Understanding What is an example of a high risk compounding?

October 10, 2025 •

4 min read

According to the FDA, poor compounding practices can result in contaminated drugs, leading to serious injury or death. A key example of a high risk compounding is the preparation of sterile injectables from non-sterile raw drug powders, a process that requires meticulous controls and terminal sterilization.

Quick Summary

This article explores high-risk sterile compounding, focusing on the process of preparing sterile injectable solutions from non-sterile bulk powders, and outlines the rigorous safety and quality controls mandated by USP guidelines.

Key Points

Defining High-Risk: High-risk compounding involves using non-sterile ingredients and complex procedures that increase the potential for microbial and endotoxin contamination.
Primary Example: A prime example is the preparation of injectable solutions from non-sterile bulk drug or nutrient powders, which must be terminally sterilized.
Compounding from Bulk Powders: Using bulk drug substances requires meticulous verification of the ingredient's identity and concentration, as well as strict control over the environment and process.
Central Nervous System Risk: Products for intrathecal or epidural injection are extremely high-risk due to the potential for severe, life-threatening infection if contamination occurs.
Mitigating Risk: Mitigation relies on terminal sterilization, strict adherence to USP <797> guidelines, continuous environmental monitoring, and rigorous end-product testing.
Personnel Competency: Individuals performing high-risk compounding must demonstrate and renew their competency through testing every six months.

What Defines a High-Risk Compounding Process?

High-risk compounding is defined by procedures and conditions that present the greatest potential for microbial, chemical, and physical contamination of a compounded sterile preparation (CSP). This classification is primarily driven by the use of non-sterile starting ingredients or environments, which inherently increases the risk profile of the final product. Unlike low-risk compounding, which involves minimal manipulation of sterile products within a highly controlled environment, high-risk compounding introduces complexities and potential points of failure that demand stringent control measures. The ultimate goal is to prevent patient harm from contaminated, excessively potent, or incorrectly formulated products.

The Defining Characteristic: Non-Sterile Starting Materials

The most significant factor that elevates a compounding process to high-risk is the incorporation of non-sterile ingredients. These raw materials, often in the form of bulk drug powders, must undergo a final sterilization step, known as terminal sterilization, to be considered a safe CSP. In contrast, low-risk compounding utilizes only sterile components throughout the process, significantly reducing the potential for contamination. The use of bulk powders also requires additional quality assurance steps to verify their identity and purity, as they have not been subjected to the same manufacturing and testing rigor as commercial sterile products.

A Prominent Example of a High Risk Compounding

An example of a high risk compounding is dissolving non-sterile bulk drug powders to create a solution that will be terminally sterilized for injection. This is one of the most critical and heavily regulated types of compounding due to the severity of harm that could result if the final product is contaminated and subsequently injected into a patient. Examples of such preparations include:

Intrathecal or epidural injections: These are particularly high-risk as the final product is administered directly into the central nervous system, where any contamination can cause devastating and life-threatening infections, such as meningitis.
Fortified antibiotic ophthalmic eye drops: While not injected, these preparations are considered high-risk because they are administered into the eye, a sensitive area where sterility is paramount. Creating these from non-sterile raw powders and then sterilizing them is a high-risk process.
Custom preservative-free solutions: Making special formulations of drugs like corticosteroids for epidural use requires starting with raw powders and terminally sterilizing them, which falls squarely into the high-risk category.

The Risks Involved in High-Risk Compounding

The elevated risk in these processes stems from several factors:

Contamination: Non-sterile starting materials are a major source of microbial and endotoxin contamination. If the final sterilization step is ineffective, the finished product can be highly hazardous.
Lack of Potency/Purity: Compounding from bulk substances requires rigorous testing to ensure the correct concentration and purity. Without proper quality assurance, the final product could be superpotent, subpotent, or contain unintended contaminants, leading to adverse patient outcomes.
Process Complexity: High-risk procedures often involve multiple complex steps, increasing the chance for human error, such as inaccurate measurements or improper aseptic techniques.
Improper Storage: Extended storage of non-sterile intermediates before sterilization can allow for microbial proliferation, further complicating the sterilization process.

Rigorous Quality Assurance and Control

To mitigate these risks, regulatory bodies like the United States Pharmacopeia (USP) have established strict guidelines, such as USP Chapter <797>, for high-risk compounding. These guidelines cover:

Facilities and Environmental Controls: The compounding must occur in a cleanroom environment that meets specific ISO Class standards. This includes using a Primary Engineering Control (PEC) like a biological safety cabinet or isolator within an appropriately classified buffer room.
Personnel Competency: Staff involved in high-risk compounding must undergo extensive training and be re-evaluated for competency every six months through procedures like media-fill tests.
End-Product Testing: Every batch of high-risk CSPs must be tested for sterility and bacterial endotoxins to ensure safety before release. High-risk products are often assigned a shorter beyond-use date (BUD) unless stability and sterility testing can justify a longer one.

Comparison of Compounding Risk Levels


Feature	Low-Risk Compounding	High-Risk Compounding
Starting Materials	Only sterile ingredients and components.	Includes non-sterile bulk drug powders or other non-sterile components.
Sterilization Method	No terminal sterilization required. Aseptic processing is sufficient if all materials are sterile.	Requires terminal sterilization (e.g., steam, dry heat, filtration) to achieve sterility.
Environmental Control	Performed in an ISO Class 5 Primary Engineering Control (PEC), potentially within a less controlled area like a Segregated Compounding Area (SCA).	Requires a fully classified cleanroom suite, with strict ISO standards for the buffer room and ante-room.
Process Complexity	Minimal manipulations using sterile components.	Complex procedures involving multiple manipulations and handling of non-sterile powders.
Personnel Competency	Assessed annually.	Assessed every six months due to higher risk.
End-Product Testing	May not be required for every batch under standard BUDs.	Sterility and bacterial endotoxin testing is mandatory for every batch to extend BUDs.

The Critical Role of Terminal Sterilization

For high-risk compounding procedures involving non-sterile bulk powders, terminal sterilization is a non-negotiable step. The process is applied to the final sealed container, eradicating all viable microorganisms without compromising the drug's potency. Common methods include steam sterilization (autoclave), dry heat, or sterile filtration through a 0.2 micron filter. The choice of method depends on the drug's heat sensitivity and the type of container. This final sterilization provides the highest level of sterility assurance and is why facilities capable of terminal sterilization can assign longer Beyond-Use Dates (BUDs) to their products.

Conclusion

While compounding offers a vital solution for patients with unique medical needs, understanding the different risk levels is essential for ensuring safety. An example of a high risk compounding—creating a sterile injectable from non-sterile bulk powders—highlights the complexities and potential dangers involved. The tragic 2012 meningitis outbreak linked to improperly compounded sterile injections serves as a stark reminder of the devastating consequences when safety protocols are ignored. Strict adherence to USP standards regarding facilities, procedures, personnel training, and end-product testing is paramount to mitigating these risks and protecting patient health.

For more detailed information on USP regulations for sterile compounding, refer to resources from reputable organizations like the American Society of Health-System Pharmacists.

Frequently Asked Questions

A compounding process is classified as high-risk when it incorporates non-sterile ingredients or when sterile components are exposed to an environment with air quality inferior to ISO Class 5 for more than one hour before terminal sterilization.

This process is dangerous because the non-sterile raw powders can introduce microorganisms and endotoxins. If the final sterilization step fails, the contaminated injectable can cause severe infections, especially when administered into a sterile body space like the nervous system.

Terminal sterilization is the process of applying a lethal method (like steam or dry heat) to a drug after it has been placed in its final container and sealed. This is a crucial step for high-risk compounded products made from non-sterile ingredients.

USP Chapter <797> sets the standards for high-risk compounding, including strict requirements for facilities (ISO Class 5 environment), personnel training, quality assurance, environmental monitoring, and mandatory sterility and endotoxin testing of the final product.

Personnel involved in high-risk compounding must demonstrate their competency through media-fill tests at least every six months to ensure their aseptic technique is flawless.

After terminal sterilization, every batch of high-risk compounded products must undergo sterility testing and bacterial endotoxin testing to confirm they are safe for patient use.

The tragic 2012 meningitis outbreak, caused by contaminated steroid injections from a compounding pharmacy, highlighted the critical need for strict federal and state oversight of high-risk compounding to prevent patient harm and fatality.