determining是什么意思英语,implementation是什么意思

2022-07-23 14:57:25 经济时评

　　近日，FDA官网于2020年3月18日发布了一封关于生物制药公司的警告信(Invitrx Therapeutics Inc.)，DST专家注意到，其中的许多缺陷应该引起生物制药公司的注意和警惕。现在DST会和同事一起关注这家公司涉及的缺陷，查漏补缺，提高现有的差距水平，避免所有部门出现同样的缺陷。这些问题如下：　　

　　1.产品定义和覆盖法律法规不明确，存在有法不依的缺陷；　　

　　2.生物制剂许可证42 u . s . c . 262(a)申请保护(BLA)未获批准，且无有效IND 21 u . s . c . 355(I)；《美国法典》第42篇第262(a)(3)节；21 CFR第312部分；　　

　　3.Invitrx的供体资格确认不充分，未建立审查确认程序及相关记录；　　

　　4.生产过程、无菌过程和灭菌过程是未经验证,无菌操作存在混淆和交叉污染；　　

　　5.尚未建立材料和产品的放行程序和放行指标；　　

　　6.未配备适当的监测系统和人员监控系统；　　

　　7.没有建立书面投诉处理程序；　　

　　8.生物稳定性研究还没有建立。　　

　　以下为警告信全文及翻译 　　

　　WARNING LETTER 　　

　　Invitrx Therapeutics Inc.MARCS-CMS 581182 ― MARCH 16, 2020 　　

　　WARNING LETTER警告信 　　

　　2020年3月16日2020年3月16日　　

　　Warning Letter #OBPO 20-581182 　　

　　亲爱的托菲先生，　　

　　在2019年3月25日至2019年4月3日对贵公司Invitrx Therapeutics，Inc .进行的检查中，食品药品监督管理局(FDA)记录了贵公司加工用于同种异体用途的产品，包括以下产品(在本函中统称为“贵公司产品”)、人脐带血或脐带衍生产品、Invitra CBSCTM和Invitra WJTM(细胞和非细胞)；羊水衍生产品Invitra AFTM；和羊膜衍生产品Invitra ATTM。您将产品分销到位于(b)(4)的(b)(4)。这些产品用于注射，并声称是无菌的。　　

　　美国美国食品药品监督管理局(FDA)在2019年3月25日至2019年4月3日对贵公司Invitrx Therapeutics，Inc .的检查过程中，记录了贵公司生产的用于同种异体使用的产品，包括以下产品(在本函中统称为“贵公司产品”):人脐带血或脐带衍生产品、Invitra CBSCTM和Invitra WJTM(细胞和非细胞)羊水衍生产品Invitra；ATTM羊膜衍生物。将您的产品分发到位于(b)(4)的(b)(4)。这些产品用于注射，据说是无菌的。　　

　　检查过程中收集的信息和记录以及贵公司网站——www.invitrx.com和(b)(4)上的信息表明，贵公司的产品符合国际标准　　

nded to treat a variety of diseases or conditions. Therefore, your products are drugs 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 biological products as defined in section 351(i) of the Public Health Service Act (PHS Act) <42 U.S.C. 262(i)>.1

在检查过程中收集的信息和记录以及您的网站www.invitrx.com和（b）（4）上提供的信息表明，您的产品旨在治疗多种疾病或病症。因此，您的产品属于《联邦食品药品和化妆品法》（FD＆C法）<21 U.S.C. 321（g）>和《公共卫生服务法》（PHS Act）<42 U.S.C. 262（i）>。1

Certain of your products are also human cells, tissues, or cellular or tissue-based products (HCT/Ps) as defined in 21 CFR 1271.3(d)2 and are subject to regulation under 21 CFR Part 1271, issued under authority of section 361 of the PHS Act <42 U.S.C. 264>. Invitrx does not qualify for any exception in 21 CFR 1271.15, and your HCT/Ps fail to meet all the criteria in 21 CFR 1271.l0(a). Therefore, your HCT/Ps are not regulated solely under section 361 of the PHS Act <42 U.S.C. 264> and the regulations in 21 CFR Part 1271.

您的某些产品也属于21 CFR 1271.3（d）2中定义的人体细胞、组织或细胞或组织制品（HCT/Ps），并受21 CFR第1271部分（根据PHS法案第361节授权发布）的监管【42 U.S.C.264】。Invitrx不符合21 CFR 1271.15中的任何例外，并且您的HCT/Ps不符合21 cfr1271.l0（a）中的所有标准。因此，您的HCT/Ps并非仅受《PHS法案》【42 U.S.C.264】第361节和21 CFR Part 1271中的规定进行监管。

Specifically, an HCT/P meets the criterion established by 21 CFR 1271.10(a)(2) if it is “intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer's objective intent.”3 As noted above, your products are intended to treat a variety of diseases or conditions. The umbilical cord blood and umbilical cord products are intended to treat orthopedic conditions, for example, and are not intended to perform the same basic function or functions of umbilical cord blood or umbilical cord in the recipient as in the donor, such as forming and replenishing the lymphohematopoietic system (for cord blood) and serving as a conduit (for umbilical cord). It appears that your product derived from amniotic membrane is also intended to treat orthopedic conditions, for example, and is not intended to perform the same basic function or functions of amniotic membrane in the recipient as in the donor, such as covering, protecting, serving as a selective barrier for the movement of nutrients between the external and in utero environment, and retaining fluid in utero. Using these products to treat orthopedic conditions is not homologous use as defined in 21 CFR 1271.3(c).

具体而言，如果HCT/P“仅用于同一用途，如标签、广告或制造商目标意图的其他指示所反映的，则符合21 CFR 1271.10（a）（2）所确立的标准”，3如上文所述，您的产品旨在在治疗多种疾病或状况。例如，脐带血和脐带产品旨在治疗骨科疾病，并且不打算在受赠者中执行与脐带血或脐带相同的基本功能，如成形和补充淋巴造血系统（用于脐带血）并用作导管（用于脐带）。看来，您的衍生自羊膜的产品也是为了治疗骨科疾病，例如，并不是为了在受体中发挥与供体相同的基本功能，如覆盖、保护，作为营养物质在外界和子宫内流动的选择性屏障，并在子宫内保留液体。按照21 CFR 1271.3（c）的定义，使用这些产品治疗骨科疾病并非同源。

Your HCT/Ps fail to meet other criteria set forth in 21 CFR 1271.10(a). Your products derived from umbilical cord blood fail to meet 21 CFR 1271.10(a)(4). These products, manufactured from donated umbilical cord blood, are dependent on the metabolic activity of living cells for their primary function and are not for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use. In addition, your products derived from umbilical cord and amniotic membrane fail to meet the minimal manipulation criterion set forth in 21 CFR 1271.10(a)(1) and defined for structural tissue in 21 CFR 1271.3(f)(1), because your processing alters the original relevant characteristics of the umbilical cord and amniotic membrane related to their utility for reconstruction, repair, or replacement.

您的HCT/Ps不符合21 CFR 1271.10（a）中规定的其他标准。你的脐带血产品不符合21 CFR 1271.10（a）（4）。这些产品由捐献的脐带血制成，主要功能依赖于活细胞的代谢活性，不用于本体、一级或二级血液的同种异体使用或生殖用途。此外，您的衍生自脐带和羊膜的产品不能满足21 CFR 1271.10（a）（1）中规定的和21 CFR 1271.3（f）（1）中针对结构组织定义的最低操作标准，因为您的处理过程改变了脐带和羊膜的原始相关特征，这些特征与它们的重建，修复或替换用途有关。

As stated above, because your HCT/Ps do not meet all the criteria in 21 CFR 1271.10(a), and Invitrx does not qualify for any exception in 21 CFR 1271.15, your HCT/Ps are regulated as drugs as defined in section 201(g) of the FD&C Act <21 U.S.C. 321(g)> and biological products as defined in section 351(i) of the PHS Act <42 U.S.C. 262(i)>.

如上所述，由于您的HCT/P不符合21 CFR 1271.10（a）中的所有标准，且Invitrx不符合21 CFR 1271.15中的任何例外，您的HCT/P被视为第201（g）FD＆C法案<21 U.S.C.321（g）>第201（g）节中定义的药物和PHS法案<42 U.S.C.262（i）>第351（i）节中定义的生物制品。

Please be advised that 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 showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use 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>. None of your products are the subject of an approved biologics license application (BLA), nor is there an IND in effect for any of them. Based on this information, we have determined that your actions have violated the FD&C Act and the PHS Act.

请注意，要合法销售生物制品药品，必须具有有效的生物制品许可<42 U.S.C.262（a）>。只有在证明产品是安全的、纯净且有效的之后，才能颁发此类许可证。在研发阶段，只有在申办者拥有FDA法规<21 U.S.C. 355（i）；42 U.S.C. 262（a）（3）；21 CFR Part 312>规定的有效的试验性新药申请（IND）时，此类产品才能分发给人类临床使用。您的所有产品均未获得批准的生物制剂许可证申请（BLA）的保护，也没有有效的IND。根据这些信息，我们确定您的行为违反了FD＆C法案和PHS法案。

Additionally, during the inspection, FDA investigators documented evidence of significant deviations from current good manufacturing practice (CGMP) and current good tissue practice (CGTP), including deviations from section 501(a)(2)(B) of the FD&C Act and 21 CFR Parts 210, 211, and 1271. The deviations in manufacturing processes observed as well as those noted in documents collected during the inspection indicate that the use of your products raises potential significant safety concerns. For example, Invitrx’s deficient donor eligibility practices, unvalidated manufacturing processes, deficient environmental monitoring, and inadequate aseptic practices, as described below, pose a significant risk that your products may be contaminated with viruses or microorganisms or have other serious product quality defects.

此外，在检查过程中，FDA审查人员记录了与当前良好生产规范（CGMP）和当前良好组织规范（CGTP）存在重大偏差的证据，包括与FD＆C法案第501（a）（2）（B）条和第21条的偏离CFR第210、211和1271部分的偏差。审查到的生产过程中的偏差以及检查期间收集的文件中记录的偏差表明，产品的使用会引起潜在的重大安全隐患。例如，如下文所述，Invitrx的供体资格实践不足、生产工艺未经验证、环境监测不足和无菌操作不充分，都会给您的产品带来很大的风险，使其可能受到病毒或微生物的污染，或有其他严重的产品质量缺陷。

At the close of the inspection, the FDA investigators issued a Form FDA 483 to you listing inspectional observations, which described a number of significant deviations from CGMP applicable to your products as well as significant CGTP deviations applicable to your HCT/Ps. FDA has found additional significant deviations upon further review of the information collected during the inspection, as discussed below. The deficiencies include, but are not limited to, the following:

在检查结束时，FDA审查员向您发布了FDA 483表格，列出了审查结果，其中描述了与适用于您的产品的CGMP的一些重大偏差以及适用于您的HCT/Ps的CGTP重大偏差。如下所述，FDA在进一步审查期间收集的信息后发现了其他重大偏差。缺陷包括但不限于以下方面：

1. Failure of a responsible person to determine and document the eligibility of a cell or tissue donor based upon the results of donor screening and donor testing <21 CFR 1271.50(a)>. For example:

负责人未能根据供体筛选和供体测试的结果确定和记录细胞或组织供体的资格<21 CFR 1271.50（a）>。例如：

a. Invitrx is the establishment responsible for making the donor eligibility determination, but since operations began in March 2018, Invitrx has failed to document whether over (b)(4) HCT/P donors are eligible.

Invitrx是负责确定捐赠者资格的机构，但自2018年3月开始运作以来，Invitrx未能记录超过（b）（4）个HCT/P捐赠者是否符合资格。

b. When Invitrx receives relevant medical records, including the donor medical history interview and physical exams from its suppliers, those records are not reviewed to determine donor eligibility.

当Invitrx接收相关的医疗记录，包括来自供应商的捐赠者病史访谈和体检，这些记录未进行审核以确定捐赠者的资格。

2. Failure to determine a donor to be ineligible whose specimen tests reactive on a screening test for a communicable disease agent in accordance with 21 CFR 1271.85 <21 CFR 1271.80(d)(1)>. Specifically, cord blood donor (b)(6) tested positive for Hepatitis B (HBc) on August 24, 2018, and donor eligibility was not determined. The cord blood was used to manufacture thirty-three vials of Invitra CBSCTMproduct (label number (b)(4)) on August 18, 2018. (b)(4) of these vials were distributed. We acknowledge below that your firm initiated a voluntary recall of the distributed product.

未能确定一名捐献者不合格，根据21 CFR 1271.85<21 CFR 1271.80（d）（1）>，其样本检测结果与进行的传染病药物筛查试验结果一致。具体而言，脐血捐献者（b）（6）于2018年8月24日检测出乙型肝炎（HBc）阳性，且未确定供血者资格。2018年8月18日，脐带血被用于生产33瓶Invitra CBSCTM产品（标签号（b）（4））（b）（4）已被放行。兹确认贵公司主动召回所经销产品。

3. Failure to screen a donor of human cells or tissue by reviewing the donor’s relevant medical records for risk factors for, and clinical evidence of, relevant communicable disease agents and diseases <21 CFR 1271.75(a)>. For example, FDA has identified Zika virus (ZIKV) as a relevant communicable disease agent or disease (RCDAD) under 21 CFR 1271.3(r)(2). Therefore, review of relevant medical records, as defined in 21 CFR 1271.3(s), must indicate that a potential donor is free from risk factors for, or clinical evidence of, ZIKV infection for the purpose of determining donor eligibility. The DT-001 Form 4 “Donor Risk Assessment Interview” you receive from your primary cord blood supplier, (b)(4), does not adequately assess a donor's risk for ZIKV. We note that (b)(4) is located in (b)(4), which has been identified by the Centers for Disease Control and Prevention as an area with current or past transmission of ZIKV. We recommend that you review FDA Guidance for Industry, Donor Screening Recommendations to Reduce the Risk of Transmission of Zika Virus by Human Cells, Tissues, and Cellular and Tissue-Based Products (updated May 2018). This and all tissue guidances available to industry can be found at:

未能通过审查捐赠者的相关医疗记录来筛选人类细胞或组织的捐赠者，以确定相关传染病原和疾病的危险因素和临床证据<21 CFR 1271.75（a）>。例如，FDA已根据21 CFR 1271.3（r）（2）将寨卡病毒（ZIKV）确定为相关传染病病原体或疾病（RCDAD）。因此，对21 CFR 1271.3（s）中定义的相关医疗记录的审查必须表明，为了确定捐赠者的资格，潜在捐赠者不存在ZIKV感染的危险因素或临床证据。您从主要脐带血供应商（d）（b）（4）处收到的DT-001表4“捐赠者风险评估访谈”未充分评估捐赠者的ZIKV风险。我们注意到（b）（4）位于（b）（4）中，已被疾病控制和预防中心确定为当前或过去传输ZIKV的区域。我们建议您审查FDA的行业指南、减少人类细胞、组织、细胞和组织制品传播寨卡病毒风险的捐赠者筛选建议（2018年5月更新）。可在以下网址找到本指南和所有行业可用的工业指南：

https://www.fda.gov/vaccines-blood-biologics/biologics-guidances/tissue-guidances.

4. Failure to establish and maintain procedures for all steps performed in testing, screening, and determining donor eligibility, and complying with all other requirements of Subpart C “Donor Eligibility” in 21 CFR 1271.45-1271.90. “Establish and maintain” means define, document (in writing or electronically), and implement; then follow, review, and as needed, revise on an ongoing basis <21 CFR 1271.47(a)>. Specifically, you failed to establish and maintain procedures for determining donor eligibility to adequately and appropriately reduce the risk of transmission of relevant communicable diseases.

未能建立和维护测试、筛选和确定捐赠者资格的所有步骤的程序，以及未能遵守21 CFR 1271.45-1271.90中C部分“捐赠者资格”的所有其他要求。“建立和维护”是指定义、记录（书面或电子形式）并实施；然后遵循、审查并根据需要持续修订【21 CFR 1271.47（a）】，具体来说，您未能建立和维持程序，以确定捐赠者是否有充分资格和适当地降低有关传染病的传播风险。

5. Failure to retain the accompanying records with the HCT/Ps at all times following a donor eligibility determination including a statement whether, based on the results of screening and testing, the donor has been determined to be eligible or ineligible; and a summary of records used to make the donor-eligibility determination <21 CFR 1271.55(a)>. For example, your HCT/Ps distributed to (b)(4), were distributed without a statement of donor eligibility.

在确定捐赠者资格之后，未能始终将所附记录保存在HCT/Ps中，其中包括根据筛查和测试的结果确定捐助者是否合格或不合格的声明；以及用于确定捐赠者资格的记录摘要<21 CFR 1271.55（a）>.例如，您分发给（b）（4）的HCT / P并未声明捐赠者资格。

6. 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:

未能建立和遵循适当的书面程序，以防止无菌的药品受到微生物污染，包括所有无菌和灭菌工艺的验证程序<21 CFR 211.113（b）>。例如：

a. Your firm failed to validate the aseptic process used to manufacture Invitra AFTM, Invitra ATTM, Invitra CBSCTM, and Invitra WJTM since product manufacturing began in 2018. By the nature of their routes of administration, your products purport to be sterile and are expected to be sterile.

自2018年开始生产产品以来，贵公司未能验证用于制造Invitra AFTM、Invitra ATTM、Invitra CBSCTM和Invitra WJTM的无菌工艺。根据其给药途径的性质，您的产品据称是无菌的，预期是无菌的。

b. During the inspection, FDA investigators observed personnel practices that do not adequately protect against microbiological contamination of your products, including:

在检查过程中，FDA的审查人员观察到人员的行为不足以防止产品受到微生物污染，包括：

i. Operators donned sterile outer gloves over non-sterile inner gloves in the Biological Safety Cabinets (BSCs).

操作人员在生物安全柜（BSC）中将无菌外手套戴在非无菌内手套上。

ii. An operator was observed processing cord blood in a BSC with only the inner non-sterile gloves.

观察到操作员仅使用内部非无菌手套在BSC中处理脐带血。

c. Open sharps containers were observed with visible accumulation of debris and dried residues inside the BSCs where human umbilical cord blood is aseptically processed.

在BSCs内无菌处理人脐带血，观察到开放式尖锐容器内可见碎屑和干燥残留物的堆积。

7. Failure to reject drug products that do not meet established standards or specifications and any other quality control criteria <21 CFR 211.165(f)>. For example:

未能拒绝不符合既定标准或规范以及任何其他质量控制标准的药品【21 CFR 211.165（f）】。例如：

a. You failed to reject batch (b)(4), (b)(6) of umbilical cord blood product due to microbial growth on the initial cord blood (donor (b)(6)) plate. (b)(4) vials of final product (label number (b)(4)) were distributed.

由于初始脐带血（供体（b）（6））板上的微生物生长，您未能拒绝批次（b）（4），（b）（6）的脐带血产品。（b）（4）最终产品（标签编号（b）（4））被放行。

b. You failed to reject batch (b)(4), (b)(4) of umbilical cord blood product due to the inprocess plasma (b)(4) sterility positive test result for gram positive cocci. (b)(4) vials of final product (label number (b)(4)) were distributed.

由于生产过程中血浆（b）（4）革兰氏阳性球菌无菌阳性结果，您未能拒绝（b）（4）批次。（b）（4）成品（标签编号（b）（4））被放行。

8. Failure to establish and follow written procedures for cleaning and maintenance of equipment used in the manufacture, processing, packing, or holding of a drug product <21 CFR 211.67(b)>. For example:

未建立并遵循用于药品生产、加工、包装或存放的设备清洁和维护的书面程序<21 CFR 211.67（b）>。例如：

a. Your firm failed to validate the cleaning process for your BSCs.

您的公司未能验证BSC的清洁过程。

b. There is no data or rationale for the cleaning agents used or their rotation.

没有数据或理由说明使用的清洗剂或它们的轮换。

9. Failure to thoroughly investigate any unexplained discrepancy, or the failure of a batch or any of its components to meet any of its specifications <21 CFR 211.192>. Specifically, you failed to adequately investigate all sterility failures from March 2018 to present. Numerous batches of your umbilical cord blood and umbilical cord products failed sterility and were discarded after speciation without further investigation, including identification of the contamination source, and without implementing corrective actions.

未能彻底调查任何无法解释的差异，或批次或其任何组件未能满足其任何规范<21 CFR 211.192>。具体而言，您未能充分调查2018年3月至今的所有无菌失误。您的多个批次脐带血和脐带产品无菌不合格，并且在物种形成后被丢弃，未经进一步调查，包括确定污染源，也没有采取纠正措施。

10. Failure to establish written procedures for production and process control 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, the manufacturing process has not been validated for your products.

未能建立生产和过程控制的书面程序，以确保药物产品具有其声称或代表具有的特性、强度、质量和纯度<21 CFR 211.100（a）>。具体而言，尚未对产品的生产过程进行验证。

11. 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)>. For example:

在生产和加工过程中，没有单独或规定的区域或其他必要的操作控制系统，以防止污染或混淆<21 CFR 211.42（c）（5）>。例如：

a. FDA investigators observed operators conducting processing of two separate umbilical cord product lots ((b)(4) and (b)(4)), in separate BSCs, and removing unlabeled vials from the BSCs for centrifugation using one shared (b)(4). Products manufactured from different donors lacked unique identifiers.

FDA审查人员观察到操作人员在单独的BCS中处理两个单独的脐带产品批次（（b）（4）和（b）（4）），并使用一个共享的（b）（4）从BSC中取出未标记的小瓶进行离心分离。不同捐助者生产的产品缺乏唯一的标识。

b. Freezers for quarantine of finished product and released finished product are not labeled.

成品和放行成品检疫用冷冻箱未贴标签。

12. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area <21 CFR 211.42(c)(10)(iv)>. Specifically, your firm has not established an adequate system for environmental and personnel monitoring in the aseptic processing areas where the products are manufactured.

未能在无菌生产区配备适当的系统来监控环境条件<21 CFR 211.42（c）（10）（iv）>。具体而言，贵公司没有在生产产品的无菌生产区建立足够的环境和人员监测系统。

13. Failure to test your Invitra ATTM and Invitra WJTM products, non-penicillin drug products, for the presence of penicillin although a reasonable possibility exists that the non-penicillin drug products have been exposed to cross contamination with penicillin <21 CFR 211.176>. Specifically, penicillin was used in an antibiotic wash during manufacture of approximately (b)(4) vials of Invitra ATTM and approximately (b)(4) vials of Invitra WJTM from March 2018 to April 2019, and there is no documentation that testing for penicillin has been performed.

无法测试您的Invitra ATTM和Invitra WJTM产品（非青霉素药物产品）是否存在青霉素，尽管存在非青霉素药物产品与青霉素交叉污染的合理可能性<21 CFR 211.176>，在2018年3月至2019年4月生产约（b）（4）瓶Invitra ATTM和约（b）（4）瓶Invitra WJTM的过程中，青霉素用于抗生素清洗，没有任何文件证明青霉素测试已经进行。

14. 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)>. You have not established and followed written procedures that describe a process for documenting and investigating complaints. The inspection revealed that Invitrx received at least 19 complaints, in the form of an e-mail, but there was no documentation that your firm performed adequate follow-up and/or investigations of those complaints.

未能建立和遵循书面程序，说明如何处理与药品有关的所有书面和口头投诉<21 CFR 211.198（a）>。您尚未建立和遵循书面程序，说明记录和调查投诉的过程。检查显示，Invitrx收到了至少19份电子邮件形式的投诉，但没有任何文件表明贵公司对这些投诉进行了充分的跟踪和/或调查。

15. Failure to establish and follow a written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates <21 CFR 211.166(a)>. Specifically, you assign a two-year expiration date without supporting data.

未能建立和遵循书面测试程序，该程序旨在评估药品的稳定性特征，并使用此类稳定性测试的结果来确定适当的储存条件和有效期<21 CFR 211.166（a）>。具体而言，您指定了两年的有效期，但没有支持数据。

16. Failure to establish and follow written procedures describing in sufficient detail the control procedures employed for the issuance of labeling <21 CFR 211.125(f)>. For example:

未能建立并遵循书面程序，详细说明标签发行所采用的控制程序【21 CFR 211.125（f）】。例如：

a. Your firm has not established a written procedure for the control of printed labels.

贵公司尚未建立标签印刷控制的书面程序。

b. Four additional primary labels are printed and included in every shipment for “physician use” without documentation, accounting, or reconciliation.

另外四个主要标签打印并包含在每批货物中，以供“医生使用”，无需文件、会计或核对。

17. Failure to withhold from use each lot of components, drug product containers, and closures 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:

在适当取样、测试或检查该批次并由质量控制单位放行使用前<21 CFR 211.84（a）>，没有停止使用每批次的所有组件、药品容器和密闭容器。例如，以下组件和容器在放行前未经检验或检查：

a. (b)(4) used to homogenize amniotic and umbilical cord tissue in the manufacture process of Invitra ATTM and Invitra WJTM.

（b）（4）用于Invitra ATTM和Invitra WJTM生产过程中羊水和脐带组织的均质化。

b. (b)(4) used to “wash” amniotic and umbilical cord tissue in the manufacture process of Invitra ATTM and Invitra WJTM.

（b）（4）在Invitra ATTM和Invitra WJTM生产过程中用于“清洗”羊水和脐带组织。

c. (b)(4) GMP grade cryopreservation solution used in the final formulation of Invitra AFTM, Invitra CBSCTM, and Invitra WJTM.

（b）（4）用于Invitra AFTM、Invitra CBSCTM和Invitra WJTM最终配方的GMP级冷冻保存液。

We received your written responses, dated May 1 and October 1, 2019, to the inspectional observations on the Form FDA 483, and we have reviewed their contents. FDA acknowledges your decision to voluntary recall distributed Invitra CBSCTM (label number (b)(4)) manufactured from cord blood of a donor who tested positive for Hepatitis B, and your decision to temporarily cease the receipt of HCT/Ps from (b)(4), located in (b)(4). We also acknowledge the other corrective actions you represent that you have taken in response to the observations and your hiring of (b)(4), a third-party consultant, to assist with investigations and the implementation of corrective actions. However, the responses do not provide sufficient detail to fully assess the adequacy of your corrective actions to date, lack a timeline for completion of all necessary corrective actions, and lack documentation to demonstrate that you have corrected your violations.

我们收到了您于2019年5月1日和10月1日对FDA 483表格的检查意见的书面回复，我们已经审查了它们的内容。FDA承认你决定自愿召回由乙型肝炎检测呈阳性的捐赠者脐血制成的Invitra CBSCTM（标签号（b）（4）），以及你决定暂时停止接收（b）（4）中（b）（4）的HCT/Ps。我们也承认您所代表的其他纠正措施，您已经采取了回应意见和您聘请（b）（4）第三方顾问，以协助调查和实施纠正措施。然而，这些回复没有提供足够的细节来全面评估你迄今为止的纠正措施的充分性，没有完成所有必要纠正措施的时间表，也没有证明你已经纠正了你的违规行为的文件。

In addition, as noted above, 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 showing that the product is safe, pure, and potent. While in the development stage, such products may be distributed for clinical use in humans only if the sponsor has an 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 products are not the subject of an approved BLA nor is there an IND in effect for your products.

此外，如上所述，为了合法地销售属于生物制品的药物，有效的生物制品许可证必须有效 <42 U.S.C. 262(a)>。只有在证明产品是安全的、纯净的和有效的之后，才能颁发此类许可证。在研发阶段，只有当赞助人具有FDA法规规定的有效IND时，此类产品才能分发给人类临床使用 <21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312>。您的产品不属于经批准的BLA的主题，您的产品也没有有效的IND。

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.

本函和FDA 483表格上的意见（在检查结束时与您进行了讨论）均不打算成为您工厂可能存在的所有缺陷清单。您有责任确保完全遵守FD&C 法案、PHS法案和所有适用法规。

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

你应该立即采取行动纠正这些违规行为。未能及时采取行动可能会导致监管行动而无需另行通知。此类诉讼包括扣押和/或禁令。