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  1. Warning Letters

WARNING LETTER

Neobiosis, LLC MARCS-CMS 662985 —


Delivery Method:
VIA UPS
Product:
Biologics

Recipient:
Recipient Name
Ian A. White, Ph.D.
Recipient Title
President, Chief Executive Officer and Co-owner
Neobiosis, LLC

305 SW 7th Terrace
Gainesville, FL 32601-6458
United States

Issuing Office:
Division of Biological Products Operations I

United States


WARNING LETTER

June 5, 2024

24-662985

Dear Dr. White:

During an inspection of your firm, Neobiosis, LLC (hereinafter, “Neobiosis”), located at 305 SW 7th Terrace, Gainesville, FL 32601-6458, conducted between January 23, 2023, and February 21, 2023, the United States Food and Drug Administration (FDA) documented that you manufacture products derived from human amniotic fluid and umbilical cord. Specifically, your firm manufactures an amniotic fluid product, Purified Amniotic Fluid (PAF), as well as human umbilical cord derived products, Wharton’s Jelly Cellular and Wharton’s Jelly Acellular,1 (hereinafter, “your products” and “your amniotic fluid and umbilical cord derived products”). Your products are intended for allogeneic use.

Your firm has sold and distributed these products directly to customers, including, but not limited to, third-party distributors, medical centers, pain clinics, wellness centers, and physicians, throughout the (b)(4). You told FDA investigators that your products are sold to physicians for research purposes. However, you have not distributed your products in accordance with the requirements for clinical investigations under 21 CFR part 312.

Unapproved Drug and Biological Product Violations
Your amniotic fluid and umbilical cord derived products lack specific information regarding administration and indications for use in their labeling, and you told FDA investigators that your firm does not promote or suggest any intended use of their products. However, based on statements on your Facebook page, YouTube channel, and in public interviews, you intend your amniotic fluid and umbilical cord derived products for uses including wound healing and orthopedic uses. For example, your slide presentation found on Neobiosis’ YouTube channel touting the healing benefits of your amniotic fluid product that you gave at the grand opening of one of your facilities in Alachua, Florida (posted to your YouTube channel, https://www.youtube.com/watch?v=Kh3shqh0HRw, titled, “Neobiosis Grand Opening Highlights,” last visited May 2024) states:

“[T]hey called me and said is there anything we can do and I said put the product in a spray bottle and spray it all over her legs and just keep doing that until you run out of product…it’s like something just erased the injuries…her doctors were floored by her progress never seen wounds heal so quickly.”

Further, you shared a patient’s post on your Facebook page (https://www.facebook.com/NeoCyte/, last visited May 2024) praising their results from Neobiosis’ amniotic fluid treatment that states:

“…I was being donated Purified Amniotic Fluid to aid in my wound healing process…After my first round, I was able to completely come off of my opioid pain medication. I had made drastic healing progress in just 24 hours…I am beyond grateful to all of those at IMG and Neobiosis who have helped give me my life back.”

You also gave an interview in your capacity as President and CSO of Neobiosis to Longevity Technology (see “Ian White: ‘We’re right on the precipice of fundamental changes in longevity research,’” at https://www.youtube.com/watch?v=fwhQX2nX6LM?, last visited May 2024), in which you state, with respect to your amniotic fluid and umbilical cord derived products:

“I now have a CDMO, which is a contract development and manufacturing organization, where we contract for the manufacturing of perinatal tissues – everything from amniotic fluid to cord to cord blood, placenta tissue as well, because what we realized very early on is that these young tissues have the ability to transplant, the ability to heal…”

“… this is a very light process, but it still renders the entire cord, which means it liquifies the cord essentially, and from that we’re able to extract the Wharton’s Jelly without damaging it, because mostly Wharton’s Jelly is an extracellular matrix and we really want to preserve that integrity so that when it’s used for orthopedic uses or for any other soft tissues…”

We also note that the package inserts for your amniotic fluid and umbilical cord derived products state, “Federal law requires this product to be sold by or on the order of a licensed health professional (e.g., physician).”

This information indicates that your products are intended for use in the treatment or prevention of disease or conditions and to affect the structure or function of the body. Therefore, your products are drugs as defined in section 201(g)(1)(B) and (C) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 321(g)(1)(B)-(C)] and are biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. § 262(i)].

Your umbilical cord derived 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.

Based on a review of the materials described above, Neobiosis does not qualify for any exception in 21 CFR 1271.15, and your umbilical cord derived products fail to meet the criteria in 21 CFR 1271.10(a). Specifically, your umbilical cord derived products fail to meet the criterion in 21 CFR 1271.10(a)(2) that the HCT/P be “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.” An HCT/P meets the homologous use criterion if the “labeling, advertising, or other indications of the manufacturer’s objective intent” demonstrate that the HCT/P is intended to “perform[] the same basic function or functions in the recipient as in the donor” (21 CFR 1271.3(c) & 1271.10(a)(2)). The basic functions of umbilical cord in the donor (before removal) include serving as a conduit. The labeling, advertising, and other indications of your firm’s objective intent indicate that your umbilical cord derived products are not intended to perform the same basic function or functions in the recipient as in the donor (e.g., to serve as a conduit). Rather, using umbilical cord derived products for the treatment of diseases or conditions, such as orthopedic diseases and healing of damaged tissue is not considered homologous use as defined in 21 CFR 1271.3(c) because the treatment of these diseases or conditions is not a basic function of umbilical cord tissue in the donor.

In addition, your umbilical cord derived 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). Umbilical cord is processed by Neobiosis by initially (b)(4) the umbilical cord into (b)(4) followed by (b)(4). The processing of umbilical cord from the form of a conduit to a flowable form drastically alters the physical state of the HCT/P. The umbilical cord is considered more than minimally manipulated because such processing alters the original relevant characteristics relating to the tissue’s utility to serve as a conduit by effectively altering or eliminating its physical integrity and tubular form.

Therefore, your umbilical cord derived 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. Because these HCT/Ps do not meet all the criteria in 21 CFR 1271.10(a), and your products do not qualify for any exception in 21 CFR 1271.15, the products are regulated as drugs as defined in section 201(g)(1)(B) and (C) of the FD&C Act [21 U.S.C. § 321(g)(1)(B)-(C)] and biological products as defined in section 351(i) of the PHS Act [42 U.S.C. § 262(i)].

With respect to your amniotic fluid product, the definition of HCT/Ps in 21 CFR 1271.3(d) excludes secreted or extracted human products, such as amniotic fluid. Because your product meets the definition of a drug under section 201(g)(1)(B) and (C) of the FD&C Act and a biological product under section 351(i) of the PHS Act, this product is regulated as a drug and biological product and requires premarket review and approval.

New drugs may not be legally introduced or delivered for introduction into interstate commerce without prior approval from FDA, as described in section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. To lawfully market a drug that is a biological product, a valid 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]. Your amniotic fluid and umbilical cord derived products are not the subject of approved biologics license applications (BLAs) nor are there INDs in effect for these products. Your firm’s introduction or delivery for introduction of these unapproved products into interstate commerce violates sections 301(d) [21 U.S.C. § 331(d)] and 505(a) of the FD&C Act and section 351(a)(1) of the PHS Act [42 U.S.C. § 262(a)(1)].

Current Good Manufacturing Practice Violations

Additionally, during the inspection, FDA investigators documented significant deviations from current good manufacturing practice (CGMP) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act [21 U.S.C. § 351(a)(2)(B)] and 21 CFR 210 and 211.

At the conclusion of the inspection, FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described significant CGMP deviations applicable to your amniotic fluid and umbilical cord products. These CGMP deviations, involving (b)(4) units of amniotic fluid products processed since (b)(4) and (b)(4) units of umbilical cord derived products manufactured since (b)(4), 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)]. For example:

a. The aseptic processes used to manufacture your products have not been validated (e.g., by performing media fill simulations). 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 small instruments (e.g., forceps), glass beakers, and sometimes PPE, used in aseptic processing of your products.

2. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. Your firm has not established an adequate system for environmental monitoring in the aseptic processing areas where your products are manufactured. For example:

a. Prior to October 2022, except for surface settling plates within the biological safety cabinets (BSCs), your firm failed to establish a routine environmental and personnel monitoring program for your aseptic processing environment. Additionally, prior to October 2022, your firm did not have a program that designated the sampling locations throughout the cleanroom and gowning room. The sample technique, frequency, and alert and action levels were also not established.

b. Your firm has not performed routine non-viable particulate monitoring of the critical area (i.e., inside the biological safety cabinet (BSC) where your products are exposed to the environment).

c. Your firm does not require microbiological monitoring of operators’ arm coverings used in the critical area for (b)(4) processing your products.

d. Your firm did not perform environmental monitoring of surfaces in the aseptic processing area covering all production shifts. Your firm only conducts such monitoring (b)(4). This frequency is insufficient to provide control of contamination in the aseptic processing environment during production of each batch.

3. Failure to establish laboratory controls that include scientifically sound and appropriate specifications designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. Specifically, your firm has not established laboratory controls that include appropriate final specifications for testing and release of your products to assure that each batch conforms to appropriate standards of identity and purity during routine production. Your finished product testing is limited to visual inspection, sterility testing, endotoxins testing, and infectious disease testing as measurements of product attributes.

4. Failure to have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. For example, your firm has failed to validate the cleaning process for the ISO 7 clean room and BSCs used in the production of all your products purported to be sterile.

5. 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)]. For example, you have not validated the manufacturing process for your products with respect to identity, strength, quality, and purity. In addition, your firm reprocessed at least three batches of the firm’s amniotic fluid products since production began in (b)(4). This reprocessing has not been validated.

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, you assigned a two-year expiration date to your products without establishing a testing program to determine the stability characteristics.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding your drugs do not conform to CGMP, your drugs are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act [21 U.S.C. § 351(a)(2)(B)]. Your firm’s introduction or delivery for introduction of adulterated drugs into interstate commerce violates section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].

We acknowledge receipt of your firm’s initial 483 Response Letter dated March 14, 2023, and eight subsequent status reports dated April 14, 2023, May 15, 2023, June 13, 2023, July 21, 2023, September 15, 2023, October 16, 2023, December 15, 2023, and February 23, 2024, which provide responses and corrective actions to FDA’s inspectional observations (FDA-483). Your ninth status report, dated April 26, 2024, and your tenth status report, dated May 24, 2024, are currently under review. We acknowledge the corrective actions within your responses, including that your firm is working with a consulting firm to assist you with remediation efforts, some of which are in progress.

We also acknowledge you have paused all aseptic processing activities for your amniotic fluid and umbilical cord derived products pending validation of aseptic processes. However, your responses do not indicate whether your firm has also paused commercial distribution of your remaining in-house inventory of these products. These products were not manufactured in accordance with CGMP.

Additionally, your products manufactured and distributed prior to the January/February inspection are labeled with a two-year expiration and were manufactured under the violations noted above. However, your responses do not address your firm’s plans regarding product that has been distributed and is still within your labeled expiry. Your responses also do not address your intentions regarding obtaining BLAs or INDs for your products.

Some of the corrective actions described in your responses are not adequate to address the above-referenced deficiencies. We note that certain corrective actions cannot be evaluated because they lack supporting documentation. Examples of additional inadequacies include but are not limited to:

1. In response to Form FDA 483 Observation 1A, we acknowledge that you have initiated CAPA-2 and CAPA-3 to implement aseptic process validation for your amniotic fluid and umbilical cord derived products. Your response details that you have completed media fill simulations as part of the aseptic process validation for the amniotic fluid product. Your (b)(4) aseptic process validation (APV) runs for the amniotic fluid product media fills included different vial sizes for the (b)(4) media fill runs. The differences in vial sizes impact the filling time and size of the capping device. You have not repeated runs using the same vial size; therefore, these media fills were not performed in a consistent manner. Further, your growth promotion studies only included S. aureus and A. brasiliensis. It is recommended that the media selected should be demonstrated to promote growth of gram-positive and gram-negative bacteria, and yeast and mold (e.g., USP indicator organisms).

2. In response to Form FDA 483 Observation 2, we acknowledge that you have initiated CAPA-8 to address your corrective and preventative actions for your environmental program which includes a revision to SOP-48 “Routine Environmental Microbiological Monitoring Program”. This SOP does not define “(b)(4)” as to whether this is in reference to (b)(4) versus (b)(4), which could result in confusion, and it does not specify whether the samples are to be collected during or at the conclusion of operations to ensure monitoring represents aseptic processing conditions. Furthermore, CAPA-8 does not address the products manufactured in an aseptic processing environment without an established routine environmental and personnel monitoring program prior to October 2022. These products were distributed without verifying their control of microbial hazards in their production environment.

3. In response to Form FDA 483 Observation 3, you have committed to initiating CAPA-9 to develop a Process Performance Qualification Program which will include critical product attributes and release criteria for product safety, quality, and purity for both your amniotic fluid and umbilical cord derived products. You did not submit documentation of your corrective actions for review. Please submit to the agency evidence of your completed corrective actions.

4. In response to Form FDA 483 Observation 4, we acknowledge that the stability studies for your existing products have been modified to (b)(4) expiry until additional stability studies can be completed. Additionally, you stated that SOP-81 Product Stability Program (Version 1.0, Effective date: 2023-05-01) is complete. However, SOP-81 is inadequate. For example, it does not include the stability testing intervals, which is critical to a stability program to monitor product quality attributes at intervals over the course of the product’s shelf-life per 211.166(a)(1). It does not include the stability test intervals, the test methods, and procedures, and testing that demonstrates sterility is maintained throughout the labeled expiration dating period. Further, a stability program should include more than just sterility testing to ensure product quality throughout the proposed shelf-life. For instance, the stability program should also include tests for strength and identity along with sterility test results.

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 that your establishment is in full compliance with applicable requirements in 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 for biological products, contact the Center for Biologics Evaluation and Research (CBER), Division of Regulatory Project Management, Office of Therapeutic Products, at (240) 402-8190, or OTPRPMS@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.

Concerns Regarding (b)(4)

Based on statements on your former client’s website ((b)(4), last visited May 2024) and Facebook page ((b)(4), last visited May 2024), the (b)(4) product that you manufactured is intended to be administered (b)(4) for use in the treatment of “(b)(4),” “(b)(4),” “(b)(4),” and symptoms including (b)(4). These intended uses cause (b)(4) to be a drug under section 201(g)(1)(B) of the FD&C Act [21 U.S.C. § 321(g)(1)(B)] and a biological product under section 351(i) of the PHS Act [42 U.S.C. § 262(i)], which requires the (b)(4) product to be the subject of an approved BLA, or for it to have an IND in effect. We previously notified you of this by copying you on our (b)(4) to (b)(4), the distributor/owner of (b)(4). However, your firm continued to contract manufacture and ship the (b)(4) product to (b)(4) without an approved BLA or IND in effect.

You stated in your responses that you have discontinued manufacturing (b)(4), canceled the manufacturing agreement with your client, and rejected and removed all remaining (b)(4) from inventory. However, you failed to provide documentation of this cancelled manufacturing agreement. Also, the number of rejected (b)(4) vials provided in your response does not align with the in-house inventory (b)(4) noted and photographed during the inspection.

Additional Concern

In response to Form FDA 483 Observation 5, you have indicated that as part of CAPA-11, “Contract Development and Manufacturing Program” you will be creating a policy POL-14 “Contract Manufacturing Policy” to establish procedures for contract processing by your firm. You also indicated your firm will require quality agreements with your contract customers. Your policy is not detailed enough to address specifically what will be required regarding CGMP between the owner/distributor and the contract manufacturer. These items include quality unit activities, facilities and equipment validation and qualification, material management, laboratory controls, and documentation review and approval. Please note, as you are a contract manufacturer, you are a party engaged in the manufacture of a drug and are therefore responsible for ensuring compliance with CGMP for the manufacturing activities you perform. For both owners and contract facilities that conduct manufacturing operations, CGMP “includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.”2 You are required to ensure that your drug products are made in accordance with section 501(a)(2)(B) of the FD&C Act. For additional information, refer to FDA’s guidance document, “Contract Manufacturing Arrangements for Drugs: Quality Agreements” at https://www.fda.gov/media/86193/download.

Your response to this letter should be sent via email to orabioinspectionalcorrespondence@fda.hhs.gov with attention to Senior Compliance Officer Colleen Aspinwall and Compliance Officer Alice Silva. If you have any questions, please contact Colleen Aspinwall or Alice Silva using the email address noted above.

Sincerely,
/S/

Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division 1

Cc:(b)(4)

________________________

1 Wharton’s Jelly Cellular and Wharton’s Jelly Acellular are manufactured for (b)(4) under a (b)(4) as (b)(4), respectively.

2 Section 501 of the FD&C Act as amended by the Food and Drug Administration Safety and Innovation Act (Public Law 112-144, Title VII, section 711).

 
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