近日，FDA發(fā)布了Sun Pharmaceuticals Medicare的483缺陷報(bào)告，其中提及不良無菌生產(chǎn)操作的缺陷：
操作人員似乎不熟悉無菌連接流程
在進(jìn)行無菌連接、無菌物品傳遞、添加膠塞、裝機(jī)和調(diào)機(jī)等操作前和過程中，未對(duì)手部進(jìn)行消毒，也未使用恰當(dāng)?shù)臒o菌操作技術(shù)。
B級(jí)區(qū)物品傳入A級(jí)前未消毒
操作人員未對(duì)手部消毒便進(jìn)行A 級(jí)區(qū)域的操作。
手部伸入A級(jí)區(qū)域后才進(jìn)行消毒，且消毒劑噴灑在了 A 級(jí)環(huán)境監(jiān)測(cè)（EM）沉降菌和浮游菌采樣器附近
在添加膠塞的過程中，F(xiàn)DA檢查人員看到操作人員將包裝袋直接置于膠塞斗上方倒入膠塞，F(xiàn)DA認(rèn)為：這阻擋了流向裝有無菌膠塞的首過空氣。
FDA檢查人員看到：清潔過程中，操作人員重復(fù)使用抹布的同一面多達(dá) 3 次。FDA表示：潔凈室操作人員并未采用正確的清潔技術(shù)：即每次使用抹布的干凈面，以平行單向且重疊的方式擦拭。
無菌操作人員使用的護(hù)目鏡鏡框頂部帶有孔洞，F(xiàn)DA認(rèn)為：這會(huì)導(dǎo)致在無菌操作過程中皮膚暴露在外，影響無菌性。
缺少針對(duì)操作人員移動(dòng)路線的程序要求。
操作人員在 B 級(jí)灌裝間xx與無菌走廊之間隨意進(jìn)出。B 級(jí)無菌走廊與 B 級(jí)灌裝間之間的人員流動(dòng)未得到嚴(yán)格管控
具體翻譯如下：
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, followed, or including adequate validation of the sterilization process. Specifically,
未建立、遵循用以防止無菌藥品微生物污染的書面程序，也未包含對(duì)滅菌過程的充分驗(yàn)證。具體如下：
A. On 09/13/2025, (I, EL) observed the aseptic assembly, set-up, and filling of (b)(4) Injection, U.S. Batch (b)(4) in Block (b)(4) vial filling line (b)(4) Room (b)(4) The following deficient aseptic practice was observed.A.
在2025年9月13日，我們觀察了注射劑產(chǎn)品在西林瓶灌裝線XX房間內(nèi)的無菌組裝、設(shè)置和灌裝操作，發(fā)現(xiàn)了以下不良無菌操作：
a) The operator appeared unfamiliar with the sterile connection process. He did not sanitize his hands or use appropriate aseptic technique in performing sterile connections. Specifically,
操作人員似乎不熟悉無菌連接流程。在進(jìn)行無菌連接操作時(shí)，未對(duì)手部進(jìn)行消毒，也未使用恰當(dāng)?shù)臒o菌操作技術(shù)。具體如下：
During the critical S2S (sterile-to-sterile) connection between the sterile product transfer tank (in Grade B) and the filling machine (in Grade A), (b)(4) observed that without sanitizing his hands, the operator grabbed the sterile connector end (in (b)(4) cover) of the manifold tubing from the Grade A filling line. He attempted but failed to hang the tubing over the (b)(4) RABS (b)(4) He next took the tubing with the sterile connector from the transfer tank. He held both tubing in one hand, using a sterile pair of forceps he removed the (b)(4) cover from each connector including the cover he previously handled with his unsanitized hand. He proceeded to use his unsanitized hands opening the (b)(4) (cover) from each sterile connector to perform the sterile to sterile connection. He sanitized his hands only after completing the S2S connection. Your firm’s MF video shows operator sanitized his hands prior to conducting the S2S connection.
在無菌產(chǎn)品中轉(zhuǎn)罐（B級(jí)）與 灌裝機(jī)（A級(jí)）之間的關(guān)鍵 S2S（無菌對(duì)無菌）連接過程中，觀察到：操作人員未對(duì)手部消毒，便從 A 級(jí)灌裝線抓取管道的無菌連接器端。嘗試將管道掛在RABS 的XX上，但未成功。隨后，又拿起了中轉(zhuǎn)罐處帶有無菌連接器的管道，然后一只手握住兩根管道，同時(shí)使用無菌鑷子取下了連接器上的蓋子（包括他此前用未消毒的手觸碰過的蓋子）。之后，他直接用未消毒的手打開了每個(gè)無菌連接器的（b）（4）（蓋子），完成了無菌對(duì)無菌的連接操作。僅在 S2S 連接完成后，才對(duì)手部進(jìn)行了消毒。貴公司的培養(yǎng)基模擬灌裝視頻則顯示，操作人員在進(jìn)行 S2S 連接前會(huì)對(duì)手部進(jìn)行消毒。
b). Items exposed to a less controlled Grade B environment were not sanitized prior to introducing them to a highly controlled Grade A RABS Specie A area. Also, operators without sanitizing hands were seen conducting Grade A activities. Specifically,
b). 暴露于 B 級(jí)環(huán)境中的物品，在被移入 A 級(jí)RABS 區(qū)域前未經(jīng)過消毒。此外，還發(fā)現(xiàn)操作人員未對(duì)手部消毒便開展了 A 級(jí)區(qū)域的操作。具體情況如下：
The (b)(4) were (b)(4) sterilized in (b)(4) bags. During installation of the sterile (b)(4) observed the (b)(4) wrapper was removed in the Grade B filling room, exposing the (b)(4) wrapper containing the sterile (b)(4) to the Grade B air. I observed that without sanitizing the (b)(4) wrapper surfaces, the operator bag was transferred into the Grade A filling line area via (b)(4) I observed the (b)(4) staged his unsanitized hands (b)(4) to receive the bag, proceeded to open the (b)(4) bag inside the Grade A area, and remove the sterile (b)(4) from the bag. I then observed the operator touched the Grade A side of the (b)(4) with his unsanitized hands in order to find the correct orientation for installation. All the (b)(4) for the Grade A filling line were installed this way. Your firm’s MF video shows operator sanitized his hands prior to conducting (b)(4) installation.
（b）（4）是在（b）（4）包裝袋中進(jìn)行（b）（4）滅菌的。在無菌（b）（4）的安裝過程中，觀察到（b）（4）外包裝在 B 級(jí)灌裝間內(nèi)便被拆除，這使得裝有無菌（b）（4）的（b）（4）內(nèi)包裝暴露在了 B 級(jí)環(huán)境的空氣中。我們看到，操作人員未對(duì)（b）（4）內(nèi)包裝表面進(jìn)行消毒，便通過（b）（4）將包裝袋轉(zhuǎn)移至 A 級(jí)灌裝線區(qū)域。我看到（b）（4）用未消毒的手（b）（4）接過包裝袋，隨后在 A 級(jí)區(qū)域內(nèi)打開了（b）（4）包裝袋，并從袋中取出了無菌（b）（4）。之后我又觀察到，操作人員用未消毒的手觸碰了（b）（4）的 A 級(jí)區(qū)域側(cè)，以確認(rèn)安裝的正確方向。A 級(jí)灌裝線的所有（b）（4）均是以這種方式安裝的。貴公司的培養(yǎng)基模擬灌裝視頻則顯示，操作人員在進(jìn)行（b）（4）安裝前對(duì)手部進(jìn)行了消毒。
d). During the assembly and set-up operations, operators did not sanitize their hands before (b)(4) the Grade A filling area. Hands were sanitized after (b)(4) the (b)(4) RABS (b)(4) while they were already inside the Grade A filling line. Also, during hand sanitization, I observed sterile (b)(4) was sprayed near the Grade A EM setting plates and active air sampler, possibly contaminating the (b)(4) media.
d). 在組裝和調(diào)試操作過程中，操作人員在（b）（4）進(jìn)入 A 級(jí)灌裝區(qū)域前未對(duì)手部進(jìn)行消毒。他們是在（b）（4）（b）（4）RABS（b）（4）之后，且已處于 A 級(jí)灌裝線內(nèi)時(shí)，才對(duì)手部進(jìn)行消毒的。此外，在手部消毒過程中，我們觀察到無菌（b）（4）被噴灑在了 A 級(jí)環(huán)境監(jiān)測(cè)（EM）沉降菌和浮游菌采樣器附近，這可能會(huì)污染（b）（4）培養(yǎng)基。
e). Sterile articles were transferred to the Grade B filling room using a (b)(4) LAF (b)(4) Operators did not sanitize their hands before reaching inside the Grade A (b)(4) LAF (b)(4) Also, the interior Grade A side of the (b)(4) LAF (b)(4) that had been exposed to the Grade B environment was not sanitized before (b)(4)
e). 無菌物品通過（b）（4）層流罩（LAF）（b）（4）被轉(zhuǎn)移至 B 級(jí)灌裝間。操作人員在將手伸入 A 級(jí)層流罩（b）（4）內(nèi)部前，未對(duì)手部進(jìn)行消毒。此外，曾暴露于 B 級(jí)環(huán)境的（b）（4）層流罩（b）（4）的 A 級(jí)內(nèi)側(cè)區(qū)域，在（b）（4）前也未經(jīng)過消毒。
f). During (b)(4) the stoppers, I observed (b)(4) bags containing sterile stoppers were placed on the Grade B (b)(4) The (b)(4) wrapper of the bag was cut open by (b)(4) operator exposing the (b)(4) wrapper to the Grade B environment. However, without sanitizing the surfaces of the (b)(4) wrapper, the bag was moved into the Grade A filling line. During (b)(4) addition of stoppers, I observed the (b)(4) operator holding the bag directly over the (b)(4) blocking the first air to the (b)(4) containing sterile stoppers.f).
在（b）（4）膠塞的過程中，我們觀察到裝有無菌膠塞的（b）（4）包裝袋被放置在 B 級(jí)（b）（4）上。（b）（4）操作人員剪開了包裝袋的（b）（4）外包裝，使該外包裝暴露于 B 級(jí)環(huán)境中。但操作人員未對(duì)（b）（4）包裝表面進(jìn)行消毒，便將包裝袋移入了 A 級(jí)灌裝線。在（b）（4）添加膠塞的過程中，我們觀察到（b）（4）操作人員將包裝袋直接置于（b）（4）上方，阻擋了流向裝有無菌膠塞的（b）（4）的首過空氣。
g). During the (b)(4) intervention for removal of fallen vials from the (b)(4) I observed the operator placed his hand directly over adjacent open vials blocking first air to the vials. The impacted vials were not removed.g).
在（b）（4）干預(yù)操作（從（b）（4）中取出掉落的西林瓶）過程中，我們觀察到操作人員將手直接置于相鄰的敞口西林瓶上方，阻擋了流向這些西林瓶的首過空氣。受影響的西林瓶并未被移出。
h). During the cleaning of the Grade A side of the (b)(4) RABS (b)(4) before (b)(4) the (b)(4) I observed operators using the same side of a wipe up to 3 times. The appropriate technique of using the clean side of a wipe each time to apply parallel unidirectional and overlapping strokes was not observed by the cleanroom operators.h).
在（b）（4）RABS（b）（4）的 A 級(jí)側(cè)清潔過程中（于（b）（4）（b）（4）前進(jìn)行），我們觀察到操作人員重復(fù)使用抹布的同一面多達(dá) 3 次。潔凈室操作人員并未采用正確的清潔技術(shù)：即每次使用抹布的干凈面，以平行單向且重疊的方式擦拭。
i). I observed aseptic operators using goggles that have holes on top of the frame, allowing exposed skin during aseptic processing. Holes in goggles create pathways for contaminations to enter the cleanroom environment impacting product sterility.
i). 我們觀察到無菌操作人員使用的護(hù)目鏡鏡框頂部帶有孔洞，這導(dǎo)致在無菌操作過程中皮膚暴露在外。護(hù)目鏡上的孔洞會(huì)成為污染物進(jìn)入潔凈室環(huán)境的通道，進(jìn)而影響產(chǎn)品的無菌性。
j). There is a lack of procedure providing requirement for operator movement. During the inspection, I observed operators going in and out between the Grade B filling Room (b)(4) and the sterile corridor.j).
目前缺少針對(duì)操作人員移動(dòng)路線的程序要求。在檢查過程中，我們觀察到操作人員在 B 級(jí)灌裝間xx與無菌走廊之間隨意進(jìn)出。
Personnel movement between the Grade B sterile corridor and the Grade B filling room did not appear carefully controlled to prevent contamination.
B 級(jí)無菌走廊與 B 級(jí)灌裝間之間的人員流動(dòng)未得到嚴(yán)格管控，無法有效防止污染。
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