FDA cites drug manufacturers, compounders over sterility issues

The US Food and Drug Administration (FDA) has issued warning letters to several drug manufacturers and compounders for violations of current good manufacturing practices (CGMP) and for marketing products without agency approval. A common theme across several of the letters is that the manufacturers failed to ensure their products were made in sterile, sanitary conditions.

On 21 April, FDA published a slew of warning letters for CGMP and other violations. They were issued to drugmakers Par Health in Michigan, New Life Pharma in New Jersey, and Xiamen Kang Zhongyuan Biotechnology in China, as well as outsourcing compounding manufacturers RC Outsourcing in Ohio, Thrive Health and Wellness in Colorado, and Apollo Care in Missouri. There was also a warning letter to UCSF Radiopharmaceutical Facility, which is a part of the University of California, San Francisco (UCSF) radiology department.

Par Health

Par Health, a contract manufacturer of sterile injectable drugs, was cited for failing to manufacture products within designated areas that are of adequate size and have areas that prevent contaminations or mix-ups in aseptic processing areas. The agency said its processing lines are not restricted access barrier systems (RABS) and were designed as traditional aseptic filling lines surrounded by barriers under high efficiency particulate air (HEPA) systems.

"These processing lines required manually intensive operations during equipment setup and throughout routine production, and did not provide appropriate separation and protection of the ISO 5 areas," said FDA.

"Your aseptic processing cleanroom layout, filling equipment design, protection of ISO 5 areas, and the number and complexity of personnel interventions during setup and filling operations are deficient," the agency added. "These basic design deficiencies and manually intensive interventions affect multiple processing lines and compromise your ability to maintain aseptic conditions."

Par Health was told it had inadequate environmental monitoring and inadequate unidirectional airflow. Additionally, the company was cited for lacking adequate written procedures to prevent microbiological contamination of its sterile products.

FDA said the company should use automated visual inspection for particulates to augment its visual inspection program.

"Significant findings in this letter demonstrate that your firm does not operate an effective quality system in accord with CGMP," said FDA. "In addition to the lack of effective management oversight of your production operations, we found 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.

New Life Pharma

Similarly, New Life Pharma was cited by FDA for lacking adequate written procedures to prevent microbiological contamination of its sterile products.

"Your firm manufactured multiple GLP-1 finished drug products such as sterile, multi-dose vials of semaglutide and tirzepatide, without appropriate procedures to prevent microbiological contamination of your drug products, purporting to be sterile," said FDA. "Your firm did not adequately validate the conditions under which you manufactured drug products intended to be sterile.

"These deficiencies demonstrate that your firm lacked the fundamental controls necessary to ensure the sterility of your drug products," the agency added. "Your failure to implement these requirements placed patients at serious risk of receiving non-sterile products, which could result in severe infections or other life-threatening complications."

Xiamen Kang Zhongyuan

FDA told Xiamen Kang Zhongyuan that it did not have adequate controls to prevent contamination of its products. The agency noted that its investigators found its manufacturing facility "in a state of disrepair, poorly cleaned, and poorly maintained."

FDA listed several examples of its observations, including grime and discolored lubricant on manufacturing equipment, flies and standing water in the manufacturing area, mold in the air conditioning vents, and a cockroach in the packaging area.

FDA also said that Xiamen Kang Zhongyuan made misleading or deceptive statements to investigators and may have delayed their inspection. More specifically, the agency said that the company's chief quality officer admitted to providing testing documents and false manufacturing records, including falsifying data in a logbook.

Sterility concerns

Apollo Care, RC Outsourcing, and Thrive Health were all sent warning letters containing the same boilerplate language stating that their products did not meet sterile manufacturing requirements.

"The FDA investigator noted that drug products intended or expected to be sterile were prepared, packed, or held under insanitary conditions, whereby they may have become contaminated with filth or rendered injurious to health, causing your drug products to be adulterated under section 501(a)(2)(A) of the FDCA," said FDA.

For example, Apollo Care was told it used sanitizing and sporicidal agents without providing adequate segregation to prevent contamination of in-process bulk drug solution, it did not perform adequate product evaluation and take appropriate corrective action after microbial contamination was found in the aseptic processing area, and its production areas and equipment were difficult to clean or contain porous, particle-generating, or visibly dirty equipment or surfaces.

Similarly, RC Outsourcing was told it exposed sterile drugs and materials to lower than ISO 5 quality air.

"Specifically, your handling of container-closure system components for Povidone-Iodine Sterile Ophthalmic Solution may result in contamination," said FDA. "During the repackaging process, dropper bottle caps containing the applicator tips are staged [redacted] on the surface of your ISO 5 laminar flow hood.

"This practice exposes critical surfaces—specifically, the interior of the dropper bottle cap and the applicator tip—to the non-sterile surface of the ISO 5 hood," the agency added.

Investigators found Thrive's personnel were conducting aseptic operations outside of a certified ISO 5 area, and some performing sterile operations had never performed media fills to test whether the aseptic procedures were sufficient to prevent contamination during drug production. Furthermore, investigators found that the processing area and its surroundings were difficult to clean, personnel working in the aseptic manufacturing process were wearing non-sterile gloves and had exposed skin and hair, and they failed to use sporicidal agents to disinfect critical areas.

UCSF Radiopharmaceutical Facility was also cited for failing to ensure its equipment was clean, among other violations cited in its warning letter. Investigators said its procedures lacked sufficient detail to ensure aseptic conditions were maintained.

"During our inspection, investigators observed your technician performing contact plating of the ISO 7 area of the [redacted] immediately after disinfection of surfaces with [redacted], a practice which is likely to inhibit microbial growth on the sampling media and produce false negative results," said FDA. "Additionally, you lacked [environmental monitoring (EM)] of the ISO 5 area of the [redacted] where aseptic manipulations of sterile [redacted] drug products occur [redacted].

"An effective environmental monitoring program, with samples that appropriately represent production conditions, is essential for detecting microbial contamination in critical areas and triggering prompt actions to maintain a state of control," the agency added.

Unauthorized products

In addition to concerns about ensuring sterile manufacturing areas, practices, and products, FDA also cited several of the companies for manufacturing products without authorization. Thrive, which was told that FDA does not have an application on file for drug products that it repackages, such as NAD+ 50 mg/mL and MEGALean (Tirzepatide/Cyanocobalamin) Injections 10mg/20mg/mL; New Life was told that it did not properly register itself or its products with the agency; and RC Outsourcing was cited for repackaging drug products such as Povidone-Iodine 5% Ophthalmic Solution without FDA authorization.

SaNOtize, a Canadian drug maker, also received a warning letter from FDA for marketing unapproved products.

"Your 'NOWONDER™ Nasal Cleanser' is a 'drug' as defined by section 201(g)(1)(B) of the FD&C Act, 21 U.S.C. 321(g)(1)(B), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or under section 201(g)(1)(C) of the FD&C Act, 21 U.S.C. 321(g)(1)(C), because it is intended to affect the structure or any function of the body," said FDA. "No FDA-approved applications pursuant to section 505 of the FD&C Act, 21 U.S.C. 355, are in effect for this drug product.

"Accordingly, 'NOWONDER™ Nasal Cleanser' is a new drug in violation of section 505(a) of the FD&C Act, 21 U.S.C. 355(a)," the agency added. "The introduction or delivery for introduction of such a product into interstate commerce violates section 301(d) of the FD&C Act, 21 U.S.C. 331(d)."

Warning letters