Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
|Silver Spring, MD 20993|
December 30, 2015
VIA FACSIMILE AND UPS
Thomas A. Gionis, MD, JD, MPH, MBA, MHA, LLM, FICS, FAIHQ
Surgeon-in-Chief, and Owner
Irvine Stem Cell Treatment Center
Surgeon-in-Chief, and Owner
Irvine Stem Cell Treatment Center
20072 SW Birch Street, Suite 170
Newport Beach, CA 92660
Miami Stem Cell Treatment Center
1515 N. Federal Highway, Suite 105
Boca Raton, FL 33432
Dear Dr. Gionis:
During inspections of your three firms: the Irvine Stem Cell Treatment Center (hereafter referred to as “CA”), previously located at 3500 Barranca Parkway, Suite 315, Irvine, CA 92606-8289, conducted July 27 - September 8, 2015; the Miami Stem Cell Treatment Center (hereafter referred to as “FL”), located at 1515 N. Federal Highway, Suite 105, Boca Raton, FL 33432-1951, conducted July 27 – September 11, 2015; and the Manhattan Regenerative Medicine Medical Group (hereafter referred to as “NY”), located at 30 Central Park South, Suite 10A, New York, NY 10019, conducted July 27 – September 19, 2015, the Food and Drug Administration (FDA) determined that your firms recover and process adipose tissue, a structural tissue, from donors for autologous use. During the inspections, FDA further noted that each of your firms use (b)(4) to isolate cellular components from adipose tissue, which are further processed into stromal vascular fraction (SVF) (aka adipose-derived stem cells). Your SVF product is administered intravenously (IV) or through a combination of IV injections, intrathecal spinal injections, and nasal/oral nebulization.
Your SVF product is intended to treat a variety of diseases and conditions, including, but not limited to, autism, Parkinson’s disease, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), multiple sclerosis (MS), cerebral palsy, and amyotrophic lateral sclerosis (ALS), and is therefore a drug under 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 and tissuebased product (HCT/P) as defined in 21 CFR 1271.3(d).
Your SVF product does not meet all of the criteria in 21 CFR 1271.10(a) and therefore does not qualify for regulation solely under section 361 of the PHS Act [42 U.S.C. 264] and the regulations in 21 CFR Part 1271. Specifically, your processing alters the original relevant characteristics of the adipose tissue relating to the tissue's utility for reconstruction, repair, or replacement. Therefore, the processing would not meet the definition of minimal manipulation for structural tissue such as adipose tissue. As a result, your SVF product does not meet the criterion in 21 CFR 1271.10(a)(l).
In addition, your SVF product fails to meet 21 CFR 1271.10(a)(2)’s 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.” Records collected during the inspections indicate that the SVF product is intended for use in the treatment of a variety of medical conditions, including, but not limited to, autism, Parkinson’s disease, pulmonary fibrosis, COPD, MS, cerebral palsy and ALS. Because the SVF product is not intended to perform the basic function or functions of adipose tissue, which generally is to cover, connect, or cushion, using the SVF product for treatment of these and other conditions is not homologous use. As a result, your SVF product cannot 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 such a biological drug product, a valid biologics license must be in effect [21 U.S.C. 355(a); 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 (IND) application in effect as specified by FDA regulations [21 U.S.C. 355(i); 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.
Additionally, during the inspections, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP) from February 2013 and August 2015, in the manufacture of your SVF product. These deviations from CGMP and CGTP include deviations from Section 501(a)(2)(B) of the FD&C Act, and Title 21, Code of Federal Regulations, (21 CFR) Parts 210, 211, and 1271.
At the close of each of the inspections, our investigators issued a list of inspectional observations (Form FDA 483), which described a number of significant objectionable conditions relating to your facilities’ compliance with CGMP and CGTP. These 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. You failed to validate your aseptic manufacturing process and establish written procedures to prevent microbiological contamination of your SVF product.
b. You failed to validate the process used to sterilize critical equipment used in your aseptic processing.
c. On multiple occasions, manufacturing personnel were observed using poor aseptic technique. Some examples of this include not wearing appropriate sterile gowns, having exposed jewelry, not regularly sanitizing or changing gloves, and allowing individuals not directly involved in manufacturing to enter and exit the room during the manufacturing process.
d. Routine personnel monitoring and qualification is not performed for individuals involved in the aseptic manufacturing process of your SVF product.
2. 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 sterility testing on more than (b)(4) batches of SVF product manufactured between February 2013 and August 2015 at your CA, FL and NY locations and administered to treat various cardiovascular/pulmonary, neurologic, orthopedic, spinal and autoimmune conditions.
3. Failure to establish and follow 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)]. For example:
a. You isolate the cellular components from adipose tissue through (b)(4), which are further processed by (b)(4) into your SVF product. You failed to validate your manufacturing process, which incorporates the use of (b)(4), and the (b)(4).
b. You failed to establish and maintain standard operating procedures (SOPs) describing the manufacturing equipment and the operating parameters used during your manufacturing process.
4. Failure to maintain laboratory controls that include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity, including a determination of conformance to written descriptions of sampling procedures and appropriate specifications for acceptance of each lot of drug products [21 CFR 211.160(b)].
5. Failure to ensure that batch production and control records are prepared for each batch of drug product produced [21 CFR 211.188]. Specifically, you do not document each significant step in your process, including the major equipment and key personnel used to manufacture your SVF product.
6. 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, your firm utilizes: (b)(4), in the manufacture of your SVF product. There are no procedures in place that describe the receipt, identification, storage, handling, sampling, testing, and approval or rejection of these materials.
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(a)]. For example, the following components and containers are not tested or examined before release:
a. The (b)(4) used during the SVF manufacture and final formulation.
b. The (b)(4) used to prepare the (b)(4).
c. The (b)(4) used to isolate the cellular components from the adipose tissue.
d. The (b)(4) used in manufacturing and for the final SVF product.
8. Failure to assure a system for monitoring environmental conditions is in place to prevent contamination during aseptic processing [21 CFR 211.42(c)(10)(iv)]. Specifically, your CA, FL and NY facilities’ do not have established environmental monitoring programs.
9. Failure to assure that automatic, mechanical and electronic equipment used in the manufacture, processing, packing and holding of a drug product is routinely calibrated, inspected or checked according to a written program designed to assure proper performance, and that written records of those calibration checks and inspections are maintained [21 CFR 211.68(a)]. For example:
a. There is no evidence that installation, operational or performance qualification has been performed for your (b)(4)
b. You routinely move your manufacturing equipment from CA to NY without any requalification prior to use.
10. 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)]. Your firm had not established procedures that describe a process for documenting and investigating complaints relating to your SVF product until the FDA inspection. The inspection revealed five complaints at your FL location to date. You failed to thoroughly investigate those complaints, which related to treatment of degenerative joint disease, neuromyelitis optica, dementia and Parkinson’s disease.
11. 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, your firm does not have an established Quality Control Unit (QCU) and procedures applicable to the QCU in order to approve or reject manufacturing components, drug product containers, in-process materials, review production records, and to prevent, investigate and correct errors in manufacturing of your SVF product.
12. Failure to establish and follow written procedures for cleaning and maintenance of equipment, including utensils, used in manufacture, processing, packing, or holding of a drug product, including a description in sufficient detail of the methods, equipment, and materials used in cleaning and maintenance operations [21 CFR 211.67(b)]. Specifically, you had not established written procedures for cleaning, sanitization or sterilization of your equipment until the FDA inspection. During the inspection you provided a cleaning procedure and cleaning logs. This information was incomplete and did not provide the necessary detail to show that the equipment is appropriately cleaned.
13. Failure to ensure that each container or grouping of containers for components or drug product containers, or closures is identified with a distinctive code for each lot in each shipment received [21 CFR 211.80(d)]. Specifically, prior to the FDA inspection, your firm failed to record the lot numbers of the following components and supplies utilized in manufacturing of your SVF product: (b)(4). These components and supplies were utilized to manufacture over (b)(4) batches of your SVF product from February 2013 to August 2015.
14. Failure to label each HCT/P in accordance with the requirements in 21 CFR 1271.370. For example:
a. The following information did not appear on the SVF product label: a distinct identification number in accordance with 21 CFR 1271.290(c); a description of thetype of HCT/P; and an expiration date, if any.
b. The SVF product, which is for autologous use, was not prominently labeled as being "For autologous use only" and "Not evaluated for infectious substances." These warnings are required under 21 CFR 1271.90(b).
REVIEW OF INSPECTIONAL RESPONSES
We acknowledge receipt of your written responses for CA, FL and NY, all dated October 2, 2015, which seek to address the inspectional observations on the Form FDA 483’s issued at the close of the inspections. We have reviewed your responses and have concluded that they do not provide sufficient detail to fully assess the adequacy of your corrective actions.
Your responses explained that (1) you have terminated your relationship with the (b)(4), (2) you have discontinued use of (b)(4) or methodology in your manufacturing process as of September 20, 2015, and (3) you have required all personnel to take and pass the NIH course on “Protecting Human Research Participants.” Additionally, you noted that you closed your New York facility as of October 20, 2015.
It appears that you have updated your websites (www.IrvineStemCellsUSA.com; www.MiamiStemCellsUSA.com; www.NYStemCellsUSA.com) to reflect that you “do not utilize the addition of chemicals or enzymes to produce your SVF, but rather remain consistent with all FDA Guidance relating to stem cell therapy.” However, you have not provided any information regarding the changes you have made to your manufacturing process; therefore, we cannot assess whether such changes are adequate to address the serious deviations described above. Please be advised that processing by various means (e.g., (b)(4)) that alters the original relevant characteristics of the structural tissue relating to the tissue’s utility for reconstruction, repair, or replacement generally would be considered more than minimal manipulation.
Neither this letter nor the observations noted on the form FDA 483, which were discussed with you at the conclusion of each inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facilities. It is your responsibility as management to assure that your establishments are in compliance with the provisions of the FD&C Act and the PHS Act, and all applicable federal laws and regulations.
You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in regulatory action without further notice. Such actions include seizure and/or injunction.
For further information about IND requirements, contact Dr. Patrick Riggins, Director of Regulatory Management Staff, Office of Cellular, Tissue, and Gene Therapies, at (240) 402-8346. 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 additional 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. Corrective actions addressed in your prior responses may be referenced in your subsequent response. If you do not believe your product is in violation of the FD&C Act and PHS Act, 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 the corrections will be completed.
Your response should be sent to the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, 10903 New Hampshire Avenue, Bldg. 71, Silver Spring, MD 20993. If you have any questions regarding this letter, please contact LT Shannon Aldrich in the Division of Case Management, CBER, at (240) 402-9156.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
This page was posted on June 23, 2016.