Shortcuts, coverups in drug plants often precede quality problems, shortages

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When US Food and Drug Administration (FDA) inspectors visited Integra LifeSciences' drug manufacturing facility in Boston in March through May, the company's collagen-based Durepair product failed bacterial endotoxin testing.

The FDA issued a warning letter to the company on July 17 for that and other violations of good manufacturing practices (GMP) tied to its wound care, soft-tissue repair, and reconstructive surgery products. Durepair is a nonsynthetic dura mater substitute used in neurosurgery.

As a result, the company recalled the Durepair products and issued a statement saying it wouldn't distribute them again until it can conform to quality system regulations, hopefully by the end of the year.

Such quality problems are common both in the United States and abroad and often lead to drug recalls, plant closures, and product shortages, said David Margraf, PharmD, PhD, pharmaceutical research scientist at the Resilient Drug Supply Project (RDSP). RDSP is part of the University of Minnesota's Center for Infectious Disease Research and Policy (CIDRAP), publisher of CIDRAP News.

"Failure to follow current good manufacturing practice regulations leads to product defects, contamination, and other issues that harm patient health," Margraf said.

"Additionally, there is a strong positive correlation between maintaining quality standards and drug shortages," he added. "As products are pulled from the market, or citations force the shutdown for cleaning and retooling, the high-quality products we expect to be available for patients are absent from the market."

Drugs for cancer, respiratory diseases

As an example of the fallout of entrenched quality problems, on October 2021, the FDA issued a warning letter citing possible mold contamination from unaddressed water leaks at Teva's Irvine, California, manufacturing facility.

The company responded by recalling more than 2.5 million vials of injectables used for indications such as cancer, arthritis, schizophrenia, and muscle relaxation for intubation. Then it closed the plant permanently. Affected products with more than a 15% market share included, among others, the cancer drugs bleomycin, dacarbazine, and streptozocin.

As products are pulled from the market, or citations force the shutdown for cleaning and retooling, the high-quality products we expect to be available for patients are absent from the market.

David Margraf, PharmD, PhD

Similarly, Akorn Pharmaceuticals shut down all US operations in February 2023 after a string of regulatory and financial problems, including a series of FDA warning letters, citations, and Form 483s. Among the more than 100 generic drugs affected, the company was noted for making liquid albuterol, used to treat breathing difficulties, and acute-care injectables and ophthalmologic preparations.

Leaking ceiling, document destruction

Other quality issues recently flagged by the FDA include:

After visiting Aurobindo Pharma's formulation manufacturing facility in Telangana, India, in July, the FDA issued a Form 483 for three infractions involving nonadherence to cleaning, maintenance, and lab-control procedures. Form 483s represent violations of the Food, Drug, and Cosmetic Act and Related Acts. Inspectors observed the quality-control lab ceiling leaking next to the refrigerator used to store chemicals for analytic testing and a layer of solid, dark-colored flakes covering the lab's testing apparatus.
Also in July, the FDA inspected Biocon Ltd's insulin manufacturing facility in Malaysia, flagging it for eight violations involving drug substances, drug product units, quality-control labs, and its delivery-device unit. The Form 483 details issues such as repeated nonadherence to protocols to prevent microbiological contamination of drug products purporting to be sterile, failure to review the failure of a batch or its components to meet specifications, failure to review any discrepancy, lack of employee training to adequately perform their jobs, and a lack of documentation of corrective and preventive actions. The company recently announced that it expected approval of its generic insulin Aspart within the year.
In late July, the FDA sent a warning letter to Intas Pharmaceuticals about a November and December 2022 inspection of its drug manufacturing plant in Sanand, India, that uncovered, for example, an analyst pouring acetic acid into a trash can containing analytic balance slips for testing standardization. Among its lengthy list of infractions, the FDA also noted plastic bags filled with torn original good manufacturing practice documents in scrap areas and on a truck. The agency said it may continue to refuse US entry to products made at this facility if the violations aren't adequately addressed.

"It is crucial for manufacturers to adhere to GMP not only as a regulatory requirement but also as an ethical responsibility owed to patients and the healthcare system," Margraf said.

"Cutting corners to reduce costs can be more costly than the investments required to maintain GMP standards by damaging a manufacturer's reputation and eroding trust, costly recalls, regulatory fines, litigation, or plant shutdowns," he concluded. "Companies that prioritize GMP adherence show commitment to quality, safety, and patient health, which is key to the long-term viability of a company."