FDA cites drugmakers and testing lab for CGMP violations

The US Food and Drug Administration (FDA) recently warned two drug makers and a drug testing lab for current good manufacturing practices (CGMP) violations, such as marketing products after detecting microbes and particles. It has also cited half a dozen online retailers for selling unapproved eye drops.

Pharmacal

FDA said Wisconsin Pharmacal's quality unit (QU) failed to ensure that its products complied with CGMP requirements before being marketed. As an example, regulators said the unit rejected products from a vessel that failed assay test specifications, but the products were marketed anyway.

"In addition, your QU failed to exercise its responsibility by not withholding from distribution all rejected units filled from vessel [redacted] and instead allowing the distribution of approximately half of the rejected drug product," said FDA. "Your practice of rejecting a partial drug product batch is an indication that your firm does not have well-controlled manufacturing and release procedures."

The over-the-counter (OTC) drugmaker said the mistake was due to a procedural error and had taken corrective actions by revising procedures and retraining staff. Investigators, however, said that was insufficient because Pharmacal didn't explain how the changes would prevent similar incidents in the future.

"You fail to address the fundamental deficiencies in your QU that led to these failures," said FDA. "You do not provide a comprehensive corrective action and preventive action (CAPA) plan with a systematic approach to correct these oversight deficiencies."

Pharmacal was also cited for not thoroughly investigating instances when a batch or its components fail to meet specifications. More specifically, investigators said the company didn’t adequately investigate cases of potential microbial contamination.

FDA noted that in August and November 2024, the company found Staphylococcus aureus (S. aureus) bacteria in its products but still allowed the associated products on the market without conducting proper investigations into the root causes of the contamination. While the company said it will begin additional sanitization of its products until it identifies the root cause of the contamination and has revised its procedures, FDA said that is not enough.

"Your response is inadequate because you fail to provide a comprehensive assessment of microbial contamination in your OTC drug products, including but not limited to, a review of elements of your operation that may introduce bioburden or permit microbial proliferation," said the agency. "Your response lacks a comprehensive drug product impact assessment."

Pharmacal was also cited for not having appropriate controls on its computer systems to ensure that only authorized personnel can make changes to its master production and control records. FDA recommended that it bring in an outside consultant to help comply with CGMP requirements.

Chromatography Institute of America

Colorado-based drug testing company Chromatography Institute of America, also known as Compounder’s International Analytical Laboratory, received a warning letter for several CGMP violations. FDA investigators said there weren't adequate laboratory control mechanisms for testing active pharmaceutical ingredients (API) and drugs compounded by outsourcing facilities. They note that the company recorded sterility failures with samples in several instances but failed to show that it performed growth promotion testing on the lot before use.

"In your investigations into these sterility failures, you noted 'false positives' with this lot, but you did not include appropriate negative controls corresponding to this lot in your tests and lacked sufficient evidence to support your 'false positives' statement," said FDA. "Moreover, after obtaining a failing sterility test result, you repeated the test on a fraction of the original sample amount, which is not in accordance with USP <71> and is an unacceptable practice."

FDA also said that the Chromatography Institute's investigation of several failed sterility tests was inadequate because the data did not support the root cause conclusions they provided.

The company's QU was also cited for failing to adequately perform its job. investigators said it didn't enforce proper controls on computer systems to ensure data integrity, implement effective document control to track changes, and review uncontrolled documents.

"Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accordance with CGMP," said FDA. "In addition to the lack of effective management oversight of your laboratory operations, we found that your quality unit is not enabled to exercise proper authority and/or has insufficiently implemented its responsibilities.

"Executive management should immediately and comprehensively assess your company’s global manufacturing operations to ensure that your systems, processes, and products conform to FDA requirements," the agency added.

While the Chromatography Institute has stated that it plans to cease its contract testing laboratory, FDA said that some of its later statements suggest otherwise. The agency asked the company to clarify what its future plans are. If it decides to sell its contract testing laboratory to another company, the agency wants details on who that is.

Amneal

New York-based drugmaker Amneal Pharmaceuticals was cited for CGMP violations as well. FDA inspected the company's manufacturing facility in India and found that it failed to thoroughly investigate a recurring problem with particulates contaminating its products.

"In 2024, your firm initiated an investigation when two batches of ropivacaine hydrochloride injection, supplied in polypropylene bags, exceeded your acceptance criteria for visual inspection," said FDA. "You identified the polypropylene bags as the source of the inordinately high levels of particulate contamination (predominately, white fibers).

"You performed an additional visual inspection and conducted a risk assessment that you believed justified releasing these batches," the agency added. "However, your risk assessment was inadequate as it minimized the severity associated with particle contamination in a sterile injectable drug product that can be administered into the epidural space."

The investigators said Amneal didn't adequately evaluate the potential risks the particulates pose to patients. They said long-term use of the products could cause an epidural inflammatory process, epidural abscess, meningitis, and, in some cases, permanent nerve injury.

While Amneal concluded that the polypropylene bags themselves were the source of the visible white fibers, FDA said the company continued to use them and didn't implement a CAPA plan. Instead, the agency said the company reduced its threshold for how much of the fibers was acceptable in its product.
"The inappropriately high tolerance for defective polypropylene bags accommodated the use of poor-quality polypropylene bags in the production of parenteral drug product batches," said FDA. "It is unacceptable to increase lot acceptance specifications to excessive levels to enable use of unsuitable polypropylene bags received from your supplier."

While the company said it will revise its major defect and total defect limits for polypropylene bag visual inspection, the agency said the level for determining whether the product is defective is still too high.
Furthermore, the FDA cited Amneal for not having adequate, scientifically sound laboratory controls to ensure its products conform to specifications.

Unapproved eye drops

FDA also issued warning letters to seven US-based online retailers for selling unapproved eye drops often marketed as holistic or homeopathic. Several retailers have also advertised their products on social media sites like Instagram.

In all cases, FDA said the marketing of unapproved eye drops is especially concerning from a public health perspective because the route of administration of such products bypasses the body's natural defenses.

Warning letters

FDA cites drugmakers and testing lab for CGMP violations

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