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Dear Ms. Panah and Mr. Kosolcharoen,

During the inspection of your firms Liveyon Labs Inc. (Liveyon Labs) and Liveyon LLC, co-located at 22667 Old Canal Road, Yorba Linda, CA 92887, conducted between May 13, 2019 and May 23, 2019, the Food and Drug Administration (FDA) documented that Liveyon Labs processes human umbilical cord blood derived cellular products PURE® and PURE PRO® for allogeneic use (hereinafter, “umbilical cord blood products” or “products”). The products are marketed and distributed, among other responsibilities, by Liveyon LLC. The route of administration for the umbilical cord blood products includes intra-articular injection.

Information and records gathered at the time of and after the inspection, including product labeling and information on the Liveyon LLC website, https://liveyon.com, reflect that your products are intended to treat a variety of orthopedic conditions. Therefore, your products are drugs as defined in section 201(g) of the Federal Food, Drug, and Cosmetic Act (the 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)]. They are also human cell, tissue, or cellular or tissue-based products (HCT/P) as defined in 21 CFR 1271.3(d)1 and are subject to regulation under 21 CFR Part 1271, issued under authority of section 361 of the PHS Act [42 U.S.C. 264]. However, Liveyon Labs does not qualify for any exception in 21 CFR 1271.15, and the 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, the umbilical cord blood products fail to meet the 21 CFR 1271.10(a)(2) criterion 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.”2 As noted above, the umbilical cord blood products are intended to treat a variety of orthopedic conditions. Because the umbilical cord blood products are not intended to perform the same basic function or functions of umbilical cord blood in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system, using the umbilical cord blood products to treat orthopedic conditions is not homologous use as defined in 21 CFR 1271.3(c).

In addition, the umbilical cord blood products fail to meet the criterion set forth in 21 CFR 1271.10(a)(4). Specifically, the products, manufactured from donated umbilical cord blood, are dependent on the metabolic activity of living cells for their primary function and are not for autologous use, allogeneic use in a first-degree or second-decree blood relative, or reproductive use.

As stated above, because your products do not meet all the criteria in 21 CFR 1271.10(a), and Liveyon Labs does not qualify for any exception in 21 CFR 1271.15, the products are regulated as drugs as defined in section 201(g) of the FD&C Act [21 U.S.C. 321(g)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. 262(i)]. 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); and 21 CFR Part 312]. The umbilical cord products are not the subject of an approved biologics license application (BLA) nor is there an IND in effect. Based on this information, we have determined that 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) and current good tissue practice (CGTP), including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210, 211, and 1271. The deviations in manufacturing processes observed as well as those noted in documents collected during the inspection indicate that the use of your products raises potential significant safety concerns. For example, Liveyon Lab’s deficient donor eligibility practices, inadequate aseptic practices, and deficient environmental monitoring, as described below, pose a significant risk that your products may be contaminated with microorganisms or have other serious product quality defects.

At the close of the inspection, FDA investigators issued a Form FDA 483 to Erin M. Sairafe, Chief Compliance Officer for both Liveyon Labs and Liveyon LLC, listing inspectional observations, which described a number of significant deviations from CGMP and CGTP. FDA has found additional significant deviations upon further review of the information collected during the May 2019 inspection, as discussed below. The deficiencies include, but are not limited to, the following:

1. Failure to screen a donor of cells or tissues by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases [21 CFR 1271.75(a)]. Since operations began in January 2019, Liveyon Labs has processed cord blood units from (b)(4) donors supplied by (b)(4), located in (b)(4), and cord blood units from (b)(4) donors supplied by (b)(4), located in (b)(4). For example:

a. FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s), must indicate that a potential donor is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility. The “DT-001 Form 1 Recovery Site Assessment” received from cord blood supplier (b)(4) did not adequately assess a donor’s residence in, or travel to, areas identified by the Centers for Disease Control and Prevention with active ZIKV transmission. We recommend that you review FDA Guidance for Industry, Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products (updated May 2018), available at https://www.fda.gov/downloads/biologicsbloodvaccines/guidancecomplianceregulatoryinformation/guidances/tissue/ucm488582.pdf.

b. The “DT-001 Form 4 Donor Risk Assessment Interview” received from cord blood supplier (b)(4) did not indicate if the donor has been diagnosed with Creutzfeldt-Jacob disease (CJD) or variant Creutzfeldt-Jacob disease (vCJD).

2. Failure to test donor specimens using appropriate FDA-licensed, approved or cleared donor screening tests, in accordance with the manufacturer’s instructions, to adequately and appropriately reduce the risk of transmission of relevant communicable disease agents or diseases [21 CFR 1271.80(c)]. Specifically, Liveyon Labs tested (b)(4) umbilical cord blood donors for ZIKV with a test that was not FDA licensed, approved, or cleared for HCT/P donor screening. Liveyon Labs relied on such tests, which is not appropriate to prevent the introduction, transmission, or spread of ZIKV through HCT/Ps.

3. Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR 211.113(b)]. For example:

a. Liveyon Labs failed to adequately validate the aseptic process used to manufacture your PURE® and PURE PRO® products since operations began in January 2019. By the nature of their routes of administration, your products purport to be sterile and are expected to be sterile. The media fill batch sizes used for your validation study LL-VAL-004, entitled “Validation of Aseptic Processing of the PURE® Product”, did not represent the maximum commercial batch size. The study utilized (b)(4) vials per batch, however batches were observed to be manufactured with up to (b)(4) vials.

b. Liveyon Labs processed cord blood units from two different donors (b)(4). This practice, which you refer to as (b)(4) processing”, is considered high risk and significantly increases the potential for cross-contamination and mislabeling. Since manufacturing operations began in (b)(4), you (b)(4) processed (b)(4)% of your (b)(4) batches. In addition, you failed to track which batches have been processed (b)(4) potentially failing to identify contaminated umbilical cord blood product if one of the batches failed sterility or was processed using cord blood from an ineligible donor.

c. The gowning procedure LL-QA-014, entitled “Gowning Qualification Program,” has not been implemented. Appropriate gowning reduces the potential for the manufacturing personnel to inadvertently contaminate the product during the aseptic manufacturing process.

d. Liveyon Labs used a non-sterile (b)(4) and the associated non-sterile (b)(4) to manufacture approximately (b)(4) batches of your products between January 16, 2019 and May 20, 2019, raising the potential for microbiological contamination. This (b)(4) and (b)(4) are labeled “For research use only.”

4. Failure to thoroughly investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications, [21 CFR 211.192]. For example:

a. From January 16, 2019 to May 20, 2019, Liveyon Labs failed to thoroughly investigate 15 sterility failures and batches processed with cord blood units from ineligible donors:

i. You identified the contaminating organism(s) for your sterility failures but destroyed these batches without initiating/conducting an investigation using FORM-LL-037, entitled “Positive Sterility or EM Failure-Root Cause Analysis”.

ii. You processed cord blood units from ineligible donors and destroyed the final product batches from donors who tested positive for relevant communicable diseases without conducting an investigation. During this time period, donors tested positive for ZIKV, Hepatitis B, and syphilis.

iii. Despite (b)(4) processing (b)(4)% of your cord blood units, your investigations failed to extend to the (b)(4) processed batches. During this time period, your firm did not fail or destroy two batches manufactured on the same day due to positive sterility or infectious disease testing results.

iv. Your firm did not implement corrective or preventive actions.

b. Liveyon Labs failed to thoroughly investigate five in-process BSC settling plates failures. Three of the five settling plates were positive for P. glucanolyticus. The root cause and source of the contaminating organisms was not identified. No corrective actions were implemented, and four impacted in-process batches were subsequently distributed. In addition, you failed to use FORM-LL-037 to formally initiate and document your investigation.

 

Date of Failure	Lot Number	Organism	CFUs from raw EM Data	Date Shipped	Number of Vial Distributed
1/22/19	(b)(6)	Paeniebacillus glucanolyticus	TNTC	2/11/19	(b)(4)
2/25/19	(b)(6)	No organism identified	1+	3/12/19	(b)(4)
3/11/19	(b)(6)	Paeniebacillus glucanolyticus	1+	4/3/19	(b)(4)
4/22/19	(b)(6)	Staphylococcus warneri	1+	5/2/19	(b)(4)

 

5. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. For example:

a. Liveyon Labs failed to conduct surface and active air environmental monitoring from January 20 to February 16, 2019. During this time, (b)(4) vials of umbilical cord blood products were manufactured and subsequently distributed.

b. Surface monitoring is not conducted in the BSC for each fill. Such monitoring is only conducted (b)(4) for surface sampling despite the manufacturing of (b)(4) lots per day.

c. From February 9 to February 13, 2019, Liveyon Labs used contact (b)(4) plates as settling (b)(4) plates to monitor the BSCs during each fill when your firm no longer had any settling plates in stock. Contact plates are not an appropriate substitute for settling plates, as they are intended to recover organisms through direct contact with surfaces and not passive air sampling. During this time, (b)(4) lots were manufactured, totaling (b)(4) final product vials. (b)(4) vials were distributed without any environmental monitoring data demonstrating control of the immediate manufacturing environment.

d. Liveyon Labs failed to accurately record the number of colony-forming units (CFUs) for each positive settling plate:

i. The number of colonies were not counted if greater than 1 and marked as “1+”. Additionally, “1+” was inaccurately recorded as 1 CFU in the “Positive Sterility and EM Log”.

ii. The CFUs for lot number (b)(6) were noted as too numerous to count (TNTC) in the raw environmental monitoring data, however it was recorded officially as “1+” CFUs in the “In-Process EM Data” and 1 CFU in the “Positive Sterility and EM Log”.

6. Failure to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. Specifically, your validation LL-VAL-010, entitled “Validation of Biological Safety Cabinet Cleaning”, v1, failed to challenge your procedures and cleaning agents to determine efficacy.

7. Failure to establish written procedures for production and process controls 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)]. Specifically, the Liveyon Labs SOP LL-LAB-004v1, entitled “PURE Product Production”, failed to assure that the (b)(4) containers used during the manufacture of approximately (b)(4) batches of your products between January 16, 2019 and May 20, 2019, did not alter the final product identity, strength, quality, and purity. These containers are labeled “For research use only. Not intended for diagnostic or therapeutic procedures.”

8. 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, the following components were not tested before release:

a. (b)(4) used in association with the (b)(4) to remove the red blood cells from the umbilical cord blood.

b. (b)(4) used in the manufacture of your products.

9. Failure to establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)]. Your complaint procedure LL-QA-015, entitled “Product Complaint” is not followed and is inadequate:

a. Step 3.1 states that “Customer Service and Sales department shall inform Quality Assurance department of any complaint and shall provide pertinent information to allow QA to perform investigation.” In addition, step 3.4 states “Quality Assurance shall record, review, investigate and close product complaints.” However, you failed to follow this procedure. All complaints are forwarded directly to the Chief Compliance Officer (CCO) of Liveyon LLC/Liveyon Labs for logging into the Liveyon LLC complaint system prior to routing to Liveyon Labs QA for logging into the Liveyon Labs complaint system, which initiates the investigation. Complaint closure is also performed by the CCO of Liveyon LLC/Liveyon Labs instead of Liveyon Labs QA.

b. Your procedure fails to include a timeframe for complaint submission to QA by the Customer Service and Sales department or other Liveyon staff, potentially delaying QA notification and investigation.

c. Step 3.4 states that “investigations shall be initiated on the day information is received by QA.” However, complaint investigations were not initiated on the day of receipt by QA. For example:

i. Complaint C-19-001 was received on April 26, 2019, forwarded to QA on the same day, and QA did not commence their investigation until May 1, 2019.

ii. Complaint C-19-003 was received on March 7, 2019, forwarded to QA on the same day, and QA did not commence their investigation until May 1, 2019.

We received Liveyon Labs’ written response, dated June 12, 2019, to the inspectional observations on the Form FDA 483, and we have reviewed its contents. FDA acknowledges Liveyon Labs’ decision to cease the receipt of umbilical cord blood from (b)(4), located in (b)(4). We also acknowledge the other corrective actions you have taken in response to the observations. However, the response does not provide sufficient detail to fully assess the adequacy of your corrective actions to date and lacks copies of any updated procedures or additional documents to demonstrate that you have corrected the deficiencies noted in the inspectional observations. Nor did you commit to providing any follow-up response(s) to address any corrective actions once implemented. We recommend that you review the violations listed above, consider the potential serious risks to patients your manufacturing violations present, and consult with third-party experts to implement comprehensive corrective action.

Your response also does not address your continued failure to have an IND in effect to study your products, nor your lack of an approved BLA to lawfully market your products. As noted above and in the FDA Warning Letter issued on November 29, 2018, to your former contract manufacturer Genetech, Inc. with a copy to Liveyon LLC and Mr. Kosolcharoen, 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 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]. The umbilical cord products are not the subject of an approved BLA nor is there an IND in effect for your products.

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 exist at your facility. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations.

You should take prompt action to correct these violations. Failure to promptly do so may result in regulatory action without further notice. Such actions include seizure and/or injunction.

For further information about IND requirements for biological products, 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 correct the noted violations and prevent their recurrence. Include any documentation necessary to show that correction has been achieved. 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 complete all corrections within fifteen (15) working days, please explain the reason for your delay and the time frame within which the remaining corrections will be completed.

Your response should be sent to the following address: Daniel W. Cline, Compliance Officer, U.S. Food and Drug Administration, 19701 Fairchild, Irvine, CA 92612 or emailed to Daniel.Cline@fda.hhs.gov. If you have any questions, please contact Mr. Cline at (949) 608-4433 or via e-mail.

Sincerely,
/S/
Karlton Watson
Program Division Director
Office of Biological Products Operations - Division 2

• 1HCT/Ps are defined as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” 21 CFR 1271.3(d).
• 2Under 21 CFR 1271.3(e), manufacture means, but is not limited to, any or all steps in the recovery, processing, storage, labeling, packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor. Because both Liveyon Labs and Liveyon LLC manufacture the umbilical cord blood products, within the meaning of 21 CFR 1271.3(e), FDA considered both firms’ objective intent in evaluating whether the products are “intended for homologous use only” under 21 CFR 1271.10(a)(2).