FDA警告信掛網，事涉世界500強企業子公司！

據藥智網獲悉，10月29日FDA掛出一則警告信，事涉西門子子公司Petnet Solutions。該公司在10月17日收到了FDA的警告信，信中提到在2019年3月19日至4月5日期間，FDA檢查工廠時發現工廠年久失修、在無菌區域中檢測出微生物等問題，要求公司儘快整改。

Petnet Solutions Inc.是西門子旗下的健康服務公司，經營著全球50多家PET（正電子發射斷層掃描）藥品藥店。Petnet Solutions擁有一個由製造業務和PET藥物藥店組成的全球網絡。

FDA官網掛出的警告信具體內容如下：

WARNING LETTER

CMS # 584016

October 17, 2019

Dear Mr. Scott:

The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, PETNET Solutions Inc., FEI 3006577728, at 350 Washington Street, Unit 268, Woburn, Massachusetts, from March 19 to April 5, 2019.

美國食品和藥物管理局（FDA）於2019年3月19日至4月5日檢查了Petnet Solutions Inc.的藥品生產設施。

This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for positron emission tomography (PET) drugs. See 21 CFR, part 212.

本警告信匯總了正電子發射斷層掃描（PET）藥物CGMP法規的重大違規。詳見美國聯邦法規第21卷、第212章。

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

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，你們的PET藥物根據《聯邦食品、藥品和化妝品法》（FD&C）第501(a)(2)(B)章節，《美國法典》第21卷第351(a)(2)(B)節被認定為違規。

We reviewed your April 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我們詳細審查了你們於2019年4月26日對FDA 483表格的回覆，並確認收到你們之後的回覆。

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

在檢查期間，我們的檢查員發現的具體違規包括但不限於如下：

1. Your firm’s facilities are not adequate to ensure the prevention of contamination of equipment or product by environmental conditions that could reasonably be expected to have an adverse effect on product quality (21 CFR 212.30(a)).

貴公司的設施不足以確保防止環境條件的汙染對設備或產品在質量方面可能產生的不利影響。

Facility Suitability

設施適用性

During the inspection, our investigator observed a state of disrepair and lack of cleanliness in your facility that commercially manufactures sterile injectable PET drugs. For example, rusted screws were observed holding up a light fixture in the ISO 5 area of the (b)(4) where you aseptically fill PET drug products. Furthermore, our investigator observed a hole in the top of your (b)(4) enclosure, approximately three inches in diameter, open to the surrounding room. The top of the (b)(4) surrounding the open hole was visibly dirty. Also, our investigator observed filth and damaged floor tiles in the immediately surrounding area of the room directly in front of the (b)(4).

在檢查過程中，我們的調查員觀察到貴公司生產無菌注射PET藥品的工廠年久失修，清潔不好。例如，在無菌填充PET藥品的 (b)(4) 的ISO 5區域，觀察到生鏽的螺釘托住了一個燈具。此外，我們的研究人員在你的 (b)(4) 外殼頂部觀察到一個洞，直徑大約為三英寸，打通了周圍的房間。洞口周圍 明顯髒了。此外，我們的調查人員在房間正前方的周邊區域觀察到骯髒和損壞的地磚。

Your response stated that the (b)(4) is negatively pressured to protect the operator and draws air from the surrounding environment. The presence of a negatively pressured area adjacent to an ISO 5 area requires careful facility and equipment design, as well as attentiveness to ongoing control, maintenance, cleaning, and disinfection activities to ensure appropriate air quality for your aseptic filling environment.

你們對此回覆，(b)(4)是負壓區以保護操作員，並與周圍環境通風。與ISO 5區域相鄰的負壓區域的存在需要仔細的設施和設備設計，並注意持續的控制、維護、清潔和消毒活動，以確保無菌灌裝環境的適當空氣質量。

Environmental Conditions

環境條件

Between March 2016 and March 2019, adverse trends were identified in environmental and personnel monitoring samples taken from the ISO 5 areas where you conduct aseptic manipulations. Isolates from these samples frequently included Bacillus, spp., and related bacterial sporeforming species. Also, during the (b)(4) certifications conducted by a third party between July 2017 and January 2019, sporeforming fungi were repeatedly identified in the ISO 8 area of your (b)(4) immediately adjacent to your ISO 5 area.

2016年3月至2019年3月期間，從你們進行無菌操作的ISO 5區域採集的環境和人員監測樣品中發現了不利因素。這些樣本中的分離物包括芽孢桿菌和相關的細菌孢子形成菌。此外，在2017年7月至2019年1月期間由第三方進行的(b)(4)檢查期間，在緊鄰(b)(4)ISO 5區域的(b)(4)ISO 8區域內重複檢測出孢子形成真菌。

In 2017, your firm also had a sterility test failure for a batch of Fludeoxyglucose (FDG) F18 injection. You identified the microbial contaminant as the sporeforming bacteria, Brevibacillus limnophilus.

2017年，貴公司也有一批氟脫氧葡萄糖（FDG）F18注射液的沒有通過無菌檢測。確認了微生物汙染物是孢子形成菌，即短桿菌。

Sporeforming organisms can pose a significant challenge to disinfection processes. We note you implemented a (b)(4) disinfection regimen. However, significant trends of sporeforming organisms continue in your facility. For example, in January and February 2019, your environmental monitoring identified Bacillus species in multiple surface samples for the ISO 5 Biological Safety Cabinet (BSC) you use to aseptically prepare final product vial assemblies. Over approximately three years, you failed to adequately respond to data indicating insufficient microbial control in the areas where you conduct aseptic manipulations, as well as adjacent areas.

孢子形成菌可能是消毒過程的重點清潔對象。我們注意到你們實施了一個消毒方案。然而，在你的設施中，孢子形成菌仍然存在。例如，在2019年1月和2月，你們的環境監測在用於無菌製備的ISO 5生物安全櫃（BSC）的多個表面樣品中監測出芽孢桿菌。在大約三年的時間裡，在你進行無菌操作的區域，以及鄰近區域，你沒有對數據做出充分的反應，數據顯示該地區的微生物控制不嚴。

Excursions and trends in environmental monitoring results should be monitored and promptly reviewed. Adverse trends should trigger a comprehensive evaluation of the state of control of your manufacturing operation.

應監測和及時審查環境監測結果的變化和趨勢。不利的趨勢應該會引起對你們生產操作控制狀態的全面評估。

In your response, you stated that your facility is being remodeled. However, your risk assessment for facility remediation lacked sufficient details. Your response also did not include a plan for ensuring that your facility is adequately maintained, and environmental conditions are appropriate, to ensure product quality.

在你們的回覆中，說是設施正在改建。但是，對設施修復的風險評估缺乏足夠的詳細信息。回覆也沒有包括確保您的設施得到充分維護的計劃，以及確保產品質量的適當環境條件。

In response to this letter, provide:

針對本函，請提供：

• Comprehensive risk assessment of all contamination hazards with respect to your aseptic processes, equipment, and facilities. Provide an independent assessment that includes, but is not limited to:

對所有與無菌過程、設備和設施相關的汙染危害進行全面的風險評估。提供獨立評估，包括但不限於：

• All human interactions within the ISO 5 area
• Equipment placement and ergonomics
• Air quality in the ISO 5 area and surrounding room
• Facility layout
• Personnel flows and material flows (throughout all rooms used to conduct and support sterile operations)
• Adequacy of procedures to ensure ongoing maintenance and control of your facility
• ISO5區域內所有的人員活動
• 設備的佈置和效率
• ISO5區域和周圍房間的空氣質量
• 設施佈局
• 人員流動和物質流動（用於進行和支持無菌操作的所有房間）
• 確保設施持續維護和控制程序的充分性

• Your results for all environmental and personnel monitoring conducted from April 2019 to present. Describe each interim measure implemented to ensure risk mitigation and provide all testing and all monitoring results obtained during remodeling. Also include facility monitoring trends and any excursions (e.g., differential pressure, humidity, non-viable particles, viable particles) during this period. List the date of production, name of product, lot number, and equipment used. Describe in detail when the overall remodeling work began and ended, and what construction was performed each day and the location.

從2019年4月至今，你們對所有環境和人員的監測結果。描述為確保風險緩解而實施的每項臨時措施，並提供整改期間獲得的所有測試和所有監測結果。還包括在此期間的設施監測結果和任何偏移（例如，壓差、溼度、非活性顆粒、活性顆粒）。列出生產日期、產品名稱、批號和使用的設備。詳細描述整個改建工程何時開始和結束，以及每天進行的施工和位置。

• Your Planned Variance (PV00000182) document and Enhanced Environmental Monitoring protocols (D0013699 and D0013698) referenced in your risk assessment.

風險評估中引用了計劃偏差文檔（PV00000182）和增強環境監測協議（d0013699和d0013698）。

• Your facility qualifications, media fills, and most recent static and dynamic smoke studies performed for both the BSC and (b)(4) during and since completion of the facility remodeling.

在設施改造期間和改造完成後，設備資質、介質填充以及最近為BSC和(b)(4) 進行的靜態和動態煙霧研究。

• Your investigations for any failed (b)(4) tests since the FDA’s March 2016 inspection of your facility.

自FDA於2016年3月對工廠進行檢查以來，對任何未通過的(b)(4) 測試的調查。

2. Your firm’s laboratory failed to develop and follow adequate written procedures for testing components, in-process materials, and finished PET drug products to ensure conformance with appropriate standards, including established standards of identity, strength, quality, and purity (21 CFR 212.60(a) and (b)).

貴公司的實驗室未能制定並遵循適當的書面程序來測試成分、加工材料和成品PET藥物，以確保符合適當的標準，包括確定的強度、質量和純度標準（《美國聯邦法規》第21卷第212.60（a）和（b）條）。

You failed to establish adequate testing procedures for environmental monitoring for your aseptic manufacturing operations. For example, the action levels in your standard operating procedure (SOP D0012118) for environmental monitoring are not appropriate. For surface samples taken from the ISO 5 area of your (b)(4), your procedure does not require an investigation unless (b)(4) colony-forming units (CFU) are recovered from a single sample or there are (b)(4) occurrences of growth (not exceeding the single sample action limit) in a (b)(4).

你們沒有為無菌生產操作建立足夠的環境監測測試程序。例如，環境監測標準操作程序（sop d0012118）中的操作級別不合適。對於從 (b)(4)的ISO 5區域採集的表面樣品，除非 (b)(4)菌落形成單位（CFU）是從單個樣品中回收的，或者 在 (b)(4)中出現生長（不超過單個樣品作用極限），否則不需要進行調查。

These action levels in your environmental monitoring SOP are not appropriate, are of particular concern when considering the repeated recoveries of sporeforming microorganisms in your ISO 5 areas.

環境監測標準操作程序中的這些是不合格的，特別值得關注在ISO 5區域中孢子形成菌的回收。

An ongoing goal for environmental control of ISO 5 areas is to remain free of microbial contamination. Action levels should be set appropriately. PET drug manufacturing requires vigilant environmental control, which requires prompt, appropriate attention to microbial recovery in ISO 5 areas.

ISO5區域環境監控的一個持續目標是保持無微生物汙染。應適當設置操作。PET藥物的生產需要嚴格的環境控制，這就需要及時、適當地注意ISO 5領域的微生物回收。

We note you committed to identify any microbial contamination in both the ISO 5 BSC and the ISO 5 area of the (b)(4) for (b)(4) after the remodeling of the facility is completed. However, you did not include a justification for limiting this identification to a (b)(4). Environmental monitoring in ISO 5 areas should include routine identification of any microorganism.

我們注意到，你們承諾在設施改造完成後，在ISO 5的BSC和ISO 5區域的（b）（4）中識別微生物汙染。但是，沒有包括將此標識鑑定為a (b)(4)的理由。ISO 5區域的環境監測應包括任何微生物的常規鑑定。

You also failed to follow your established sterility testing procedure (SOP D0001993) and your procedure lacks details on disinfecting and material flow. For example, your operator omitted the (b)(4) for sterility testing of (b)(4) of your PET drug product Fludeoxyglucose F-18 Injection, USP. During another sterility test, your operator omitted the (b)(4) media tube for sterility testing for (b)(4) of Amyvid, Florbetapir F-18 Injection. Additionally, on a separate occasion, your operator incubated the sterility test tubes for both the (b)(4) and (b)(4) media at the wrong temperature for sterility testing of your PET drug product F-18 Florbetapir.

你也沒有遵循你建立的無菌檢測程序（sop d0001993），你的程序缺乏消毒和物質流通的細節。例如，操作人員省略了用於PET藥品氟脫氧葡萄糖F-18注射液（USP）的無菌檢測。在另一次無菌檢查中，遺漏了阿美維德F-18注射液無菌檢查用的培養基管。此外，在另一個場合，在錯誤的溫度下檢測PET藥物產品F-18 Florbetapir的無菌檢測培養基和無菌試管。

Testing is a critical control that provides assurance that your PET drug products are sterile and therefore suitable for intended use. It is important that you follow established, appropriate procedures to ensure your sterility testing is able to detect the presence of microorganisms.

檢測是一個非常重要的步驟，它保證PET藥物產品是無菌的，適合預期效果。重要的是，必須遵循既定的、適當的程序，以確保無菌檢測能夠檢測到微生物的存在。

Your response did not address whether you will have additional quality oversight for sterility testing, given the issues were attributed to operator error. Additionally, we note your procedure (SOP D0001993) for sterility testing lacks details on disinfecting and flow of testing supplies between unclassified and ISO 5 areas.

你們的回覆沒有說明是否會對無菌檢測進行額外的質量監督，因為這些問題是由操作失誤引起的。另外，我們注意到你方無菌檢測程序（sop d0001993）缺乏消毒，還缺乏非無菌區域與ISO 5區域之間檢測用品流動的詳細信息。

In response to this letter, provide:

針對本函，請提供：

• A comprehensive 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.

全面評估實驗室實踐、程序、方法、設備、文檔和分析能力。在此審查的基礎上，提供一個詳細的計劃來修正和評估實驗室系統的有效性。

• Your investigations for any microorganisms recovered in ISO 5 areas or on operator gloves, as well as any trending data you have regarding detection of 1 CFU or more since January 2019. Include all organism identifications and the locations where organisms were recovered.

自2019年1月以來，對在ISO 5區域或操作員手套上發現的任何微生物的調查，以及關於檢測1 CFU或更多CFU的數據。包括所有的有機體識別和有機體被回收的位置。

• Your process for qualification of the media used for sterility testing and whether the media is prepared off site or supplied by a vendor.

對無菌檢測所用介質的鑑定過程，以及該介質是在場外製備還是由供應商提供。

• A comprehensive assessment of your sterility testing program, including, but not limited to, disinfection of material, material flow, and environmental monitoring.

對無菌檢測程序的全面評估，包括但不限於材料消毒、物流和環境監測。

CGMP Consultant Recommended

CGMP顧問推薦

Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified to evaluate your operations to assist your firm in meeting CGMP requirements.

根據我們在貴公司發現的違規行為的性質，我們強烈建議聘請一名有資格評估貴公司運營的顧問，協助貴公司滿足CGMP的要求。

Your use of a consultant does not relieve your firm’s obligation to comply with CGMP. Your firm’s executive management remains responsible for resolving all deficiencies and systemic flaws to ensure ongoing CGMP compliance.

您使用顧問並不免除貴公司遵守CGMP的義務。貴公司的執行管理層仍然負責解決所有缺陷和系統缺陷，以確保持續的CGMP合規性。

Multiple Facilities

公司設備

We note that this facility is part of a larger corporation, with PETNET facilities throughout the United States that share corporate quality oversight and procedures.

我們注意到，該設施是一家大型公司的一部分，在美國各地設有PETNET設施，共享公司質量監督和程序。

You should comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to CGMP requirements for PET drug products.

你們應該全面評估您公司的全球生產運營，以確保系統、流程和生產的產品符合CGMP對PET藥品的要求。

Quality Assurance Program Audits

質量保證計劃審核

In your response, you stated that you identified the need for facility improvements through “internal audits.” FDA reminds you of your responsibility to correct CGMP deficiencies found during quality assurance program audits, also referred to as “internal audits” in your correspondence with the FDA.

在你們的回覆中，聲明通過“內部檢查”確定了設施改進的必要性。FDA提醒您，你們有責任糾正在質量保證計劃檢查期間發現的CGMP缺陷，在您與FDA的通信中也稱為“內部檢查”。

Guidance on Positron Emission Tomography (PET) Drugs

正電子發射斷層掃描（pet）藥物指南

See FDA’s guidance document, PET Drugs—Current Good Manufacturing Practice, to help you meet the CGMP requirements when manufacturing PET drugs, at https://www.fda.gov/media/71013/download. This guidance document also references FDA’s guidance document, Sterile Drug Products Produced by Aseptic Processing—Current Good Manufacturing Practice for additional concepts and expectations that may apply to PET drug manufacturing.

參考FDA的指導文件，PET藥物當前良好生產規範，以幫助您在生產PET藥物時滿足CGMP要求。還需參考FDA的指導文件，無菌加工生產的無菌藥品目前的良好生產規範，以瞭解可能適用於PET藥品生產的其他要求。

Conclusion

結論

The violations cited in this letter are not intended to be an all-inclusive list 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.

這封信中列舉的違規行為並不是在你的設施內的違規行為清單裡只有一個。你們負責調查和確定這些違規行為的原因，並防止其再次發生或發生其他違規行為。

If you are considering an action that is likely to lead to a disruption in the supply of drugs produced at your facility, FDA requests that you contact CDER’s Drug Shortages Staff immediately, at [email protected], so that FDA can work with you on the most effective way to bring your operations into compliance with the law. Contacting the Drug Shortages Staff also allows you to meet any obligations you may have to report discontinuances or interruptions in your drug manufacture under 21 U.S.C. 356C(b). This also allows FDA to consider, as soon as possible, what actions, if any, may be needed to avoid shortages and protect the health of patients who depend on your products.

如果你們正在考慮一項可能導致工廠生產的藥品供應中斷的行動，FDA要求你們立即聯繫CDER的藥品短缺人員，以便能夠與FDA合作，以最有效的方式使你們的經營符合法律。根據《美國法典》第21卷第356c（b）節的規定，與藥品短缺人員聯繫還可以讓你們履行義務，報告藥品生產中斷。這也使FDA能夠儘快考慮採取什麼行動（如果有的話），以避免短缺和保護依賴你的產品的患者的健康。

Correct the violations cited in this letter promptly. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Unresolved violations in this warning letter may also prevent other Federal agencies from awarding contracts.

及時糾正本函所述違規行為。如果未能及時糾正這些違規行為，可能會導致法律訴訟，而無需另行通知，包括但不限於扣押和禁令。本警告信中未解決的違規行為也可能阻止其他聯邦機構授予合同。

FDA may also withhold approval of requests for export certificates and approval of pending new drug applications or supplements listing your facility as a supplier or manufacturer until the above violations are corrected. We may re-inspect to verify that you have completed your corrective actions.

在上述違規行為得到糾正之前，FDA還可能拒絕批准出口證書申請，以及FDA可能會拒絕批准任何新的藥物申請或將貴公司列為藥物製造商的補充產商。我們可能會重新檢查，以確認您已完成糾正措施。

We request you email Kent Bui, [email protected], within five days of receipt of this letter to schedule a regulatory meeting.

我們要求您在收到本函後五天內給Kent Bui發送電子郵件，以安排監管會議。

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.

收到此信後，請在15個工作日內以書面形式回覆本辦公室。請說明自我們檢查以來，您為糾正您的違規行為並防止其再次發生所做的工作。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 [email protected] and [email protected]. Please identify your response with FEI: 3006577728 and CMS # 584016.

Sincerely,

/S/

Craig Swanson for Diana Amador-Toro Program Division Director/District Director U.S. Food and Drug Administration OPQO Division I / New Jersey District