FDA warns contract manufacturer for GMP violations, clinical investigator for not following trial protocol

The US Food and Drug Administration (FDA) has issued warning letters to a contract drug maker for failing to meet current good manufacturing practices (CGMP) and a clinical investigator for failing to ensure site staff complied with the clinical investigation plan.

Contract manufacturer woes

Australian drug contract manufacturer Cosmetic Manufacturers Pty was sent a warning letter for failing to meet CGMP requirements. Among the violations recorded by agency inspectors, the company was cited for failing to ensure its final products met specifications. More specifically, they stated that it did not ensure that it evaluated its products for all critical quality attributes, did not test them for the identity and strength of the active ingredient or for foreign matter, and did not evaluate the preservative content.

While Cosmetic Manufacturers Pty said it would validate its analytical test method and implement assay testing for future batches, FDA said the company did not commit to reevaluating its batch release criteria to ensure they are appropriate.

Furthermore, FDA cited Cosmetic Manufacturers Pty for failing to have laboratory controls to ensure the final product meets specifications.

"Your testing and specifications of your [redacted] are inadequate," said FDA. "You did not test samples of [redacted] for all significant quality attributes, including [redacted].

"You also have not established suitability of test methods, including evaluating whether your drug product formulations intrinsically inhibit microbiological growth during bioburden testing," the agency added.

Inspectors also noted that the company lacked written production and process control procedures to ensure that final products meet specifications and said it did not use the right production equipment in the right places to allow it to be cleaned and maintained. More specifically, the agency said the company was using the wrong filler machine for filling the wrong drugs.

"You have also not established whether your cleaning procedures consistently reduce chemical and microbiological residues to acceptable levels," said FDA. "The cleaning validation protocol was not designed to demonstrate reproducibility of the cleaning process.

"For example, the cleaning validation protocol required [redacted] swab samples to be taken from different locations for each of the [redacted] qualification runs," the agency added. "Your cleaning validation also did not adequately justify the decision to use a [redacted] tank in lieu of the [redacted] tank used to manufacture the [redacted] drug products."

Regardless of its agreement with its customer as a drug contract manufacturer, the FDA said Cosmetic Manufacturers Pty still bears responsibility for the quality of the drugs it produces. While the company stated that it has ceased drug production, the agency asked it to notify regulators if it plans to restart manufacturing any regulated products.

Trial investigator

FDA sent a warning letter to Bertrand Cole, an internal medicine doctor in New Hampshire and a researcher at Activmed Practices and Research, for failing to follow the investigational plan of a study that he was leading. The agency said that he failed to ensure his staff followed a study protocol on multiple occasions.

"As a clinical investigator, you are required to ensure that your clinical investigations are conducted in accordance with the investigational plan," said FDA. "The investigational plan for Protocol [redacted] required the randomization of subjects to receive one of three weekly doses (1.5 mg, 4.5 mg, or 9.0 mg) of the investigational drug [redacted] or the matching placebo.

"Subjects in the 4.5 mg and 9.0 mg treatment arms were subdivided into two different titration arms (a and b), with different titration regimens beginning at 1.5 mg and increasing to the target randomized dose," the agency added. "You failed to adhere to this requirement for four out of four enrolled subjects over multiple study visits."

More specifically, FDA listed instances when the study subjects received excessive doses of the investigational drug.

Cole told FDA that the error occurred because the site staff erroneously believed the investigational drug vials were pre-dosed, didn't follow the pharmacy manual instructions. He also noted that they were not originally assigned to the study.

While Cole provided corrective and preventive actions to prevent the error from recurring, the agency said they were insufficient.

"While we acknowledge the corrective and preventive actions that your site has taken, your written response is inadequate, because you did not include sufficient details regarding the training or procedures implemented at your site to prevent similar violations in the future," said FDA. "In addition, your written response does not provide sufficient details about how you, as the clinical investigator, will ensure adequate oversight of study procedures (for example, adherence to protocol-specified dosing requirements).

"Without this information, we are unable to determine whether your corrective actions appear adequate to prevent similar violations in future clinical investigations," the agency added.

Regulators reminded Cole that, ultimately, he bears responsibility for the conduct of the trial, regardless of the site staff's erroneous actions. They said that his failure to follow the study protocol and the fact that four out of four subjects were overdosed during the trial raised significant concerns about the integrity of the trial data and the protection of the trial subjects.

Warning letters

FDA warns contract manufacturer for GMP violations, clinical investigator for not following trial protocol

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