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by Melissa Merrell Rhoads, PharmD, PCCA Director of Formulations
The revised USP Chapter 797 becomes official on November 1, 2023. USP 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, the requirements of USP 797 must be met to ensure the sterility of CSPs, which include but are not limited to injections, irrigations (for internal body cavities), ophthalmics and inhalations.
Changes that will occur in the PCCA sterile formulas related to USP 797 revisions are primarily seen in updates to the compounding procedures and notes.
Sterilization and depyrogenation procedures are described in Section 10 of USP 797, which states, “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.”
We will be updating the specific compounding sterilization process to comply with the revisions to USP 797. Note that one of the biggest differences is the requirement to pre-filter 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 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 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 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 and SporeView® Steam Biological Indicators 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. This process must be verified and documented with each sterilization run or load through the use of SporeView® Culture Set Biological Indicators and temperature monitoring per USP guidelines. Refer to USP 1229, Sterilization of Compendial Articles, for more information.
Remove from oven immediately and allow to cool to room temperature.
When dry-heat sterilizing compounded oil suspensions, the initial filter step is removed. After the dry-heat process, it is important to provide constant agitation while the preparation is cooling to prevent clumping of the suspension.
Revisions to USP 797 also state the requirement for preserved multiple-dose CSPs. According to USP 797, a multiple-dose CSP must be prepared as a Category 2 or Category 3 CSP. An aqueous multiple-dose CSP must additionally pass antimicrobial effectiveness testing in accordance with 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 for the first time, the beyond-use date (BUD) of the preparation becomes 28 days or less.
We will not list specific BUDs on our sterile formulations, as there are several parameters for consideration when establishing BUDs. As a guide, we will include the following on all PCCA sterile formulations:
Note: USP Chapter 797 sets forth parameters to consider when establishing beyond-use dates (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. Review the requirements of your state board(s) of pharmacy with whom you are licensed. For more information, refer to current USP Chapter 797 and other relevant USP Chapters.
Note: USP Chapter 797 sets forth parameters to consider when establishing beyond-use dates (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. Review the requirements of your state board(s) of pharmacy with whom you are licensed. For more information, refer to current USP Chapter 797 and other relevant USP Chapters.
As a reminder, PCCA FormulaPlus™ sterile formulations comply with the requirements set forth by the revised USP 797 for extending a BUD when all applicable requirements are met. FormulaPlus extended BUDs address the chemical stability of the formulation determined by a stability-indicating assay. A passing sterility test is required prior to considering applying for this extended BUD.
PCCA members may access more information related to the revisions in USP 795 and USP 797 on PCCA Play.
For information on revisions to PCCA nonsterile formulas related to the USP 795 changes, see the Spring 2023 Apothagram Formula Spotlight column, available to PCCA members on our Members-Only Website.
Members with clinical services may also contact our Clinical Services team with any questions.
A version of this article originally appeared entirely in PCCA’s members-only magazine, the Apothagram.