Transparency in GMP Pharmaceutical Oversight

I think it is unfortunate that two of the world’s most influential regulatory agencies, the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have taken markedly different approaches to transparency in sharing Good Manufacturing Practice (GMP) observations and non-compliance information with the public.

The Foundation of Regulatory Transparency

FDA’s Transparency Initiative

The FDA’s commitment to transparency traces back to the Freedom of Information Act (FOIA) of 1966, which required federal agencies to provide information to the public upon request. However, the agency’s proactive transparency efforts gained significant momentum under President Obama’s Open Government Initiative. In June 2009, FDA Commissioner Dr. Margaret Hamburg launched the FDA’s Transparency Initiative, creating new webpages, establishing FDA-TRACK performance monitoring system, and proposing steps to provide greater public understanding of FDA decision-making.

EMA’s Evolution Toward Transparency

The EMA’s journey toward transparency has been more gradual and complex For many years, EU inspectorates did not publish results of their inspections, unlike the FDA’s long-standing practice of making Form 483s and Warning Letters publicly accessible. This changed significantly in 2014 when the EMA launched a new version of the EudraGMDP database that included, for the first time, the publication of statements of non-compliance with Good Manufacturing Practice.

The EMA’s approach to transparency reflects its commitment to transparency, efficiency, and public health protection through structured partnerships with agencies worldwide 1. However, the agency’s transparency policy has faced criticism for being “marred by too many failings,” particularly regarding pharmaceutical companies’ ability to redact clinical study reports.

FDA’s Comprehensive Data Infrastructure

The FDA operates several interconnected systems for sharing inspection and compliance information:

Form 483 Database and Public Access
The FDA maintains extensive databases for Form 483 inspectional observations, which are publicly accessible through multiple channels. The agency’s Office of Inspections and Investigations provides spreadsheets summarizing inspection observations by fiscal year, broken down by product areas including biologics, drugs, devices, and other categories.

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/inspection-references/inspection-observations

FDA Data Dashboard
Launched as part of the agency’s transparency initiative, the FDA Data Dashboard presents compliance, inspection, and recall data in an easy-to-read graphical format. The dashboard provides data from FY 2009 onward and allows access to information on inspections, warning letters, seizures, injunctions, and recall statistics. The system is updated semi-annually and allows users to download information, manipulate data views, and export charts for analysis.

https://www.fda.gov/about-fda/performance-data/fda-data-dashboard

Warning Letters and Public Documentation
All FDA-issued Warning Letters are posted on FDA.gov in redacted form to permit public access without requiring formal FOIA requests. This practice has been in place for many years, with warning letters being publicly accessible under the Freedom of Information Act.

https://www.fda.gov/about-fda/office-inspections-and-investigations/oii-foia-electronic-reading-room

EMA’s EudraGMDP Database

The EMA’s primary transparency tool is the EudraGMDP database, which serves as the Community database on manufacturing, import, and wholesale-distribution authorizations, along with GMP and GDP certificates. A public version of the database has been available since 2011, providing access to information that is not commercially or personally confidential.

The EudraGMDP database contains several modules including Manufacturing Import Authorisation (MIA), GMP certificates, Wholesale Distribution Authorisation (WDA), and Active Product Ingredient Registration (API REG). The database is publicly accessible without login requirements and is maintained by the EMA with data populated by EEA national competent authorities.

Non-Compliance Reporting and Publication

A significant milestone in EMA transparency occurred in 2014 when the agency began publishing statements of non-compliance with GMP . These documents contain information about the nature of non-compliance and actions taken by issuing authorities to protect public health, aiming to establish coordinated responses by EU medicines regulators.

A major difference here is that the EMA removes non-compliance statements from EudraGMDP following successful compliance restoration. The EMA’s procedures explicitly provide for post-publication modifications of non-compliance information. Following publication, the lead inspectorate authority may modify non-compliance information entered in EudraGMDP, for example, following receipt of new information, with modified statements distributed to the rapid alert distribution list.

This is unfortunate, as it requires going to a 3rd party service to find historical data on a site.

Category	FDA	EMA
Volume of Published Information	Over 25,000 Form 483s in databases	83 non-compliance reports total (2007-2020)
Annual Inspection Volume	Every 483 observation is trackable at a high level	Limited data available
Database Update Frequency	Monthly updates to inspection databases	Updates as available from member states
Dashboard Updates	Semi-annual updates	Not applicable
Historical Data Availability	Form 483s and warning letters accessible for decades under FOIA	Non-compliance information public since 2014
Information Scope	Inspections, warning letters, seizures, injunctions, recalls, import alerts	Primarily GMP/GDP certificates and non-compliance statements
Geographic Distribution of Non-Compliance	Global coverage with detailed breakdowns	India: 35 reports, China: 22 reports, US: 4 reports
Real-Time Access	Yes – monthly database updates	Limited – dependent on member state reporting
Public Accessibility	Multiple channels: direct database access, FOIA requests	Single portal: EudraGMDP database
Data Manipulation Capabilities	Users can download, manipulate data views, export charts	Basic search and view functionality
Login Requirements	No login required for public databases	No login required for EudraGMDP
Commercial Confidentiality	Redacted information	Commercially confidential information not published
Non-Compliance Statement Removal	Form 483s remain public permanently	Statements can be removed after successful remediation

While both the FDA and EMA have made significant strides in regulatory transparency, the FDA clearly shares more information about GMP observations and non-compliance issues. The FDA’s transparency advantage stems from its longer history of public disclosure under FOIA, more comprehensive database systems, higher volume of published enforcement actions, and more frequent updates to public information.

My next post will be on the recent changes at the FDA and what that means for ongoing transparency.

Quality Unit Oversight Failures: A Critical Analysis of Recent FDA Warning Letters

The continued trend in FDA warning letters citing Quality Unit (QU) deficiencies highlights a concerning reality across pharmaceutical manufacturing operations worldwide. Three warning letters recently issued to pharmaceutical companies in China, India, and Malaysia reveal fundamental weaknesses in Quality Unit oversight that extend beyond isolated procedural failures to indicate systemic quality management deficiencies. These regulatory actions demonstrate the FDA’s continued emphasis on the Quality Unit as the cornerstone of pharmaceutical quality systems, with expectations that these units function as independent guardians of product quality with sufficient authority, resources, and expertise. This analysis examines the specific deficiencies identified across recent warning letters, identifies patterns of Quality Unit organizational failures, explores regulatory expectations, and provides strategic guidance for building robust quality oversight capabilities that meet evolving compliance standards.

Recent FDA Warning Letters Highlighting Critical Quality Unit Deficiencies

Multiple Geographic Regions Under Scrutiny

The FDA has continues to provide an intense focus on Quality Unit oversight through a series of warning letters targeting pharmaceutical operations across Asia. As highlighted in a May 19, 2025 GMP Compliance article, three notable warning letters targeted specific Quality Unit failures across multiple regions. The Chinese manufacturer failed to establish an adequate Quality Unit with proper authority to oversee manufacturing operations, particularly in implementing change control procedures and conducting required periodic product reviews. Similarly, the Indian manufacturer’s Quality Unit failed to implement controls ensuring data integrity, resulting in unacceptable documentation practices including torn batch records, damaged testing chromatograms, and improperly completed forms. The Malaysian facility, producing OTC products, showed failures in establishing adequate training programs and performing appropriate product reviews, further demonstrating systemic quality oversight weaknesses. These geographically diverse cases indicate that Quality Unit deficiencies represent a global challenge rather than isolated regional issues.

Historical Context of Regulatory Concerns

FDA’s focus on Quality Unit responsibilities isn’t new. A warning letter to a Thai pharmaceutical company earlier in 2024 cited Quality Unit deficiencies including lack of control over manufacturing operations, inadequate documentation of laboratory preparation, and insufficient review of raw analytical data. These issues allowed concerning practices such as production staff altering master batch records and using erasable markers on laminated sheets for production records. Another notable case involved Henan Kangdi Medical Devices, where in January 2020 the FDA stated explicitly that “significant findings in this letter indicate that your quality unit is not fully exercising its authority and/or responsibilities”. The consistent regulatory focus across multiple years suggests pharmaceutical manufacturers continue to struggle with properly empowering and positioning Quality Units within their organizational structures.

Geographic Analysis of Quality Unit Failures: Emerging vs. Mature Regulatory Markets

These FDA warning letters highlighting Quality Unit (QU) deficiencies reveal significant disparities between pharmaceutical manufacturing practices in emerging markets (e.g., China, India, Malaysia, Thailand) and mature regulatory jurisdictions (e.g., the U.S., EU, Japan). These geographic differences reflect systemic challenges tied to regulatory infrastructure, economic priorities, and technological adoption.

In emerging markets, structural weaknesses in regulatory oversight and quality culture dominate QU failures. For example, Chinese manufacturers like Linghai ZhanWang Biotechnology (2025) and Henan Kangdi (2019) faced FDA action because their Quality Units lacked the authority to enforce CGMP standards, with production teams frequently overriding quality decisions. Similarly, Indian facilities cited in 2025 warnings struggled with basic data integrity controls, including torn paper records and unreviewed raw data—issues exacerbated by domestic regulatory bodies like India’s CDSCO, which inspects fewer than 2% of facilities annually. These regions often prioritize production quotas over compliance, leading to under-resourced Quality Units and inadequate training programs, as seen in a 2025 warning letter to a Malaysian OTC manufacturer whose QU staff lacked GMP training. Supply chain fragmentation further complicates oversight, particularly in contract manufacturing hubs like Thailand, where a 2024 warning letter noted no QU review of outsourced laboratory testing.

By contrast, mature markets face more nuanced QU challenges tied to technological complexity and evolving regulatory expectations. In the U.S. and EU, recent warnings highlight gaps in Quality Units’ understanding of advanced manufacturing technologies, such as continuous manufacturing processes or AI-driven analytics. A 2024 EU warning letter to a German API manufacturer, for instance, cited cybersecurity vulnerabilities in electronic batch records—a stark contrast to emerging markets’ struggles with paper-based systems. While data integrity remains a global concern, mature markets grapple with sophisticated gaps like inadequate audit trails in cloud-based laboratory systems, whereas emerging economies face foundational issues like erased entries or unreviewed chromatograms. Regulatory scrutiny also differs: FDA inspection data from 2023 shows QU-related citations in just 6.2% of U.S. facilities versus 23.1% in Asian operations, reflecting stronger baseline compliance in mature jurisdictions.

Case comparisons illustrate these divergences. At an Indian facility warned in 2025, production staff routinely overruled QU decisions to meet output targets, while a 2024 U.S. warning letter described a Quality Unit delaying batch releases due to inadequate validation of a new AI-powered inventory system. Training gaps also differ qualitatively: emerging-market QUs often lack basic GMP knowledge, whereas mature-market teams may struggle with advanced tools like machine learning algorithms.

These geographic trends have strategic implications. Emerging markets require foundational investments in QU independence, such as direct reporting lines to executive leadership, and adoption of centralized digital systems to mitigate paper-record risks. Partnerships with mature-market firms could accelerate quality culture development. Meanwhile, mature jurisdictions must modernize QU training programs to address rapidly changing technologies and strengthen oversight of decentralized production models.

Data Integrity as a Critical Quality Unit Responsibility

Data integrity issues feature prominently in recent enforcement actions, reflecting the Quality Unit’s crucial role as guardian of trustworthy information. The FDA frequently requires manufacturers with data integrity deficiencies to engage third-party consultants to conduct comprehensive investigations into record inaccuracies across all laboratories, manufacturing operations, and relevant systems. These remediation efforts must identify numerous potential issues including omissions, alterations, deletions, record destruction, non-contemporaneous record completion, and other deficiencies that undermine data reliability. Thorough risk assessments must evaluate potential impacts on product quality, with companies required to implement both interim protective measures and comprehensive long-term corrective actions. These requirements underscore the fundamental importance of the Quality Unit in ensuring that product decisions are based on accurate, complete, and trustworthy data.

Patterns of Quality Unit Organizational Failures

Insufficient Authority and Resources

A recurring theme across warning letters is Quality Units lacking adequate authority or resources to fulfill their responsibilities effectively. The FDA’s warning letter to Linghai ZhanWang Biotechnology Co. in February 2025 cited violations that demonstrated the company’s Quality Unit couldn’t effectively ensure compliance with CGMP regulations. Similarly, Lex Inc. faced regulatory action when its “quality system was inadequate” because the Quality Unit “did not provide adequate oversight for the manufacture of over-the-counter (OTC) drug products”.

These cases reflect a fundamental organizational failure to empower Quality Units with sufficient authority and resources to perform their essential functions. Without proper positioning within the organizational hierarchy, Quality Units cannot effectively challenge manufacturing decisions that might compromise product quality or regulatory compliance, creating systemic vulnerabilities.

Documentation and Data Management Deficiencies

Quality Units frequently demonstrate inadequate oversight of documentation and data management processes, allowing significant compliance risks to emerge. According to FDA warning letters, these issues include torn batch records, incompletely documented laboratory preparation, inadequate retention of weight printouts, and insufficient review of raw analytical data. One particularly concerning practice involved “production records on laminated sheets using erasable markers that could be easily altered or lost,” representing a fundamental breakdown of documentation control. These examples demonstrate how Quality Unit failures in documentation oversight directly enable data integrity issues that can undermine the reliability of manufacturing records, ultimately calling product quality into question. Effective Quality Units must establish robust systems for ensuring complete, accurate, and contemporaneous documentation throughout the manufacturing process.

Inadequate Change Control and Risk Assessment

Change control deficiencies represent another significant pattern in Quality Unit failures. Warning letters frequently cite the Quality Unit’s failure to ensure appropriate change control procedures, highlighting inadequate risk assessments as a particular area of concern. FDA inspectors have found that inadequate change control practices present significant compliance risks, with change control appearing among the top ten FDA 483 violations. These deficiencies often involve failure to evaluate the potential impact of changes on product quality, incomplete documentation of changes, and improper execution of change implementation. Effective Quality Units must establish robust change control processes that include thorough risk assessments, appropriate approvals, and verification that changes have not adversely affected product quality.

Insufficient Batch Release and Production Record Review

Quality Units regularly fail to conduct adequate reviews of production records and properly execute batch release procedures. A frequent citation in warning letters involves the Quality Unit’s failure to “review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated”. In several cases, the Quality Unit reviewed only analytical results entered into enterprise systems without examining the underlying raw analytical data, creating significant blind spots in quality oversight. This pattern demonstrates a superficial approach to batch review and release decisions that fails to fulfill the Quality Unit’s fundamental responsibility to ensure each batch meets all established specifications before distribution. Comprehensive batch record review is essential for detecting anomalies that might indicate quality or compliance issues requiring investigation.

Regulatory Expectations for Effective Quality Units

Core Quality Unit Responsibilities

The FDA has clearly defined the essential responsibilities of the Quality Unit through regulations, guidance documents, and enforcement actions. According to 21 CFR 211.22, the Quality Unit must “have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products”. Additionally, the unit must “review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated”. FDA guidance elaborates that the Quality Unit’s duties include “ensuring that controls are implemented and completed satisfactorily during manufacturing operations” and “ensuring that developed procedures and specifications are appropriate and followed”. These expectations establish the Quality Unit as both guardian and arbiter of quality throughout the manufacturing process, with authority to make critical decisions regarding product acceptability.

Independence and Organizational Structure

Regulatory authorities expect Quality Units to maintain appropriate independence from production units to prevent conflicts of interest. FDA guidance specifically states that “under a quality system, it is normally expected that the product and process development units, the manufacturing units, and the QU will remain independent”. This separation ensures that quality decisions remain objective and focused on product quality rather than production metrics or efficiency considerations. While the FDA acknowledges that “in very limited circumstances, a single individual can perform both production and quality functions,” such arrangements require additional safeguards including “another qualified individual, not involved in the production operation, conduct[ing] an additional, periodic review of QU activities”. This guidance underscores the critical importance of maintaining appropriate separation between quality and production responsibilities.

Quality System Integration

Regulatory authorities increasingly view the Quality Unit as the central coordinator of a comprehensive quality system. The FDA’s guidance document “Quality Systems Approach to Pharmaceutical CGMP Regulations” positions the Quality Unit as responsible for creating, monitoring, and implementing the entire quality system. This expanded view recognizes that while the Quality Unit doesn’t assume responsibilities belonging to other organizational units, it plays a crucial role in ensuring that all departments understand and fulfill their quality-related responsibilities. The Quality Unit must therefore establish appropriate communication channels and collaborative mechanisms with other functional areas while maintaining the independence necessary to make objective quality decisions. This integrated approach recognizes that quality management extends beyond a single department to encompass all activities affecting product quality.

Strategic Approaches to Strengthening Quality Unit Effectiveness

Comprehensive Quality System Assessment

Organizations facing Quality Unit deficiencies should begin remediation with a thorough assessment of their entire pharmaceutical quality system. Warning letters frequently require companies to conduct “a comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function”. This assessment should examine whether procedures are “robust and appropriate,” how the Quality Unit provides oversight “throughout operations to evaluate adherence to appropriate practices,” the effectiveness of batch review processes, and the Quality Unit’s investigational capabilities. A thorough gap analysis should compare current practices against regulatory requirements and industry best practices to identify specific areas requiring improvement. This comprehensive assessment provides the foundation for developing targeted remediation strategies that address the root causes of Quality Unit deficiencies.

Establishing Clear Roles and Adequate Resources

Effective remediation requires clearly defining Quality Unit roles and ensuring adequate resources to fulfill regulatory responsibilities. FDA warning letters frequently cite the absence of “written procedures for QU roles and responsibilities” as a significant deficiency. Organizations must develop detailed written procedures that clearly articulate the Quality Unit’s authority and responsibilities, including approval or rejection authority for components and drug products, review of production records, and oversight of quality-impacting procedures and specifications. Additionally, companies must assess whether Quality Units have sufficient staffing with appropriate qualifications and training to effectively execute these responsibilities. This assessment should consider both the number of personnel and their technical capabilities relative to the complexity of manufacturing operations and product portfolio.

Implementing Robust Data Integrity Controls

Data integrity represents a critical area requiring focused attention from Quality Units. Companies must implement comprehensive data governance systems that ensure records are attributable, legible, contemporaneous, original, and accurate (ALCOA principles). Quality Units should establish oversight mechanisms for all quality-critical data, including laboratory results, manufacturing records, and investigation documentation. These systems must include appropriate controls for paper records and electronic data, with verification processes to ensure consistency between different data sources. Quality Units should also implement risk-based audit programs that regularly evaluate data integrity practices across all manufacturing and laboratory operations. These controls provide the foundation for trustworthy data that supports sound quality decisions and regulatory compliance.

Developing Management Support and Quality Culture

Sustainable improvements in Quality Unit effectiveness require strong management support and a positive quality culture throughout the organization. FDA warning letters specifically call for “demonstration of top management support for quality assurance and reliable operations, including timely provision of resources to address emerging manufacturing and quality issues”. Executive leadership must visibly champion quality as an organizational priority and empower the Quality Unit with appropriate authority to fulfill its responsibilities effectively. Organizations should implement programs that promote quality awareness at all levels, with particular emphasis on the shared responsibility for quality across all departments. Performance metrics and incentive structures should align with quality objectives to reinforce desired behaviors and decision-making patterns. This culture change requires consistent messaging, appropriate resource allocation, and leadership accountability for quality outcomes.

Conclusion

FDA warning letters reveal persistent Quality Unit deficiencies across global pharmaceutical operations, with significant implications for product quality and regulatory compliance. The patterns identified—including insufficient authority and resources, documentation and data management weaknesses, inadequate change control, and ineffective batch review processes—highlight the need for fundamental improvements in how Quality Units are structured, resourced, and empowered within pharmaceutical organizations. Regulatory expectations clearly position the Quality Unit as the cornerstone of effective pharmaceutical quality systems, with responsibility for ensuring that all operations meet established quality standards through appropriate oversight, review, and decision-making processes.

Addressing these challenges requires a strategic approach that begins with comprehensive assessment of current practices, establishment of clear roles and responsibilities, implementation of robust data governance systems, and development of a supportive quality culture. Organizations that successfully strengthen their Quality Units can not only avoid regulatory action but also realize significant operational benefits through more consistent product quality, reduced manufacturing deviations, and more efficient operations. As regulatory scrutiny of Quality Unit effectiveness continues to intensify, pharmaceutical manufacturers must prioritize these improvements to ensure sustainable compliance and protect patient safety in an increasingly complex manufacturing environment.

Key Warning Letters Discussed

Linghai ZhanWang Biotechnology Co., Ltd. (China) — February 25, 2025
- (For the original FDA letter, search the FDA Warning Letters database for “Linghai ZhanWang Biotechnology Co” and the date “02/25/2025”)
Henan Kangdi Medical Devices Co. Ltd. (China) — December 3, 2019
- (For the original FDA letter, search the FDA Warning Letters database for “Henan Kangdi Medical Devices” and the date “12/03/2019”)
Drug Manufacturing Facility in Thailand — February 27, 2024
- (For the original FDA letter, search the FDA Warning Letters database for “Thailand” and the date “02/27/2024”)
BioAsia Worldwide (Malaysia) — February 2025
- (For the original FDA letter, search the FDA Warning Letters database for “BioAsia Worldwide” and the date “02/2025”)

For the most authoritative and up-to-date versions, always use the FDA Warning Letters database and search by company name and date.

FDA Warning Letter Analysis: Critical CGMP Violations at BEO Pharmaceuticals

The FDA’s recent warning letter to BEO Pharmaceuticals highlights significant compliance failures that serve as crucial lessons for pharmaceutical manufacturers. The inspection conducted in late 2024 revealed multiple violations of Current Good Manufacturing Practice (CGMP) regulations, spanning from inadequate component testing to serious process validation deficiencies. This analysis examines the key issues identified, contextualizes them within regulatory frameworks, and extracts valuable insights for pharmaceutical quality professionals.

Component Testing and Supplier Qualification Failures

BEO Pharmaceuticals failed to adequately test incoming raw materials used in their over-the-counter (OTC) liquid drug products, violating the fundamental requirements outlined in 21 CFR 211.84(d)(1) and 211.84(d)(2). These regulations mandate testing each component for identity and conformity with written specifications, plus validating supplier test analyses at appropriate intervals.

Most concerning was BEO’s failure to test high-risk components for diethylene glycol (DEG) and ethylene glycol (EG) contamination. The FDA emphasized that components like glycerin require specific identity testing that includes limit tests for these potentially lethal contaminants. The applicable United States Pharmacopeia-National Formulary (USP-NF) monographs establish a safety limit of not more than 0.10% for DEG and EG. Historical context makes this violation particularly serious, as DEG contamination has been responsible for numerous fatal poisoning incidents worldwide.

While BEO eventually tested retained samples after FDA discussions and found no contamination, this reactive approach fundamentally undermines the preventive philosophy of CGMP. The regulations are clear: manufacturers must test each shipment of each lot of high-risk components before incorporating them into drug products9.

Regulatory Perspective on Component Testing

According to 21 CFR 211.84, pharmaceutical manufacturers must establish the reliability of their suppliers’ analyses through validation at appropriate intervals if they intend to rely on certificates of analysis (COAs). BEO’s failure to implement this requirement demonstrates a concerning gap in their supplier qualification program that potentially compromised product safety.

Quality Unit Authority and Product Release Violations

Premature Product Release Without Complete Testing

The warning letter cites BEO’s quality unit for approving the release of a batch before receiving complete microbiological test results-a clear violation of 21 CFR 211.165(a). BEO shipped product on January 8, 2024, though microbial testing results weren’t received until January 10, 2024.

BEO attempted to justify this practice by referring to “Under Quarantine” shipping agreements with customers, who purportedly agreed to hold products until receiving final COAs. The FDA unequivocally rejected this practice, stating: “It is not permissible to ship finished drug products ‘Under Quarantine’ status. Full release testing, including microbial testing, must be performed before drug product release and distribution”.

This violation reveals a fundamental misunderstanding of quarantine principles. A proper quarantine procedure is designed to isolate potentially non-conforming products within the manufacturer’s control-not to transfer partially tested products to customers. The purpose of quarantine is to ensure products with abnormalities are not processed or delivered until their disposition is clear, which requires complete evaluation before leaving the manufacturer’s control.

Missing Reserve Samples

BEO also failed to maintain reserve samples of incoming raw materials, including APIs and high-risk components, as required by their own written procedures. This oversight eliminates a critical safeguard that would enable investigation of material-related issues should quality concerns arise later in the product lifecycle.

Process Validation Deficiencies

Inadequate Process Validation Approach

Perhaps the most extensive violations identified in the warning letter related to BEO’s failure to properly validate their manufacturing processes. Process validation is defined as “the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product”.

The FDA identified several critical deficiencies in BEO’s approach to process validation:

BEO shipped products as early as May 2023, but only prepared and approved validation reports in October 2024-a clear indication that validation was retroactively conducted rather than implemented prior to commercial distribution.
Process validation reports lacked essential details such as comprehensive equipment lists, appropriate critical process parameters, adequate sampling instructions, and clear acceptance criteria.
Several validation reports relied on outdated data from 2011-2015 from manufacturing operations at a different facility under a previous business entity.

These findings directly contradict the FDA’s established process validation guidance, which outlines a systematic, three-stage approach:

Process Design: Defining the commercial manufacturing process based on development and scale-up activities.
Process Qualification: Evaluating process capability for reproducible commercial manufacturing.
Continued Process Verification: Ongoing assurance during routine production that the process remains controlled.

The FDA guidance emphasizes that “before any batch from the process is commercially distributed for use by consumers, a manufacturer should have gained a high degree of assurance in the performance of the manufacturing process”. BEO’s retroactive approach to validation fundamentally violated this principle.

Pharmaceutical Water System Failures

A particularly concerning finding was BEO’s failure to establish that their purified water system was “adequately designed, controlled, maintained, and monitored to ensure it is consistently producing water that meets the USP monograph for purified water and appropriate microbial limits”. This water was used both as a component in liquid drug products and for cleaning manufacturing equipment and utensils.

Water for pharmaceutical use must meet strict quality standards depending on its intended application. Purified water systems used in non-sterile product manufacturing must meet FDA’s established action limit of not more than 100 CFU/mL. The European Medicines Agency similarly emphasizes that the control of the quality of water throughout the production, storage and distribution processes, including microbiological and chemical quality, is a major concern.

BEO’s current schedule for water system maintenance and microbiological testing was deemed “insufficient”-a critical deficiency considering water’s role as both a product component and cleaning agent. This finding underscores the importance of comprehensive water system validation and monitoring programs as fundamental elements of pharmaceutical manufacturing.

Laboratory Controls and Test Method Validation

BEO failed to demonstrate that their microbiological test methods were suitable for their intended purpose, violating 21 CFR 211.160(b). Specifically, BEO couldn’t provide evidence that their contract laboratory’s methods could effectively detect objectionable microorganisms in their specific drug product formulations.

The FDA noted that while BEO eventually provided system suitability documentation, “the system suitability protocols for the methods specified in USP <60> and USP <62> lacked the final step to confirm the identity of the recovered microorganisms in the tests”. This detail critically undermines the reliability of their microbiological testing program, as method validation must demonstrate that the specific test can detect relevant microorganisms in each product matrix.

Strategic Implications for Pharmaceutical Manufacturers

The BEO warning letter illustrates several persistent challenges in pharmaceutical CGMP compliance:

Component risk assessment requires special attention for high-risk ingredients with known historical safety concerns. The DEG/EG testing requirements for glycerin and similar components represent non-negotiable safeguards based on tragic historical incidents.
Process validation must be prospective, not retroactive. The industry standard clearly establishes that validation provides assurance before commercial distribution, not after.
Water system qualification is fundamental to product quality. Pharmaceutical grade water systems require comprehensive validation, regular monitoring, and appropriate maintenance schedules to ensure consistent quality.
Quality unit authority must be respected. The quality unit’s independence and decision-making authority cannot be compromised by commercial pressures or incomplete testing.
Testing methods must be fully validated for each specific application. This is especially critical for microbiological methods where product-specific matrix effects can impact detectability of contaminants.

FDA’s Warning Letter to Advanced Pharmaceutical Technology: Insights on Process Validation

The recent FDA warning letter issued to Advanced Pharmaceutical Technology highlights critical deficiencies in process validation and compliance with Current Good Manufacturing Practices (CGMP).

What the Warning Letter Reveals About Process Validation

The FDA’s inspection identified several violations that directly pertain to inadequate process validation. Process validation is essential for ensuring that drug manufacturing processes consistently produce products meeting their intended specifications. Here are the notable findings:

Failure to Validate Sterilization Processes:

The firm did not establish adequate controls to prevent microbiological contamination in drug products purporting to be sterile. Specifically, it relied on sterilization processes without monitoring pre-sterilization bioburden or maintaining appropriate environmental conditions.
The FDA emphasized that sterility testing alone is insufficient to assure product safety. It must be part of a broader validation strategy that includes pre-sterilization controls and environmental monitoring.

Inadequate Validation of Controlled-Release Dosage Forms:

The company failed to demonstrate that its controlled-release products conformed to specifications for active ingredient release rates. This lack of validation raises concerns about therapeutic efficacy and patient safety.
The response provided by the firm was deemed inadequate as it lacked retrospective assessments of marketed products and a detailed plan for corrective actions.

Insufficient Procedures for Production and Process Control:

The firm increased batch sizes without validating the impact on product quality and failed to include critical process parameters in batch records.
The FDA highlighted the importance of process qualification studies, which evaluate intra-batch variations and establish a state of control before commercial distribution.

Key Learnings for Pharmaceutical Manufacturers

The violations outlined in this warning letter provide valuable lessons for manufacturers aiming to maintain CGMP compliance:

Comprehensive Process Validation is Non-Negotiable

Process validation must encompass all stages of manufacturing, from raw materials to finished products. Manufacturers should:

Conduct rigorous qualification studies before scaling up production.
Validate sterilization processes, including pre-sterilization bioburden testing, environmental controls, and monitoring systems.

Sterility Testing Alone is Insufficient

Sterility testing should complement other preventive measures rather than serve as the sole assurance mechanism. Manufacturers must implement controls throughout the production lifecycle to minimize contamination risks.

Quality Control Units Must Exercise Oversight

The role of quality control units (QU) is pivotal in ensuring compliance across all operations, including oversight of contract testing laboratories and contract manufacturing organizations (CMOs). Failure to enforce proper testing protocols can lead to regulatory action.

Repeat Violations Signal Systemic Failures

The letter noted repeated violations from prior inspections in 2019 and 2021, indicating insufficient executive management oversight.

From PAI to Warning Letter – Lessons from Sanofi

Through the skilled work of a very helpful FOIA officer at the FDA I have been reviewing the 2020 483 and EIR for the pre-approval inspection at the Sanofi Framingham, MA site that recently received a Warning Letter:

Click to access foia-2025-1030-genzyme-corp.-framingham-ma-fei-1220423-eir-dtd-9-4-20_redacted-1.pdf

Click to access foia-2025-1030-genzyme-corp.-framingham-ma-fei-1220423-fda-483-dtd-9-4-20_redacted-1.pdf

The 2020 pre-approval inspection (PAI) of Sanofi’s facility in Framingham, MA, uncovered critical deviations that exposed systemic weaknesses in contamination controls, equipment maintenance, and quality oversight. These deficiencies, documented in FDA Form 483 (FEI 1220423), violated 21 CFR 211 regulations and FDA Compliance Program 7346.832 requirements for PAIs. The facility’s failure to address these issues and to make systeatic changes over time (and perhaps backslide, but that is conjecture) contributed to subsequent regulatory actions, including a 2022 Form 483 and the 2024 FDA warning letter citing persistent CGMP violations. This analysis traces the 2020 findings to their regulatory origins, examines their operational consequences, and identifies lessons for PAI preparedness in high-risk API manufacturing.

Regulatory Foundations of Pre-Approval Inspections

The FDA’s PAI program operates under Compliance Program 7346.832, which mandates rigorous evaluation of facilities named in NDAs, ANDAs, or BLAs. Three pillars govern these inspections:

Commercial Manufacturing Readiness: PAIs assess whether facilities can reliably execute commercial-scale processes while maintaining CGMP compliance. This includes verification of validated equipment cleaning procedures, environmental monitoring systems, and preventive maintenance programs. The FDA prioritizes sites handling novel APIs, narrow therapeutic index drugs, or first-time applications—criteria met by Sanofi’s production of drug substances.
Application Conformance: Inspectors cross-validate submission data against actual operations, focusing on batch records, process parameters, and analytical methods. Discrepancies between filed documentation and observed practices constitute major compliance risks, particularly for facilities like Sanofi that utilize complex biologics manufacturing processes.
Data Integrity Assurance
Per 21 CFR 211.194, PAIs include forensic reviews of raw data, equipment logs, and stability studies. The 2020 inspection identified multiple QC laboratory lapses at Sanofi that undermined data reliability—a red flag under FDA’s heightened focus on data governance in PAIs.

Facility Maintenance Deficiencies

Sterilization Equipment Contamination
On September 2, 2020, FDA investigators documented (b)(4) residue on FB-2880-001 sterilization equipment and its transport cart—critical infrastructure for bioreactor probe sterilization. The absence of cleaning procedures or routine inspections violated 21 CFR 211.67(a), which mandates written equipment maintenance protocols. This lapse created cross-contamination risks for (b)(4) drug substances, directly contradicting the application’s sterility claims.

The unvalidated cleaning process for those chambers further breached 21 CFR 211.63, requiring equipment design that prevents adulteration. Historical data from 2008–2009 FDA inspections revealed similar sterilization issues at Allston facility, suggesting systemic quality control failures which suggests that these issues never were really dealt with systematically across all sites under the consent decree.

Environmental Control Breakdowns
The August 26, 2020 finding of unsecured pre-filters in Downflow Booth —a critical area for raw material weighing—exposed multiple CGMP violations:

21 CFR 211.46(b): Failure to maintain HEPA filter integrity in controlled environments
FDA Aseptic Processing Guidance: Loose filters compromise ISO 5 unidirectional airflow
21 CFR 211.42(c): Inadequate facility design for preventing material contamination

Ceiling diffuser screens in Suite CNC space with unsecured fasteners exacerbated particulate contamination risks. The cumulative effect violated PAI Objective 1 by demonstrating poor facility control—a key factor in the 2024 warning letter’s citation of “unsuitable equipment for microbiologically controlled environments”.

Quality Control Laboratory Failures

Analytical Balance Non-Compliance
The QC microbiology laboratory’s use of an unqualified balance breached multiple standards:

21 CFR 211.68(a): Lack of calibration for automated equipment
USP <41> Guidelines: Failure to establish minimum weigh limits
FDA Data Integrity Guidance (2018): Unguaranteed accuracy of microbiological test results

This deficiency directly impacted the reliability of bioburden testing data submitted in the application, contravening PAI Objective 3’s data authenticity requirements.

Delayed Logbook Reviews
Three QC logbooks exceeded the review window specified in the site’s procedure:

Temperature logs for water baths
Dry state storage checklists

The delays violated 21 CFR 211.188(b)(11), which requires contemporaneous review of batch records. More critically, they reflected inadequate quality unit oversight—a recurring theme in Sanofi’s 2024 warning letter citing “lackluster quality control”.

And if they found 3 logbooks, chances are there were many more in an equal state.

Leak Investigations – A Leading Indicator

there are two pages in the EIR around leak deviation investigations, including the infamous bags, and in hindsight, I think this is an incredibly important inflection point from improvement that was missed.

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

The inspector took the time to evaluate quite a few deviations and overall control strategy for leaks and gave Sanofi a clean-bill of health. So we have to wonder if there was not enough problems to go deep enough to see a trend or if a sense of complacency allowed Sanofi to lower their guard around this critical aspect of single use, functionally closed systems.

2022 Follow-Up Inspection: Escalating Compliance Failures

Click to access foia-2025-1030-genzyme-corp.-framingham-ma-fei-1220423-fda-483-dtd-7-25-22_redacted-2.pdf

Click to access foia-2025-1030-genzyme-corp.-framingham-ma-fei-1220423-eir-dtd-7-25-22_redacted-1.pdf

The FDA’s July 2022 reinspection of Sanofi’s Framingham facility revealed persistent deficiencies despite corrective actions taken after the 2020 PAI. The inspection, conducted under Compliance Program 7356.002M, identified critical gaps in data governance and facility maintenance, resulting in a 2-item Form FDA 483 and an Official Action Indicated (OAI) classification – a significant escalation from the 2020 Voluntary Action Indicated (VAI) status.

Computerized System Control Failures

The FDA identified systemic weaknesses in data integrity controls for testers used to validate filter integrity during drug substance manufacturing. These testers generated electronic logs documenting failed and canceled tests that were never reviewed or documented in manufacturing records. For example:

On June 9, 2022, a filter underwent three consecutive tests for clarification operations: two failures and one cancellation due to operator error (audible “hissing” during testing). Only the final passing result was recorded in logbooks.
Between 2020–2022, operators canceled 14% of tests across testers without documented justification, violating 21 CFR 211.68(b) requirements for automated equipment review.

The firm had improperly classified these testers as “legacy electronic equipment,” bypassing mandatory audit trail reviews under their site procedure. I am not even sure what legacy electronic equipment means, but this failure contravened FDA’s Data Integrity Guidance (2018), which requires full traceability of GxP decisions.

Facility Degradation Risks

Multiple infrastructure deficiencies demonstrated declining maintenance standards:

Grade-A Area Compromises

Biological Safety Cabinet: Rust particles and brown residue contaminated interior surfaces used for drug substance handling in April 20223. The material was later identified as iron oxide from deteriorating cabinet components.
HVAC System Leaks: A pH probe in the water system leaked into grade-D areas, with standing water observed near active bioreactors3.

Structural Integrity Issues

Chipped epoxy floors in grade-C rooms created particulate generation risks during cell culture operations.
Improperly sloped flooring allowed pooling of rinse water adjacent to purification equipment.

These conditions violated 21 CFR 211.42(c), requiring facilities to prevent contamination through proper design, and demonstrated backsliding from 2020 corrective actions targeting environmental controls.

Regulatory Reckoning

These cultural failures crystallized in FDA’s 2024 citation of “systemic indifference to quality stewardship”. While some technological upgrades provided tactical fixes, the delayed recognition of cultural rot as root cause transformed manageable equipment issues into existential compliance threats—a cautionary tale for pharmaceutical manufacturers navigating dual challenges of technological modernization and workforce transition.

Conclusion: A Compliance Crisis Decade

The Sanofi case (2020–2024) exemplifies the consequences of treating PAIs as checklist exercises rather than opportunities for quality system maturation. The facility’s progression from 483 observations to OAI status and finally warning letter underscores three critical lessons:

Proactive Data Governance: Holitisic data overnance and data integrity, including audit trail reviews that encompass all GxP systems – legacy or modern.
Infrastructure Investment: Episodic maintenance cannot replace lifecycle-based asset management programs.
Cultural Transformation: Quality metrics must drive executive incentives to prevent recurrent failures.

Manufacturers must adopt holistic systems integrating advanced analytics, robust knowledge management, and cultural accountability to avoid a costly regulatory debacle.

PAI Readiness Best Practices

Pre-Inspection Preparation

Gap Analysis Against CPGM 7346.832
Facilities should conduct mock inspections evaluating:
- Conformance between batch records and application data
- Completeness of method validation protocols
- Environmental monitoring trend reports
Data Integrity Audits
Forensic reviews of electronic records (e.g., HPLC chromatograms, equipment logs) using FDA’s “ALCOA+” criteria—ensuring data is Attributable, Legible, Contemporaneous, Original, and Accurate.
Facility Hardening
Preventive maintenance programs for critical utilities:
- Steam-in-place systems
- HVAC airflow balances
- Water for injection loops

Post-Approval Vigilance

The Sanofi case underscores the need for ongoing compliance monitoring post-PAI:

Quality Metrics Tracking: FDA-required metrics like lot rejection rates and CAPA effectiveness
Regulatory Intelligence: Monitoring emerging focus areas through FDA warning letters and guidance updates
Process Robustness Studies: Continued process verification per 21 CFR 211.110(a)