- Delivery Method:
- VIA UNITED PARCEL SERVICE
Recipient NameMiriam McKinney
Recipient TitlePresident and Co-Owner
- Vitti Labs, LLC
834 W. Kansas St., Suite C
Liberty, MO 64068
- Issuing Office:
- Office of Biological Products Operations – Division 2
July 28, 2022
Warning Letter #OBPO 22-627699
Philipp R. Vitti
Chief Science Officer and Co-Owner
Christopher Bartalos, DO
Medical Director and Co-Owner
Dear Mr. Vitti, Dr. Bartalos, and Ms. McKinney:
During an inspection of your firm, Vitti Labs, LLC (Vitti Labs), located at 834 W. Kansas St., Suite C, Liberty, MO 64068, conducted between December 6, 2021, and December 20, 2021, the United States Food and Drug Administration (FDA) documented your manufacture of products derived from human umbilical cord, EV-PURE+, WJ-PURE+, and VITTI-PURE, or human amniotic membrane, NS-PURE, and EV-OPTI DROPS (collectively, “your products”) for allogeneic use1. You have distributed your products to third-party distributors, some under private label, and directly to health care professionals and medical facilities for use in patients2. Your products are intended for injection, ophthalmic administration, and/or topical application and purport to be sterile.
Information and records gathered prior to, during and/or after the inspection, including information on your website www.vittilabs.com, reflect that your products are intended for clinical use in humans to treat a variety of diseases or conditions. Therefore, your products are drugs 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)].
Your products are also human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d) and are subject to regulation under 21 CFR Part 1271, issued under the authority of section 361 of the PHS Act [42 U.S.C. 264]. HCT/Ps that do not meet all the criteria in 21 CFR 1271.10(a), and when no exception in 21 CFR 1271.15 applies, are not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Such products are regulated as drugs, devices, and/or biological products under the FD&C Act and/or the PHS Act, and are subject to additional regulation, including appropriate premarket review.
Vitti Labs does not qualify for any exception in 21 CFR 1271.15, and your products fail to meet all the criteria in 21 CFR 1271.10(a). Therefore, your products are not regulated solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271.
Specifically, your umbilical cord derived products, EV-PURE+, WJ-PURE+, and VITTI-PURE, fail to meet the criterion in 21 CFR 1271.10(a)(2) that the HCT/Ps be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent.” These products are not intended to perform the same basic function or functions of umbilical cord in the recipient as in the donor, such as serving as a conduit. Rather, using these products to treat orthopedic diseases or conditions, for example, is not homologous use as defined in 21 CFR 1271.3(c).
In addition, your products fail to meet other criteria set forth in 21 CFR 1271.10(a). Your products fail to meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) and defined for structural tissue in 21 CFR 1271.3(f)(1), because your processing alters the original relevant characteristics of the umbilical cord or amniotic membrane related to their utility for reconstruction, repair, or replacement.
Please be advised that to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an investigational new drug application (IND) in effect as specified by FDA regulations [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]. None of your products are the subject of an approved biologics license application (BLA), nor is there an IND in effect for your products. Based on this information, your actions have violated the FD&C Act and the PHS Act.
Additionally, during the inspection, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210 and 211.
At the close of the inspection, the FDA investigators issued a Form FDA 483 to you listing inspectional observations, which described significant CGMP deviations applicable to your products. FDA identified additional significant deviations upon further review of the information collected during the December 2021 inspection, as discussed below. The CGMP deviations, involving tens of thousands of vials of products manufactured and distributed between July 2020 and December 2021, include, but are not limited to, the following:
1. Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, including procedures for validation of all aseptic and sterilization processes [21 CFR 211.113(b)].
a. The aseptic processes used to manufacture your products have not been validated (e.g., by performing media fill simulations) since your firm’s manufacturing operations began in July 2020. These products purport to be sterile and are expected to be sterile.
b. The (b)(4) sterilization process used for equipment that comes into direct contact with your products has not been adequately validated. For example, you have not defined the optimal parameters and conditions, including the load configuration, for sterilizing equipment such as the (b)(4) used to process your products.
c. You did not establish and follow appropriate written procedures for environmental monitoring. For example:
i. Your action limit for microbiological monitoring of surfaces within the critical area was observed to be greater than (b)(4) colony forming units (CFUs) per “plate & floor” for Biological Safety Cabinets, greater than (b)(4) CFUs per plate for personnel sterile gloves, and greater than (b)(4) CFUs per plate in the supporting cleanroom. Such high numbers of microorganisms could contribute to product contamination and pose a potentially significant safety concern.
ii. Your action limit for non-viable particulates in the supporting cleanroom is greater than or equal to (b)(4) μm particles per m3. Your allowance of such high particulate numbers could contribute to product contamination and pose a potentially significant safety concern.
iii. You have not established alert and action limits for samples collected using settle plates during each processing run.
iv. You do not require microbiological monitoring of operators’ arm coverings used in the critical area for manually processing your products.
v. You do not perform non-viable particulate monitoring, active viable air sampling, or sampling of critical surfaces for microorganisms in association with each production batch.
vi. During the inspection, our investigators documented that personnel don gowning, including sterile sleeves and sterile gloves, in an area that is not environmentally monitored prior to performing aseptic processing in the critical area. This practice increases the risk of introduction of contaminants.
2. Failure to have ceilings of smooth, hard surfaces that are easily cleanable in an aseptic processing area [21 CFR 211.42(c)(10)(i)]. Specifically, during the inspection, our investigators observed unused pieces of equipment, remnants of a surgical suite operated by a previous tenant of your facility, suspended from the ceiling of your cleanroom such that the ceiling and attached, unused equipment is not easily cleanable.
3. Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example, you have not established scientifically sound and appropriate specifications and test procedures to assure that your products conform to appropriate standards of identity, strength, quality, and purity.
4. Failure to establish and follow written procedures for production and process control designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100(a)-(b)]. Specifically:
a. You have not adequately validated the manufacturing processes for your products with respect to identity, strength, quality, and purity. Your validation did not include amniotic membrane processing3. Additionally, your validation for umbilical cord processing only included sterility testing and endotoxin testing as measurements of product attributes.
b. At the time of the FDA inspection, your written procedures for processing your umbilical cord derived products did not reflect your actual practice. The procedures in effect at the start of the inspection indicate that (b)(4) should be removed from the umbilical cord tissue for further processing into your finished products. In contrast, you indicated that your firm’s practice has been to use the entire umbilical cord tissue except for (b)(4).
5. Failure to withhold from use each lot of components, drug product containers, and closures until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit [21 CFR 211.84(a)]. For example, you failed to appropriately test or examine before release for use (b)(4) used in the manufacture of your products and the vials that contain the final product.
6. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use the results of such stability testing to determine appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. Specifically, your firm has assigned a two-year expiration date to your products without adequate data regarding the stability characteristics of the products. For example, the shelf-life study performed, completed September 27, 2021, only included sterility and endotoxin testing as part of the stability protocol.
FDA received your written response, dated January 10, 2022, to the inspectional observations on the Form FDA-483 issued at the conclusion of the inspection, and we have reviewed its contents. The corrective actions described in your response are not adequate to address the above-noted violations. We note that certain of your planned corrective actions cannot be evaluated because of a lack of supporting documentation. Additionally, your response does not address your firm’s continued manufacture and distribution of your products under the violative conditions outlined above or your plans for the disposition of the product inventory you may still have at your facility. We note your products carry a two-year shelf life.
While you assert that your products should be regulated solely under section 361 of the PHS Act, as explained above, the available evidence shows that your products do not meet all the criteria in 21 CFR 1271.10(a) for regulation solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271. Your response also does not adequately address your failure to have an IND in effect to study your products addressed in this letter or your lack of an approved BLA to lawfully market your products. As noted above, to lawfully market a drug that is a biological product, a valid biologics license must be in effect [42 U.S.C. 262(a)]. Such licenses are issued only after showing that the product is safe, pure, and potent. While in the development stage, such a product may be distributed for clinical use in humans only if the sponsor has an IND in effect for that product, as specified by FDA regulations, that covers such clinical use [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312].
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may be associated with your products. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations.
This letter notifies you of our findings and provides you an opportunity to address them. Failure to adequately address these matters may lead to regulatory action without further notice. Such actions include seizure and/or injunction.
For further information about IND requirements, please contact the Center for Biologics Evaluation and Research (CBER), Division of Regulatory Project Management, Office of Tissues and Advanced Therapies, at (240) 402-8190, or OTATRPMS@fda.hhs.gov. Please include a copy of this letter with your initial submission to CBER.
We request that you respond in writing within fifteen (15) working days from your receipt of this letter, outlining the specific steps you have taken or plan to take to address any violations and prevent their recurrence. Include any documentation necessary to show that the matters have been addressed. If you do not believe your products are in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration. If you cannot address these matters completely within fifteen (15) working days, please explain the reason for your delay and the time frame for completion.
Your response should be sent to the following address: Amy Graf, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 2, 300 River Place Dr. – Suite 5900, Detroit, MI 48207 or emailed to Amy.Graf@fda.hhs.gov. If you have any questions, please contact Ms. Graf at (313) 393-2034 or via e-mail.
Karlton T. Watson
Program Division Director
Office of Biological Products Operations – Division 2
1 This letter does not address Vitti’s EV-PURE and WJ-PURE products, which are excluded from any reference to “your products” in this letter.
2 Your umbilical cord derived products are manufactured for private label distributors using the same manufacturing process used for EV-PURE+, WJ-PURE+, and VITTI-PURE. The same instructions for use are provided. EVPURE+ is privately labeled as (b)(4). WJ-PURE+ is privately labeled as (b)(4), (b)(4), and (b)(4). VITTI-PURE is privately labeled as (b)(4), (b)(4), and (b)(4).
3 Your documentation of “Amniotic Membrane Processing Validation” only included (b)(4) batches. According to information you provided during the inspection, (b)(4) is an umbilical cord derived product.