Warning letter due to lacking cleaning validation, stability testing and content determination

Recommendation

23-25 April 2024
Barcelona, Spain

Global Registration and Life Cycle Management for APIs

If different API syntheses are performed in a shared system, it is advisable in case of an FDA inspection to furnish explicit evidence that there is no chance of cross contamination due to the cleaning procedures established. Otherwise, this could lead to a warning letter. When FDA inspectors examined the facility of Chinese API manufacturer Sichuan Friendly Pharmaceutical, they did not only find severe defects regarding the validation of cleaning procedures for the non-dedicated production equipment. The stability testing of active substance batches did not comply with cGMP standards, either. Moreover, the determination of active substance content performed lead to completely false, out of specification (OOS) results. The warning letter published afterwards contained the following details:

Cleaning/Cleaning validation
There were no cleaning validation studies demonstrating that cross contamination could be eliminated beyond doubt. While cleaning runs had been carried out, only parts of the equipment had been cleaned, not the whole production system. They also neglected taking the possible carryover of class 2 and 3 solvents used in various syntheses into consideration. The company further failed to conduct residual solvent testing for intermediates and final products and thereby proving that the relevant limits - especially for potentially toxic class 2 solvents (e.g. chloroform, cyclohexane, methanol, etc.; see guideline ICH Q3C) - were not exceeded. In the company's response, the FDA criticised that there was no risk assessment for all API batches distributed into the USA regarding contamination with residual solvents.

Stability testing
Stability studies using stability-indicating measures in accordance with USP had not been conducted. The testing of retain samples followed the provisions of another pharmacopoeia. For products entering the US market however, the mandatory standards are those of the USP, according to which expiration dates and retesting periods must be determined. The company has therefore been prompted to submit a complete USP compliant stability program including all retain samples of active substance batches distributed to the USA.

Content determination
The Excel spreadsheet used by quality control to release finished product (as well as for the not USP compliant stability tests) had no password protection and no protection for the formulas to calculate release assay results. At closer inspection, the inspector also found the formula to be incorrect. Thereby, many certificates of analysis contained false values. Due to these OOS results of the API content, the batches should not have been released. The QC manager had already admitted to the mistake in the calculation formula during the inspection. The company's response did not address the insufficient procedures for reviewing data and analyses results; furthermore, there had been no information on how data integrity is to be ensured in the future.

Following the FDA warning letter to Sichuan Friendly Pharmaceutical the authority placed the company on Import Alert.