Threat to Patient Safety leads to FDA Warning Letter

The Warning Letter describes the FDA's inspection of Berkeley Biologics, LLC, which took place in September 2023 and identified serious violations of regulatory requirements. These violations relate to the manufacture and distribution of products derived from human bone tissue used in orthopaedic and reconstructive surgery. The main deviations identified include:

Non-compliance for human cell, tissue or cell-based products (HCT/Ps)

• Berkeley Biologics' products did not meet the required criteria under 21 CFR 1271.10(a). Specifically, the processing of the products was found to alter the original properties of the tissue, which means that the minimal manipulation requirements are not met. This affects the structural functions of the cartilage, such as strength, flexibility and resistance to deformation.
• In addition, the products were combined with other materials in violation of regulations stating that HCT/Ps may not be combined with any substance other than water, crystalloids or a sterilising, preservative or storage agent.

Violations of the regulations for Good Tissue Practice and Good Manufacturing Practice (CGMP)

The inspection uncovered that the company's procedures and controls for manufacturing the products did not meet CGMP requirements. This resulted in the products being considered 'contaminated'. The inspection revealed several specific violations:

• Donor eligibility: The company failed to classify donors with a documented risk of sepsis as unsuitable. Several donors who had a medical diagnosis of sepsis were found to have been used in the manufacture of products that were later distributed to medical facilities. This is particularly serious as some of these products have been linked to an outbreak of Mycobacterium tuberculosis infections.
• Production and process controls: The company has not established adequate written procedures to ensure that the products have the claimed characteristics of identity, strength, quality and purity. For example, qualification of the production processes identified several batches that did not meet the acceptance criteria for sterility. In addition, the manufacturing processes were not fully validated, which means that the safety and efficacy of the products is not guaranteed.
• Aseptic processes: Deficiencies were found in the system for preventing contamination and mix-ups during aseptic manufacturing. These included that the limits for microbiological monitoring in critical areas were too high and that insufficient sampling of critical surfaces and adequate monitoring of personnel was carried out.
• Laboratory controls: The company's laboratory procedures were inadequate to ensure that products met the required standards. In particular, testing was limited to sterility testing, which is insufficient to ensure the identity, strength, quality and purity of the products. In addition, samples were frozen prior to sterility testing, which could affect the reliability of the results.

Lack of authorisations

Berkeley Biologics also does not have the necessary regulatory approvals to market its products as medicinal products or biologics. It lacks both an approved Biologics Licence (BLA) and an Investigational New Drug Application (IND), which are required to legally market these products.

Read the full Warning Letter on the FDA website.