近期FDA官網於2020年03月18日發佈一封關於生物藥公司警告信（Invitrx Therapeutics Inc.

1、對產品定義以及涵蓋法規不明確，存在未遵循法規缺陷；

2、未獲得批准的生物製劑許可證[42 U.S.C.262（a）]申請（BLA）的保護，也沒有有效的IND[21 U.S.C. 355（i）；42 U.S.C. 262（a）（3）；21 CFR Part 312]；

3、Invitrx的供體資格確認不充分，未建立審查、確認程序以及相關記錄；

4、生產工藝、無菌工藝和滅菌工藝未經驗證，無菌操作存在混淆與交叉汙染；

5、未建立物料與產品放行程序與放行指標；

6、未配備適當監測系統和人員監測系統；

7、未建立投訴處理書面程序；

8、未建立生物穩定性研究。

以下為警告信全文及翻譯

WARNING LETTER

Invitrx Therapeutics Inc.

MARCS-CMS 581182 — MARCH 16, 2020

WARNING LETTER警告信

March 16, 2020 2020年3月16日

Warning Letter #OBPO 20-581182

Dear Mr. Torfi,

During an inspection of your firm Invitrx Therapeutics, Inc., located at 20503 Crescent Bay Drive, Lake Forest, CA 92630, conducted between March 25, 2019 and April 3, 2019, the Food and Drug Administration (FDA) documented that your firm processes products for allogeneic use, including the following products (referred to collectively in this letter as “your products”): human umbilical cord blood, or umbilical cord derived products, Invitra CBSCTM and Invitra WJTM (Cellular and Acellular); amniotic fluid derived product Invitra AFTM; and amniotic membrane derived product Invitra ATTM. You distribute your products to (b)(4), located in (b)(4). These products are intended for injection and are purported to be sterile.

在2019年3月25日至2019年4月3日期間對您的公司Invitrx Therapeutics，Inc.進行的檢查中，美國食品藥品管理局（FDA）記錄了您的公司生產供異基因使用的產品，包括以下產品（在本函中統稱為“貴司產品”）：人臍帶血或臍帶衍生產品，Invitra CBSCTM和Invitra WJTM（細胞和非細胞）；羊水衍生產品Invitra；羊膜衍生產品Invitra ATTM。您將產品分發給位於（b）（4）的（b）（4）。這些產品旨在注射，據稱是無菌的。

Information and records gathered during the course of the inspection and information available on your website, www.invitrx.com, and the (b)(4), reflect that your products are intended 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

在檢查過程中收集的信息和記錄以及您的網站www.invitrx.com和（b）（4）上提供的信息表明，您的產品旨在治療多種疾病或病症。因此，您的產品屬於《聯邦食品藥品和化妝品法》（FD＆C法）[21 U.S.C. 321（g）]和《公共衛生服務法》（PHS Act）[42 U.S.C. 262（i）]。

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.

您的某些產品也屬於21 CFR 1271.3（d）2中定義的人體細胞、組織或細胞或組織製品（HCT/Ps），並受21 CFR第1271部分（根據PHS法案第361節授權發佈）的監管【42 U.S.C.264】。Invitrx不符合21 CFR 1271.15中的任何例外，並且您的HCT/Ps不符合21 cfr1271.l0（a）中的所有標準。因此，您的HCT/Ps並非僅受《PHS法案》【42 U.S.C.264】第361節和21 CFR Part 1271中的規定進行監管。

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).

具體而言，如果HCT/P“僅用於同一用途，如標籤、廣告或製造商目標意圖的其他指示所反映的，則符合21 CFR 1271.10（a）（2）所確立的標準”，3如上文所述，您的產品旨在在治療多種疾病或狀況。例如，臍帶血和臍帶產品旨在治療骨科疾病，並且不打算在受贈者中執行與臍帶血或臍帶相同的基本功能，如成形和補充淋巴造血系統（用於臍帶血）並用作導管（用於臍帶）。看來，您的衍生自羊膜的產品也是為了治療骨科疾病，例如，並不是為了在受體中發揮與供體相同的基本功能，如覆蓋、保護，作為營養物質在外界和子宮內流動的選擇性屏障，並在子宮內保留液體。按照21 CFR 1271.3（c）的定義，使用這些產品治療骨科疾病並非同源。

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）中規定的其他標準。你的臍帶血產品不符合21 CFR 1271.10（a）（4）。這些產品由捐獻的臍帶血製成，主要功能依賴於活細胞的代謝活性，不用於本體、一級或二級血液的同種異體使用或生殖用途。此外，您的衍生自臍帶和羊膜的產品不能滿足21 CFR 1271.10（a）（1）中規定的和21 CFR 1271.3（f）（1）中針對結構組織定義的最低操作標準，因為您的處理過程改變了臍帶和羊膜的原始相關特徵，這些特徵與它們的重建，修復或替換用途有關。

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，由於您的HCT/P不符合21 CFR 1271.10（a）中的所有標準，且Invitrx不符合21 CFR 1271.15中的任何例外，您的HCT/P被視為第201（g）FD＆C法案[21 U.S.C.321（g）]第201（g）節中定義的藥物和PHS法案[42 U.S.C.262（i）]第351（i）節中定義的生物製品。

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.

請注意，要合法銷售生物製品藥品，必須具有有效的生物製品許可[42 U.S.C.262（a）]。只有在證明產品是安全的、純淨且有效的之後，才能頒發此類許可證。在研發階段，只有在申辦者擁有FDA法規[21 U.S.C. 355（i）；42 U.S.C. 262（a）（3）；21 CFR Part 312]規定的有效的試驗性新藥申請（IND）時，此類產品才能分發給人類臨床使用。您的所有產品均未獲得批准的生物製劑許可證申請（BLA）的保護，也沒有有效的IND。根據這些信息，我們確定您的行為違反了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，在檢查過程中，FDA審查人員記錄了與當前良好生產規範（CGMP）和當前良好組織規範（CGTP）存在重大偏差的證據，包括與FD＆C法案第501（a）（2）（B）條和第21條的偏離CFR第210、211和1271部分的偏差。審查到的生產過程中的偏差以及檢查期間收集的文件中記錄的偏差表明，產品的使用會引起潛在的重大安全隱患。例如，如下文所述，Invitrx的供體資格實踐不足、生產工藝未經驗證、環境監測不足和無菌操作不充分，都會給您的產品帶來很大的風險，使其可能受到病毒或微生物的汙染，或有其他嚴重的產品質量缺陷。

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:

在檢查結束時，FDA審查員向您發佈了FDA 483表格，列出了審查結果，其中描述了與適用於您的產品的CGMP的一些重大偏差以及適用於您的HCT/Ps的CGTP重大偏差。如下所述，FDA在進一步審查期間收集的信息後發現了其他重大偏差。缺陷包括但不限於以下方面：

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:

負責人未能根據供體篩選和供體測試的結果確定和記錄細胞或組織供體的資格[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是負責確定捐贈者資格的機構，但自2018年3月開始運作以來，Invitrx未能記錄超過（b）（4）個HCT/P捐贈者是否符合資格。

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.

當Invitrx接收相關的醫療記錄，包括來自供應商的捐贈者病史訪談和體檢，這些記錄未進行審核以確定捐贈者的資格。

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.

未能確定一名捐獻者不合格，根據21 CFR 1271.85[21 CFR 1271.80（d）（1）]，其樣本檢測結果與進行的傳染病藥物篩查試驗結果一致。具體而言，臍血捐獻者（b）（6）於2018年8月24日檢測出乙型肝炎（HBc）陽性，且未確定供血者資格。2018年8月18日，臍帶血被用於生產33瓶Invitra CBSCTM產品（標籤號（b）（4））（b）（4）已被放行。茲確認貴公司主動召回所經銷產品。

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

未能通過審查捐贈者的相關醫療記錄來篩選人類細胞或組織的捐贈者，以確定相關傳染病原和疾病的危險因素和臨床證據[21 CFR 1271.75（a）]。例如，FDA已根據21 CFR 1271.3（r）（2）將寨卡病毒（ZIKV）確定為相關傳染病病原體或疾病（RCDAD）。因此，對21 CFR 1271.3（s）中定義的相關醫療記錄的審查必須表明，為了確定捐贈者的資格，潛在捐贈者不存在ZIKV感染的危險因素或臨床證據。您從主要臍帶血供應商（d）（b）（4）處收到的DT-001表4“捐贈者風險評估訪談”未充分評估捐贈者的ZIKV風險。我們注意到（b）（4）位於（b）（4）中，已被疾病控制和預防中心確定為當前或過去傳輸ZIKV的區域。我們建議您審查FDA的行業指南、減少人類細胞、組織、細胞和組織製品傳播寨卡病毒風險的捐贈者篩選建議（2018年5月更新）。可在以下網址找到本指南和所有行業可用的工業指南：

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.

未能建立和維護測試、篩選和確定捐贈者資格的所有步驟的程序，以及未能遵守21 CFR 1271.45-1271.90中C部分“捐贈者資格”的所有其他要求。“建立和維護”是指定義、記錄（書面或電子形式）並實施；然後遵循、審查並根據需要持續修訂【21 CFR 1271.47（a）】，具體來說，您未能建立和維持程序，以確定捐贈者是否有充分資格和適當地降低有關傳染病的傳播風險。

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.

在確定捐贈者資格之後，未能始終將所附記錄保存在HCT/Ps中，其中包括根據篩查和測試的結果確定捐助者是否合格或不合格的聲明；以及用於確定捐贈者資格的記錄摘要[21 CFR 1271.55（a）].例如，您分發給（b）（4）的HCT / P並未聲明捐贈者資格。

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:

未能建立和遵循適當的書面程序，以防止無菌的藥品受到微生物汙染，包括所有無菌和滅菌工藝的驗證程序[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年開始生產產品以來，貴公司未能驗證用於製造Invitra AFTM、Invitra ATTM、Invitra CBSCTM和Invitra WJTM的無菌工藝。根據其給藥途徑的性質，您的產品據稱是無菌的，預期是無菌的。

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

在檢查過程中，FDA的審查人員觀察到人員的行為不足以防止產品受到微生物汙染，包括：

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

操作人員在生物安全櫃（BSC）中將無菌外手套戴在非無菌內手套上。

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

觀察到操作員僅使用內部非無菌手套在BSC中處理臍帶血。

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內無菌處理人臍帶血，觀察到開放式尖銳容器內可見碎屑和乾燥殘留物的堆積。

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:

未能拒絕不符合既定標準或規範以及任何其他質量控制標準的藥品【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.

由於初始臍帶血（供體（b）（6））板上的微生物生長，您未能拒絕批次（b）（4），（b）（6）的臍帶血產品。（b）（4）最終產品（標籤編號（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

由於生產過程中血漿（b）（4）革蘭氏陽性球菌無菌陽性結果，您未能拒絕（b）（4）批次。（b）（4）成品（標籤編號（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:

未建立並遵循用於藥品生產、加工、包裝或存放的設備清潔和維護的書面程序[21 CFR 211.67（b）]。例如：

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

您的公司未能驗證BSC的清潔過程。

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

沒有數據或理由說明使用的清洗劑或它們的輪換。

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.

未能徹底調查任何無法解釋的差異，或批次或其任何組件未能滿足其任何規範[21 CFR 211.192]。具體而言，您未能充分調查2018年3月至今的所有無菌失誤。您的多個批次臍帶血和臍帶產品無菌不合格，並且在物種形成後被丟棄，未經進一步調查，包括確定汙染源，也沒有采取糾正措施。

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.

未能建立生產和過程控制的書面程序，以確保藥物產品具有其聲稱或代表具有的特性、強度、質量和純度[21 CFR 211.100（a）]。具體而言，尚未對產品的生產過程進行驗證。

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:

在生產和加工過程中，沒有單獨或規定的區域或其他必要的操作控制系統，以防止汙染或混淆[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審查人員觀察到操作人員在單獨的BCS中處理兩個單獨的臍帶產品批次（（b）（4）和（b）（4）），並使用一個共享的（b）（4）從BSC中取出未標記的小瓶進行離心分離。不同捐助者生產的產品缺乏唯一的標識。

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

成品和放行成品檢疫用冷凍箱未貼標籤。

12. Failure to have an adequate system for monitoring environmental conditions in an aseptic processing area [21 CFR 211.42(c)(10)(iv)].

未能在無菌生產區配備適當的系統來監控環境條件[21 CFR 211.42（c）（10）（iv）]。具體而言，貴公司沒有在生產產品的無菌生產區建立足夠的環境和人員監測系統。

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.

無法測試您的Invitra ATTM和Invitra WJTM產品（非青黴素藥物產品）是否存在青黴素，儘管存在非青黴素藥物產品與青黴素交叉汙染的合理可能性[21 CFR 211.176]，在2018年3月至2019年4月生產約（b）（4）瓶Invitra ATTM和約（b）（4）瓶Invitra WJTM的過程中，青黴素用於抗生素清洗，沒有任何文件證明青黴素測試已經進行。

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.

未能建立和遵循書面程序，說明如何處理與藥品有關的所有書面和口頭投訴[21 CFR 211.198（a）]。您尚未建立和遵循書面程序，說明記錄和調查投訴的過程。檢查顯示，Invitrx收到了至少19份電子郵件形式的投訴，但沒有任何文件表明貴公司對這些投訴進行了充分的跟蹤和/或調查。

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)].

未能建立和遵循書面測試程序，該程序旨在評估藥品的穩定性特徵，並使用此類穩定性測試的結果來確定適當的儲存條件和有效期[21 CFR 211.166（a）]。具體而言，您指定了兩年的有效期，但沒有支持數據。

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:

未能建立並遵循書面程序，詳細說明標籤發行所採用的控制程序【21 CFR 211.125（f）】。例如：

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

貴公司尚未建立標籤印刷控制的書面程序。

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

另外四個主要標籤打印幷包含在每批貨物中，以供“醫生使用”，無需文件、會計或核對。

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:

在適當取樣、測試或檢查該批次並由質量控制單位放行使用前[21 CFR 211.84（a）]，沒有停止使用每批次的所有組件、藥品容器和密閉容器。例如，以下組件和容器在放行前未經檢驗或檢查：

a.

（b）（4）用於Invitra ATTM和Invitra WJTM生產過程中羊水和臍帶組織的均質化。

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生產過程中用於“清洗”羊水和臍帶組織。

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

（b）（4）用於Invitra AFTM、Invitra CBSCTM和Invitra WJTM最終配方的GMP級冷凍保存液。

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.

我們收到了您於2019年5月1日和10月1日對FDA 483表格的檢查意見的書面回覆，我們已經審查了它們的內容。FDA承認你決定自願召回由乙型肝炎檢測呈陽性的捐贈者臍血製成的Invitra CBSCTM（標籤號（b）（4）），以及你決定暫時停止接收（b）（4）中（b）（4）的HCT/Ps。我們也承認您所代表的其他糾正措施，您已經採取了回應意見和您聘請（b）（4）第三方顧問，以協助調查和實施糾正措施。然而，這些回覆沒有提供足夠的細節來全面評估你迄今為止的糾正措施的充分性，沒有完成所有必要糾正措施的時間表，也沒有證明你已經糾正了你的違規行為的文件。

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，為了合法地銷售屬於生物製品的藥物，有效的生物製品許可證必須有效 [42 U.S.C. 262(a)]。只有在證明產品是安全的、純淨的和有效的之後，才能頒發此類許可證。在研發階段，只有當贊助人具有FDA法規規定的有效IND時，此類產品才能分發給人類臨床使用 [21 U.S.C. 355(i); 42 U.S.C. 262(a)(3); 21 CFR Part 312]。您的產品不屬於經批准的BLA的主題，您的產品也沒有有效的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表格上的意見（在檢查結束時與您進行了討論）均不打算成為您工廠可能存在的所有缺陷清單。您有責任確保完全遵守FD&C 法案、PHS法案和所有適用法規。

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.

你應該立即採取行動糾正這些違規行為。未能及時採取行動可能會導致監管行動而無需另行通知。此類訴訟包括扣押和/或禁令。

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實驗室管理丨工廠廠房設計

模擬GMP認證檢查丨數據可靠性審計

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