U.S. PHARMACOPEIA

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VERIFICATION OF COMPOUNDING ACCURACY AND STERILIZATION
The compounding procedures and sterilization methods for CSPs correspond to correctly designed and verified written documentation in the compounding facility. Verification requires planned testing designed to demonstrate effectiveness of all procedures critical to the accuracy and purity of finished CSPs. For example, sterility testing (see Test for Sterility of the Product to be Examined under Sterility Tests 71) may be applied to specimens of low- and medium-risk CSPs, and standard nonpathogenic bacterial cultures may be added to nondispensable specimens of high-risk CSPs before terminal sterilization for subsequent evaluation by sterility testing. Packaged and labeled CSPs are visually inspected for physical integrity and expected appearance, including final fill amount. To ensure that the identities and concentrations of ingredients are accurate, and in the absence of reliable observations and data to confirm and extrapolate those parameters, samples of CSPs are assayed.
Sterilization Methods
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:
  1. CSPs have been ascertained to remain physically and chemically stable when subjected to the selected sterilization method.
  2. Glass and metal devices may be covered tightly with aluminum foil, then exposed to dry heat in an oven at a mean temperature of 250 for 2 hours to achieve sterility and depyrogenation (see Dry-Heat Sterilization under Sterilization and Sterility Assurance of Compendial Articles 1211). Such items are either used immediately or stored until use in an environment suitable for compounding low- and medium-risk CSPs.
  3. Personnel ascertain from appropriate information sources that the sterile microporous membrane filter used to sterilize CSP solutions, either during compounding or administration, is chemically and physically compatible with the CSP.
STERILIZATION BY FILTRATION
Commercially available sterile filters must be approved for human-use applications in sterilizing pharmaceutical fluids. Both filters that must be sterilized before processing CSPs and those filters that are commercially available, disposable, sterile, and pyrogen-free have a nominal porosity of 0.2 µm, which includes 0.22-µm porosity. They should be certified by the manufacturer to retain at least 107 microorganisms of a strain of Brevundimonas (Pseudomonas) diminuta on each cm2 of upstream filter surface under conditions similar to those in which the CSPs will be sterilized. In emergency situations when sterile 0.2-µm porosity membranes are not available, filters of the same composition and 0.45-µm nominal porosity may be used. Sterilizing filters with 0.2-µm and 0.45-µm nominal porosities will not remove bacterial endotoxins and viruses by physical retention.
The supervising health care professional must ensure, directly or from appropriate documentation, that the filters are chemically and physically stable at the pressure and temperature conditions to be used, and that the filters will achieve sterility and maintain prefiltration pharmaceutical quality of the specific CSP. The filter dimensions and material must permit the sterilization process to be completed rapidly without the replacement of the filter during the process. When CSPs are known to contain excessive particulate matter, a prefilter or larger porosity membrane is placed upstream from the sterilizing filter to remove gross particulate contaminants in order to maximize the efficiency of the sterilizing filter.
When filter devices are assembled from separate nonsterile components by compounding personnel, such devices shall be identified to be sterile and ascertained to be effective under relevant conditions before they are used to sterilize CSPs. For example, sterility can be identified using biological indicators (see Biological Indicators 1035). Filter units used to sterilize CSPs can also be subjected to the manufacturer's recommended integrity test, such as the bubble point test.
When commercially available sterile disposable filter devices are used, the compounding personnel may accept the written certification from suppliers that the filters retain at least 107 cfu, of Brevundimonas (Pseudomonas) diminuta on each cm2 of filter surface. Compounding personnel must ascertain that selected filters will achieve sterilization of the particular CSPs being sterilized. Large deviations from usual or expected chemical and physical properties of CSPs may cause undetectable damage to filter integrity and shrinkage of microorganisms to sizes smaller than filter porosity.
Sterile, commercially available sterilizing filter devices for use on handheld syringes may be checked by feeling for greater resistance on the plunger when filtering air after an aqueous fluid has been filtered.
STEAM STERILIZATION
The process of thermal sterilization employing saturated steam under pressure, or autoclaving, is the preferred method to terminally sterilize aqueous preparations that have been verified to maintain their full chemical and physical stability under the conditions employed (see Steam Sterilization under Sterilization and Sterility Assurance of Compendial Articles 1211). To achieve sterility, it is necessary that all materials be exposed to steam at 121, under a pressure of about one atmosphere or 15 psi, for the duration verified by testing to achieve sterility of the items, which is usually 20 to 60 minutes for CSPs. An allowance must be made for the time required for the material to reach 121 before the sterilization exposure duration is timed.
Items that are not directly exposed to pressurized steam may result in survival of microbial organisms and spores. Before their sterilization, plastic, glass, and metal devices are tightly wrapped in low particle shedding paper or fabrics, or sealed in envelopes that prevent poststerilization microbial penetration. Immediately before filling ampuls and vials that will be steam sterilized, solutions are passed through a filter having a porosity not larger than 1.2 µm for removal of particulate matter. Sealed containers must be able to generate steam internally; thus, stoppered and crimped empty vials must contain a small amount of moisture to generate steam.
The description of steam sterilization conditions and duration for specific CSPs is included in written documentation in the compounding facility. The effectiveness of steam sterilization is verified using appropriate biological indicators (see Biological Indicators 1035) or other confirmation methods (see Sterilization and Sterility Assurance of Compendial Articles 1211 or Sterility Tests 71).