天津达仁堂京万红药业限制 FDA 检查并提交删节文件，获进口警示与警告信

During a March 2024 inspection of a finished drug company in China, FDA investigators Brandy N Lepage and Karen A Briggs encountered company management that limited access to manufacturing areas, disallowed photography, and supplied fewer documents than requested, many of them heavily redacted.

For example, requested batch records for an over-the-counter (OTC) drug product were redacted to exclude critical information such as weights, critical processing parameters, and acceptable ranges.

An FDA request for the list of corrective actions and preventive actions (CAPAs) initiated from 2016 to 2024 resulted in only the 2024 CAPAs being provided.

When the inspection team attempted to take photos of filling machines, “which were observed to be dirty and in an apparent state of disrepair, despite the equipment status being identified as clean,” the request was denied.

Despite these impediments, the March 18 to 22, 2024 inspection of the Tianjin Darentang Jingwanhong Pharmaceutical Co., Ltd., at No. 20 Daming Street, Xiqing, Tianjin, Tianjin, China, revealed serious Good Manufacturing Practice (GMP) violations including inadequate cleaning and validation of production equipment and issues in the lab around method validation and specifications.

As a result of the inspection, an Import Alert (66-40), “Detention Without Physical Examination of Drugs from Firms Which Have Not Met Drug GMPs,” was issued August 19, 2024. While in effect, the import alert will prevent any drug products from the facility from entering the U.S. On October 30, 2024, the firm received an FDA Warning Letter.

A Closer Look at the 483

The four-page 483 issued on March 22, 2024, referenced in the warning letter does not include any statements regarding the company limiting the inspection—those details are contained in the Warning Letter and were likely conveyed to the agency in the Establishment Inspection Report (EIR).

The letter notes that when the inspection team explained that the firm’s failure to provide the requested records or allow photography would be documented as a refusal, “you acknowledged the refusal,” but that refusal is not documented in the 483.

The 483 instead focuses on the GMP issues the investigators were able to discover despite the limitations of what they were able to see and evaluate.

It includes five numbered observations that focus on (GMP) issues. The 483 has not been proactively released by FDA but has been obtained by Redica Systems through a Freedom of Information Act (FOIA) request.

The Redica Quality System Labeling (QSL) model evaluates the language used in inspection document observations and categorizes the deficiencies by quality system and subtopics as appropriate. While a 483 observation has a primary deficiency area, supporting example text can point out secondary shortcomings. Evaluating the secondary text provides valuable actionable insights. In addition, our algorithm communicates the likely severity of each observation as minor, major, or critical.

Our analysis of this 483 reveals the following:

In summary:

• 19 of the 21 observations are classified as Major
• The biggest areas of concern by number of observations are Laboratory (7), Production (6), Quality Unit (4), and Facilities and Equipment (4):

The Warning Letter

The October 30, 2024, Warning Letter states first, pro forma, that it summarizes “significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals,” then continues with sections that include examples of how the firm limited the inspection, including access to records and facilities and refusal to permit photography.

It cites the FDA guidance, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection (June 2024), as the authority for using the inspection limitations to deem the company’s products adulterated.

That guidance finalizes the draft guidance of the same title issued on December 16, 2022, and supersedes the October 2014 guidance entitled, “Circumstances that Constitute Delaying, Limiting, or Refusing a Drug Inspection.” Although the guidance has been around a while, its citation in warning letters has accelerated since the 2022 draft was issued.

The letter also summarizes GMP violations around cleaning and maintaining equipment, a lack of procedures for production and process control, and failure to establish lab control mechanisms, including those related to stability studies, and provides the company with specific action items it needs to complete. It also points out that the FDA’s assessment of the company’s systems and adherence to GMPs were hampered due to the limitations the company placed on the FDA investigators.

Summary

The Redica Systems model identified 19 major deficiencies and two minor ones across four quality systems from a five-item, four-page 483.

While this analysis of the 483 paints a picture of a company with major issues across four quality systems, by itself it would not seem to solidly predict a warning letter, especially since there were no critical deficiencies identified.

However, as shown by the additional detail in the warning letter, the 483 does not tell the entire story of the inspection, a valuable lesson for those who analyze inspection documents.