Warning Letter to Chinese API Manufacturer

Inadequate Analytical Test Methods and Specifications

According to the FDA, the lack of a scientific basis for the analytical test methods and specifications was a major deficiency. For example, the manufacturer used test methods for impurities based on the Chinese Pharmacopeia without demonstrating that they were equivalent to or better than the methods of the United States Pharmacopeia (USP). In addition, the specified limits for individual and total impurities exceeded the USP specifications.
The FDA is particularly critical regarding the fact that one batch exported to the USA actually exceeded the USP limits. The FDA is demanding that all retained samples of API batches delivered to the USA be checked to ensure that they fulfil the US quality requirements. The manufacturer must also provide a risk analysis for products already in circulation, including possible recalls.

Inadequate Cleaning for Multipurpose Production Facilities

According to the FDA, the deficiencies identified in the area of cleaning procedures for non-dedicated production equipment are particularly serious. The manufacturer uses the same equipment for the production of various APIs, but the effectiveness of the cleaning was only assessed by visual inspection and no analytical or microbiological tests were carried out. There was also a lack of clear acceptance criteria for residues and a systematic worst-case assessment with regard to potentially poorly soluble, toxic or difficult-to-purify APIs. The FDA is calling for a fundamental revision of cleaning validation, whereby worst-case scenarios in particular must be taken into account. This includes the identification of substances that are difficult to remove, the selection of suitable sampling points for testing the cleaning process and the definition of maximum holding times before cleaning. The FDA also requires that the manufacturer establish a change management system to ensure that new production equipment or products are only introduced after proper cleaning validation. As with point 1, the FDA requires a risk assessment that considers potential cross-contamination for APIs that have already been exported to the US.

Insufficient Stability Data

Another critical deficiency was identified in the area of quality control. The manufacturer's quality department was unable to provide sufficient stability data to support the shelf life of its products.
As a direct result of these violations, the FDA placed the company on the Import Alert 66-40 list, which means that no more products may be imported into the USA. The FDA also emphasises that the deficiencies identified indicate fundamental deficiencies in quality management. The FDA recommends that the API manufacturer engage an external GMP consultant to conduct a comprehensive compliance assessment and implement sustainable corrective actions.

The Warning Letter to the Chinese manufacturer can be found on the FDA website.