Two Paths in Our Regulatory World: Leading Through Strategic Engagement

In pharmaceutical quality, we face a fundamental choice that defines our trajectory: we can either help set the direction of our regulatory landscape, or we can struggle to keep up with changes imposed upon us. As quality leaders, this choice isn’t just about compliance—it’s about positioning our organizations to drive meaningful change while delivering better patient outcomes.

The reactive compliance mindset has dominated our industry for too long, where companies view regulators as adversaries and quality as a cost center. This approach treats regulatory guidance as something that happens to us rather than something we actively shape. Companies operating in this mode find themselves perpetually behind the curve, scrambling to interpret new requirements, implement last-minute changes, and justify their approaches to skeptical regulators.

But there’s another way—one where quality professionals actively engage with the regulatory ecosystem to influence the development of standards before they become mandates.

The Strategic Value of Industry Group Engagement

Organizations like BioPhorum, NIIMBL, ISPE, and PDA represent far more than networking opportunities—they are the laboratories where tomorrow’s regulatory expectations are forged today. These groups don’t just discuss new regulations; they actively participate in defining what excellence looks like through standard-setting initiatives, white papers, and direct dialogue with regulatory authorities.

BioPhorum, with its collaborative network of 160+ manufacturers and suppliers deploying over 7,500 subject matter experts, demonstrates the power of collective engagement. Their success stories speak to tangible outcomes: harmonized approaches to routine environmental monitoring that save weeks on setup time, product yield improvements of up to 44%, and flexible manufacturing lines that reduce costs while maintaining regulatory compliance. Most significantly, their quality phorum launched in 2024 provides a dedicated space for quality professionals to collaborate on shared industry challenges.

NIIMBL exemplifies the strategic integration of industry voices with federal priorities, bringing together pharmaceutical manufacturers with academic institutions and government agencies to advance biopharmaceutical manufacturing standards. Their public-private partnership model demonstrates how industry engagement can shape policy while advancing technical capabilities that benefit all stakeholders.

ISPE and PDA provide complementary platforms where technical expertise translates into regulatory influence. Through their guidance documents, technical reports, and direct responses to regulatory initiatives, these organizations ensure that industry perspectives inform regulatory development. Their members don’t just consume regulatory intelligence—they help create it.

The Big Company Advantage—And Why Smaller Companies Must Close This Gap

Large pharmaceutical companies understand this dynamic intuitively. They maintain dedicated teams whose sole purpose is to engage with these industry groups, contribute to standard-setting activities, and maintain ongoing relationships with regulatory authorities. They recognize that regulatory intelligence isn’t just about monitoring changes—it’s about influencing the trajectory of those changes before they become requirements.

The asymmetry is stark: while multinational corporations deploy key leaders to these forums, smaller innovative companies often view such engagement as a luxury they cannot afford. This creates a dangerous gap where the voices shaping regulatory policy come predominantly from established players, potentially disadvantaging the very companies driving the most innovative therapeutic approaches.

But here’s the critical insight from my experience working with quality systems: smaller companies cannot afford NOT to be at these tables. When you’re operating with limited resources, you need every advantage in predicting regulatory direction, understanding emerging expectations, and building the credibility that comes from being recognized as a thoughtful contributor to industry discourse.

Consider the TESTED framework I’ve previously discussed—structured hypothesis formation requires deep understanding of regulatory thinking that only comes from being embedded in these conversations. When BioPhorum members collaborate on cleaning validation approaches or manufacturing flexibility standards, they’re not just sharing best practices—they’re establishing the scientific foundation for future regulatory expectations. When the ISPE comes out with a new good practice guide they are doing the same. The list goes on.

Making the Business Case: Job Descriptions and Performance Evaluation

Good regulatory intelligence practices requires systematically building this engagement into our organizational DNA. This means making industry participation an explicit component of senior quality roles and measuring our leaders’ contributions to the broader regulatory dialogue.

For quality directors and above, job descriptions should explicitly include:

Active participation in relevant industry working groups and technical committees
Contribution to industry white papers, guidance documents, and technical reports
Maintenance of productive relationships with regulatory authorities through formal and informal channels
Intelligence gathering and strategic assessment of emerging regulatory trends
Internal education and capability building based on industry insights

Performance evaluations must reflect these priorities:

Measure contributions to industry publications and standard-setting activities
Assess the quality and strategic value of regulatory intelligence gathered through industry networks
Evaluate success in anticipating and preparing for regulatory changes before they become requirements
Track the organization’s reputation within industry forums as a thoughtful contributor

This isn’t about checking boxes or accumulating conference attendance credits. It’s about recognizing that in our interconnected regulatory environment, isolation equals irrelevance. The companies that will thrive in tomorrow’s regulatory landscape are those whose leaders are actively shaping that landscape today.

Development plans for individuals should have clear milestones based on these requirements, so as individuals work their way up in an organization they are building good behaviors.

The Competitive Advantage of Regulatory Leadership

When we engage strategically with industry groups, we gain access to three critical advantages that reactive companies lack. First, predictive intelligence—understanding not just what regulations say today, but where regulatory thinking is headed. Second, credibility capital—the trust that comes from being recognized as a thoughtful contributor rather than a passive recipient of regulatory requirements. Third, collaborative problem-solving—access to the collective expertise needed to address complex quality challenges that no single organization can solve alone.

The pharmaceutical industry is moving toward more sophisticated quality metrics, risk-based approaches, and integrated lifecycle management. Companies that help develop these approaches will implement them more effectively than those who wait for guidance to arrive as mandates.c

As I’ve explored in previous discussions of hypothesis-driven quality systems, the future belongs to organizations that can move beyond compliance toward genuine quality leadership. This requires not just technical excellence, but strategic engagement with the regulatory ecosystem that shapes our industry’s direction.

The choice is ours: we can continue struggling to keep up with changes imposed upon us, or we can help set the direction through strategic engagement with the organizations and forums that define excellence in our field. For senior quality leaders, this isn’t just a career opportunity—it’s a strategic imperative that directly impacts our organizations’ ability to deliver innovative therapies to patients who need them.

The bandwidth required for this engagement isn’t overhead—it’s investment in the intelligence and relationships that make everything else we do more effective. In a world where regulatory agility determines competitive advantage, being at the table where standards are set isn’t optional—it’s essential.

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.

Understanding the FDA Establishment Inspection Report (EIR): Regulations, Structure, and Regulatory Impact

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.

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)