FDA 483 - Alvotech HF - September 17, 2024

During an inspection conducted from September 9-17, 2024, the U.S. Food and Drug Administration (FDA) issued a Form 483 to Alvotech HF, a biological drug substance and product manufacturer located in Reykjavik, Iceland. This document outlines significant observations regarding the firm"s quality systems and adherence to regulatory standards.

The FDA noted deficiencies in the responsibilities and procedures of the company"s Quality Unit. Specifically, the Quality Unit failed to implement adequate controls to ensure the quality of distributed drug products. Investigations into nine complaints between March 2023 and August 2024, which identified a root cause for product issues, did not prevent the continued release of affected batches based on a risk assessment that concluded minimal patient harm. Furthermore, a Biological Product Deviation Report was not submitted for a critical defect that could render the drug unusable by patients.

Additionally, the firm failed to thoroughly investigate unexplained discrepancies, particularly around approximately 100 invalidated endotoxin tests for in-process and drug substance/product samples from January 2022 to August 2024. Out-of-specification results, attributed to factors like analyst error, contamination, and cartridge defects ("hot wells"), lacked conclusive evidence to support their invalidation. Investigations also did not clearly document implemented corrective actions. The Quality Unit also failed to engage with the cartridge supplier to resolve the recurring "hot wells" issue, impacting the reliability of critical quality tests.

These observations highlight a need for Alvotech HF to implement robust corrective and preventive actions to ensure compliance with good manufacturing practices, thereby safeguarding product quality and patient safety.