FINISHED PREPARATION RELEASE CHECKS AND TESTS
All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25identical individual single-dose packages (such as ampuls,bags,syringes,and vials),or in multiple dose vials for administration to multiple patients,or are exposed longer than 12hours at 2
to 8and longer than 6hours at warmer than 8before they are sterilized are tested to ensure that they are sterile (see Sterility Tests á71ñ)and do not contain excessive bacterial endotoxins (see Bacterial Endotoxins Test á85ñ).All CSPs that are intended to be solutions must be visually examined for the presence of particulate matter and not administered or dispensed when such matter is observed.The prescription orders,written compounding procedure,preparation records,and expended materials used to make CSPs in all contamination risk levels are inspected for accuracy of correct identities and amounts of ingredients,aseptic mixing and sterilization,packaging,labeling,and expected physical appearance before they are administered or dispensed.
to 8and longer than 6hours at warmer than 8before they are sterilized are tested to ensure that they are sterile (see Sterility Tests á71ñ)and do not contain excessive bacterial endotoxins (see Bacterial Endotoxins Test á85ñ).All CSPs that are intended to be solutions must be visually examined for the presence of particulate matter and not administered or dispensed when such matter is observed.The prescription orders,written compounding procedure,preparation records,and expended materials used to make CSPs in all contamination risk levels are inspected for accuracy of correct identities and amounts of ingredients,aseptic mixing and sterilization,packaging,labeling,and expected physical appearance before they are administered or dispensed.
Physical Inspection
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 CSPwith defects,such as precipitation,cloudiness,and leakage,which may develop between the time of release and the time of distribution,is not released.
Compounding Accuracy Checks
Written procedures for double-checking compounding accuracy must be followed for every CSPduring 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 CSPfacility.
Sterility Testing
All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25identical individual single-dose packages (such as ampuls,bags,syringes,vials),or in multiple dose vials for administration to multiple patients,or exposed longer than 12hours at 2to 8and longer than 6hours at warmer than 8before they are sterilized must be tested to ensure that they are sterile (see Sterility Tests á71ñ)before they are dispensed or administered.The Membrane Filtrationmethod is the method of choice where feasible (e.g.,components are compatible with the membrane).Amethod not described in the USPmay be used if verification results demonstrate that the alternative is at least as effective and reliable as the USPMembrane Filtrationmethod or the USPDirect Inoculation of the Culture Mediummethod where the membrane filtration method is not feasible.
to 8and longer than 6hours at warmer than 8before they are sterilized must be tested to ensure that they are sterile (see Sterility Tests á71ñ)before they are dispensed or administered.The Membrane Filtrationmethod is the method of choice where feasible (e.g.,components are compatible with the membrane).Amethod not described in the USPmay be used if verification results demonstrate that the alternative is at least as effective and reliable as the USPMembrane Filtrationmethod or the USPDirect Inoculation of the Culture Mediummethod 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 CSPwas 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.
Bacterial Endotoxin (Pyrogen)Testing
All high-risk level CSPs for administration by injection into the vascular and central nervous systems that are prepared in groups of more than 25identical individual single-dose packages (such as ampuls,bags,syringes,vials),or in multiple dose vials for administration to multiple patients,or exposed longer than 12hours at 2to 8and longer than 6hours at warmer than 8before they are sterilized must be tested to ensure that they do not contain excessive bacterial endotoxins (see Bacterial Endotoxins Test á85ñ).In the absence of a bacterial endotoxins limit in the official monograph or other CSPformula source,the CSPmust not exceed the amount of USP Endotoxin Units (EUper hour per kg of body weight or m2of body surface area)specified in the above chapter for the appropriate route of administration.
to 8and longer than 6hours at warmer than 8before they are sterilized must be tested to ensure that they do not contain excessive bacterial endotoxins (see Bacterial Endotoxins Test á85ñ).In the absence of a bacterial endotoxins limit in the official monograph or other CSPformula source,the CSPmust not exceed the amount of USP Endotoxin Units (EUper hour per kg of body weight or m2of body surface area)specified in the above chapter for the appropriate route of administration.
Identity and Strength Verification of Ingredients
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:
- That labels of CSPs bear correct names and amounts or concentrations of ingredients;the total volume;the beyond-use date;the appropriate route(s)of administration;the storage conditions;and other information for safe use.
- That there are correct identities,purities,and amounts of ingredients by comparing the original written order to the written compounding record for the CSP.
- That correct fill volumes in CSPs and correct quantities of filled units of the CSPs were obtained.When the strength of finished CSPs cannot be confirmed to be accurate,based on the above three inspections,the CSPs must be assayed by methods that are specific for the active ingredients.
To inhibit microbial growth from undetected contamination,finished CSPs that will not be immediately dispensed and administered must be refrigerated at 2to 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 30for more than 24hours,the chemical and physical stability at such temperatures and durations must be confirmed from either appropriate literature sources or direct testing.
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 30for more than 24hours,the chemical and physical stability at such temperatures and durations must be confirmed from either appropriate literature sources or direct testing.