FDA issues Warning Letter to Manufacturer of Human Cells, Tissue or Cell based Products

During an inspection at Cord for Life, Inc. in November 2018, the FDA determined that the company processes cellular products from human umbilical cord blood for allogeneic applications. The products are then distributed and sold, also through third parties. The instructions for use show that these products were intended for both application and injection to/on patients. In the manufacturer's product documentation, the products are referred to as "regenerative products" or "regenerative medicine" which are intended for "therapeutic purposes", for example to treat orthopaedic diseases.

Fundamental deficiencies

Because of this application, these products are pharmaceuticals within the meaning of the Federal Food, Drug, and Cosmetic Act and biological products within the meaning of the Public Health Service Act (PHS Act).  Since these are also human cells, tissues or cellular or tissue-based products (HCT/Ps), they also fall under the provisions of 21 CFR 1271.3(d). However, the company does not have the appropriate exemption to have the products regulated exclusively under Section 361 of the PHS Act and the provisions of 21 CFR Part 1271 - and these do not meet the necessary criteria in all respects. In addition, the claims for therapeutic use in orthopaedic conditions do not meet the criteria for homologous use, as the cord blood products are not intended to perform the same basic function or functions of cord blood in the recipient as in the donor.

This results in a regulation according to the specifications for medicinal products and biological products. Accordingly, a valid license is required for the distribution of biologics. However, this can only be granted once the safety and efficacy of the product has been proven, or for clinical use when a corresponding application for approval of a new investigational product (IND) has been submitted. However, the umbilical cord blood products are not the subject of an approved license application for biologics (BLA) nor is there an IND classification. Accordingly, this is a violation of the existing laws.

Deviations in production

In addition to these fundamental failures, the FDA inspectors documented significant deviations from the current Good Manufacturing Practice (GMP) during the inspection. The FDA stated: "The deviations observed in the manufacturing processes and the deviations noted in the documents collected during the inspection indicate that the use of your products raises potentially significant safety concerns. For example, Cord for Life's untested manufacturing processes, uncontrolled environment, and inadequate aseptic practices of personnel, as described below, pose a significant risk that your products may be contaminated with microorganisms or have other serious quality defects."

The following deficiencies were listed:

• No written determination and application to prevent microbiological contamination
• In spite of the claim of sterile products, no validation of the aseptic processes took place.
• Inadequate personnel behaviour that carries the risk of microbiological contamination, e.g. no change of gloves, no change of clothes, no hoods, masks, glasses, use of non-sterile gloves
• Poor handling of open product in/at the sterile workbench
• Missing Variance Management in Personnel Monitoring
• Inadequate and/or faulty environmental monitoring and non-compliant monitoring limits
• Lack of written definition of cleaning and maintenance requirements and non-valid cleaning processes
• Absence of written procedures for production and process control
• Inadequate laboratory controls
• Missing product specifications
• Inadequate testing for sterility
• Insufficient stability control measures/procedures

As the company has not presented substantial evidence so far that one of the proposed corrective measures has been implemented since the inspection with the documented deviations, the FDA's CBER Warning Letter to Cord for Life now followed.