Warning Letter for Manufacturer of HCT/P Products

During an inspection of Pinnacle Transplant Technologies LLC in August 2022, the FDA found that the company's products made from amniotic membranes and amniotic fluid and intended for injection are considered medicinal and biological products. These products, in particular PalinGen, are advertised for the treatment of wounds and tissue regeneration and therefore fail to meet the requirements for so-called HCT/P products, which are only authorised for homologous uses.

Deficiencies found

The inspection also revealed several serious violations of Good Manufacturing Practice (CGMP) regulations, such as insufficient validation of aseptic processes, inadequate laboratory standards and a lack of investigations into quality deviations.

These deficiencies include:

• Inadequate validation of aseptic processes:
  Pinnacle did not adequately validate aseptic manufacturing processes for units of PalinGen® and PalinGen® products. Specifically, media fill simulations did not follow commercial manufacturing processes and critical manufacturing steps were not simulated during validations. This is problematic as the products are advertised as sterile and therefore sterile manufacturing processes are expected. 
• Inadequate laboratory standards:
  Pinnacle failed to establish appropriate laboratory controls to ensure that the products met the required specifications for identity, strength, quality and purity. The products tested were only analysed for sterility and endotoxins without further testing for identity or strength. 
• Failure to investigate quality deviations:
  Between July 2020 and February 2022, the company failed to thoroughly investigate eight cases of sterility failure. Although the contaminating organisms were identified, there was no investigation into the cause of the failures or preventative measures. 
• Inadequate monitoring of environmental conditions:
  Pinnacle did not establish adequate systems to monitor environmental conditions in aseptic processing areas. Sampling points for monitoring microbiological risks were not positioned in critical locations where there was the greatest risk of contamination. For example, passive sampling points were positioned in non-critical locations. 
• Inadequate cleaning and disinfection of cleanrooms:
  Pinnacle did not validate the effectiveness of the disinfectants used to clean the cleanrooms. Without this validation, it cannot be demonstrated that the disinfection measures are sufficient to ensure aseptic conditions. 
• Poor maintenance of equipment:
  The HEPA filters used in the cleanrooms to aseptically process products were not maintained at the required intervals. Despite evidence of a significant leak in a HEPA filter during a test, the company did not take adequate measures to ensure the safety and cleanliness of the products.

Reasoning for the Warning Letter

The deficiencies had already been listed in a 483 letter and the firm had taken actions to correct them. However, the FDA did not consider them sufficient. The FDA writes: "We have reviewed the corrective actions outlined in the response, and we have determined that the corrective actions are inadequate to address our concerns. For example, even though you have added the missing manufacturing steps to the process simulations, the use of a sterile substitute for the tissue does not accurately represent real-world situations or the worst-case scenario for potential cross-contamination of the processing area. Further, you performed a retrospective analysis of sterility failures, which showed a correlation between sterility failures and pre-processing cultures, but you did not investigate this correlation."

In addition, the FDA raised concerns about another Pinnacle product that also does not meet regulatory requirements. Further details can be found directly in the FDA's Warning Letter.