FDA cites firms for CGMP and testing violations

The US Food and Drug Administration (FDA) has issued several recent warning letters to companies, including for failing to comply with current good manufacturing practices (CGMP), marketing unauthorized products, and failing to obtain proper informed consent from trial participants.

CGMP violations

FDA sent warning letters to two drugmakers, Signature Formulations in Phoenix, AZ and Bio-Medical Pharmaceutical Manufacturing Corporation in Houston, TX, for failing to meet CGMP requirements. Among the concerns raised by inspectors, the companies were cited for lacking procedures and processes to ensure their products are manufactured in a clean and sterile environment.

In their letter to Bio-Medical Pharmaceutical, a contract manufacturing organization (CMO), investigators said the company failed to have written procedures in place to prevent microbial contamination of their drugs and failed to perform operations within controlled areas specifically intended to prevent contaminations and mix-ups.

"Our investigators observed that your facility lacked classified cleanrooms for production, as well as ISO 5 conditions for aseptic filling and sealing," said FDA. "Furthermore, your manufacturing facility lacks appropriate equipment and practices, including environmental controls to ensure your [redacted] drug product is sterile.

"Your drug products intended to be sterile are at risk of contamination due to the insanitary conditions observed at your facility," the agency added. "This includes the condition of the production tank, filling lines lying on an unclean floor made of a rough, porous surface (e.g., concrete) in an open area, lack of appropriate sanitary fittings, and the general overall poor conditions of the facility for manufacturing drug products intended to be sterile."

Bio-Medical Pharmaceutical was also cited for failing to use properly designed equipment, located in areas that allow for cleaning and maintenance.

"You use [redacted] as a component to manufacture your sterile and non-sterile OTC drug products," said FDA. "Your [redacted] system is inadequately designed and maintained for its intended use.

"For example, your ambient non-circulating [redacted] system included dead legs which could foster the development of biofilms," the agency added. "When not in use, stagnant [redacted] remained in the sampling hose and distribution system. You use (b)(4) from this system to manufacture your drug products."

Signature Formulations, an over-the-counter (OTC) drug manufacturer, was similarly cited for failing to perform its manufacturing operations within defined areas to prevent contamination and mix-ups. The agency noted that their drug products share the equipment used to make children's toothpaste, raising concerns about cross-contamination.

Furthermore, Signature Formulations was cited for failing to properly clean, sanitize and sterilize equipment at appropriate intervals to prevent malfunctions and contaminations that otherwise could change the final product.

While the company has already told FDA that it has updated its standard operating procedures (SOP) to ensure the equipment is cleaned to prevent cross-contamination, the agency said it should consider dedicated facilities and equipment to prevent harming children.

"[Redacted] in [redacted] OTC [redacted] products pose a significant risk to public health," said FDA. "In children, exposure to even low levels of [redacted] can lead to developmental and reproductive harm.

"Therefore, dedication of facilities and equipment should be considered," the agency added.

Lacking informed consent

Mark Dacey, a Colorado-based ophthalmologist at Rocky Mountain Uveitis and a clinical investigator, was sent a warning letter for failing to obtain legally effective informed consent. More specifically, the agency said the researcher obtained aqueous humor samples from a trial participant despite the subject having declined the procedure in their informed consent form.

Dacey told FDA that collecting the samples was inadvertent and was reported to the institutional review board (IRB), and the subject was notified of the mistake at their next visit. Furthermore, he said that the samples were destroyed and procedures were updated to prevent such an incident from recurring.

However, FDA said his response was inadequate because they lacked sufficient detail.

"We also remain concerned that in this clinical investigation, it was clearly documented in Subject [redacted]’s records that the subject twice declined consent, yet the optional sample collection procedure was performed," said FDA. "As a result, the subject was exposed to unnecessary potential risks from the performance of this procedure, such as blurred vision, bleeding on the surface of or inside the eye, damage to the lens of the eye, and inflammation or infection inside the eye.

"We emphasize that as the clinical investigator, you are ultimately responsible for compliance with all applicable FDA regulations governing the conduct of clinical investigations and the protection of human subjects, including obtaining legally effective informed consent from subjects in accordance with 21 CFR part 50," the agency added. "Your failure to obtain informed consent before conducting study-related procedures jeopardizes the rights, safety, and welfare of subjects by denying them an opportunity to fully assess the risks and benefits of their participation in the clinical investigation."

No marketing authorization

FDA issued a warning letter to ProDx Health for selling HIV test kits on its website without marketing authorization.

"Based on our review of these materials, your firm offers its sample self-collection kits for delivery to individuals and intends for these individuals to use the kits to self-collect serological samples and ship those samples to laboratories for HIV testing," said FDA. "FDA has not authorized your firm’s sample self-collection kits for use in HIV serological diagnostic testing.

"Without appropriate testing, data review, and marketing authorization, there is a lack of assurance of the safety and effectiveness of your sample self-collection kits," the agency added. "We note that there are FDA-approved over-the-counter HIV self-tests that can help meet the needs of individuals who wish to test themselves at home or who are unable to access other testing options."

FDA also sent Beach Weekend Management a warning letter for marketing unauthorized products. The agency notes that the company sells Nicotina Energy Citrus Surge Lite 3 MG and Nicotina Energy Grapefruit Spark Lite 3 MG on its website which makes medical claims that require regulatory oversight.

Some of the claims listed by the FDA, based on the company's blog posts, include that their products may enhance attention and memory, reduce the risk or progression of diseases such as Parkinson's and Alzheimer's disease, work similarly to stimulants such as Adderall, and help with mood regulation.

"Your 'Nicotina Energy Citrus Surge Lite 3 MG' and 'Nicotina Energy Grapefruit Spark Lite 3 MG' products are 'new drugs' under section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because they are not generally recognized as safe and effective (GRASE) for use under the above-described conditions prescribed, recommended, or suggested in their labeling," said FDA. "Subject to certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act, 21 U.S.C. 355(a)."

Warning letters

FDA cites firms for CGMP and testing violations

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