污染或交叉污染未得到控制，工艺未验证，环境监测不符合要求以及偏差调查不彻底，FDA发出警告信。
WARNING LETTER
OsteoLife Biomedical I LLC
MARCS-CMS 626889 — 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].
美国食品和药物管理局(FDA)在2021年12月6日至2022年2月4日期间对贵公司OsteoLife Biomedical I LLC进行了检查，该公司位于佛罗里达州迈阿密Sanibel Suite, 1951 NW 7th Avenue。在检查中，一名FDA检查员记录了严重偏离《联邦法规》(CFR)第1271部分[21 CFR 1271]第21篇规定的人类细胞、组织以及基于细胞和组织的产品(HCT/Ps)，该规定根据《公共卫生服务法》第361条[42 U.S.C.§264]的授权发布。
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:
检查结束时与企业进行了讨论，并将观察清单(FDA-483表格)上记录的偏差提交给企业。这些有关项目包括但不限于下列事项:
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:
1)未能以合适的方式加工每一HCT/P，即不会在加工过程中造成污染或交叉污染，并能防止经由使用该HCT / P引入、传播或扩散传染病。(21 CPR 1271.220(a))[21 CFR 1271.220(a)]。具体讲:
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:
a.企业在同一天，由相同的加工技术人员在相同的环境条件下，使用相同的设备，处理来自单一供体的多批次冻干颗粒骨。每批中(b)(4)没有对设备和设施进行清洗。来自一个供体的一个或多个批次的小瓶的后处理培养检测出微生物呈阳性，其中一些微生物在多个场合被发现。虽然在一些批次中发现了阳性微生物培养，但来自同一供体的其他批次已放行。例如:
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.
i. 2021年11月16日，(b)(4)批冻干颗粒骨由供体(b)(6)制成。在该供体生产的一批样品中，后处理培养对芽孢杆菌(不是炭疽杆菌)呈阳性。
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.
ii. 2021年7月7日，(b)(4)批冻干颗粒骨由(b)(6)制成。后处理培养在从该供体生产的两批嗜麦芽窄食单胞菌中呈阳性。
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.
iii. 2021年5月13日，(b)(4)批冻干颗粒骨由(b)(6)制成。后处理培养在该供体制造的4个批次中均为嗜麦芽窄食单胞菌或铜绿假单胞菌阳性。
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.
iv. 2020年4月30日，(b)(4)批冻干颗粒骨由(b)(6)制成。该供体生产的一批黄体微球菌的后处理培养呈阳性。
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.
b.在检查中，FDA检查员在2021年12月28日观察到来自供体(b)(6)的HCT/Ps的加工过程中，显著增加了污染的可能性，并没有阻止通过使用HCT/Ps引入、传播或扩散传染病。具体来说，研究人员注意到，层流工作台的高速回风口（无菌布覆盖）位于工作台的前沿，用于防止脏空气“反流”进入工作区域。
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:
2)在加工结果无法通过后续检查和检验完全核实的情况下未能按照既定程序验证和批准工艺[21 CFR 1271.230(a)]。例如:
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.
企业未能充分验证柔性板、柔性膜和冻干颗粒骨产品的生产工艺。企业的“柔性板和膜移植工艺确认总结报告”(日期为2019年10月14日)和“颗粒组织工艺确认总结报告”(日期为2019年10月4日)未包括过程中的微生物检测，以确保在工艺过程中没有引入污染，并且企业的工艺取消了存在任何污染的可能。此外，上述文件不包括任何与HCT/Ps的微生物污染或此类HCT/Ps上通常遇到的微生物类型有关的验收标准。
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:
3)未能监测可能导致HCT/Ps或设备污染或交叉污染的环境条件，或导致HCT/Ps意外暴露于传染病原中[21 CFR 1271.195(c)]。例如:
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.
企业于2020年1月至2021年11月的处理记录显示，对微生物进行了大约xx的环境监测。此外，在处理过程中不执行环境监控。在加工过程中可能会发生传染病的传入、传播或扩散，因此，需要对加工过程中的微生物进行环境监测。
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:
4)未调查和记录与关键现行良好组织规范（CGTP）要求相关的HCT/P偏差和HCT/P偏差趋势。根据适用的法规，每次调查必须包括对HCT/P偏差的审查和评估，为确定原因所做的努力，以及为解决HCT/P偏差并防止再次发生而采取的纠正措施[21 CFR 1271.160(b)(6)]。具体地说:
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.
a.在2019年7月22日一封无标题信函发布后，企业于2019年9月17日向FDA提交了一份初始HCT/P偏差报告，内容为收到阳性后处理培养物后HCT/P分布情况。企业于2019年11月1日和2020年4月14日提交了补充信息。偏差报告称企业进行了调查，并提出了后处理培养呈阳性的原因，是进行微生物检测的实验室打开了装有样品的塑料袋，无意中污染了微生物实验室的样品。
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:
如上所述，企业进行了后处理培养。随后，对2020年4月至2021年12月期间加工的骨制品开展了22项阳性后处理培养物调查;然而，调查已经结束，企业再次未能确定纠正措施来解决持续的偏差并防止其再次发生。例如:
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.
i. 2021年5月24日，来自供体(b)(6)的冻干颗粒骨后处理培养结果显示嗜麦芽窄食单胞菌和铜绿假单胞菌呈阳性。企业在检查后启动了“HCT/P 005号偏差”，并于2021年12月7日结束调查。
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.
ii. 2020年5月8日，来自供体(b)(6)的冻干颗粒骨的后处理培养检测出黄体微球菌阳性。企业在检查开始后启动“HCT/P偏差#001”，并于2021年12月7日结束调查。
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:
b.在2020年1月至2021年11月期间，企业在清洁功能间之前进行了环境监测，结果发现(b)(4)中有10种阳性微生物培养物，一种来自用于多个加工步骤（包括(b)(4)的(b)(4)中的阳性微生物培养液，以及一种来自(b)(4)层流台的阳性微生物。例如：:
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.
i. 2021年7月29日，来自(b)(4)表的环境沉降板(S-072221-09235)检测真菌和芽孢杆菌(非炭疽病)呈阳性。企业在检查开始后启动了“HCT/P偏差#E002”;然而，该工厂于2021年12月7日关闭，没有进行调查或实施纠正措施以防止再次发生。
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.
ii. 2021年7月12日，来自xx层流试验台的一个环境沉降板(S-070421-03649)检测出革兰氏阳性球菌和petrasii葡萄球菌阳性。企业在检查开始后启动了“HCT/P偏差#E001”;然而，该工厂于2021年12月7日关闭，没有进行调查或实施纠正措施以防止再次发生。
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.
iii. 2020年9月8日，来自xx的环境触摸板(S-090220-08144)检测出芽孢杆菌(非炭疽)、凝固酶阴性葡萄球菌和marisflavi芽孢杆菌呈阳性。企业在检查开始后启动了“HCT/P偏差#E-006”;然而，该工厂于2021年12月7日关闭，没有进行调查或实施纠正措施以防止再次发生。
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.
上述发现的偏差并非企业缺陷的全部清单。企业有责任确保符合所有适用的监管要求。有责任审查企业的整体运作，以确保完全遵守法律。
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:
FDA确认收到企业于2022年2月23日针对FDA-483表格的信函，该表格是在检查结束时发给贵公司的。FDA已审查了回复中所述的纠正措施，并提出以下意见:
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.
1. 在对观察报告1的回复中，根据第1(a)段，企业修订的SOP 110-006，加工组织的放行声明:“……如果培养结果为阳性，则同一供体在处理过程中处理的全部批次将被丢弃。”企业的回复没有涉及已经分发的违反21 CFR 1271的HCT/Ps的计划，以及目前使用的HCT/Ps。
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.
2. 针对观察报告2，在第2(b)段中，企业表示，将“重新验证柔性板、柔性膜移植物和颗粒组织的整个加工过程”。FDA注意到，根据21 CFR 1271.230(a)，生产HCT/Ps之前必须进行工艺验证。企业的回复并不表示将停止生产柔性板和柔性膜移植物以及颗粒组织产品，直到生产工艺得到验证。
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.
3.针对意见4和5，企业表示“CAPA#002，生产监控以降低污染”和“CAPA#003，环境监控”作为纠正措施启动，并将于2022年4月完成。企业的变更将在下一次工厂检查中进行审核，以确认是否符合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.
4. 在回复观察6时，企业表示CAPA #001“质量计划持续改进和执行”已经启动，其中包括起草一份关于如何进行详细分析并调查根本原因的新SOP，将于2022年4月前完成。企业的变更将在下一次工厂检查中进行审核，以确认是否符合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.
应该立即采取行动纠正本函中提到的违规行为，并防止其再次发生。未能及时纠正这些违规行为可能会导致FDA在不另行通知的情况下采取监管行动。
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.
FDA要求企业在收到本函后的十五(15)个工作日内以书面形式做出回应，概述企业已采取或计划采取的具体步骤，以纠正所指出的违规行为，包括企业计划如何防止此类违规或类似违规行为再次发生。如果企业认为产品没有违反法律，请提供理由和任何支持信息，以供FDA考虑。此外，包括任何必要的文件，以表明已纠正上述任何违规行为。如果不能在十五(15)个工作日内完成所有整改，请解释延迟原因以及完成整改的时间范围。
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.
鉴于这些违规行为的严重性，FDA还要求企业在收到这封信后的30天内出席监管会议，讨论企业自检查以来为纠正这些违规行为所采取的具体步骤的状态。我们将在Zoom网上主持会议。本次会议还将允许企业提出任何问题，并向FDA提供有关纠正措施实施的额外信息。请致电(561)416-1065 ext. 1105或通过电子邮件Colleen.Aspinwall@fda.hhs.gov与合规官科琳·阿斯平沃尔(Colleen Aspinwall)联系，以确认会议日期和时间。届时将提供Zoom会议的号码。
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.
回复应该通过电子邮件发送到Colleen.Aspinwall@fda.hhs.gov。如果有任何问题，请致电(561)416-1065 ext. 1105或通过电子邮件与合规官科琳·阿斯平沃尔(Colleen Aspinwall)联系。
Sincerely,
/S/
Michael W. Roosevelt
Program Division Director
Office of Biological Products Operations – Division I
