Warning Letter in the Area of Allogenic Umbilical Cord and Amniotic Membrane Products

Based on an FDA inspection in December 2021, the company Vitti Labs, LLC (Vitti Labs), received a Warning Letter. The company distributes allogeneic umbilical cord and amniotic membrane products to third party suppliers, partly under its own label. It further supplies these products directly to health care professionals and medical institutions for use in patients. The products are used as injections or for ophthalmic administration and/or topical application and are therefore supposed to be sterile. The FDA determines that the products are medicinal products as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)].

Because Vitti's products are also human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d), they are regulated as medicinal products, devices, and/or biological products under the FD&C Act and/or the PHS Act and are subject to additional regulations, including appropriate premarket testing. At the same time, Vitti Labs' products also do not qualify for any of the exemptions in 21 CFR 1271.15.

Specifically, the marketed umbilical cord-derived products do not meet the criterion in 21 CFR 1271.10(a)(2), for homologous use. They are not intended to perform the same essential function(s) of the umbilical cord in the recipient as in the donor, such as serving as a conduit. Rather, the use of these devices to treat orthopaedic diseases or conditions, for example, is not a homologous use within the meaning of 21 CFR 1271.3(c). Similarly, the requirements for minimal manipulation/processing defined for so-called structural tissue do apply, as the processing alters the original relevant properties of the umbilical cord or amniotic membrane in terms of their usability for reconstruction, repair or replacement.

To date, none of the products has the necessary biologics licence nor has an Investigational New Drug Application (IND) been submitted in accordance with FDA regulations.

In addition to the aforementioned deviations with regard to applications for approval, the Warning Letter also lists a whole series of deviations from the requirements of current good manufacturing practice (CGMP). The identified CGMP deviations, which affect tens of thousands of vials of products manufactured and distributed between July 2020 and December 2021, include the following:

• Lack of procedures and measures to prevent microbiological contamination of the purportedly sterile products including validation of all aseptic and sterilisation procedures, i.e. no process simulations, inadequate environmental monitoring, lack of alarm and action limits and lack of particle monitoring. 
• The lack of ceilings with smooth, hard and easy-to-clean surfaces in an aseptic processing area. 
• The failure to establish laboratory controls that include scientifically sound and adequate specifications, standards, sampling plans, and testing procedures to ensure that ingredients, drug product containers, closures, in-process materials, labelling, and drug products meet the appropriate standards for identity, strength, quality, and purity [21 CFR 211.160(b)]. 
• Failure to establish and follow written production and process control procedures designed to ensure that drug products have the identity, strength, quality, and purity they purport or represent [21 CFR 211.100(a)-(b)]. Specifically: Lack of process validation with respect to identity, strength, quality and purity. In addition, the written procedures for processing umbilical cord products differed from the actual practice performed. 
• Release prior to all necessary test results being available. 
• Lack of stability testing programme

The FDA received a written response to the issued 483 in January. However, the corrective actions described therein were not sufficient to address the above violations. In addition, some documentation was not as complete, making it impossible to evaluate the actions taken. Furthermore, information was missing on how to proceed with the remaining product stock or how to proceed with manufacturing and distribution.

For more detailed information please see the FDA's Warning Letter to Vitti Labs, LLC.