Industry: Biotechnology

FDA Expands Unannounced Inspections for Foreign Manufacturing Facilities

Posted on by Brandon Miller

Regulatory Compliance Associates® (RCA) Executive Pharma Compliance Expert & Principal Consultant, Anita Michael, recently shared important FDA updates impacting pharmaceutical manufacturers. With over 25 years of global regulatory and quality experience—including 16 years as the FDA’s Global Pharmaceutical Expert—Anita emphasizes the need for heightened inspection readiness.

 

Key FDA Updates

  • Unannounced Inspections Abroad: The FDA will now conduct unannounced inspections at foreign manufacturing facilities, similar to those already performed in the U.S. This expansion ensures drug substances, finished products, and critical excipients entering the U.S. meet safety and quality standards.
  • Rigorous Reviews: Expect science-based audits across manufacturing operations and quality systems. Companies should ensure their
  • six quality systems (Quality, Production, Laboratory, Facilities & Equipment, Materials, and Packaging/Labeling) are fully inspection-ready.
  • Pre-Approval Program Updates: The FDA has refined its pre-approval inspection focus to include:
    • Readiness for commercial manufacturing (QMS and six systems)
    • Conformance to application and data integrity requirements
    • Commitment to quality and pharmaceutical development
    • Audit preparedness and documentation management

Preparing for Compliance

  • To stay ahead, companies should:Conduct robust internal and external audits
  • Maintain a centralized FDA document repository
  • Ensure subject matter experts are prepared to address complex regulatory questions

 

Why It Matters

These changes highlight the FDA’s commitment to protecting U.S. patients by ensuring consistent global manufacturing standards. Proactive preparation will be critical for pharmaceutical companies with international facilities or partnerships.

 

Need support preparing for FDA inspections or audits? Contact RCA today to speak with our compliance experts and ensure your organization is inspection-ready.

Integrating Device Design into a Biosimilar Program

Background

An established pharmaceutical company with a strong background in biologics and biosimilars was preparing to enter Phase 3 clinical trials with a biosimilar product. While their drug development and manufacturing teams were experienced and well-resourced, the organization had no prior experience with medical devices.

With the introduction of FDA’s combination product regulations and 21 CFR Part 4, the company realized they needed to house their drug product in a drug delivery system—triggering a set of new design and regulatory requirements. Despite their mature quality system aligned to 21 CFR Parts 210/211, they lacked the internal expertise and infrastructure to integrate device development, design controls, and risk management into their QMS.

RCA Approach

Regulatory Compliance Associates® (RCA). was brought in to establish a compliant and sustainable combination product development framework. The engagement began with a comprehensive gap assessment to evaluate the client’s current quality system against the regulatory requirements in 21 CFR Part 820 and Part 4.

While foundational systems like CAPA were already robust, gaps were identified in design controls, risk management, and supplier controls. RCA worked closely with the client to integrate these new requirements into the organization’s operations.

Key activities included:

  • Developing and revising SOPs: 
    • Multiple SOPs were created covering design controls, risk management, and management responsibilities. 
    • Existing SOPs (such as Purchasing Controls) were updated to reflect device-specific needs. 
  • Training cross-functional teams: 
    • RCA conducted training sessions for QA, regulatory affairs, manufacturing operations, and marketing on combination product regulations and new procedures. 
  • Establishing design documentation: 
    • Created complete design history files (DHFs) using new SOPs. 
    • Developed design and development plans, design input requirements, and detailed design specifications for all components, packaging, and labeling. 
    • Facilitated risk assessments through cross-functional collaboration. 
  • Technical and manufacturing support: 
    • Integrated device tests into ongoing stability studies. 
    • Worked with external vendors on component specifications. 
    • Helped develop and qualify an in-house final assembly process and supported manufacturing process qualifications for new equipment. 
    • Conducted and documented a design transfer to manufacturing. 
  • Verification & validation (V&V): 
    • Executed comprehensive testing, including: 
      • Container Closure Integrity 
      • Delivered Volume 
      • Break Loose and Glide Force 
      • Human Factors (Formative and Summative) per IEC 62366 
  • Regulatory support: 
    • Assisted in authoring the Device Section of the BLA, ensuring alignment with FDA expectations. 

Result

Thanks to RCA’s support, the company was able to initiate its Phase 3 clinical trials on schedule, with a fully compliant combination product. 

Over the next two years, the organization successfully launched three commercial combination products—two prefilled syringes and one vial kit—all of which passed FDA audits. The quality system enhancements and DHFs stood up to regulatory scrutiny, and the trained internal teams were able to carry the work forward independently. 

RCA also temporarily stood up a Device Development Department, mentoring internal staff and ensuring a seamless handoff post-acquisition. The company has since maintained compliance and continues to expand its biosimilar product portfolio with confidence. 

A Regulatory Roadmap for Combination Product Submissions

Posted on by Brandon Miller

Combination product submissions require a tailored regulatory strategy that blends device, drug, and biologic requirements. The complexity increases when multiple FDA centers could be involved.

 

The journey begins with identifying the product’s primary mode of action (PMOA). This determines which FDA center will lead the review:

  • CDER: Center for Drug Evaluation and Research
  • CBER: Center for Biologics Evaluation and Research
  • CDRH: Center for Devices and Radiological Health

If the PMOA is unclear, companies can submit a Request for Designation (RFD) to the Office of Combination Products.

 

Once the lead center is determined, companies must ensure their submission addresses the regulatory requirements of both drug/biologic and device frameworks. This includes integrating device GMPs (21 CFR Part 820) with existing pharma QMS (21 CFR Part 210/211).

 

Key requirements typically include:

  • Quality system alignment with 21 CFR Part 4
  • Documentation of design controls, CAPA, and purchasing controls
  • Evidence of human factors testing for design validation
  • Management responsibility and risk management processes

Recent FDA draft guidance (e.g., on essential performance outputs) further clarifies what must be demonstrated in combination product submissions. The focus is shifting toward system-level outputs that directly impact drug delivery and therapeutic performance.

 

For companies planning international expansion, the regulatory roadmap extends beyond the U.S. CE marking under the EU MDR often requires a Notified Body Opinion confirming that the device component is adequately controlled.

 

Success starts with early planning and cross-functional alignment. Regulatory, quality, and product development teams must work together to:

  • Identify regulatory gaps
  • Align SOPs and systems
  • Develop submission-ready documentation
  • Engage proactively with regulatory bodies

Navigating the regulatory maze of combination product submissions is complex but manageable—with the right roadmap, tools, and expertise in place.

 

Work with RCA to Streamline Your Submission Process Regulatory Compliance Associates helps companies navigate the complexities of combination product submissions in both U.S. and global markets. From regulatory strategy to documentation support, RCA is your trusted partner. Reach out today to get started.

Do You Actually Have a Combination Product? Here’s How to Know

Posted on by Brandon Miller

Many companies don’t realize they have a combination product until it’s too late. With increased regulatory scrutiny from the FDA, properly identifying your product type is not just important—it’s essential for compliance, market access, and patient safety.

 

A combination product, as defined by the FDA, is a therapeutic and diagnostic product that combines drugs, devices, and/or biological products. These products can take multiple forms, including:

  • Prefilled syringes (drug + delivery device)
  • Drug-eluting stents (device coated with a drug)
  • Convenience kits (e.g., vials packaged with filters and needles)
  • Cross-labeled products (e.g., drug and device sold separately but intended for combined use)

Some of these combinations are obvious, but many are not. A product that seems like simple packaging may actually trigger combination product regulations under FDA’s 21 CFR Part 4, effective since 2013. The FDA began strict enforcement in 2014, prompting many companies to reevaluate their portfolios.

 

One of the biggest risks is operating under outdated assumptions. If your company has historically marketed a device or drug in conjunction with another regulated product, you may already be in combination product territory without knowing it.

 

If there’s uncertainty, the FDA allows companies to submit a Request for Designation (RFD). This formal process helps determine which regulatory center (CDER, CBER, or CDRH) will have primary jurisdiction over your product based on its primary mode of action (PMOA).

 

Identifying whether your product qualifies as a combination product is a foundational step. Doing so early allows for proper planning of your development pathway, avoids regulatory surprises, and helps build a robust compliance strategy.

 

Partner with Regulatory Experts Regulatory Compliance Associates (RCA) has extensive experience helping companies identify and navigate combination product requirements. Contact RCA today to ensure you’re on the right path from the start.

Avoiding Common 503B GMP Deficiencies: Key Lessons from FDA Warning Letters

Posted on by Brandon Miller

503B outsourcing facilities play a critical role in addressing drug shortages and providing large-scale compounded medications. However, with this privilege comes the responsibility of adhering to stringent FDA regulations under Current Good Manufacturing Practices (CGMP). Repeated violations can lead to FDA warning letters, product recalls, and even shutdowns. Understanding common pitfalls is essential for maintaining compliance and ensuring patient safety.

 

In this blog, we examine some of the most frequent deficiencies cited in FDA warning letters to 503B facilities and how you can proactively prevent them.

 

Inadequate Aseptic Processing Controls

A recurring theme in FDA inspections is the failure to maintain proper aseptic technique and conditions. This includes:

  • Inadequate aseptic employee techniques
  • Improper personnel gowning and behavior
  • Poor cleanroom design and maintenance
  • Inadequate airflow and HEPA filter placement
  • Insufficient monitoring of environmental conditions
  • Poor cleaning, disinfection and sanitation controls

How to Avoid: Conduct a comprehensive GMP review of your aseptic processes, validate cleanroom performance, and implement rigorous training for all personnel involved in sterile compounding.

 

Deficient Environmental Monitoring Programs

Many facilities fall short in establishing adequate environmental monitoring (EM) protocols. Common issues include:

  • Irregular or infrequent sampling
  • Lack of meaningful trending and analysis
  • Delayed response to out-of-specification (OOS), alert and action results
  • Insufficient timely corrective actions

How to Avoid: Develop a robust EM and PM program that includes real-time data collection, regular review of trends, and timely corrective actions. Use EM data as a proactive quality tool, not just a compliance checkbox.

 

Incomplete or Inaccurate Documentation

Documentation is the backbone of GMP compliance. FDA has consistently cited 503B facilities for:

  • Missing batch records, incomplete entries and poor GDPs
  • Failure of thorough and timely deviations and investigations
  • Lack of CAPAs
  • Lack of traceability in production processes

How to Avoid: Enforce strict documentation procedures and requirements. Ensure all entries are legible, contemporaneous, original, accurate and reviewed regularly by quality assurance experts. Implement validated electronic systems where feasible to reduce human error.

 

Insufficient Process Validation

Many 503B facilities do not adequately validate their compounding processes. This includes:

  • Limited or no validation of sterile filtration and filling processes
  • Absence of complete media fill simulations
  • Failure to scientifically demonstrate repeatability and reliability of processes

How to Avoid: Develop and execute a thorough validation master plan (VMP) and perform validation studies. Conduct media fills under worst-case conditions and ensure all critical parameters are tested and documented and the facility is operating in a state of control.

 

Poor Quality Unit Oversight

The FDA expects a robust and independent quality unit (QU) to oversee all aspects of production. Common failures include:

  • QU lacking authority or involvement in decision-making
  • Quality responsibilities split among unqualified personnel
  • Inadequate review of batch records and investigations
  • Poor or incomplete quality SOPs

How to Avoid: Empower your quality unit with the necessary resources, training, and authority to act independently. Quality should not be siloed—it must be embedded into every layer of your operation.

 

Final Thoughts

503B outsourcing facilities operate under intense regulatory scrutiny, and for good reason: they are entrusted with producing high risk sterile medications on a large scale. By studying past deficiencies and strengthening internal systems, facilities can avoid the missteps that lead to enforcement actions.

 

Stay proactive, stay informed, and remember that compliance is not a one-time task—it’s an ongoing commitment to excellence.

 

Need help assessing your compliance and strengthening your quality systems? Contact RCA today to get expert guidance tailored to your facility’s needs.