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嘉峪檢測網(wǎng) 2025-05-26 20:30
近日，F(xiàn)DA 發(fā)布了浙江華海藥業(yè)有限公司 Zhejiang Huahui Pharmaceutical Co., Ltd.的483表。
FDA本次檢查安排在春節(jié)假期前夕，2025年1月16-17日和20-24日（中間1月18-19是周末），持續(xù)時間一周半，檢查官是：Justin A. Boyd和Jeffrey P.Raimondi，檢查過程包含對設(shè)備清潔極為細(xì)致的檢查，煙霧試驗(yàn)（氣流流型）、100%目視檢查、偏差等。
包括提及：
煙霧試驗(yàn)過程中煙霧發(fā)生器朝下（與氣流方向相同）進(jìn)行的，而不是將煙霧發(fā)生器垂直于氣流；
清潔驗(yàn)證僅兩個取樣點(diǎn)，未包含最難清潔的區(qū)域。例如：設(shè)備底部、內(nèi)表面、墊圈、頂部區(qū)域或管道等難清潔區(qū)域
高效空氣過濾器（HEPA）下方張貼非無菌膠帶
翻譯如下：
OBSERVATION #1
觀察項(xiàng) 1
Equipment and utensils are not cleaned at appropriate intervals to prevent contamination that would alter the safety, identity, strength, quality or purity of the drug product.
設(shè)備和器具未按適當(dāng)間隔進(jìn)行清潔，以防止可能會改變藥品安全性、鑒定、劑量、質(zhì)量或純度的污染。
Cleaning of non - dedicated xx used to manufacture US market products was not effective. There are xx non - dedicated xx used for US market products. The following was observed on cleaned equipment:
非專用 xx 清潔效果不佳。在已清潔非專用設(shè)備上觀察到以下情況：
a. The non - dedicated GJC100 - 01 xx was not clean on January 16, 2025, immediately before it was intended to be used to manufacture batch xx of xx and xx Tablets USP xx (US market). The non - dedicated piece of equipment is used to manufacture xx different US market products.
a. 2025 年 1 月 16 日，在投入生產(chǎn)XX片劑之前，非專用設(shè)備 GJC100 - 01 xx 并不干凈。
Prior to batch xx the equipment had undergone “Type C” changeover cleaning on January 15, 2025, that should have removed all product from the previous batch. On the morning of January 16, 2025, a production operator had visually inspected the equipment for cleanliness and approved the cleaning without identifying any xx residues.
在 xx 批次之前，該設(shè)備于 2025 年 1 月 15 日進(jìn)行了 “類別C” 的清場，這本應(yīng)清除上一批次的所有產(chǎn)品。2025 年 1 月 16 日上午，一名生產(chǎn)操作員對設(shè)備的清潔狀況進(jìn)行了目視檢查，并在未發(fā)現(xiàn)任何 xx 殘留的情況下批準(zhǔn)了清潔。
When the equipment was inspected later in the morning, after initial xx for batch xx had already started, visible residues were observed in the following locations:
當(dāng)天上午晚些時候，在 xx 批次的初始 xx 已經(jīng)開始后，再次檢查設(shè)備時，在以下位置發(fā)現(xiàn)了明顯的殘留物：
i. xx and xx residues were observed in the xx duct and on the valve of the xx duct. Swab sampling detected the presence of xx and xx in this area.
i. 在 管道及管道閥門處發(fā)現(xiàn) xx 和 xx 殘留。棉簽取樣檢測到該區(qū)域存在 xx 和 xx。
xx was last manufactured December 21, 2024. Since that time, batches of xx Tablets, xx Tablets, xx Tablets, and xx and xx Tablets had been manufactured on this equipment.
xx（指被發(fā)現(xiàn)的殘留物）的上次生產(chǎn)是在 2024 年 12 月 21 日。從那時起，在該設(shè)備上生產(chǎn)過 xx 片劑、xx 片劑、xx 片劑以及 xx 和 xx 片劑。
This site was previously cited on an FDA 483 for failing to appropriately clean the xx products of the xx
該場所此前曾因未能對 xx 產(chǎn)品進(jìn)行適當(dāng)清潔而被列入 FDA 483 表格。
ii. xx and xx residues were observed on equipment surfaces on the underside of the xx at the bottom of the product container. No sampling of this area was conducted before the equipment was cleaned.
ii. 在產(chǎn)品容器底部 xx 下方的設(shè)備表面觀察到 xx 和 xx 殘留。設(shè)備清潔前未對該區(qū)域進(jìn)行取樣。
iii. xx was observed on surfaces in the xx. No sampling of this area was conducted before the equipment was cleaned.
iii. 在 xx 內(nèi)的表面觀察到 xx。設(shè)備清潔前未對該區(qū)域進(jìn)行取樣。
iv. xx were observed on the surface of the xx zone. Swab sampling of this area detected xx
iv. 在 xx 區(qū)域的表面觀察到 xx。該區(qū)域的棉簽取樣檢測到 xx
v. xx were observed in the chute that transfers product from xx to the xx. Swab sampling of this area detected xx
v. 在將產(chǎn)品從 xx 輸送至 xx 的斜槽中觀察到 xx。該區(qū)域的棉簽取樣檢測到 xx
vi. xx residues were observed on the rim of the product container. Swab sampling identified xx and xx
vi. 在產(chǎn)品容器邊緣觀察到 xx 殘留。棉簽取樣識別出 xx 和 xx
vii. xx residues were observed on the gasket between the product container and xx zone. Swab sampling identified xx and xx
vii. 在產(chǎn)品容器與 xx 區(qū)域之間的墊圈上觀察到 xx 殘留。棉簽取樣識別出 xx 和 xx
viii. xx was observed on external surfaces of the equipment. No sampling of this area was conducted before the equipment was cleaned.
viii. 在設(shè)備外表面觀察到 xx。設(shè)備清潔前未對該區(qū)域進(jìn)行取樣。
ix. During additional inspection of the equipment on January 20, 2025, the xx duct and valve were observed to have xx build - up on them.
ix. 在 2025 年 1 月 20 日對設(shè)備的額外檢查中，觀察到 xx 管道和閥門上有 xx 堆積。
b. On January 16, 2025, xx was observed on the xx valve on the xx of the cleaned xx GJC349 - 05. The investigation conducted by quality personnel was not going to include sampling of this visible xx or the area behind the xx valve on the xx duct. These areas were only swabbed after discussions during the inspection. When swab sampling of the xx residues was conducted and tested against the previous product, no peak was identified.
b. 2025 年 1 月 16 日，在已清潔的 xx GJC349 - 05 的 xx 上的 xx 閥門處觀察到 xx。質(zhì)量人員進(jìn)行的調(diào)查不包括對這一可見位置或 xx 管道上 xx 閥門后面的區(qū)域。這些區(qū)域僅在檢查期間討論后才進(jìn)行棉簽取樣。對 xx 殘留進(jìn)行棉簽取樣并與之前的產(chǎn)品進(jìn)行測試時，未檢測到峰值。
On January 20, 2025, a buildup of xx was observed on the xx duct and valve for this piece of equipment.
2025 年 1 月 20 日，在該設(shè)備的 xx 管道和閥門上觀察到 xx 堆積。
c. On January 20, 2025, xx residues were observed on the xx valve on the xx of xx GJC348 - 05. The investigation conducted by quality personnel was not going to include sampling of this area. These areas were only swabbed after discussions during the inspection. When sampling was performed, the APIs xx and xx were detected.
c. 2025 年 1 月 20 日，在 xx GJC348 - 05 的 xx 上的 xx 閥門處觀察到 xx 殘留。質(zhì)量人員進(jìn)行的調(diào)查原本不包括對該區(qū)域取樣。這些區(qū)域僅在檢查期間討論后才進(jìn)行棉簽取樣。取樣時，檢測到了活性藥物成分（APIs）xx 和 xx。
There was also stagnant liquid in the xx duct.
在 xx 管道中也有積液。
A buildup of xx was observed on the xx duct and valve.
在 xx 管道和閥門上觀察到 xx 堆積。
Equipment surfaces on the top of the xx also appeared to have xx residues.
xx 頂部的設(shè)備表面似乎也有 xx 殘留。
d. On January 20, 2025, xx was observed on the surfaces of the xx duct and valve of the xx GJC350 - 05.
d. 2025 年 1 月 20 日，在 xx GJC350 - 05 的 xx 管道和閥門表面觀察到 xx。
The xx duct and valve was not sampled as part of the quality investigation before it was cleaned.
在清潔前，質(zhì)量調(diào)查未對 xx 管道和閥門進(jìn)行取樣。
e. On January 20, 2025, xx was observed on the surfaces of the xx duct and valve on xx GJC101 - 01.
e. 2025 年 1 月 20 日，在 xx GJC101 - 01 的 xx 管道和閥門表面觀察到 xx。
During investigation sampling by quality personnel, xx was detected in the xx duct and valve.
質(zhì)量人員在調(diào)查取樣期間，在 xx 管道和閥門中檢測到 xx。
2. Cleaning of non - dedicated xx equipment used to manufacture US market products was not effective. There are xx non - dedicated xx used for US market products. On January 21, 2025, the following was observed on cleaned equipment:
2. 用于生產(chǎn)美國市場產(chǎn)品的非專用 xx 設(shè)備清潔效果不佳。有 xx 非專用 xx 用于美國市場產(chǎn)品。2025 年 1 月 21 日，在已清潔設(shè)備上觀察到以下情況：
a. There appeared to be residues where the xx connect to the product bowl on xx GJC104, GJC105, and GJC106.
a. 在 xx GJC104、GJC105 和 GJC106 上，xx 與產(chǎn)品料斗連接處似乎有殘留。
b. There appeared to be residues on the xx equipment and on the gasket of the door with the xx equipment on xx GJC105.
b. 在 xx GJC105 的 xx 設(shè)備上以及帶有 xx 設(shè)備的門的墊圈上似乎有殘留。
c. There were residues on equipment surfaces inside the xx equipment that surrounds the product drum on xx GJC104, GJC105, and GJC106.
c. 在 xx GJC104、GJC105 和 GJC106 上，圍繞產(chǎn)品轉(zhuǎn)鼓的 xx 設(shè)備內(nèi)部的設(shè)備表面有殘留。
d. There was buildup of unidentified material in the xx duct in xx GJC104, GJC105, GJC106, and GJC201.
d. 在 xx GJC104、GJC105、GJC106 和 GJC201 的 xx 管道中有不明物質(zhì)堆積。
e. It appeared that pieces of unidentified material from the xx duct had fallen onto the xx that attaches to the xx bowl on xx GJC104, GJC105, and GJC106.
e. 看起來，來自 xx 管道的不明物質(zhì)碎片落到了 xx GJC104、GJC105 和 GJC106 上連接到 xx 料斗的 xx 上。
3. Cleaning validation studies did not identify the hardest - to - clean areas of equipment. For example:
3. 清潔驗(yàn)證研究未確定設(shè)備最難清潔的區(qū)域。例如：
a. Cleaning validation for xx in Workshop xx Initial xx did not include sampling of difficult - to - clean areas like the bottom of the product xx, surfaces in the xx, gaskets, areas at the top of the xx, or xx ducts to evaluate cleaning effectiveness.
a. 某車間 xx 初始 xx 的清潔驗(yàn)證未對產(chǎn)品 xx 底部、xx 內(nèi)表面、墊圈、xx 頂部區(qū)域或 xx 管道等難清潔區(qū)域進(jìn)行取樣，以評估清潔效果。
b. Cleaning validation for the Workshop xx Unit xx was limited to two sampling points, including the product bowl and a xx. It did not consider other difficult - to - clean areas including the xx, the xx, the door of the equipment outside of the product bowl, or xx ducts.
b. 某車間 xx 單元 xx 的清潔驗(yàn)證僅限于兩個取樣點(diǎn)，即產(chǎn)品料斗和一個 xx。它未考慮其他難清潔區(qū)域，包括 xx、xx、產(chǎn)品料斗外設(shè)備的門，或 xx 管道。
OBSERVATION #2
觀察項(xiàng) 2
Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.
旨在防止聲稱無菌的藥品受到微生物污染的程序，未對滅菌工藝進(jìn)行充分驗(yàn)證。
1. Smoke studies regarding Workshop xx used for aseptically filling xx injection, USP xx ng xx ng/mL and xx ng/mL vials for the US Market:
關(guān)于用于無菌灌裝注射液的 xx 車間的煙霧試驗(yàn)：
a. Air turbulence was observed for the following interventions:
a. 在以下操作過程中觀察到了氣流紊亂：
i. Installation of xx for Stoppers
i. 安裝膠塞xx
ii. Installation of Stopper Bowl into Line
ii. 安裝膠塞料斗
b. The following dynamic interventions were not evaluated in the smoke studies:
b. 以下動態(tài)操作在煙霧研究中未進(jìn)行評估：
i. The xx of stopper bags from Grade B onto the Grade A filling line platform, which occurs routinely during filling operations and up to xx bags at a time.
i. 在灌裝操作期間，通常會將膠塞袋子從 B 級區(qū)域轉(zhuǎn)移到 A 級灌裝線平臺，一次最多轉(zhuǎn)移 xx 袋。
ii. The xx of stoppers into the xx with the remaining bags of previously xx stopper bags on the filling line platform. Stoppers are xx Smoke studies did not evaluate this entire intervention and how the airflow during stopper xx might be impacted by the remaining bags stored on the platform.
ii. 將膠塞裝入 xx，同時灌裝線平臺上還留有之前已 xx 的膠塞袋子。膠塞是 xx 煙霧研究未對這一整套操作以及在瓶塞 xx 過程中氣流可能因平臺上存放的剩余袋而受到的影響進(jìn)行評估。
c. Smoke studies for dynamic xx intervention of xx Disassemble and Installation was performed with the smoke generator pointing down, in the same direction as the airflow. It was not performed with the smoke generated pointing perpendicular to the airflow.
c. 關(guān)于 xx 拆卸和安裝的動態(tài) xx 操作的煙霧研究，是將煙霧發(fā)生器朝下（與氣流方向相同）進(jìn)行的，而不是將煙霧發(fā)生器垂直于氣流方向進(jìn)行的。
2. Smoke studies regarding Workshop xx used for aseptically filling xx Injection, USP xx ng vial for the US market:
2. 關(guān)于用于美國市場無菌灌裝美國藥典 xx ng 小瓶 xx 注射液的某車間的煙霧研究：
a. The dynamic xx loading of the xx vials into the xx was not evaluated as part of smoke studies.
a. 將 xx 小瓶動態(tài) xx 裝入 xx 的過程未作為煙霧研究的一部分進(jìn)行評估。
b. Smoke studies for dynamic xx interventions were performed with the smoke generator pointing down, in the same direction as the airflow. It was not performed with the smoke generated pointing perpendicular to the airflow. These include:
b. 動態(tài) xx 操作的煙霧研究是將煙霧發(fā)生器朝下（與氣流方向相同）進(jìn)行的，而不是將煙霧發(fā)生器垂直于氣流。這些操作包括：
i. Calibration of Scale prior to filling
i. 灌裝前秤的校準(zhǔn)
ii. Calibration of Scale after being filled
ii. 灌裝后秤的校準(zhǔn)
iii. Adjustment of xx
iii. xx 的調(diào)整
iv. Adjustment of xx
iv. xx 的調(diào)整
v. Removing Vials at xx
v. 在 xx 處移除小瓶
vi. Adjustment leading to xx
vi. 導(dǎo)致 xx 的調(diào)整
3. Smoke studies for Workshop xx and xx were performed using xx generated from xx. There has been no evaluation of whether this produces neutrally buoyant smoke.
3. 某車間 xx 和 xx 的煙霧研究使用了由 xx 產(chǎn)生的 xx。尚未評估這是否能產(chǎn)生中性浮力煙霧。
OBSERVATION #3
觀察項(xiàng) 3
There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.
沒有為確保藥品具有其聲稱或表示所具有的屬性、效力、質(zhì)量和純度而設(shè)計(jì)的生產(chǎn)和工藝控制書面程序。
1. The visual inspection qualification process for 100% manual visual inspection is deficient in the following ways:
1. 100% 人工目視檢查的目視檢查確認(rèn)過程存在以下缺陷：
a. The visual inspection kits for liquid vials do not contain glass, metal, elastomer material, and fiber of known size.
a. 液體小瓶目視檢查套件中不包含已知尺寸的玻璃、金屬、彈性體材料和纖維。
b. The visual inspection kits for liquid vials do not contain defect for precipitate (critical defect), group of particles (critical defect), smoke - like particle deposit (critical defect), protein floccule (critical defect), appearance defect with impact on container closure system (critical), and significant appearance xx (major defect), which are defect categories listed in the visual inspection record of each batch. There is no assurance operators can adequately identify these type of defects, where applicable, during manual visual inspection process.
b. 液體小瓶目視檢查套件中沒有沉淀（關(guān)鍵缺陷）、顆粒群（關(guān)鍵缺陷）、煙狀顆粒沉積（關(guān)鍵缺陷）、蛋白絮凝物（關(guān)鍵缺陷）、對容器密封系統(tǒng)有影響的外觀缺陷（關(guān)鍵缺陷）以及顯著外觀 xx（主要缺陷）等缺陷樣本，而這些是每批目視檢查記錄中列出的缺陷類別。無法保證操作人員在人工目視檢查過程中能夠充分識別這些類型的缺陷（如適用）。
c. The visual inspection kits for xx vials do not contain defect vials for xx (critical defect), xx (major defect), and xx (major defect), which are defect categories listed in the visual inspection record of each batch.
c. xx 小瓶的目視檢查套件中沒有 xx（關(guān)鍵缺陷）、xx（主要缺陷）和 xx（主要缺陷）等缺陷小瓶樣本，而這些是每批目視檢查記錄中列出的缺陷類別。
d. There is no complete defect library containing all defects for the liquid and xx vials.
d. 沒有包含液體和 xx 小瓶所有缺陷的完整缺陷庫。
e. Visual inspectors are required to be able to identify the defect vials during qualification and record the vial number in the corresponding defect row (such as critical, major, minor). The qualification records do not indicate what specific defect (such as glass, metal, etc.) was observed for each of these vials.
e. 目視檢查人員需在確認(rèn)過程中能夠識別缺陷小瓶，并在相應(yīng)的缺陷類別（如關(guān)鍵、主要、次要）欄中記錄小瓶編號。但確認(rèn)記錄未注明針對每個小瓶所觀察到的具體缺陷（如玻璃、金屬等）。
f. There is no answer key for the current set of liquid test kits used to qualify operators for 100% visual inspection. After the most recent visual inspection qualification, the vial numbers were changed, but there is no record identifying the vial which contains what defect after the change.
f. 目前用于 100% 目視檢查操作人員確認(rèn)的液體檢測套件沒有參考答案。在最近一次目視檢查確認(rèn)后，小瓶編號發(fā)生了變化，但沒有記錄標(biāo)明變更后每個小瓶所含的缺陷。
2. The xx used during visual inspection of sterile liquid drug products distributed to the US market in workshop xx is not qualified. The original qualification performed in 2018 required a two - stage qualification. The second stage of the qualification has never been performed, and to date, there is no active protocol or schedule to complete Stage 2.
2. 某車間用于美國市場無菌液體藥品目視檢查的 xx 未通過確認(rèn)。2018 年進(jìn)行初始確認(rèn)要求分兩階段進(jìn)行。但第二階段的確認(rèn)從未開展，至今也沒有有效的方案或計(jì)劃來完成第二階段。
Additionally, prior to use of this equipment for commercial batches, a pre - and post - rejection test, using standard vials, is required to be performed. These standard vials do not contain glass, metal, elastomer material, and fiber of known size.
此外，在將該設(shè)備用于商業(yè)批次生產(chǎn)前，需使用標(biāo)準(zhǔn)小瓶進(jìn)行拒收前和拒收后測試。這些標(biāo)準(zhǔn)小瓶中不包含已知尺寸的玻璃、金屬、彈性體材料和纖維。
3. Acceptable ranges have not been established for operating the tablet compression machines. Examples include, but are not limited to xx Tablets and xx Tablets for the US market:
3. 尚未確定壓片機(jī)操作的可接受范圍。以美國市場的 xx 片劑和 xx 片劑為例（但不限于這些）：
a. Studies have not been completed to establish the reject rates for reject compression of tablets. There are no limits set in batch records and there is no process for setting the reject limits described in procedures used by the compression operators. Additionally, the operators have the ability to change the values for reject limits for each batch and to make changes during the batch. There has been no review of the electronic data to see what values were used during US market batches and to evaluate whether these values would have appropriately rejected non - conforming tablets.
a. 尚未完成確定片劑不合格壓縮拒收率的研究。批次記錄中未設(shè)定拒收限，壓片操作人員使用的程序中也未描述設(shè)定拒收限的流程。此外，操作人員可針對每個批次更改拒收限數(shù)值，且在批次生產(chǎn)過程中也能進(jìn)行更改。尚未對電子數(shù)據(jù)進(jìn)行審查，以了解美國市場批次生產(chǎn)中使用的拒收限數(shù)值，也未評估這些數(shù)值是否能恰當(dāng)拒收不合格片劑。
b. Acceptable ranges for compression machine parameters that the operators can change have not been established. For example: feeder speed, fill depth, or target main compression force.
b. 尚未確定操作人員可更改的壓片機(jī)參數(shù)（如進(jìn)料速度、填充深度或目標(biāo)主壓壓力）的可接受范圍。
4. During process validation, sampling plans have not been established that would allow for evaluation of variation that could be caused by different parameters used to operate equipment or evaluate variability within a batch. For example:
在工藝驗(yàn)證過程中，尚未制定抽樣計(jì)劃，以評估因設(shè)備操作參數(shù)不同而可能導(dǎo)致的變化，或評估批次內(nèi)的變異性。例如：
a. Different compression speeds were used during process validation studies for xx Tablets and xx Tablets. There was no plan to establish acceptable ranges for commercial batches. Tablets manufactured at the different speeds were not separately sampled and tested to evaluate whether the different speeds led to variability within the batch.
a. 在 xx 片劑和 xx 片劑的工藝驗(yàn)證研究中使用了不同的壓片速度。沒有制定確定商業(yè)批次可接受范圍的計(jì)劃。以不同速度生產(chǎn)的片劑未分別進(jìn)行抽樣和測試，以評估不同速度是否會導(dǎo)致批次內(nèi)的變異性。
b. During xx Tablets process validation, xx sampling was used for xx during the compression, xx and finished product testing stages. xx content testing during xx Tablets process validation was based on xx sampling.
b. 在 xx 片劑的工藝驗(yàn)證過程中，在壓片、xx 以及成品測試階段，xx 抽樣用于 xx。在 xx 片劑工藝驗(yàn)證過程中的 xx 含量測試是基于 xx 抽樣。
OBSERVATION #4
觀察項(xiàng) 4
There is a failure to thoroughly review any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications whether or not the batch has been already distributed.
對于任何無法解釋的差異，或批次及其任何組件未能符合其任何規(guī)格要求的情況，無論該批次是否已分發(fā)，均未進(jìn)行徹底審查。
1. Deviation DF - 23012 was opened when foreign matter was observed in xx of batch xx of xx Tablets (US Market). The batch was rejected. The investigation failed to perform any identification of the foreign matter or take any pictures. During the investigation, foreign matter similar in appearance was observed in the xx duct of the xx GZ5029. The area was cleaned without any analytical evaluation of the observed residues and no pictures were taken.
當(dāng)在 xx 批次的美國市場 xx 片劑的 xx 中觀察到異物時，啟動了偏差 DF - 23012。該批次被拒收。調(diào)查未能對異物進(jìn)行任何鑒定，也未拍攝任何照片。在調(diào)查過程中，在 xx GZ5029 的 xx 管道中觀察到外觀類似的異物。該區(qū)域在未對觀察到的殘留物進(jìn)行任何分析評估的情況下被清潔，且未拍攝照片。
The investigation did not thoroughly assess whether contamination in this area could have impacted other batches made on this equipment. Additional batches made as part of the same campaign were not thoroughly inspected for the presence of foreign particles.
調(diào)查未徹底評估該區(qū)域的污染是否會影響在該設(shè)備上生產(chǎn)的其他批次。作為同一生產(chǎn)批次一部分的其他批次，未對異物顆粒的存在進(jìn)行徹底檢查。
The investigation was not expanded to inspect the xx ducts and document findings in other xx used for the US market products.
The cleaning procedures were not re - evaluated to consider cleaning of this area during changeover between products. The area is cleaned during maintenance xx but there is no requirement for the maintenance personnel to document if they observe residues during maintenance activities.
調(diào)查未擴(kuò)大范圍以檢查用于美國市場產(chǎn)品的其他 xx 管道并記錄結(jié)果。未重新評估清潔程序，以考慮在產(chǎn)品轉(zhuǎn)換期間對該區(qū)域的清潔。該區(qū)域在維護(hù) xx 期間進(jìn)行清潔，但未要求維護(hù)人員記錄在維護(hù)活動期間是否觀察到殘留物。
2. Complaint investigation CF - 23274 was opened when a customer obtained an OOS for dissolution on xx and xx of retain samples. The Tablet xx mg batch xx (EU market). The OOS was confirmed during the testing of retain samples. The investigation identified higher main compression force during tableting, which had no established limits, as well as increased disintegration times during storage. The cause of the higher compression force for the identification in the investigation as batch - to - batch variation, without further investigation of causes for the variation.
The investigation was not extended to US market tablet products, which similarly had no established ranges for the main compression force, to determine whether portions of batches were subject to variation leading to higher compression forces that could have produced non - conforming tablets.
當(dāng)客戶在保留樣品的 xx 和 xx 中獲得溶出度超標(biāo)（OOS）結(jié)果時，啟動了投訴調(diào)查 CF - 23274。涉及的是歐盟市場的 xx 毫克片劑批次 xx。在保留樣品測試中確認(rèn)了 OOS 結(jié)果。調(diào)查發(fā)現(xiàn)壓片過程中主壓壓力較高（該壓力沒有既定限度），以及儲存期間崩解時間增加。調(diào)查將較高壓縮力的原因確定為批次間變異，但未對變異原因作進(jìn)一步調(diào)查。
調(diào)查未擴(kuò)展到美國市場的片劑產(chǎn)品（這些產(chǎn)品同樣沒有確定主壓壓力的范圍），以確定批次的某些部分是否因變異而導(dǎo)致壓縮力過高，進(jìn)而產(chǎn)生不合格片劑。
3. Investigation OOT - FQC22020 was opened during stability testing of process validation batches of xx Tablets for the US market at the xx timepoint. The product is labeled with a xx expiration date and has a specification for unknown impurities of not more than xx %. Batch xx had a result of xx % and batch xx had a result of xx % for unknown impurities. The production investigation identified inter - batch variability as the reason for higher impurities in these batches, but failed to understand what was causing this variation or what caused the impurity to form. The investigation did not thoroughly evaluate whether a xx expiration date was appropriate for ongoing commercial manufacturing given this data and the lack of understanding of the cause of variability that generated this impurity.
在美國市場 xx 片劑工藝驗(yàn)證批次的穩(wěn)定性測試中，在 xx 時間點(diǎn)啟動了調(diào)查 OOT - FQC22020。該產(chǎn)品標(biāo)注的 xx 有效期，且對未知雜質(zhì)的規(guī)格要求為不超過 xx%。xx 批次的未知雜質(zhì)結(jié)果為 xx%，xx 批次為 xx%。生產(chǎn)調(diào)查將批次間變異性確定為這些批次中雜質(zhì)含量較高的原因，但未能弄清楚導(dǎo)致這種變異的原因或雜質(zhì)形成的原因。鑒于這些數(shù)據(jù)以及對產(chǎn)生該雜質(zhì)的變異性原因缺乏了解，調(diào)查未徹底評估 xx 有效期對于正在進(jìn)行的商業(yè)生產(chǎn)是否合適。
A different unknown peak was detected in some xx Tablets stability batches. For example, batches xx and xx each had a result of xx % at xx compared to a specification of not more that xx %. The peak was attributed to an excipient, but the specific excipient was not identified. No investigation was evaluated if this was a risk to not be in all stability tablets if it is coming from an excipient, which should be present in all batches.
在一些 xx 片劑穩(wěn)定性批次中檢測到不同的未知峰。例如，xx 批次和 xx 批次在 xx 時的結(jié)果均為 xx%，而規(guī)格要求不超過 xx%。該峰被歸因于一種輔料，但未確定具體是哪種輔料。未評估如果該峰來自一種應(yīng)存在于所有批次中的輔料，是否會對所有穩(wěn)定性片劑構(gòu)成風(fēng)險(xiǎn)。
4. Investigation OOS - FQC23008 was opened for a batch uniformity OOS result for batch xx of xx Tablets (US market). The batch was rejected. The investigation concluded the operators did not properly reject tablets at the end of the batch, resulting in lower assay results for tablets at the end of the batch, which caused the failure. No confirmatory testing of tablets from the end of the batch was conducted to support this conclusion. The investigation concluded the incident was isolated to this batch.
針對美國市場 xx 片劑 xx 批次的批次均勻度 OOS 結(jié)果，啟動了調(diào)查 OOS - FQC23008。該批次被拒收。調(diào)查得出結(jié)論，操作人員未正確在批次結(jié)束時剔除片劑，導(dǎo)致批次末尾片劑的檢測結(jié)果偏低，從而導(dǎo)致不合格。未對批次末尾的片劑進(jìn)行驗(yàn)證性測試以支持這一結(jié)論。調(diào)查得出結(jié)論，該事件僅局限于該批次。
Another batch in the campaign xx had a content uniformity stage one AV of xx and stage two of xx compared to an AV limit not more than xx. This was higher than historical data. The investigation included additional xx testing for this batch, but no testing specific to the end of the batch to evaluate whether a similar incident had occurred.
該生產(chǎn)活動中的另一個 xx 批次，其含量均勻度第一階段的 AV 值為 xx，第二階段為 xx，而 AV 限度要求不超過 xx。這高于歷史數(shù)據(jù)。調(diào)查對該批次進(jìn)行了額外的 xx 測試，但未針對批次末尾進(jìn)行特定測試，以評估是否發(fā)生了類似事件。
OBSERVATION #5
觀察項(xiàng) 5
Aseptic processing areas are deficient regarding systems for maintaining any equipment used to control the aseptic conditions.
無菌加工區(qū)域在維護(hù)用于控制無菌條件的設(shè)備系統(tǒng)方面存在缺陷。
On 16 - Jan - 2025, a 2 x 126 cm piece of non - sterile tape was observed between xx sharing xx. These sit below the HEPA filters and above where empty vials enter the line from the xx before being aseptically filled within Workshop xx. The tape was placed between these xx to seal an approximate 3mm gap, which was observed sometime after the HEPA filters had been replaced around April 2024. This aseptic filling line is used to fill xx Injection xx mg for the US Market.
2025 年 1 月 16 日，在共享 xx 的 xx 之間觀察到一塊 2×126 厘米的非無菌膠帶。這些位于高效空氣過濾器（HEPA）下方，以及在無菌灌裝車間 xx 內(nèi)空小瓶從 xx 進(jìn)入生產(chǎn)線的上方。該膠帶被放置在這些 xx 之間，以密封一個約 3 毫米的縫隙，該縫隙是在 2024 年 4 月左右更換 HEPA 過濾器后的某個時間被觀察到的。這條無菌灌裝線用于灌裝美國市場的 xx 毫克 xx 注射液。
There is no record documenting when the gap was observed, who it was observed by, and if the gap was reported to the appropriate department including the Quality Unit. No investigation and subsequent CAPA plan into the cause of the gap has been made.
沒有記錄表明何時發(fā)現(xiàn)該縫隙、由誰發(fā)現(xiàn)，以及該縫隙是否已報(bào)告給包括質(zhì)量部門在內(nèi)的相關(guān)部門。未對縫隙產(chǎn)生的原因進(jìn)行調(diào)查并制定后續(xù)的糾正和預(yù)防措施（CAPA）計(jì)劃。
There is no record documenting the approval and use of the non - sterile tape to seal the gap within the Grade A filling line, and there is no workorder or documentation detailing the installation, and subsequent replacement (if performed) of the tape.
沒有記錄證明對使用非無菌膠帶密封 A 級灌裝線內(nèi)縫隙的批準(zhǔn)情況，也沒有工作訂單或文件詳細(xì)說明膠帶的安裝及后續(xù)更換情況（如有更換）。
An assessment was not performed to evaluate how the gap between the HEPA filter xx in the aseptic filling line and the use of the non - sterile tape within the area might impact airflow, cleaning, environmental monitoring, and product quality.
未對無菌灌裝線中 HEPA 過濾器 xx 之間的縫隙以及該區(qū)域內(nèi)非無菌膠帶的使用可能對氣流、清潔、環(huán)境監(jiān)測和產(chǎn)品質(zhì)量產(chǎn)生的影響進(jìn)行評估。
OBSERVATION #6
觀察項(xiàng) 6
Laboratory controls do not include the establishment of scientifically sound and appropriate test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity.
實(shí)驗(yàn)室控制未包括建立科學(xué)合理且適當(dāng)?shù)臏y試程序，以確保藥品符合適當(dāng)?shù)膶傩?、效力、質(zhì)量和純度標(biāo)準(zhǔn)。
Analytical method validation studies have not included forced degradation studies for methods used for stability testing. For example, the US market products: xx Tablets, xx Tablets, xx Tablets, and xx Tablets.
分析方法驗(yàn)證研究未包括對用于穩(wěn)定性測試的方法進(jìn)行強(qiáng)制降解研究。例如美國市場的產(chǎn)品：xx 片劑、xx 片劑、xx 片劑和 xx 片劑。
OBSERVATION #7
觀察項(xiàng) 7
The quality control unit lacks authority to review production records to assure that no errors have occurred.
質(zhì)量控制部門缺乏審查生產(chǎn)記錄以確保未出現(xiàn)錯誤的權(quán)限。
Procedures for audit trail reviews for production equipment have not been established:
尚未建立生產(chǎn)設(shè)備審計(jì)追蹤審查程序：
a. Production operators can make changes to compression settings. Quality personnel do not review audit trails that document parameters and changes.
a. 生產(chǎn)操作員可以更改壓片設(shè)置。質(zhì)量人員不審查記錄參數(shù)和更改情況的審計(jì)追蹤。
b. Production personnel can make changes to recipes for production and xx in the Workshop xx. Quality personnel do not review audit trails that document this information.
b. 生產(chǎn)人員可以更改生產(chǎn)配方以及車間 xx 內(nèi)的 xx。質(zhì)量人員不審查記錄這些信息的審計(jì)追蹤。
xx GJC100 - 01 and GJC101 - 01 do not have an audit trail, do not save data, and requires personnel to manually input operating parameters for production and xx. There is no quality unit verification of the manually entered information.
xx GJC100 - 01 和 GJC101 - 01 沒有審計(jì)追蹤功能，不保存數(shù)據(jù)，且需要人員手動輸入生產(chǎn)和 xx 的操作參數(shù)。質(zhì)量部門未對人工輸入的信息進(jìn)行核實(shí)。
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