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)

2024 FDA 483 Data

The FDA has published the 2024 Inspectional Observation Data Sets. I don’t think there are any surprise that on what the inspection observations data for fiscal year 2024 shows and what key GMP inspection themes emerge for drug manufacturers:

Quality Systems and Documentation

Inadequate Procedures and Documentation

Failure to establish or follow written procedures for various operations, including quality control, production, and process controls.
Lack of complete documentation for investigations, batch records, and laboratory testing.

Quality Control Unit Deficiencies

Inadequate responsibilities and authority of the quality control unit.
Failure to approve or reject components, products, procedures, or specifications.

Manufacturing and Process Controls

Equipment and Facility Issues

Inadequate design, maintenance, or cleaning of manufacturing equipment.
Deficiencies in facility maintenance, sanitation, and environmental controls.

Process Validation and Control

Lack of adequate process validation, especially for sterile drug products.
Insufficient control procedures to monitor and validate manufacturing processes.

Laboratory Controls

Inadequate Laboratory Practices

Failure to establish scientifically sound laboratory controls.
Deficiencies in test methods validation and stability testing programs.

Component Testing

Inadequate testing of drug components and reliance on supplier certificates without proper verification.

Sterile Drug Manufacturing

Aseptic Processing Deficiencies

Inadequate procedures and validation for sterile drug products.
Deficiencies in environmental monitoring and control systems for aseptic processing areas.

Training and Personnel

Inadequate Employee Training

Insufficient training of employees in GMP and specific job function.

Complaint Handling and Product Quality Reviews

Deficient Complaint Procedures

Inadequate procedures for handling product complaints.

Annual Product Quality Review

Failure to conduct adequate annual product quality reviews.

Equipment Related

Out of the 365 observations that mention equipment, 277 are from just 5 regulations. Let’s take a deeper look.

Reference Number	Short Description	Long Description	Frequency
21 CFR 211.63	Equipment Design, Size and Location	Equipment used in the manufacture, processing, packing or holding of drug products is not [of appropriate design] [of adequate size] [suitably located] to facilitate operations for its [intended use] [cleaning and maintenance]. Specifically, ***	85
21 CFR 211.67(a)	Cleaning / Sanitizing / Maintenance	Equipment and utensils are not [cleaned] [maintained] [sanitized] at appropriate intervals to prevent [malfunctions] [contamination] that would alter the safety, identity, strength, quality or purity of the drug product. Specifically, ***	76
21 CFR 211.67(b)	Written procedures not established/followed	Written procedures are not [established] [followed] for the cleaning and maintenance of equipment, including utensils, used in the manufacture, processing, packing or holding of a drug product. Specifically, ***	60
21 CFR 211.68(a)	Calibration/Inspection/Checking not done	Routine [calibration] [inspection] [checking] of [automatic] [mechanical] [electronic] equipment is not performed according to a written program designed to assure proper performance. Specifically, ***	30

Improper design and qualification, improper cleaning, improper calibration and inspections. Yes these take work, but these are all areas that effort can improve.

Limiting and Delaying Inspections – Brands International as Example

I think many of us have been discussing the blatant obstruction demonstrated in the December 2024 Warning Letter to Brands International Corporation, a drug manufacturer located in Ontario, Canada, citing it for limiting and delaying FDA’s inspection. Which it is important to remember congress has said is a big no-no.

I just want to stress that the Quality Manager there had a really bad day, week, month, year.

Good writeup of what to do around building your procedure for interviewing of employees during an inspection over at FDA Law blog.

FDA Inspections: Lesson 1 – Interviewing Employees

FDA Inspections – GAO Report

The GAO has published a report on FDA’s Inspections that found a 36% decrease compared to fiscal year 2019 in the number of inspections, partly due to reduced investigator capacity. A piece of information that should surprise noone.

The report highlights a concerning trend in the FDA’s drug inspection workforce. From November 2021 to June 2024, the vacancy rate among investigators who inspect foreign and domestic manufacturers increased from 9% to 16%.

I think we’ve all seen the impact of this. It’s worth spending a little time reading the report.

FDA Guidance on Delaying, Denying, Limiting, or Refusing Drug or Device Inspection

The FDA guidance “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection” published in June 2024 outlines the behaviors and circumstances that the FDA considers to be non-compliant with inspection requirements under section 501(j) of the Federal Food, Drug, and Cosmetic Act (FD&C Act). This guidance is essential for ensuring that drugs and devices are not deemed adulterated due to inspection-related issues.

The guidance aims to make sure transparency and compliance during FDA inspections to protect public health by ensuring that drugs and devices are manufactured by regulatory standards.

Legal Background

The Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012 added section 501(j) to the FD&C Act, which deems a drug adulterated if the owner, operator, or agent of a facility delays, denies, or limits an FDA inspection, or refuses to permit entry or inspection.

The FDA Reauthorization Act of 2017 extended these provisions to include medical devices.

Scope

The guidance applies to all facilities involved in the manufacture, processing, packing, or holding of drugs or devices. It defines what constitutes delaying, denying, limiting, or refusing an inspection, providing specific examples to illustrate these behaviors.

Examples of Non-Compliant Behaviors:

Delaying: Postponing an inspection without a reasonable explanation.
Denying: Explicitly refusing to allow an inspection to take place.
Limiting: Restricting the scope of an inspection, like limiting access to certain areas or records.
- I want to stress that this includes the situation where a facility provides some, but not all, records requested by the FDA investigator that FDA has authority to inspect. Everyone’s favorite delaying tactic.
- This also includes omitting or limiting the data contained in the electronic records when providing electronic copies of the records to FDA. This includes but is not limited to actions like removing data columns in Excel, removing data from the electronic record when providing the record to FDA, exporting data into reports without including all of the data fields (unless otherwise requested by FDA), or locking the electronic worksheet so that the data cannot be searched, sorted, or analyzed by FDA.
- Preventing an authorized representative of FDA from collecting statutorily authorized samples may be considered limiting the inspection. Examples of sample limitations include, but are not limited to, declining to allow or impeding FDA from collecting the following types of samples: environmental samples, finished product samples, raw material samples, in-process material samples, reserve samples in bioequivalence and bioanalytical studies, and labeling.
Refusing: Not allowing the FDA to enter the premises for inspection.

Background on FDA Guidance

The FDA issues guidance documents to communicate its current thinking on regulatory issues. These documents are not legally binding but give insight into how the FDA interprets and enforces laws and regulations. The guidance on delaying, denying, limiting, or refusing inspections was necessitated by the need to clearly define what constitutes non-compliance under section 501(j) of the FD&C Act. This clarity helps facilities understand their obligations and avoid actions that could lead to their products being deemed adulterated.

The guidance was finalized to replace the previous version issued in October 2014 and incorporates feedback and updates to reflect current practices and challenges in the inspection process. It is a critical tool for both the FDA and industry stakeholders to ensure that inspections are conducted smoothly and effectively, thereby safeguarding the quality and safety of drugs and devices available to the public.