StemGenex Biologic Laboratories, LLC - 557907 - 10/31/2018

WARNING LETTER

UNITED PARCEL SERVICE

SIGNATURE REQUIRED

October 31, 2018

Warning Letter #OBPO - 19-02

Rita F. Alexander, Owner/Manager

Jenny R. Galloway, MD, Laboratory and Medical Director

StemGenex Biologic Laboratories, LLC

11515 El Camino Real, Suite 100

San Diego, CA 92130-3034

Dear Ms. Alexander and Dr. Galloway:

During an inspection of your firm, StemGenex Biologic Laboratories (SGBL), LLC, located at 11515 El Camino Real, Suite 100, San Diego, CA 92130, conducted between January 16 and 26, 2018, the Food and Drug Administration (FDA) documented that your firm processes adipose tissue, a structural tissue, from donors for autologous use. Your firm uses (b)(4), which are further processed into stromal vascular fraction (SVF). Your SVF product is administered in a variety of ways, including (b)(4).[1]

Records gathered during the inspection and the information available on your website reflect that your SVF product is intended to treat a variety of diseases and conditions, including, but not limited to, Alzheimer’s disease, Crohn’s disease, Type I and Type II diabetes, fibromyalgia, spinal cord injury, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), muscular dystrophy, Parkinson’s disease, peripheral neuropathy, and rheumatoid arthritis.

Therefore, your SVF product is a drug 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 a biological product as defined in section 351(i) of the Public Health Service Act (PHS Act) [42 U.S.C. 262(i)]. It is also a human cell, tissue, or cellular or tissuebased product (HCT/P) as defined in 21 CFR 1271.3(d)[2] and is subject to regulation under 21 CFR Part 1271, issued under authority of section 361 of the PHS Act [42 U.S.C. 264]. However, SGBL does not qualify for any exception in 21 CFR 1271.15, and this product fails to meet all the criteria in 21 CFR 1271.10(a). Therefore, your SVF 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.

Specifically, your SVF product does not meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) as defined for structural tissue, such as adipose tissue, in 21 CFR 1271.3(f)(1). Your product does not meet this criterion because your processing alters the original relevant characteristics of the adipose tissue relating to its utility for reconstruction, repair, or replacement.

In addition, your SVF product fails to meet 21 CFR 1271.10(a)(2) criterion 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.” As noted above, your SVF product is intended for use in the treatment of a variety of diseases and conditions. Because your SVF product is not intended to perform the same basic function or functions of adipose tissue, which generally is to cushion and support the body, using the SVF product for treatment of these diseases and conditions is not homologous use as defined in 21 CFR 1271.3(c). As a result, your SVF product does not qualify for regulation solely under section 361 of the PHS Act and 21 CFR Part 1271.

Please be advised that 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 a showing of safety and efficacy for the product’s intended use. While in the development stage, such products may be used 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 SVF product is not the subject of an approved biologics license application (BLA) nor is there an IND in effect. 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), including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210 and 211. The deviations in manufacturing processes observed as well as those noted in documents collected during the inspection indicate that the use of your SVF product raises potential significant safety concerns. For example, SGBL’s unvalidated manufacturing processes, uncontrolled environment, lack of control of components used in production, such as the (b)(4) and lack of sufficient and validated product testing (sterility and endotoxin testing), as described below, pose a significant risk that your SVF product may be contaminated with microorganisms or have other serious product quality defects. Furthermore, your SVF product is intended to treat a variety of serious or life-threatening diseases or conditions, all of which are non-homologous uses. Such uses raise potential significant safety concerns because there is less basis on which to predict the product’s behavior in the recipient, and use of these unapproved products may cause users to delay or discontinue medical treatments that have been found safe and effective through the New Drug Application or BLA approval processes. Because the product is administered to humans by various higher risk routes of administration, including (b)(4), if contaminated, its use could cause a range of adverse events, from infections to death.

At the close of the inspection, FDA investigators issued Ms. Rita F. Alexander a Form FDA 483, list of inspectional observations, which described a number of significant objectionable conditions relating to your compliance with CGMP. FDA has found some additional significant deviations upon further review of the information collected during the January 2018 inspection, as discussed below. The deficiencies include, but are not limited to, the following:

1. Failure to establish and follow 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. Your firm failed to perform media fill simulations to evaluate the state of control of the aseptic process used to manufacture approximately (b)(4) batches of your SVF product between January 2012 and January 2018. This product is administered by various methods, including (b)(4) for a variety of diseases and conditions. By the nature of its routes of administration, the SVF product purports to be sterile and is expected to be sterile.

b. Your SOP STEM-LAB-011: Gowning, does not specify that manufacturing personnel should wear appropriate sterile gowns or other garments, including: sterile overalls, surgical masks, disposable shoe covers and bouffant caps. Appropriate gowning reduces the potential for the manufacturing personnel to inadvertently contaminate the product during the aseptic manufacturing process.

c. Routine personnel monitoring and qualification is not performed for individuals involved in the aseptic manufacturing process for your SVF product.

d. Your firm added nonsterile (b)(4) to approximately (b)(4) batches of your SVF product which is administered by various higher risk routes of administration, including (b)(4) between January 2012 and January 2018.

2. Failure to establish written production and process control procedures 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, you isolate the cellular components from adipose tissue through (b)(4) and (b)(4), which are further processed into your SVF product by (b)(4) and (b)(4). By manufacturing approximately (b)(4) batches of SVF product without validating the manufacturing process, you failed to adequately establish such production and process controls.

3. Failure to perform appropriate laboratory testing, as necessary, of each batch of drug product required to be free of objectionable microorganisms [21 CFR 211.165(b)]. Specifically, you failed to perform appropriate laboratory testing, including sterility and endotoxin testing, on approximately (b)(4) batches of your SVF product manufactured from January 2012 to January 2018. Such laboratory testing is necessary for the SVF product, which by the nature of its routes of administration, is required to be free of objectionable microorganisms.

4. Failure to have separate or defined areas or such other control systems for operations as are necessary to prevent contamination or mix-ups during the course of manufacturing and processing operations [21 CFR 211.42(c)(5)]. On January 18, 2018, FDA investigators observed SGBL personnel manufacturing two different SVF batches in the (b)(4) at the same time.^{^[3]}

5. Failure to have a system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)]. Specifically, your firm has not established a system for monitoring environmental conditions in the aseptic processing area where the SVF product is manufactured.

6. Failure to establish and follow written procedures for cleaning and maintenance of equipment, including utensils [21 CFR 211.67(b)]. Specifically, SOP STEM-LAB-020, Laboratory Cleaning, does not address the cleaning or maintenance of equipment, including your two (b)(4) (#SN (b)(4), #SN (b)(4)), the (b)(4), or the (b)(4) Centrifuge (b)(4). Additionally, this SOP does not address cleaning between batches.

7. Failure to maintain laboratory controls that include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure the components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality and purity [21 CFR 211.160(b)]. For example, you have not established specifications, standards, sampling plans and test procedures for testing your SVF product for identity, strength, quality, and purity.

8. 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(a)]. For example, the following components and containers are not tested or examined before release:

a. (b)(4), used in the final formulation of your SVF product;

b. The (b)(4) used in the manufacture of the SVF product. Of critical note, this component is for research use only, as stated on the manufacturer’s certificate of conformance. This component is also nonsterile and not sterilized prior to use;

c. The (b)(4) used to isolate the cellular components from the adipose tissue;

d. The (b)(4) used to reconstitute the (b)(4);

e. The syringes used for the final SVF product.

9. Failure to establish and follow written procedures describing in sufficient detail the receipt, identification, storage, handling, sampling, testing, and approval or rejection of components and drug product containers and closures [21 CFR 211.80(a)]. Specifically, you failed to establish and follow written acceptance criteria for components and drug product containers and closures used to manufacture approximately (b)(4) batches of SVF product during the period January 2012 and January 2018. Components and drug product containers and closures received and used by your firm without such procedures to manufacture the SVF product include, but are not limited to: (b)(4) syringes.

10. Failure to establish a quality control unit that has the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no errors have occurred or, if errors have occurred, that they have been fully investigated [21 CFR 211.22(a)]. Specifically, you had no quality control unit from January 2012 through the time of the inspection.

11. Failure to establish and follow written procedures describing the handling of all written and oral complaints regarding a drug product [21 CFR 211.198(a)]. For example:

a. Patient records indicate that, although you received multiple complaints involving possible adverse events regarding the SVF product, there was no supporting documentation to show that SGBL performed adequate follow-up and/or investigations of those complaints.

b. Procedures describing the handling of all written and oral complaints do not include provisions for review to determine whether the complaint represents a serious and/or unexpected adverse drug experience.

Review of Inspectional Responses

We received your written responses, dated February 16, 2018, March 19, 2018, April 18, 2018, and July 13, 2018, to the inspectional observations listed on the Form FDA 483, and we have reviewed their contents. We acknowledge your commitment to implement comprehensive corrective actions in response to the inspectional observations. Based on the limited information you provided for review, we are unable to assess the adequacy of your corrective actions to date, including but not limited to, those pertaining to aseptic process validation, environmental monitoring, or product testing for safety, purity, potency, and identity using validated methods.[4] We also note that you have (b)(4) to perform corrective actions, but it remains unclear to FDA whether and how your firm will handle these responsibilities at your facility on an ongoing basis. In addition, after reviewing your responses, we have the following comments or questions:

Response to Form FDA 483 Observations 1 and 2

You submitted process validation SOPs, STEM-QUA-0019.1: Validation Master Plan for the StemGenex Injectable Stromal Vascular Fraction (SVF) Product and STEM-QUA-0020.1, Process Validation Report for the StemGenex Injectable Stromal Vascular Fraction (SVF) Product. You state that you performed production runs, and you represent that all final test results except endotoxin were acceptable. Upon reassessment of the endotoxin test results, you conclude that the limits initially set should be adjusted, allowing the achieved results to fall within specification. Based on the information provided, we disagree with your conclusion that the achieved results are acceptable and we disagree with your revised endotoxin specification.

You state in some of your responses that you are no longer using the (b)(4), but your first response stated that you are seeking a “like-for-like replacement . . . of a higher quality.”[5] The process validation you submitted in your April 2018 response included the use of “(b)(4).” It is unclear whether you have discontinued the use of (b)(4) altogether or whether you are seeking a replacement. Either way, it appears that your process has changed and will need to be revalidated. For information on FDA recommendations regarding process validation, see FDA Guidance for Industry, Process Validation: General Principles and Practices (January 2011), https://www.fda.gov/downloads/drugs/guidances/ucm070336.pdf.

In addition, based on the information you provided, it also does not appear that you conducted environmental monitoring during process validation. We would expect environmental monitoring to be performed during process validation and for you to achieve results within acceptable levels.

Response to Form FDA 483 Observation 4

The chart in your SOP STEM-QUA-0022.1: Cleaning Validation for the StemGenex Injectable Stromal Vascular Fraction (SVF) Product Manufacturing Process, provides acceptance criteria and states that a bioburden of less than (b)(4) CFU/mL for all areas, including critical areas, would be acceptable. While insufficient data are provided regarding this acceptance level, we note that (b)(4) CFU is not acceptable in a critical area. For example, FDA recommendations on aseptic processing are provided in Guidance for Industry Sterile Drug Products Produced by Aseptic Processing, which states on page 5, “Class 100 (ISO 5), environments should normally yield no microbiological contaminants.”

Additionally, on page 10 of STEM-QUA-0022.1, Cleaning Validation Report for the StemGenex Injectable Stromal Vascular Fraction (SVF) Product Manufacturing Process, it states that: “(b)(4).” The fact that you recovered bacteria after cleaning is concerning to us.

Response to Form FDA 483 Observation 6

We understand that you are evaluating the need to test each lot of product for sterility. For example, your April 11, 2018 response states: “After evaluation of the manufacturing process and individual uniqueness of each sample, sterility testing on each lot (patient) is being evaluated.” It is unclear from your responses whether you intend to test each lot of drug product for sterility as we would expect product that is administered by various higher risk routes of administration, including IV, inhalation by nebulizer, by catherization, and intrathecally. Regarding your endotoxin testing, as previously noted, a failure during validation resulted in your changing your endotoxin specification, which is not based on individual patients’ weights (i.e. (b)(4)) and appears to be above acceptable limits for many patients. Please submit for our review your protocol and calculations for the validation runs with respect to endotoxin.

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 exist at your facility. It is your responsibility to ensure full compliance with the FD&C Act, PHS Act, and all applicable regulations.

You should take prompt action to correct these deviations. Failure to do so may result in regulatory action without further notice. Such actions include seizure and/or injunction.

Further information about IND requirements for biological products may be obtained through the 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.

Please notify this office in writing, within 15 working days of receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If you do not believe your product is in violation of the FD&C Act, PHS Act, or applicable regulations, include your reasoning and any supporting information for our consideration. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which all corrections will be completed.

Your response should be sent to the U.S. Food and Drug Administration, 622 Main Street, Suite 100, Buffalo, New York 14202, attention: Patricia A. Clark, or emailed to patricia.clark@fda.hhs.gov. If you have any questions regarding this letter, please contact Patricia A. Clark, Compliance Officer, at (716) 846-6236.

Sincerely,

/S/

Karlton T. Watson

Program Division Director

Office of Biological Products Operations – Division 2

cc:

Andre Lallande, DO

Medical Director

StemGenex Medical Group, Inc.

11515 El Camino Real, Suite 100

San Diego, CA 92130-3034

Scott C. Sessions, MD, F.A.C.S.

Owner

Stem Cell Research Centre

11515 El Camino Real, Suite 100

San Diego, CA 92130-3034

Rita F. Alexander, Owner

StemGenex, Inc.

1200 Prospect Street, Suite G-100

La Jolla, CA 92037

[1] The SVF product is administered to patients at StemGenex Medical Group, Inc., and StemGenex Stem Cell Research Center, both located at the same address as SGBL.

[2] HCT/Ps are defined as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.” 21 CFR 1271.3(d).

[3] This violation also represents a failure to establish and follow written procedures for cleaning and maintenance of equipment [21 CFR 211.67(b)], as no cleaning was performed between manufacturing these two batches of your SVF product. See Warning Letter Item #6.

[4] You also have not submitted pertinent data, documentation, or other information supporting your responses to FDA for review. For example, your third response references SOP STEM-GEN-0011.1, Laboratory Cleaning & Maintenance Procedure; however, this SOP was not enclosed.

[5] If you are replacing the (b)(4) with a higher quality alternative, among other concerns, we question whether this replacement will be sterile and how it will be qualified, to include leachable/extractable studies, to avoid contaminating your SVF product.