Warning Letter caused by incomplete Impurity Profiles

In January 2025, the U.S. FDA issued a Warning Letter on its website to the Indian company "Global Calcium Pvt. Limited" after having inspected its site in July / August 2024.

The significant violations of CGMP regulations for active pharmaceutical ingredients (APIs), which are mentioned in the Warning Letter, are listed as follows:

• "Failure of your quality unit to prepare, review, and approve documents related to the manufacturing of APIs in accordance with written procedures."
• "Failure to properly maintain buildings and facilities used in the manufacture of APIs."
• "Failure to establish an impurity profile for identified and unidentified impurities."

Especially, the third observation mentioned in the Warning Letter is related to the lack of evaluation of impurities - also during the stability studies. It is additionally listed that the manufacturer failed to do a "retrospective risk assessment for distributed APIs with incomplete impurity profiles". According to the ICH Q3A guideline, section 3.1 "…the applicant should summarise the laboratory studies conducted to detect impurities in the new drug substance. This summary should include test results of batches manufactured during the development process and batches from the proposed commercial process, as well as the results of stress testing (see ICH Guideline Q1A on Stability) used to identify potential impurities arising during storage." This observation caused a long list of actions requested to be done by the company.

Coming to the final conclusion mentioned in the Warning Letter, the U.S. FDA highly recommended to appoint a consultant to ensure that the company will be CGMP compliant from now on. Additionally, related to the first observation mentioned in the Warning Letter, a long list of Data Integrity remediation activities and CAPA measurements are requested. Since end of December 2024, the U.S. FDA put the products of the facility on import alert for the United States. New applications or supplements of the company may be withheld, until the U.S. FDA confirms the compliance of the facility with CGMP. A reinspection could be possible.

To view the complete list of violations and the conclusion given by the U.S. FDA, please see the Warning Letter Global Calcium Pvt. Limited.