WARNING LETTER

Regenerative Processing Plant, LLC MARCS-CMS 672154 — August 16, 2024

Delivery Method:: VIA UNITED PARCEL SERVICE SIGNATURE REQUIRED
Reference #:: 24-672154
Product:: Biologics
Drugs

Recipient:: Recipient Name

Carl R. Harrell, MD; Recipient Title

Owner, Chairman, CEO, and Medical Director; Regenerative Processing Plant, LLC; 34176 US Highway 19 N
Palm Harbor, FL 34684-2144
United States; dr.harrell@regenerativeplant.org

Issuing Office:: Center for Biologics Evaluation and Research; United States

Secondary Issuing Offices

Center for Drug Evaluation and Research (CDER)

United States

WARNING LETTER

August 16, 2024

Dear Dr. Harrell:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Regenerative Processing Plant, LLC (hereafter “RPP”), FEI 3011320041, located at 34176 US Highway 19 N, Palm Harbor, FL, between June 20, 2023, and June 30, 2023. FDA investigators documented that you manufacture two ophthalmic drug products, Regener-Eyes® Professional (PRO) Ophthalmic Solution and Regener-Eyes® LITE Ophthalmic Solution (hereinafter, “Regener-Eyes® PRO and Regener-Eyes® LITE” or “your Regener-Eyes® products” or “your ophthalmic products”). FDA investigators also documented that prior to manufacturing these ophthalmic drug products, you manufactured a Regener-Eyes ophthalmic drug product containing amniotic fluid. You have distributed your ophthalmic products directly to optometrists, eye clinic facilities, and patients throughout the United States. Your Regener-Eyes® products purport to be sterile and preservative free and are packaged in a multiple-dose container.

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR parts 210 and 211. Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) [21 U.S.C. § 351(a)(2)(B)].

In addition, your Regener-Eyes® PRO and Regener-Eyes® LITE products are unapproved new drugs introduced or delivered for introduction into interstate commerce in violation of section 505(a) of the FD&C Act [21 U.S.C. § 355(a)]. Furthermore, Regener-Eyes® Professional and Regener-Eyes® LITE products are also misbranded under sections 502(a) and 502(ee) of the FD&C Act [21 U.S.C. §§ 352(a) and 352(ee)].

Introduction or delivery for introduction of such products into interstate commerce is prohibited under sections 301(a) and (d) of the FD&C Act [21 U.S.C. §§ 331(a) and (d)]. These violations are described in more detail below.

Unapproved New Drug and Misbranding Violations

Your Regener-Eyes® products are drugs under section 201(g)(1) of the FD&C Act [21 U.S.C. § 321(g)(1)], because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body.

Examples of claims from your websites and product labeling that provide evidence of the intended use of these products as drugs include but may not be limited to, the following:

Your product labeling for both Regener-Eyes® Lite and Regener-Eyes® Professional at www.regenereyes.com (last visited August 2024):

“Relieve Dryness of the Eye.”
“Dry Eye Relief Made Simple”

Your webpage www.regenereyes.com/pages/government (last visited August 2024):

“Regener-Eyes® Tonicity Solution™ employs patented technology to combat dry eye-triggering hyperosmolarity.”
“A New Therapeutic Agent to Relieve Dryness of the Eye for Tear Hyperosmolarity-Induced Pathological Changes in the Eyes of Patients Suffering From Dry Eye Discomfort.”

Unapproved New Drug Violations

Based on the above labeling evidence, your Regener-Eyes® products are intended for use as ophthalmic demulcent (lubricant) drug products. As described below, these drug products are unapproved new drugs marketed in violation of sections 505(a) and 301(d) of the FD&C Act [21 U.S.C. 355(a) and 331(d)].

A drug product is a “new drug” within the meaning of section 201(p) of the FD&C Act [21 U.S.C. 321(p)], if it is not generally recognized as safe and effective (GRASE) for use under the conditions prescribed, recommended, or suggested in its labeling. 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 [21 U.S.C. 355(a)]. No FDA-approved applications pursuant to section 505 of the FD&C Act [21 U.S.C. § 355], are in effect for your Regener-Eyes® products.

Under section 505G of the FD&C Act, certain nonprescription drugs marketed without an approved application – commonly referred to as “OTC monograph drugs” – may be legally marketed if they meet applicable requirements. With respect to ophthalmic demulcent (lubricant) drug products, such as your Regener-Eyes® products, in order to be deemed to be GRASE and not a new drug, the product must, among other things, conform to the conditions in the applicable OTC monograph, here Over-the-Counter Monograph M018: Ophthalmic Drug Products for Over-the-Counter Human Use (hereinafter Monograph M018). However, your Regener-Eyes® products do not conform to the conditions specified in OTC Monograph M018 because these products fail to meet certain conditions of the applicable monograph.

First, your Regener-Eyes® products are formulated with the active ingredients “Tonicity Solution Sodium Chloride” and glycerin. “Tonicity Solution Sodium Chloride,” or sodium chloride, is not an active ingredient that is permitted for ophthalmic demulcents under the Monograph M018.¹

We note that although you identify your “Tonicity Solution Sodium Chloride” as an inactive ingredient on the product labels, statements on your website show that this ingredient is an active ingredient in your products because it is intended to furnish pharmacological activity for the treatment of a disease or condition.² Examples of these statements are:

“Regener-Eyes® Tonicity SolutionTM . . . combats dry eye-triggering hyperosmolarity”
“Tear hyper-osmolarity (THO) is a primary culprit in dry eye problems.”
Regener-Eyes® Tonicity SolutionTM is a “Breakthrough Solution…[I]ts hypotonic solution, enriched with osmoprotectants, target tear hyperosmolarity directly, enhancing tear stability crucial for symptom relief. This innovative formula represents a significant advancement in the treatment of dry eye.”

Additionally, your Regener-Eyes® products fail to include certain required labeling statements. Specifically, your products are not labeled with the warnings required for ophthalmic demulcents under the Monograph M018.

Thus, your Regener-Eyes® products do not comply with the applicable conditions specified in Monograph M018 and have not otherwise been found to be GRASE. Accordingly, these products are new drugs within the meaning of section 201(p) of the FD&C Act [21 U.S.C. § 321(p)], and there is no basis under section 505G of the FD&C Act under which these products would be legally marketed without an approved application. Because there are no approved applications in effect for these products, they are unapproved new drugs. The introduction or delivery for introduction of such products into interstate commerce violates sections 505(a) and 301(d) of the FD&C Act [21 U.S.C. § 355(a) and 331(d)].

Misbranded Drug Violations

Furthermore, your Regener-Eyes® products are misbranded under section 502(a) of the FD&C Act [21 U.S.C. § 352(a)]; the labeling of these products is false or misleading for several reasons. First, the labeling for your products identifies “Tonicity Solution Sodium Chloride” as an inactive ingredient, but the above statements, such as “combat dry eye-triggering hyperosmolarity,” show that this ingredient is intended to furnish pharmacological activity for the treatment of a disease or condition.

See 21 CFR 207.1. Furthermore, you represent that your products are “in full compliance with the FDA.” As stated above, your Regener-Eyes® products are not in full compliance with statutory requirements enforced by the FDA because these products are unapproved new drugs that are not exempt from approval, and misbranded drugs. You also state that “Regener-Eyes® is a ... FDA registered OTC drug” and that “FDA approvals are typically associated with prescription drugs, whereas [OTC] drugs undergo FDA registration and regulation.” Your statements imply that registration (or listing) with FDA for OTC drugs is comparable to approval of prescription drugs, or that “registration and regulation” means that an OTC drug may be legally marketed. Registration of an establishment or listing of a drug does not denote approval of the establishment, the drug, or any other drugs of the establishment, nor does it mean that a product may be legally marketed (21 CFR 207.77(a)). We also note that to state that any drug product is “FDA registered” is inaccurate; pursuant to section 510 of the FD&C Act [21 U.S.C. § 360], drugs are subject to listing with FDA, not registration.

Additionally, Regener-Eyes® products are misbranded under section 502(ee) of the FD&C Act [21 U.S.C. § 352(ee)], because these products are nonprescription drugs subject to section 505G of the FD&C Act [21 U.S.C. § 355h], but do not comply with the requirements for marketing under that section and are not the subject of an application approved under section 505 of the FD&C Act [21 U.S.C. § 355].

The introduction or delivery for introduction of a misbranded drug into interstate commerce violates section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].

Current Good Manufacturing Practice (CGMP) Violations

During the inspection, FDA investigators documented significant violations from CGMP requirements. At the conclusion of the inspection, FDA investigators issued a Form FDA FDA-483, List of Inspectional Observations, which described significant violations from CGMP requirements applicable to your ophthalmic products. These violations involved the manufacture of (b)(4) bottles and distribution of (b)(4) bottles of your Regener-Eyes® products between August 2022 and June 2023 as well as the previous manufacture and distribution of your amniotic fluid-derived Regener-Eyes® ophthalmic solution product prior to June 2021. The violations include, but are not limited to, the following:

1. Your firm failed to establish and follow appropriate written procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes [21 CFR 211.113(b)].

Your firm has not adequately validated the aseptic processes used to manufacture Regener-Eyes® PRO and Regener-Eyes® LITE since commencing manufacturing operations for these products in December 2021. For example:

i. During the initial media fill studies performed in June 2022, two of the (b)(4) batches contained contaminated units. Regener-Eyes® LITE batch (b)(4) contained three contaminated units out of (b)(4) units filled. Regener-Eyes® PRO batch (b)(4) contained one contaminated unit out of (b)(4) units. Neither batch was evaluated for an assignable cause of contamination or followed by successful revalidation.

ii. During additional media fill studies conducted between November 2022 and April 2023, your firm incubated and examined a select number of filled units based on an acceptable quality level (AQL) sampling plan, rather than all integral, filled units. For example, only (b)(4) of the total units filled (Regener-Eyes® PRO batches (b)(4)) were incubated and examined for microbial contamination. All filled units representative of the routine commercial process should be incubated and examined to provide a meaningful assessment of the capability of your aseptic process.

iii. Your media fill data were not reliable because you did not conduct growth promotion testing for (b)(4) media utilized to fill units during both media fill studies. Growth promotion testing demonstrates whether the media is capable of supporting the growth of microorganisms that may be present.

2. 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,

i. You did not establish appropriate written procedures for environmental monitoring (EM) in the aseptic processing areas where your ophthalmic products are manufactured. For example, EM alert or action levels are not defined for viable microorganism monitoring such as active air sampling, surface sampling, and personnel monitoring within your procedures. Further, the action level for viable microorganism EM located in form R-MICRO-F006 “Cleanroom Environmental Sample Incubation Log” is listed as “N/A”.

ii. Your environmental monitoring data for viable microorganisms in your aseptic processing area used to manufacture your ophthalmic products was not reliable because your firm did not conduct growth promotion testing for media utilized. Growth promotion testing demonstrates whether the media is capable of supporting the growth of microorganisms that may be present.

3. Your firm failed to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of stability testing to determine appropriate storage conditions and expiration dates [21 CFR 211.166(a)]. For example, your stability studies for Regener-Eyes® PRO ophthalmic solution do not support storage of the product at room temperature for 24 months as provided on product labeling. The stability studies you conducted as per protocol STB-22-0029 and STB-22-0030 titled “Stability Study Protocol for Regener-Eyes® Ophthalmic Solution, (b)(4) Professional Strength” failed to meet defined objectives, such as (b)(4) failures under (b)(4) conditions at (b)(4) and (b)(4) time points and pH values exceeding defined range under room temperature conditions at (b)(4).

4. Your firm failed to conduct at least one test to verify the identity of each component of a drug product [21 CFR 211.84(d)(1)]. For example, your firm does not conduct identity tests when receiving lots of sterile (b)(4) sodium chloride, an ingredient used to manufacture the “tonicity solution” and glycerin contained in your Regener-Eyes® PRO and Regener-Eyes® LITE products.

5. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced, including specific identification of each batch of component or in-process material used [21 CFR 211.188(b)(3)]. For example, during the inspection on June 20, 2023, you stated that the “tonicity solution” manufactured as an intermediate for your Regener-Eyes® PRO and Regener-Eyes® LITE products contains only sterile (b)(4) sodium chloride. However, completed batch records for your Regener-Eyes® PRO and Regener-Eyes® LITE products do not identify that sterile (b)(4) sodium chloride is used as a component within the manufacture of your Regener-Eyes® PRO and Regener-Eyes® LITE products.

6. Failure to have an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions [21 CFR 211.42(c)(10)(v)]. For example, you had not validated your process for cleaning and disinfecting the Biological Safety Cabinets (BSCs) and supporting cleanrooms where your ophthalmic products were manufactured.

7. Your firm failed to maintain production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch [21 CFR 211.180(a)] For example, according to your Chief Strategist, the last batch of your Regener-Eyes® product containing amniotic fluid was manufactured in June 2021. Given that this product was labeled with a two-year expiration date, this batch would have expired in June 2023. You would have been required to maintain records until June 2024. However, during the inspection on June 22, 2023, in response to a request for records pertaining to this amniotic fluid-derived Regener-Eyes® ophthalmic solution product, (which your Chief Strategist claims was discontinued in June 2021), your Chief Strategist stated that she could not locate any records such as complaint records, distribution records, receiving records, storage records, and manufacturing records. She further stated that she could not remember where the records went or whether they were destroyed or not.

8. Your firm failed to retain an appropriately identified reserve sample that is representative of each lot or batch of drug product [21 CFR 211.170(b)]. For example, according to your Chief Strategist, your firm discontinued manufacturing your Regener-Eyes® product containing amniotic fluid in approximately June 2021. Given that this product had a labeled two-year expiration date, any batches that your firm manufactured in June 2021 would have expired in June 2023 based on product labeling. You would be required to maintain reserve samples until June 2024. However, during the inspection, your Chief Strategist indicated that the firm was no longer in possession of reserve samples of amniotic fluid derived Regener-Eyes® and no longer kept documentation pertaining to these activities.

Corrective Actions

We have reviewed your correspondences dated July 24, 2023, August 16, 2023, September 26, 2023, November 15, 2023, January 30, 2024, and February 16, 2024, responding to FDA’s inspectional observations on the Form FDA-483. We acknowledge the corrective actions within your responses, including the following:

Your decision to voluntarily suspend manufacturing operations and not distribute any Regener-Eyes® products filled after June 14, 2023 (when the last batch was filled prior to your shutdown) until after completion of your planned corrective actions (originally anticipated no earlier than January 2024).
Your replacement of the (b)(4) Multidose Eye Dropper eyedropper bottle used for your Regener-Eyes® PRO and Regener-Eyes® LITE ophthalmic solution products since product launch and up until June 14, 2023, with the (b)(4) Multidose Eye Dropper Bottle.
Your commitment to immediately quarantine and hold for (b)(4) all inventory of your Regener-Eyes® products manufactured prior to (b)(4) (date corrective actions were implemented for failing (b)(4) results) consisting of (b)(4) lots (or (b)(4) bottles) of your Regener-Eyes® products and to delay (b)(4) of the quarantined product until you learn from FDA whether it wishes to supervise (b)(4) or to review and approve your (b)(4) method if requested.
Your retainment of a consultant to assist your firm in meeting CGMP requirements. Your consultant should be qualified as set forth in 21 CFR 211.34 to evaluate your operations and to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market.

Some of the corrective actions described in your responses are not adequate to address the above-referenced violations. We note that certain corrective actions cannot be evaluated because they lack supporting documentation. In addition, your responses do not address your specific plans for disposition of the inventory of your ophthalmic products at your facility. Additionally, for your previously distributed product, you do not describe actions you have taken or plan to take that adequately address the impact of the above-noted violations on your distributed Regener-Eyes® products labeled with a two-year shelf life and manufactured under the above-described conditions. Examples of additional inadequacies include but are not limited to:

Although your firm committed to (b)(4) Regener-Eyes® products manufactured prior to implementing corrective actions on (b)(4) to address failing (b)(4) results, the response states that your firm believes no market action is required for bottles manufactured prior to this date (before corrective actions were implemented) that were distributed and remain within labeled expiry. In the impact assessment, your firm concludes the Regener-Eyes® products are safe and stable based on a review of customer complaints, along with analytical and sterility results from stability studies (that were discontinued at three months). Such data do not provide a sufficient level of assurance that the products, intended for application to the eye and packaged in bottles with known (b)(4) issues, would be sterile over the shelf-life of the product. We are concerned about product you have distributed in the market using the previous bottle. Please inform FDA in response to this letter whether you are willing to take additional voluntary actions with respect to this distributed product.
Additionally, we acknowledge your corrective actions related to aseptic process validation (i.e., media fill studies) of Regener-Eyes® products within your responses. However, review of your media fill study records associated with product tentatively planned to be manufactured after January 2024 revealed critical study design issues, such as use of media not validated for microbial growth (e.g., results of media growth promotion studies were not provided to demonstrate the media can detect microbial growth) and failure to ensure the study is representative of the entire manufacturing process (e.g., lack of evidence that the container closure used in the media fill studies is comparable to the new (b)(4) Multidose Eye Dropper Bottle and lack of (b)(4) to represent the (b)(4) of glycerin and tonicity solution into the sterile (b)(4)). Please be advised, it is important that media fill samples represent the entire batch, the commercial container-closure system, and processing conditions.
Further, review of cleaning and disinfecting agents validation (August 16, 2023 response Exhibit D; “Disinfectant Efficacy Study 23-03309”) included results “outside of study acceptance criteria” for reduction of spores for (b)(4) and (b)(4) disinfecting reagents. Specifically, Tables 4 and 5 of the referenced document indicate B. subtilis spore reduction values of (b)(4), which does not meet your acceptance criteria.
Regarding your failure to conduct specific identity tests on components and failure to identify components in your batch records, your response did not include sufficient details to provide assurance that sodium chloride was, in fact, used to manufacture batches of your ophthalmic products prior to revising your procedures in response to the Form FDA-483.
We acknowledge your corrective actions to the Form FDA-483 observations pertaining to environmental monitoring. However, we are unable to fully evaluate your corrective actions due to lack of adequate supporting documentation. For example, you did not provide data showing that there have been “no instances of microbial excursions in the BSC ISO 5 hood environmental testing for the entire manufacturing of all products,” as your response states. With respect to growth promotion testing of media, while you purport to have tested all media lots in inventory, you did not provide evidence that lots of media used for environmental monitoring during production of distributed lots were suitable for use, nor did you discuss the potential impact to distributed lots. Additionally, you did not provide the growth promotion testing procedure for our review.
We acknowledge receipt of your stability data submitted in the February 16, 2024 submission. However, the data provided is only for (b)(4) of stability under (b)(4) conditions ((b)(4) relative humidity (RH)) and long-term conditions ((b)(4) RH) and does not support a proposed two-year expiry. For example, under both conditions, the pH results are demonstrating a downward trend, and it is unclear whether the pH will meet requirements at the end of a proposed two year expiry.

Additional Concerns

Contamination Risks
Your Regener-Eyes® PRO and Regener-Eyes® LITE were packed in multi-dose vials that do not have a mechanism for backflow prevention and are labeled preservative-free. The products do not contain a substance to inhibit the growth of organisms, and the container type did not provide adequate protection and minimize the hazard of injury from contamination during use. Multi-dose ophthalmic drug products should contain one or more suitable substances that will preserve a product and minimize the hazard of injury resulting from incidental contamination during use. FDA therefore remains concerned that your container closure system may not be able to afford adequate protection from contamination in storage and use for multi-dose, preservative-free drug products.³ There are numerous ways in which such presentations might fail to prevent microbial contamination. Any ophthalmic drug product that lacks adequate preservative properties, when exposed to in-use contamination, is especially vulnerable to proliferation of microbes that can pose severe harm to consumers.⁴

Additionally, your unapproved ophthalmic drug products are especially concerning from a public health perspective, particularly given your firm’s significant CGMP violations. Ophthalmic drug products, which are intended for administration into the eyes, in general, pose a heightened risk of harm to users, because the route of administration for these products bypasses some of the body’s natural defenses.

Products Potentially Containing Amniotic Fluid
FDA sent you a copy of the Untitled Letter dated October 5, 2022 issued to your subsidiary, Regener-Eyes, LLC, notifying you that your product, Regener-Eyes® Ophthalmic Solution, derived from “placental-derived biomaterial” and intended to mitigate or treat dry eye disease appeared to be a drug and a biological product requiring a valid biologics license under 42 U.S.C. § 262(a) in order to lawfully market the product. During the inspection, your Chief Strategist claimed that your firm discontinued manufacturing Regener-Eyes® Ophthalmic Solution containing amniotic fluid in approximately June 2021, and represented that any remaining amniotic fluid at your facility is used for research purposes.

However, FDA investigators documented that you continue to receive shipments of amniotic fluid from (b)(4), and many of the (b)(4)-distributed amniotic fluid unit donor IDs identically matched (b)(4) lot codes observed within RPP inventory and Regener-Eyes® PRO and Regener-Eyes® LITE manufacturing batch records for products manufactured after June 2021. These facts, combined with some of the violations described above, such as failure to test sodium chloride for identity and failure to document use of sodium chloride in your batch records, raise questions about whether your Regener-Eyes® products manufactured after June 2021 may still contain amniotic fluid. FDA has serious safety concerns about the use of amniotic fluid in eyedrops. We direct your attention to FDA’s Public Safety Notice on Amniotic Fluid Eyedrops available at https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/public-safety-notification-amniotic-fluid-eyedrops#:~:text=FDA%20has%20taken%20steps%20to,available%20on%20the%20FDA%20website.

Amniotic fluid is not an active ingredient identified in OTC Monograph M018. As discussed above, Regener-Eyes® products are drugs under section 201(g)(1) of the FD&C Act [21 U.S.C. § 321(g)(1)], because they are intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease, and/or intended to affect the structure or any function of the body. If your Regener-Eyes® products contain amniotic fluid as an active ingredient, they would also be biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. § 262(i)] because they are applicable to the prevention, treatment, or cure of a disease or condition of human beings.⁵

To lawfully market a drug that is a biological product, a valid biologics license application (BLA) 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 ophthalmic products are not the subject of an approved BLA nor is there an IND in effect for either product.

Records
We have significant concerns that FDA investigators were unable to obtain records pertaining to the manufacture and distribution of your Regener Eyes® ophthalmic solution product containing amniotic fluid upon request from you during the inspection. Be advised that section 501(j) of the FD&C Act [21 U.S.C. § 351(j)] deems a drug to be adulterated if “it has been manufactured, processed, packed, or held in any factory, warehouse, or establishment and the owner, operator, or agent of such factory, warehouse, or establishment delays, denies, or limits an inspection, or refuses to permit entry or inspection.” For more details, review FDA’s Guidance titled, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection”, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/circumstances-constitute-delaying-denying-limiting-or-refusing-drug-inspection.

Additional Information

In-Use Stability Studies
Ophthalmic drug products should be appropriately designed and controlled to prevent harmful microbial contamination throughout their shelf life and in-use period, which must be supported by stability data.⁶ We note that your website indicates that your Regener-Eyes® PRO and Regener-Eyes® LITE products can be “stored at room temperature and used within 90 days” after opening. Note that stability studies are needed to support such a statement. Without such studies, the risk for microbial contamination and growth is unknown.

Products Containing Glycerin
You manufacture ophthalmic drug products that contain glycerin. Identity testing for these and certain other high-risk drug components includes a limit test in the United States Pharmacopeia (USP) to ensure that the component meets the relevant safety limits for levels of diethylene glycol (DEG) or ethylene glycol (EG). The use of ingredients contaminated with DEG or EG has resulted in various lethal poisoning incidents in humans worldwide. See FDA’s May 2023 Guidance titled, “Testing of Glycerin, Propylene Glycol, Maltitol Solution, Hydrogenated Starch Hydrolysate, Sorbitol Solution, and Other High-Risk Drug Components for Diethylene Glycol and Ethylene Glycol” at https://www.fda.gov/media/167974/download, for additional information describing CGMP requirements when manufacturing drugs containing ingredients at high-risk for DEG or EG contamination.

Conclusion

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 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 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.

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 cannot address these matters within fifteen (15) working days, please explain the reason for your delay and the timeframe for completion. If you do not believe your ophthalmic products are in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration.

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 your 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

/S/
Melissa J. Mendoza
Director, Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

/S/
Jill Furman
Director, Office of Compliance
Center for Drug Evaluation and Research

CC:
Carl R. Harrell, MD
Medical Director & Owner
Regenerative Processing Plant, LLC
13700 Reptron Blvd.
Tampa, FL 33626-3040
dr.harrell@regenerativeplant.org
FEI: 3025422586

Carl R. Harrell, MD
Medical Director & Owner
Regener-Eyes, LLC
13700 Reptron Blvd.
Tampa, FL 33626-3040
dr.harrell@regenerativeplant.org
FEI: 3023093657

___________________

1 We note that “sodium chloride” is a permitted active ingredient in Monograph M018 as a hypertonicity agent. Even if your products were hypertonicity agents rather than demulcents, the products would nevertheless fail to conform to Monograph M018 because they are not labeled as required under the monograph for hypertonicity agents, including for the required indication of “For the temporary relief of corneal edema.” Furthermore, the Monograph M018 does not permit the combination of hypertonicity agent ingredients with demulcent ingredients such as glycerin.

2 See e.g., 21 CFR 207.1, which defines an active ingredient as “any component that is intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of man.”

3 21 CFR 211.94(b).

4 21 CFR 200.50(a)(2) states, in relevant part, “…liquid preparations offered or intended for ophthalmic use that are not sterile may be regarded as adulterated…”

5 The definition of human cells, tissues, or cellular or tissue based products (HCT/Ps) in 21 CFR 1271.3(d) excludes secreted or extracted human products, except semen. 21 CFR 1271.3(d)(3). Accordingly, amniotic fluid, which is a secreted bodily fluid, is not considered an HCT/P and is not regulated under section 361 of the Public Health Service Act and the regulations in 21 CFR part 1271.

6 21 CFR 211.166(a).