10月27日，FDA公布一封針對美國本土企業(yè)的警告信。主要的違規項包括未執行清潔驗證和不遵守批記錄問(wèn)題，FDA認為反復出現的失效表明，管理層對藥品生產(chǎn)的監督和控制不足。
值得注意的是，在此檢查期間，為了確定數據真實(shí)性，FDA檢查員在多個(gè)日志之間進(jìn)行比較，確定樣品色譜分析時(shí)間比實(shí)驗室收到樣品的時(shí)間要早5個(gè)小時(shí)；同時(shí)檢查員調查了廠(chǎng)房門(mén)禁讀卡器的記錄，最終確定日志中涉及的分析員當天根本不在公司。
Warning Letter CMS # 608236
October 8, 2020
Dear Mr. Tabasso:
警告信CMS＃608236
2020年10月8日
親愛(ài)的塔巴索先生：
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, KVK-Tech, Inc., FEI 301367632, at 100 Campus Drive, Newtown, Pennsylvania, from February 4 to March 13, 2020.
2020年2月4日至3月13日，美國食品藥品監督管理局(FDA)檢查了你處的藥品生產(chǎn)設施，KVK-Tech,Inc.，FEI 301367632位于賓夕法尼亞州紐敦。
This warning letter summarizes significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR 210 and 211).
該警告信總結了嚴重違反制劑CGMP規定的情況。請參閱21CFR第210和211部分。
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).
由于你用于生產(chǎn)、加工、包裝或儲存的方法、設施或控制措施不符合CGMP，因此根據FD＆C法案501(a)(2)(B)條及21 U.S.C.351(a)(2)(B) 條的規定，你藥品被認為是摻假。
We reviewed your April 4, 2020, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我們詳細審查了你們2020年4月4日對FDA 483表格的答復，并確認收到你們的后續信件。
During our inspection, our investigator observed specific violations including, but not limited to, the following.
在我們的檢查過(guò)程中，調查員發(fā)現了具體的違規行為，包括但不限于以下行為。
清潔驗證
1. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
1.你公司未建立并遵循適當的書(shū)面程序，來(lái)清潔和維護設備(21 CFR 211.67(b))。
You performed packaging operations for approximately (b)(4) solid oral dosage form drug products at this facility. You did not validate the processes used to clean your non-dedicated packaging equipment such as your slat counter prior to use, as required by your cleaning validation standard operating procedure SOP-0030.
在此工廠(chǎng)，采樣對大約XX中固體口服制劑進(jìn)行了包裝操作。你們沒(méi)有按照清潔驗證標準操作程序SOP-0030的要求，在使用之前，驗證用于清潔非專(zhuān)用包裝設備(如板條數粒機)的工藝。
Inadequate removal of residues from product contact surfaces of non-dedicated manufacturing (e.g., packaging) equipment can lead to cross-contamination of drug products subsequently manufactured on that equipment.
對于非專(zhuān)用生產(chǎn)(例如包裝)設備產(chǎn)品接觸表面，不充分去除殘留，可能導致隨后在該設備上生產(chǎn)的藥品產(chǎn)生交叉污染。
Your response stated that you did not perform cleaning validation on the slat counter because you believed the slat counter was constructed of materials similar to the (b)(4) tablet counters used at your second facility in Newtown, Pennsylvania.
你們的回答表明，你們未對板條數粒機執行清潔驗證，因為你們認為板條數粒機的材料類(lèi)似于賓夕法尼亞州紐敦的第二家工廠(chǎng)使用的XX片劑數粒機。
We acknowledge that you are now initiating cleaning validation of your slat counter, and tested swab samples for residues of (b)(4) of your drug products ((b)(4)). You also committed to performing cleaning validation for the remaining (b)(4) drug products. In addition, you stated that the cleaning validation procedure will be revised to specify that an assessment will be performed whenever modifications impacting equipment or cleaning procedures are made.
我們知曉你們現在開(kāi)始對板條數粒機進(jìn)行清潔驗證，并測試了棉簽樣品中藥品的殘留。你們還承諾對其余XX藥品進(jìn)行清潔驗證。此外，你們還說(shuō)過(guò)將對清潔驗證程序進(jìn)行修訂，以指定每當進(jìn)行影響設備或清潔程序的修改時(shí)，都需要進(jìn)行評估。
Your response is inadequate. Both the design and most difficult to clean surfaces of your (b)(4) tablet counter significantly differ from your slat counter. You did not establish the worst-case scenario for cross-contamination in your new cleaning validation studies because you lacked swab sites within the slat cavities, which can be one of the most difficult-to-clean locations and a potential site of carryover. Furthermore, your response failed to explain why you did not document your rationale to deviate from your cleaning validation SOP or specify how you would improve your overall change management system to prevent recurrence.
你們的答復不充分。XX片劑數粒機的設計和最難清潔的表面都與板條數粒機明顯不同。在新的清潔驗證研究中，你們沒(méi)有為交叉污染建立最壞的情況，因為你們在板條腔內沒(méi)有進(jìn)行棉簽取樣，因為該位置可能是最難清潔的位點(diǎn)之一，有潛在殘留的可能性。此外，你們的答復無(wú)法解釋?zhuān)簩τ谄x清潔驗證SOP，為什么你們沒(méi)有記錄相應的理由；或說(shuō)明如何改進(jìn)總體變更管理系統，以防止再次發(fā)生。
In your response to this letter, provide the following:
針對此信，請提供：
· Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
對清潔驗證程序進(jìn)行了適當的改進(jìn)，特別著(zhù)重于納入在藥品生產(chǎn)工藝中確定為最差情況的條件。最差情況的識別和評估，應包括但不限于：
· Appropriate improvements to your cleaning validation program, with special emphasis on incorporating conditions identified as worst-case in your drug manufacturing operation. This should include but not be limited to identification and evaluation of all worst-case:
o drugs with higher toxicities
o drugs with higher drug potencies
o drugs of lower solubility in the cleaning solvents specified in your procedures
o drugs with characteristics that make them difficult to clean, (e.g., uncoated tablets)
o swabbing locations for areas most difficult to clean, including but not limited to slat cavities
o maximum hold times before cleaning
o具有較高毒性的
o產(chǎn)品具有較高活性的
o在你們程序指定的清潔溶劑中溶解度較低的藥物
o具有難以清潔特性的的藥物(例如未包衣的藥片)
o擦拭最難清潔區域的位置，包括但不限于板條腔
o清潔前的最長(cháng)放置時(shí)間
In addition, describe the steps that must be taken in your change management system before introduction of new manufacturing equipment or a new product.
另外，描述在引入新的生產(chǎn)設備或新產(chǎn)品之前，變更管理系統必須采取的步驟。
· A summary of updated SOPs that ensure an appropriate program is in place to verify and validate cleaning procedures for products, processes, and equipment.
更新的SOP的摘要，以確保制定適當的程序，來(lái)驗證和確認產(chǎn)品、工藝和設備的清潔程序。
批記錄
2. Your firm failed to prepare batch production and control records with complete information relating to the production and control of each batch of drug product produced. (21 CFR 211.188)
2.你們的公司未能準備批生產(chǎn)和控制記錄，以提供與每批生產(chǎn)的藥品的生產(chǎn)和控制有關(guān)的完整信息。(21 CFR 211.188)
During packaging of one lot of hydroxyzine HCl tablets, USP 50 mg, our investigator observed that the air pressure gauge reading was outside the acceptable range for your capper, although a conforming value was recorded in the batch record. In addition, our investigator observed readings on other gauges that were lower than your validated parameters.
在包裝一批鹽酸羥嗪USP 50 mg的過(guò)程中，盡管批記錄中記錄了合格值，但我們的調查員觀(guān)察到壓力值超出了封蓋鉗可接受的范圍。此外，我們的調查員觀(guān)察到：其它儀表的讀數低于你們驗證的參數。
Our investigator also noted that in the batch record for promethazine HCl tablets, USP 25 mg, your employees failed to record actual readings for the air pressure for several pieces of packaging equipment, including your slat counter, capper, and (b)(4).
我們的調查員還注意到，在鹽酸異丙嗪片USP 25 mg的批記錄中，你們的員工未能記錄幾套包裝設備的實(shí)際壓力讀數，包括你們的板條數粒機，封蓋機和XX。
In your response, you explained that during the packaging of the hydroxyzine HCl tablets your mechanic observed that the caps were not feeding into the capper properly, and he adjusted the air pressure of the capper machine below qualified limits. However, the deviation was not documented. You also stated that you found that some equipment gauges were malfunctioning and replaced them. In addition, you retrained your personnel to document the actual values in batch records.
在你們的答復中，你們解釋說(shuō)，在包裝鹽酸羥嗪片劑時(shí)，你們的機械師觀(guān)察到瓶蓋未正確送入封蓋機，因此他將封蓋機的壓力調節到合格限度以下。但是，沒(méi)有記錄偏差。你們還指出，你們發(fā)現某些儀器的壓力表出現故障，并進(jìn)行了更換。此外，你們還對人員進(jìn)行了再培訓，以在批處理記錄中記錄實(shí)際值。
Your response is inadequate because you did not conduct a comprehensive review to determine the scope and impact of inaccurate data recording in production records, and did not provide a plan for improving management oversight of operations.
你們的答復是不充分的，因為你們沒(méi)有進(jìn)行全面的審查，來(lái)確定生產(chǎn)記錄中不正確的數據記錄的范圍和影響，并且沒(méi)有提供改善運營(yíng)管理監督的計劃。
In your response to this letter, provide the following:
針對此信，請提供：
· A complete 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, and contemporaneous records throughout your operation.
·對整個(gè)生產(chǎn)和實(shí)驗室運營(yíng)中使用的文檔系統進(jìn)行全面評估，以確定哪些地方文檔實(shí)踐不充分。包括詳細的糾正和預防措施(CAPA)計劃，以全面補救公司的文件編制慣例，以確保你們在整個(gè)運營(yíng)過(guò)程中保留可歸因的、清晰的、完整的、原始的、準確的和同步的記錄。
· Your CAPA plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facility performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.
·你們的CAPA計劃：對設施和設備實(shí)施例行的、警惕的運營(yíng)管理監督。該計劃應確保除其它事項外，迅速發(fā)現設備/設施性能問(wèn)題，有效執行維修，遵守適當的預防性維護計劃，及時(shí)對設備/設施基礎設施進(jìn)行技術(shù)升級，以及改進(jìn)系統以進(jìn)行持續的管理審查。
Your plan should also ensure that appropriate actions are taken throughout the company network.
你們的計劃還應確保在整個(gè)公司網(wǎng)絡(luò )中采取適當的措施。
· A comprehensive, independent assessment of your change management system. This assessment should include, but not be limited to, your procedure(s) to ensure changes are justified, reviewed, and approved by your quality unit. Your change management program should also include provisions for determining change effectiveness.
·對變更管理系統進(jìn)行全面、獨立的評估。該評估應包括但不限于你們的程序，以確保質(zhì)量部門(mén)對變更進(jìn)行合理的審核和批準。你們的變更管理計劃還應包括：確定變更有效性的規定。
其它觀(guān)察
Other Observations
During this inspection, we found that the cleaning validation sample for oxybutynin chloride tablets, USP 5 mg lot 15749, was documented in the incoming sample logbook as received on September 24, 2019, at 10:50 PM. The chromatographic analysis for this sample was completed at approximately 5:50 PM on September 24, about five hours before the sample was received, according to your logbook.
在此檢查期間，我們發(fā)現，在2019年9月24日晚上10:50樣品接受日志中，記錄了奧昔布寧氯化物片劑的清潔驗證樣品(USP 5 mg批次15749)。根據你們的日志，此樣品的色譜分析于9月24日下午5:50左右完成，大約在收到樣品前五個(gè)小時(shí)。
A review of the building access card reader record showed that the analyst who logged in the sample was not in the building at approximately 10:50 PM that day. Your analyst gave conflicting accounts for this discrepancy but eventually admitted to putting incorrect information in the logbook.
對廠(chǎng)房門(mén)禁讀卡器記錄的檢查顯示，登記樣品的分析員在當天晚上10:50不在廠(chǎng)房中。你們的分析員針對此差異給出了相互矛盾的說(shuō)明，但最終承認在日志中輸入了錯誤的信息。
在多個(gè)工廠(chǎng)重復違規
Repeat Violations at Multiple Sites
FDA cited similar CGMP violations at other facilities in your company’s network. Your 110 Terry Drive site received an FDA warning letter dated February 11, 2020. These repeated failures at multiple sites demonstrate that management oversight and control over the manufacture of drugs is inadequate.
對于你們公司網(wǎng)絡(luò )中其它設施，FDA曾指出了有類(lèi)似CGMP違規行為。你們的110 Terry Drive工廠(chǎng)頁(yè)收到過(guò)FDA的警告信，日期為2020年2月11日。這些在多個(gè)工廠(chǎng)上反復出現的失效表明，管理層對藥品生產(chǎn)的監督和控制不足。
Your executive management remains responsible for fully resolving all deficiencies and ensuring ongoing CGMP compliance. You should immediately and comprehensively assess your company’s global manufacturing operations to ensure that systems, processes, and the products manufactured conform to FDA requirements.
你們的執行管理層有責任完全解決所有缺陷，并確保CGMP持續合規。你們應該立即全面評估公司的全球生產(chǎn)運營(yíng)，以確保系統、工藝和生產(chǎn)的產(chǎn)品符合FDA要求。
CGMP顧問(wèn)推薦
CGMP Consultant Recommended
Based upon the nature of the violations we identified at your firm, we strongly recommend engaging a consultant qualified as set forth in 21 CFR 211.34 to assist your firm in meeting CGMP requirements if your firm intends to resume manufacturing drugs for the U.S. market. We also recommend that the qualified consultant perform a comprehensive audit of your entire operation for CGMP compliance and that the consultant evaluates the completion and efficacy of your corrective actions and preventive actions before you pursue resolution of your firm’s compliance status with FDA.
根據我們發(fā)現的違規行為的性質(zhì)，我們強烈建議聘請符合21 CFR 211.34規定的合格顧問(wèn)，來(lái)協(xié)助你們公司滿(mǎn)足CGMP要求，前提是你們的公司打算恢復為美國市場(chǎng)生產(chǎn)藥品。我們還建議合格的顧問(wèn)對你們的整個(gè)運營(yíng)過(guò)程進(jìn)行全面審核，以確保其符合CGMP要求，并建議顧問(wèn)在你們尋求公司與FDA的合規性解決方案之前，對你們的糾正和預防措施的完成情況和有效性進(jìn)行評估。
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.
你聘用顧問(wèn)并不能免除公司遵守CGMP的義務(wù)。你公司的執行管理層仍然負責解決所有缺陷和系統性缺陷，以確保持續符合CGMP。
暫停藥品生產(chǎn)
Drug Production Suspended
We acknowledge your commitment to suspend manufacture of drugs at the (b)(4) facility. In response to this letter, clarify whether you intend to resume manufacturing any drugs at this facility in the future. If you plan to resume manufacturing drugs, notify this office before resuming your operations.
我們知曉你們承諾在XX工廠(chǎng)暫停藥品生產(chǎn)。針對此信，請澄清你們將來(lái)是否打算在該工廠(chǎng)恢復生產(chǎn)任何藥物。如果你們打算恢復生產(chǎn)藥品，請在恢復操作之前通知FDA辦公室。
結論
Conclusion
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.
本信函中引用的違規行為并非旨在列出與你產(chǎn)品相關(guān)的所有違規行為。你有責任調查和確定這些違規的原因，并防止其再次發(fā)生或發(fā)生其它違規情況。
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.
如果你們正在考慮可能會(huì )導致你們的工廠(chǎng)生產(chǎn)的藥物供應中斷的行動(dòng)，則FDA要求你們立即聯(lián)系CDER的藥物短缺人員(drugshortages@fda.hhs.gov)，以便FDA可以與你們以最有效的方式使你們的運營(yíng)符合法律規定。與藥品短缺人員聯(lián)系還可以使你們履行報告21 USC 356C(b)規定的藥品生產(chǎn)中斷或暫停的義務(wù)。這也使FDA可以盡快考慮可能需要采取什么措施，以避免短缺和保護依賴(lài)你們產(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(shí)糾正此信中引用的違規行為。不及時(shí)糾正這些違法行為，可能會(huì )導致采取法律行動(dòng)(恕不另行通知)，包括但不限于：扣押和強制令。此警告信中未解決的違反行為也可能阻止其它聯(lián)邦機構給予合同。
FDA還可能拒絕批準出口證書(shū)申請，對于新藥申請或補充申請，也不會(huì )批準將你工廠(chǎng)列為供應商或生產(chǎn)商，直到上述違法行為得到糾正。我們可能會(huì )重新檢查，以確認你已完成糾正措施。
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.
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.
收到這封信后，請在15個(gè)工作日內以書(shū)面形式答復FDA辦公室。說(shuō)明自我們檢查以來(lái)，你所做的事情，以糾正你違規行為，并防止其再次發(fā)生。如果你無(wú)法在15個(gè)工作日內完成糾正措施，請說(shuō)明延誤原因和完成時(shí)間表。
If you believe that your products are not in violation of the FD&C Act (or you have complied with FDA regulations), include your reasoning and any supporting information for our consideration.
如果你認為你產(chǎn)品未違反FD＆C法案(或你已遵守FDA法規)，請提供你理由和任何支持信息，以供我們考慮。
參考:
FDA Warning Letters, PT. KVK-Tech, Inc., MARCS-CMS 608236. OCTOBER 08, 2020. US Food and Drug Administration (FDA). www.fda.gov.
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