How a Chinese Manufacturer Could Have Avoided a Warning Letter

Ming Fai Industrial, a Chinese manufacturer of ultrasound gel and probe cover products, received an FDA warning letter in June that, according to a former FDA investigator, could have been avoided.

Vincent F. Cafiso, an investigator-turned-consultant, shared the warning letter on LinkedIn on Wednesday.

"This [FDA warning letter] could have been avoided with a proper Form FDA 483 response and periodic updates demonstrating a comprehensive and robust approach to addressing observations," Cafiso wrote.

Cafiso, founder of Practical Compliance Results, leverages his 30-year experience at FDA to help medical device and diagnostics firms become "inspection ready." He pointed to the following statement from the FDA warning letter as a reoccurring theme related to Ming Fai's Form 483 response: "There is no evidence of procedure effectiveness and documentation of training on the new procedure."

FDA inspected the firm's facility in Shenzhen, China in March. The inspection revealed that the company's methods used in, or the facilities or controls used for, the manufacture, packing, storage, or installation of Ming Fai's medical devices are not in conformity with the current good manufacturing practice requirements of the quality system regulation (Title 21, Code of Federal Regulations, Part 820). The company responded to the Form FDA 483 observations on March 23. FDA seems to have found much to be desired in the response.

According to the FDA warning letter, Ming Fai failed to adequately ensure that when the results of a process cannot be fully verified by subsequent inspection and test, the process shall be validated with a high degree of assurance and approved according to established procedure. For example, FDA noted that the firm did not maintain documentation of validation for the ethylene oxide (EO) sterilization of the probe cover kit containing the sterile gel pouch.

"Your firm’s EO sterilization validation was conducted for a kit containing another device, C-Arm Drape, that is also packaged in a Tyvek pouch," FDA wrote. "However, the C-Arm Drape kit differs from the ultrasound gel probe cover kit, as the probe cover kit contains a sterile gel pouch. Your firm did not maintain documentation with justification that the EO validation conducted on the C-Arm Drapes packaged in a Tyvek pouch is representative for the probe cover kit."

The FDA warning letter also noted that Ming Fai did not maintain validation records for the software used to calculate the amounts for the ingredients to be mixed for the ultrasound gel formulation.

Likewise, the firm allegedly failed to document cleaning validation conducted for the mixing tank equipment used for manufacturing its ultrasound gel.

FDA acknowledged that Ming Fai provided a new procedure to document the irradiation validation dose like the validation report, however, this document does not address the concern of the firm not being able to provide adequate records of the gel lots used during the sterilization validation. The agency added that there is no evidence of procedure effectiveness and documentation of training on the new procedure.

In the company's response to FDA's Form 483 observations, Ming Fai provided a procedure for evaluating the medical device sterilization methods and parameters of devices to determine how to select a representative model for sterilization of a device family. However, FDA noted that the evaluation had not been completed by the firm and only the procedure to evaluate the representative device has been provided. Once again, FDA found this response to be inadequate because the company did not provide documentation on training and effectiveness of the new procedure. This means the agency was unable to determine if Ming Fai's corrections adequately address the requirements of the regulation.

The FDA warning letter also notes that Ming Fai established a procedure for the validation of formulation systems, and that the procedure documents how an installation qualification (IQ), operational qualification (OQ), and performance qualification (PQ) should be performed. The agency found this response to be inadequate because there is no specific documentation of the IQ/OQ/PQ protocol and report related to the formulation of the ultrasound gel that include acceptance criteria. FDA noted the lack of CAPA to track and evaluate effectiveness of corrective actions as well as the lack of documentation of training on the new procedure.

"Your firm states that their cleaning validation incorrectly did not list the mixing tank used in the manufacture of ultrasound gel. In your response, your firm provided an equipment list that only lists the mixing tank used for the ultrasound gel manufacturing process. Your firm states that the assigned QA engineer is responsible to review and check the mixer code for each validation report," FDA wrote.

Once again, the agency found this response inadequate because there was no documentation of the investigation and evidence to show that the mixing tank was incorrectly listed on the report information. There was no documentation of any updated procedure instructing the QA engineer to review and check the mixer code for each validation report, nor was there any documentation of training on the new procedure.

According to the FDA warning letter, the company also failed to identify by suitable means the acceptance status of the product to indicate the conformance or nonconformance of product with acceptance criteria.

"For example, your firm had several pallets of in-process product held next to finished products in an area designated for finished sterile product ready for release," the agency noted. "Additionally, the sterility status of product was not identified (e.g., stickers affixed directly to finished product). Only a single loose paper with the lot number and one sterile color identifier was taped to the pallet."

In the FDA warning letter, the agency noted that the firm provided an updated warehouse layout where it proposed storage of sterilized semi-finished products and stated that “labeling on the rack is corrected immediately.” Additionally, the company has provided a revised procedure for "finished device acceptance."

Still, according to FDA, no evidence of the labeling on the rack was provided in the company's response, no documentation was provided demonstrating personnel were trained on the updated layout and procedure, and there was no documentation of a review or evaluation on the effectiveness of the layout change and revised finished device acceptance procedure.

"Should FDA determine that you have quality system regulation violations that are reasonably related to premarket approval applications for Class III devices, such devices will not be approved until the violations have been addressed," the letter warns.