- Delivery Method:
- VIA UNITED PARCEL SERVICE
- Reference #:
- OBPO 621465
Recipient NameRobert D. Maguire
Recipient TitlePresident and Chief Executive Officer
- BioLab Sciences, Inc.
13825 N. Northsight Blvd., Suite 101
Scottsdale, AZ 85260
- Issuing Office:
- Office of Biological Products Operations – Division 2
August 23, 2022
Dear Mr. Maguire:
During an inspection of your firm, BioLab Sciences, Inc. (hereinafter, “BioLab Sciences”), located at 7662 E. Gray Rd., Suite 107, Scottsdale, AZ 85260, conducted between August 23, 2021, and September 3, 2021, the United States Food and Drug Administration (FDA) documented that you manufacture products derived from human amniotic fluid, specifically, Fluid GF™, Restore GF™, Fluid Flow™, Amnio Restore™, (b)(4), and Stimuleyes™, for allogeneic use, and an epidermal skin tissue product, MyOwnSkin™ and MySkinRestore™, for autologous use (collectively, “your products”).1,2 You have distributed your products to third-party distributors, some under private label, as well as directly to healthcare professionals throughout the United States. Your amniotic fluid products are intended for injection and are purported to be sterile.
Information and records gathered prior to and during the inspection, including information on your website, www.biolabsciences.com, reflect your products are intended to treat various diseases or conditions. Additionally, information collected indicates your products fit within the definition of a biological product in the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)]. Therefore, your 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 PHS Act.
MyOwnSkin™ and MySkinRestore™ 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. 21 CFR 1271.20.
Based on a review of materials described above, BioLab Sciences does not qualify for any exception in 21 CFR 1271.15, and MyOwnSkin™ and MySkinRestore™ fail to meet all the criteria in 21 CFR 1271.10(a).
Specifically, MyOwnSkin™ and MySkinRestore™ fail to meet the criterion set forth in 21 CFR 1271.10(a)(1) that they not be more than minimally manipulated as such term is defined for structural tissue in 21 CFR 1271.3(f)(1). Because your processing alters the original relevant characteristics of the skin related to its utility for reconstruction, repair, or replacement, MyOwnSkin™ and MySkinRestore™ are more than minimally manipulated.
MyOwnSkin™ and MySkinRestore™ also fail to meet other criteria set forth in 21 CFR 1271.10(a). An HCT/P meets the criterion in 21 CFR 1271.10(a)(2) if the HCT/P is “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.” MyOwnSkin™ and MySkinRestore™ are not intended to perform the same basic function or functions of skin in the recipient as in the donor, such as serving as a protective covering. Rather, these products are intended as advanced wound care therapies, including to regenerate skin in various wounds. Such use is not homologous use as defined in 21 CFR 1271.3(c).
An HCT/P meets the criterion in 21 CFR 1271.10(a)(3) if “the manufacture of the HCT/P does not involve the combination with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P.” Based on the processing and product information available for MyOwnSkin™ and MySkinRestore™, skin cells from a patient’s skin are (b)(4) prior to shipment and implantation in the same individual. Therefore, this criterion is also not met.
Because Biolab Sciences does not qualify for any exception in 21 CFR 1271.15, and because MyOwnSkin™ and MySkinRestore™ do not meet all the criteria in 21 CFR 1271.10(a), these products are not regulated solely under section 361 of the PHS Act and the regulations in 21 CFR Part 1271. MyOwnSkin™ and MySkinRestore™ appear to be combination products and would be regulated under the statutory authorities applicable to 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)].3
Please be advised that the definition of HCT/Ps in 21 CFR 1271.3(d) excludes secreted or extracted human products. Accordingly, secreted bodily fluids, such as amniotic fluid, are generally not considered HCT/Ps subject to regulation under 21 CFR Part 1271. Amniotic fluid intended to treat diseases or conditions in humans is generally regulated as a drug under the FD&C Act and a biological product under the PHS Act and requires premarket review and approval. As such, your products derived from amniotic fluid, Fluid GF™, Restore GF™, Fluid Flow™, Amnio Retore™, Stimuleyes™, and (b)(4), are also regulated as drugs and biological products under section 351 of the PHS Act and the FD&C Act.
In order 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]. None of your products are 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) requirements, including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210 and 211.
At the close of the inspection, the FDA investigators issued a Form FDA-483, List of Inspectional Observations, which described a number of significant CGMP deviations applicable to your products. FDA identified additional significant deviations upon further review of the information collected during the inspection, as described below. Additionally, we have received a safety concern about one of your products.
Your CGMP deficiencies, involving over (b)(4) units of products manufactured between March 2019 and the present, include, but are not limited to, the following:
1. 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)]. For example:
a. You failed to validate the aseptic processes used to manufacture over (b)(4) units of Fluid Flow™, Amnio Restore™,(b)(4), Stimuleyes™, Fluid GF™, and Restore GF™ (i.e., by performing media fill simulations) since your manufacturing operations began in March 2019. Based on your product labeling, these products purport to be sterile and are expected to be sterile.
b. Your firm failed to validate the sterilization process for Fluid GF™ and Restore GF™. You have manufactured and distributed over (b)(4) units of these products since June 22, 2021.
c. Your Fluid Flow™ (b)(4) sterilization validation, entitled “(b)(4) Sterilization Validation Report,” RST-1052, dated May 20, 2019, is inadequate. For example:
i. You have had failures during your dose verification audit where it was noted that the established dose to achieve sterility was not adequate and for which you made no changes to your process.
ii. You did not assess the impact of the (b)(4) sterilization on the integrity of the amniotic fluid product’s container-closure system to assure that sterility is maintained.
d. The frequency of monitoring conducted in the critical aseptic areas is insufficient to detect problems and demonstrate control. For example:
i. Surface samples for microbiological monitoring are not collected in the Biological Safety Cabinets (BSCs) directly after processing of your amniotic fluid products. Environmental monitoring should be conducted directly after processing, before cleaning is performed, in order to monitor processing conditions and demonstrate control of the critical area during aseptic processing.
ii. Personnel monitoring is required only every (b)(4) for personnel who process your amniotic fluid products.
e. In accordance with your cleanroom gowning procedure, personnel performing aseptic processing wear non-sterile personal protective equipment (PPE), such as hair covers, beard covers, and shoe covers, that does not adequately protect against microbiological contamination of your products.
f. During the inspection, FDA investigators observed personnel practices that do not adequately protect against microbiological contamination of your products. For example, operators were observed exiting and entering the cleanroom quickly and frequently during manufacturing operations. This practice potentially disturbs the airflow in the cleanroom environment and could introduce contaminants into the cleanroom.
g. Your written environmental monitoring procedure now describes that (b)(4) colony forming units (CFUs) is an acceptable result on environmental monitoring plates intended to detect the presence of microorganisms in the critical processing area. This allowance for such high numbers of microorganisms could contribute to product contamination and pose a potentially 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 www.fda.gov/downloads/Drugs/Guidances/ucm070342.pdf. FDA’s guidance documents do not establish legal requirements.
2. Failure to establish laboratory controls that include scientifically sound and appropriate specifications, standards, sampling plans, 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, your firm has not established appropriate specifications and test procedures to assure that your amniotic fluid products conform to appropriate standards of identity, strength, quality, and purity. Your finished product testing is limited to a visual examination.
3. Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product [ 21 CFR 211.67(b)]. For example:
a. Your firm failed to validate the cleaning process for your BSCs.
b. Your firm has not adequately established and followed written procedures for cleaning the (b)(4) BSCs used to manufacture your products. For example, your written procedure for cleaning does not include the (b)(4) when (b)(4) is used to clean the BSCs during (b)(4) cleanings.
4. Failure to establish and follow written procedures describing in sufficient detail the methods and materials used for sanitation [21 CFR 211.56(b)]. For example:
a. Your firm failed to validate the cleaning process for your cleanrooms.
b. Your firm has not adequately established and followed written procedures for cleaning the cleanrooms used to manufacture your products. For example:
i. In accordance with your cleanroom cleaning procedure, a (b)(4) cleaning of all contact surfaces in the cleanrooms is required at the (b)(4) processing operations. However, a review of your (b)(4) cleaning records revealed that this required cleaning is not always performed, and a justification is not always provided.
ii. You failed to ensure sufficient use of (b)(4), a sporicidal agent, in your disinfection program, as required by your cleanroom cleaning procedure. For example, your firm identified Bacillus, species, a spore-forming organism, on your cleanroom floors. You noted that (b)(4) was not used to disinfect the area because the floors were constructed of materials not normally used in cleanrooms.
iii. Your written procedure for cleanroom cleaning does not include the (b)(4) when (b)(4) is used during (b)(4) cleanings.
iv. The cleaning records do not include dilutions or contact times. During the inspection, no data or rationale for the cleaning agents used or their rotation was provided.
5. Your aseptic processing areas are deficiently designed in that the floors are not smooth, hard surfaces that are easily cleanable in order to prevent contamination [21 CFR 211.42(c)(10)(i)]. For example, your cleanrooms floors have seams and gaps rendering them difficult to clean and disinfect.
6. 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 been already distributed [21 CFR 211.192]. For example, between October 30, 2020, and July 30, 2021, you failed to investigate approximately 90% of your excursions for microbiological monitoring of the cleanroom environment, including two excursions in the critical processing area (i.e., inside your BSCs). While you identified the contaminating organisms, you did not thoroughly investigate the excursions to determine the root cause, product impact, and corrective and preventive actions. Examples of microorganisms identified in your cleanroom include Bacillus species non-anthracis, Fictibacillus species, Bacillus pumilus, Gram Positive Cocci, fungi, and Bacillus megaterium.
7. Failure to ensure that each lot of components, drug product containers, and closures are withheld from use until the lot has been sampled, tested, or examined, as appropriate, and released for use by the quality control unit [21 CFR 211.84]. For example:
a. Your firm used (b)(4) to manufacture approximately (b)(4) batches of MyOwnSkin™ and MySkinRestore™ between June 27, 2019, and September 24, 2021, even though such components had not been examined and released for use by the quality control unit. These components are labeled for research use only.
b. Your firm used (b)(4), to manufacture MyOwnSkin™ and MySkinRestore™, even though such components had not been examined and released for use by the quality control unit. The labeling of those components advises against their use in “Human or Animal Drugs.”
c. Your firm lacks evidence, such as testing, to demonstrate that these components meet all specifications of identity, strength, quality, and purity.
8. 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)]. Specifically, your firm has not validated the manufacturing processes for Fluid GF™, Restore GF™, Fluid Flow™, Amnio Restore™, (b)(4), Stimuleyes™, MyOwnSkin™, and MySkinRestore™.
9. 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, your firm has assigned a twelve-month expiration date to your amniotic fluid products and a 24-hour expiration date to your skin products without supporting data from stability testing.
We have reviewed your written responses, dated September 27, 2021, November 30, 2021, February 14, 2022, March 26, 2022, May 26, 2022, and July 26, 2022, to the inspectional observations on the Form FDA-483, and we have determined that they are inadequate to address our concerns.
We acknowledge your commitment to voluntarily cease the manufacture and distribution of MyOwnSkin™ and MySkinRestore™ until an IND is in effect for such products.4 You also explain that you currently market amniotic membrane products, Membrane Wrap™ and Membrane Restore™, and amniotic fluid products, Fluid GF™ and Restore GF™, and commit that all other tissue products marketed in the past under additional brand names have been discontinued. Please note that amniotic fluid products are not considered tissue products. We acknowledge that you report having discontinued manufacturing (b)(4), Stimuleyes™, Fluid Flow™, and Amnio Restore™.
Your responses, however, do not adequately address your failure to have an IND in effect for your amniotic fluid products and your lack of an approved BLA to lawfully market those 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].
Your response also does not adequately address any inventory of Fluid GF™, Fluid Flow™, Restore GF™, and Amnio Restore™ at your facility. In response to this letter, provide your specific plans for the disposition of all of these products. Please also explain in detail your intention to use your inventory of Fluid Flow™ and Amnio Restore™, currently in quarantine, for “potential research use.”
We note that you have previously marketed Amnio Breathe™, a nebulizer bundle containing Fluid Flow™. In response to this letter, please also inform FDA whether you are currently marketing this product or intend to in the future.
Finally, we note that in your responses you discuss updates to your procedures in an attempt to comply with CGMP requirements. We have reviewed those updates and listed your CGMP deficiencies above. We are not providing further input on your updates to procedures in this letter.
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. 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.
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 correct the noted violations and prevent their recurrence. Include any documentation necessary to show that 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 to the following address: Amy Graf, Compliance Officer, U.S. Food and Drug Administration, Office of Biological Products Operations – Division 2, 300 River Place Dr. – Suite 5900, Detroit, MI 48207 or emailed to Amy.Graf@fda.hhs.gov. If you have any questions, please contact Ms. Graf at (313) 393-2034 or via e-mail.
Karlton T. Watson
Program Division Director
Office of Biological Products Operations – Division 2
Cc: Robert D. Maguire
President and Chief Executive Officer
BioLab Sciences, Inc.
7662 East Gray Road, Suite 107
Scottsdale, AZ 85260
1 This letter only pertains to Fluid GF™, Restore GF™, Fluid Flow™, Amnio Restore™, (b)(4), Stimuleyes™, MyOwnSkin™, and MySkinRestore™. You also manufacture products derived from amniotic membrane, including Membrane Wrap™, Membrane Restore™, and Vision Sphere™. Please be advised that Membrane Wrap™ does not appear to meet the homologous use only criterion at 21 CFR 1271.10(a)(2). You describe this product as a “human tissue allograft derived from amniotic membrane that provides structural tissue for use as a wound and protectant covering.” Use of Membrane Wrap™ as a wound covering would be considered a homologous use. However, you also market this product, for example, to reduce pain and scarring, adhere wounds, heal, and as “anti-bacterial” and for “immune privileged and neovascularization.” Such uses are considered nonhomologous uses for amniotic membrane. Membrane Wrap™ must meet all the criteria at 21 CFR 1271.10(a), including the homologous use criterion at 21 CFR 1271.10(a)(2), to be regulated solely under section 361 of the Public Health Service Act and the regulations in 21 CFR Part 1271. This letter does not otherwise address your amniotic membrane products.
2 Some of your products are the same products marketed under different brand names. For example, you represented to FDA that (b)(4) is the same product as Stimuleyes™. Likewise, MyOwnSkin™ and MySkinRestore™ are the same product marketed under different brand names.
3 As combination products, MyOwnSkin™ and MySkinRestore™ would be appropriately assigned to the Center for Biologics Evaluation and Research (CBER) based on the combination products’ primary mode of action. (b)(4).
4 We note that you had been informed by FDA prior to FDA’s inspection that MyOwnSkin™ appeared to be regulated as a combination product. Nevertheless, you continued to manufacture and distribute this product without premarketing approval until September 24, 2021.