FDA Warning Letters Week of 1/19/2020: Monitoring Import Alerts

FDA published a variety of warning letters this week including from the Center for Tobacco Products and two more regarding the Foreign [Food] Supplier Verification Program and failure to comply with those requirements (we covered one of the earlier FSVP warning letters here).

FDA also posted four GMP drug warning letters, all to firms outside the US.  One of the letters reinforces the need to monitor import alerts to ensure that suppliers and CMOs are not on the list; the consequences of missing this can be serious as this firm learned.

DRUG | Tismore Health and Wellness Pty Limited

Tismore Health and Wellness Pty Limited (Kingsgrove, Australia) received a warning letter on December 5, 2019, based on the outcome of an inspection ending May 24, 2019. The firm manufactures OTC drug products, along with distribution of unapproved new drugs in the US.

• The firm does not exercise appropriate controls over computer systems. The GC in the laboratory is mentioned where admin privileges are assigned to analysts. In reviewing audit trails, FDA investigators found that more than 100 test results had been deleted since October 2017 and more than 100 sample sets were aborted in the same timeframe, all without investigation. FDA states: “Your quality system does not adequately ensure the accuracy and integrity of the data to support the safety, effectiveness and quality of the drugs you manufacture. Without complete and accurate records, you cannot assure appropriate decisions regarding batch release, product stability, and other matters that are fundamental to ongoing assurance of quality.” FDA found fault with the firm’s response because they did not commit to assess GC data related to all batches of product distributed to the US, did not commit to an independent review of why these practices occurred and what decisions led to data deletion. Note again the requirement for an “independent review” where it appears that the FDA does not trust the firm to perform this activity accurately.
• The firm has not qualified equipment used in manufacture and thus there is no guarantee that it is suitable for its intended use and implicates the quality of all products made using this equipment.
• The firm failed to validate the excel spreadsheet used in calculate assay results. Procedures did not provide instruction on how to verify the calculations. Further, the investigator identified a calculation error: the incorrect formula for averaging the Internal standard was used. FDA also states: “There is no assurance that the associated assay results recorded are reliable and accurate…your computerized systems must perform their functions satisfactorily and that your firm establish a written program to ensure ongoing proper system performance.”
• FDA reminds the firm about its responsibilities as a contract manufacturer and that they are responsible for the quality of drugs they produce regardless of any agreement they may have with their client.
• FDA states: “Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture.”
• Some products contain glycerin and FDA is concerned that the firm may not be appropriately testing for the presence of a contaminant diethylene glycol.

DRUG | CGA Limited

CGA Limited (Trinidad & Tobago) received a warning letter on December 19, 2019, based on the outcome of an inspection ending May 31, 2019. The firm manufactures OTC drug products, and one of their soap products is an unapproved new drug. FDA recommends the firm hire a consultant to assist them in coming into GMP compliance. FDA placed the firm on Import Alert 66-40 on November 21, 2019.

Deficiencies include but are not limited to:

• The firm did not test incoming components for identity and other quality attributes, particularly identity and impurity testing according to USP. The firm stated they did not have the capability to perform the required testing and will contract an external lab to complete testing on the API. FDA deemed their response to be inadequate because the API testing was not described nor did the firm describe how they would qualify suppliers and validate their test results, including qualification of the contract laboratory. 
• Drug products were released to the US without adequate testing including testing of the active ingredient and assay. These were lacking from the CoA. Further, they did not have stability data to demonstrate drug attributes are acceptable and meet specifications through their labeled expiry date.
• Rust and peeling paint were observed on product contact surfaces of non-dedicated equipment. Both drugs and cosmetics are manufactured in this equipment. And finally, cleaning methods have not been validated.
• Though this deficiency is well redacted it appears to address a water production and distribution system that is not adequately qualified, validated, and monitored to produce water that is suitable for use in the manufacture of drug products.

DRUG | Zhuhai Aofute Medical Technology Co., Ltd

Zhuhai Aofute Medical Technology Co., Ltd (China) received a warning letter on January 9, 2020, based on the outcome of an inspection ending July 18, 2019.  The firm manufactures OTC drug products including “Magic Spray for Pain Relief” which is adulterated, an unapproved new drug, and misbranded—the enforcement trifecta in classification. The firm was placed on Import Alert 66-40 on November 13, 2019. FDA recommends the firm hire a qualified consultant to assist them in coming into GMP compliance. FDA also recommends that the qualified consultant perform a comprehensive audit of the entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of corrective actions and preventive actions before the firm pursues resolution of its compliance status with FDA.

Deficiencies identified include but are not limited to:

• The firm failed to test identity and strength of each lot of product released for distribution. During the audit, staff stated they did not evaluate the suitability of incoming raw materials and components either.
• The firm does not have an independent, effective Quality Unit. For example, they failed to approve or reject all components and materials, failed to review all production and laboratory records, failed to assure adequate batch records and failed to approve procedures and specifications. Further, the firm does not have adequate production and laboratory records, and in fact, no meaningful production records existed. The firm also said they routinely discarded original raw data. And last but not least the Quality Unit was not independent of the manufacturing area.
• The firm has not validated the manufacturing process, nor do they have a process for ongoing monitoring.
• While heavily redacted, the firm seems to have a water system used for cleaning that is not validated and subject to ongoing control and monitoring.

DRUG | Cosmelab Co Ltd

Cosmelab Co Ltd (South Korea) received a warning letter on January 9, 2020, based on the outcome of an inspection ending July 17, 2019. The firm manufactures OTC drug products. FDA placed the firm on Import Alert 66-40 on November 12, 2019. The firm is cited for having firms on their suppliers list who have been placed on Import Alert by FDA. FDA states that “…your use of this supplier on Import Alert 66-40 led to the appearance of adulteration of your drugs.” FDA suggests the firm hire a qualified consultant to assist them in coming into GMP compliance. The warning letter includes only one deficiency, failure to establish an adequate Quality Unit, with multiple examples of failure to comply with GMPs.

The deficiency and examples include but are not limited to:

• The firm failed to establish an adequate Quality Unit. Examples include but are not limited to failure to conduct and review assay tests prior to distribution of drug product, and release of drug product manufactured by a contract manufacturer that is on Import Alert 66-40. Further, the firm being inspected was unaware that their CMO was on Import Alert. FDA stated “…that a lack of understanding of FDA drug regulations contributed to your not establishing a dedicated quality unit. You committed to hire a consultant knowledgeable about FDA regulations.” Note again the FDA asks for an “independent assessment” indicating that they don’t feel the firm is capable of conducting a valid and effective assessment.