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Recipient NameTheodore I. Malinin, MD
Recipient TitleMedical Director and Co-Owner
- OsteoLife Biomedical I LLC
1951 NW 7th Avenue
Miami, FL 33136
- Issuing Office:
- Office of Biological Products Operations – Division I
March 31, 2022
Dear Dr. Malinin:
The United States Food and Drug Administration (FDA) conducted an inspection of your firm, OsteoLife Biomedical I LLC, located at 1951 NW 7th Avenue, Sanibel Suite, Miami, FL, between December 6, 2021 and February 4, 2022. 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 (CFR) 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 the Form FDA-483, List of Inspectional Observations (Form FDA-483), were presented to and discussed with you at the conclusion of the inspection. These items of concern include, but are not limited to, the following:
1) Failure to process HCT/Ps 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 [21 CFR 1271.220(a)]. Specifically:
a. Your establishment processes multiple batches of Freeze-Dried Particulate Bone from a single donor on the same day, by the same processing technician, under the same environmental conditions, and using the same equipment. Cleaning of equipment and facilities is not performed in (b)(4) each batch. Post-processing cultures of vials from one or more batches from a single donor tested positive for microorganisms, several of which were identified on multiple occasions. Although positive microbiological cultures were found in some batches, other batches from the same donor were distributed. For example:
i. On November 16, 2021, (b)(4) batches of Freeze-Dried Particulate Bone were manufactured from donor (b)(6). A post-processing culture was positive for Bacillus (not anthracis) in one batch manufactured from this donor.
ii. On July 7, 2021, (b)(4) batches of Freeze-Dried Particulate Bone were manufactured from donor (b)(6). Post-processing cultures were positive for Stenotrophomonas maltophilia in two batches manufactured from this donor.
iii. On May 13, 2021, (b)(4) batches of Freeze-Dried Particulate Bone were manufactured from donor (b)(6). Post-processing cultures were positive for Stenotrophomonas maltophilia or Pseudomonas aeruginosa in four batches manufactured from this donor.
iv. On April 30, 2020, (b)(4) batches of Freeze-Dried Particulate Bone were manufactured from donor (b)(6). A post-processing culture was positive for Micrococcus luteus in one batch manufactured from this donor.
b. During the inspection, the FDA investigator observed processing of HCT/Ps, from donor (b)(6) on December 28, 2021, that significantly increased the potential for contamination and did not prevent the introduction, transmission, or spread of communicable disease through the use of the HCT/Ps. Specifically, the investigator noted the high velocity return air slots of the (b)(4) Laminar Flow Bench, located along the front edge of the work surface and that provide protection from a “backwash” of dirty air into the work area, were covered with a sterile sheet/drape.
2) Failure to validate and approve processes according to established procedures where the results of processing cannot be fully verified by subsequent inspections and tests [21 CFR 1271.230(a)]. For example:
You failed to adequately validate the manufacturing process for the Flexo-Plate, and Flexo-Membrane, and Freeze-Dried Particulate Bone products. Your “Processing of Flexo-plate and Membrane Grafts Process Qualification Summary Report” (dated October 14, 2019) and “Processing of Particulate Tissue Process Qualification Summary Report” (dated October 4, 2019) fail to include in-process microbiological testing to ensure that you are not introducing contamination during processing and that your process removes any contamination present. In addition, the documents noted above do not include any acceptance criteria related to microbiological contamination of HCT/Ps or the types of microorganisms typically encountered on such HCT/Ps.
3) Failure to monitor environmental conditions where they could reasonably be expected to cause contamination or cross contamination of HCT/Ps or equipment, or accidental exposure of HCT/Ps to communicable disease agents [21 CFR 1271.195(c)]. For example:
Your January 2020 through November 2021 processing session logs indicate that you conduct environmental monitoring for microorganisms approximately (b)(4). Additionally, you do not perform environmental monitoring during processing. The introduction, transmission, or spread of communicable diseases could reasonably be expected to occur during processing, therefore, you would be expected to perform environmental monitoring for microorganisms during processing.
4) Failure to investigate HCT/P deviations and trends of HCT/P deviations relating to core CGTP requirements. Under the applicable regulation, 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)]. Specifically:
a. After the issuance of an Untitled Letter dated July 22, 2019, you submitted an initial HCT/P deviation report to FDA on September 17, 2019, regarding the distribution of HCT/Ps after receipt of positive post-processing cultures. You submitted supplemental information on November 1, 2019, and April 14, 2020. The deviation reports stated you performed an investigation and proposed the reason for the positive post-processing cultures as inadvertent contamination of the sample at the microbiology laboratory when the plastic pouch containing the sample was opened by the testing laboratory that performed the microbiological testing.
As noted above, you continued to have positive post-processing cultures. You subsequently opened 22 investigations of positive post-processing cultures for bone products processed between April 2020 and December 2021; however, the investigations were closed and once again, you failed to identify corrective actions to address the ongoing deviations and to prevent their recurrence. For example:
i. On May 24, 2021, post-processing cultures for Freeze-Dried Particulate Bone from donor (b)(6) tested positive for Stenotrophomonas maltophilia and Pseudomonas aeruginosa. You opened “HCT/P Deviation #005” after the initiation of the inspection and closed the investigation on December 7, 2021.
ii. On May 8, 2020, post-processing cultures for Freeze-Dried Particulate Bone from donor (b)(6) tested positive for Micrococcus luteus. You opened “HCT/P Deviation #001” after the initiation of the inspection and closed the investigation on December 7, 2021.
b. Between January 2020 and November 2021, you performed environmental monitoring prior to cleaning your processing room, which resulted in 10 positive microbiological cultures from the (b)(4), one positive microbiological culture from the (b)(4) used for multiple processing steps to include (b)(4), and one positive microbiological culture from the (b)(4) Laminar Flow Bench. For example:
i. On July 29, 2021, an environmental settling plate (S-072221-09235) from the (b)(4) table tested positive for Fungi, and Bacillus species (not anthracis). You opened “HCT/P Deviation #E002” after the initiation of the inspection; however, it was closed on December 7, 2021, without an investigation or implementation of corrective actions to prevent recurrence.
ii. On July 12, 2021, an environmental settling plate (S-070421-03649) from the (b)(4) Laminar Flow Bench tested positive for gram-positive cocci and Staphylococcus petrasii. You opened “HCT/P Deviation #E001” after the initiation of the inspection; however, it was closed on December 7, 2021, without an investigation or implementation of corrective actions to prevent recurrence.
iii. On September 8, 2020, an environmental touch plate (S-090220-08144) from the (b)(4) tested positive for Bacillus species (not anthracis), coagulase-negative Staphylococcus, and Bacillus marisflavi. You opened “HCT/P Deviation #E-006” after the initiation of the inspection; however, it was closed on December 7, 2021, without an investigation or implementation of corrective actions to prevent recurrence.
The deviations identified above are not intended to be an all-inclusive list of deficiencies. It is your responsibility to ensure that your establishment is operating in compliance with all the applicable regulatory requirements. You are responsible for reviewing your firm’s operations as a whole to ensure that you fully comply with the law.
We acknowledge receipt of your letter dated February 23, 2022, in response to the Form FDA-483, issued to your establishment at the close of the inspection. We have reviewed the corrective actions outlined in the response and we have the following comments:
1. In your response to Observation 1, under paragraph 1(a), your revised SOP 110-006, Release of Processed Tissues states, “... in the event of a positive culture(s) the entire number of batches processed from the same donor during a processing session will be discarded.” Your response does not address your plan for the HCT/Ps you have already processed in violation of 21 CFR 1271 that have already been distributed, as well as the HCT/Ps that currently remain in storage.
2. In response to Observation 2, under paragraph 2(b) you stated you would, “Revalidate entire process for Processing of Flexo-Plate & Flexo-Membrane Grafts and Particulate Tissue.” We note that under 21 CFR 1271.230(a), process validation must be performed before manufacturing HCT/Ps. Your response does not indicate that you will halt processing of Flexo-Plate & Flexo-Membrane Grafts and Particulate Tissue products until your processes have been validated.
3. In response to Observations 4 and 5, you stated that “CAPA#002, Manufacturing monitoring to mitigate contamination” and “CAPA#003, Environmental monitoring” were initiated as corrective actions and that they would be completed by April 2022. Your changes will be reviewed during the next inspection of your establishment to confirm compliance with 21 CFR 1271.
4. In response to Observation 6, you stated that CAPA #001, “Quality Program Continuous Improvement and Enforcement” was initiated that includes drafting a new SOP on how to perform investigations detailing root cause analysis to be completed by April 2022. Your changes will be reviewed during the next inspection of your establishment to confirm compliance with 21 CFR 1271.
You should take prompt action to correct the violations addressed in this letter and prevent their recurrence. Failure to promptly correct these violations 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, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. If you believe that your product is not in violation of the law, include your reasoning and any supporting information for our consideration. Additionally, include any documentation necessary to show that correction of any of the above-noted violations has been achieved. 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.
Given the seriousness of these violations, we also request your attendance at a Regulatory Meeting, within 30 calendar days of receipt of this letter, to discuss the status of the specific steps you have taken since the inspection to correct the noted violations. We will host the meeting virtually on Zoom. This meeting will also allow you to ask any questions you may have and to provide FDA additional information regarding implementation of corrective actions. Please contact Colleen Aspinwall, Compliance Officer, at (561) 416-1065, ext. 1105 or by email at Colleen.Aspinwall@fda.hhs.gov for confirmation of the meeting date and time. A call-in phone number for the Zoom meeting will be provided at that time.
Your response should be emailed to Colleen.Aspinwall@fda.hhs.gov. If you should have any questions, please contact Colleen Aspinwall, Compliance Officer, at (561) 416-1065, ext. 1105 or via email.
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division I