FDA Warning Letter due to Lack of Validation of the Aseptic Manufacturing Process

In November 2019 and February 2020 respectively, the US-American manufacturer of biological products EUCYT Laboratories LLC received visits from FDA inspectors, who looked at the production of human cellular and tissue-based preparations (umbilical cords, cord blood, amniotic fluid, etc.). They not only found deviations from the regulations of current Good Tissue Practice (cGTP; 21 CFR 1271), but also had to complain about several violations of the basic requirements of Good Manufacturing Practice (cGMP; 21 CFR 211).

As the products of this company all undergo aseptic manufacturing processes, the main risk is the occurrence of non-sterile batches. During their investigation, the inspectors found a high number of non-sterile batches - 152 in a period of 8 months - which is not surprising given the lack of minimum GMP standards.

The Warning Letter to EUCYT describes the following GMP violations:

Validation of aseptic manufacturing processes (21 CFR 211.42; 211.100; 211.113)

The methods used to produce sterile preparations are not validated. There are no instructions for gowning and behaviour in the cleanroom nor is there adequate environmental monitoring. There are also no in-process controls to ensure that product specifications are met.

Cleaning and maintenance (21 CFR 211.67)

Cleaning protocols for the sterile workplaces and their maintenance are not available and the cleaning procedures are not validated. As a result, there is no rationale for the use and sequence of the various cleaning agents; in some cases cleaning agents are used whose expiry date has already passed.

Incoming goods inspection; release / rejection (21 CFR 211.80)

Written instructions for the initial testing of materials (umbilical cords, cord blood, etc.) are not available, nor is a detailed description of the criteria for release or rejection in place.

Deviations and root cause analysis (21 CFR 211.192)

In the case of the non-sterile batches, the microorganisms were identified, but the cause for this was not clarified. Corrective and preventive measures were not taken.

Stability assessment (21 CFR 211.166)

A 2-years expiration date is declared for a number of products. However, there is a lack of data from stability tests to support this time limit.

Batch records (21 CFR 211.188)

Although there exists an SOP for the individual steps of the aseptic production process, documentation on these steps with details of times is missing.

Complaint management and penicillin cross-contamination (21 CFR 211.198; 211.176)

The company has no procedural instructions for documenting and investigating complaints. Penicillin is used in the manufacture of some products. According to cGMP, evidence must be provided that there is no cross-contamination with other penicillin-free preparations. This evidence is missing.

This Warning Letter not only describes the violations of cGTP and cGMP, but also criticizes that the company promotes one of its exosome products as effective for the treatment of COVID-19. Several adverse reactions have already been reported for this unauthorised drug. In the Warning Letter, the FDA explicitly refers to its announcement on the safety of exosome products.