503A Sterile Compounders Urged to Rethink Material Selection
USP <797> and FDA expectations place growing emphasis on component quality, documentation, and depyrogenation practices
As scrutiny sharpens around complex sterile drug compounding (especially nonsterile-to-sterile processes, batched compounding, and compounds having extended beyond use dating), 503A pharmacies are encountering increased regulatory attention regarding how components used in compounded sterile preparations (CSPs) are evaluated against the quality and documentation expectations described in USP <797> Section 9.3.1 and related FDA guidance.
While much attention in recent years has focused on air handling, garbing, and microbial control, industry experts are increasingly emphasizing the importance of material selection.
Choosing the Right Materials
USP <797> states that “conventionally manufactured sterile products should be used when available and appropriate for the intended CSP.” This language reflects USP’s preference for the use of FDA-approved sterile drug products when such products are clinically appropriate and operationally feasible.
When a sterile commercial product is unavailable, inappropriate, or does not meet the clinical need, USP <797> addresses circumstances under which the use of an active pharmaceutical ingredient (API) may be considered.
As per USP, all APIs and other components used must be evaluated for suitability for use in sterile drug preparations. USP <797> specifies that components labeled with “not for pharmaceutical use”, “not for injectable use”, “not for human use” or an equivalent statement are not considered suitable for use in sterile compounding.
Also per USP <797>:
The API must comply with a USP–NF monograph, if one exists
A Certificate of Analysis (COA) must be available that includes specifications and test results
The API must be manufactured by an FDA-registered facility (if U.S.-based), or comply with the relevant laws and regulations of its jurisdiction (if international)
Similar quality expectations apply to other components, such as excipients and preservatives.
Examples of CSP Starting Material Noncompliance
Inspectional observations, FDA guidance, and expert audits have identified recurring material-related issues that may raise compliance concerns, depending on context and implementation:
Use of APIs labeled “for dietary use only” in CSPs, particularly injectables, which may not meet pharmaceutical-grade standards
Preservatives or other components with COAs that explicitly state “not for parenteral use” being included in injectable CSPs
APIs repackaged in the pharmacy without required labeling information, such as full substance name, lot number, expiration date, repackaged date, and “use by” date (typically 180 days from repackaging unless otherwise justified)
Storage temperature deviations, such as APIs requiring frozen storage being kept in a refrigerator
Damaged or compromised container closures for bulk APIs, raising concerns about contamination and identity
These types of practices have been cited by regulators and inspectors as inconsistent with USP <797> requirements and, in certain circumstances, have been referenced in discussions of insanitary conditions.
It’s Not Just the Ingredients—It’s Also the Supplies
Beyond APIs and excipients, compounding supplies such as stir bars, glassware, and metal tools must also be appropriately treated before being introduced into sterile processing.
USP <797> describes expectations that commercially available sterile, depyrogenated containers and container closure systems be supported by documentation such as a Certificate of Analysis (COA) or other documentation showing conformance with established specifications (i.e., sterility and depyrogenation requirements). If sterilization and depyrogenation of supplies or container closure systems are performed on site, the efficacy of each process must be established and documented.
In summary, USP <797> outlines expectations intended to support sterility and depyrogenation control, including:
Thermostable items (e.g., glassware, metal implements) must be depyrogenated using dry heat
Non-thermostable items (e.g., certain plastic or coated tools) must be rinsed multiple times with sterile, nonpyrogenic water, such as Sterile Water for Injection (SWFI) or Sterile Water for Irrigation, and then dried immediately before use
Examples of scenarios cited during inspections or audits include:
Stir bars that cannot withstand dry heat but are not rinsed with sterile water prior to use
Beakers reused in sterile compounding after only basic cleaning without validated depyrogenation
The absence of depyrogenation cycle efficacy, missing documented procedures or records for depyrogenation of utensils and tools, etc.
Accountability Falls on the “Designated Person(s)”
USP <797> makes it clear: the designated person(s) at the compounding facility is responsible for ensuring the selection of acceptable and reliable sources for all materials. If a component is not sourced from an FDA-registered facility, the compounding team must establish its identity, strength, purity, and quality by reasonable means.
According to USP, reasonable means may include:
Visual inspections for physical integrity
Evaluation of manufacturer COAs
Analytical testing to verify conformance with specifications
Staying Compliant: A Call to Action
From a regulatory and inspection perspective, ingredient quality and documentation have become areas of increased focus in sterile compounding oversight. State boards and the FDA have consistently emphasized that compounding sterile products with questionable or undocumented materials jeopardizes both patient safety and licensure.
503A pharmacies should consider:
Auditing all vendors and incoming materials
Verifying FDA registration for domestic suppliers
Updating SOPs for depyrogenation and component qualification
Training staff to recognize and reject components lacking proper documentation
Restore Health Consulting helps 503A pharmacies identify and remediate gaps in material selection, depyrogenation procedures, and documentation practices—all aligned with USP <797> and FDA expectations.
Disclaimer:
This article summarizes publicly available regulatory standards, guidance, and inspectional themes for educational purposes only. It does not interpret law, establish binding requirements, or assert that the practices discussed are the exclusive means of achieving compliance. Regulatory compliance is assessed on a case-by-case, risk-based basis by the appropriate authority