Segment: Quality Assurance

Strategic CGMP Remediation for a Major Pharmaceutical Company

Background

In the highly regulated pharmaceutical industry, compliance with FDA regulations is paramount to ensuring product safety and overall quality. When a large pharmaceutical company received a Form FDA 483 and warning letter across multiple of its manufacturing sites, it faced significant operational, quality, and reputational risks. The warning letter cited systemic deficiencies in key quality systems, including environmental monitoring, batch record review, corrective and preventive action (CAPA), Investigations, validation, and shop floor quality.

Recognizing the urgency and complexity of the situation, the company engaged RCA (Regulatory Compliance Associates) to guide its forward efforts for holistic corrective actions across all their sites. What began as a small-scale audit by a former FDA executive after the firm’s initial 483, quickly evolved into a comprehensive, multi-year compliance project involving dozens of RCA consultants at its peak across the various sites.

RCA’s approach emphasized indoctrinating a more robust quality culture, ensuring regulatory compliance, and implementing sustainable process improvements in order to bring the company back into (and strive to exceed) CGMP compliance as efficiently and effectively as possible.

Phase 1: Initial Assessment and Strategic Planning

The engagement began with an RCA ex-FDA executive and team conducting an in-depth audit at one of the impacted sites. This assessment focused on identifying the root causes of non-compliance and evaluating the company’s existing quality systems against FDA’s Current Good Manufacturing Practices (CGMPs).

The initial audit revealed several key systematic deficiencies at the site, which extended to the other sites within the organization. There were issues with the Batch Record Review process, resulting in inconsistencies in product documentation. Additionally, the CAPA (Corrective and Preventive Actions) program showed inadequacies, as corrective actions were either ineffective or not properly followed through. Investigations for environmental monitoring and other issues were also found to be weak, which contributed to recurring quality issues that were not fully addressed. Lastly, gaps in shop floor oversight were identified, which increased compliance risks during manufacturing operations.

Based on the findings from the original scope of work, the RCA expert developed an initial compliance improvement strategy and roadmap. This outlined the necessary interim controls and long-term sustainable system improvements. The plan was designed to prioritize high-risk compliance gaps while maintaining operational continuity.

Phase 2: Deployment of Interim Controls and Scaled Expansion by building an RCA-Led Compliance Team

With FDA scrutiny at other sites increasing, the company agreed to expand RCA’s role. RCA deployed a team of consultants with expertise in compliance, quality assurance, microbiology, and validation. Over the following two years, RCA and the firm had to scale up to the total number of consultants, embedding personnel at multiple sites to oversee the execution of interim controls and systemic improvements.

Interim Controls for Compliance Stabilization.

These included a comprehensive overhaul of the Batch Record Review process, where RCA trained company personnel on proper documentation techniques, Good Documentation Practices (GDPs), data integrity, investigation rigor, and introduced a real-time review process. In addition, the company and consultant team implemented standardized templates and checklists to ensure uniform documentation through document control systems in alignment with the CGMPS. In strengthening the investigation and CAPA system, RCA consultants helped to establish updated procedures. This included developing a solid escalation process to ensure critical issues were elevated to the executive level of the firm and assessed at all their manufacturing sites. In tandem, the collaborative firm and consultant team worked to ensure investigations and their resultant CAPAs were risk-based, data-driven and effective. They also introduced CAPA effectiveness checks to ensure the implemented CAPAs worked as designed and corrected the problem(s), as well as prevented recurrence.

Specific to investigations, RCA helped define clear workflows for documenting and addressing such issues, helped to implement a root cause analysis framework based on industry best practices, and established cross-functional teams including Quality, Manufacturing, and Quality Control to foster collaboration and improve the rigor of their investigations and CAPAs. RCA also led an initiative to help the firm mitigate a large investigations backlog.

To aid in enhancing shop floor quality oversight, RCA deployed quality experts on-site to provide real-time guidance to operations and quality staff during real-time manufacturing operations. This collaborative coaching proved to help strengthen their shop floor operations. It also helped improve the company’s overall quality culture by helping to educate personnel on the “why” things need to be done a certain way, through informal coaching, as well as formal training. It also helped reinforce CGMP compliance at all levels – from the line-level associates to the supervisors.

An ex-FDA executive and a team also collaborated closely with company executives on their FDA correspondence throughout the entirety of the project. This involved helping to draft comprehensive FDA response letters outlining the company’s remediation efforts, conducting periodic progress reviews to ensure commitments to the FDA were met, and preparing the company for follow-up FDA inspections. By maintaining direct and transparent communication with the FDA, RCA helped the firm demonstrate their commitment to quality, compliance, and continuous improvement.

Phase 3: Culture Shift and Sustainable Compliance

As interim controls stabilized and the firm improved the quality of their operations, RCA shifted focus to long-term compliance sustainability. The goal here was to impart practices which would ensure the company maintained their compliance posture by further embedding quality-centric behaviors across each of the site’s operations and quality units. This, in turn, helped to further bolster their quality culture and led to further reducing the risk of non-compliance and potential future regulatory issues.

To institutionalize best practices, RCA worked closely with executive leadership to integrate compliance objectives into the company’s current quality culture. Standard Operating Procedures (SOPs) and governance structures were developed to maintain inspection readiness, while RCA conducted training to empower internal personnel to independently sustain improvements.

In terms of monitoring and continuous improvement, RCA helped the firm to implement improved quality metrics and compliance dashboards. The dashboards helped provide executives with real-time visibility into the performance of the quality system and progress of the remediation. The result of this effort was the establishment of a strong quality culture helping to ensure implemented improvements remained effective over time.

Further Operational Efficiency Gains:

After RCA worked collaboratively with the company to streamline and improve the batch record review process, the firm was able to reduce review cycle times and improve overall right-first-time reviews. CAPA closure rates also improved, with all tasked corrective actions being completed on a more accelerated schedule, but with better depth, rigor, and overall effectiveness.

Cultural Transformation:

Employee engagement in quality initiatives saw a notable increase, shifting the mindset from compliance and quality being an obligation to it being viewed as a core value. Leadership also adopted a more proactive stance on CGMP expectations, positioning the company for long-term success and growth.

Results

RCA’s involvement in this large-scale compliance remediation effort demonstrates how a collaborative approach, combined with expert guidance, strategic interim controls, and a strong focus on quality culture, can transform an organization facing significant regulatory challenges. By deploying a team of experienced consultants, including former FDA executives who provided regulatory oversight, RCA successfully guided the company through a complex compliance journey. This support helped restore operational integrity and reinforced a sustainable quality mindset. This case study highlights RCA’s ability to respond rapidly, scale strategically, and implement long-term quality improvements that position clients for continued compliance and success in the pharmaceutical industry.

 

Drug Shortages and Complying with FDA’s 21 CFR 211.110 Guidance

Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Rona LeBlanc-Rivera, PhD, principal consultant, Regulatory Affairs at Regulatory Compliance Associates, answer some questions about FDA’s January 2025 21 CFR 211.110 guidance document.

 

Q: How does FDA’s guidance, Considerations for Complying with 21 CFR 211.110, impact our current approach in complying with 21 Code of Federal Regulations (CFR) 211.110 (1)?

A: This guidance is currently in draft. However, when finalized, it will describe areas to be considered to ensure batch uniformity and drug product integrity. The guidance also discusses quality considerations for drug products manufactured using advanced in-process manufacturing techniques. Allowing flexibility to use new technological advances to determine drug product integrity and batch uniformity during manufacturing could reduce product reject rates because in-process results could be reported sooner (perhaps in-real time) and manufacturing corrections could be made to ensure the batch integrity. Drug products manufactured using advanced in-process techniques may have non-traditional quality considerations to determine the suitability of the product, and this guidance allows for flexibility and latitude on how to implement these controls effectively. It should be noted that the scope of this guidance pertains to commercial processes and not to products in development. The drug substance/API is also not within the scope of this guidance.

 

Q: How flexible is FDA in allowing alternative approaches to in-process controls, and what would be the process for gaining approval for such approaches?

A: FDA does allow manufacturers some flexibility to use better and more efficient methods to meet current good manufacturing practice (CGMP) requirements. It is recommended that companies gather the data and seek early FDA feedback regarding the use of alternative approaches for both in-process and quality parameters before submission of an application. Companies trying to introduce novel and new in-process test controls that yield more accurate and real-time measurements will have more success in getting approval by partnering with the FDA early in the process of introducing the new technology to the manufacturing process.

 

Q: What are FDA’s expectations for in-process material sampling frequency and methodology?

A: In-process sampling would be dictated by the nature of the drug and manufacturing process. It is not always feasible to obtain an in-process sample. In this guidance, FDA advises that innovative technologies may allow in-line, at-line, or on-line measurements in lieu of physical sample removal for testing.

 

Q: How does this guidance address the role of in-process controls in preventing drug shortages?

A: In the guideline, FDA states that it “supports the adoption of advanced manufacturing as a foundation for improving the overall quality and availability of drug products for patients.” Exploring how to improve manufacturing oversight through the use of the innovative technologies mentioned above could help enhance supply chain stability and eliminate some drug shortages. Advanced in-process and quality parameter controls may help reduce production failures that contribute to these shortages.

 

Q: If a more efficient in-process control method could reduce shortages but it is not covered in the guidance, how should companies seek FDA approval?

A: For an FDA-approved drug product, the application holder should gather the necessary data and documentation for filing a supplement (i.e., CBE [changes being effected]-30, PAS [prior approval supplement]) to their application regarding the use of alternative approaches. FDA would then review and provide comments on the proposed change and help identifying the best pathway forward for regulatory acceptance of innovative manufacturing techniques.

 

This new guidance offers flexibility to manufacturers, including contract manufacturing organizations, to introduce new, more efficient methodologies to measure batch uniformity and product integrity required to determine product suitability to ensure continued access to necessary pharmaceutical products. It is up to pharmaceutical industry to work with FDA and determine the best implementation strategy for realizing the benefits of modernizing manufacturing processes.

 

Reference

1. FDA. Considerations for Complying with 21 CFR 211.110, Draft Guidance (CDER, January 2025).

 

About the Article

 

Pharmaceutical Technology
Vol. 49, No. 3
Page: 34

 

 

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Ask the Expert: Complying with 21 CFR 211.110

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of FDA’s new draft guidance on complying with 21 CFR 211.110.

 

Link to the Video and Article on Pharmaceutical Technology

 

In January 2025, FDA published a draft guidance document that provides considerations for complying with 21 Code of Federal Regulations (CFR) 211.110 (1). This specific section of the CFR focuses on production and process controls for sampling and testing of in-process materials and drug products. The guidance, Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance, applies to human drug products and biologics, but not to the manufacture of APIs. The guidance document also discusses how process models can be incorporated into commercial manufacturing control strategies.

 

In this episode of the Ask the Expert video series, Susan J. Schniepp, distinguished fellow at Regulatory Compliance Associates, and Siegfried Schmitt, PhD, vice president, Technical at Parexel, discuss the implications of this draft guidance and best practices for complying.

 

“What [the guidance document] really seems to be aimed at is new manufacturing techniques that are coming on board and some flexibility for biopharmaceuticals as we get into, you know, personalized medicines, continuous manufacturing, and the use of artificial intelligence (AI) to identify some of the key process parameters for new manufacturing and processes … giving manufacturers more flexibility in that arena,” explains Schniepp.

 

“FDA is trying to look to the future, is trying to address what’s current, what’s happening now. And as you said, use of AI; although, I don’t think a lot of companies are really, really implementing this yet in day-to-day operations. Perhaps another aspect here of this guidance is it speaks a lot about continuous manufacturing, which, again, in my experience, is a process that’s rarely applied in most of manufacturing because the vast majority of processes are still back by batch,” says Schmitt.

 

Reference

1. FDA. Considerations for Complying With 21 CFR 211.110, Guidance for Industry, Draft Guidance (CDER, CBER, January 2025).
https://www.fda.gov/media/184825/download

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

 

 

Drug Digest: Advances in Small-Molecule Manufacturing

In this exclusive Drug Digest video interview Anil Kane from Thermo Fisher Scientific will be tackling the topic of advances in small-molecule manufacturing and several other experts will provide brief commentaries on associated topics. Regulatory Compliance Associates’ (RCA) distinguished fellow and a member of the Editorial Advisory Boards for Pharmaceutical Technology, Susan J. Schniepp is featured in this interview for her industry insight into small-molecule manufacturing.

 

Link to the Video and Article on Pharmaceutical Technology

 

In this exclusive Drug Digest video interview, Felicity Thomas, Associate Editorial Director, and Patrick Lavery, Editor, Pharmaceutical Technology Group, will be tackling the topic of advances in small-molecule manufacturing with Anil Kane from Thermo Fisher Scientific. Additionally, their is  also some extra commentaries on the trends shaping the oral solid dosage market with Uwe Hannenberg from Recipharm, the manufacturing hurdles associated with challenging molecules with Jens Schmidt from Lonza, and some advice from our Ask the Expert columnists about changing excipient providers.

 

About Drug Digest

Drug Digest is a tech talk video series with the Pharmaceutical Technology editors, who interview industry experts to discuss the emerging opportunities, obstacles, and advances in the pharmaceutical and biopharmaceutical industry for the research, development, formulation, analysis, upstream and downstream processing, manufacturing, supply chain, and packaging of drug products.

 

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected].

 

FDA’s QMSR Final Rule: What Manufacturers Need to Know

Posted on by Brandon Miller

Listen to hear RCA’s Director of Regulatory Affairs, Jordan Elder, review the key differences regarding the new Quality Management System Regulation (QMSR) final rule and the current Quality System Regulation (QSR).

The FDA has recently issued the Quality Management System Regulation (QMSR) final rule, marking a significant update to the longstanding Quality System Regulation (QSR). This change is designed to harmonize medical device quality system requirements with the globally recognized ISO 13485 standard. While the original QSR emphasized product safety and effectiveness through rigorous FDA oversight, the new QMSR aims to reduce regulatory redundancies and streamline compliance, aligning more closely with international standards. This regulatory shift promotes a unified approach to global market access, making it critical for manufacturers to understand and implement the updated requirements.

The QMSR rule is set to take effect on February 2, 2026. The FDA has made it clear that enforcement will begin immediately upon implementation, and manufacturers must be fully compliant by this date. Firms that fail to comply with the updated requirements may be subject to 483 observations and warning letters during future FDA inspections.

Key Differences Between QSR and QMSR

While the fundamental principles of ensuring device safety and effectiveness remain unchanged, several critical updates distinguish QMSR from its predecessor:

  • Terminology Updates: The QMSR aligns with ISO 13485 terminology, replacing FDA-specific terms used in QSR. For example:
    • Design History File (DHF) becomes Design and Development File
    • Design Master Record (DMR) transitions to Medical Device File
    • Device History Record (DHR) aligns with ISO-equivalent documentation
  • Risk Management Integration: The previous QSR addressed risk management implicitly through various regulatory requirements. The new QMSR explicitly incorporates risk management throughout the device lifecycle, aligning with ISO 14971. While compliance with ISO 14971 is not mandatory, manufacturers must now adopt a proactive and systematic approach to risk assessment and mitigation.
  • Enhanced Design Controls: The QMSR refines design control processes by fully integrating ISO 13485’s design and development requirements. Where the QSR set specific design control mandates, the QMSR ensures manufacturers adhere to globally recognized best practices.
  • Stronger Supplier Management Requirements: Under QMSR, manufacturers must establish quality agreements and ensure supplier compliance with regulatory requirements. This added emphasis on supplier management reflects an industry-wide shift toward accountability throughout the supply chain.
  • Updated Labeling and Packaging Controls: While QMSR retains the labeling and packaging control requirements from QSR, it places a greater emphasis on verification and inspection processes to enhance quality assurance and reduce compliance risks.

What This Means for Manufactures

To ensure seamless compliance with QMSR, manufacturers must take the following proactive steps:

  • Revise Quality Documentation: Update quality manuals, procedures, and records to reflect the new terminology and requirements.
  • Personnel Training: Educate employees on the new standard and its implications for day-to-day operations.
  • Strengthen Risk Management Processes: Implement systematic risk assessment and mitigation strategies in alignment with the new regulatory framework.
  • Update Supplier Agreements: Review and modify existing supplier agreements to ensure alignment with QMSR requirements.
  • Plan for a Smooth Transition: Manufacturers should initiate internal audits, update compliance strategies, and engage regulatory professionals to facilitate a successful transition before the enforcement date.

The QMSR final rule represents a pivotal shift in regulatory oversight, providing a streamlined, internationally aligned framework for medical device manufacturers. Preparing now will help ensure compliance, avoid regulatory scrutiny, and support continued success in the global market. Manufacturers should act swiftly to integrate these changes into their quality systems and maintain a proactive approach to FDA compliance.

How RCA Can Help

At Regulatory Compliance Associates® (RCA), we specialize in guiding manufacturers through regulatory changes. Our expert team can help your organization transition to the new QMSR by conducting comprehensive GAP assessments, developing a tailored remediation strategy, and assisting with implementation as needed. Ensuring compliance with evolving FDA regulations is crucial, and RCA is here to support your team every step of the way.

To begin the Regulatory Compliance Associates scoping process today, please enter your information in the blue form below and click the submit button at the bottom of the webpage. You may also email us at [email protected]