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  5. Berkeley Biologics, LLC, previously operating as Elutia, Inc. – Orthobiologics Business Unit, formerly Aziyo Biologics, Inc. - 676984 - 06/28/2024
  1. Warning Letters

WARNING LETTER

Berkeley Biologics, LLC, previously operating as Elutia, Inc. – Orthobiologics Business Unit, formerly Aziyo Biologics, Inc. MARCS-CMS 676984 —

Delivery Method:
VIA UNITED PARCEL SERVICE SIGNATURE REQUIRED
Reference #:
OBPO 676984
Product:
Biologics
Recipient:
Recipient Name
Mesfin Mengesha
Recipient Title
Chief Executive Officer
Berkeley Biologics, LLC, previously operating as Elutia, Inc. – Orthobiologics Business Unit, formerly Aziyo Biologics, Inc.

880 Harbour Way S., Suite 100
Richmond, CA 94804
United States

Issuing Office:
Center for Biologics Evaluation and Research (CBER)

United States

WARNING LETTER

June 28, 2024

Dear Mr. Mengesha:

During an inspection of your firm, Berkeley Biologics, LLC, (operating during the inspection as Elutia, Inc. – Orthobiologics Business Unit, formerly Aziyo Biologics, Inc.), located at 880 Harbour Way S., Suite 100, Richmond, CA 94804, conducted between September 05, 2023 and September 25, 2023, the United States Food and Drug Administration (FDA) documented your manufacture of viable bone matrix products derived from human bone tissue and marketed as Viable Bone Matrix (VBM), Fiber Viable Bone Matrix (FVBM), Cellular Fiber Matrix (CFM)/Excel Viable Bone Matrix (EFM),1 and Osteo Viable Bone Matrix (OVM). You have distributed these products throughout the United States to medical facilities. You intend these products to be used in orthopedic or reconstructive bone grafting procedures for bone repair and regeneration, and you purport them to be sterile.

Human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d) 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 Federal Food, Drug, and Cosmetic Act (FD&C Act) and/or the Public Health Service Act (PHS Act) [42 U.S.C. § 262], and are subject to additional regulation, including appropriate premarket review.

Your products do not qualify for any exception in 21 CFR 1271.15, and your VBM, CFM/EFM, and OVM products fail to meet all the criteria in 21 CFR 1271.10(a). Specifically, VBM, CFM/EFM, and OVM 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 cartilage relating to its utility to perform its load-bearing and other physical functions, which generally include firmness, smoothness, flexibility, and resistance to deformation.

Your products also fail to meet the criterion under 21 CFR 1271.10(a)(3) that the manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent. Your VBM, CFM, and OVM products are a combination of bone (cancellous and cortical) and another article, (b)(4).

Therefore, these three products – VBM, CFM/EFM, and OVM – 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 products do not meet all the criteria in 21 CFR 1271.10(a), and you do not qualify for any exception in 21 CFR 1271.15, these 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)].

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. 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. 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 312]. None of your products are the subject of an approved BLA, nor is there an IND in effect for any of them. Based on our review, these products are unapproved new drugs that you are introducing or delivering for introduction into interstate commerce in violation of 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.

Additionally, during the inspection, FDA investigators documented significant deviations from current good tissue practice (CGTP) requirements, including deviations from 21 CFR 1271, for FVBM and OVM. Upon further review of information collected during the inspection, FDA also identified significant deviations from current good manufacturing practice (CGMP) requirements for VBM, CFM/EFM, and OVM, including 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.

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP requirements, your VBM, CFM/EFM, and OVM drug 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). Under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)], your introduction or delivery for introduction into interstate commerce of these three drug products is a prohibited act.

Your CGTP deviations for your FVBM and OVM products manufactured between January 2022 and June 2023, include, but are not limited to, the following:

1. Failure to determine as ineligible a donor who is identified as having a risk factor for, or clinical evidence of, any of the relevant communicable disease agents or diseases for which screening is required under 21 CFR 1271.75(a)(1) [21 CFR 1271.75(d)(1)]. For example, you failed to determine as ineligible (b)(4) deceased donors who have a documented medical diagnosis of sepsis. As discussed in the 2007 Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) (2007 DE Guidance), donor screening to reduce the risk of transmission of disease agents associated with sepsis is required. Tissues from these donors were manufactured into FVBM and OVM, and distributed for implantation into patients/recipients, some of which were associated with an outbreak of Mycobacterium tuberculosis infections. It appears this is a systemic issue not limited to these (b)(4) donors or products because this violation resulted from you following your SOP-0006 Donor Eligibility Determination Criteria, which does not require you to determine as ineligible a donor who is identified as having a risk factor for, or clinical evidence of, sepsis.

We have received and reviewed your written responses, dated October 14, 2023, and November 30, 2023, to FDA’s inspectional observations on the Form FDA-483. The corrective actions described in your response are not adequate to address the above noted violation that was on the FDA-483.

In your October response, you provided your revised procedure, SOP-006 Donor Eligibility Determination Criteria (as Attachment 2.2). Your “Donor Screening Guidance Document” in Attachment 2.2 and the revised sepsis algorithm in SOP-0006 do not determine as ineligible, donors who have a documented medical diagnosis of sepsis. Sepsis is a relevant communicable disease agent and disease (RCDAD) under 1271.3(r)(2), as described in the 2007 DE Guidance. Under 1271.75(d)(1), you must determine as ineligible a donor who is identified as having a risk factor for or clinical evidence of any RCDAD. You should revise Berkeley’s Donor Screening Guidance Document for sepsis and revise your sepsis algorithm in SOP-0006 so that these documents are compliant with 1271.75(d)(1).

This donor eligibility issue applies across your products, including those regulated solely under section 361 of the PHS Act. Based on information available to FDA, you have received tissues from at least (b)(4) donors who have sepsis documented in their medical records. We request that you provide us a list of all donors that have had risk factors for or clinical evidence of sepsis that you have determined to be eligible along with the products you have manufactured and distributed from these donors.

Your CGMP deviations for VBM, CFM/EFM, and OVM manufactured between January 2022 and June 2023, include, but are not limited to, the following:

2. 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,

a. According to your Process Qualification Reports (dated January 17, 2017, March 16, 2020, and April 7, 2023), you only required (b)(4) donors to meet your process qualification acceptance criteria even if some donor batches in the validation/qualification failed to meet the criteria. For example, (b)(4) of (b)(4) OVM donor batches failed to meet your acceptance criteria, and (b)(4) of the (b)(4) donor batches failed to meet your acceptance criteria for sterility testing.

b. You have not validated the manufacturing processes for VBM, CFM/EFM, and OVM with respect to identity, strength, quality, and purity. Your Process Qualification Reports document product bioburden testing, sterility testing, environmental and personnel monitoring, and in some cases (b)(4) testing, as the only tests included in your acceptance criteria. These tests are inadequate to assure the identity, strength, quality, and purity of these products.

Based on our review of the “retrospective validation addendums” you provided in your November 2023 response, you have not addressed the issues noted above. For example, your validations continue to focus on sterility assurance controls, rather than identity, strength, quality, and purity.

3. Failure to have an adequate system necessary to prevent contamination or mix-ups during aseptic processing [21 CFR 211.42(c)(10)(iv)]. For example:

a. Your action limits for microbiological monitoring (i.e., active viable air and surface samples) within the critical area (i.e., inside the Biological Safety Cabinet (BSC)) were observed to be greater than (b)(4) colony forming units (CFUs). Such high numbers of microorganisms can contribute to product contamination and pose a potentially significant safety concern.

b. You do not perform sampling of critical surfaces in the BSC for microorganisms in association with each production batch.

c. Your personnel monitoring sample locations are inadequate for personnel performing aseptic processing. For example, your firm does not conduct personnel monitoring of the forearms/sleeves of operators working in the BSC where your products are aseptically processed.

4. Failure to establish laboratory controls that include scientifically sound and appropriate specifications and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality, and purity [21 CFR 211.160(b)]. For example:

a. You have not established scientifically sound and appropriate specifications and test procedures to assure that VBM, CFM/EFM, and OVM conform to appropriate standards of identity, strength, quality, and purity. Your finished product testing is limited to sterility testing, which is inadequate to measure appropriate standards of identity, strength, quality, and purity.

b. Sterility samples of VBM, CFM/EFM, and OVM are frozen prior to sterility testing. Freezing product has the potential to destroy or compromise any microbial content in the samples before testing, if present; therefore, any contamination that was present prior to freezing may not be reliably detected.

In your responses, you have committed to stopping the manufacture and distribution of all viable bone matrix products until, you state, you have met, “FDA’s standards for tissue processing validation.” However, you have not addressed the products manufactured under the violative conditions described above that remain on the market and available for implantation nor have you addressed the above CGMP violations. We acknowledge that the above CGMP violations were not included in the FDA-483; we expect you to address them in response to this letter.

Additionally, your response fails to address your failure to have an IND in effect to study your VBM, CFM/EFM, and OVM products or your lack of an approved BLA to lawfully market these products.

Please also be advised that FDA has conducted a preliminary review of your HCT/P, Fiber Viable Bone Matrix (FVBM). Based on the limited information available to FDA, we do not have a basis at this time for concluding that 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 are met for Berkeley Biologics’ FVBM allogeneic 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 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 believe that your products are not in violation of the FD&C Act, the 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 timeframe for completion.

Your response to this letter should be sent to the following address: Amy Graf, Compliance Officer, U.S. Food & Drug Administration, Office of Biological Product Operations – Division 2, 300 River Place Drive – Suite 5900, Detroit, MI 48207 or emailed to Amy.Graf@fda.hhs.gov. If you have any questions, please contact Amy Graf, Compliance Officer via e-mail.

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

cc:
(b)(6), (b)(7)(C)

____________________

1 We note that the product name was changed from Excel Fiber Matrix to Cellular Fiber Matrix on April 21, 2023.

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