CSP MICROBIAL CONTAMINATION RISK LEVELS
The appropriate risk level—low,medium,or high—is assigned according to the corresponding probability of contaminating a CSPwith (1)microbial contamination (microbial organisms,spores,and endotoxins)and (2)chemical and physical contamination (foreign chemicals and physical matter).Potential sources of contamination include,but are not limited to,solid and liquid matter from compounding personnel and objects;nonsterile components employed and incorporated before terminal sterilization;inappropriate conditions within the restricted compounding environment;prolonged presterilization procedures with aqueous preparations;and nonsterile dosage forms used to compound CSPs.
The characteristics described below for low-risk,medium-risk,and high-risk CSPs are intended as a guide to the breadth and depth of care necessary in compounding,but they are neither exhaustive nor prescriptive.The licensed health care professionals who supervise compounding are responsible for determining the procedural and environmental quality practices and attributes that are necessary for the risk level they assign to specific CSPs.
These risk levels apply to the quality of CSPs immediately after the final aseptic mixing or filling or immediately after the final sterilization,unless precluded by the specific characteristics of the preparation,such as lipid-based emulsions where administration must be completed within 12hours of preparation.Upon subsequent storage and shipping of freshly finished CSPs,an increase in the risks of chemical degradation of ingredients,contamination from physical damage to packaging,and permeability of plastic and elastomeric packaging is expected.In such cases,compounding personnel consider the potential additional risks to the integrity of CSPs when assigning beyond-use dates.The pre-administration exposure duration and temperature limits specified in the following low-risk,medium-risk,and high-risk level sections apply in the absence of direct testing results or appropriate information sources that justify different limits for specific CSPs.For a summary of the criteria according to risk levels,please see the Appendix.
Low-Risk Level CSPs
CSPs compounded under all of the following conditions are at a low risk of contamination.
Low-Risk Conditions—
  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 48hours at controlled room temperature (see General Notices and Requirements),for not more than 14days at a cold temperature (see General Notices and Requirements),and for 45days in solid frozen state at –20or colder.
Examples of Low-Risk Compounding—
  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.
Quality Assurance— Quality assurance practices include,but are not limited to,the following:
  1. Routine disinfection and air quality testing of the direct compounding environment to minimize microbial surface contamination and maintain ISO Class 5air 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.
Example of a Media-Fill Test Procedure— This,or an equivalent test,is performed at least annually by each person authorized to compound in a low-risk level under conditions that closely simulate the most challenging or stressful conditions encountered during compounding of low-risk level CSPs.Once begun,this test is completed without interruption.Within an ISO Class 5air quality environment,(see Table 1)three sets of four 5-mLaliquots of sterile Soybean–Casein Digest Medium are transferred with the same sterile 10-mLsyringe and vented needle combination into separate sealed empty sterile 30-mLclear vials (i.e.,four 5-mLaliquots into each of three 30-mLvials).Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials,then the vials are incubated as described in the Personnel Training and Evaluation in Aseptic Manipulation Skills section.
Medium-Risk Level CSPs
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.
Medium-Risk Conditions—
  1. Multiple individual or small doses of sterile products are combined or pooled to prepare a CSPthat 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 30hours at controlled room temperature (see General Notices and Requirements),for not more than 7days at a cold temperature (see General Notices and Requirements),and for 45days in solid frozen state at –20or colder.
Examples of Medium-Risk Compounding—
  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 25and 40.
  4. Transfer of volumes from multiple ampuls or vials into a single,final sterile container or product.
Quality Assurance— Quality assurance procedures for medium-risk level CSPs include all those for low-risk level CSPs,as well as a more challenging media-fill test passed annually,or more frequently.
Example of a Media-Fill Test Procedure— This,or an equivalent test,is performed under conditions that closely simulate the most challenging or stressful conditions encountered during compounding.This test is completed without interruption within an ISO Class 5air quality environment (see Table 1).Six 100-mLaliquots of sterile Soybean–Casein Digest Medium are aseptically transferred by gravity through separate tubing sets into separate evacuated sterile containers.The six containers are then arranged as three pairs,and a sterile 10-mLsyringe and 18-gauge needle combination is used to exchange two 5-mLaliquots of medium from one container to the other container in the pair.For example,after a 5-mLaliquot from the first container is added to the second container in the pair,the second container is agitated for 10seconds,then a 5-mLaliquot is removed and returned to the first container in the pair.The first container is then agitated for 10seconds,and the next 5-mLaliquot is transferred from it back to the second container in the pair.Following the two 5-mLaliquot exchanges in each pair of containers,a 5-mLaliquot of medium from each container is aseptically injected into a sealed empty sterile 10-mLclear vial using a sterile 10-mLsyringe and vented needle.Sterile adhesive seals are aseptically affixed to the rubber closures on the three filled vials,then the vials are incubated as described in the Personnel Training and Evaluation in Aseptic Manipulation Skills section.
High-Risk Level CSPs
CSPs compounded under any of the following conditions are either contaminated or at a high risk to become contaminated with infectious microorganisms.
High-Risk Conditions—
  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 5of opened or partially used packages of manufactured sterile products that lack antimicrobial preservatives.
  3. Nonsterile preparations are exposed for at least 6hours 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 (seeIngredient SelectionunderPharmaceutical Compounding—Nonsterile Preparations á795ñ).
  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 24hours at controlled room temperature (see General Notices and Requirements),for not more than 3days at a cold temperature (see General Notices and Requirements),and for 45days in solid frozen state at –20or colder.
All nonsterile measuring,mixing,and purifying devices are rinsed thoroughly with sterile,pyrogen-free water,and then thoroughly drained or dried immediately before use for high-risk compounding.All high-risk CSPsolutions subjected to terminal steam sterilization are passed through a filter with a nominal porosity not larger than 1.2µm preceding or during filling into their final containers.Sterilization of high-risk level CSPs by filtration is conducted entirely with an ISO Class 5or superior air quality environment (see Table 1).
Examples of High-Risk Compounding—
  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 5of 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.
Quality Assurance— Quality assurance procedures for high-risk level CSPs include all those for low-risk level CSPs.In addition,a media-fill test that represents high-risk level compounding is performed semi-annually by each person authorized to compound high-risk level CSPs.
Example of a Media-Fill Test Procedure— This,or an equivalent test,is performed under conditions that closely simulate the most challenging or stressful conditions encountered when compounding high-risk level CSPs.This test is completed without interruption in the following sequence:
  1. Dissolve 3g of nonsterile commercially available Soybean–Casein Digest Medium in 100mLof nonbacteriostatic water to make a 3%solution.
  2. Draw 25mLof the medium into each of three 30-mLsterile syringes.Transfer 5mLfrom each syringe into separate sterile 10-mLvials.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 10mLfrom each syringe into three separate 10-mLsterile 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 25to 35.Inspect for microbial growth over 14days as described in the Personnel Training and Evaluation in Aseptic Manipulation Skills section.