USP Chapter 797 sets compounding risk levels based on the likelihood of contamination of a compounded sterile preparation (CSP).
Knowing the level of risk corresponding to each compounded preparation is important because different rules apply to the compounding process depending on the level of risk. Proposed revisions to USP 797 are still under review and pandemic-related interim guidance is still applicable. It can be challenging to navigate which standards to follow to ensure the quality and safety of CSPs under the current conditions.
Here's a quick guide comparing some of the key considerations when evaluating risk level to CSPs in your organization. As of today, USP 797 (2008) is the currently official chapter and low, medium, or high-risk levels apply. For case-by-case determination of risk level, please refer to current state waivers and federal interim guidance documents and consult the licensed healthcare professional who supervises compounding at your pharmacy.
General principles of compounding risk level
In USP 797 (2008), the risk level is defined primarily on the complexity of the compounding process. Fewer components for admixture or a lower level of product manipulation indicate low-risk conditions. Combining three or more ingredients or packages, multiple additive injections, or non-sterile ingredients indicate medium to high risk. The higher the risk level, the greater risk for contamination or lack of sterility, leading to increased risk for patient harm.
USP 797 (2019, proposed) and interim guidance issued by FDA and USP in 2020 consider additional factors that may introduce risk to the final CSP. These focus primarily on the environment in which the compound is prepared. Examples include air quality, facility design, and shortage of standard personal protective equipment. All of these factors increase the risk for microbial contamination in the final CSP. While USP 797 (2019, proposed) is not currently enforceable, minding the state of control and compounding environment should guide decisions nonetheless.
Refer to Table 1 for a comparative summary of current and interim BUDs, in the absence of passing a sterility test. FDA and USP Interim Guidance is indicated in bold. Note there is no interim guidance for high-risk compounding and the current USP <797> standards apply.
Operational implications of risk level determination
Determining risk level is important because it establishes the beyond-use date (BUD) for each CSP. The BUD is the date and time by which administration of a CSP must begin. In other words, the safe storage limit to ensure reasonable sterility of a CSP under certain conditions – without performing a sterility test.
Low-risk compounding conditions
Compounding with aseptic manipulations using only sterile ingredients, products and devices in ISO Class 5 or higher air quality will generally fall in a low-risk category.
Low-risk compounding includes using sterile needles and syringes to transfer sterile liquids from manufacturer-sealed ampules or vials to sterile devices or other sterile packages. It also covers manually mixing and measuring up to three manufactured products to create a CSP or nutritional solution. Examples include:
- Simple withdrawal and transferring of not more than three sterile products (including diluents and solutions) to compound a final preparation.
- Single-volume transfer from one sterile container or package to another.
Low-risk with 12 hour or less BUD criteria* apply when a CSP is prepared under less-than-ideal circumstances, including environmental or procedural conditions, that increase the risk for microbial contamination. Examples include:
- A segregated compounding area (SCA) with inadequate filtration, air pressure or air exchanges to meet ISO 7 classification criteria.
- Temporary break in the state of control of a classified buffer area, such as power failure resulting in loss of pressure.
- Lack of standard personal protective equipment (PPE) and garbing procedures, such as re-use of disposable PPE that is allowed under interim guidance.
*Per USP <797> (2008), only non-hazardous and radiopharmaceutical CSPs may be prepared in an (SCA) under low-risk with 12 hour BUD conditions. However, USP <800> describes the criteria for Containment-Segregated Compounding Areas (C-SCAs) that allows for compounding of hazardous drugs with 12 hour or less BUD. Minimally, C-SCAs must have: at least 12 air changes per hour (ACPH) and maintain negative pressure of -0.01 to -0.03 i.w.c. for the room, with an externally vented containment primary engineering control (C-PEC).
Medium-risk compounding conditionsIf you compound or pool multiple doses of sterile products for administration to multiple patients or to a single patient on multiple occasions and the compounding process involves more than single-volume transfer or takes a long time (such as complete dissolution or homogenous mixing), the process will usually be considered medium-risk. Generally, medium-risk CSPs do not have broad-spectrum bacteriostatic substances and are administered over multiple days. Medium-risk compounding examples include:
- Compounded total parenteral nutrition fluids that require multiple injections of nutritional products or connections to a device that delivers all the nutritional components to the final sterile container.
- Filling injection or infusion devices with more than three sterile drug products.
- Transfer of volumes from multiple packages into one or more final sterile containers.
- Anticipatory preparation of products and subsequent storage for future use.
High-risk compounding conditions
Use of non-sterile ingredients or non-sterile devices usually creates a high-risk condition, as there is inherently greater risk of contamination from non-sterile products. Additional conditions resulting in high-risk level state include:
- Exposing sterile ingredients and devices to air quality below ISO Class 5
- Storage of opened or partially-used products that lack antimicrobial preservatives in an environment in less than ISO Class 5 conditions for greater than 1 hour.
- Inadequate validation of chemical purity and strength of bulk ingredients.
- Improper garbing and gloving of compounding personnel.
High-risk compounding would include making a solution that will be terminally sterilized from non-sterile bulk drug or nutrient powders or measuring or mixing sterile ingredients in a non-sterile device prior to sterilization.
Ultimately, establishing risk levels for CSPs is about protecting patients from harm. The more complex the procedure, the lower state of control of the environment, or when standard operating procedures are challenged, the risk of contamination increases. When conditions are compromised, a more conservative risk level and BUD is advised.
USP 797 may be on hold, but with The Joint Commission resuming inspections, it's time to reenergize programs. Learn more in our on-demand webinar, Update on recent proposed revisions to USP Chapters 795 and 797.