Human Biologics of Texas/Globus Medical - 557325 - 10/30/2018

WARNING LETTER

VIA UNITED PARCEL SERVICE

SIGNATURE REQUIRED

Warning Letter #OBPO 19-01

October 30, 2018

David M. Demski, CEO

Globus Medical

2560 Armistead Ave.

Audubon, PA 19403

Dear Mr. Demski:

The United States Food and Drug Administration (FDA) conducted an inspection of your firm, Human Biologics of Texas (HBT), located at 14805 Omicron Drive, San Antonio, TX, from April 10 through April 19, 2018. During the inspection, an FDA investigator documented significant deviations from the regulations for human cells, tissues, and cellular and tissue-based products (HCT/Ps) set forth in Title 21, Code of Federal Regulations, Part 1271 (21 CFR 1271), and issued under the authority of Section 361 of the Public Health Service Act (42 U.S.C. § 264).

The deviations documented on a Form FDA-483, Inspectional Observations, were presented to and discussed with Human Biologics of Texas (HBT) management at the conclusion of the inspection. The items of concern include, but are not limited to, the items discussed below. Following our review of HBT’s responses dated May 10, 2018 and September 14, 2018, we identified additional concerns that are also included below.

1. Failure to investigate and document HCT/P deviations and trends of HCT/P deviations relating to core current good tissue practice (CGTP) requirements and make reports if required under §1271.350(b) or other applicable regulations. Each investigation must include a review and evaluation of the HCT/P deviation, the efforts made to determine the cause, and the implementation of corrective action(s) to address the HCT/P deviation and prevent recurrence [21 CFR 1271.160(b)(6)]. For example, since the start of ViaCell processing in October 2016 through August 2017, you have had monthly sterility failure rates of (b)(4) during seven of those months, with one month having a sterility failure rate of (b)(4). Your firm failed to conduct an investigation of all these sterility failures to determine the cause. You also failed to investigate additional sterility failures that occurred from October 2017 through February 2018. By neglecting to identify the cause of the sterility failures, you also failed to take appropriate corrective action(s) to prevent recurrence of the failures.

2. Failure to validate and approve a process according to established procedures where the results of processing cannot be fully verified by subsequent inspection and tests. The validation activities and results must be documented, including the date and signature of the individual(s) approving the validation. [21 CFR 1271.230(a)]. For example, you failed to adequately validate the ViaCell manufacturing process, which cannot be fully verified, to ensure that your process removes contamination that is present, and to ensure that processing prevents the introduction, transmission, or spread of communicable disease through the use of the HCT/P. From October 2016 to December 2017, your firm processed HCT/Ps into ViaCell products and distributed those products without a validated process.

We acknowledge receipt of HBT’s responses dated May 10, 2018 and September 14, 2018, describing the corrective actions taken in response to FDA’s inspectional observations. We have reviewed the responses and have the following comments and concerns:

1. In the May 10, 2018 response to Observation 1.a., HBT stated (b)(4). However, the response strictly focuses on the results of sterility testing, which are often not reliable, and does not address the decision to continue manufacturing ViaCell products without a fully validated process and the high number of sterility failures that were not investigated and corrected.

2. In the May 10, 2018 response to Observation 3, HBT stated, (b)(4). We note that there is no expectation that human tissue be sterile at the time of recovery, however it is your responsibility to show that your process does not cause contamination or cross contamination and that it prevents the introduction, transmission, or spread of communicable disease through the use of the HCT/P(s). Although your response stated that your overall sterility failure rate for ViaCell has decreased (b)(4), you did not discuss any plan to determine the cause of all the sterility failures that occurred between October 2016 and February 2018 and why the sterility failure rate was so high.

The response also stated (b)(4). However, we note that 21 CFR 1271.160(b)(6) requires your quality program to investigate each HCT/P deviation related to core CGTP requirements, including a review and evaluation of the deviation, the efforts made to determine the cause, and the implementation of corrective action(s) to address the HCT/P deviation and prevent recurrence.

3. In the September 14, 2018 response that provided updated corrective actions to Observation 2, HBT stated that additional validation activities of the ViaCell process were initiated in May 2018 under Protocol (b)(4) and approved under Validation Report VR.106, (b)(4), dated August 2018. Following our review of the validation protocol and report, we continue to have concerns about your firm’s validation of the ViaCell process.

Protocol (b)(4), which discusses bioburden acceptance criteria, states, “(b)(4).” We note that you are relying on the results of final sterility testing, which is often not reliable, instead of demonstrating that your process removes the bioburden that is present on the incoming HCT/Ps and that it does not add bioburden during processing. For example, the validation protocol and report do not include an evaluation of incoming bioburden in order to set adequate acceptance criteria based on the capacity of the process.

Step (b)(4) in Protocol (b)(4) states, “(b)(4).” This statement is problematic, as 21 CFR 1271.220(a) states that you must process each HCT/P in a way that does not cause contamination or cross contamination during processing, and that prevents the introduction, transmission, or spread of communicable disease through the use of the HCT/P. This requirement is met, in part, through in-process control and testing under 21 CFR 1271.220(c). Your validation must show that the ViaCell process can eliminate the bioburden present on the incoming HCT/Ps.

Pre-processing cultures for musculoskeletal HCT/Ps are a critical in-process control, as discussed in FDA’s Guidance for Industry: Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells Tissues and Cellular and Tissue-Based Products (HCT/Ps). A disinfection or sterilization process must be validated based on the capability of that process to reduce or eliminate an expected level and mix of microorganisms on the particular product that will be put through the process. Thus, you should carefully consider the capability of your microbiological testing, disinfection, and sterilization processes when you evaluate pre-processing cultures to determine whether or not the HCT/Ps should be processed. If musculoskeletal HCT/Ps are processed with bioburden in excess of the level that the process has been validated to remove or inactivate, there is no assurance that the process will result in the reduction or removal of bioburden to acceptable limits or reduce the risk of transmission of communicable disease. If you do not perform incoming bioburden studies, the type or number of microorganisms on your products is unknown. Therefore, you cannot evaluate to what degree your process minimizes the risk of communicable disease transmission.

4. In Validation Report (b)(4), submitted with your September 14, 2018 response, the Discussion section (b)(4) states, “(b)(4).” Section (b)(4) of the report lists the bioburden results for the (b)(4) donors that were processed for the validation study. The bioburden results show that samples from (b)(4) donors collected during your processing and prior to the antibiotic/antimycotic rinse were positive for Staphylococcus epidermidis or Propionibacterium acnes, but these same organisms were not present in the post-antibiotic/antimycotic bioburden samples. Our review of the recovery cultures for these donors found that the same organisms were identified in those cultures on the specific bones that were used for processing the HCT/Ps from these donors. However, it does not appear that you considered the results of the recovery cultures from other bone samples from the same donor(s). For example, donor (b)(6), whose recovery culture and pre-antibiotic/antimycotic bioburden samples on the left humerus were positive for Propionibacterium acnes, also had positive recovery cultures on other bone samples, including multiple Enterobacter organisms.

In the Current Good Tissue Practice (CGTP) and Additional Requirements for Manufacturers of Human Cells Tissues and Cellular and Tissue-Based Products (HCT/Ps) Guidance, FDA recommends that you discard all musculoskeletal HCT/Ps from a donor that has any musculoskeletal pre-processing cultures positive for Clostridium, Streptococcus pyogenes (group A strep), or any other microorganism that you have determined to be difficult to eliminate, unless you have a terminal sterilization process validated to a sterility assurance level (SAL) of 10^-6. In addition, FDA recommends discarding all musculoskeletal HCT/Ps from a donor who has multiple musculoskeletal pre-processing cultures positive for enteric or pathogenic microorganisms, unless you have a terminal sterilization process validated to a SAL of 10^-6. Since your ViaCell process does not have a terminal sterilization step, donors with such results on pre-processing cultures should not be used. Therefore, donor (b)(6), whose recovery cultures were positive for Clostridium innocuum and Enterobacter should have been rejected.

5. Our review of Validation Report (b)(4), dated August 28, 2018, as well as the prior validation reports for the ViaCell process, found that all of the environmental and personnel monitoring results showed no growth for every sample tested. We note having no positive results for any environmental monitoring samples is highly unusual, especially when your sterility failure rates were so high. We strongly suggest that you review your environmental monitoring program to ensure that it is capable of detecting microorganisms in your environment and on your personnel.

The deviations identified above are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that your establishment is in compliance with all applicable requirements of the federal regulations. You are responsible for reviewing your firm’s operations as a whole in order to assure that you are in compliance with all applicable FDA regulatory requirements.

You should take prompt action to correct the violations addressed in this letter and prevent their recurrence. Failure to do so may result in regulatory action being initiated by the FDA without further notice.

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. If you cannot complete all corrections within fifteen (15) working days, please explain the reason for your delay and the time frame within which the remaining corrections will be completed.

Your response should be sent to the following address: Daniel W. Cline, U.S. Food and Drug Administration, 19701 Fairchild, Irvine, CA 92612 or emailed to Daniel.Cline@fda.hhs.gov. If you should have any questions, please contact Daniel Cline, Compliance Officer at 949-608-4433 or via e-mail.

Sincerely,

/S/

Karlton Watson

Program Division Director

Office of Biological Products Operations

cc:

Aditya M. Muzumdar, General Manager

Human Biologics of Texas

14805 Omicron Drive

San Antonio, TX 78245