate from conditions in the approved labeling of manufactured products contained in CSPs, compounding personnel may consult the manufacturer of particular products for advice on assigning beyond-use dates based on chemical and physical stability parameters. Beyond-use dates for CSPs that are prepared strictly in accordance with manufacturers' product labeling must be those specified in that labeling, or from appropriate literature sources or direct testing. Beyond-use dates for CSPs that lack justification from either appropriate literature sources or by direct testing evidence must be assigned as described in the section Stability Criteria and Beyond-Use Dating in the general test chapter Pharmaceutical Compounding—Nonsterile Preparations 795.

In addition, the pharmacist may refer to applicable publications to obtain relevant stability, compatibility, and degradation information regarding the drug or its congeners. When assigning a beyond-use date, pharmacists should consult and apply drug-specific and general stability documentation and literature where available, and they should consider the nature of drug and its degradation mechanism, the container in which it is packaged, the expected storage conditions, and the intended duration of therapy (see Expiration Date and Beyond-Use Date under Labeling in the General Notices and Requirements). Stability information must be carefully interpreted in relation to the actual compounded formulation and conditions for storage and use. Predictions based on other evidence, such as publications, charts, tables, and so forth would result in theoretical beyond-use dates. Theoretically predicted beyond-use dating introduces varying degrees of assumptions, and hence a likelihood of error or at least inaccuracy. The degree of error or inaccuracy would be dependent on the extent of differences between the CSP's characteristics (such as composition, concentration of ingredients, fill volume, or container type and material) and the characteristics of the products from which stability data or information are to be extrapolated. The greater the doubt of the accuracy of theoretically predicted beyond-use dating, the greater the need to determine dating periods experimentally. Theoretically predicted beyond-use dating periods should be carefully considered for CSPs prepared from nonsterile bulk active ingredients having therapeutic activity, especially where these CSPs are expected to be compounded routinely. When CSPs will be distributed to and administered in residential locations other than health care facilities, the effect of potentially uncontrolled and unmonitored temperature conditions must be considered when assigning beyond-use dates. It must be ascertained that CSPs will not be exposed to warm temperatures (see General Notices and Requirements) unless the compounding facility has evidence to justify stability of CSPs during such exposure.

It should be recognized that the truly valid evidence of stability for predicting beyond-use dating can be obtained only through product-specific experimental studies. Semi-quantitative procedures, such as thin-layer chromatography (TLC), may be acceptable for many CSPs. However, quantitative stability-indicating assays, such as high performance liquid chromatographic (HPLC) assays, would be more appropriate for certain CSPs. Examples include CSPs with a narrow therapeutic index, where close monitoring or dose titration is required to ensure therapeutic effectiveness and to avoid toxicity; where a theoretically established beyond-use dating period is supported by only marginal evidence; or where a significant margin of safety cannot be verified for the proposed beyond-use dating period. In short, because beyond-use dating periods established from product-specific data acquired from the appropriate instrumental analyses are clearly more reliable than those predicted theoretically, the former approach is strongly urged to support dating periods exceeding 30 days.

To ensure consistent practices in determining and assigning beyond-use dates, the pharmacy should have written policies and procedures governing the determination of the beyond-use dates for all compounded products. When attempting to predict a theoretical beyond-use date, a compounded or an admixed product should be considered as a unique system that has physical and chemical properties and stability characteristics that differ from its components. For example, antioxidant, buffering, or antimicrobial properties of a sterile vial for injection (SVI) might be lost upon its dilution, with the potential of seriously compromising the chemical stability of the SVI’s active ingredient or the physical or microbiological stability of the SVI formulation in general. Thus, the properties stabilized in the SVI formulation usually cannot be expected to be carried over to the compounded or admixed product. Product-specific, experimentally determined stability data evaluation protocols are preferable to published stability information. Pharmacists should consult the general information chapter under Pharmaceutical Stability 1150 for the appropriate stability parameters to be considered when initiating or evaluating a product-specific stability study.

Compounding personnel who assign beyond-use dates to CSPs when lacking direct chemical assay results must critically interpret and evaluate the most appropriate available information sources to decide a conservative and safe beyond-use date. The standard operating procedures manual of the compounding facility and each specific CSP formula record must describe the general basis used to assign the beyond-use date and storage conditions.

If multiple-dose parenteral medication vials (MDVs) are used, refrigerate the MDVs after they are opened unless otherwise specified by the manufacturer. Discard the MDVs when empty, when suspected or visible contamination occurs, or when the manufacturer's stated expiration date is reached, provided the manufacturer’s storage conditions have been adhered to. Expiration dating not specifically referenced in the package insert should not exceed 30 days once the vial has been opened.

To ensure that product potency is retained through the manufacturer's labeled expiration date, pharmacists must monitor the drug storage areas within the pharmacy. Controlled temperature storage areas in the pharmacy (refrigerators, 2 to 8; freezers, 20 to 10; and incubators, 30 to 35; etc.) should be monitored at least once daily and the results documented on a temperature log. Additionally, pharmacy personnel should note the storage temperature when placing the product into or removing the product from the storage unit in order to monitor any temperature aberrations. Suitable temperature recording devices may include a calibrated continuous recording device or an NBS calibrated thermometer that has adequate accuracy and sensitivity for the intended purpose and should be properly calibrated at suitable intervals. If the pharmacy uses a continuous temperature recording device, pharmacy personnel should verify at least once daily that the recording device itself is functioning properly.

The temperature sensing mechanisms should be suitably placed in the controlled temperature storage space to reflect accurately its true temperature. In addition, the pharmacy should adhere to appropriate procedures of all controlled storage spaces to ensure that such spaces are not subject to significantly prolonged temperature fluctuations as may occur, for example, by leaving a refrigerator door open too long.

This section pertains to the responsibilities of the pharmacy for maintaining product quality and control after the CSP leaves the pharmacy for distribution and use within the organized health care system to which the pharmacy belongs. The pharmacy is responsible for the quality of all CSPs prepared by or dispensed from the pharmacy, throughout the life cycle of the CSP, regardless of where the CSP exists physically within the organized health care system. In fulfilling this general responsibility, the pharmacy is responsible for the proper packaging, handling, transport, and storage of CSPs prepared by or dispensed from it, including the appropriate education, training, and supervision of pharmacy personnel assigned to these functions. The pharmacy should assist in the education and training of nonpharmacy personnel responsible for carrying out any aspect of these functions.

Establishing, maintaining, and assuring compliance with comprehensive written policies and procedures encompassing these responsibilities is a further responsibility of the pharmacy. Where nonpharmacy personnel are assigned tasks involving any of these responsibilities, the policies and procedures encompassing those tasks should be developed by the pharmacy in consultation with other institutional departments as appropriate. Activities or concerns that should be addressed as the pharmacy fulfills these responsibilities are as follows.

PACKAGING, HANDLING, and TRANSPORT

USE and STORAGE

ADMINISTRATION

REDISPENSED CSPs

EDUCATION and TRAINING

The following sections on Packing CSPs for Transit and Transit of CSPs describe how to maintain sterility and stability of CSPs until they are delivered to patient care locations for administration.

PACKING CSPs FOR TRANSIT

TRANSIT OF CSPs

STORAGE IN LOCATIONS OUTSIDE CSP FACILITIES

1. Labels and accessory labeling for CSPs include clearly readable beyond-use dates, storage instructions, and disposal instructions for out-of-date units.
2. Each patient or other recipient is able to store the CSPs properly, including the use of a properly functioning refrigerator and freezer if CSPs are labeled for such storage.