8月1日，F(xiàn)DA連續(xù)發(fā)布了8封涉嫌違反GMP的警告信，包括2封美國(guó)本土藥企和6封國(guó)外藥企（主要是印度藥企）的警告信，如下：
Intas Pharmaceuticals Limited
英塔斯制藥公司
Iso-Tex Diagnostics, Inc.
Baxter Healthcare Corporation
百特醫(yī)藥有限公司（印度工廠）
Medgel Private Limited
Centaur Pharmaceuticals Private Ltd.
Avlon Industries, Inc.
Jamol Laboratories, Inc.
LXR Biotech, LLC
部分警告信缺陷翻譯如下：
Warning Letter 320-23-18
The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Baxter Pharmaceuticals India Pvt. Ltd., 3004610460, at Village Vasana Chacharwadi, Taluka Sanand, Ahmedabad, India, from January 19 to January 27, 2023.
FDA于 2023 年 1 月 19 日至 1 月 27 日檢查了你們的藥品制造工廠，位于印度艾哈邁達(dá)巴德塔盧卡薩南德瓦薩納瓦迪村的百特制藥印度有限公司。
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 parts 210 and 211).
本警告信總結(jié)了藥物制劑嚴(yán)重違反CGMP法規(guī)的情況。請(qǐng)參閱聯(lián)邦法規(guī) 21 CFR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).
由于你們的制造、加工、包裝或保存方法、設(shè)施或控制不符合 CGMP，你們的藥品按照《聯(lián)邦食品、藥品和化妝品法案》（FD&C法案）第 501（a）（2）（B） 條（21 U.S.C. 351（a）（2）（B） 為摻假。
We reviewed your February 17, 2023 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.
我們?cè)敿?xì)審查了你們于 2023 年 2 月 17 日對(duì)我們 FDA 483 表格的回復(fù)，并確認(rèn)收到你們的后續(xù)信件。
During our inspection, our investigators observed specific violations including, but not limited to, the following.
在我們的檢查過(guò)程中，我們的檢查人員觀察到的具體的違規(guī)行為，包括但不限于以下：
1. Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed (21 CFR 211.192).
貴公司未能徹底調(diào)查批次或其任何組分的任何無(wú)法解釋的差異或不符合其任何標(biāo)準(zhǔn)的情況，無(wú)論該批次是否已放行（21 CFR 211.192）。
You failed to conduct adequate investigations into endotoxin testing and your 100% automated visual inspection system. You conducted investigations that were not thorough, expanded to an appropriate scope, or based on scientifically supported root cause(s). You did not identify and implement appropriate corrective actions and preventive actions (CAPA). Specifically,
你們未能對(duì)內(nèi)毒素檢測(cè)和100%自動(dòng)燈檢系統(tǒng)進(jìn)行充分調(diào)查。你們進(jìn)行了不徹底、未能擴(kuò)展到適當(dāng)范圍或基于科學(xué)支持的根本原因的調(diào)查。你們沒有確定并實(shí)施適當(dāng)?shù)募m正措施和預(yù)防措施（CAPA）。具體說(shuō)來(lái)：
Your firm invalidated multiple endotoxin tests for finished products upon discovery of particulate matter in one or more wells used to perform the kinetic-turbidimetric assay (KTA) method. You failed to characterize the particulate matter and attributed the particulates to environmental and laboratory conditions, such as air ducts and activities being performed by personnel in the immediate vicinity of the analysis. You did not definitively identify the source or sources of the particulate matter, define the scope of potentially impacted operations (including potential manufacturing causes), and implement scientifically justified CAPA in a timely manner.
貴公司在用于執(zhí)行動(dòng)力學(xué)比濁測(cè)定（KTA）方法的一個(gè)或多個(gè)孔中發(fā)現(xiàn)顆粒物后，判定多個(gè)成品的內(nèi)毒素測(cè)試無(wú)效。你們未能確認(rèn)這些顆粒物，并將顆粒歸因于環(huán)境和實(shí)驗(yàn)室條件，例如空氣管道和檢測(cè)（區(qū)域）附近人員正在進(jìn)行的活動(dòng)。你們沒有明確確定顆粒物的來(lái)源，定義可能受影響的范圍（包括潛在的生產(chǎn)原因），并及時(shí)實(shí)施科學(xué)合理的 CAPA。
In a previous inspection (May 2022), FDA cited your firm for inadequate investigations into these and other similar out-of-specification (OOS) endotoxin testing that you invalidated due to uncharacterized particulate contamination in one or more wells during KTA analyses. Prior to and during an October 5, 2022 regulatory meeting with your firm, we requested you perform a retrospective assessment of investigations associated with OOS endotoxin results or endotoxin testing deviations. During the current inspection, your personnel explained that these investigations were not reopened or otherwise reassessed. Although you retained a third-party consultant to perform a retrospective assessment of endotoxin investigations associated with OOS endotoxin result investigations, you did not provide the third-party consultant with an investigation cited during the May 2022 inspection. You also did not ensure the assessment included approximately 20 invalidated laboratory tests generated in 2021 and 2022 (including multiple investigations since the May 2022 inspection).
在之前的檢查（2022 年 5 月）中，F(xiàn)DA 引用了貴公司對(duì)這些和其他類似的不合格 （OOS） 內(nèi)毒素測(cè)試的調(diào)查不充分，這些測(cè)試在 KTA 分析期間一個(gè)或多個(gè)孔中存在未表征的顆粒污染被判定無(wú)效。在 2022 年 10 月 5 日與貴公司舉行監(jiān)管會(huì)議之前和期間，我們要求你們對(duì)與 OOS 內(nèi)毒素結(jié)果或內(nèi)毒素檢測(cè)偏差相關(guān)的調(diào)查進(jìn)行回顧性評(píng)估。在本次檢查期間，你們的人員解釋說(shuō)，這些調(diào)查沒有重新開始或以其他方式重新評(píng)估。盡管你們聘請(qǐng)了第三方顧問(wèn)對(duì)與 OOS 內(nèi)毒素結(jié)果調(diào)查相關(guān)的內(nèi)毒素調(diào)查進(jìn)行回顧性評(píng)估，但你們沒有向第三方顧問(wèn)提供 2022 年 5 月檢查期間引用的調(diào)查。你們也沒有確保評(píng)估包括 2021 年和 2022 年產(chǎn)生的大約 20 項(xiàng)無(wú)效實(shí)驗(yàn)室測(cè)試（包括自 2022 年 5 月檢查以來(lái)的多項(xiàng)調(diào)查）。
Your firm did not adequately investigate failures of the (b)(4) automatic inspection machine to detect known defects, including particulate matter in injectable drug products. Despite the data indicating significant deficiencies in the machine’s ability to detect known defects during its use, you continued to employ the (b)(4) automatic inspection machine to inspect commercially distributed products (e.g., several batches of (b)(4) injection (b)(4) mg/mL USP). Notably, you fully relied on this automated visual inspection system to detect various defects including particulate contamination for an extended period and did not perform a 100% manual visual inspection for all defects.
貴公司未能充分調(diào)查（b）（4）自動(dòng)燈檢機(jī)未能檢測(cè)已知缺陷的失敗，包括注射用藥品中的顆粒物。盡管數(shù)據(jù)表明機(jī)器在使用過(guò)程中檢測(cè)已知缺陷的能力存在嚴(yán)重不足，但你們?nèi)岳^續(xù)使用（b）（4）自動(dòng)燈檢機(jī)檢測(cè)商業(yè)產(chǎn)品（例如，多批（b）（4）注射用（b）（4）mg /mL USP）。值得注意的是，你們完全依靠這種自動(dòng)燈檢系統(tǒng)來(lái)檢測(cè)各種缺陷，包括顆粒污染，并且沒有對(duì)所有缺陷進(jìn)行 100% 的手動(dòng)目視檢查。
Challenges with defect kits indicated failing rejection rates or other deficiencies. For example, an October 2022 challenge excluded the use of(b)(4) particles despite their lower detectability than other “dark” particles in (b)(4) mL amber glass vials. The challenge also used a highly detectable particle range of (b)(4) μm, but still indicated detection and capability issues. Similar challenges to the (b)(4) automatic inspection machine utilized commercial inspection parameters. You did not initiate adequate investigations into these detection issues. You lacked adequate assurance that sterile injectable drug batches visually inspected with the (b)(4) automatic inspection machine were free from visible particulates.
缺陷組合的挑戰(zhàn)表明剔除率失敗或其他缺陷。例如，2022 年 10 月的一項(xiàng)挑戰(zhàn)踢出了（b）（4） 顆粒的使用，盡管在（b）（4） mL 琥珀色玻璃瓶中的可檢測(cè)性低于其他“深色”顆粒 。該挑戰(zhàn)還使用了（b）（4）μm范圍的高可檢測(cè)性顆粒，但仍表明檢測(cè)和能力問(wèn)題。與（b）（4）自動(dòng)燈檢機(jī)類似的挑戰(zhàn)是使用商業(yè)檢測(cè)參數(shù)。你們未能對(duì)這些檢測(cè)問(wèn)題進(jìn)行充分調(diào)查。你們沒有足夠的保證確保使用（b）（4）自動(dòng)燈檢機(jī)檢查的無(wú)菌注射劑批次沒有可見顆粒。
Your response is inadequate. Your firm previously committed to evaluate and implement improvements to your procedures and practices associated with the conduct of investigations following the conclusion of the July 27 to August 4, 2017, inspection of this facility and in response to the warning letter sent to your firm on July 5, 2018. You also reported significant CAPA activities to address the frequency of endotoxin testing OOS results and deviations following the October 5, 2022, regulatory meeting.
你們的回復(fù)不充分。貴公司此前承諾，在2017年7月27日至8月4日結(jié)束對(duì)該設(shè)施的檢查以及回復(fù)2018年7月5日發(fā)給貴公司的警告信后，評(píng)估和實(shí)施與調(diào)查相關(guān)的程序和操作的改進(jìn)。在 2022 年 10 月 5 日監(jiān)管會(huì)議之后，你們還報(bào)告了重要的 CAPA 活動(dòng)以解決內(nèi)毒素檢測(cè) OOS 結(jié)果的頻率和偏差。
In your February 17, 2023, response to the Form FDA 483 issued at the conclusion of the most recent inspection, you commit to further revisions of your investigation procedures.
在 2023 年 2 月 17 日對(duì)最近一次檢查結(jié)束時(shí)發(fā)布的 FDA 483 表格的回復(fù)中，你們還承諾進(jìn)一步修訂你們的調(diào)查程序。
However, you do not adequately address your failure to conduct timely investigations into recurring and persistent issues. Your response did not adequately address the use of insufficiently qualified(b)(4) equipment for 100% visual inspection of injectable drug products for approximately five years (until October 2022) and the excessive number of samples contaminated with endotoxins or particles in your laboratory.
但是，你們沒有充分解決未能及時(shí)調(diào)查反復(fù)出現(xiàn)和持續(xù)存在的問(wèn)題的缺陷。你們的答復(fù)沒有充分解決使用不合格的（b）（4）設(shè)備對(duì)注射藥品進(jìn)行100%目視檢查約五年（至2022年10月）以及實(shí)驗(yàn)室中被內(nèi)毒素或顆粒污染的樣品數(shù)量過(guò)多的問(wèn)題。
We encourage the use of automated visual inspection for particulates to augment the 100% manual visual inspection program. Automated methods should be rigorously studied for their capability and robustness under various conditions, machine settings, container-closure sizes, defect types, and other variables. In addition, any use of automated particulate inspection does not supplant the need for 100% manual visual inspection for various other attributes (e.g., cracks).
我們鼓勵(lì)對(duì)顆粒物使用自動(dòng)目視檢測(cè)，以增強(qiáng)100%人工目視檢測(cè)程序。應(yīng)嚴(yán)格研究自動(dòng)化方法在各種條件下的能力和穩(wěn)健性、機(jī)器設(shè)置、容器尺寸、缺陷類型和其他變量。此外，任何使用自動(dòng)燈檢都不能取代對(duì)各種其他屬性（例如裂縫）進(jìn)行100%手動(dòng)目視檢測(cè)的需要。
2. Your firm failed to establish and follow adequate written procedures for cleaning and maintenance of equipment (21 CFR 211.67(b)).
貴公司未能建立并遵循適當(dāng)?shù)臅娉绦騺?lái)清潔和維護(hù)設(shè)備（21 CFR 211.67（b））。
An FDA investigator observed white spots at the bottom of a(b)(4) L bulk solution holding tank used to supply a non-dedicated filling machine despite the vessel being documented as clean. You subsequently analyzed and identified the white spots as (b)(4) (the product previously processed on this equipment) at levels of up to (b)(4) parts per million (ppm). Your limit for post-cleaning residues is not more than (b)(4) ppm.
FDA檢查人員觀察到（b）（4）L散裝溶液儲(chǔ)罐底部有白點(diǎn)，該罐用于供應(yīng)非專用灌裝機(jī)，盡管該罐被記錄為已清潔。隨后，你們分析并確定了白點(diǎn)（b）（4）（先前在此設(shè)備上加工的產(chǎn)品），其水平高達(dá)（b）（4）ppm。清潔后殘留物的限值不超過(guò) （b）（4） ppm。
Your response is inadequate. Although you revised your cleaning procedure to require vessels to be dry before conducting the visual inspection for cleanliness and implemented visual verification of the vessel interior via a sight glass following the cleaning and(b)(4) activities, you did not provide scientific justification for your use of visual inspection to verify the removal of residues to levels as low as (b)(4) ppm. Your response noted (b)(4) injection, not (b)(4) injection, is the “worst-case product” processed in this vessel, but you did not provide a comprehensive investigation to assess the impact of this cleaning deviation on products previously manufactured on this and other non-dedicated equipment. You also did not propose a systemic assessment of your equipment cleaning program.
你的回復(fù)是不充分的。盡管你們修改了清潔程序，要求在進(jìn)行清潔度目視檢查之前對(duì)容器進(jìn)行干燥，并在清潔和 （b）（4） 活動(dòng)后通過(guò)視鏡對(duì)容器內(nèi)部進(jìn)行了目視確認(rèn)，但你們沒有提供科學(xué)依據(jù)來(lái)驗(yàn)證殘留物去除到低至 （b）（4） ppm 的水平。你們的答復(fù)指出，（b）（4）注射劑，而不是（b）（4）注射劑，是該容器處理的“最差情況產(chǎn)品”，但你們沒有提供全面的調(diào)查來(lái)評(píng)估這種清潔偏差對(duì)以前在此和其他非專用設(shè)備上生產(chǎn)的產(chǎn)品的影響。你們也沒有對(duì)你們的設(shè)備清潔程序進(jìn)行系統(tǒng)評(píng)估。
3. Your firm failed to establish adequate written procedures for production and process control designed to assure that drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess, and to follow all of your written production and process control procedures (21 CFR 211.100(a) and (b)).
貴公司未能為生產(chǎn)和工藝控制建立適當(dāng)?shù)臅娉绦?，以確保你們生產(chǎn)的藥品具有其特性、含量、質(zhì)量和純度，并符合你們的所有書面生產(chǎn)和工藝控制程序（21 CFR 211.100（a） 和 （b））。
Your program for the visual inspection of sterile injectable drug products does not provide adequate assurance that finished products manufactured at your facility possess their purported quality attributes, including that they are free from particulate matter. For example,
你們的無(wú)菌注射藥品目視檢查程序未能充分保證你們的工廠生產(chǎn)的成品具有其所謂的質(zhì)量屬性，包括它們不含顆粒物。例如
Personnel performed 100% manual visual inspection of sterile injectable units for less than the minimum amount of time required by your written procedures.
人員對(duì)無(wú)菌注射單元進(jìn)行100%手動(dòng)目視檢查，時(shí)間少于你們的書面程序要求的最短時(shí)間。
You lacked scientific justification for removing vials containing (b)(4) particles from the defect kits used to qualify visual inspection processes. For example, although (b)(4) particles were more difficult to reproducibly detect than (b)(4) stopper particles in the (b)(4) mL amber vials, you elected to only use the (b)(4) stopper particles in the defect kits.
你們?nèi)狈茖W(xué)依據(jù)從用于確認(rèn)目視檢查過(guò)程的缺陷套件中踢出含有 （b）（4） 顆粒的瓶子。例如，盡管在（b）（4） mL 琥珀色樣品瓶中的 （b）（4） 顆粒比 （b）（4） 瓶膠塞顆粒更難重現(xiàn)檢測(cè)，但你們?nèi)赃x擇在缺陷套件中僅使用 （b）（4） 膠塞顆粒。
Your response is inadequate. You commit to using a “pacing device” during the 100% manual visual inspections and requiring a supervisor to periodically verify the inspection times. You did not provide a description of the pacing device or commit to requalify operators following implementation of the pacing device. Additionally, you did not commit to evaluate operator performance throughout a(b)(4).
你們的回復(fù)是不充分的。你們承諾在 100% 手動(dòng)目視檢查期間使用“限速設(shè)備”，并要求主管定期確認(rèn)檢查時(shí)間。你們沒有提供限速設(shè)備的描述，也沒有承諾在實(shí)施限速設(shè)備后重新確認(rèn)操作人員。此外，你們沒有承諾在整個(gè) （b）（4） 中評(píng)估操作人員的性能。
You also state a successful qualification program does not evaluate “… an inspector’s ability to differentiate and identify various types and morphologies of particles.” However, it is critical to be able to reproducibly detect particulate defects of different types, morphologies, and sizes.
你們還聲明成功的確認(rèn)程序不會(huì)評(píng)估“......檢查人員區(qū)分和識(shí)別各種類型和形態(tài)的顆粒的能力。然而，能夠可重復(fù)地檢測(cè)不同類型、形態(tài)和大小的顆粒缺陷至關(guān)重要。
4. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).
貴公司未能在制造、加工、包裝或保存藥品時(shí)使用適當(dāng)設(shè)計(jì)、規(guī)格和安裝的設(shè)備以適合其預(yù)期用途的操作以及清潔和維護(hù)（21 CFR 211.63）。
Equipment used in the manufacture of terminally sterilized drugs at your facility is not designed or maintained appropriately. Our inspection revealed instances of damaged metal and plastic parts, open vials exposed to worn bolt threading, and process flow that required employees to duck underneath the sterile processing line conveyer in order to perform interventions near open vials (e.g., stopper addition on the(b)(4) filling line).
在你們的工廠中用于制造最終滅菌藥物的設(shè)備設(shè)計(jì)或維護(hù)不當(dāng)。我們的檢查發(fā)現(xiàn)了損壞的金屬和塑料部件、暴露于磨損螺栓螺紋的未加塞瓶子以及要求員工彎身在無(wú)菌加工線輸送機(jī)下方以便在未加塞瓶子附近進(jìn)行干預(yù)的工藝流程（例如，在 （b）（4） 灌裝線上添加膠塞）。
Your response is inadequate. Although you commit to replacing the threaded bolt(b)(4) on the (b)(4) filling line with a different part that will not expose a threading over open vials, you did not commit to evaluate production rooms and production equipment for wear, damage, or poor design that may lead to the generation of particulate matter in the vicinity of open vials. You also plan to install a (b)(4) conveyor at the capping machine outfeed, and merge filling and capping areas, for two filling lines ((b)(4) and (b)(4)), but you did not commit to perform a comprehensive assessment of your facility’s production lines to ensure they are appropriately designed and controlled.
你們回復(fù)是不充分的。盡管你們承諾將 （b）（4） 灌裝線上的螺紋螺栓 （b）（4） 更換為不會(huì)暴露開口小瓶上的螺紋的不同部件，但你們并未承諾評(píng)估生產(chǎn)車間和生產(chǎn)設(shè)備是否存在可能導(dǎo)致在未加塞瓶子附近產(chǎn)生顆粒物質(zhì)的磨損、損壞或設(shè)計(jì)不良。你們還計(jì)劃在軋蓋機(jī)出口處安裝（b）（4）輸送機(jī)，并合并兩條灌裝線（（b）（4）和（b）（4）的灌裝和軋蓋區(qū)域），但你們沒有承諾對(duì)工廠的生產(chǎn)線進(jìn)行全面評(píng)估，以確保它們得到適當(dāng)?shù)脑O(shè)計(jì)和控制。
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