Initial FDA approval gets all the glory in the world of drugs and biologics. However, that approval has limited value if patients cannot rely upon receiving the original FDA-approved drug product (or an FDA-approved generic or biosimilar).
For over one hundred years, the U.S. Food and Drug Administration (FDA) has followed the precept that unsafe medicines are most often the result of improper and inconsistent manufacturing and inadequate quality control. The modern framework—spanning traditional pharmaceutical manufacturers and compounding entities—reflects that quality failures are systemic risks that require systemic solutions.
“Regulation of US Drug Manufacturing Since 1900” can be viewed as an almost-completed jigsaw puzzle. While a few pieces may still be missing, the picture is clear: FDA has the authority and the intent to require all drug manufacturers to conform to its rules and standards. There is no room for, or benefit from, having two pathways with different rules (here and here).
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From Episodic Crises to System Design (useful histories here, here, here, and here)
FDA’s modern quality framework is rooted in a series of well-documented twentieth-century public health failures, including repeated incidents of contaminated biologics (here) and the infamous 1937 elixir sulfanilamide disaster (here). These tragic incidents demonstrated that — in the absence of enforceable standards — manufacturers could not be relied upon to test products for safety or to standardize and control production processes.
The Federal Food, Drug, and Cosmetic Act of 1938 created the first comprehensive federal framework for drug oversight, including facility inspections and premarket safety requirements. But subsequent events, including additional contamination incidents, made clear that premarket review alone was insufficient.
The core problem was not simply defective products; it was defective manufacturing processes.
The introduction of Good Manufacturing Practice (GMP) regulations in the 1960’s represented a structural shift. The focus moved to how drugs should be manufactured, on a routine, ongoing basis. In effect, the agency moved from post hoc correction to prospective, continuous control.
cGMP As A Flexible and Resilient Regulatory Tool Today’s “current” Good Manufacturing Practice (cGMP) framework remains the central mechanism for implementing this strategy (here). The regulations establish baseline expectations for facilities, equipment, personnel, and process controls to ensure that drugs meet specifications for identity, strength, quality, and purity.
cGMP requirements are designed to identify and mitigate risks before they result in patient harm. In principle, the goal is straightforward: unsafe manufacturing should be engineered out of the system. (FDA)
Enforcement As Signal and Leverage
While cGMP establishes upstream expectations…they are meaningful only if inspections and enforcement are consistent, credible, sustained, and incorruptible downstream.
In recent years, FDA has continued to cite manufacturers for recurring failures in sterility assurance, contamination control, and data integrity–underscoring that foundational quality problems persist across the industry.
Enforcement in this context serves not only to correct deficiencies, but also to signal regulatory expectations more broadly and deter future violations.
Compounding: A Parallel Regulatory Track With Ongoing Manufacturing Safety Concerns
Traditional pharmacy compounding—intended to produce patient-specific formulations rather than manufactured products—has historically been regulated primarily at the state level. The regulatory challenge arises when compounding becomes comparable to manufacturing in scale and scope yet lacks corresponding federal oversight and reliable supply chains.
The 2012 fungal meningitis outbreak linked to the New England Compounding Center (NECC)– killing sixty-four people and sickening hundreds more–is a defining event. It demonstrated the risks of large-scale compounding without robust quality controls.
From a regulatory standpoint, NECC did not introduce a new category of risk; rather, it reaffirmed a familiar problem: contamination control failures, inadequate process validation, and weak quality systems—issues long associated with manufacturing — were present in a setting that lacked FDA standards and oversight.
Drug Quality and Security Act (DQSA) and the Extension of cGMP Principles
Congress responded to the horrific NECC incident by passing the Drug Quality and Security Act (DQSA) of 2013, which established a category of “outsourcing facilities” subject to FDA oversight and cGMP requirements.
In practical terms, DQSA extended core manufacturing quality principles into an area that had previously operated outside of the federal framework.
This development reflects a broader pattern in FDA’s regulatory evolution: the progressive closure of gaps through which unsafe manufacturing practices can occur. At the same time, large-scale compounding introduces additional risks, particularly regarding supply chain sourcing and the quality of active and inactive ingredients.
Globalization Has Added More Complexity to Drug Safety
Globalization has increased the complexity of oversight, requiring FDA to monitor facilities across multiple jurisdictions with varying regulatory environments. Enforcement data continue to reveal recurring deficiencies, particularly in procedural controls, investigation of discrepancies, and contamination prevention (here).
Significant resource constraints and variability in inspection outcomes–especially for foreign facilities–further complicate matters. These realities reinforce a central point: regulatory requirements alone are not sufficient. Effective implementation and enforcement are equally critical to reducing manufacturing risk. At a time of flat FDA budgets, volatility in FDA leadership, and the loss of experienced agency personnel, the adequacy of FDA’s efforts is a serious and ongoing concern.
Conclusion
The FDA’s century-long effort to limit—and ultimately eliminate—unsafe drug manufacturing reflects a steady progression from reactive enforcement to proactive system design. The development of cGMP established a durable framework for embedding quality into all aspects of drug production, while enforcement tools provide the accountability necessary to sustain compliance. Despite these many advances, the elimination of unsafe drug manufacturing remains unfinished business.
I began by comparing this history to a nearly-completed jigsaw puzzle. That analogy still holds. Even with a couple of pieces missing, the picture is clear:
FDA must continue to strengthen its oversight of drug manufacturing, particularly as new risks emerge and existing challenges persist.
Part 2–forthcoming–will examine areas for improvement, including FDA’s current initiatives, that will incentivize higher-quality manufacturing and improve supply chain reliability.
