When pharmacy leaders look to purchase compounded preparations from 503B outsourcing facilities, questions arise as to the best approach for evaluating the facility, operation, and quality to ensure patient safety. This is exacerbated by a historic volume of conventionally manufactured products on shortage, reduced travel budgets impacting the ability to conduct onsite assessments, an ever-changing regulatory landscape, and current good manufacturing practices (CGMP) expertise gaps.¹ This guide highlights key information for pharmacy leaders to conduct and maintain evaluations of outsourcing facilities, meet accreditation requirements, and ensure patient safety.

Evaluating 503B Outsourcing Facilities

When produced by conventional pharmaceutical manufacturers under the full provisions of the FD&C Act, drugs are evaluated through the FDA approval process for quality, safety, and efficacy. Further, post-marketing surveillance programs are in place to monitor the safety of approved drugs once they reach the market. Since 503B outsourcing facilities produce compounded preparations, the produced drugs are categorized as unapproved drugs, and thus do not have the same level of assurances. This highlights the importance of evaluating these facilities prior to purchasing compounded preparations for patient use and maintaining the evaluations on an ongoing basis. This can be a daunting task, as pharmacy’s experience with standards for sterile compounding (eg, USP <797>) does not apply to these types of facilities, necessitating understanding of CGMP regulations.

A proper evaluation of a 503B outsourcing facility should include an assessment of at least the following areas:

• Quality assurance and culture
• Regulatory compliance history
• Preparation methods and sterilization
• Patient safety
• Supply reliability
• Cost efficiency
• Risk management
• Documentation and transparency
• Customization and flexibility
• Partnership and support
• Contracting terms and conditions
• Physical assessment (onsite)

Accreditation and Documentation

Aside from the safety responsibility for our patients, evaluating 503B outsourcing facilities is a requirement of accreditation organizations. Given the various (and often overlapping) performance standards from the commonly used accreditation organizations (see TABLE 1), the following approach is likely to satisfy all accreditation requirements.

1. Evaluate 503B outsourcing facility services for safety and efficacy prior to purchasing compounded preparations for patient use.
2. Maintain a list of approved 503B outsourcing facilities with scope of services for your organization.
3. Identify and monitor performance metrics on at least a quarterly basis.
4. Document and communicate any identified issues and corrective actions.
5. Develop a policy for medication procurement from 503B outsourcing facilities that includes requirements for evaluation, identifying approved facilities, and documentation that must be maintained.

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CGMP requirements outline the need for the quality control units to periodically review records to evaluate the quality standards and need for changes. This review should identify trends and evaluate quality indicators, and include areas such as:

• Results of environment monitoring
• Results of personnel monitoring
• Results of finished drug product testing
• Media fills/process simulations performed
• Complaints, discrepancies, failures, and yield variation

503B outsourcing facilities maintain quarterly quality reports that contain much of this essential information and are usually available on the customer ordering portal or via direct request. Reviewing each quarterly quality report should be part of the organization’s ongoing assessment process, and it should be archived for accreditation review. When trends, out of specification, or other issues are identified, organizations should review those with the outsourcing facility personnel to determine their corrective actions and preventive actions (CAPA) and efficacy of actions taken to minimize risk to their patients.⁸

Ensuring Patient Safety

As part of the evaluation process, there a few key areas to consider for patient safety. Carefully consider the following elements:

• Regulatory history: The best predictor for future performance is the outsourcing facility’s past history. A thorough review of their regulatory history should be prioritized and include FDA inspection documents (eg, Form FDA 483), FDA actions (eg, Warning Letters), state board of pharmacy inspection documents, DEA inspections, recalls, and other available information.
• Firm’s response to regulators: While much of the regulatory history is publicly available through the FDA, the firm’s response to inspection observations or FDA actions is typically not public record. As such, organizations should request to review the firm’s response to the regulatory agency and include that information in the evaluation. These documents are essential, as they provide context and additional information, and demonstrate the firm’s commitment to quality and patient safety.
• Ingredients: Outsourcing facilities can produce compounded preparations using finished drug product from commercial manufacturers, which have been sterilized, or they can utilize bulk drug substances, which must undergo a sterilization step. If an outsourcing facility uses bulk drug substances, there are additional requirements that must be evaluated to ensure the outsourcing facility is procuring the bulk drug substances from FDA registered facilities and have quality agreements in place.
• Sterilization methods and sterility assurance: If an outsourcing facility is only using finished drug product, they likely are only performing aseptic processing (eg, sterile-to-sterile); however, if an outsourcing facility is using bulk drug substances, various sterilization methods can be used (eg, sterile filtration, terminal sterilization, etc). The effectiveness of the sterilization method itself should be evaluated as this is essential to ensure the final drug products can be deemed as sterile, regardless of whether a sterility test has been passed given the significant limitations of the sterility test.⁹
• Labeling: Since outsourcing facilities are not subject to the same labeling and packaging safety standards as pharmaceutical manufacturers, there exists potential opportunities for confusing, misleading, or inaccurate labeling that can cause significant patient harm if misinterpreted. Labeling and packaging safety issues have been reported through the Institute of Safe Medication Practices (ISMP) National Medication Errors Reporting Program. A detailed review of each label should be conducted to ensure that it conforms with safety best practices for labeling, including accurate representation of the total drug amount, volume, and concentration per mL; look-alike medication names or labels; use of tall man (mixed case) letters; and high-alert indications.¹⁰

Develop Mitigation Strategies

To minimize the impact to patients during recalls, shortages, shutdowns, or other sourcing events, pharmacy leaders must have a proactive mitigation strategy for each outsourced compound (see TABLE 2). Include standardized concentrations and fluids and an insourced back-up plan in each strategy.

When establishing a list of medications that the organization would like to outsource, consider standardizing medication concentrations and base fluid types across the organization for every outsourced preparation and match to options available from multiple outsourcing facilities. This approach will allow the organization to establish a primary, secondary, and even tertiary supplier for these medications to use in the event a supply chain disruption occurs for a specific preparation made by an outsourcing facility.

A proactive mitigation plan should detail how the organization will provide the medication if the primary and secondary facilities are unable to deliver sufficient quantities to meet patient needs. This can include in-house compounding following an established master formulation record (MFR) under USP <797>, or temporarily providing the medication in a vial form from a commercial manufacturer. Either approach will require advanced planning and communication to impacted areas addressing how to manage the temporary switch and any modifications to the operationalized strategy (eg, refrigerated storage versus room temperature storage).

Maintaining Evaluation Status

It is prudent that once the evaluation is complete and the decision is made to purchase products from the outsourcing facility, that the evaluation status be updated and maintained on an ongoing basis. The use of an internal 503B outsourcing facility evaluation dashboard can help satisfy this need (see TABLE 3). This approach makes it clear to accreditors that the organization has a continual process for reviewing the outsourcing facility for safety and efficacy, and helps the organization prioritize additional reviews or documentation requests (eg, quarterly quality reports).

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Further Considerations

Performing 503B outsourcing facility evaluations is a process that requires careful attention, expertise, and prioritization. Not all organizations will have personnel with the experience or expertise to perform these evaluations, and as such should consider utilizing consultants or services available through their group purchasing organization. Regardless of the approach, the organization is ultimately responsible for the patients they serve, and proper evaluation and review is essential to ensuring this safety is delivered.

Once the evaluation process is established, it can extended to other outsourced compounding services, such as 503A compounding pharmacies and nuclear pharmacies. USP <1083> on supplier qualifications highlights a life cycle approach, and underscores that the level of effort, formality, and documentation should be commensurate with the risk level of the service provided and the availability of mitigation strategies. Following the recommendations within this guide, pharmacy leaders can be confident in their evaluation of 503B outsourcing facilities in order to purchase important compounded preparations to meet their patient needs.

REFERENCES

1. ASHP. ASHP Drug Shortage Statistics. Accessed September 19, 2024. www.ashp.org/Drug-Shortages/Shortage-Resources/Drug-Shortages-Statistics
2. Centers for Medicare & Medicaid Services. “Accreditation of Medicare Certified Providers & Suppliers.” CMS.gov. Accessed June 9, 2024. www.cms.gov/
3. The Joint Commission. “Federal Deemed Status Fact Sheet.” JointCommission.org. Accessed June 9, 2024. www.jointcommission.org/
4. DNV GL Healthcare. “Healthcare Accreditation and Certification.” DNVGLHealthcare.com. Accessed June 9, 2024. www.dnv.us/supplychain/healthcare/
5. Healthcare Facilities Accreditation Program. “Accreditation and Certification Programs.” HFAP.org. Accessed June 9, 2024. www.hfap.org/
6. Accreditation Commission for Health Care. “Accreditation Services.” ACHC.org. Accessed June 9, 2024. www.achc.org/
7. Center for Healthcare Quality. “Quality Standards and Accreditation Programs.” CHQ.org. Accessed June 9, 2024. cihq.org/
8. FDA. Corrective and Preventive Actions (CAPA). Accessed September 9, 2024. www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-guides/corrective-and-preventive-actions-capa
9. United States Pharmacopeia (USP). General Chapter, 〈1211〉 Sterilization and Sterility Assurance of Compendial Articles. USP-NF. Rockville, MD. Official March 1, 2019.
10. ISMP. Patient Safety Issues with 503B Labeling and Packaging: Making the Case for Outsourcers to Follow FDA Guidance. www.medsafetyboard.com/patient-safety-issues-with-503b-labeling-and-packaging-making-the-case-for-outsourcers-to-follow-fda-guidance/

Kevin Hansen, PharmD, MS, BCSCP, is the pharmacy director, 503B program at Premier Inc. He earned his Doctor of Pharmacy degree from LECOM, completed a PGY1/PGY2/MS health-system pharmacy administration and leadership presidency program at the University of North Carolina Medical Center, and is a board certified sterile compounding pharmacist.