藥智網獲悉湖北兵兵藥業(yè)（集團）有限公司在10月3日收到了FDA的警告信，信中指出該公司2018年由于搬廠導致在原廠址生產的一些批次藥品的CGMP書面資料和樣品丟失，并且在收到對這些批次藥品的投訴后用不同批次的樣品進行檢測等問題。11月5日，F(xiàn)DA官網掛出了警告信全文。

       湖北兵兵藥業(yè)（集團）有限公司原名武漢兵兵藥業(yè)有限公司（BINGBING PHARMA），成立于2006年，是一家專業(yè)從事以水凝膠為主體的研發(fā)、生產和銷售的現(xiàn)代化新型制藥企業(yè)。公司于2011年8月4日獲取了吲哚美辛巴布膏生產批件，該產品為國內首家也是國內獨家獲批的巴布劑品種。

       11月5日，F(xiàn)DA官網掛出的警告信具體內容如下：

Dear Mr. Yu:

尊敬的余先生：

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Bingbing Pharmaceutical (Hubei) Co. Ltd., FEI 3014538973, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, from May 7 to 10, 2019.

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See 21 CFR, parts 210 and 211.

…翻譯…

美國食品藥品監(jiān)督管理局（FDA）于2019年5月7日至10日檢查了湖北兵兵藥業(yè)（集團）有限公司。 本警告函匯總了成品藥CGMP法規(guī)的重大違規(guī)。詳見美國聯(lián)邦法規(guī)第21卷，第210和211章。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

…翻譯…

因為你們的方法、設施、生產工藝、包裝或者儲存的方式不符合CGMP法規(guī)，你們的藥品根據(jù)《聯(lián)邦食品、藥品和化妝品法》（FD&C）第501(a)(2)(B)章節(jié)，《美國法典》第21卷第351(a)(2)(B)節(jié)被認定為違規(guī)。

We reviewed your May 31, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

…翻譯…

我們詳細審查了你們于2019年5月31日對FDA 483表格的回復，并確認收到你們之后的回復。

During our inspection, our investigator observed specific violations including, but not limited to, the following.

…翻譯…

在檢查期間，我們的檢查員發(fā)現(xiàn)的具體違規(guī)包括但不限于如下。

1. Your firm failed to maintain written production, control, or distribution records specifically associated with a batch of a drug product for at least one year after the expiration date of the batch (21 CFR 211.180(a)).

…翻譯…

你們公司未能在一批藥品有效期后至少一年內保持與該批藥品相關的書面的生產、控制或分銷記錄（《美國聯(lián)邦法規(guī)》第21卷第211.180（a）條）。

You manufactured drugs at your Wuhan facility at Building (b)(4), No. 5, Kangda Street, Longyang Avenue, Hanyang District, Wuhan, and then transferred drug production to your Hubei facility and closed the Wuhan facility. Your firm failed to maintain manufacturing records, raw material and finished product testing records, retain samples, stability samples, and other CGMP records for your over-the-counter (OTC) (b)(4) drug products manufactured at your Wuhan facility. During the inspection at the Hubei facility, you stated that you lost CGMP manufacturing documentation and drug product samples during the transfer of your manufacturing facility from Wuhan to Hubei in May 2018.

…翻譯…

你們在武漢市漢陽區(qū)龍陽大道康達街5號樓的武漢工廠生產藥品，然后將藥品生產轉移到湖北工廠并關閉了武漢工廠。但是未能為武漢工廠生產的非處方藥（OTC）保留生產記錄、原材料和成品測試記錄、樣品、穩(wěn)定性樣品和其他CGMP記錄。在湖北工廠檢查期間，你方聲明，你方在2018年5月從武漢轉移到湖北期間丟失了CGMP生產文件和藥品樣本。

In your response, you stated that you initiated an investigation to assess the scope of impacted product, will attempt to collect samples from the market to evaluate and take “all mandatory and necessary measures,” and will conduct a quality system evaluation using a third-party consultant. Your response is inadequate because you failed to appropriately address the impact of missing records and samples on drug products already on the market. Maintaining all manufacturing and testing records, as well as representative product samples, is critical to establish that your products meet their required quality attributes.

…翻譯…

在你們的回復中聲明，你們發(fā)起了一項調查，以評估受影響產品的范圍，將嘗試從市場收集樣品進行評估并采取“所有強制性和必要的措施”，并將使用第三方顧問進行質量體系評估。你們的回復是不充分的，因為沒有適當?shù)亟鉀Q丟失記錄和樣品對已經上市的藥品的影響。維護所有的生產和測試記錄，以及有代表性的產品樣品，對于確定產品符合所要求的質量屬性是至關重要的。

In response to this letter, provide:

…翻譯…

針對本函，請?zhí)峁?/p>

· A complete, independent assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient. Include a detailed corrective action and preventive action (CAPA) plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

…翻譯…

對整個生產和實驗室操作過程中使用的文件系統(tǒng)進行完整、獨立的評估，以確定記錄規(guī)范的不足之處。包括詳細的糾正措施和預防措施（CAPA）計劃，全面糾正公司的文記錄規(guī)范，以確保公司在整個經營過程中保留可歸屬的、清晰的、完整的、原始的、準確的、同期的記錄。

· A detailed risk assessment of drug products on the market without any manufacturing documentation and without retains or stability samples to support investigations and expiration dating. Specify actions, with timelines, that you will take in response to the risk assessment, such as customer notifications and initiating recalls.

…翻譯…

對市場上沒有生產文件和沒有保留樣品的藥品進行詳細的風險評估，以支持調查和有效期的確定。詳細說明針對風險評估將要采取的行動，例如客戶通知和發(fā)起召回。

2. Your firm failed to have, for each batch of drug product, appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release (21 CFR 211.165(a))

…翻譯…

你們未能對每批藥品進行適當?shù)膶嶒炇覝y定，以確定其是否符合藥品的最終規(guī)格（包括每種活性成分的特性和強度）。

Your firm released OTC drug products to the United States market without testing the identity and strength of each active ingredient. For example, your firm failed to test for the active ingredients, (b)(4), in your (b)(4)products. Testing is essential to ensuring that the drug products you manufacture meet established specifications for the required chemical attributes.

…翻譯…

你們公司向美國市場投放的非處方藥產品，沒有測試每種活性成分的特性和強度例如，沒有檢測產品中的活性成分。測試對于確保您生產的藥品符合所需化學特性的規(guī)范至關重要。

We acknowledge your commitment to discontinue the manufacture and distribution of (b)(4) products until analytical methods for (b)(4) active ingredients have been established and validated or verified. However, your response is inadequate. You failed to provide details for establishing that your OTC drug products in distribution meet their specifications.

…翻譯…

我們收到了你方承諾在活性成分分析方法建立、驗證或驗證之前停止生產和銷售產品。然而，你們的回復是不充分的，你們沒有提供詳細資料證明你的非處方藥產品符合規(guī)格。

In response to this letter, provide a list of chemical and microbial specifications, including test methods, used to analyze each lot of your drug products before a lot disposition decision. The list should include:

…翻譯…

針對本函，你們需要提供一份化學和微生物規(guī)格清單，包括測試方法，用來分析每一批藥品，然后再做一個批量處置的決定。清單應該包括：

An action plan and timelines for conducting full chemical and microbiological testing of retain samples to determine the quality of all batches of drug product distributed to the United States within expiry as of the date of this letter.

…翻譯…

一份行動計劃和時間表，用于對保留樣品進行全面的化學和微生物測試，以確定自本函日期起有效期內在美國銷售的所有批次藥品的質量。

A summary of all results obtained from testing retain samples from each batch. If such testing reveals substandard quality drug products, take rapid corrective actions, such as notifying customers and product recalls.

…翻譯…

從測試中獲得的所有結果的匯總，保留每個批次的樣品。如果檢測發(fā)現(xiàn)藥品質量不合格，應迅速采取措施，如通知顧客和產品召回。

3. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).

…翻譯…

你們公司的質量控制部門未能履行其職責，以確保所生產的藥品符合CGMP的要求，符合規(guī)定的特性、強度、質量和純度規(guī)范。

During the inspection, our investigator observed that your quality unit (QU) did not provide adequate oversight for the manufacture of your OTC (b)(4). For example, your QU failed to ensure:

…翻譯…

在檢查過程中，我們的調查員發(fā)現(xiàn)你們公司的質量部門沒有對公司的OTC的生產提供足夠的監(jiān)督。例如，他們未能確保：

Full testing of drug products and review of their results are performed prior to batch release.

Contract laboratory used for identity testing is qualified following your written procedures.

Cleaning validation of shared (b)(4) tanks include justifications for the worst-case sampling locations following your cleaning validation procedure.

Written procedures for sampling and testing of the (b)(4) system are followed.

Procedures to review electronic data generated from GC, HPLC, IR, and TOC systems are written and followed.

Controlled records, including logs, are maintained to track receipt of all components used to manufacture drug products.

Every OOS result is appropriately investigated and each investigation is extended to all affected batches, as applicable.

…翻譯…

在批量銷售之前，對藥品進行全面測試并審查結果。 

用于鑒定測試的合作實驗室符合你們的書面程序。 

共享罐的清潔檢測包括根據(jù)清潔檢測程序對最壞情況下的采樣位置進行檢測。 

遵循系統(tǒng)取樣和測試的書面程序。 

編寫并遵循審查氣相色譜、高效液相色譜、紅外光譜和運輸系統(tǒng)生成的電子數(shù)據(jù)的程序。 

保存受控記錄包括日志，以用于跟蹤生產藥品的所有成分的接收情況。 

對每一個超標測試結果進行適當?shù)恼{查，并在適用的情況下將每一調查擴展到所有受影響的批次。

In your response, you admitted that due to cash flow problems you “were unable to ensure all products were completely tested and ensure conformance with all pre-determined specification prior to be shipped out”. You also submitted numerous CAPA to address each example of your quality unit failures cited above.

…翻譯…

在你們的回復中，你們承認由于資金問題，你們“無法確保所有產品在出廠前都經過了完整的測試，并確保符合所有預先確定的規(guī)格”還提交了許多CAPA，以解決上面提到的每個質量問題。

Because you failed to include supporting documentation, your response is inadequate and cannot be fully evaluated. You also failed to conduct a comprehensive review of your quality unit to identify deficiencies. You did not provide evidence that you have implemented procedures that ensure adequate control over your drug manufacturing processes. In addition, you failed to include a plan to address the quality of your drugs that were manufactured without appropriate quality oversight.

…翻譯…

因為你們沒有包含輔助文件，所以你們的回復不充分，無法進行全面評估。也沒有對質量部門進行全面的審查，以找出不足之處。沒有提供證據(jù)證明已經實施了確保對藥品生產過程進行充分控制的程序。此外，也沒有一個計劃，以解決你的藥品是在沒有適當?shù)馁|量監(jiān)督下生產的。

In response to this letter, provide:

…翻譯…

針對本函，請?zhí)峁?/p>

· A comprehensive assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should include, but not be limited to:

…翻譯…

全面的評估和補救計劃，以確保你們的質量部門獲得有效運作的權力和資源評估，應包括但不限于：

A determination of whether procedures used by your firm are robust and appropriate.

Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

A complete and final review of each batch and its related information before the QU disposition decision.

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

Also describe how top management supports quality assurance and reliable operations, including but not limited to timely provision of resources to proactively address emerging manufacturing/quality issues and assure a continuing state of control.

…翻譯…

確定貴公司所采用的程序是否有效合適。

在整個運營過程中，為質量部門提供監(jiān)督，以評估對規(guī)定的遵守情況。

在質量部門處置決定之前，對每批產品及其相關信息進行完整和最終審查。

監(jiān)督和批準調查并履行所有其他質量管理職責，以確保所有產品的特性、強度、質量和純度。

還應說明最高管理層如何支持質量保證和可靠的操作，包括但不限于及時提供信息，以主動解決新出現(xiàn)的生產/質量問題，并確保持續(xù)可控制狀態(tài)。

· A comprehensive, independent assessment of your overall system for investigating deviations, discrepancies, complaints, OOS results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, quality assurance oversight, and written procedures. Describe how your firm will ensure all phases of investigations are appropriately conducted.

…翻譯…

對整個系統(tǒng)進行全面、獨立的評估，以調查偏差、差異、投訴、測試超標結果和故障。提供修復此系統(tǒng)的詳細操作計劃。行動計劃應包括但不限于在調查能力、范圍確定、根本原因評估、CAPA有效性、質量保證監(jiān)督和書面程序方面的重大改進，請描述將如何確保調查的所有階段都得到有效適當?shù)膱?zhí)行。

See FDA’s guidance document Quality Systems Approach to Pharmaceutical CGMP Regulations for help implementing quality systems and risk management approaches to meet the requirements of CGMP regulations 21 CFR, parts 210 and 211 at https://www.fda.gov/media/71023/download.

…翻譯…

參見FDA的指導文件《藥品CGMP法規(guī)的質量體系方法》，以幫助實施質量體系和風險管理方法，以滿足 美國聯(lián)邦法規(guī)第21卷第210和211部分的CGMP要求。

4. Your firm failed to maintain an adequate written record of each complaint (21 CFR 211.198(b)).

…翻譯…

你們公司沒有對每一項投訴保留充分的書面記錄。

You firm failed to maintain a complete and accurate record of your complaint investigations. You opened investigations B-18002 and B-19001 in response to complaints of poor (b)(4) for batches manufactured in Wuhan. In these investigations you stated that you evaluated reserve samples and found no deficiencies. However, you had previously stated that all reserve samples were lost for batches manufactured at your Wuhan site and therefore reserve samples were not available for evaluation.

…翻譯…

你們公司未能保留針對武漢生產的批次的不良投訴的調查的完整和準確記錄，你們展開的調查B-18002和B-19001，在這些調查中，表示你們評估了保留樣品，沒有發(fā)現(xiàn)任何缺陷。但是，你們之前已經聲明，武漢工廠生產的批次的所有保留樣品都丟失，因此無法對保留樣品進行評估。

In your response, you stated that testing was performed on reserve samples manufactured in your Hubei facility. Your response is inadequate because testing a batch that is different from the complaint batch does not provide you with batch specific information needed to identify potential quality defects in the complaint batch.

…翻譯…

在你們的回復中，聲明測試是在湖北工廠生產的保留樣品上進行的。你們的回復不充分，因為測試與投訴批次是不同的批次，并不能提供識別投訴批次中潛在質量缺陷和所需的批次特定信息。

In response to this letter, provide:

…翻譯…

針對本函，請?zhí)峁?/p>

· The status of lots identified in investigations B-18002 and B19001.

· Your plan for evaluating complaints for batches manufactured in your Wuhan facility.

· The process you will follow if a complaint cannot be appropriately investigated. Indicate the corrective actions you will take including notifying customers and initiating recalls.

…翻譯…

調查B-18002和B19001中所說的批次狀態(tài)。 

你們對武漢工廠生產批次的投訴進行調查評估的計劃。 

如果投訴無法得到適當調查，你們應遵循流程指出將采取的糾正措施，包括通知客戶和發(fā)起召回。

Data Integrity Remediation

…翻譯…

數(shù)據(jù)完整性修復

Your quality system does not adequately ensure the accuracy and integrity of data to support the safety, effectiveness, and quality of the drugs you manufacture. See FDA’s guidance document Data Integrity and Compliance With Drug CGMP for guidance on establishing and following CGMP compliant data integrity practices at https://www.fda.gov/media/119570/download.

…翻譯…

你們的質量體系不能充分確保數(shù)據(jù)的準確性和完整性，以支持生產的藥物的安全性、有效性和質量。關于建立和遵循符合CGMP的數(shù)據(jù)完整性實踐的指導，請參見FDA的指導文件里數(shù)據(jù)完整性和CGMP藥物的一致性。

We strongly recommend that you retain a qualified consultant to assist in your remediation. In response to this letter, provide the following:

…翻譯…

我們強烈建議您聘請一名合格的顧問協(xié)助你們進行補救。針對本函，請?zhí)峁┮韵聝热荩?/p>

A comprehensive investigation into the extent of the inaccuracies in data records and reporting, including results of the data review for drugs distributed to the United States. Include a detailed description of the scope and root causes of your data integrity lapses.

A current risk assessment of the potential effects of the observed failures on the quality of your drugs. Your assessment should include analyses of the risks to patients caused by the release of drugs affected by a lapse of data integrity and analyses of the risks posed by ongoing operations.

A management strategy for your firm that includes the details of your global corrective action and preventive action plan. The detailed corrective action plan should describe how you intend to ensure the reliability and completeness of all data generated by your firm including microbiological and analytical data, manufacturing records, and all data submitted to FDA.

…翻譯…

對數(shù)據(jù)記錄和報告不準確度的全面調查，包括對在美國銷售的藥物的數(shù)據(jù)審查結果。包括對數(shù)據(jù)完整性失效的范圍和根本原因的詳細描述。 

當前觀察到的問題對藥物質量的潛在影響的風險評估。評估應包括分析由于數(shù)據(jù)完整性失效而影響藥物對患者造成的風險，以及分析正在進行的操作所帶來的風險。 

公司的管理策略，包括全球補救措施和預防措施計劃的細節(jié)。詳細的補救措施計劃應說明你們打算如何確保生成的所有數(shù)據(jù)的可靠性和完整性，包括微生物和分析數(shù)據(jù)、生產記錄以及提交給FDA的所有數(shù)據(jù)。

Conclusion

…翻譯…

結論

The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence or the occurrence of other violations.

…翻譯…

這封信中所列舉的違規(guī)行為并不是對你們公司存在的違規(guī)行為的全面陳述。你們負責調查和確定這些違規(guī)行為的原因，并防止其再次發(fā)生或發(fā)生其他違規(guī)行為。

FDA placed your firm on Import Alert 66-40 on August 22, 2019.

…翻譯…

FDA在2019年8月22日將貴公司放在重要警報66-40。

Until you correct all violations completely and we confirm your compliance with CGMP, FDA may withhold approval of any new drug applications or supplements listing your firm as a drug manufacturer.

…翻譯…

在你們完全糾正所有違規(guī)行為，并且我們確認符合CGMP規(guī)定之前，F(xiàn)DA可能會拒絕批準任何新的藥物申請或將貴公司列為藥物制造商的補充產商。

Failure to correct these violations may also result in the FDA continuing to refuse admission of articles manufactured at Bingbing Pharmaceutical (Hubei) Co., Ltd, at No. 698 Bingbing Road, Economic Development Zone, Shiyan, Hubei, into the United States under section 801(a)(3) of the FD&C Act, 21 U.S.C. 381(a)(3). Articles under this authority may be subject to refusal of admission, in that the methods and controls used in their manufacture do not appear to conform to CGMP within the meaning of section 501(a)(2)(B) of the FD&C Act, 21 U.S.C. 351(a)(2)(B).

…翻譯…

如果不糾正這些違規(guī)行為，食品和藥物管理局可能會按照《食品和藥品法》的規(guī)定，拒絕將兵兵藥業(yè)（湖北）有限公司生產的物品進口美國。本授權下的物品可能會被拒絕入境，因為其制造過程中使用的方法和控制措施不符合《美國法典》的CGMP規(guī)定。

After you receive this letter, respond to this office in writing within 15 working days. Specify what you have done since our inspection to correct your violations and to prevent their recurrence. If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

…翻譯…

收到此信后，請在15個工作日內以書面形式回復。請說明自我方檢驗以來，你們?yōu)榧m正偏差并防止其再次發(fā)生所做的工作。如果您無法在15個工作日內完成糾正措施，請說明延遲的原因和完成計劃。

Send your electronic reply to CDER-OC-OMQ-Communications@fda.hhs.gov or mail your reply to:

Carlos M. González   

Compliance Officer

 U.S. Food and Drug Administration

 White Oak Building 51, Room 4359

10903 New Hampshire Avenue

Silver Spring, MD 20993

USA

Please identify your response with FEI 3014538973.

Sincerely,

/S/

Francis Godwin

Director

Office of Manufacturing Quality

Office of Compliance

Center for Drug Evaluation and Research