By Jerry Chapman, M.S., Redica Systems
The December 2022 FDA Warning Letter to DuPont Nutrition USA Inc., an excipient manufacturer, was the first Warning Letter to be issued to an excipient-only manufacturer. What can we learn from that letter?
Let’s start with defining an excipient and where FDA’s authority to inspect excipients comes from.
According to the U.S. Pharmacopeia, excipients are, “often referred to as ‘inactive ingredients’ because, in drugs, they comprise of everything except the active pharmaceutical ingredients (APIs). Excipient functions range from helping to guarantee the stability and bioavailability of the API to the drug product’s manufacturability to its texture and taste. Excipients are a major component of almost all drugs, as well as foods, cosmetics, and dietary supplements.”
Note that “almost all” drugs contain excipients. Since an issue with an excipient could indicate a problem with the drug it is used in, drug manufacturers must be aware when problems arise with the excipients they use in their finished products. The excipient targeted in the Dupont inspection is widely used in numerous drug products.
At the PDA-FDA Joint Regulatory Conference in Washington, DC in mid-September 2023, FDA Center for Drug Evaluation and Research Office of Manufacturing Quality Office of Compliance Regulatory Counsel Joseph Pham explained what facilities in the drug supply chain his agency has the authority to inspect and under what circumstances (see Figure 1).
Figure 1. Who in the Drug Supply Chain Can FDA Inspect?
Pham explained that while there are “no current regulations governing excipients,” there are regulations for finished pharmaceuticals, and excipients can be inspected as components of finished drug products.
He emphasized that “if FDA is inspecting an excipient manufacturer, that typically means something has triggered that inspection – it is a for-cause inspection.”
What Prompted FDA to Inspect Dupont Nutrition?
A close look at the Dupont Nutrition’s November-December 2021 inspection, the EIR, the resulting 483, the company’s 483 response, and the subsequent December 2022 Warning Letter, which are all available on the Redica Systems platform, reveals a timeline leading up to the DuPont Warning Letter.
The 31-page EIR identifies the DuPont inspection as a “For Cause Inspection” requested by the FDA Center for Drug Evaluation and Research (CDER).
Pham reported that FDA had received Field Alert Reports, which reported significant quality problems with distributed drug product, from numerous drug manufacturers, regarding out-of-specification (OOS) testing results concerning an excipient used widely in both over-the-counter (OTC) and approved drug products.
It is important to note that this excipient's quality standards are delineated in its respective USP monograph, he stressed, and upon testing it must meet the monograph requirements.
After learning about these reported quality problems, FDA investigated the issue and conducted a for-cause inspection of DuPont.
What Did FDA Find?
Upon inspection, FDA found that:
• the excipient was failing its compendial (USP) conductivity specification (used to limit impurities)
• the failures were not being caught by the manufacturer before release of the excipient to the market
• this had been occurring for months, and
• the manufacturer stated, in their determination, that there were no significant OOS trends, despite receiving about 50 complaints.
The Dupont Warning Letter issued in December 2022 states that the agency considers the microcrystalline cellulose excipient in question, Avicel®, adulterated because its controls for manufacturing, processing, packing, or holding do not conform to GMP, and because the excipient failed to conform to compendial standards for strength, quality, or purity.
In addition, the agency includes a section on “Data Integrity Remediation” that begins with the statement, “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the excipient you manufacture.”
What is the Risk?
A focus on pharmaceutical excipients appears new for FDA. However, it is actually an extension of the agency’s expectations for oversight of suppliers by drug manufacturing companies and compliance with the FDA Quality Agreement Guidance .
For example, in June 2017, a Contract Manufacturing Organization (CMO), ChemRite CoPac in Wisconsin, was making oral pharmaceutical solutions for another company using the same equipment it used to make toxic car washes and waxes without appropriate cleaning in between. It was cited in a warning letter for, among other things, the lack of a quality agreement with the firm that it was making the solutions for (Sage Products).
The FDA sent a similar warning letter to Sage Products in July 2017 for the lax oversight of the contractor (ChemRite CoPac) that was producing the oral solutions. This is what one FDA investigator calls a “twofer”—two warning letters from one inspection. One was to the product owner and one to the CMO.
In the case of a prominent excipient, Avicel, quality issues with the excipient as identified at the manufacturing site have been made public in a warning letter, putting all drug companies who use the excipient on notice that they are using a product in the formulation of their drug that is potentially adulterated. Notably, the warning letter says the Avicel excipient is “extensively used as a major component in a wide variety of drug products.” It is possible by extrapolation that users of the excipient may be at risk for regulatory action as well.
What Should Companies Do?
FDF manufacturers: Ensure that your on-site audits of excipient suppliers are robust and well-documented, with any issues addressed. Also ensure you have a robust excipient qualification program and your suppliers are qualified. Keep informed on FDA warning letters and import alerts and compare those against your list of suppliers, taking action if necessary.
Excipient manufacturers: Study the Dupont warning letter and the quality system areas where the deficiencies were found to evaluate your operations against the issues FDA found there. Ensure your quality systems are robust.