WARNING LETTER
Akan Biosciences, Inc.
MARCS-CMS 654674 —
April 30, 2024
Delivery Method:
VIA UNITED PARCEL SERVICE SIGNATURE REQUIRED
Product:
Biologics
Recipient:
Recipient Name
Mukesh NMI Kumar
Recipient Title
President
Akan Biosciences, Inc.
610 Professional Drive, Ste 103
Gaithersburg
,
MD
20879-3460
United States
Issuing Office:
Office of Biological Products Operations – Division I
United States
April 30, 2024
WARNING LETTER
24-654674
Dear Mr. Kumar,
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Akan Biosciences, Inc., located at 610 Professional Drive, Ste 103; Gaithersburg, MD 20879-3460 from September 20-30, 2022. During the inspection, an FDA investigator documented your manufacture of an adipose derived, stromal vascular fraction (SVF) cellular product for allogenic use with the brand name Ayama™ (hereinafter, also referred to as “your product”). The product’s labeling indicates it is sterile. You and your distributor,
(b)(4)
, have distributed this product to practitioners and medical facilities throughout the United States.
Information and records gathered prior to, during, and after the inspection, including information on your website, https://akanbio.com/ayama/, reflect that your product is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease or a condition in humans. For example, according to your website at https://akanbio.com/ayama/ (last visited April 2024), your product is an injectable product intended to “repair, reconstruct and replace your skin tissue”. Because these intended uses indicate that your product is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, your product is a drug as defined in section 201(g)(1)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 321(g)(1)(B)]. Your product is also a drug under section 201(g)(1)(C) of the FD&C Act because it is intended to affect the structure or any function of the body. Your product is also a biological product as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. § 262(i)] because it is applicable to the prevention, treatment, or cure of a disease or condition of human beings.
Your product is also a human cell, tissue, or cellular or tissue-based product (HCT/P) as defined in 21 CFR 1271.3(d) and is 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.
Akan Biosciences, Inc. does not qualify for any exception in 21 CFR 1271.15, and your product fails to meet all the criteria in 21 CFR 1271.10(a). Specifically, your product fails 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 adipose tissue related to its utility for reconstruction, repair, or replacement.
In addition, your product fails 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.” Your product is not intended to perform the same basic function or functions of adipose tissue in the recipient as in the donor, such as cushioning and support for other tissues, including the skin and internal organs, storing energy in the form of lipids, and insulating the body, among other functions. Using your product for the repair, reconstruction, and replacement of skin tissue, for example, is not homologous use as defined in 21 CFR 1271.3(c).
Therefore, your product is not regulated solely under section 361 of the PHS Act [42 U.S.C. § 264] and the regulations in 21 CFR Part 1271. Because your product does not meet all the criteria in 21 CFR 1271.10(a), and Akan Biosciences, Inc. does not qualify for any exception in 21 CFR 1271.15, your product is regulated as a drug as defined in section 201(g)(1)(B) of the FD&C Act [21 U.S.C. § 321(g)(1)(B)] and a biological product as defined in section 351(i) of the PHS Act [42 U.S.C. § 262(i)].
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]. Your product is not the subject of an approved biologics license application (BLA), nor is there an IND in effect for your product.
Additionally, during the inspection, an FDA investigator documented significant violations for human cells, tissues, and cellular and tissue-based products (HCT/Ps) from 21 CFR 1271 and issued under the authority of Section 361 of the PHS Act [42 U.S.C. § 264]. Further, FDA investigators documented evidence of significant violations from current good manufacturing practice (CGMP) requirements, including violation of section 501(a)(2)(B) of the FD&C Act [21 U.S.C. § 351(a)(2)(B)] and 21 CFR 210 and 211.
The violations documented on the Form FDA-483, List of Inspectional Observations, were presented to and discussed with you at the conclusion of the inspection. Additional violations were noted upon further review of the records collected during the inspection. The violations, involving 585 vials of product manufactured between May 2021 and April 2022 from three donors, include, but are not limited to, the following:
1.
Failure to test a specimen from a donor of cells or tissue, whether viable or non-viable, for evidence of infection due to relevant communicable disease agents [21 CFR 1271.85(a)]
. For example, FDA has identified human immunodeficiency virus, type 1 (HIV-1), hepatitis C virus (HCV), and hepatitis B virus (HBV) as relevant communicable disease agents [21 CFR 1271.3(r)], and donors of HCT/Ps must be tested for such agents to adequately and appropriately reduce the risk of transmission of relevant communicable disease. The donor specimens collected from donors
(b)(6), (b)(7)(C)
and
(b)(6), (b)(7)(C)
were not tested for the antibody to hepatitis B core antigen (anti-HBc) and HIV-1, HCV, and HBV by the nucleic acid test (NAT) method. Such donors were not tested to adequately and appropriately reduce the risk of transmission of these diseases because NAT testing can detect evidence of infection at a significantly earlier stage than is possible under other tests. These donors were determined eligible on 3/30/2022 and 3/31/2022, respectively.
2.
Failure to collect a donor specimen for testing for relevant communicable diseases at the time of recovery of cells or tissue from the donor or up to seven days before or after recovery [21 CFR 1271.80(b)]
. For example, HCT/Ps were recovered from donor
(b)(6), (b)(7)(C)
on
(b)(6), (b)(7)(C)
, however a donor specimen for testing was collected from the donor on
(b)(6), (b)(7)(C)
, which is not within the required timeframe for collection of a specimen for testing.
3.
Failure to test 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)]
. For example, the specimens for communicable disease testing, collected from donors
(b)(6), (b)(7)(C)
and
(b)(6), (b)(7)(C)
, were tested for the antibody to human immunodeficiency virus, types 1 and 2 (anti-HIV-1/2), hepatitis B surface antigen (HBsAg), the antibody to hepatitis C virus (anti-HCV), and
Treponema pallidum
using test kits that were not FDA-licensed, approved, or cleared for donor screening. Donor
(b)(6), (b)(7)(C)
was determined eligible on 3/30/2022. Donor
(b)(6), (b)(7)(C)
was determined eligible on 3/31/2022.
4.
Failure to screen a donor of cells or tissue 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)(1)]
. For example:
a) Your Form, DS-01-02 (Version 1.0) "Donor Screening Questionnaire,” is used as a relevant medical record to determine donor eligibility and was used to screen donors
(b)(6), (b)(7)(C)
and
(b)(6), (b)(7)(C)
. However, the form does not address certain risk factors for relevant communicable disease agents and diseases, including, for example, a donor’s risk of having West Nile Virus (WNV), among other risk factors.
The following provides examples of conditions and behaviors that increase a donor’s relevant communicable disease risk. You should determine to be ineligible any potential donor who exhibits one or more of the following conditions or behaviors:
i. Men who have had sex with another man in the preceding 5 years.
ii. Persons who have engaged in sex in exchange for money or drugs in the preceding 5 years. Your questionnaire only asks whether the donor has had “sexual contact with a prostitute or anyone else who takes money or drug or other payment for sex” in the past 12 months.
iii. Persons who have been in juvenile detention, lock up, jail or prison for more than 72 consecutive hours in the preceding 12 months.
iv. Persons who have had a past diagnosis of clinical, symptomatic viral hepatitis after their 11th birthday.
v. Persons who have had a medical diagnosis or suspicion of WNV infection.
vi. Persons who have tested positive or reactive for WNV infection using an FDA-licensed or investigational WNV NAT donor screening test in the preceding 120 days.
vii. Persons who have been treated for or had syphilis within the preceding 12 months.
viii. Persons who are at increased risk for Creutzfeldt-Jakob Disease (CJD) due to receiving a non-synthetic dura mater transplant, human pituitary-derived growth hormone, or having one or more blood relatives diagnosed with CJD.
ix. Persons with a medical diagnosis of Zika Virus (ZIKV) in the past 6 months.
x. Persons who have engaged in sex within the past 6 months with a person who has residence in, or travel to, an area with an increased risk for ZIKV transmission.
xi. Persons who have had a diagnosis with dementia or any degenerative or demyelinating disease of the central nervous system or other neurological disease of unknown etiology.
xii. Persons who have had intimate contact with a xenotransplantation product recipient.
b) A review of records for donor
(b)(6), (b)(7)(C)
found that the donor did not complete a “Donor Screening Questionnaire” and was not screened for almost all risks of relevant communicable disease agents or diseases. From 4/2022 to 7/2022, you distributed
(b)(4)
vials of Ayama™ that had been manufactured from 5/27/2021 to 4/4/2022 from adipose tissue recovered from donor
(b)(6), (b)(7)(C)
.
5.
Failure to clearly identify an HCT/P that is in quarantine pending completion of a donor-eligibility determination and failure to ship HCT/Ps with the required accompanying records for which the donor eligibility determination has not been completed [21 CFR 1271.60(b) and (c)]
. For example, your firm distributed
(b)(4)
vials of Ayama™ to
(b)(4)
physician/clinic locations in
(b)(4)
shipments between 4/6/2022 and 7/5/2022. The
(b)(4)
vials were part of
(b)(4)
batch vials of Ayama™ manufactured from 5/27-28/2021 (
(b)(4)
batches,
(b)(4)
batch vials total) from adipose tissue recovered from donor
(b)(6), (b)(7)(C)
. Donor screening and donor testing had not been completed for donor
(b)(6), (b)(7)(C)
; therefore, a donor-eligibility determination had not been documented. The
(b)(4)
vials of Ayama were not clearly identified as quarantined and were not accompanied by records stating that the product must not be implanted, transplanted, infused, or transferred until completion of donor eligibility determination.
6.
Failure to ship in quarantine a pre-distribution shipment of HCT/Ps between establishments for which the pre-established criteria designed to prevent communicable disease transmission have not been documented as being met [21 CFR 1271.265(b)]
. For example, your firm delivered
(b)(4)
vials of Ayama™ (part of
(b)(4)
batch vials manufactured between 3/31/2022 and 4/4/2022 from adipose tissue recovered from donors
(b)(6), (b)(7)(C)
and
(b)(6), (b)(7)(C)
) to your distributor on 5/11/2022 that were not shipped in quarantine to prevent improper release. The products had not been determined to be available for distribution, as described in 21 CFR 1271.265(c), as there was no documentation that the pre-established criteria designed to prevent communicable disease transmission had been met.
7.
Failure to establish 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)]
. For example, your firm has not validated the manufacturing process for the adipose tissue product, Ayama™, with respect to identity, strength, quality and purity.
8.
Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area necessary to prevent contamination or mixups [21 CFR 211.42(c)(10)(iv)]
. For example,
a) You have not performed environmental monitoring of the aseptic processing area in association with each production run. You process batches on
(b)(4)
basis. However, SOP
(b)(4)
(Version 3, Effective date: August 8, 2020) indicates that “
(b)(4)
plates” sampling (i.e., contact plates and settle plates) for evaluation of viable microbial contamination of the biosafety cabinet will be performed
(b)(4)
. Infrequent monitoring during production of the subject drug product may preclude identification of potential microbial contaminants that could adulterate your product.
b) Your incubation conditions of
(b)(4)
plates used as contact plates and settle plates for environmental monitoring is not appropriate for the detection of viable microbial contamination. SOP
(b)(4)
(Version 3, Effective date: August 8, 2020) indicates that settle and contact plates should be incubated at
(b)(4)
for
(b)(4)
hours. Incubation at
(b)(4)
temperature for
(b)(4)
hours may exclude detection of certain microbial contaminants.
We acknowledge receipt of your letter dated 10/25/2022, which provides a response and corrective actions to FDA’s inspectional observations (FDA-483). We have reviewed the corrective actions outlined in the response. We also acknowledge your voluntary product recall of Ayama™, initiated on 09/29/2022, as well as your commitment to correct firm operations and/or procedures involving donor eligibility (including donor screening/testing); product quarantine; equipment calibration/inspection; and labeling controls. However, we have determined that the response is inadequate to address our concerns regarding the above-noted violations as indicated below.
21 CFR 211.100(a) requires written procedures for the 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. Process validation studies determine whether
(b)(4)
state of control has been established while routine monitoring of process performance attributes determines whether control is maintained. Establishment of appropriate attributes and validation of processing method(s) of your sterile, allogeneic/non-autologous, non-family related, HCT/P product, Ayama,™ to be completed, approved, and documented prior to implementation of manufacturing operations, is essential for assuring product quality over the product lifecycle.
According to your voluntary product recall documentation, you initiated a voluntary recall based upon available information regarding your product (i.e., associated deficiencies in donor screening processes affecting three batches sourced from two donors), although you “believe that no specific concerns existed for the safety of the product”. Your response to the FDA-483 states that you believe “the corrective and preventive actions taken by [you] adequately address the inspectional observations.” Regarding your responses to observations 4 and 5 (shipping under quarantine) and observation 7 (procedures appropriate to meet core CGTP requirements), we acknowledge that you have updated your donor eligibility determination criteria and procedures. These updated documents will be reviewed and verified during the next inspection of your establishment. However, your response does not provide sufficient information as well as corrective/preventative actions such as:
a) Your response lacks detail about remaining product on hand outside the recalled product and its disposition. Please identify all finished product produced, on-hand, and shipped as well as your intended disposition of this product.
b) Your revised process validation report for Ayama lacks significant documentation to assure that the product has the identity, strength, purity, and quality it purports or is represented to possess. For example, it lacks donor eligibility information as well as full, proper validation (with approved protocol[s]) and approval of your processing methods (including test method suitability) for your sterile, HCT/P product - Ayama™ in order to ensure your processing method:
• reduces the risk of transmission of communicable disease by an HCT/P (i.e., sterility); and
• does not cause contamination or cross-contamination during processing; and prevents the introduction, transmission, or spread of communicable disease through the use of the HCT/P.
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 violations that may exist at your facilities. 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. You should take prompt action to correct any violations and prevent their recurrence. Failure to adequately address these matters may lead to regulatory action without further notice. Such actions include seizure and/or injunction.
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 via email to: Jason D. Abel, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 1, email address: orabioinspectionalcorrespondence@fda.hhs.gov (Cc: Jason.Abel@fda.hhs.gov, please include firm name and FEI # within email subject line). If you have any questions, please contact Jason D. Abel via email.
Sincerely,
/S/
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division I
Content current as of:
05/21/2024
Regulated Product(s)
Biologics