Chara Biologics, Inc.

The United States Food and Drug Administration (FDA) inspected your facility, Chara Biologics, Inc., located at the above address, between July 23, 2024, and August 16, 2024. During the inspection, FDA documented that Chara Biologics, Inc. (“you”) manufactures and distributes a human amniotic fluid product, CharaExo, as well as cellular products derived from human umbilical cord, CharaCore and CharaOmni, for allogeneic use (collectively, “your products”).1

This letter is to advise you that your products are unapproved new drugs in violation of section 505(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. § 355(a). Your products are also unlicensed biological products in violation of section 351(a)(1) of the Public Health Service Act (PHS Act), 42 U.S.C. § 262(a)(1). A biological product for which a biologics license application (BLA) has been approved under section 351(a) of the PHS Act is not required to have an approved application under section 505 of the FD&C Act, 21 U.S.C. § 355; 42 U.S.C. § 262(j). Otherwise, with certain exceptions not applicable here, a new drug may not be introduced or delivered for introduction into interstate commerce without an approved application from FDA in effect, as described in section 505(a) of the FD&C Act. Your introduction or delivery for introduction of your products into interstate commerce, or the causing thereof, is prohibited under section 301(d) of the FD&C Act, 21 U.S.C. § 331(d).

This warning letter also summarizes significant violations of current good manufacturing practice (CGMP) requirements, including violations of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. § 351(a)(2)(B), and 21 CFR parts 210 and 211. Your firm is responsible for ensuring that your products comply with CGMP requirements regardless of who manufactures, processes, packs, or holds them. This letter also explains you are in violation of current good tissue practice (CGTP) requirements set forth in 21 CFR part 1271 in the manufacture of your CharaCore and CharaOmni products. Because your methods, facilities, or controls for manufacturing, processing, packing, or holding drugs do not conform to CGMP, your products are adulterated within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. § 351(a)(2)(B). Furthermore, CharaExo is also misbranded under sections 502(a) of the FD&C Act, 21 U.S.C. § 352(a). Your introduction or delivery for introduction of your products into interstate commerce, or the causing thereof is a prohibited act under section 301(a) of the FD&C Act, 21 U.S.C. § 331(a).

Based on information and records reviewed by FDA, your products are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or conditions in humans. For example:

• CharaExo o Chara Biologics’ brochure, “Let the Joy of Healing Begin,” tells prospective customers to choose its products because “Chara offers the most comprehensive stem cell product CharaCore and high potency growth factor/extracellular vesicle product CharaExo.” It explains that “stem cells have been shown to have clinical benefits in” a long list of conditions including various autoimmune disorders, “neurodegenerative conditions (Parkinson’s, Alzheimers, Multiple Sclerosis, ALS, etc.)”, diabetes, cardiovascular and lung diseases, autism, spinal cord injuries, and cirrhosis. It also explains stem cell treatment can benefit its audience by reducing inflammation, improving immune function, and enhancing tissue repair. o AAICT “Exosome Protocols” provide sample CharaExo dosing for the following diseases or conditions: Infertility, Osteoporosis, Diabetes, Autism, Cardiac, Renal, Hepatic, Pulmonary conditions, etc…. Musculoskeletal…Shoulder/Hip/Knees…Ligaments/Tendons/Meniscus /Labrum… Elbow/Wrist/Ankle/Fingers… Spine…Erectile Dysfunction… Female Urinary Incontinence…Autoimmune Diseases… Neuropathy… CNS Disease… Wound, Ulcers & Burns…” These protocols, which are part of AAICT’s Fundamentals of Stem Cell Practice course, accompany Chara Biologics’ CharaExo products when Chara Biologics sells them to physicians as part of Starter Package 3. o Chara Biologics’ “FAQs for Physicians,” which you said you provide all your purchasing physicians, explains: “CharaExo also contains larger extracellular vesicles, as well as concentrated growth factors from amniotic fluid… Extracellular vesicles contain proteins, microRNAs and lipids, and all eukaryotic cells secrete and take up these nanoparticles, and they are a means of communication between cells. These nanoparticles have been increasingly recognized as playing an important role as the mediator of many of the MSC-associated therapeutic benefits. They can be quite useful therapeutically, as they may elicit a more immediate therapeutic response, although the benefits tend to be shorter-lasting than that of cell therapy.”

• CharaCore o Statements in Chara Biologics’ “Let the Joy of Healing Begin” brochure (discussed above) o Chara Biologics’ FAQ for Physicians includes the following statements:  “CharaCore® is highly rich in MSC’s…MSC’s: have anti-microbial properties, helpful in fighting acute, chronic or systemic infections… shown to be effective against protozoa (as in Lyme disease)”  “How Can CharaCore help my patients? REGULATE INFLAMMATION, SCARRING & PAIN Birth tissue products have been shown to reduce inflammation, fibrous tissue growth, and potential scar tissue formation.”  “How Can CharaCore help my patients? ANTI-MICROBIAL Application of birth tissue products has been shown to reduce bacteria counts in the wound…”

• CharaOmni o Chara Biologics’ FAQ for Physicians and CharaOmni promotional brochure state: “[W]hat set[s] CharaOmni apart from all other skincare products on the market: 1) Regenerative Stem Cell Components… Wharton’s Jelly Extract… reduces scar formation, and enhances wound healing…. Amniotic Extracellular Matrix - possesses powerful anti-inflammatory...properties.” o Your website at www.charaomni.com explains “The stem cell regenerative elements in CharaOmni… have been known to provide crucial and powerful growth factors, extracellular matrix, as well as other cell signaling molecules that highly beneficial in skin repair and regeneration.”

• Chara Biologics also promotes its products for the following diseases at www.charabiologics.com/science, which links to https://aaict.org/clinical-evidence/: o “…Alzheimer’s…Asthma…Autism…Chronic Pain…COPD…Crohn’s Disease…Degenerative Disc Disease…Heart Disease…Kidney Failure…Liver Cirrhosis…Lupus…Macular Degeneration…Migraines & Tension Headache…Multiple Sclerosis…Nerve Injury…Osteoarthritis… Osteoporosis…Parkinson’s…”

Therefore, CharaExo, CharaCore, and CharaOmni are drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i).

Your CharaCore and CharaOmni 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. § 264.2 HCT/Ps that do not meet all the criteria in 21 CFR 1271.10(a) are not regulated solely under section 361 of the PHS Act and the regulations in 21 CFR part 1271. Unless an exception in 21 CFR 1271.15 applies, 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 applicable premarket review. Based on a review of relevant materials, Chara Biologics, Inc. does not qualify for any exception in 21 CFR 1271.15, and your CharaCore and CharaOmni products fail to meet all criteria in 21 CFR 1271.10(a).

For example, your CharaCore and CharaOmni 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 the processing alters the original relevant characteristics of the umbilical cord related to its utility for reconstruction, repair, or replacement. The processing of the umbilical cord from the form of a conduit into a flowable form significantly alters the physical state of the HCT/P. The umbilical cord is more than minimally manipulated because such processing alters the original relevant characteristics of the HCT/P relating to its utility to serve as a conduit by effectively altering or eliminating its physical integrity and tubular form.

In addition, your CharaCore and CharaOmni products fail to meet the criterion that the HCT/Ps be “intended for homologous use only,” which means that 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) and 1271.10(a)(2)). These products are not intended solely to perform the same basic function or functions of the HCT/P in the recipient as in the donor (e.g., serving as a conduit). Rather, these products are intended for use in the treatment of a number of diseases and conditions listed above, which are not basic functions of umbilical cord in the donor.

Therefore, these HCT/Ps are not regulated solely under section 361 of the PHS Act, 42 U.S.C. § 264, and the regulations in 21 CFR part 1271.3 See 21 CFR 1271.20. In addition to being regulated under section 361 of the PHS Act and 21 CFR part 1271, your CharaCore and CharaOmni products are regulated as drugs as defined in section 201(g)(1) of the FD&C Act, 21 U.S.C. § 321(g)(1), and biological products as defined in section 351(i) of the PHS Act, 42 U.S.C. § 262(i), as stated above.

Subject to certain exceptions not applicable here, to lawfully introduce or deliver for introduction into interstate commerce a drug that is a biological product, a valid BLA must be in effect under section 351(a)(1) of the PHS Act, 42 U.S.C. § 262(a)(1). Such licenses are issued only after showing that the product is safe, pure, and potent. Your products are not the subject of an approved BLA, nor is there an investigational new drug application (IND) in effect for any of them.

FDA’s inspection of your facility documented evidence of significant CGMP and CGTP violations. At the conclusion of the inspection, the FDA investigators issued a Form FDA-483, List of Inspectional Observations (Form FDA-483). FDA also identified additional significant violations upon further review of the evidence collected during the inspection, as set forth below.

The violations applicable to your products include, but are not limited to, the following:

1. Your firm failed to establish a quality unit with the responsibility and authority to approve or reject all labeling and drug products, and the responsibilities and procedures applicable to the quality control unit are not in writing and followed, as required by 21 CFR 211.22(a) and 211.22(d).

Your firm is a manufacturer subject to CGMP requirements. See 21 CFR 210.3(b)(12). For example, at the time of the inspection, your firm relabeled, stored, and distributed CharaCore and stored and distributed CharaOmni.4

An adequate quality unit overseeing all elements of CGMP is necessary to ensure drug products are consistently manufactured in compliance with CGMP and meet established specifications for identity, strength, quality and purity. However, your firm does not receive documentation, such as production records or test results, for each lot received for approval or rejection by your firm before distribution. Additionally, your firm has not established responsibilities and procedures applicable to the quality unit such as the following:

a. 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))b. Written procedures for production and process control designed to assure drug products have the identity, strength, quality, and purity purported or represented to possess (21 CFR 211.100(a))c. Review and approval of drug product production and control records, including those for packaging and labeling, to determine compliance with all established, approved written procedures before a batch is released or distributed (21 CFR 211.192)d. Written procedures describing the handling of all written and oral complaints regarding a drug product (21 CFR 211.198(a))e. Written procedures designed to assure that correct labels, labeling, and packaging are used (21 CFR 211.130)

2. Documentation of the donor-eligibility determination, including the name of the responsible person who made the determination and the date of the determination, was not maintained, as required by 21 CFR 1271.55(d)(1)(iii).

Specifically, Chara did not maintain documentation of the donor eligibility determination, including the name of the responsible person who made the determination and the date of the determination, for donors of umbilical cord. Umbilical cord is used to manufacture CharaCore, which is used to manufacture CharaOmni.

Your CharaExo product is also misbranded under section 502(a) of the FD&C Act, 21 U.S.C. § 352(a), because your labeling is false or misleading. Specifically, your firm extended the manufacturer’s expiration date for CharaExo lots by one year or more without supporting data. This false or misleading representation about your CharaExo product on your labeling causes this product to be misbranded under section 502(a) of the FD&C Act, 21 U.S.C. § 352(a).

We have reviewed your responses, received on September 1, 2024 and December 23, 2024,5 to FDA’s Form FDA-483 in detail. Your responses are inadequate to address the violations noted above and on the Form FDA-483. While you assert that your products were manufactured according to section 361 of the PHS Act, the evidence collected shows that your products do not meet the relevant criteria to be regulated solely under section 361 of the PHS Act.

We acknowledge that you state in your September and December 2024 responses that, “Chara Biologics is not [now], nor has it ever been a Stem Cell processor/manufacturer.” We also acknowledge that you state in your December 2024 response that an agreement has been made with “the manufacturers to label all products prior to coming into the building.” Be advised that manufacture, processing, packing, or holding of a drug product includes packaging and labeling operations, testing, and quality control of drug products. See 21 CFR 210.3(b)(12)6 and 1271.3(e). Based on your responses, it appears that Chara continues to package, store, and distribute drug products. For the reasons described above, Chara Biologics is a manufacturer subject to applicable CGMP requirements. This is consistent with your signed affidavit from the inspection, in which you state, “Chara Biologics, Inc. – This is the primary manufacturing entity for the Chara products CharaCore, CharaExo and CharaOmni.”

Be advised that Chara is responsible for ensuring its products are manufactured in compliance with CGMP. Drugs not manufactured in compliance with CGMP are adulterated. The FD&C Act prohibits any person from introducing or delivering for introduction an adulterated or misbranded drug into interstate commerce.

We refer you to the following document for additional information, Guidance for Industry: Contract Manufacturing Arrangements for Drugs: Quality Agreements (November 2016), found at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/contract-manufacturing-arrangements-drugs-quality-agreements-guidance-industry. Also, be advised that, under the CGMP regulations, a “quality control unit shall be responsible for approving or rejecting drug products manufactured, processed, packed, or held under contract by another company.” 21 CFR 211.22(a).

With respect to donor eligibility, you state in your response that your contract manufacturers determine donor eligibility for the HCT/Ps used for your products. However, you are required to retain the donor-eligibility determination of the tissue donors for products that remain in inventory at your facility or have been distributed and remain in the marketplace as required by 21 CFR 1271.55(d)(1)(iii).

Your responses do not adequately address the status of your manufacturing and distribution operations or your specific plans for disposition of the inventory of CharaExo, CharaCore, and CharaOmni at your facility that were manufactured under the conditions described in this letter. This includes the disposition of finished product received from your contract manufacturers prior to being re-labeled by your firm. Further, your responses do not adequately describe actions you have taken or plan to take to address the impact of the above-described deficiencies on your distributed products that remain in the marketplace. Your responses do not 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. Subject to certain exceptions not applicable here, to lawfully introduce or deliver for introduction into interstate commerce a drug that is a biological product, a valid BLA must be in effect under section 351(a)(1) of the PHS Act, 42 U.S.C. § 262(a)(1). Such licenses are issued only after showing that the product is safe, pure, and potent. Your products are not the subject of an approved BLA.

FDA has previously provided notice to you in a letter dated November 25, 2019, that based on a review of your website it appeared your firm was marketing a biological drug product (CharaCore) that does not qualify for any exception under 21 CFR 1271.15, as is also explained in this letter. Your response dated December 17, 2019, stated that you would remove all testimonials from your websites. However, a review of your various social media accounts, which are linked to your websites, revealed patient testimonials for Chara Biologics that describe treatment of various diseases and conditions. In addition, your March 13, 2020, response stated your intention to (b)(4), however your products are not the subject of an approved BLA, nor is there an IND in effect for any of them.

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 in connection with your products. You are responsible for investigating and determining the causes of any violations and for preventing their recurrence or the occurrence of other violations. It is your responsibility to ensure full compliance with all applicable requirements in the FD&C Act, PHS Act, and all applicable regulations.

This letter notifies you of our concerns and provides you an opportunity to address them. Failure to adequately address these matters may result in action without further notice including, without limitation, seizure and/or injunction.

Send your electronic response to CBERDCMRecommendations@fda.hhs.gov. If you have questions regarding this letter, contact the Division of Case Management, CBER at (240) 402-9156.