摘 要

 

美國FDA于2024年03月22日對Antaria Pty.Ltd.簽發了警告信，主要包括了如下重大缺陷：

 

超標結果(OOS)重復發生，調查未確定根本原因，糾正預防措施無法確認有效性。

警告信中提到，該公司對 API 實驗室測試（包括含量和熾灼失重(LOI) 測試）期間獲得的大量 OOS 結果缺乏充分的調查和糾正措施。根本原因未得到明確定義，且未充分記錄，并且質量部門 (QU) 放行了 OOS 結果批次。

企業的回復沒有得到FDA認可，主要體現在沒有描述對所有調查的根本原因分析和糾正措施充分性的整體審查，沒有通知收到 OOS 批次的客戶進行檢測，也沒有對留樣樣品進行回顧性評估。同時，給出了需要進一步開展的工作與需要提供的資料，值的充分研究和學習。（該條缺陷很有代表性，OOS調查是企業的難點，FDA不僅闡明了具體問題，并且給出了解題思路，值得深入研究和學習）

 

產品檢測的分析方法未進行驗證，無法確認企業自身的分析方法相當于或優于USP方法。

警告信提到，該公司未能按照美國藥典 (USP) 專論現行版本對產品進行適當的分析測試（含量和熾灼失重），也沒有數據支持其測試方法相當于或優于 USP 方法。（既沒有按USP方法執行測試，又沒有進行相關分析方法驗證，與USP的方法進行對比研究）

 

實驗室控制記錄信息不完整，缺少部分檢測過程中的信息數據。

警告信中提到，該公司未能在實驗室記錄中納入所有實驗室分析項目的完整數據，并且依賴不完整的信息來確定產品是否符合質量標準。例如，缺少在 API 測試期間使用的儲備溶液、樣品溶液、稀釋劑、流動相和試劑的制備記錄。還未能記錄進行分析測試時所使用的儀器和設備。（該問題在國內的公司還是比較常見的，體現了實驗室記錄設計存在不足，違背了記錄可追溯性的原則）

 

未能設計充分書面的、持續的穩定性測試程序來監控 API 的穩定性特性，并使用結果來確認適當的存儲條件和復驗期或有效期。

警告信中提到，該公司的穩定性計劃不夠充分。在2019 年、2020 年或 2021 年生產的API，未能進行年度至少一批穩定性考察。穩定性程序缺乏有關適當測試方法的具體要求。此外，穩定性研究僅包括 2015 年生產的批次，并且僅在 2022 年建立了年度持續穩定性計劃。

該公司的回復是不充分的，因為沒有討論對流通中已經生產而未經適當穩定性測試的 API 批次的回顧性審查。（不能僅僅是“我目前符合要求”了，而且要證明與確認之前的做法是否已經產生了風險！）

 

從缺陷可以看到此封警告信的關注點主要為超標結果調查和糾正措施實施的有效性、實驗室控制模塊工作存在不足，無法確保銷售產品的質量可控。

 

【基礎信息:】

 

Posted Date：2024.4.9

 

Letter lssue Date：2024.3.22

 

FEI：3025978151

 

Firm name：Antaria Pty.Ltd.

 

Type establishment inspected：Drug Manufacturing Facility

 

Investigator：N/A

 

警告信正文

 

The U.S.Food and Drug Administration (FDA) inspected your drug manufacturing facility, Antaria Pty.Ltd., FEI 3025978151, at 81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia, from November 13 to 17, 2023.

美國食品藥品監督管理局 (FDA) 于2023 年11月13日至17日檢查了你們位于81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia的藥品生產工廠Antaria PtyLtd.，FEI 3025978151。

 

This warning letter summarizes significant deviations from Current Good Manufacturing Practice (CGMP) for active pharmaceutical ingredients (API)

本警告信總結了原料藥（API）現行良好生產規范（CGMP）的重大偏差。

 

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).

由于你們的生產、工藝、包裝或貯存的方法、設施或控制不符合 CGMP， 依據《聯邦食品、藥品和化妝品法案》（FD&C 法案）501(a)(2)(B) 節、21 U.S.C. 351(a)(2)(B) 的規定，你們的 API被判定為摻假。

 

We reviewed your December 7, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我們詳細審查了你們公司于 2023 年 12 月 7 日對我們的 FDA 483 表的回復，并確認收到了你們后續的應對。

 

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

在檢查過程中，我們的調查人員發現的具體偏差包括但不限于以下內容。

 

1.Failure to adequately investigate and document out-of-specification results and implement appropriate corrective actions.

未能充分調查和記錄超標結果(OOS)并實施適當的糾正措施。

 

Your firm manufactures API (b)(4) USP, labeled in part to be the active ingredient used in (b)(4).You failed to adequately investigate out-of-specification (OOS) test results.Specifically, your firm lacked adequate investigations and corrective actions for numerous OOS results obtained during laboratory testing of your API, including assay and loss on ignition (LOI) testing.The root causes were not clearly defined nor adequately documented, and lots with OOS results were released by your quality unit (QU).

你公司生產 API (b)(4) USP，部分標簽顯示其為 (b)(4) 中使用的活性成分。你們未能充分調查超標（OOS）的測試結果。具體來說，你們公司對在 API 實驗室測試（包括含量和熾灼失重(LOI) 測試）期間獲得的大量 OOS 結果缺乏充分的調查和糾正措施。根本原因未得到明確定義，且未充分記錄，并且你們的質量部門 (QU) 放行了 OOS 結果批次。

 

In your response, you state that staff turnover and insufficient staff training attributes to the lack of competency in good laboratory practices.Additionally, you state that you will revise your OOS procedures.You also state that you will review historical LOI OOS to identify a root cause and retrain your laboratory staff. Your response is inadequate because you failed to describe a holistic review of all investigations’ root cause analyses and corrective actions for adequacy.In addition, you did not inform your customers who received OOS lots for assay nor perform a retrospective assessment of retain samples.

在你們的回復中，你們指出員工流動和員工培訓不足導致缺乏良好的實驗室實踐能力。此外，你們表示將修改您的 OOS 程序。你們還表示，你們將回顧歷史LOI OOS數據，以識別根本原因并重新培訓你們的實驗室工作人員。你們的回復不充分，因為你們沒有描述對所有調查的根本原因分析和糾正措施充分性的整體審查。此外，你們沒有通知收到 OOS 批次的客戶進行檢測，也沒有對留樣樣品進行回顧性評估。

 

Inadequate investigations can lead to unidentified root causes, ineffective corrective action and preventive action (CAPA), and recurring problems that compromise the ability to manufacture safe and effective drugs.

調查不充分可能導致無法確定根本原因、無效的糾正措施和預防措施 (CAPA) 以及影響生產安全有效藥物能力的反復出現的問題。

 

For more information about handling OOS results and documentation of your investigations, please refer to the FDA guidance for industry publication Investigating Out-of-Specification at https://www.fda.gov/media/158416/download

有關處理 OOS 結果和調查文件的更多信息，請參閱 FDA 行業出版物《超標調查》指南，網址為 https://www.fda.gov/media/158416/download

 

In response to this letter, provide:

在回復此信時，請提供：

 

A retrospective, independent review of all invalidated OOS (including in-process and release/stability testing) results for U.S. products irrespective of whether the batch was ultimately distributed in the United States and a report summarizing the findings of the analysis, including the following for each OOS:

對美國注冊的產品所有無效的OOS（包括中控和放行/穩定性測試）結果進行回顧性的、獨立的審查，無論該批次最終是否在美國分銷，并提交一份總結分析結果的報告，包括針對每項 OOS 的以下內容：

 

※ Determine whether the scientific justification and evidence relating to the invalidated OOS result conclusively or inconclusively demonstrates causative laboratory error.

對于無效的 OOS 結果，確定相關的科學依據和證據是否確鑿或不確鑿地證明了導致實驗室錯誤的原因。

 

※ For investigations that conclusively establish laboratory root cause, provide rationale, and ensure that all other laboratory methods vulnerable to the same or similar root cause are identified for remediation.

對于最終確定實驗室根本原因的調查，提供合理依據，并確保被認為所有其他易受相同或類似根本原因影響的實驗室方法已進行補救。

 

※ For all OOS results found by the retrospective review to have an inconclusive or no root cause identified in the laboratory, include a thorough review of production (e.g., batch manufacturing records, adequacy of the manufacturing steps, suitability of equipment/facilities, variability of raw materials, process capability, deviation history, complaint history, batch failure history).Provide a summary of potential manufacturing root causes for each investigation, and any manufacturing operation improvements.

對于回顧性審查發現的所有 OOS 結果，如果其在實驗室中沒有確定的根本原因或沒有發現根本原因，則需要對生產進行徹底審查（例如，批生產記錄、生產步驟的充分性、設備/設施的適用性、原材料的變化、過程能力、偏差歷史、投訴歷史、批次不合規歷史）。匯總每次調查的潛在生產根本原因和任何的生產操作改進。

 

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, QU oversight, and written procedures.Address how your firm will ensure all phases of investigations are appropriately conducted.

對你們的整個系統進行全面、獨立的評估，以調查偏差、異常情況、投訴、OOS 結果和不合格事件。提供詳細的行動計劃來改進該系統。你們的行動計劃應包括但不限于調查能力、范圍確定、根本原因評估、CAPA 有效性、QU 監督和書面程序方面的重大改進。說明你們公司將如何確保調查的所有階段均得到適當執行。

 

2.Failure to ensure that, for each batch of API, appropriate laboratory tests are conducted to determine conformance to specifications.

未能確保對每批 API 進行適當的實驗室測試以確定符合質量標準。

 

Based on review of your laboratory results, you failed to appropriately perform analytical testing (assay and LOI) of your (b)(4) USP in accordance to the current version of United States Pharmacopeia (USP) monograph, nor did you have data to support that your test method was equivalent or better than the USP method.In your response, you state that you will revise your (b)(4) USP assay and LOI test methods to better align with the USP.

根據對你們實驗室結果的審查，你們未能按照美國藥典 (USP) 專論現行版本對你們的 (b)(4) USP 進行適當的分析測試（含量和熾灼失重），也沒有數據支持你們的測試方法相當于或優于 USP 方法。在你們的回復中，你們表示將修改 (b)(4) USP 的含量和 LOI 檢測方法，以更好地與 USP 保持一致。

 

Without adequate testing, there is no scientific evidence to assure that your APIs conform to appropriate specifications before release.

如果沒有經過充分的測試，就沒有科學證據來保證您的 API 在放行之前符合適當的質量標準。

 

See FDA’s guidance document, Analytical Procedures and Methods Validation for Drugs and Biologics, for general principles and approaches that FDA considers appropriate elements of analytical method validation at https://www.fda.gov/media/87801/download.

請參閱 FDA 的指導文件《藥品和生物制品的分析程序和方法驗證》，了解 FDA 認為適合分析方法驗證要素的一般原則和方法，網址為https://www.fda.gov/media/87801/download

 

In response to this letter provide:

在回復此信時請提供：

 

A list of chemical and microbial test methods and specifications used to analyze each lot of your API before making a lot disposition decision, and the associated written procedures.

在做出批次處置決定之前，用于分析每批 API 的化學和微生物測試方法和質量標準的列表，以及相關的書面程序。

 

A comprehensive, independent assessment of your laboratory practices, procedures, methods, equipment, documentation, and analyst competencies. Based on this review, provide a detailed plan to remediate and evaluate the effectiveness of your laboratory system.

對你們的實驗室實踐、程序、方法、設備、文檔和分析人員能力進行全面、獨立的評估。根據此審查，提供詳細的計劃來改進并評估你們公司實驗室系統的有效性。

 

3.Failure to have laboratory control records that include complete data derived from all laboratory tests conducted to ensure your API complies with established specifications and standards.

未能提供包含所有實驗室測試的完整數據的實驗室控制記錄，以確保你們的 API 符合既定的規范和質量標準。

 

You failed to include complete data in your laboratory records for all laboratory analyses, and accordingly relied on incomplete information to determine whether your (b)(4) USP met established specifications.For example, you lacked documentation of the preparation of stock solutions, sample solutions, diluents, mobile phases, and reagents used during testing of your API.You also failed to document the instruments and equipment used when performing analytical testing.

你們未能在實驗室記錄中納入所有實驗室分析項目的完整數據，并且依賴不完整的信息來確定你們的 (b)(4) USP 是否符合既定的質量標準。例如，你們缺少在 API 測試期間使用的儲備溶液、樣品溶液、稀釋劑、流動相和試劑的制備記錄。你們還未能記錄進行分析測試時所使用的儀器和設備。

 

In your response, you acknowledge that your laboratory records lack complete testing information.You also state that you update your worksheets to record pertinent information.Your response is inadequate because it does not address the overall lack of traceability of previous analytical data, nor does it include a comprehensive strategy to confirm the validity of the previous analytical data used to release your (b)(4) USP.

在你們的回復中，承認你們的實驗室記錄缺乏完整的測試信息。你們還聲明你們更新了工作表以記錄相關信息。你們的回復是不充分的，因為它沒有解決先前分析數據整體缺乏可追溯性的問題，也沒有包括一個全面的策略來證實用于放行你們 (b)(4) USP 的先前分析數據的有效性。

 

Without adequate documentation of analytical tests and equipment used, you lack basic data to support that each API product batch conforms to appropriate specifications before release and distribution.

如果沒有足夠的分析測試和所用設備的記錄，你們將缺乏基本數據來支持每個批次API 產品在放行和分銷之前符合適當的質量標準。

 

In response to this letter provide a complete assessment of documentation systems used throughout your manufacturing and laboratory operations to determine where documentation practices are insufficient.Include a detailed CAPA plan that comprehensively remediates your firm’s documentation practices to ensure you retain attributable, legible, complete, original, accurate, contemporaneous records throughout your operation.

在回復此信時，請提供對你們整個生產和實驗室操作過程中使用的文件系統的完整評估，以確定哪些地方的文檔記錄不足。包括一份詳細的 CAPA 計劃，全面補救你們公司的文件記錄規范性，以確保你們在整個運營過程中保留可追溯、清晰、完整、原始、準確、同步的記錄。

 

4.Failure to design an adequate documented, on-going stability testing program to monitor the stability characteristics of API and to use the results to confirm appropriate storage conditions and retest or expiry dates.

未能設計充分書面的、持續的穩定性測試程序來監控 API 的穩定性特性，并使用其結果來確認適當的存儲條件和復驗期或有效期。

 

Your firm’s stability program is inadequate.Your firm failed to place at least one lot of your API manufactured in 2019, 2020, or 2021 on stability annually.

你們公司的穩定性計劃不夠充分。你們公司在2019 年、2020 年或 2021 年生產的API，未能進行年度至少一批穩定性考察。

 

In your response, you acknowledge that your stability procedure lacks specificity regarding appropriate testing.Additionally, you acknowledge that your stability study only consists of lots manufactured in 2015 and that you only establish your annual, ongoing stability program in 2022.Your response is inadequate because you did not discuss a retrospective review of API lots in distribution that were manufactured without appropriate stability testing

在你們的回復中，你們承認你們的穩定性程序缺乏有關適當測試方法的具體要求。此外，你們承認，你們的穩定性研究僅包括 2015 年生產的批次，并且你們僅在 2022 年建立了年度持續穩定性計劃。你們的回復是不充分的，因為你們沒有討論對流通中已經生產而未經適當穩定性測試的 API 批次的回顧性審查。

 

Without an adequate stability program, you cannot ensure that your APIs meet established specifications and all pre-determined quality criteria throughout the APIs’ assigned shelf-life.

如果沒有適當的穩定性程序，你們就無法確保你們的 API 在指定的貨架期內符合既定的質量標準和所有預定的質量要求。

 

In response to this letter provide:

在回復此信時請提供：

 

A comprehensive, independent assessment and CAPA plan to ensure the adequacy of your stability program. Your remediated program should include, but not be limited to:

全面、獨立的評估和 CAPA 計劃可確保你們的穩定性計劃的充分性。你們的補救計劃應包括但不限于：

 

※ Stability-indicating methods

穩定性指示方法

 

※ Stability studies for each drug product in its marketed container-closure system before distribution is permitted.

在允許分銷之前，對每種藥品在其上市容器封閉系統中進行穩定性研究。

 

※ An ongoing program in which representative batches of each product are added each year to the program to determine if the shelf-life claim remains valid.

這是一項持續進行的計劃，每年都會將每種產品的代表性批次添加到計劃中，以確定聲稱的貨架期是否仍然有效。

 

※ Detailed definition of the specific attributes to be tested at each station (timepoint).

詳細定義每個站點（時間點）要測試的具體屬性。

 

All procedures that describe these and other elements of your remediated stability program.

描述這些內容以及穩定性補救計劃的其他要素的所有程序。

 

Additional API CGMP Guidance

其他 API CGMP 指南

 

FDA considers the expectations outlined in ICH Q7 when determining whether API are manufactured in conformance with CGMP.See FDA’s guidance document Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients for guidance regarding CGMP for the manufacture of API at https://www.fda.gov/media/71518/download.

在確定 API 是否符合 CGMP條件下生產時，FDA 會考慮 ICH Q7 中概述的期望。有關 API 制造的 CGMP 指導，請參閱 FDA 指南 Q7原料藥良好生產規范指南，網址為https://www.fda.gov/media/71518/download

 

Conclusion

結論

 

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

本信中引用的偏差并非你們工廠存在的所有偏差的完整列表。你們公司有責任調查并確定任何偏差的原因，并防止其再次發生或發生其他偏差。

 

Correct any deviations promptly.FDA may withhold approval of new applications or supplements listing your firm as a drug manufacturer until any deviations are completely addressed and we confirm your compliance with CGMP.We may re-inspect to verify that you have completed corrective actions to any deviations.

及時糾正任何偏差。FDA 可能會拒絕批準將你們公司列為藥品制造商的新申請或補充申請，直到所有偏差得到徹底解決且我們確認你們公司符合 CGMP。我們可能會重新檢查以驗證你公司是否完成所有偏差的糾正措施。

 

Failure to address any violations may also result in the FDA refusing admission of articles manufactured at Antaria Pty.Ltd.81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia 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 that appear to be adulterated may be detained or refused 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).

根據聯邦食品、藥品和化妝品法案第 801(a)(3) 節,21 U.S.C. 381(a)(3)，未能解決所有違規行為也可能導致 FDA 拒絕接納 Antaria Pty.Ltd.81 Shettleston St, Units 1 & 2 Rocklea, Queensland, Australia生產的物品到美國。根據該授權，如果物品疑似摻假，則可能被扣留或拒絕入境。因為其制造過程中使用的方法和控制疑似不符合 FD&C 法案（21 U.S.C. 351(a)(2)(B)）第 501(a)(2)(B) 條 CGMP 的規定。

 

This letter notifies you of our findings and provides you an opportunity to address the above deficiencies.After you receive this letter, respond to this office in writing within 15 working days.Specify what you have done to address any deviations and to prevent their recurrence.In response to this letter, you may provide additional information for our consideration as we continue to assess your activities and practices.If you cannot complete corrective actions within 15 working days, state your reasons for delay and your schedule for completion.

這封信函告知你們我們的調查結果并為您提供解決上述缺陷的機會。收到此信后，請在15個工作日內以書面形式回復本辦公室。詳細說明你們為解決偏差并防止其再次發生所做的努力。在回復此信時，你們可以提供更多信息供我們考慮，因為我們會繼續評估你們的活動和做法。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。