The Pattern Behind FDA Warning Letters: What Startups & CDMOs Often Miss

Expertly curated by George Kwiecinski, Shreestuti Neelam, Kevin Y. & Sujay Sundar

In today’s competitive pharmaceutical and medical device industries, a corporation’s commitment to uphold itself to the highest standards is much more than mere regulatory procedure; it is a critical self-examination in ensuring operational integrity and patient safety, and is required by law (FDA Regulatory Procedures Manual). If such regulations are not adhered to, severe consequences follow, including substantial financial losses, supply chain interruptions, mandatory product recalls, and severe reputational harm among regulators, business partners, and patients.

Such consequences include using a Warning Letter issued by the Food and Drug Administration (FDA). Corporations work diligently to ensure compliance standards are met, spending hours on assembling skilled teams, and investing billions of dollars in ensuring product quality and addressing quality failures–all with the goal of maintaining strict compliance with every regulatory requirement. Besides their consequential nature, they are vital signs that a company is clearly failing to address deep-seated deficiencies within their operations. Those signs become a mirror from which companies can themselves witness the internal fragmentations taking place. 

Warning Letters are mere administrative advisories, but this perspective completely ignores the value they provide for the corporation. They often provide insight into underlying flaws within the company’s operation, and if ignored, could lead to consequential results, including, but not limited to financial losses and reputation tarnishment. Therefore, it is essential for interested parties to understand the factors behind receiving one of these letters before it becomes too late. 

Biopharmaceutical companies and their outsourced partners (CDMOs) are under increasing scrutiny, as health agencies intensify oversight in response to global supply chain complications, the growing reliance on outsourcing, and the expansion of early-phase operations. This has created a broad and complex landscape that America’s top health agency must now navigate.

Health agencies also face growing challenges as global supply chains strain, outsourced manufacturing expands, and early-phase operations broaden. It is ever more important to keep up and truly comprehend the compliance expectations set forward–problems in one region easily become the norm everywhere else. Companies must disregard all other factors, strive to understand this behavior, and act in accordance, with a mandated focus on top-notch quality. 

This article is intended to serve corporations within the pharmaceutical and medical device industries. Executives will gain critical insight into what proactive quality and compliance truly require, while Quality Assurance (QA) and Quality Control (QC) leaders will benefit from delving into the many grievances that lead to warning letters and the most effective measures to counteract this.

CDMO operators who are critical to the supply chain, gain more insight into the preventable compliance obstacles they routinely encounter. Regulatory affairs managers, vying to exit the entanglement of regulations that follow their path, will find a comprehensive game plan for dealing with FDA communications. Finally, pharmaceutical stakeholders, whose financial support plays a crucial role in everything, through thick and thin, will find themselves at the crossroads with another perspective in the art of assessing and mitigating regulatory risks. 

1. FDA Warning Letters: A Global Primer

"FDA Enforcement Escalation Path Flowchart"

An FDA Warning Letter is primarily intended to inform a corporation that federal regulators have identified serious violations of current compliance protocols, and these should be addressed with urgency before further disciplinary action is pursued. The FDA not only highlights the consequential importance of these violations, but also carves out a pathway for effective remediation. A typical Warning Letter is therefore structured such that it includes both the evidence surrounding the FDA's claims and the regulatory framework that those concerns fall under, along with a focus on deadlines by which the company must respond and propose a corrective action plan. 

Credits: springer.com

After a warning letter is issued, the enforcement protocol that follows begins to accelerate and can carry negative implications if not addressed sooner. If a firm decides to ignore the contents of the letter or lays out an inadequate remediation plan, the FDA could unleash a wide range of compliance tools that could financially and/or legally decimate a corporation, such as the impoundment of noncompliant products, the issuing of injunctions that prevent their production/distribution, the temporary acceptance of new product submissions, and sounding the alarm of import alerts that effectively stop these products from even entering the US.

In more severe scenarios, the FDA may impose civil monetary fines and/or pursue criminal charges against those responsible. This procedural approach, commonly known as the FDA's "enforcement escalation path," demonstrates the need for stronger regulatory action present in a stride towards ensuring patient safety. 

As pharmaceutical and medical device manufacturing become increasingly globalized and the FDA begins to knock on international doors, it has become crucial to understand these regulatory tools. In other words, a corporation with a base of operations elsewhere must follow all applicable US FDA regulations if they intend to ship their products to the US market.  

The Patterns Behind FDA Warning Letters

When Warning Letters are issued, they rarely result from a single mistake or a bad batch. They reveal something simpler, but more meaningful: a quality system that is not doing its job. Points where controls that should have prevented, detected, or corrected problems were not strong enough. When companies scale quickly, outsource aggressively, or push products to market under pressure, the vulnerabilities tend to appear in predictable places. These are not isolated failures, but rather they are signals of weak foundations.

Data Integrity Failures

One of the leading factors behind FDA Warning Letters is data integrity failures that manifest in many forms. These include the deliberate or negligent disregard of audit trials, reliance on uncontrolled Excel spreadsheets for critical data governance, backdating of data entries, incomplete or missing raw data, and the failure to ensure proper metadata capture and review. These actions potentially compromise the integrity and dependability of records, which are at the core of safeguarding product quality and patient welfare in highly regulated sectors. For example, in 2024, 42% of Warning letters cited missing or altered records, showing how widespread data integrity issues really are, and emphasizing their effect on regulatory compliance. 

Ensuring such failures never occur requires a holistic approach. One such way is through the use of the ALCOA+ framework–Attributable, Legible, Contemporaneous, Original, Accurate, plus Complete, Consistent, Enduring, and Available–is critical towards instituting sound data management practices. Additionally, rigorous electronic system validation (CSV) ensures that automated platforms utilized for data collection and management perform as expected and safeguard the reliability of such data. The systematic implementation of detailed audit logs generates an invaluable trail of all data-related actions taken, supporting comprehensive investigations into any discrepancies. However, the appreciation of the value of audit trail review on a consistent basis is severely ignored or misunderstood across the industry. By addressing these issues in advance, organizations can increasingly lower their chance of receiving FDA warning letters concerning data integrity and preserving the reliability of such information. 

Inadequate Supplier & Third-Party Oversight

One of the consistent challenges of the pharmaceutical and life science industry is reliance on global supply chains, particularly with Active Pharmaceutical Ingredient (API) manufacturers and contract service providers. While outsourcing can bring efficiency and cost advantages, it does not shift the burden of regulatory accountability. A company cannot delegate responsibility for product quality and patient safety. 

For instance, in 2024, roughly 19% of FDA warning letters were directly linked to offshore API suppliers (Office of Pharmaceutical Quality Report on the State of Pharmaceutical Quality). Some lapses include insufficient quality oversight, inadequate process and product knowledge, inadequate change management, and lack of performance monitoring. In several cases, ANDA (Abbreviated New Drug Application) holders were cited because their contracted suppliers failed to maintain compliance with current Good Manufacturing Practices (GMP). Consequently, both the application holder and supplier will be prone to facing regulatory enforcement actions. 

A core component of this issue involves ineffective oversight mechanisms. Often, companies depend on paper-based vendor qualifications or rely heavily on supplier self-assessments, which fail to capture real-world risks. Without robust monitoring, hidden vulnerabilities such as data integrity concerns or substandard production practices can manifest as compliance failures. 

Mitigation strategies include adopting a risk-based vendor qualification program that prioritizes high-risk materials and suppliers for deeper scrutiny. Clear and enforceable technical quality agreements should delineate responsibilities, ensuring alignment on cGMP requirements, change control, and deviation management. By embedding these practices, organizations move beyond a transactional vendor relationship to a partnership model of accountability, significantly reducing the likelihood of supplier-driven regulatory citations. This not only protects regulatory compliance but also safeguards patient trust in the final product. 

Credits: pharmaceuticalonline.com

Where systems break down

One of the first signals of a weak foundation is the state of the quality management system. Many CDMOs, especially those growing rapidly, build their QMS from generic templates. On paper, the procedures look complete. In practice, they do not accurately reflect how work is actually done. As operations expand, this gap widens, leaving systems that are reactive rather than preventive.

This weakness extends to related areas. Validation, for example, is often viewed as a milestone on the path to launch, not as a lifecycle commitment. Without continued verification, FDA questions whether processes can hold up under routine manufacturing. The same mindset is evident in environmental monitoring programs, where data is collected but not trended, and excursions are closed without understanding why they occurred. In both cases, signals are missed because the system is focused on checking boxes rather than learning from data.

Change control is another area where speed collides with structure. Adjustments to equipment, suppliers, or materials are made quickly to keep projects moving, but without the discipline of documented risk assessments. To inspectors, this reflects a culture where decisions are made outside, and without the consent of the quality system.

Credits: Global Key Solutions

Avoiding the Warning Letter: Strategies That Work & Why Startups & CDMOs Miss the Mark

The vulnerabilities that lead to Warning Letters are often magnified in startups and CDMOs. These organizations move quickly, take on complex projects with lean teams, and stretch compliance across roles that were never meant to carry it. We noted that many young firms rely on generic SOPs, assume their size shields them from full GxP expectations, and treat validation or monitoring as one-time hurdles. On paper, the systems may look sufficient, but under inspection pressure, the shortcuts become obvious — incomplete validation, environmental data with no trending, changes made without impact assessment, and CAPAs that close without proving effectiveness. What regulators see is not isolated mistakes, but a culture that struggles to anticipate and adapt.

Avoiding this cycle means embedding quality from the start. That begins with planning tools like FMEA to surface risks before launch, and CAPA programs that go beyond fixing symptoms to address root causes at the occurrence, detection, and systemic levels. It also means making inspection readiness routine through mock audits, structured change control, and real-time trending of deviations. These habits transform compliance from a scramble into a steady rhythm of improvement. For startups and CDMOs, the lesson is clear: scale is not the barrier. Resilience comes from systems, leadership, and culture that see quality not as overhead, but as the foundation for sustainable growth. 

Don't Be Reactive. Be more than proactive, Be Resilient.

FDA Warning Letters follow predictable patterns, making them preventable. The real issue is not isolated errors but systems that crack under pressure: incomplete validation, weak oversight, or CAPAs that fail to address root causes.

The solution is not more paperwork but a stronger culture. Companies that design quality into daily operations, verify their fixes, and treat readiness as routine are the ones that avoid repeat findings. For startups and CDMOs, the lesson is clear: compliance does not depend on size, but on intentionality. Even small organizations with limited resources can meet regulatory expectations if they design processes thoughtfully, build a culture of ownership and accountability, and prioritize quality from the outset. Responsibility for product quality is non-negotiable, and patient safety must remain the ultimate priority. Quality should never be treated as a cost to control - it is the foundation for sustainable growth.