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by Melissa Merrell Rhoads, PharmD, PCCA Director of Formulations
USP Chapter 795 describes the full guidelines for pharmaceutical compounding of nonsterile preparations (CNSPs). Specifically looking at the revisions related to BUDs, USP states the BUDs presented “are based on the ability of the CNSP to maintain chemical and physical stability and to suppress microbial growth.” The dosage forms are described as aqueous and nonaqueous based on water activity (aw or Aw). An aqueous preparation is one that has an aw ≥ 0.6 (e.g., emulsions, gels, creams, solutions, sprays or suspensions). Nonaqueous dosage forms have an aw of < 0.6 and are separated into two categories: “nonaqueous oral liquid” and “other nonaqueous dosage forms” (e.g., capsules, tablets, granules, powders, nonaqueous topicals, suppositories and troches or lozenges).
The following shows the revised BUDs and Notes that were added to all PCCA nonsterile formulas.
Note: According to USP guidelines, “in the absence of an USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a non-preserved aqueous dosage form with a water activity (Aw) of >/= 0.6 is 14 days stored in a refrigerator, unless such storage affects the physical or chemical properties of the CNSP.*
Note: According to USP guidelines, “in the absence of an USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a preserved aqueous dosage form with a water activity (Aw) of >/= 0.6 is 35 days.*
Note: According to USP guidelines, “in the absence of an USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a CNSP that is a nonaqueous oral liquid dosage form with a water activity (Aw) of < 0.6 is 90 days.*
Note: According to USP guidelines, “in the absence of an USP-NF Compounded Preparation Monograph or CNSP-Specific Stability Information,” the maximum BUD for a compounded CNSP that is a nonaqueous dosage form (excluding nonaqueous oral liquids) with a water activity (Aw) of < 0.6 is 180 days.*
*For more information, refer to current USP Chapter 795.
Additional Notes were added to bring awareness to new requirements of USP Chapter 795 during the compounding process. Examples of the notes include visually inspecting all components prior to use and visually inspecting the final preparation, including the container closure integrity. The Notes are not all encompassing. We recommend you become familiar with USP Chapter 795 to ensure compliance with all requirements.
Note: USP Chapter 795 sets forth parameters to consider when establishing a BUD and states, “BUDs for CNSPs should be established conservatively to ensure that the preparation maintains its required characteristics to minimize the risk of contamination or degradation.” Stability testing may be performed by an FDA-registered laboratory using a stability-indicating assay to extend the BUD. An antimicrobial effectiveness test (see USP Chapter 51) must also be performed by an FDA-registered laboratory when extending the BUD of an aqueous CNSP.
USP Chapter 797 describes the minimum standards to follow for the preparation of compounded sterile preparations (CSPs) for human and animal drugs. If adopted by your state board of pharmacy, you must meet the requirements of USP 797 to ensure the sterility of CSPs, which include but are not limited to injections, irrigations (for internal body cavities), ophthalmics and inhalations.
Notable changes in the PCCA sterile formulas for USP 797 appear as updates in the compounding procedures and Notes, as well as BUD revisions.
Sterilization and depyrogenation procedures described in Section 10 of USP 797 state, “The sterilization method used must sterilize the CSP without degrading its physical and chemical stability or the packaging integrity. The primary means of sterilizing compounded preparations are: terminal sterilization, which includes dry heat or autoclave, and filtration.” Note: USP 797 requires pre-filtering solutions through a 1.2-micron filter to remove potential particulate matter prior to sterilizing the preparation through autoclave or dry heat.
Filter the solution through a sterile and depyrogenated filter (appropriate for pharmaceutical use) with a nominal pore size of 0.22 micron (PCCA #35-1156) or smaller into an appropriate sterilized and depyrogenated container-closure system. According to USP guidelines, a bubble point test must be performed on the used filter to ensure integrity of that filter. Refer to product specifications for the required minimum pressure.
Filter the solution through a sterile and depyrogenated Teflon® filter (appropriate for pharmaceutical use) with a nominal pore size of 0.2 micron (PCCA #35-2720) or smaller into an appropriate sterilized and depyrogenated container-closure system. According to USP guidelines, a bubble point test must be performed on the used filter to ensure integrity of that filter. Refer to product specifications for the required minimum pressure.
Filter the solution through a sterile and depyrogenated filter (appropriate for pharmaceutical use) with a nominal pore size of not larger than 1.2 micron (PCCA #35-5755) for removal of potential particulate matter into an appropriate sterilized and depyrogenated container-closure system.
Crimp and seal the serum bottle. Autoclave the preparation until the contents within the vial have reached 121°C, 15 psi for the length of time necessary to render the preparation sterile.
The duration of this process can vary between 20 to 60 minutes, depending on preparation volume and load configuration. This process must be verified and documented with each sterilization run or load through the use of Sterilization Integrators, Steam (PCCA #35-3848) and SporeView® Steam Biological Indicators (PCCA #35-3634) per USP guidelines. Refer to USP 1229, Sterilization of Compendial Articles, for more information.
When autoclaving compounded suspensions, the initial filter step is removed. After the autoclave process, it is important to provide constant agitation while the preparation is cooling to prevent clumping of the suspension.
Crimp and seal the serum bottle. Dry heat the oil solution in a convection oven until the contents of the vial have reached a temperature of 160°C or higher for a sufficient time to render the preparation sterile.
The duration of time for this process can vary and will depend upon preparation volume and load configuration. Per USP guidelines, this process must be verified and documented with each sterilization run or load through the use of SporeView® Culture Set Biological Indicators (PCCA #35-3632) and temperature monitoring. Refer to USP 1229, Sterilization of Compendial Articles, for more information. Remove from oven immediately and allow to cool to room temperature.
For dry-heat sterilizing compounded oil suspensions, remove the initial filter step. After the dry-heat process, provide constant agitation while the preparation is cooling to prevent clumping of the suspension.
USP 797 requires preserved multiple-dose CSPs: a multiple dose CSP must be prepared as a Category 2 or Category 3 CSP. An aqueous multiple-dose CSP must pass antimicrobial effectiveness testing per USP 51 Antimicrobial Effectiveness Testing (AET) standards. After a multiple-dose CSP (aqueous or nonaqueous) is dispensed and upon initially entering or puncturing the container on first use, the preparation’s BUD is 28 days or less.
We do not list specific BUDs on our sterile formulations due to several parameters for consideration when establishing BUDs. As a guide, we include the following Note on all PCCA sterile formulations:
Note: USP Chapter 797 sets forth parameters to consider when establishing BUDs, stating, “BUDs for CSPs should be established conservatively to ensure that the drug maintains its required characteristics (i.e., stability and sterility) until its BUD.” According to USP Chapter 797, “BUDs for CSPs must be established in accordance with Table 12 for Category 1 CSPs, Table 13 for Category 2 CSPs and Table 14 for Category 3 CSPs. One day is equivalent to 24 hours. The BUD limits in these tables are based on the risk of microbial contamination or not achieving and maintaining sterility despite implementation of the requirements in this Chapter. The CSP formulation must remain chemically and physically stable, and its packaging must maintain its integrity for the duration of the BUD.”
Extending the BUD of a sterile preparation per current USP Chapter 797 requires sterility testing for each batch in compliance with USP Chapter 71, including method suitability. Alternative sterility testing methods may be used per USP 797 if they are verified to be at least as effective and reliable as those described in USP 71. Other necessary data may include published or unpublished stability studies utilizing stability-indicating methods, endotoxin testing, container-closure integrity, antimicrobial effectiveness testing (where relevant), potency testing after compounding, as well as other relevant release checks, testing and documentation.
Members with clinical services access may contact our Clinical Services team for help with compounding sterile and non-sterile formulations in compliance with USP Chapters 795 and 797, as well as other compounding concerns.
Versions of this Blog originally appeared in PCCA’s members-only magazine, the Apothagram, as well as in separate Blog posts.