FDA官網(wǎng)掛出的警告信具體內(nèi)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）于2019年3月19日至4月5日檢查了Petnet Solutions Inc.的藥品生產(chǎn)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(fā)射斷層掃描（PET）藥物CGMP法規(guī)的重大違規(guī)。詳見美國聯(lián)邦法規(guī)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(chǎn)工藝、包裝或者儲存的方式不符合CGMP法規(guī)，你們的PET藥物根據(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 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于2019年4月26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 investigators observed specific violations including, but not limited to, the following.
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’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(huán)境條件的污染對設備或產(chǎn)品在質(zhì)量方面可能產(chǎn)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(diào)查員觀察到貴公司生產(chǎn)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(qū)域，觀察到生銹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 明顯臟了。此外，我們的調(diào)查人員在房間正前方的周邊區(qū)域觀察到骯臟和損壞的地磚。
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.
你們對此回復，(b)(4)是負壓區(qū)以保護操作員，并與周圍環(huán)境通風。與ISO 5區(qū)域相鄰的負壓區(qū)域的存在需要仔細的設施和設備設計，并注意持續(xù)的控制、維護、清潔和消毒活動，以確保無菌灌裝環(huán)境的適當空氣質(zhì)量。
Environmental Conditions
環(huán)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(qū)域采集的環(huán)境和人員監(jiān)測樣品中發(fā)現(xiàn)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(qū)域的(b)(4)ISO 8區(qū)域內(nèi)重復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。確認了微生物污染物是孢子形成菌，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(huán)境監(jiān)測在用于無菌制備的ISO 5生物安全柜（BSC）的多個表面樣品中監(jiān)測出芽孢桿菌。在大約三年的時間里，在你進行無菌操作的區(qū)域，以及鄰近區(qū)域，你沒有對數(shù)據(jù)做出充分的反應，數(shù)據(jù)顯示該地區(qū)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(jiān)測和及時審查環(huán)境監(jiān)測結果的變化和趨勢。不利的趨勢應該會引起對你們生產(chǎn)操作控制狀態(tài)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.
在你們的回復中，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?；貜鸵矝]有包括確保您的設施得到充分維護的計劃，以及確保產(chǎn)品質(zhì)量的適當環(huán)境條件。
In response to this letter, provide:
針對本函，請?zhí)峁?/p>
· 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、設備和設施相關的污染危害進行全面的風險評估。提供獨立評估，包括但不限于：
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(qū)域內(nèi)所有的人員活動
設備的布置和效率
ISO5區(qū)域和周圍房間的空氣質(zhì)量
設施布局
人員流動和物質(zhì)流動（用于進行和支持無菌操作的所有房間）
確保設施持續(xù)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(huán)境和人員的監(jiān)測結果。描述為確保風險緩解而實施的每項臨時措施，并提供整改期間獲得的所有測試和所有監(jiān)測結果。還包括在此期間的設施監(jiān)測結果和任何偏移（例如，壓差、濕度、非活性顆粒、活性顆粒）。列出生產(chǎn)日期、產(chǎn)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(huán)境監(jiān)測協(xié)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后，設備資質(zhì)、介質(zhì)填充以及最近為BSC和(b)(4) 進行的靜態(tài)和動態(tài)煙霧研究。
· Your investigations for any failed (b)(4) tests since the FDA’s March 2016 inspection of your facility.
自FDA于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(diào)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并遵循適當?shù)臅娉绦騺頊y試成分、加工材料和成品PET藥物，以確保符合適當?shù)臉藴剩ù_定的強度、質(zhì)量和純度標準（《美國聯(lián)邦法規(guī)》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(chǎn)操作建立足夠的環(huán)境監(jiān)測測試程序。例如，環(huán)境監(jiān)測標準操作程序（sop d0012118）中的操作級別不合適。對于從 (b)(4)的ISO 5區(qū)域采集的表面樣品，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(xiàn)生長（不超過單個樣品作用極限），否則不需要進行調(diào)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(huán)境監(jiān)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(qū)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(qū)域環(huán)境監(jiān)控的一個持續(xù)目標是保持無微生物污染。應適當設置操作。PET藥物的生產(chǎn)需要嚴格的環(huán)境控制，這就需要及時、適當?shù)刈⒁釯SO 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后，在ISO 5的BSC和ISO 5區(qū)域的（b）（4）中識別微生物污染。但是，沒有包括將此標識鑒定為a (b)(4)的理由。ISO 5區(qū)域的環(huán)境監(jiān)測應包括任何微生物的常規(guī)鑒定。
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(zhì)流通的細節(jié)。例如，操作人員省略了用于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(yǎng)基管。此外，在另一個場合，在錯誤的溫度下檢測PET藥物產(chǎn)品F-18 Florbetapir的無菌檢測培養(yǎng)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(chǎn)品是無菌的，適合預期效果。重要的是，必須遵循既定的、適當?shù)某绦?，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.
你們的回復沒有說明是否會對無菌檢測進行額外的質(zhì)量監(jiān)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(qū)域與ISO 5區(qū)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?zhí)峁?/p>
· 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(tǒng)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(qū)域或操作員手套上發(fā)現(xiàn)的任何微生物的調(diào)查，以及關于檢測1 CFU或更多CFU的數(shù)據(jù)。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(zhì)的鑒定過程，以及該介質(zhì)是在場外制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，包括但不限于材料消毒、物流和環(huán)境監(jiān)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(jù)我們在貴公司發(fā)現(xiàn)的違規(guī)行為的性質(zhì)，我們強烈建議聘請一名有資格評估貴公司運營的顧問，協(xié)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.
您使用顧問并不免除貴公司遵守CGMP的義務。貴公司的執(zhí)行管理層仍然負責解決所有缺陷和系統(tǒng)缺陷，以確保持續(xù)的CGMP合規(guī)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(zhì)量監(jiān)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(chǎn)運營，以確保系統(tǒng)、流程和生產(chǎn)的產(chǎn)品符合CGMP對PET藥品的要求。
Quality Assurance Program Audits
質(zhì)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.
在你們的回復中，聲明通過“內(nèi)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(zhì)量保證計劃檢查期間發(fā)現(xiàn)的CGMP缺陷，在您與FDA的通信中也稱為“內(nèi)部檢查”。
Guidance on Positron Emission Tomography (PET) Drugs
正電子發(fā)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(chǎn)規(guī)范，以幫助您在生產(chǎn)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(chǎn)的無菌藥品目前的良好生產(chǎn)規(guī)范，以了解可能適用于PET藥品生產(chǎn)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(guī)行為并不是在你的設施內(nèi)的違規(guī)行為清單里只有一個。你們負責調(diào)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。
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 drugshortages@fda.hhs.gov, 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(chǎn)的藥品供應中斷的行動，F(xiàn)DA要求你們立即聯(lián)系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(jīng)營符合法律。根據(jù)《美國法典》第21卷第356c（b）節(jié)的規(guī)定，與藥品短缺人員聯(lián)系還可以讓你們履行義務，報告藥品生產(chǎn)中斷。這也使FDA能夠盡快考慮采取什么行動（如果有的話），以避免短缺和保護依賴你的產(chǎn)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(guī)行為。如果未能及時糾正這些違規(guī)行為，可能會導致法律訴訟，而無需另行通知，包括但不限于扣押和禁令。本警告信中未解決的違規(guī)行為也可能阻止其他聯(lián)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(guī)行為得到糾正之前，F(xiàn)DA還可能拒絕批準出口證書申請，以及FDA可能會拒絕批準任何新的藥物申請或?qū)①F公司列為藥物制造商的補充產(chǎn)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, Kent.Bui@fda.hhs.gov, within five days of receipt of this letter to schedule a regulatory meeting.
我們要求您在收到本函后五天內(nèi)給Kent Bui發(fā)送電子郵件，以安排監(jiān)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.
收到此信后，請在15個工作日內(nèi)以書面形式回復本辦公室。請說明自我們檢查以來，您為糾正您的違規(guī)行為并防止其再次發(fā)生所做的工作。如果您無法在15個工作日內(nèi)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 and ORAPharm1_responses@fda.hhs.gov. 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
Cc: Craig Sawyer, Pharm.D.
Woburn Facility Site Manager
350 Washington Street, Unit 268
Woburn, MA 01801
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