Tag: fda

Safecor Health Warning Letter Closeout

I got a post on my RSS feed today from the FDA for a closeout letter to Safecor Health in response to the 2023 Warning Letter. Always happy to see an actual closeout letter.

The main takeaways from the FDA warning letter:

Inadequate Line Clearance and Packaging Controls:

    • Safecor failed to properly inspect packaging and labeling facilities before use, leading to potential mix-ups of drug products. This was evidenced by the presence of unrelated tablets and capsules during the packaging of a specific product.
    • The company has a history of product mix-ups, including instances where a vitamin was found in a drug meant to prevent organ transplant rejection and mislabeled blood clot prevention medication.

    Insufficient Cleaning and Maintenance Procedures:

      • The firm lacked adequate procedures for cleaning and maintaining equipment, with unidentified residues found on supposedly clean equipment. This poses a risk of cross-contamination.
      • The company’s cleaning validation program was deemed inadequate, particularly in addressing worst-case scenarios.

      Failure to Test Components:

        • Safecor did not adequately test incoming components, such as water used in drug manufacturing, for purity, strength, and quality.
        • The company relied on visual inspections without performing necessary chemical and microbiological tests.

        Quality Control Unit Deficiencies:

          • The quality control unit failed to ensure compliance with CGMP regulations, including inadequate document control and data integrity issues.
          • Manufacturing records were not properly controlled, and corrections were made using correction fluid, raising concerns about data authenticity.

          Understanding the Distinctions Between 503B Outsourcing Facilities and Compounding Pharmacies

          I get really confused on the differences between compounding pharmacies and outsourcing facilities. I’ve never worked at either, but see a lot of 483s and warning letters. So today I spent some snow day time doing some reading. I then wrote this up as a reminder to myself.

          The Drug Quality and Security Act (DQSA) of 2013 introduced significant changes by distinguishing between compounding pharmacies under Section 503A and outsourcing facilities under Section 503B of the Federal Food, Drug, and Cosmetic Act (FDCA). This distinction is crucial for ensuring the safety and quality of compounded drugs.

          Compounding Pharmacies (503A)

          Definition and Purpose: Compounding pharmacies are licensed by state boards of pharmacy and primarily focus on creating customized medications for individual patients when commercially available drugs do not meet their needs. These pharmacies must adhere to standards set by the United States Pharmacopeia (USP), such as USP 797 for sterile compounding and USP 800 for hazardous drugs.

          Regulatory Framework: Compounding pharmacies operate under the supervision of a licensed pharmacist and require a prescription for each compounded product. They are generally limited to small batches and are not allowed to engage in office-use compounding without a prescription.

          Outsourcing Facilities (503B)

          Definition and Purpose: Outsourcing facilities, on the other hand, are registered with the FDA and specialize in producing large batches of sterile drugs, often without the need for individual prescriptions. These facilities are designed to address drug shortages and provide complex or rarely compounded preparations to healthcare organizations.

          Regulatory Framework: Unlike 503A pharmacies, 503B facilities must comply with FDA’s Current Good Manufacturing Practices (CGMP) to ensure the quality and safety of their products. They are subject to regular FDA inspections and must report on their compounded products.

          Recent Regulatory Actions: The Case of ProRx, LLC

          This research came about because I was reading a recent warning letter issued to ProRx, LLC, which basically stated they were failing to comply with CGMP regulations for 503B outsourcing facilities. The FDA identified serious deficiencies in sterile drug production practices, posing significant patient safety risks.

          Implications for 503B Facilities

          The warning letter to ProRx, LLC, serves as a reminder of the high regulatory bar set for 503B outsourcing facilities. Key implications include:

          • Enhanced Oversight: The FDA’s ability to inspect and enforce cGMP compliance means that 503B facilities must maintain meticulous quality control and production standards.
          • Patient Safety: The primary concern is ensuring that compounded drugs are safe for use. Facilities must address any deficiencies promptly to avoid recalls and protect patient health.
          • Partnerships and Supply Chain: The ability of 503B facilities to supply compounded drugs to healthcare organizations and pharmacies relies on their compliance with FDA regulations. Non-compliance can disrupt supply chains and impact patient access to necessary medications.

          What I take away from my research is that 503B outsourcing facilities are GMP facilities, and are held to the same standard. Good to know as I evaluate their regulatory actions in the future. I think I’ve tended to dismiss them as not being in the same class of regulatory expectations.

          Also, this is the second time this month where I really wonder what regulatory agencies fascination with pharmacists are in GMP facilities. Seems pretty clear to me that being a pharmacist is no indication of any capability around GMP activities.

          Leaks in Single-Use Manufacturing: A Critical Challenge in Bioprocessing

          The recent FDA warning letter to Sanofi highlights a critical issue in biopharmaceutical manufacturing: the integrity of single-use systems (SUS) and the prevention of leaks. This incident serves as a stark reminder of the importance of robust control strategies in bioprocessing, particularly when it comes to high-pressure events and product leakage.

          The Sanofi Case: A Cautionary Tale

          In January 2025, the FDA issued a warning letter to Sanofi regarding their Genzyme facility in Framingham, Massachusetts. The letter cited significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (APIs). One of the key issues highlighted was the company’s failure to address high-pressure events that resulted in in-process product leakage.

          Sanofi had been using an unapproved workaround, replacing shipping bags to control the frequency of high-pressure and in-process leaking events. This deviation was not properly documented or the solution validated.

          A proper control strategy in this context would likely involve:

          1. A validated process modification to prevent or mitigate high-pressure events
          2. Engineering controls or equipment upgrades to handle pressure fluctuations safely
          3. Improved monitoring and alarm systems to detect potential high-pressure situations
          4. Validated procedures for responding to high-pressure events if they occur
          5. A comprehensive risk assessment and mitigation plan related to pressure control in the manufacturing process

          The Importance of Leak Prevention in Single-Use Systems

          Single-use technologies have become increasingly prevalent in biopharmaceutical manufacturing due to their numerous advantages, including reduced risk of cross-contamination and increased flexibility. For all this to work, the integrity of these systems is paramount to ensure product quality and patient safety.

          Leaks in single-use bags can lead to:

          1. Product loss
          2. Contamination risks
          3. Costly production delays
          4. Regulatory non-compliance

          Strategies for Leak Prevention and Detection

          To address the challenges posed by leaks in single-use systems, manufacturers need to consider implementing a comprehensive control strategy. Here are some key approaches:

          1. Integrity Testing

          Implementing robust integrity testing protocols is crucial. Two non-destructive testing methods are particularly suitable for single-use systems:

          • Pressure-based tests: These tests can detect leaks by inflating components with air to a defined pressure. They can identify defects as small as 10 µm in flat bags and 100 µm in large-volume 3D systems.
          • Trace-gas-based tests: Typically using helium, these tests offer the highest level of sterility assurance and can detect even smaller defects.

          2. Risk-Based Quality by Design (QbD) Approach

          Single-use components and the manufacturing process must be established and maintained using a risk-based QbD approach that can help identify potential failure points and implement appropriate controls. This should include:

          • Comprehensive risk assessments
          • Validated procedures for responding to high-pressure events
          • Improved monitoring and alarm systems
          Best Practices for Managing the Life-Cycle of Single-Use Systems

          Validated Process Modifications

          Instead of using unapproved workarounds, companies need to develop and validate process modifications to prevent or mitigate high-pressure events. One thing to be extra cautious about is the worry of a temporary solution becoming a permanent one.

          Conclusion

          The Sanofi warning letter serves as a crucial reminder of the importance of maintaining the integrity of single-use systems in biopharmaceutical manufacturing. By implementing comprehensive control strategies, including robust integrity testing, risk-based approaches, and validated process modifications, manufacturers can significantly reduce the risk of leaks and ensure compliance with cGMP standards.

          As the industry continues to embrace single-use technologies, it’s imperative that we remain vigilant in addressing these challenges to maintain product quality, patient safety, and regulatory compliance.

          Scale of Remediation Under a Consent Decree

          The recent Sanofi Warning Letter certainly gets me thinking about the work of a consent decree and the scale and ‘stickiness‘ within an organization.

          Scale of Remediation

          In the Sanofi-Genzyme consent decree there were these concentric circles of required activities. At the center was the plant the issue was discovered, the Allston Landing Facility, which had the full brunt of remediation.

          The next level out were the plants in Framingham and Northborough. They had remediation actions to be done, including reduced third party oversight for critical activities for a more limited time. The consent decree was on a much reduced scale at these sites.

          The next level out was the former Genzyme sites beyond the Massachusetts core. They did alignment to the new standards created as part of the consent decree. Finally the rest of Sanofi, after Sanofi bought Genzyme, pretty much ignored it.

          This balkanization meant that the culture across the organization never really changed. The cultural resistance of the site/silos fostered a culture of “us vs. them” mentality within the organization. Without a unified organizational culture, it is much harder to implement and maintain changes across the entire company.

          The Slippery Slope: How Quality Improvements Can Erode Over Time

          The erosion of quality culture at Sanofi demonstrated by this new Warning Letter isn’t unique to this case. Even when quality improvement initiatives are launched with great enthusiasm and initial success it is not uncommon for these hard-won gains to gradually erode over time, leaving organizations back where they started or even worse off. This phenomenon of “quality backsliding” can be frustrating and costly.

          Why Quality Improvements Fade

          There are several reasons why quality improvements may deteriorate over time:

          Leadership Changes: When key champions of quality initiatives leave or change roles, their successors may not prioritize maintaining those improvements. New leaders often want to make their own mark, potentially abandoning or de-emphasizing existing quality programs.

          Budget Cuts: In times of financial pressure, quality improvement efforts are often seen as “nice to have” rather than essential. Resources dedicated to sustaining improvements may be reallocated, leading to a gradual decline in performance.

          Complacency: Initial success can breed complacency. Once targets are met, there may be less motivation to continue pushing for further improvements or even maintaining current standards.

          Loss of Focus: As new priorities emerge, attention and resources can shift away from quality initiatives. Without ongoing commitment, processes can slowly revert to old, less effective ways of working.

          Lack of Standardization: If improvements aren’t fully standardized and integrated into daily operations, they remain dependent on individual efforts rather than becoming part of the organizational culture.

          Sanofi Warning Letter

          I think we will be evaluating the Sanofi Warning Letter of January 15th, 2025 for a while. Received at the Framingham manufacturing site, this Warning Letter will fuel case studies about the pendulum of compliance and how it can swing perhaps a bit too erratically.

          This site is the sister site to the former Genzyme site (last time I checked owned by Resilience and mothballed) in Allston, MA.

          The Genzyme consent decree was a significant regulatory action taken by the U.S. Food and Drug Administration (FDA) in response to ongoing manufacturing quality issues at Genzyme’s Allston Landing facility in Massachusetts. Here’s a chronological overview of the key events:

          In October 2008, an FDA inspection of the Allston plant led to the issuance of an FDA Form 483, highlighting various deficiencies. In February 2009, the FDA issued a Warning Letter to Genzyme, detailing issues with microbiological contamination control procedures and bioburden monitoring. Then in June 2009, Genzyme detected a virus in one of its bioreactors, leading to a six-week production interruption and subsequent drug shortages. A follow-up FDA inspection in November 2009 revealed ongoing significant problems, resulting in a 49-item Form 483.

          On May 24, 2010, Genzyme signed a consent decree with the FDA. The consent decree required Genzyme to adhere to a strict timetable to bring the Allston plant into compliance with FDA regulations.

          The next few years a comprehensive remediation plan was implemented with ongoing oversight from a third-party consultant. The company then went through a certification process, FDA inspection, and surveillance by a third party for another five years before being able to request an end to the consent decree.

          I believe when Sanofi sold the Allston site to Resilience (Sanofi bought Genzyme in 2011), the consent decree had pretty much finished that surveillance period, but I can find no evidence of the company petitioning the court to lift the consent decree. So I have no idea what that means.

          The Framingham sites (which this Warning Letter is addressed to) here under the consent decree but to a lesser amount of oversight. So to see this new Warning Letter, for the new construction done in the mid 2010s is pretty sad for me.

          There’s a lot to unpack here that is relevant to SUS biologics manufacturing facilities, but that will be a future post. I need to go get a drink.