Smart Surgical, Inc dba Burst Biologics

During an inspection of your firm, Smart Surgical, Inc., dba Burst Biologics (hereinafter, Burst Biologics), located at 3501 W. Elder St., Ste. 104, Boise, ID 83705, conducted between February 22, 2021 and March 5, 2021, the United States Food and Drug Administration (FDA) documented that you manufacture products derived from human umbilical cord blood, namely, BioBurst Fluid and BioBurst Rejuv, for allogeneic use. You distribute your products to health care providers and facilities throughout the United States. These products are intended for injection and are purported to be sterile.

Information and records gathered prior to and during the inspection, including information on the Burst Biologics website, burstbiologics.com, reflect that your products are intended to treat various diseases or conditions. Therefore, these 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)].

Your 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.

Burst Biologics does not qualify for any exception in 21 CFR 1271.15, and your HCT/Ps derived from human umbilical cord blood fail to meet all the criteria in 21 CFR 1271.10(a).

Specifically, your umbilical cord blood 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.” Your umbilical cord blood derived products are not intended to perform the same basic function or functions of the umbilical cord blood in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system. Rather, your products are intended to be applied to surgical and injury sites to supplement tissue defects and for orthopedic use, and your products could be administered via intra-articular injection. Using your umbilical cord blood derived products in this manner is not homologous use as defined in 21 CFR 1271.3(c).

In addition, your umbilical cord blood derived products fail to meet the criterion in 21 CFR 1271.10(a)(4) because they are manufactured from allogeneic 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-degree blood relative, or reproductive use.

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. Because these HCT/Ps do not meet all the criteria in 21 CFR 1271.10(a), and Burst Biologics 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); 21 CFR Part 312]. Your HCT/Ps derived from human umbilical cord blood are not the subject of an approved biologics license application (BLA) nor is there an IND in effect for any of them. 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) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Part 1271. The deviations in manufacturing 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, your deficient donor screening practices, inadequate aseptic practices, unvalidated manufacturing processes, 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, List of Inspectional Observations, which described a number of significant deviations from CGMP and CGTP requirements applicable to your products. These deficiencies 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)]. FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). Since ZIKV is a RCDAD, donors of umbilical cord, blood, placenta or other gestational tissues should be considered ineligible if certain risk factors are present. However, in May 2016, you began receiving umbilical cord blood units recovered from allogeneic donors in (b)(4), an area considered at increased risk for ZIKV, and you failed to determine these donors as ineligible. These umbilical cord blood units were manufactured into BioBurst Fluid and BioBurst Rejuv and distributed throughout the United States. Although you have since developed new procedures that provide for assessing eligibility based on ZIKV, your prior deficiencies raise potentially significant safety concerns.

2. Failure to establish 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)]. Your firm failed to adequately validate the aseptic process used to manufacture BioBurst Fluid and BioBurst Rejuv (i.e., by performing media fill simulations) since manufacturing began in December 2015. Since then, your firm manufactured and distributed approximately (b)(4) units of BioBurst Fluid and BioBurst Rejuv. These products purport to be sterile. More specifically:

a. Prior to October 31, 2019, you did not conduct any media fill simulations to validate the aseptic manufacturing process for BioBurst Fluid and BioBurst Rejuv to demonstrate that your aseptic process can consistently produce products free of viable microorganisms.

b. On October 31, 2019, a validation plan (VAL-PR-UCB Product Manufacturing-003) under which media fill simulations were conducted to validate your aseptic process for BioBurst Fluid and BioBurst Rejuv was approved; however, the media fills performed under this plan are inadequate1. For example, the units produced during your media fill simulations were not incubated under conditions adequate to detect microorganisms that might otherwise be difficult to culture. Media fill samples were only incubated for (b)(4) days.

3. 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)]. Your firm has not established an adequate system for environmental, including personnel, monitoring in the aseptic processing areas where BioBurst Fluid and BioBurst Rejuv are manufactured. For example:

a. Your firm does not investigate personnel monitoring excursions that exceed your action limit. Approximately (b)(4) units of product associated with personnel monitoring excursions that were not investigated were distributed since October 2020.

b. Your environmental monitoring procedure describes that up to and including (b)(4) colony forming units (CFUs) is an acceptable result for a single personnel monitoring sample, including a sample from glove fingertips that enter the ISO-5 classified biological safety cabinet (BSC) where aseptic processing is conducted. We note that the current industry standard is <1 CFU/plate for gloves or sleeves that enter the ISO-5 classified area and (b)(4) for gowning that remains in the ISO-7 classified area. Your allowance for such high numbers of microorganisms could contribute to product contamination and pose a potential significant safety concern. For additional information, we recommend that you review FDA Guidance for Industry, Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice, available at https://www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf. FDA’s guidance documents do not establish legal requirements.

4. 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)]. Specifically, you told our investigator that components utilized within UCB (umbilical cord blood) manufacturing are not sampled and tested prior to being used in production.

5. Failure to thoroughly investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed [21 CFR 211.192]. Specifically, since December 2015, your firm has had numerous sterility failures for batches of BioBurst Fluid and BioBurst Rejuv that you failed to investigate to determine the source of the contamination beyond identifying organisms (for example, a Paenibacillus species, Bacillus non-anthracis, Kocuria rhizophila, Staphylococcus hominis, and Micrococcus luteus) for a subset of these failed batches. For over 80% of the failures, you did not identify the contaminating microorganism(s). Since December 2015, your firm manufactured and distributed approximately (b)(4) units of BioBurst Fluid and BioBurst Rejuv.

In addition to the above violations, we also note that we are concerned that you may not have verified the suitability of your sterility test method, that you represent is based on USP <71>, used for final product release testing of BioBurst Fluid and BioBurst Rejuv batches from December 2015 until July 31, 2020. Numerous BioBurst Fluid and BioBurst Rejuv batches remain within expiry. Please be reminded that you are required to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods employed, in accordance with 21 CFR 211.165(e). We acknowledge receipt of your correspondences, dated April 16, 2021 and May 14, 2021, responding to FDA’s inspectional observations on the FDA-483. We have reviewed the corrective actions outlined in the response, and we have determined that the response is inadequate to address our concerns. The responses to many of the observations do not provide sufficient detail to fully assess the adequacy of your corrective actions to date, lack a timeline for completion of all necessary corrective actions, and lack documentation to demonstrate that you have corrected your violations. Additionally, your responses are unsatisfactory in that they do not address your firm’s manufacture and distribution of your products derived from umbilical cord blood under the violative conditions outlined above. Nor do your responses remedy the above-noted violations.

While you assert that your products should only be regulated under section 361 of the PHS Act, the available evidence shows that your products do not meet the relevant criteria. Your response also does not adequately address your failure to have an IND in effect to study your products and your lack of an approved BLA to lawfully market your products. As noted above, 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 a product may be distributed for clinical use in humans only if the sponsor has an IND in effect, as specified by FDA regulations, that covers such clinical use [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312].

Neither this letter nor the observations noted on the 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.

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, please 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.

Your response should be sent to the following address: Amy Graf, 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 at (313) 393-2034 or via e-mail.