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.
Since the Trump administration’s return to power in January 2025, the U.S. Food and Drug Administration (FDA) has faced sweeping changes to its regulatory framework, advisory processes, and workforce stability. These developments—driven by executive orders, leadership appointments, and policy shifts—have reshaped the agency’s operations during a critical period of public health challenges.
January 2025: Leadership Transition and Regulatory Freeze
The administration began with a regulatory freeze enacted on January 20, 2025, halting all new FDA rulemaking pending review by incoming leadership. This directly delayed critical updates, including medical device classifications and food safety protocols. Simultaneously, Robert F. Kennedy Jr. assumed leadership of the Department of Health and Human Services (HHS), bringing his longstanding opposition to vaccines into federal health policy. Despite pledging to maintain CDC vaccine recommendations, Kennedy declined to retract past claims linking vaccines to autism during his confirmation hearings, signaling his true intents.
Staffing cuts emerged immediately as a priority. HHS announced plans to reduce its workforce by 24%, translating to approximately 3,500 FDA positions. Early layoffs targeted probationary staff in food safety, medical devices, and tobacco divisions, exacerbating existing vacancies documented in a November 2024 GAO report. The FDA’s drug inspection workforce, already 36% smaller than pre-pandemic levels, faced further attrition, with 63% of investigators having fewer than five years of experience.
February 2025: Advisory Committee Disruptions and Workforce Pressures
February saw the cancellation of two pivotal advisory committee meetings: the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and the CDC’s Advisory Committee on Immunization Practices (ACIP). These groups, which traditionally review flu vaccine strains and public health recommendations, were sidelined despite a severe 2024–2025 flu season causing up to 92,000 deaths. The administration’s reluctance to convene independent experts marked a departure from decades of transparent vaccine policy development.
Workforce challenges deepened with the February 11 executive order mandating a 4:1 attrition-to-hiring ratio across federal agencies. At the FDA, this exacerbated recruitment struggles in specialized roles, particularly food safety inspectors—25% of whom were retirement-eligible by mid-2024. GAO data revealed the agency had conducted only 917 annual foreign food inspections since 2018, far below its 19,200-target mandate. Domestic inspection backlogs worsened as experienced staff diverted time to train new hires.
March 2025: Policy Shifts and Vaccine Oversight Changes
March brought structural reforms to FDA’s regulatory processes. Secretary Kennedy directed revisions to the Generally Recognized as Safe (GRAS) rule, specifically targeting industry self-affirmed safety determinations for food additives—a move aligned with his criticism of ultra-processed foods. Simultaneously, the FDA revoked authorization for 35 PFAS-containing food contact substances, reflecting heightened chemical safety concerns but straining already limited compliance staff.
Vaccine oversight faced indirect pressure. While no formal guidance withdrawals occurred, Kennedy’s influence raised fears of stricter development criteria for future vaccines. The Office of Vaccines Research and Review (OVRR), depleted by pre-2025 staff departures, risked slowed review timelines amid ongoing attrition. Industry analysts noted that VRBPAC’s cancellation forced manufacturers to align flu vaccine production with non-U.S. markets first, complicating domestic rollout schedules.
Ongoing Impacts: Staffing, Inspections, and Public Health Risks
Workforce and Inspection Capacity
The FDA’s inspectional workforce crisis, highlighted in multiple GAO reports, has reached critical levels. Drug inspections remain 36% below pre-pandemic volumes, with foreign site evaluations particularly lagging. Food safety inspections face similar shortfalls: FDA met only 60% of high-risk domestic facility targets in 2023, contributing to preventable outbreaks like the 2024 E. coli-linked onion crisis. Training new food inspectors requires two years, ensuring gaps will persist and get worse.
Advisory Board Erosion
The administration’s dismissal of advisory committees has introduced unpredictability into vaccine policy. By bypassing VRBPAC for the 2025–2026 flu vaccine strain selection, the FDA abandoned a 50-year precedent of transparent expert review. This politicization risks public trust, particularly as Kennedy’s team weighs revisions to vaccine development guidance without formal stakeholder input.
Regulatory Uncertainty
The regulatory freeze has stalled over 170 planned guidance documents, including updates to AI-enabled medical device oversight and compounding pharmacy rules. Combined with staffing shortages, this has delayed responses to emerging issues like long COVID therapies and drug compounding disputes.
Evaluating the Broader Impact
The Trump administration’s FDA reforms prioritize deregulation and workforce reduction, but collateral damage to public health safeguards is evident:
Food and Drug Safety Risks: Inspection backlogs increase the likelihood of undetected manufacturing violations. GAO warns that inexperienced staff may miss critical compliance issues, elevating risks of adulterated products reaching consumers.
Vaccine Development Challenges: While no direct policy reversals have occurred, the erosion of advisory input and OVRR staffing cuts threaten to delay novel vaccine approvals and strain pandemic preparedness.
Industry Adaptation Costs: Pharmaceutical and food manufacturers face uncertainty as delayed guidance and abrupt policy shifts (e.g., GRAS revisions) disrupt long-term planning.
Global Health Isolation: Withdrawal from WHO collaborations like the Medical Device Single Audit Program (MDSAP) complicates international market access for U.S. device manufacturers.
Conclusion: A Agency at a Crossroads
The FDA’s first quarter under the second Trump administration leadership reveals an agency straining to with foundational public health mandates. Workforce attrition, politicized advisory processes, and stalled rulemaking have collectively undermined the FDA’s capacity to proactively address foodborne illness, drug safety, and vaccine development. With little hope for congressional action to stabilize staffing and safeguard advisory mechanisms, the FDA risks becoming a reactive rather than preventive force in U.S. healthcare—a shift with consequences that could resonate for decades.
It is rare when a journalist reports on the GMP side of the industry. Most reporting tends to be pretty shallow, and only when a major crisis happens, such as the baby food manufacturing failures. So I love it when a journalist takes the time to understand our field and write a detailed piece. Katherine Eban, who wrote the insightful Bottle of Lies, which I am known to gift copies of, being a great example of a journalist can creditably speak our language and than translate it to the general public.
The article stresses the ongoing crisis in that the FDA does not have enough inspectors, a crisis that keeps getting worse under the current administration.
The Form 483 that is linked should frighten anyone, as it has 3 pages of redacted batches that were shipped to the US.
I share the frustration and concern that Form 483s are not transparent, and that the FDA does not follow the same principle of the average health inspector for local restaurants where I see the grade when I walk in. It is pretty difficult to figure out where a medicine is made, and failing access to some expensive services, can be a real pain to figure out the status of any given manufacturing site.
The Form 483 for Glenmark is, unfortunately, all too common for an Indian generics manufacturing site. Poor validation, no real cleaning, lack of investigations – these are all very serious, and unfortunately recurring.
I am very concerned that the woes of Indian manufacturing sites (and Chinese) will just get worse as the FDA is torn apart by a bunch of authoritarian ideologues who think sunshine and bleach are cure-alls.
The Establishment Inspection Report (EIR) is a comprehensive document generated after FDA investigators inspect facilities involved in manufacturing, processing, or distributing FDA-regulated goods. This report not only details compliance with regulatory standards but also serves as a vital tool for both the FDA and inspected entities to address potential risks and improve operational practices.
Regulatory Framework Governing EIRs
The EIR is rooted in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and associated regulations under 21 CFR Parts 210–211 (Current Good Manufacturing Practices) and 21 CFR Part 820 (Quality System Regulation for medical devices). These regulations empower the FDA to conduct inspections and enforce compliance through documentation like the EIR. Key policies include:
Field Management Directive (FMD) 145: This directive mandates the release of the EIR’s narrative portion to inspected entities once an inspection is deemed “closed” under 21 CFR § 20.64(d)(3). This policy ensures transparency by providing firms with insights into inspection findings before public disclosure via the Freedom of Information Act (FOIA).
Inspectional Conclusions: EIRs classify inspections into three outcomes:
No Action Indicated (NAI): No significant violations found.
Voluntary Action Indicated (VAI): Violations identified but not severe enough to warrant immediate regulatory action.
Official Action Indicated (OAI): Serious violations requiring FDA enforcement, such as warning letters or product seizures.
Anatomy of an EIR
An EIR is a meticulous record of an inspection’s scope, findings, and contextual details. Key components include:
1. Inspection Scope and Context
The EIR outlines the facilities, processes, and documents reviewed, providing clarity on the FDA’s focus areas. This section often references the Form FDA 483, which lists observed violations disclosed at the inspection’s conclusion.
2. Documents Reviewed or Collected
Investigators catalog documents such as batch records, standard operating procedures (SOPs), and corrective action plans. This inventory helps firms identify gaps in record-keeping and align future practices with FDA expectations.
3. Inspectional Observations
Beyond the Form FDA 483, the EIR elaborates on objectionable conditions, including deviations from GMPs or inadequate validation processes.
4. Samples and Evidence
If product samples or raw materials are collected, the EIR explains their significance. Extensive sampling often signals concerns about product safety, such as microbial contamination in a drug substance.
5. Enforcement Recommendations
The EIR concludes with the FDA’s recommended actions, such as re-inspections, warning letters, or import alerts. These recommendations are reviewed by compliance officers before finalizing regulatory decisions.
How the EIR Informs Regulatory and Corporate Actions For the FDA
Risk Assessment: EIRs guide the FDA in prioritizing enforcement based on the severity of violations. For example, an OAI classification triggers immediate compliance reviews, while VAI findings may lead to routine follow-ups.
Trend Analysis: Aggregated EIR data help identify industry-wide risks, such as recurring issues in sterile manufacturing, informing future inspection strategies.
Global Collaboration: EIR findings are shared with international regulators under confidentiality agreements, fostering alignment in standards.
For Inspected Entities
Compliance Roadmaps: Firms use EIRs to address deficiencies before they escalate.
Inspection Readiness: By analyzing EIRs from peer organizations, companies anticipate FDA focus areas. For example, recent emphasis on data integrity has led firms to bolster electronic record-keeping systems.
Reputational Management: A clean EIR (NAI) enhances stakeholder confidence, while recurrent OAI classifications may deter investors or partners.
Challenges and Evolving Practices
Timeliness: Delays in EIR release hinder firms’ ability to implement timely corrections. The FDA has pledged to streamline review processes but continued workforce issues will exacerbate the problem..
Digital Transformation: The FDA’s adoption of AI-driven analytics aims to accelerate EIR generation and enhance consistency in inspection classification. Hopefully this will increase transparency.
Global Harmonization: Joint FDA-EMA inspections, though rare, highlight efforts to reduce redundant audits and align regulatory expectations.
Conclusion
The FDA Establishment Inspection Report is more than a regulatory artifact—it is a dynamic instrument for continuous improvement in public health protection. By demystifying its structure, regulations, and applications, firms can transform EIRs from compliance checklists into strategic assets. As the FDA evolves its inspectional approaches, staying abreast of EIR trends and best practices will remain pivotal for navigating the complex regulatory compliance landscape.
Proactively engaging with EIR findings for organizations subject to FDA oversight mitigates enforcement risks. It fosters a quality culture that aligns with the FDA’s mandate to protect and promote public health.
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:
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.
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.
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.
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.
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)
Investigations of a Dog 