2018年FDA 483表缺陷之六大系统分类

2018 年 FDA 483 表中缺陷项
（按六大系统分类）
目录
一．生产系统..................................................................................................................................2
二．质量系统...............................................................................................................................36
三．实验室控制系统.................................................................................................................109
四．设施和设备系统.................................................................................................................162
五．包装和贴签.........................................................................................................................185
六．物料系统.............................................................................................................................187
七．其它......................................................................................................................................188
一．生产系统
1. 印度 Alkem Laboratories 20180411

OBSERVATION 13 缺陷 13
Employees engagedin the manufacture and processing of a drug product lack the
training and experience required to perform their assigned functions.
从事药品生产和加工的员工缺乏履行其指定职责所需的培训和经验。
Specifically, your firm uses an electronic training management system, Nichelon5,
to document the training of your employees, which was accessed on 27 March
2018. Your system documents an employee that was observed using an
uncontrolled, non-validated spreadsheet to calculate %RSD, did not attend
Training on Good Documentation Practice (GDP) and Good Laboratory Practices
(GLP) conducted by your firm on 17 January 2018. According to your firm’s
written procedure, CQA\0031, “Training Management System”, cGMP refresher
training is to be completed (b)(4); missed trainings are to be completed within (b)
(4).
具体来说，你公司使用了电子培训管理系统，Nichelon5，来记录你们员工的培训，
2018-03-27 进入了该系统。你们的系统记录了一位员工被发现正使用未受控未验证的表
格来计算%RSD，缺席你公司 2018-01-17 的 GDP 培训和 GLP 培训。依据你公司的书面程
序 CQA\0031“培训管理系统”，CGMP 更新培训要 XX 完成，缺席者要在 XX 内完成。
2. 印度 Sun Pharmaceutical 20180306

Written procedures for cleaning and maintenance fail to include description in
sufficient detail of the methods of disassembling and reassembling equipment as
necessary to assure proper cleaning and maintenance.
书面清洁和维护程序未包括对于设备必要时进行拆卸和重新组装以确保适当清洗维护的足
够详细描述。
Specifically, your equipment is not installed and maintained according to a
written procedure to reduce risk to product contact surfaces or process materials.
具体来说，你们的设备未依书面程序安装和维护以减少产品接触表面或工艺物料的风险。
D. On 12 Feburary 2018, I observed bulk product (b)(4) tanks located in
the material prep area labeled as “Cleaned”. However, I observed tank
#SH159 having a (b)(4)/(b)(4) residue on the (b)(4) gasket. This tank is dedicated
to injectable (b)(4) production. I also observed tank #SH412 to have a torn and
degraded (b)(4) style gasket installed at the (b)(4). This tank was last used for bulk
(b)(4) Injection. The cleaning procedure #PAR-215/05 does not speak directly to
cleaning or replacement of the (b)(4) gasket.
2018-02—12，我查看了位于物料准备区域标示为“已清洁”的散装产品 XX 罐。我发现
罐# SH159 的 XX 垫圈上有 XX/XX 残留。该罐是注射剂 XX 生产专用设备。我还发现罐#
SH412 上 XX 处安装的 XX 型垫圈磨损降解。此罐上次用于散装 XX 注射剂。清洁程序#
PAR-215/05 未直接讲要清洁或更换 XX 垫圈。
E. On 14 February 2018, I observed degraded and discolored (b)(4)
gaskets on (b)(4) storage tank that supplies (b)(4) to the production area in
Block (b)(4). I also observed degraded and discolored gaskets in bulk (b)(4)
drug formulation equipment (product contact surface). There is no written
procedure with respectto this equipment that specifies service or replacement of
gaskets (ENG-020/11).
2018-02-14，我发现给 XX 车间生产区域提供 XX 的 XX 贮罐上的 XX 垫圈已降解变色。我
还发现散装 XX 制剂设备（产品接触表面）上垫圈已降解变色。
Written procedures are lacking which describein sufficient detail the sampling,
testing, approval and rejection of drug product containers and closures.
书面程序缺乏对取样、检测、批准和拒收药品容器密闭器的详细描述。
Specifically, the firm’s written procedure “PAR-139/10,Cleaning and Operation
of Vial/Ampoule (b)(4) Machines, Effective Date:11/11/2017” allows the
performance of 2 sequential failures without initiation of a deviation
investigation. The procedure also states, repeat rejection from the (b)(4)
operation as false rejection FR1, FR2 and FR3.
具体来说，公司的书面程序 PAR-139/10“XX 西林瓶/安瓿设备清洁和操作”生效日期
2017-11-11，允许 2 次连续性能失败而不启动偏差调查。该程序还说，重复拒收 XX 操作
作为误拒 FR1、FR2 和 FR3。
3. 印度 Alembic Pharmaceuticals 20180410

There are no written procedure forproduction and process control designed to
assure that the drug products have the identity, strength, quality, and purity they
purport or are represented to possess.
无书面的生产和工艺控制程序用以确保药品具备其理应具备的鉴别、剂量、质量和纯度。
Specifically, the (b)(4) Hold Time Studies that your firm has conducted for drug
products marketed in the US aredeficient. The batch sizes used for the
establishment of (b)(4) Hold Times donot represent the commercial batch size of
the drug products. To date, your firm has conducted (b)(4) Hold Time Studies
utilizing this approach for all (b)(4) representing approximately (b)(4) drug
products intended for the US market as evidenced by the following examples:
具体来说，你公司实施的美国市场 XX 药品 XX 存放时长研究有缺陷。用于建立 XX 存放时
间的批量并不能代表该药品的商业批量。截至今日，你公司已实施了 XX 存放时长研究，
将此方法用于代表近 XX 个美国药品的所有 XX。证据如下：
此处表格内容全被遮盖，所列表项目有药名、批量、工艺、用于 XX 存放时长研究的数量、所
建立的存放时间。
Since March 2016, approximately 113 investigations have been initiated for either
(b)(4) or Assay failure at the (b)(4)stage for products marketed in the US.
自 2016 年 3 月以来，美国销售的产品已因 XX 步骤 XX 或含量不合格启动约 113 例调查。
4. 英国 Dr. Reddy’s 20170926
Cleaning procedures or clean status is not established.
未建立清洁程序或清洁状态。
Specifically, 具体来说
 During the review of the Quality Risk Management Plan for Area (b)(4)
Equipment 161/022/MW/17, dated 08 Aug 2017. The cleaning procedures are not
validated for equipment used in production of (b)(4)API. Such as the
disassembling of (b)(4) ID # (b)(4)0015 prior to cleaning.
 在对 2017-08-08 日的 XX 区的设备 161/022/MW/17 质量风险管理计划审核过程
中发现用于 XX 原料药生产的设备的清洁程序未经验证。例如，设备 XX ID # (b)(4)0015
清洁之前的拆卸操作。
 During the walk through of the warehouse on12 Sept 2017, I observed in
the (b)(4) equipment storage area with several accessories/potable
machine/dismantled machine parts used in manufacturing of (b)(4)API that were
not identified as clean or dirty. Examples of the equipment accessories include
the following, but not limited to the glass (b)(4) bottles,Conical flask, transfer
hoses, and (b)(4). The last use of the equipment was documented in batch record
(b)(4) on 15 Nov 2015. Additionally there are no cleaning hold times established
in the procedures.
 2017-09-12 在仓库里发现 XX 设备存贮区有几个用于 XX 原料药生产的辅助/可移
动设备/拆卸后的机器部件未标识为清洁或待清洁。此设备辅助件的例子包括但不仅限于玻
璃 XX 瓶、锥形瓶、软管和 XX。该设备的最后使用日期在批记录 XX 中记载为 2015-11-15。
另外，在程序里也未设定清洁后保持时长。
5. 马来西亚 Biocon Sdn Bhd 20180312

Procedures designed to prevent microbiological contamination of drug products
purporting to be sterile are not established or followed.
未建立和遵守设计用以防止无菌产品免受微生物污染的程序。
Specifically, your process simulation studies (media fill) are inadequate.
具体来说，你们的工艺模拟研究（培养基灌装）是不充分的。
A. During my review of the media fill batch records (MFBR) for (b)(4) drug
products (i.e.(b)(4)), I found that (b)(4) stoppered vials showing (b)(4) seal
defect were rejected and not incubated.
在我对 XX 药品（即 XX）培养基灌装批记录（MFBR）的审核中，我发现 XX 加塞的瓶显
示 XX 密封缺陷被拒，没有进行培养。
For example,例如
 (b)(4) MRBR (b)(4), April 2016; 846 (b)(4) seal rejects
 2016 年 4 月，846 瓶因密封性被拒
 (b)(4) MRBR (b)(4), May 2016; 2,007 (b)(4) seal rejects
 2016 年 5 月，2007 瓶因密封性被拒
 (b)(4)MRBR (b)(4), May 2016; 1,310 (b)(4) seal rejects
 2016 年 5 月，1310 瓶因密封性被拒
 (b)(4)MRBR (b)(4), January 2016; 504 (b)(4) seal rejects
 2016 年 1 月，504 瓶因密封性被拒
 (b)(4) MRBR (b)(4), January 2016; 139(b)(4) seal rejects
 2016 年 1 月，139 瓶因密封性被拒
According to control procedure BM/QA/SOP019 “Aseptic Process Simulations”
(Media Fills) Section 6.1.5 states Units with integrity defects (example:
cracked units,broken units, container which are not sealed, vials without (b)
(4) stoppers, etc.) shall not be considered as part of incubation and shall be
reconciled and rejected accordingly. Therefore, your media fill practices and
procedures are insufficient to justify excluding units in such circumstances. Even
more, when the referenced drug products are multi dose products.
依据控制程序 BM/QA/SOP019“无菌工艺模拟”（培养基灌装），第 6.1.5 部分说“有
完整性缺陷的单位（例如，裂瓶、破瓶、容器未密封、无 XX 塞的瓶等）均不应作为培养的
一部分，应相应地进行数量衡算和拒收”。因此，你们的培养基灌装作法和程序是有缺陷
的，它未论证为何在此情形下要排除这些单位。当所指药品为多剂量药品时数量则更多。
B. There is no assurance that your process simulation studies (media fills)
performed in the (b)(4) Filling Machines (03-02(b)(4)) are truly representative of
the condition observed and/or that might occur during routine aseptic filling
operations of (b)(4). This is evidenced in that, although corrective and inherent
operator’s interventions are simulated during media fills, the frequency and
the duration at which these interventions are simulated are not established
based on a thorough evaluation of the historical and/or retrospective data.
你们在 XX 灌装机（03-02XX）上进行的工艺模拟研究（培养基灌装）无法确保真实代表
日常 XX 无菌灌装操作中可能发生和/或观察到的条件。证据如下，尽管在培养基灌装模拟
了矫正的原有操作员干预情况，但这些所模拟的干预行为的频次和时长并非基于对历史性
和/或回顾性数据的全面评估而建立。
a) Your Quality Unit established the acceptance criteria for integrity, filling
volume and seal integrity of the (b)(4) based only on the evaluation of the GOOD
units post 100% visual inspection. However, the approved re-qualification Report
BM/RQ/P/050-02, dated 02/04/2018, does not include an evaluation of the
rejected (b)(4) and the classification of the different defects found during the
initial 100% visual inspection. Moreover, there is no documented evidence that
demonstrate the initial visual inspection was performed. Therefore, there is no
assurance the results obtained during the re-qualification of the (b)(4) Filling
Machine are accurate.
你们质量部门仅是基于对好的单位 100%目视检查评估建立了 XX 的完整性、灌装体积和密
封完整性可接受标准。但是，2018-02-04 所批准的重新确认报告 BM/RQ/P/050-02 并不
包括对拒收 XX 的评估，以及对初始 100%目视检查中发现的不同缺陷的分类。另外，也没
有书面证据证明执行了初始目视检查。因此无法确保在 XX 灌装机再验证中所获得的结果
是准确的。
b) As part of the requalification activities of the (b)(4) Filling Machine(03-02-
(b)(4) for (b)(4)ml, vial format), your Quality Unit requires the visual examination
of (b)(4) vials for detecting the presence of integrity defects and contaminants in
vials filled from (b)(4)% to (b)(4)% speed range. However, the approved
requalification Report BM/PDP/RQ/P/041-01, Dated 01/25/2017, does not
describe the sampling plan that was followed and how was established the
number of samples collected in order to ensure that representatives sample were
taken for the visual examination.
作为 XX 灌装机（03-02-XX，XX 毫升西林瓶）再确认活动的一部分，你们质量部门要求
对 XX 瓶进行目视检查，以发现 XX%至 XX%速度范围内所灌装瓶的完整性缺陷和污染物。
但是，2017-01-25 批准的再确认报告 BM/PDP/RQ/P/041-01 并未描述所遵循的取样计
划，也未描述为确保目视检查所取样品具有代表性是如何订立所取样品的数量。
6. 印度 Dr.Reddy’s 20180321
There is no assurance that the equipment used in the production of (b)(4)and (b)
(4) API are always maintained and/or kept in/under proper conditions for
manufacturing operations and to prevent the contamination of the products
handled and/or processed in the equipment. The following conditions were
observed on 2018-03-05, during the walkthrough the production areas in (b)(4)-
Block (used to produce (b)(4) and (b)(4) for the US market:
未能确保 XX 和 XX 原料药生产所用设备总是维持在和/或保持在适当的生产操作条件下，
防止设备中所处理和/或加工产品发生污染。2018-03-05 在检查 XX 车间生产现场（用于
生产美国市场的 XX 和 XX）时发现以下情况：
A. A piece of (b)(4) material was observed inside (b)(4) #(b)(4)-12 used for (b)(4)
production and the equipment was issued a “cleaned” status and visually
inspected.
在 XX 生产所用 XX 设备内发现一片 XX 物料，该设备状态为“已清洁”并经过了目视检查。
B. A piece of fabric thread was observed inside (b)(4) #(b)(4)-14 used for (b)(4)
production. In addition, the (b)(4) was observed with presence of holes and was
placed in use on 2018-01-10, cleaned, and visually inspected on 2018-02-17. The
area around the gasket ofthe cover was observed with (b)(4) stain color.
XX 生产所用 XX 设备内发现一段纤维绳。另外，XX 设备于 2018-01-10 使用，2018-02-
17 清洁并经目视检查，但发现 XX 上面有洞。盖子垫圈周围发现有 XX 污渍颜色。
C. Presence of product wasobserved inside the following production equipment
although the equipment was cleaned and visually inspected after cleaning:
在以下生产设备内看到有产品残留，虽然这些设备都是清洁过并且在清洁后经过目视检查：
a. (b)(4) #(b)(4)-20 and (b)(4) #(b)(4)-09/02 located in Cleanroom (b)(4)-Block
Building #(b)(4) used for (b)(4) finished API production. XX 车间洁净区内 XX
原料药成品生产所用 XX 设备
b. (b)(4) #(b)(4)-06/01 used for (b)(4) production. 用于 XX 生产的 XX 设备
c. (b)(4) ID #(b)(4)-03 that is used for (b)(4) production 用于 XX 生产的 XX 设备
d. (b)(4) #(b)(4)-01 used for (b)(4) production although considered cleaned
and verified. 用于 XX 生产的 XX 设备，虽然认为是清洁过并确认过
e. On the (b)(4) inside (b)(4) #(b)(4)-17/01used for (b)(4) production. 用于 XX
生产的 XX 设备内的 XX 上
f. On the shaft inside (b)(4) #(b)(4)-14/02 used for (b)(4) production. 用于 XX
生产的 XX 设备内的轴上
7. 印度 Cipla Limited 20180420

Written procedures for production and process controls are not designed to assure that
the drug products have theidentity, strength, quality, and purity they purport or are
represented to possess.
生产和工艺控制书面程序设计无法确保药品具备其应有的鉴别、剂量、质量和纯度。
Specifically, there are no established reject limits, either by individual failure modes or
cumulative totals, per (b)(4)or batch, for media fill process simulations. For example, the
following table shows the number of rejected units of (b)(4) from various media fill
batches processed on (b)(4) ((b)(4)) Line (b)(4) coincidental with the simulation of
specific process interventions.
具体来说，对于培养基灌装工艺模拟按批次或按 XX，既未建立单个失败模式的拒收限度，
亦未建立累积总数拒收限度。例如，下表显示出 XX 产线上不同培养基灌装批中 XX 被拒单
位的数量以及巧合的特定工艺干预模拟。
Medi (b)(4) Intervention 干预 Approx., # of # of “other” (b)(4) reject
a Fill Units (b)(4)/Pinhole rate
培养 Potentially rejects XX 拒收率
基灌 Affected 其它 XX/针孔
装可能受影响的单拒收数量
位数量约
Batch Lot (b) Adjustment of Batch (b)(4) (b)(4) ~131.9%
(b)(4) (4) (b)(4)
XX 批调整
Batch Lot (b) Media held for Batch (b)(4) (b)(4) ~32.8%
(b)(4) (4) (b)(4) prior to filling
批 XX 在灌装之前培养
基存放
Lot Shut off of filling room (b)(4) (b)(4) ~46.6%
(b)(4) AHU for Batch (b)(4)
批号 XX 灌装间 AHU
关机
Lot (b)(4) re-(b)(4) of (b) (b)(4) (b)(4) ~87.3%
(b)(4) (4) filling line
XX 灌装线的重新 XX
Lot (b)(4) re-(b)(4) of (b) (b)(4) (b)(4) 50%
(b)(4) (4) filling line
XX 灌装线的重新 XX
Batch Lot (b) Power failure (b)(4) (b)(4) ~75.3%
(b)(4) (4) simulated for NLT (b)
(4)
NLT XX 模拟粉末失败
Batch Lot (b) Changing of (b)(4) (b)(4) (b)(4) ~101.8%
(b)(4) (4) XX 变更
Batch Lot (b) No worst-case/ (b)(4) (b)(4) ~42.0%
(b)(4) (4) unplanned
interventions
没有最差情形/计划外
干预
Lot Filling area (b)(4) (b)(4) (b)(4) ~104.5%
(b)(4) opened NLT
灌装区 XX 开放 NLT
Lot Alignment of (b)(4) (b)(4) (b)(4) ~107.0%
(b)(4) 与 XX 一致
Lot Changing of (b)(4) (b)(4) (b)(4) ~344.4%
(b)(4) XX 变更
Batch Lot (b) (b)(4) alignment (b)(4) (b)(4) ~26.9%
(b)(4) (4) 与 XX 一致
Lot Right side (b)(4) lock (b)(4) (b)(4) ~48.8%
(b)(4) non-functional
右侧 XX 锁定不动作
Lot (b)(4) adjustment (b) (b)(4) (b)(4) ~116.4%
(b)(4) (4) re-(b)(4)
XX 调整 XX 重新 XX
Media fill units that are deemed to have quality-related failures such as “other”, (b)(4),
and pinhole rejects are not incubated. Thus, the lack of quality defect reject limits for
media fill studies does not provide adequate study acceptance criteria to demonstrate
aseptic process robustness.
被认为有质量相关失败，例如“其它”、XX 和针孔拒收的培养基灌装单位未放置稳定性。因
此，培养基灌装研究缺乏质量缺陷拒收限度导致无法提供足够的研究可接受标准以证明无
菌工艺稳定性。
8. 印度 Suven Life Sciences Limited 20180424

Equipment and utensils are not cleaned and maintained to prevent
contamination that would alter the safety, identity,strength, quality or purity of
the Intermediates and APIs manufactured.
设备和工器具未清洁并保存以防止对所生产的中间体和 API 形成可能改变安全性、鉴别、剂
量、质量或纯度的污染。
Specifically, on 05 February 2018 and 08 February 2018, during the inspection of
your (b)(4) which are used in the manufacturing process for varied APIs in
Production Block-(b)(4) Area. Your firm failed to adequately clean and visually
inspect the following (b)(4).
具体来说，2018 年 2 月 5 日和 2018 年 2 月 8 日，在对生产车间 XX 区域你们用于不同
API 生产工艺的 XX 检查期间，你们公司未能充分清洁和目视检查 XX：
A. (b)(4)-3109 is used in the production of (b)(4) API/Intermediate; I observed
what appears to be discoloration resembling (b)(4) inside the (b)(4)-3109 in
areasthat come into direct contact with drug product. The status of this non-
dedicated (b)(4) was identified as cleaned.
(b)(4)-3109 用于 XX 原料药/中间体的生产：我发现在 XX-3109 内直接接触药品的区域有
类似变色的地方。该非专用 XX 的状态标识为已清洁。
B. (b)(4)-3139:I observed the gasket used to protect the (b)(4) and the (b)(4) of
(b)(4)-3139 was wrapped in Teflon tape and starting to unravel. I observed what
appeared tobe missing pieces of the Teflon tape at the bottom of the (b)(4). In
addition, Iobserved what appeared to be a white, powdery residue along the
inside of the(b)(4). The status of this equipment was identified as cleaned and a
visual inspection was documented in the Equipment Use Logbook.
(b)(4)-3139：我发现用于保护 XX-3139 的 XX 和 XX 的垫圈用聚四氟乙烯带包裹，已经开
始散开。我发现在 XX 底部有聚四氟乙烯带掉落的碎片。另外，我发现在 XX 内部有白色粉
状残留。该设备的状态被标为已清洁，设备使用日志上有记录目视检查。
C. (b)(4)-3137: I observed what appears to be (b)(4) residue and black residue
alongside the sides of this (b)(4). In addition, I observed the (b)(4) bolts located
on the bottom of the (b)(4) that comes in direct contact with drug products to
have a (b)(4) discoloration. I observed a hole at the bottom of the (b)(4)
indicatingthis (b)(4) is damaged. The Equipment Use Logbook documents the
equipment qualification were completed on 29 December 2017 and the status of
this non-dedicated equipment was identified as cleaned.
(b)(4)-3137：我发现在此 XX 的边沿有 XX 残留和黑色残留。另外，我发现位于 XX 底部的
XX 螺栓与药品有直接接触，已有 XX 变色。我发现在 XX 底部有一个孔洞，显示 XX 已受损
该设备使用日志记录了该设备确认是在 2017 年 12 月 29 日完成的，此非专用设备的状态
标识为已清洁。
Manufacturing Batch Records are deficient.
生产批记录有缺陷。
A. On 13 February 2018, your firm failed to document in-process checks
during the manufacturing of the durg product, (b)(4) Tablets, Batch #(b)(4) on
Form,F/CQO-F/320, as outlined in Step (b)(4) of the Batch Manufacturing Record.
However,this step was verified by your firm’s Quality Assurance.
2018 年 2 月 13 日，你公司未按批生产记录第 XX 中所列的在表格 F/CQO-F/320 上记录
XX 片剂批号 XX 药品生产的中控检查。但是，该步骤经过了你公司 QA 的核查。
B. Recorded weights are not verified by a second verifier.
所记录的重量并未由第二人核查。
Employees engaged in the manufacture,processing, packing, and holding of a
drug product lack the training required to perform their assigned functions.
生产、加工、包装和保存药品的员工缺乏执行其指定职责所需的培训。
***THIS IS A REPEAT OBSERVATION***此为重复缺陷
Specifically, your firm failed to conductcGMP training for (b)(4) of (b)(4) selected
employees performing Quality related functions, such as, production, quality
control, and quality assurancein 2016.
具体来说，你公司在 2016 年未向 XX 所选履行质量相关职责的员工如生产、QC 和 QA 执
行 CGMP 培训。
9. 印度 Mylan Laboratories Limited, (Nashik FDF) 20180626

Your electronic record for your production and process control system do not
comply with electronic records requirements.
你们生产和工艺控制系统的电子记录不符合电子记录要求。
Manufacturing data from the PLC related tothe manufacture of (b)(4) for (b)(4) is
absent.
与 XX 的 XX 生产有关的 PLC 中生产数据缺失。
Your firm’s process validation of (b)(4) for (b)(4) utilized batches (b)(4), (b)(4)
and (b)(4) on the compression machine ESD 416, which is operated by an (b)(4)
Programmable Logic Controller (PLC). This PLC has a record for batch (b)(4), but
not for batches (b)(4) and (b)(4). Based on the lack of a record in the PLC, there is
no evidence that batch (b)(4) and (b)(4) were actually produced on the
compression machine ESD 416, as stated in the process validation report for (b)
(4), Document No. PV/TAB/25/02/15.
你公司的 XX 工艺验证使用了压延机 ESD416 的批号 XX、XX 和 XX，该设备采用了可编程
逻辑控制器（PLC）XX 运行。该 PLC 有 XX 批次的记录，但却没有 XX 和 XX 批次的记录。
由于在 PLC 中缺少记录，没有证据证明 XX 和 XX 批次实际是在压延机 ESD416 上生产的，
而在 XX 工艺验证报告（文件号 PV/TAB/25/02/15）是如此声称的。
Note: data pertaining to a number of batches preceding batch (b)(4) was
available, demonstrating that data retention was not the reason for the absence
of data pertaining to batches (b)(4) and (b)(4).
注：XX 批次之前的数批数据都有，证明数据保存并不是 XX 和 XX 批次数据留存缺失的原
因。
Equipment and utensils are not cleaned and maintained at appropriate intervals
to prevent contamination that would alterthe safety, identity, strength, quality or
purity of the drug product.
设备和工器具未按恰当的时间间隔清洁和维护以防止污染改变药品的安全性、鉴别、剂量、
质量或纯度。
All clean equipment observed displayed deficient cleaning.
看到的所有已清洁设备显示清洁有缺陷。
(a) On September 11, 2016, I observed a non-dedicated compression machine
(ID #ESD 743) with a “CLEANED” status tag. This equipment had white residue
where the (b)(4) the compression machine (a product contact surface). This
equipment is used in the manufacture of multiple drug products, including (b)(4)
tablet for the US market.
2016 年 9 月 1 日，我发现非专用压延机（ID#ESD743）挂有“已清洁”状态牌。该设备
压延机的 XX 处（产品接触表面）上有白色残留。该设备用以生产多个药品，包括销往美
国市场的 XX 片剂。
(b) On September 12 2016, I observed a non-dedicated (b)(4) machine (ID #ESD
1077) with a completed “CLEANING CHECK LIST”. This equipmenthad white
residue around the (b)(4) and on the (b)(4) (a product contact surfaces), which
was also observed by the Head of OSD Site Operations –Nashik. Additionally, the
gasket lining in the equipment was observed to be damaged. This equipmentis
used for (b)(4). The Head of OSD Site Operations –Nashik stated that thiswas
drug product residue. This equipment is used in the manufacture of multipledrug
products, including (b)(4) tablets for the US market.
2016 年 9 月 12 日，我发现非专用 XX 设备（ID#ESD1077）挂有完整的“清洁检查清
单）。此设备上在 XX 周围和 XX 上面（产品接触表面）有白色残留，OSD 工厂运营负责
人-Nashik 也看到了。另外，还看到设备里的垫片已损坏。此设备用于 XX。OSD 工厂运营
负责人-Nashik 说这是药品残留。此设备用于多个药品的生产，包括销往美国市场的片剂
XX。
10. 浙江华海 20180809

Written procedures designed to prevent contamination of drug products
purporting to be sterile are not followed. 未遵守设计用以防止理应无菌的药品交叉污
染的书面程序。
1. During set-up and interventions using the RABS (b)(4) operators were
observed to use the (b)(4) directly above sterile surfaces and components. For
example, (b)(4) the stopper bowl and stoppers, and open vials at the (b)(4).
在使用 RABS XX 装配和干预期间，发现操作人员在无菌表面和成分正上方使用 XX。例如，
XX 加塞盘和塞子，以及在 XX 打开西林瓶。
2. Intervention during filling operations have not been defined in procedures
and were not documented in the (b)(4) submission batch records.
程序中未定义在灌装操作期间的干预，亦未记录在 XX 申报批记录中。
3. There is no preventive change frequency forthe clean room RABS (b)(4).
未规定洁净间 RABS XX 的预防性更换频次。
4. No defect set of vials is maintained for training and qualification of the visual
inspection process.
未制作目检操作培训和确认用缺陷西林瓶系列。
Processing areas are deficient regarding the system for cleaning and disinfecting
the equipment. 工艺区域的设备清洁和消毒系统有缺陷。
1. The (b)(4) ducts of the (b)(4) are not periodically inspected and cleaned. On
18 November 2016, the (b)(4) duct for (b)(4) GJC008 was observed to have
unidentified white dust on the innersurfaces of the (b)(4) duct.
XX 的 XX 风管未定期检查和清洁。2016 年 11 月 18 日，发现 XX GJC008 的 XX 风管中内
表面有不明白色粉尘。
2. (b)(4) of the filling room is done (b)(4) to control spores with a (b)(4) solution.
The validation of the (b)(4) process didnot include placement of biological
indicators in hard to reach areas, such asin RABS (b)(4) areas that may be clocked
by equipment, high areas or low areas.
灌装间的 XX 已完成用以使用 XX 溶液控制孢子。XX 工艺的验证未包括在难接近区域放置
生物指示剂，例如在可能被设备阻碍的 RABS 的 XX 区域、较高区域或较低区域。
3. Disinfectant efficacy studies did not evaluate the effectiveness on (b)(4) used
for the RABS (b)(4) or (b)(4) used as (b)(4) parts for the filling line. During
execution of the studies the challenged surfaces were physically wiped
preventing evaluation of the effectiveness of the disinfectant that is sprayed.
消毒剂有效性研究并未评估用于 RABS 的 XX 的有效性，和灌装线中用作 XX 部分的 XX 的
有效性。在研究执行期间，挑战表面进行了物理擦拭因此无法对所喷消毒剂进行有效性评
估。
4. Transfer of the filling machine (b)(4) parts from their storage in unclassified
areas to the Grade A areas was not evaluated in the validation “Efficiency
Qualification of Material Transferring by Non-Sterilization Method into Grade B”.
验证“非灭菌方法转移物料至 B 级区的有效性确认”中未评估灌装机 XX 部件从其非洁净

区存贮处转移至 B 级区的操作。
Data is not recorded contemporaneously. 数据记录不同步。
1. The “checked by” entries for batch (b)(4) of(b)(4) Tablets were not
documented at the time of batch production.
XX 片剂 XX 批次批记录中复核项未在批生产时记录。
2. The QC analyst responsible for environmental monitoring does not
document sampling at the time it occurs. It was reported the analyst remembers
the times and documents all at once after finishing.
负责环境监测的 QC 化验员未在取样时即行记录。报告说化验员凭记忆记下时间然后在完
成之后全部写下来。
11. 美国 Cook Pharmica 20180910

缺陷 2：未遵守防止 XX 原料药污染的书面程序。具体来说，2014 年 7 月 12 日 XX 批号
XX 产品的生物负载超标，偏差 PR104369 启动，其中发现回收值高达 190CFU/ML（行
动限≤XXCFU/mL）。根本原因调查显示设备（XX-160-01）安装不当：XX 连接器在 XX
期间 XX 不正确，导致清洁循环无效。
Observation3. There is a lack of quality oversight in the review of records and
proceduresfollowed in drug substance manufacture. Specifically, after deviation PR
176620(due to a bioburden excursion of the (b)(4) on 2 March 2017) was opened, an
unacceptably high level of bioburden ((b)(4) CFU/100mL) was (b)(4) detected on1 May
2017 (LIMS sample #974194) , on the same process equipment (X-165-01) used to
manufacture (b)(4) drug substance. The result (LIMS sample #974194) did not
automatically trigger a root cause investigation because the associated bioburden limit
was “report result”.
12. 印度 Unichem Laboratories 20180910

1. Cleaning procedure are not validated. 清洁程序未经验证。
The Unichem Laboratories Ltd. Procedure PPQA029/04 is not validated to assure API
manufacturing equipment are cleaned to a level that does not impact product quality
when employed for the multiple batch campaign process. The cleaning validation
protocol did not completely describe the equipment to be cleaned, procedures,
materials, acceptable cleaning levels, parameters to be monitored and controlled, and
analytical methods. In addition, stability of the worst case condition defined by the
completion of a full campaign of (b)(4) batches was not defined, even though finished
API has been distributed into the market for years.
公司程序 PPQA029/04 未经验证以确保 API 生产设备在用于多批次周期性生产时会清洁
至不影响产品质量的程度。清洁验证方案未完整描述要清洁的、清洁程序、物料、可接受清
洁水平、需监测和控制的参数以及分析方法。另外，未定义 XX 个批次的全周共用完成时最
差情形的稳定性，但 API 成品已在市场销售了数年。
13. 印度 Liva Pharmaceuticals 20180910

Procedures designedto prevent microbiological contamination of sterile small volume
parental drug products purporting to be sterile are not followed.
未遵守设计用以防止本应无菌的无菌小容量注射剂药品的微生物污染程序。
Specifically, 具体来说，
SOP entitled: “ Aseptic Process Simulation (Media Fill)”,QA-00024, Version: 4.0,
Effective date: 07/09/2018, page 31, 6.4.15 (D) readsin parts: “*** Containers having
obvious breach of container/closure integrity such as cracked container, broken
container, containers with missing (b)(4)stopper/closures shall be sorted out and
rejected **. The rejection shall be discarded with rationale justification after identifying
reasons for obvious breach of container closure integrity **. The same shall be followed
by documentation ***”. For one of the (b)(4) media fill batch performed between (b)(4) to
demonstrate commercial readiness, there is no documentation identifying the reasons
for the breach of the container closure integrity of the non-integral vials that were
rejected prior to incubation. A summary is given below:
题为“无菌工艺模拟（培养基灌装）”的 SOP，QA-00024，版本 04，生效日期 20180709，
页 31，第 6.4.15（D）部分写道“……容器有明显容器密闭器完整性问题，如容器开裂、
破损、掉塞/盖则应取出并拒收……。拒收者应在识别出完整性问题原因之后进行合理性论
证然后弃除……。上述操作要进行记录……”。有一个为证明商业准备情况的培养基灌装批
次没有记录下培养前拒收的不完整瓶的容器密闭器完整性问题的原因识别，数据汇总如下：
Medial fill number Number of defects Type of defect Reference in Batch
培养基灌装编号 observed as non- 缺陷类型 Master Record
integral vials during (b) 批记录中的索引号
(4) visual inspection
在 XX 目视检查中发现
的不完整瓶缺陷数量
(b)(4) 08 04 vials type of 129-136
defects not recorded
4 瓶缺陷类型未记录
Employees engaged in the manufacture, processing and packing of a sterile small
volume parental drug product, lack the training and experience required to perform their
assigned functions.
从事一个无菌小容量注射剂药品的生产、加工和包装的员工缺乏执行其指定工作的培训和
经验。
a) Per SOP entitled: “Qualification and requalification of Visual inspectors”, PK-002-00
Effective: 01/12/2017, the acceptance criteriafor qualifying a visual inspector is listed
below. During the inspection on 08/20/2018, I had randomly picked a qualified visual
inspector with initials (b)(4) to perform visual inspection of the visual inspection test kit
containing a sample set of (b)(4) vials, used to qualify visual inspectors. However, the
aforementioned visual inspector failed to meet the below listed acceptance criteria that is
required to qualify visual inspector.
根据题为“目检员资质确认与再确认”SOP PK-002-00，生效日期 20170112，目检员资质
确认的可接受标准列出如下。在 20180828 的检查期间，我随机抽取了一个具备资质的名为
XX 的目检员对用于确认目检员资质的目检标样系列进行目检。但是，前述目检员未能达到
下述目检员确认所需的可接受标准。
Acceptance criteria 可接受标准 Result 结果
Total Quantity of Defective Containers (Not (b)(4)
Less than (NLT) (b)(4))
缺陷容器总数（不得低于 XX） XX
Total Quantity OF Good Containers (NLT (b)(4)
(b)(4))
好容器总数（不得低于 XX） XX
Acceptance Criteria NLT (b)(4)% (Critical (b)(4)%
Defect)
可接受标准 NLT XX%（关键缺陷） XX%
Acceptance criteria ≥(b)(4)% of total (b)(4)%
defects (other than critical)
可接受标准≥总缺陷数 XX%（关键项除外） XX%
False reject rate ≤(b)(4)% (Good Vial) (b)(4)%
错误拒收率≤XX%（好瓶） XX%
b) Per SOP entitled: “Manual Visual Inspection of filled andsealed containers”, SOP
Number: PK-004-00, Effective Date: 01/10/2017, defects such as “(b)(4) and black
particles” for small volume parental, liquid vial ((b)(4)), are classified as critical defects.
Per the current SOP entitled: “ManualVisual Inspection of filled and sealed containers”,
Document Number: 2261-SOP-PK-00005, Version 2.0, Effective Date: 03/19/2018, for
small volume parental, liquid vial ((b)(4)), black particles is classified as critical defects
and (b)(4) Particles has been re-classified as a major defect. The re-classification of (b)
(4) particles in the current SOP, is not scientificallyto meet acceptance criteria for being
qualified visual inspector (see aforementioned Observation 3-a).
根据题为“已灌装密封容器的人工目检”的 SOP PK-004-00，生效日期 20170110，缺陷
如小容量注射剂的“XX 与黑色颗粒”、液体瓶 XX，均归类为关键缺陷。根据现行
SOP“已灌装密封容器的人工目检”，文件编号 2261-PK-00005，版本 2.0，生效日期
20180319，对于小容量注射液，液体瓶 XX、黑色颗粒归类为关键缺陷，且 XX 颗粒重新
分类为主要缺陷。该现行 SOP 中 XX 颗粒的重新分类无法科学地达到目检员资质确认的可
接受标准（参见前述缺陷 3-a）。
14. 浙江华海川南一分厂 20180920
Production deviations are not always reported and evaluated and critical deviations are
not always investigated and the conclusions recorded. Specifically,
未报告和评估所有生产偏差，未对所有关键偏差进行调查并记录结论。具体来说
a) Your production operators do not always follow batch production instructions for
critical processing parameters. At approximately (b)(4) on July 24, 2018, the temperature
monitor for (b)(4) II-201 used in the manufacture of (b)(4) crude (b)(4) batch (b)(4)
displayed (b)(4) degrees C. The manufacturing batch recordfor (b)(4) crude (b)(4)
showed the manufacturing process for intermediate (b)(4) from chemical synthesis (b)(4)
step was at step (b)(4) in the manufacturing process. The batch record identifies the
parameters for this step as (b)(4) °C-(b)(4)°C maintained for (b)(4). The batch record
also identifies this (b)(4) time duration as critical. The previous batch record entry
recorded at (b)(4) listsa temperature of (b)(4) °C. The temperature for step (b)(4) is
controlled by a manual (b)(4).
你们的生产操作员未能始终遵守关键工艺参数的批生产指令。20180724 约 XX 时，XX 粗
品 XX 批次生产所用 XXII-201 的温度监测显示为 XX 摄氏度。XX 粗品 XX 的批生产记录显
示中间体 XX 的生产工艺为生产工艺 XX 步骤的化学合成 XX 步骤。批记录识别此步骤的参
数为保持 XX°C-XX°CXX 时长。批记录还识别此 XX 时长为关键。之前的 XX 批记录数据列
出温度为 XX°C。步骤 XX 的温度是由手动 XX 控制的。
b) On July 25, 2018 in workshop (b)(4) a production employee was observed recording
a value of (b)(4) liters for the amount of (b)(4) at step (b)(4) in the batch manufacturing
record during the production of crude (b)(4) batch (b)(4). The flowmeter for the (b)(4)
displayed a value of (b)(4). A production operator in Workshop (b)(4) stated (b)(4)
equates to (b)(4) liters. The specification for (b)(4) at step (b)(4) in the batch
manufacturing record for crude (b)(4) is (b)(4) +/- (b)(4)L.
2018 年 7 月 25 日，在 XX 车间 XX 粗品 XX 批次生产中看到有一个生产人员正在批生产记

录上记录 XX 步骤的 XX 数量为 XX 升。XX 流量计显示值为 XX。XX 车间里一名生产操作工
声称 XX 等于 XX 升。粗品 XX 批记录里 XX 步骤的 XX 标准为 XX+/-XX 升。
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 purportor are
没有书面的生产和工艺控制程序设计用以确保药品具备其理应具备的鉴别、剂量、质量和纯
度。
Specifically, there is no line clearance required during intervention activities performed

by production operators. On 8/30/18 we observed USP (b)(4)mg being performed on
capsule filling equipment HC-084. For no less than one hour and ten minutes, we
observed the equipment to be intermittently operational. During this time, we observed
production staff perform no less than three manual interventions in an attempt to clear a
recurring critical alarm. In between these attempts, we observed capsules moving from
the filling equipment, through the in-line check weight device and in to the accepted
capsule bag. We observed one operator performing interventions inside the (b)(4)
access barrier (RABS) while wearing the protective goggles on top of his head rather
than in an appropriate manner and observed use of a (b)(4) to remove (b)(4) and
capsules from inside the filling equipment. After approximately one hour, the production
staff requested assistance from engineering department. Your Head of Operations, (b)
(4) Solid Dosage, and your Senior General Manager, Quality Non-Sterile Manufacturing,
stated that if the capsules pass the weight check, they are not rejected. Additionally, they
stated there is no line clearance required during intervention activities performed by
production operators. The same alarm occurred during production of the same lot on the
(b)(4).
具体来说，生产操作人员进行干预之后不要求进行清场。在 20180830，我们发现 USP 级

XXmg 产品在胶囊灌装机 HC-084 上进行灌装。在不到一小时 10 分钟内，我们看到该设备
是断续运行的。在此期间，我们看到生产员工进行了不少于 3 次人工干预，试图排除反复
发生的关键报警。在这些努力之间，我们看到胶囊从灌装设备，通过在线检重装置，进入
胶囊接收袋。我们看到有一个操作工在 XX 内通过 RABS 进行干预，其将防护眼镜戴在头
上而不是戴在正确位置。我们还看到使用 XX 从灌装机内清除 XX 和胶囊。在约 1 小时之后
生产人员请求工程部门协助。你们的 XX 固体制剂营运负责人和你们的非无菌生产质量高
级总经理声称如果胶囊通过了重量检查则不会被拒收。他们还声称在生产操作人员执行干
预活动中不需要清场。相同批次生产过程中相同报警在 XX 也有发生。
Filling machine HC-084 was also utilized to produce a characterization batch of (b)(4)mg
(b)(4) on (b)(4) and is one of the filling machines intended to be utilized during
commercial production of the (b)(4)mg products.
HC-084 灌装机也用于生产 XX 产品的鉴定批次，亦用于 XX 产品的商业化生产。
16. 印度 Strides Pharma 20180926
Written procedures for cleaning and maintenance fail to include description in sufficient
detail of methods, equipment and materials used and parameters relevant to the
operation.
清洁和维护书面程序未包括足够详细的方法、设备和所用物料及相关操作参数描述。
A．The cleaning procedures for formulation filling equipment such used to manufacture
(b)(4) Solution (b)(4)% and (b)(4) Solution USP (b)(4)mEq/(b)(4)%mL do not specify the
cleaning operations for the transfer pump. The transfer pump is shared for liquid
products, is unidentified, and includes product contact surfaces. Cleaning records for the
transfer pump are discarded, not included in batch records, and not recorded in log
books.
A．XX 溶液和 YY 溶液生产所用制剂灌装设备的清洁程序未写明传输泵的清洁操作。该传

输泵，包括产品接触表面共用于多个液体产品，其未标识。该传输泵的清洁记录被丢掉了，
没有放在批记录中，亦未记录在日志中。
B．After cleaning, residual clear liquid was observed in common manufacturing vessels
used for production of (b)(4) Solution (b)(4)% and (b)(4) Solution USP (b)(4)mEq/(b)
(4)mL.
B．在清洁后，在 XX 溶液与 YY 溶液生产共用生产罐中发现有残留清液。
C．Oil was observed on product contact surfaces of (b)(4) of filling equipment used for
production of (b)(4) Solution USP (b)(4)mEq/(b)(4)mL.
C．在 XX 溶液生产用灌装设备 XX 的产品接触表面发现有油。
Control procedures are not established which validate the performance of those
manufacturing processes that may be responsible for causing variability in the
characteristics of in-process material and the drug product.
未建立控制程序验证可能导致中间体和制剂特性波动的生产工艺性能。
The settings used to adjust the cap tightness of containers for (b)(4) Solution USP (b)
(4)mEq/(b)(4)mL are not specified in work instructions or recorded in batch records. The
settings to adjust the (b)(4) and height of the (b)(4) sealer used during packaging of (b)
(4) Solution USP (b)(4)mEq/(b)(4)mL are not specified or recorded in batch records. The
settings used to adjust the fill volume of (b)(4) Solution USP (b)(4)mEq/(b)(4)mL are not
specified in work instructions or recorded in batch records.
在工作指导书中未写明用于调整 XX 溶液容器盖松紧度的设置，亦未将其记录在批记录中。
在工作指导书中未写明调整 XX 溶液包装过程所用 XX 和 XX 密封高度的设置，亦未将其记
录在批记录中。在工作指导书中未写明调查 XX 溶液灌装体积的设置，亦未将其记录在批
记录中。
17. 印度 Cipla 20181022
The batch production and control records are deficient in that they do not include
documentation of the accomplishment of each significant step in manufacturing.
Specifically.
批生产和批分析记录有缺陷，其中未包括每个重要生产步骤的完成情况。具体如下，
The proposed commercial master batch record for the production of (b)(4)
Tablets. (b)(4), version 01, does not provide written instructions for the removal of
the (b)(4) from a (b)(4) bag inside your IPCs (In-Process Containers) and the
subsequent pouring of this (b)(4) back into the same IPC as needed for docking
with your compression systems.
所拟 XX 片剂商业化生产的主批记录版本 01 中没有提供关于从你们的 IPC（中间体容

器）里 XX 袋中清除 XX 的指令，后续因为要与压缩系统对接，又将此 XX 倒回了相同
的 IPC 中。
18. 美国 Thrifty White Drug #762
Sporicidal agents were not used in your facility's cleanrooms and/or ISO 5 classified
aseptic processing area.
在您工厂的洁净室和/或 ISO 5 级无菌加工区域中未使用杀孢子剂。
Specifically, on September 10, 2018 we observed your daily cleaning of ISO 5 aseptic
processing area was done without the use of any sporicidal agents. We noted that
during the cleaning process, (b)(4) was the only agent used. We also noted that there is
no sporicidal agent used in the (b)(4) cleaning of the ISO 5 aseptic processing area.
Your firm stated no sporicidal agent is used in the ISO 5 aseptic processing area.
具体而言，在 2018 年 9 月 10 日我们观察到您的 ISO 5 无菌加工区域的每日清洁在不使用

任何杀孢子剂的情况下进行。我们注意到在清洁过程中，XX 是唯一使用的药剂。我们还注
意到在 ISO 5 无菌加工区域的 XX 清洁中没有使用杀孢子剂。你公司表示 ISO 5 无菌加工
区域没有使用杀孢子剂。
Disinfecting agents and cleaning wipes used in the ISO 5 classified aseptic processing
areas were not sterile.
ISO 5 级无菌加工区域中使用的消毒剂和清洁抹布不是无菌的。
Specifically, On September 10, 2018, we observed an employee clean the ISO 5 aseptic
processing area with (b)(4) and non-sterile wipes before starting aseptic processing of
Cefazolin 2gm/100ml Prescription # (b)(6).
具体而言，在 2018 年 9 月 10 日，我们观察到一名员工在开始无菌加工头孢唑啉
2g/100ml 处方＃XX 之前用 XX 和非无菌抹布清洁 ISO 5 无菌加工区域。
Equipment was and Materials or supplies were not disinfected prior to entering the
aseptic processing areas.
设备和材料或供应品在进入无菌加工区域之前未进行消毒。
Specifically, Items are sprayed with (b)(4) in the non-classified area of the pharmacy,
then transported to the non-classified (b)(4) which leads directly to the ISO 7 buffer area.
These items are then placed into the ISO 5 aseptic processing area without further
disinfection.
具体而言，物品在药房的未分级区域喷洒 XX，然后运送到直接通向 ISO 7 缓冲区的未分
级 XX。这些物品然后被放入 ISO 5 无菌加工区域，而未进一步消毒。
The ISO 5 classified aseptic processing areas had difficult to clean equipment or
surface. Specifically, The back of the ISO-5 aseptic processing area does not have a
smooth cleanable surface and it contains (b)(4) which include (b)(4) type surfaces.
ISO 5 级无菌加工区域难以清洁设备或表面。具体而言，ISO-5 无菌处理区域的背面不具有

光滑的可清洁表面，并且其包含 XX，其包括 XX 类型的表面。
ISO 5 classified areas were not certified under dynamic conditions.
ISO 5 级区域未在动态条件下获得认证。
Specifically, Smoke studies performed in the ISO 5 laminar hood were not performed
under dynamic conditions that represent your aseptic processing practices. We
observed the aseptic processing of Cefazolin 2gm/l00ml Prescription # (b)(6) which
included (b)(4) in the ISO 5 hood, using a repeater pump with (b)(4) (b)(4) which were
not replicated during the smoke studies. There is no video or description provided of the
smoke study and no employees of your firm participated or witnessed the smoke study.
具体而言，在 ISO 5 层流罩中进行的烟雾测试并未在代表您的无菌加工实践的动态条件下

进行。我们观察了头孢唑啉 2g/100ml 处方号 XX 的无菌处理，其中包括在 ISO 5 层流罩中
XX，使用具有 XX 的中继泵，在烟雾测试期间没有重复。烟雾测试没有提供视频或描述，
并且贵公司的员工也没有参与或目睹烟雾测试。
Media fills were not performed that closely simulate aseptic production operations
incorporating, as appropriate, worst-case activities and conditions that provide a
challenge to aseptic operations.
没有进行密切模拟无菌生产操作的培养基灌装，酌情包括对无菌操作提出挑战的最差情况
活动和条件。
Specifically, Your firm follows the instructions of the (b)(4) media fill kit for risk level-1
(simple procedure) which involved (b)(4) contained in the kit and an (b)(4) provided by
your firm. We observed the aseptic processing of Cefazolin 2gm/100ml Prescription #
(b)(6) which included (b)(4) in the ISO 5 hood, using a repeater pump with (b)(4). The (b)
(4) media fill kit risk level 1 procedure does not simulate the batch size or use of
repeater pump and (b)(4) which are part of your firm's routine conditions.
具体而言，贵公司遵循 XX 培养基灌装套件中有关风险等级-1（简单程序）的说明，其中
涉及套件中包含的 XX 和您公司提供的 XX。我们观察了头孢唑啉 2g/100ml 处方号 XX 的无
菌处理，其中包括在 ISO 5 罩中 XX，使用具有 XX 的中继泵。XX 培养基灌装套件风险等
级 1 程序没有模拟批量大小或使用中继泵和 XX，这是您公司常规条件的一部分。
19. 美国 Johnson Memorial Cancer Center
Disinfecting agents and cleaning wipes used in the ISO 5 classified aseptic processing
areas were not sterile.
ISO 5 级无菌加工区域中使用的消毒剂和清洁抹布不是无菌的。
Specifically, The firm's cleaning of the ISO 5 Biological Safety Cabinet and ISO 5
Laminar Flow Hood are inadequate for the following reasons:
具体而言，由于以下原因，该公司对 ISO 5 生物安全柜和 ISO 5 层流罩的清洁不充分：
○ The firm routinely utilizes non-sterile wipes (b)(4) (b)(4) to administer sterile
(b)(4) (sporicidal disinfectant) and sterile (b)(4) (b)(4) to all interior surfaces of
the ISO 5 hoods. In addition. the firm utilizes the non-sterile wipes to dry
residual cleaning agents (b)(4) from the interior of the ISO 5 hoods. The firm
has performed no risk assessments related to the use of non-sterile wipes in
the ISO 5 classified areas where aseptic processing occurs.
○ 公司日常使用非无菌抹布 XX 以无菌 XX（杀孢子消毒剂）和无菌 XX 清洁所有

ISO 5 层流罩内表面。此外。该公司使用非无菌抹布擦干 ISO 5 层流罩内部残留
的清洁剂 XX。该公司没有对在无菌操作发生的 ISO 5 级区域使用非无菌抹布进
行风险评估。
○ Firm personnel were observed cleaning the interior of the ISO 5 classified
areas with their head and upper torso within the hood. The operator's
gowning was observed coming into contact with the interior surfaces of the
hood. The firm has performed no risk assessments related to the
aforementioned cleaning activities.
○ 观察到公司员工清洁 ISO 5 级区域内部时，其头部和上身在层流罩内。观察到
操作员的洁净服与层流罩内表面接触。该公司没有进行与上述清洁活动相关的
风险评估。
○ The firm 's contact time for the use of the sporicidal disinfectant (b)(4) differed
from the manufacturer's recommendations. The firm's contact time was (b)(4)
minutes vs. manufacturer recommended contact time (b)(4) minutes.
○ 公司使用杀孢子消毒剂 XX 的接触时间与制造商的建议不同。该公司的接触时间
为 XX 分钟，而制造商建议的接触时间为 XX 分钟。
○ An operator was observed exhibiting poor aseptic practice by cleaning the
deck of the ISO 5 Laminar Flow Hood in an elliptical motion (not cleanest to
dirtiest).
○ 观察到一名操作员通过以椭圆运动（不是从最干净至最脏）清洁 ISO 5 层流罩
的平台，表现出不良的无菌习惯。
Personnel moved rapidly in the vicinity of open sterile units and instruments, which
disrupted the airflow and increased the risk of bringing lesser quality air into the ISO 5
classified aseptic processing area.
人员在开放式无菌单位和仪器附近迅速移动，这破坏了气流并增加了将质量较差的空气带
入 ISO 5 级无菌加工区域的风险。
Specifically, poor aseptic practice was observed during the production of sterile drug
products while working within ISO 5 classified aseptic processing areas.
具体而言，在 ISO 5 分类无菌加工区域内工作期间，在无菌药品的生产过程中观察到不良

的无菌习惯。
1) On 10/1/18, an operator was observed producing (b)(4) for injection in the firm's
ISO 5 Laminar Flow Hood (LFH). The LFH is located in an ISO 7 Buffer room.
1）在 2018 年 10 月 1 日，观察到一名操作员在公司的 ISO 5 层流罩（LFH）中生产

XX 注射剂。该 LFH 位于 ISO 7 缓冲室。
○ The operator's hands exited and entered the LFH several times during
operations to gather supplies and continue production. The operator did not
sanitize their hands upon each entry to LFH.
○ 操作员的手在操作过程中多次离开并进入 LFH 以收集耗材并继续生产。操作员
没有在每次进入 LFH 时消毒他们的手。
○ The operator failed to keep all production activities at least 6 inches inside the
LFH.
○ 操作员未能将所有生产活动保持在 LFH 内至少 6 英寸。
○ The operator's movements inside the LFH were quick, abrupt and had
potential to disturb ISO 5 airflow.
○ 操作员在 LFH 内部的移动快速、突然，有可能扰乱 ISO 5 气流。
○ The operator was observed wearing eye makeup.
○ 观察到操作员戴有眼妆。
2) On 10/2/18, an operator was observed producing (b)(4) and (b)(4) for injection in
the firm's ISO 5 Laminar Flow Hood (LFH). The LFH is located in an ISO 7 Buffer
room.
2）在 2018 年 10 月 2 日，观察到一名操作员在公司的 ISO 5 层流罩（LFH）中生产
XX 和 XX 注射剂。该 LFH 位于 ISO 7 缓冲室。
○ The operator's elbows were observed resting on the deck of the LFH, where
sterile production occurs.
○ 观察到操作员的肘部搁在无菌生产发生的 LFH 的平台上。
○ The operator's movements inside the LFH were quick and abrupt and had
potential to disturb ISO 5 airflow.
○ 操作员在 LFH 内部的移动快速而突然，有可能扰乱 ISO 5 气流。
3) On 10/2/18. an operator was observed producing several chemotherapeutic drugs

for injection including, (b)(4) and (b)(4) In the firm's ISO 5 Biological Safety Cabinet
(BSC). The BSC is located in an ISO 7 Buffer room.
在 2018 年 10 月 2 日。观察到一名操作员在该公司的 ISO 5 生物安全柜（BSC）中生产

几种注射用化疗药物，包括 XX 和 XX。该 BSC 位于 ISO 7 缓冲室。
○ The operator placed a non-sterile (b)(4) on the deck of the BSC immediately
prior to initiating sterile producing activities.
○ 操作员在开始无菌生产活动之前即将非无菌的 XX 放置在 BSC 的平台上。
○ The operator's movements inside the BSC were quick and abrupt and had the
potential to disturb ISO-5 airflow.
○ 操作员在 LFH 内部的移动快速而突然，有可能扰乱 ISO 5 气流。
20. 美国 Med Shop Total Care Inc.
Time limits are not established when appropriate for the completion of each production
phase to assure the quality of the drug product.
没有在适当时为每个生产阶段的完成确定时间限制，以确保药品的质量。
Specifically, you do not have any hold time studies to support storing preservative free
stock solutions held in glass and plastic vials and assigning beyond-use-dates of more
than three months.
具体而言，您没有任何保留时间研究来支持储存在玻璃和塑料小瓶中的无防腐剂储备溶液，
并指定超过三个月的超出使用日期。
Clothing of personnel engaged in the manufacturing, processing, packing and holding of

drug products is not appropriate for the duties they perform.
从事制造、加工、包装和保存药品的人员的服装不适合他们履行的职责。
Specifically, the gown and mask worn by personnel on the veterinary side during sterile
compounding is not sterile.
具体而言，在无菌配制期间兽药人员穿戴的长袍和面罩不是无菌的。
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
没有生产和工艺控制的书面程序，旨在确保药品具有其声称或代表拥有的特性、强度、质量
和纯度。
Specifically, your formulation worksheets do not include specific instructions. For

example, you do not have specifications/parameters putting the Morphine Sulfate Stock
(b)(4) (time and temperature).
具体而言，您的配方工作表不包含具体说明。例如，您没有放置硫酸吗啡储备液 XX（时间
和温度）的标准/参数。
Equipment and utensils are not cleaned, maintained and sanitized at appropriate
intervals to prevent contamination that would alter the safety, identity, strength, quality or
purity of the drug product.
设备和器具未在适当的时间间隔进行清洁、维护和消毒，以防止污染会改变药品的安全性、
特性、强度、质量或纯度。
Specifically, 具体而言，
a) You do not use a hood to prepare non-sterile hormonal products. The capsule
equipment is only cleaned with (b)(4) after use. You have no further documentation
to show prevention of contamination from one lot to another lot.
a）您未使用层流罩来制备非无菌激素产品。胶囊设备仅在使用后用 XX 清洁。您没有进一
步的文档说明防止从一批到另一批的污染。
b) You also only use non-sterile (b)(4) to clean the cabinet area where non-sterile
operations occur.
b）您还仅使用非无菌的 XX 清洁非无菌操作发生的机柜区域。
21. 美国 Tailor Made Compounding, LLC

Protective apparel is not worn as necessary to protect drug products from
contamination.
未穿防护服，这对保护药品免受污染是必要的。
Specifically, on 8/21/18, while observing sterile operations, we observed a pharmacy
technician enter the ISO 7 room, which your firm identifies as the USP 797 room. This
room contains the ISO 5 hood. We observed your pharmacy technician enter your USP
797 room from your ISO 7 Ante room with ungloved hands (exposed skin). The Ante
room is where the technician gowns and washes hands. Upon entering the USP 797
room, we observed the technician immediately apply (b)(4) to his ungloved hands. He
then put on sterile gloves.
具体而言，在 2018 年 8 月 21 日观察无菌操作时，我们观察到一名制药技术人员进入 ISO
7 房间，您公司将其标识为 USP 797 室。该房间配有 ISO 5 层流罩。我们观察到您的制药
技术人员从 ISO 7 前室进入 USP 797 室，没有戴手套（裸露皮肤）。前室是技术人员穿衣
和洗手的地方。进入 USP 797 室后，我们观察到技术人员立即将 XX 喷到他未戴手套的手
上。然后他戴上无菌手套。
Aseptic processing areas are deficient regarding the system for cleaning and disinfecting
the room and equipment to produce aseptic conditions.
无菌加工区域在用于清洁和消毒房间和设备以产生无菌条件的系统方面存在缺陷。
Specifically, your firm's bactericidal agent ((b)(4)) used for cleaning is not sterile. Your
firm uses (b)(4) for cleaning the ISO 5 hood, ISO 7 rooms and ISO 8 rooms.
具体而言，你公司用于清洁的杀菌剂（XX）不是无菌的。你公司使用 XX 清洁 ISO 5 层流
罩、ISO 7 和 ISO 8 洁净室。
Time limits are not established when appropriate for the completion of each production
phase to assure the quality of the drug product.
没有在适当时为每个生产阶段的完成确定时间限制，以确保药品的质量。
Specifically, your firm does not have any hold time studies for how long glassware used
for sterile operations can be stored before use after being depyrogenated in the (b)(4).
Furthermore, your firm has not performed any studies to assure a 3-log reduction is
achieved for endotoxins.
具体而言，贵公司没有对用于无菌操作的玻璃器皿在 XX 中除热原后、使用前可以保存多
久进行任何保留时间研究。此外，贵公司尚未进行任何研究，以确保内毒素减少 3 个数量
级。
21. 美国 Promise Pharmacy, LLC

purporting to be sterile are not.
旨在防止声称无菌的药品微生物污染的程序不足。
Specifically, on 10/19/18, I observed the following:
具体来说，在 10/19/18，我观察到以下情况：
 An operator blocked first pass HEPA filtered air during the production of
Bremelanotide, Lot 1019018@4, BUD 12/18/18.
 在生产布美诺肽（批号 1019018@ 4，BUD 12/18/18）期间，操作员阻断首次通过
HEPA 过滤的空气。
 An operator did not move slow and deliberate in the ISO 5 environment when
transferring partially stoppered vials of Bremelanotide, Lot 1019018@4, BUD
12/18/18, from the compounding table to (b)(4).
 当将半加塞的布美诺肽（批号 1019018@4，BUD 12/18/18）小瓶从配料桌转移到
XX 时，操作员没有在 ISO 5 环境中缓慢且慎重地移动。
 An operator did not wear· a beard cover during the production of HCG 2000IU
Injectable, Lot 10192018@6, BUD 04/17/18.
在生产人绒毛膜促性腺激素 2000IU 注射剂（批号 10192018@6，BUD 04/17/18）期间，
操作员没有戴胡须套。
22. 印度 Dishman Carbogen Amcis Ltd.
1.) Blending of in-specification with out-of-specification (OOS) intermediate batches is

performed.
1.）将合格与不合格（OOS）中间体批次混合。
Specifically, (b)(4) ((b)(4) intermediate) batch tested (b)(4) OOS for impurity (b)(4).
具体来说，XX（XX 中间体）批 XX 测试 XX 杂质 OOS。
The batch was manufactured starting on 03/05/2018. QC testing of this batch yielded a
result of (b)(4)% for the (b)(4) impurity against a specification of less than or equal to (b)
(4)%. Deviation investigation DV/(b)(4)/1801, written for this incident, calls for this batch
to be blended with other batches that have an in-specification result for (b)(4)
manufacturing, The OOS batch was blended with in-specification material as follows:
该批次是从 2018 年 3 月 5 日开始制造的。该批次的 QC 测试产生了一个 XX 杂质的 XX %
的结果，标准小于或等于 XX %。为此事件写的偏差调查 DV/XX/1801，要求将此批次与合
格的其他批次混合以制造 XX，该 OOS 批与以下合格物料混合：
A.) (b)(4) kg of batch (b)(4) blended with (b)(4) kg of batch (b)(4) to manufacture (b)(4)
batch (b)(4)
A.）XX kg XX 批与 XX kg XX 批混合制造 XX 批 XX
B.) (b)(4) kg (b)(4) blended with (b)(4) kg of batch (b)(4) and (b)(4) kg of batch (b)(4) to
manufacture (b)(4) batch (b)(4)
B.）XX kg XX 与 XX kg XX 和 XX kg XX 混合以制造 XX 批次 XX
C.) (b)(4)kg of batch (b)(4) blended with (b)(4) kg of batch (b)(4) to manufacture (b)(4)
batch (b)(4)
C.）XX kg XX 批与 XX kg XX 批混合制造 XX 批 XX
D.) (b)(4) kg of batch (b)(4) blended with (b)(4) kg of batch (b)(4) and (b)(4) kg of batch
(b)(4) to manufacture (b)(4) batch (b)(4)
D.）XX kg XX 批与 XX kg XX 批和 XX kg XX 批混合制造 XX 批 XX
The manufactured (b)(4) batches were used in the production of packaged lots (b)(4) of
(b)(4).
制造的 XX 批次被用于生产 XX 的包装批次 XX。
23. 美国 Hospira Inc. A Pfizer Company 20180612

purporting to be sterile did not include adequate validation of the aseptic process.
旨在防止声称无菌的药品的微生物污染的程序不包括充分的无菌工艺验证。
A. While reviewing smoke studies conducted in room 323 for Lyophilizer (b)(4), the
following deficiencies were noted:
A. 当审查在 323 室对冻干机 XX 进行的烟雾研究时，注意到以下缺陷：
1. Prior to unloading of the HEPA cart containing partially stoppered vials, an
operator was observed checking the tray number using forceps. Tray check
performance gives the operator an opportunity .to be close to the partially
stoppered vials. The action provides possible contamination of the partially
stoppered vials.
1. 在卸载装有半加塞小瓶的 HEPA 推车前，观察到操作员用镊子检查托盘号。托
盘检查行为使操作员有机会靠近半加塞小瓶。该动作可能会对半加塞小瓶造成污
染。
2. While loading the Lyophilizer, the operator breached first air and smoke was
observed to travel from the operator onto the tray containing partially stoppered
vials.
2. 在装载冻干机时，操作员突破了第一空气，并且观察到烟雾从操作员行进到装
有半加塞小瓶的托盘上。
3. Smoke studies conducted do not demonstrate worst case scenario as the
lyophilizer was not fully loaded.
3. 由于冻干机未满载，因此进行的烟雾研究未显示最差情况。
B. You have no documented scientific justification for personnel monitoring during
aseptic filling. Per your Class 100 filling room process, personnel are monitored (b)
(4). During a shift, aseptic operators can gown and de-gown multiple times within a
day and on the same shift without additional personnel monitoring.
B. 在无菌灌装过程中，你没有文件化的科学证据来进行人员监测。根据你的百级灌装
室流程，人员应被监控 XX。但在轮班期间，无菌操作员可以在一天内同一班次多次穿
衣和脱衣，无需额外的人员监控。
C. While observing setup operations on line (b)(4) I observed tools used for
interventions located in your grade A area in room 338. In order to use the tools,
.operators must first compromise first air principles.
C. 在观察 XX 线上的准备操作时，我观察了在 338 室 A 级区域用于干预措施的工具。
为了使用这些工具，操作员必须首先违背第一空气原则。
Repeat Observation from 6/2016 and 10/2012
2016 年 6 月和 2012 年 10 月的重复缺陷
Your examination and testing of samples did not assure that the drug product and in-
process material conformed to specifications.
你对样品的检查和测试不能保证药品和加工过程中的物料符合标准。
Your manual / semi-automated / automated visual inspection processes are inadequate
for the following:
你的手动/半自动/自动视觉检查流程在以下方面是不充分的：
A. Your operators are trained via the (b)(4) visual inspection training program which
requires qualification specifically using a (b)(4). You have not performed or have
performed an inadequate scientific justification regarding your selection of (b)(4) as
representative or worst case of all primary container closure systems such as
ampules (~1 mL - 5 mL), amber vials, 100-mL vials, etc.
A. 你的操作员通过 XX 目视检查培训计划进行培训，该计划要求专门使用 XX 进行资
格确认。关于你选择 XX 作为所有主要容器封闭系统（如安瓿(约 1mL－5mL)、琥珀色
小瓶、100mL 瓶等）的代表或最差情况，您没有进行或进行了不充分的科学论证。
法规意见：用于灯检员资格确认和可见异物检查设备确认的缺陷样品集应具有代表性。
B. On 7/24/2018, I observed 100-mL vials of lyophilized Vancomycin semi-

automated inspection processes in room #623 for lot #911903A. Approximately 5
vials failed to make a complete turn during the inspection process during an
approximate duration of (b)(4). A full revolution is a requirement to adequately
inspect vials for critical A (seal integrity defects) as well critical B (particulate matter)
defects. The vial rollers of the (b)(4) semi-manual visual inspection equipment
appeared to be malfunctioning.
B. 在 2018 年 7 月 24 日，我在 623 室观察了 100mL 瓶的冻干万古霉素（批号
911903A）的半自动检查过程。在大约 XX 的持续时间内，大约 5 瓶在检查过程中未能
完全转动。完整的旋转是充分检查小瓶的关键 A（密封完整性缺陷）以及关键 B（颗
粒物质）缺陷的要求。XX 半手动视觉检查设备的小瓶滚轴似乎出现故障。
C. You have not performed a risk assessment used as an input in the development
of your acceptable quality limits (AQLs). Specifically, you have not included the risk
to consumers resulting from the use of defective product such as seal integrity
attributes and particulate matter contamination.
C. 你没有进行风险评估，作为开发可接受质量限值（AQL）的输入。具体而言，你没
有将因使用有缺陷的产品（如密封完整性属性和颗粒物污染）而导致的患者风险纳入
其中。
D. You have not adequately assessed spinning parameters, such as rotation per
minute (RPMs) of your (b)(4) semi-automated inspection equipment which affect the
capability of your visual inspection process. Specifically, you have not established
an RPM range or other parameter to control / facilitate the propulsion of particulate
matter into solution / suspension immediately preceding the presentation of vials to
your inspecting operators.
D. 你没有充分评估旋转参数，例如你的 XX 半自动检查设备的每分钟转数
（RPM），它影响视觉检查过程的能力。具体而言，你尚未建立 RPM 范围或其他参
数来控制/促进在将样品瓶呈现给检查操作员之前立即将颗粒物质推进溶液/悬浮液中。
E. You have not adequately evaluated the risk that line speed presents to semi-
automated visual inspection operations. You (b)(4) qualify your visual inspection
operators using approximately (b)(4) of inspection time per unit. On 7/24/2018, we
observed a line speed of (b)(4) during observation of Lyophilized Vancomycin HCI
lot #911903A, room #623.
E. 你没有充分评估线速度对半自动视觉检查操作的风险。你 XX 使用每单位约 XX 检
查时间来确认你的目视检查操作员。2018 年 7 月 24 日，我们在 623 室观察冻干万古
霉素（批号 911903A）期间观察到线速度为 XX。
F. You have not established in-process defect limits regarding your visual inspection
processes in the event a second visual inspection is required.
F. 在需要进行第二次目视检查时，你尚未针对视觉检查过程建立过程中的缺陷限度。
G. You do not have a requirement preventing you from modifying your in-process
limits established to monitor process control nor do you limit the amount you change
your in-process limits.
G. 你没有要求阻止你修改为监控工艺控制而建立的过程中限度，也没有限制更改过
程中限度的数量。
H. During your statistical evaluation of in-process data used to establish / re-
establish in-process limits, you exclude statistical outliers. However, you have not
performed a substantive review of the investigation to determine if the statistical
outlier is in fact a result of a special cause event.
H. 在对用于建立/重新建立过程中限度的过程中数据进行统计评估期间，你排除了统
计异常值。然而，你没有对调查进行实质性审查，以确定统计异常值是否实际上是特
殊原因事件的结果。
I. You do not monitor long term drift during your establishment / re-establishment of
in-process limits.
I. 在建立/重新建立过程中限度期间，你没有监控长期漂移。
Repeat Observation from 6/2016 2016 年 6 月的重复缺陷
24. 印度 Dr. Reddy’s 20181114

identification of persons performing each significant step in the operation.
批生产和检测记录有缺陷，未包括操作中每个重要步骤执行人员的身份识别。
Per media fill run DVD; Lot (b)(4) (dated on05/31/2017), the corrective
intervention i.e. (b)(4) is carried out by two (2) operators. One of the operator is in
the (b)(4) of the (b)(4) PR-E007 filling Line (b)(4) and the other operator is in the
(b)(4) of the (b)(4) Both operators simultaneously carried out the intervention in
the ISO-5 area of the (b)(4) PR-E007. However, the media fill batch records for
Lots (b)(4) and(b)(4) and the commercial batch records for aseptic (b)(4) process
of (b)(4) Injection (b)(4) mg/vial, Lots (b)(4) and (b)(4) aseptically filled in (b)(4)
PR-E007 filling Line (b)(4) only document the name of one (1) manufacturing
operator when the (b)(4) corrective intervention was performed.
在培养基灌装运行 DVD 中，批号 XX（日期 20170531），纠正性干预是由 2 名操作员
实施的。一名操作员在灌装线 XX 的 XX，另一名操作员在灌装线 XX 的 XX。2 名操作员
同步执行 ISO-5 区域对 XX PR-E007 西林瓶灌装线的干预。但 XX 批和 XX 批的培养基
批记录和商业化批记录对于纠正干预执行情况只记录了一名生产操作员的姓名。
25. 印度 Lupin Limited (Unit I) 20181204

API OBSERVATION 4 缺陷 4
The cleaning and disinfecting of the room and equipment used in the processing
of aseptic drug products are deficient in your firm’s aseptic processing areas. 你公
司无菌工艺区内无菌药品加工所用房间和设备清洁和消毒有缺陷。
A. Your firm does not clean areas that are found to be out of specification (OOS)
for microbial counts. For example, but are not limited to: 你未对你们发现微生物计
数超标（OOS）的区域进行清洁。例如但不仅限于：
- MB/OOS/16-01, documents (b)(4) should be done in the sterile areas after
Aspergillus sydowii (fungus) was found during a routine fingertip sampling in the
Grade –A/ISO 5 area.
- MB/OOS/16-01，记录了在 A 级区（ISO5 级）里如在常规指印取样中发现萨氏曲霉
（真菌）则应在无菌区执行 XX。
- MB/OOS/16-06, documents additional (b)(4) should be done in the sterile areas
after Verticillum aranearum (fungus) was found during a routine settle plate(air)
sampling in the Grade –A/ISO 5 area.
- MB/OOS/16-06，记录了在 A 级区（ISO5 级区）里如在常规沉降碟（空气）取样中
发现黄萎病菌（真菌）则应执行另外的 XX。
B. Your firm did not have supporting documentation ensuring the wipes and mop
heads used during routine cleaning of your firm’s aseptic areas are low shedding
particles. In addition, your firm’s Production Manager stated the mop heads are
not dedicated and can be used throughout the facility. Your firm does not have a
defined frequency when a mop head should be changed.
你公司没有支持性文件确保无菌区内常规清洁所用抹布和拖把头不会掉落颗粒。另外，
你公司的生产经理声称拖把头并不是专用的，可在以整个厂区内使用。你公司未规定拖
把头的更换频次。
C. Your firm uses the (b)(4) for (b)(4) routine cleaning conducted in the (b)(4)
aseptic processing area. However, your firm does not document cleanings of this
equipment are conducted (b)(4) per the manufacturer’s recommendations. In
addition, there is no documentation the filter is replaced every (b)(4) of use or
every (b)(4).
你公司在 XX 无菌工艺区进行 XX 常规清洁时使用的是 XX。但是并未记录按生产商建议
所执行的 XX 清洁。另外，没有文件记录过滤器每使用 XX 次或每间隔 XX 时长后即要更
换。
Written procedures are deficient in that they do not address routine maintenance
of your firm’s (b)(4) System, which is used to sanitize your firm’s aseptic areas (b)
(4) campaign or after a microbiological OOS.
书面程序有缺陷，其中未写明你公司的 XX 系统的日常维护操作，该系统用于对你公司
的无菌区 XX 周期或在微生物 OOS 之后进行消毒。
Specifically, the manufacturer recommends maintenance cleanings and
inspections are to be conducted (b)(4) uses or (b)(4). Records are not kept for the
maintenance and inspection of your firm’s (b)(4) System equipment. In addition,
your firm’s cleaning records are deficient in that they do not include sufficient
detail of the methods of disassembling and reassembling equipment as necessary
to assure proper cleaning is conducted.
具体来说，生产商建议要对 XX 使用或 XX 进行维护清洁和检查。你公司的 XX 系统设备
没有维护和检查记录。另外，你公司的清洁记录有缺陷，其中未包括有设备拆卸与重新
装配方法的详细说明，以确保执行适当的清洁。
FP OBSERVATION 3 缺陷 3
results of drug product examinations and inspections.
批生产和控制记录有缺陷，未包括药品检验检查的结果。
The written procedure for in-process checks is deficient. For example, SOP#QAD-
121-12 does not include any visual examination criteria during filling and
packaging operation for the (b)(4) type drug products. The following summarizes
complaints related visual defects and foreign objects since 2016:
中控检查的书面程序有缺陷。例如，SOP#QAD-121-12 未包括 XX 类型药品灌装和包
装操作中的目视检查标准。以下总结了 2016 年以来与目视缺陷和异物有关的投诉：
Nature of complaint 投诉情况 2016 2017 2018

Discoloration 脱色 5 1 0
Foreign objects: Examples: Plastic, Insects 2 1 2
(spider) 异物：如塑料、昆虫（蜘蛛）
Market complaints related to visual defects are deficiently closed as inconclusive
based on review of existing documentation. However, the in-process
documentation itself is deficient as there is no provision built-in to record any
visual deficiencies during product manufacturing (filling and packaging).
与目视缺陷有关的市场投诉关闭有缺陷，因为对现有文件的审核无法得出结论。但是，
中控文件本身是有缺陷的，因为没有将药品生产（灌装和包装）过程中目视检查缺陷的
要求设计至记录中。
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.
未按适当时间间隔对设备和工器具进行清洁以防止发生改变药品安全性、鉴别、剂量、质
量或纯度的污染。
A. Non-dedicated equipment which was stored as “cleaned” was found with
unknown (b)(4) residues. On 26 November 2018, a “cleaned” Tablet press
(Equipment # COM-04) was found with unknown (b)(4) residue in several product-
contact surfaces of the tablet press equipment.
存贮标为“已清洁”的非专用设备被发现有未知 XX 残留。20181126，发现一个“已清
洁”的压片机（设备编号#COM-04）与几个产品接触的表面上有未知 XX 残留。
B. The (b)(4) machine utilized for the cleaning of floors of (b)(4) multi-product
manufacturing area was found without any documentation of cleaning and usage.
As per your manufacturing employee (b)(4), this machine is regularly used to
clean corridors and product manufacturing rooms.
发现用于 XX 多产品生产区地面清洁的 XX 设备没有清洁和使用记录。根据你们生产员
工 XX 的说法，该设备日常用于清洁走廊和产品生产房间。
26. Lupin Limited 20190219

There are not written procedures for production and process controls designed to
无书面生产和工艺控制程序设计用以确保药品具备其理应具备的鉴别、剂量、质量和纯
度。
As per the approved batch records, the (b)(4) procedure is required to be
continued (b)(4) without a discharge process of the (b)(4). However, during
manufacturing, the (b)(4) is discharged into smaller bins (b)(4) procedure.
Currently, the discharge process is documented in additional data entry pages
which are not part of approved batch records. An evaluation of discharge process
and the (b)(4) uniformity after discharging into bins has never been studied as part
of the process validation. In addition, this procedure is performed without raising a
deviation which is required as per SOP# CQA-003-06, entitled as “Handling of
Deviations”. This deviation from approved batch records were observed for the
following products, but not limited to:
根据批准的批记录，XX 程序之后应接着 XX 而不要 XX 卸料过程。但是在生产中，XX
被卸至小桶内。现在，卸料的程序是记录在一张单独的数据记录纸上的，不是已批准批
记录的一部分。卸料操作和卸料至桶中后 XX 均一性从未作为工艺验证的一部分进行研
究评估。另外，该执行该程序并未按 SOP#CQA-003-06“偏差处理”所要求启动偏差
在以下产品中（但不限于）发现偏离已批准批记录的偏差：
Product 药品 Number of batches Shipment to US market since
批数开始销至美国时间
(b)(4) Tablets USP, (b)(4)mg (b)(4) 2017-02
(b)(4) Capsules, (b)(4)mg (b)(4) 2013-12
二．质量系统

The responsibilities and procedures applicable to the quality control unit are not
fully followed.
未完全遵守质量部门所适用的职责和程序。
****THIS IS A REPEAT OBSERVATION****此为重复缺陷
A. According to the spreadsheet used by your firm’s Quality Assurance
Department to track and trend (b)(4) data, your Quality Unit failed to follow your
established written procedure for handling of Out of Specifications (OOS) and
Out of Trends(OOT) results within the specified timeframe in 2017. For example,
but not limited to the following:
根据你公司 QA 部门用以追踪 XX 数据和对其进行趋势分析所用的表格，你们质量部门
2017 年未能遵守既定的书面程序在指定时间段内处理 OOS 和 OOT 结果。案例包括但不
仅限于以下：
(1) One hundred eleven OOSs: 111 个 OOS
Analysis Conducted # of OOS not
所实施的分析 completed within
specified
timeframe 在指定时
间段内未完成的 OOS
个数
Assay 含量 27
Blend uniformity 混合均一性 2
Physical Description 物理描 2
述
Dissolution 溶出度 20
Organic Impurity 有机杂质 13
Particle size 粒径 3
Related substance 有关物质 34
TOC 2
Water content 水分 6
Total # of OOS 总数≥(b) 111
(4)
(2) Twenty-three OOTs: 23 个 OOT
Analysis Conducted 所实施 # of OOT not
的分析 completed within
specified
timeframe 在指定时
间段内未完成的 OOT
个数
Assay 含量 8
Dissolution 溶出度 12
UOD 3
Total # of OOT 总数≥(b) 23
(4)
B. Your firm failed to log samples in the Central Laboratory per your written
procedure, “QC/QA/012, Sampling of In-Process, Semi-Finished and Finished
Product, Effective Date: 28/11/17”. We observed samples in the Sample
Storagearea lacking the following required information on a Sample Analysis
Sheet, Product Name, Batch No., Manufacturing Date, Expiration Date, Stage,
Test,Sampled by, and Date of sampling.
你公司未能在中心化验室依据书面程序（QC/QA/012，中间体、半成品和成品取样，生效
日期 2017-11-28）登记样品。我们发现样品存贮区域里的样品缺乏以下样品分析表中所
需信息：产品名称、批号、生产日期、有效期、步骤、检测、取样人、取样日期。
The in-process control procedures were deficient in that it did not include an
examination of tablet and capsule weight variation.
中控程序有缺陷，其中未包括对片剂和胶囊重量差异的检查。
Specifically, your firm failed to implement checks for tablets, such as: tablet
weight, before, during, and after packaging for weight, etc. for rejection during
manufacturing to prevent product mix-ups.The lack of this parameter caused
product mix-ups where a (b)(4)mg tablets of(b)(4) was found by a customer in a
(b)(4)mg bottle of tablets for XXmg product Batch #(b)(4). Furthermore, your
investigation failed to evaluate patient impact, as, the report does not address
risk to the patient that needed the higher dose, but may have received a much
lower dose than needed.
具体来说，你公司未对片剂执行检查，如：包装前、包装过程中和包装后片剂重量等，在
生产期间拒收以防止药品混淆。缺乏此参数导致客户在 XXmg 片剂瓶中发现了 XXmg 片剂
并且你们调查未评估患者影响，因为报告并未说明需要更高剂量患者可能实际摄入较低剂
量的风险。
2. 英国 Dr. Reddy’s 20170926

Procedures are not established or followed.
未建立或遵守程序。
Your firm failed to follow procedures to file a report for the following:
你公司在以下案例中未能按程序提交报告：
 No Change Control/Management of Change (MOC) was opened
following OOS 15/015, dated 21 July 2015 which stated to “update(b)(4) to
include that the material is susceptible to static and sample may be
erroneously weight. Include not to rehandle the glassware” as the corrective
action. However, the MOC #200250489 was not filed until 24 July 2017 and
completed until 2 years later on 18 Aug 2017.
 未针对 2015-07-21 的 OOS15/015 启动变更控制/变更管理（MOC），其中说
“更新 XX 加入如果物料易受静电影响，样品称重可能会产生错误，不应重新处理玻璃仪
器”作为纠正措施。但是 MOC #200250489 直到 2017-07-24 才提交，直到 2 年后
2017-08-18 才完成。
 No Change Control/Management of Change (MOC) was opened/created
for the discontinued used and removal of laboratory equipment HPLC 24 in 2015
that was used in the testing of (b)(4) API.
 化验室仪器 XX 原料药检验用 HPLC24 在 2015 年即停止使用并移除，但未启动/创
建变更控制/变更管理（MOC）。
 No Change Control/Management of Change (MOC) was created for the
rewording of raw material sampling labels from “QC Sampled” to “Sampled”
to correctly represent that raw material sampling is conducted by warehouse
staff and not Quality Control (QC) staff.
 原料取样标签从“QC 取样”改为“取样”以正确表达由仓库员工而非 QC 员工所
取的原料样品，但未创建变更控制/变更管理（MOC）。
 No incident or deviation was documented for the shutdown of HVAC for
Area (b)(4) during production of (b)(4) during (b)(4) stage on 30 Oct 2014, which
was discovered during the investigation of an Environmental Monitoring OOS
Notification #200112172, dated 15 Nov 2014.
 在 2014-11-15 的环境监测 OOS 通知#200112172 调查过程中发现，2014-10-
30 在 XX 步骤 XX 生产过程中 XX 区域的 HVAC 系统中断，但未记录为事件或偏差。

There is a failure to thoroughly review any unexplained discrepancy whether or
not the batch has been already distributed.
已销售和未销售批次中非预期差异未进行彻底审核。
Specifically, there is a failure to consistently evaluate any unexplained discrepancy
to ensure that (b)(4) drug products conform to the predetermined quality
attributes.
具体来说，未能对所有非预期差异进行一致的评估，以确保 XX 药品符合预定质量属性。
Your visual inspectors have been rejecting in-process samples of (b)(4) drug
product due to the presence of either integrity defects or foreign materials in
aseptically filled (b)(4). Nonetheless,no manufacturing neither laboratory
assessments have conducted even though the cause(s) that might be responsible
for such conditions is not characterized.
你们的目视检查人员由于在 XX 无菌灌装中发现异物或完整性缺陷而拒收了 XX 药品的中
控样品。但是，根本没有进行生产和化验室评估，甚至都没有界定此种情况发生的原因。
Your current practice is to conduct an investigation if the total number of (b)(4)
rejected with defects during the manual inspection process is More Than (MT) (b)
(4) %. This control limit applies to the different potential defects that could be
detected in the manufacturing process of (b)(4) drug products, including (b)(4)
particles,black particles, fiber, glass and broken (b)(4) among others. However,
your current practices is indicative that you failed to consider other actions such
as, technical analyses of the affected aseptically filled (b)(4) or a continuous
monitoring of your process in order to identify through a scientific evaluation the
potential source(s) and prevent re-occurrence.
你们当前的做法是如果人工检查过程中被拒缺陷 XX 总数超过（MT）XX%则进行调查。此
控制限度用于 XX 药品生产过程中可能发现的各种潜在缺陷，除其它以外还包括 XX 颗粒
物、黑色颗粒、玻璃和碎 XX。你们当前的做法显示你们未考虑其它措施如对受影响的无菌
灌装 XX 进行技术分析，或持续监测你们的工艺以通过科学评估发现潜在来源并防止其再
次发生。
Investigations of an unexplained discrepancy did not extend to other batches of
the same drug product or other drug products that may be associated with the
specific failure or discrepancy:
对非预期差异的调查未延伸至其它相同产品或可能与特定失败或差异有关的其它产品：
Specifically, your firm uses common equipment and production processes for
multiple drug products and drug substances such as (b)(4). Your Quality Unit
initiated more than 1,040 deviations from 2015 to 2018, but has failed to extend
the investigations of deviations (DR) and OOS discrepancies to other batches and
products that were manufactured under similar conditions. This practice is
indicative that you Quality unit failed to ensure the quality and production
systems are in a state of control. The following deviations are examples of events
where your quality unit did not extend the assessment of the investigation and to
consider related root causes and to establish a CAPA in order to prevent adverse
trends. In many cases the relate product batch was released.
具体来说，你们公司将设备和生产工艺用于多个制剂和原料药如 XX。你们的质量部门在
2015-2018 年间启动了超过 1040 个偏差，但并未将偏差（DR）和 OOS 差异调查延伸至
在相同条件下生产的其它批次和产品。此种做法显示出你们质量部门未能确保质量和生产
体系处于受控状态。以下偏差是你们质量部门未延伸其调查评估并考虑相关根本原因和建
立 CAPA 以防止不良趋势的例子。在多个案例中，相关产品批次均被放行。
A. AQL Failures for Drug Product (DD/MM/YY) 制剂的 AQL 不合格（年月日）
1. BM/DR-17/037 2017-05-04
2. BM/DR-17/060 2017-05-31
3. BM/DR-17/066 2017-06-06
4. BM/DR-17/082 2017-06-16
5. BM/DR-17/120 2017-07-28
6. BM/DR-17/121 2017-07-28
7. BM/DR-17/152 2017-08-16
B. (b)(4)or (b)(4) OOS for Drug Substances 原料药 XX 和 XXOOS
1. BM/DR-17/196 2017-03-10
2. BM/DR-17/217 2017-17-10
3. BM/DR-02/16/001 2016-05-05
4. BM/DR-02/16/055 2017-02-04
5. BM/DR-02/16/059 2017-03-12
6. BM/DR-02/16/060 2017-03-16
C. OOSfor (b)(4) for (b)(4) System Sampling (b)(4) or (b)(4) system) XX 的 XX 系
统取样 XX 和 XX 系统 OOS
1. BM/DR-17/204 2017-10-09
2. BM/DR-17/244 2017-10-31
3. BM/DR-17/268 2017-11-15
4. BM/DR-17/290 2017-11-23
5. BM/DR-17/296 2017-11-28
6. BM/DR-17/307 2017-12-04
7. BM/DR-17/318 2017-12-11
Written production and process control procedures are not followed in execution
of production and process controlfunctions.
未按照书面生产和工艺控制程序执行生产和工艺控制职能。
Specifically, your Quality unit has not always followed and executed your
procedure for deviation management regarding drug product and rug
substance. Your procedure BM/QA/SOP024, version 004, titled “Deviation
Management”, effective 19 January 2018 states:
具体来说，你们质量部门并未坚持遵守和执行你们的制剂和原料药偏差管理程序。你们
2018-01-19 生效的的程序 BM/QA/SOP024 版本号 004 标题为“偏差管理”中：
A. Section 6.2.4 note-1, that prior deviations of similar nature that
occurred in the last(b)(4) are considered as recurring type;
第 6.2.4 部分注-1，在过去 XX 发生的之前的类似偏差将被作为是重复发生的类型；
B. Section 6.2.12(b), that all deviations shall be closed within (b)(4) days
with a grace period of (b)(4) days;
第 6.2.12（b）部分，所有偏差均应在 XX 天后关闭，宽限期为 XX 天。
C. Section 6.2.13(a), that delays in deviation closure should be justified
with a reason and a target completion date.
第 6.2.13(a)部分，偏差关闭延迟应有理由支持并有目标完成日期。
During the years 2016-2017, your firm had over 748 deviations with an average of
17% overdue past the target date and an average of 34% recurring deviations,
per the (b)(4) deviation trending reports.
根据 XX 偏差趋势分析报告，在 2016-2017 年间，你们公司有 748 个偏差，平均有 17%
超出目标日期，平均 34%偏差重复发生。
Date range Total Open and Percent Recurring Percent
Deviation overdue Overdue (%) Recurring (%)
Target Date
日期范围总偏差数未关闭和超期平均超期重复发生重复发生百分比
偏差
(b)(4) 135 25 19% 54 40%
(b)(4) 104 13 13% 37 36%
(b)(4) 90 19 21% 37 41%
(b)(4) 88 9 10% 35 40%
(b)(4) 102 15 15% 16 16%
(b)(4) 71 20 28% *ND *ND
fully followed. Specifically,
未全面遵守质量部门的职责和程序，具体反映在：
A. Your Quality Unit failed to close multiple CAPAs within the (b)(4) allowable
timeframe and a justification extend the completion timeframe was not
requested. Specifically, your Quality Unit did not request an extension to the
following CAPAs:
你们质量部门未能在 XX 允许时间范围内关闭多个 CAPA，也没有申请延长完成时间的理
由。具体来说，你们质量部门对于以下 CAPA 未申请延期：
CAPA No. Initiation Date Due date Closure date
CAPA 编号启动日期设定完成日关闭日期
200223950 2017-02-13 (b)(4) (b)(4)
200203437 2016-10-17 (b)(4) 2018-02-28
200204765 2016-10-25 (b)(4) 2018-02-28
200204723 2016-10-25 (b)(4) 2017-04-25
200211138 2016-11-30 (b)(4) 2018-03-07
200211835 2016-12-05 (b)(4) 2018-03-07
200212526 2016-12-08 (b)(4) 2018-03-07
200213288 2016-12-13 (b)(4) 2018-03-07
200214127 2016-12-19 (b)(4) 2018-03-07
200251795 2017-07-31 (b)(4) 2018-02-27
B. The Empower 3 audit trail used in the QC laboratory for data acquisition
system revealed on 2018-02-14 that Sample Set ID 2793, Sample Method
#14318050 was aborted after injection #6 during system suitability for Agilent
HPLC #QC-143, Per SOP #GQA032-01 (Handling of Incidents) 2017-09-15
effective date, an incident report is to be raised. However,at the time of the
inspection no incident report was generated or explanation was documented on
why this sample set was aborted.
QC 用作数据采集系统的 Empower 3 的审计追踪显示在 2018-02-14 有一个进样序列号
为 2793，样品方法#14318050 在 Agilent HPLC #QC-143 系统适用性运行中#6 针进样
后被中断，依 SOP #GQA032-01（事故处理），生效日期 2017-09-15，应提交一份事
件报告。但是，直到检查时都没有填写事件报告，也没有文件记录为什么要中止这个进样
序列。
C. Your firm has not established Quality Agreements with some of its starting
materials suppliers, such as the supplier for (b)(4) used to manufacture (b)(4) for
the US market. This practiceis contrary to what is described in Section 5.5.2.1
(Quality Assessment) and Step #1.1.18 (Quality Agreement) of Annexure
GQA020/A04 (Documentation Requirement (b)(4) Form #GOA020/F03-00) of SOP
#GQA020-00 (Vendor Management) 2017-05-15 effective date.
你公司未与一些起始物料供应商签订质量协议，如用于美国市场的 XX 生产所用 XX 的供
应商。此种做法与 2017-05-15 生效的 SOP#GQA020-00（供应商管理）中附录
GQA020/A04（文件要求 XX 表#GOA020/F03-00）的第 5.5.2.1 部分（质量评估）和第
#1.1.18 步（质量协议）所述是冲突的。
D. Per Step #3.9 of SOP #GQA053-00(Electronic Data Management for Laboratory
Instruments System), “backup data shall be assessed to verify successful
completion of the backup process. In the event, if the backup process fails, the
same shall be investigated through an incident notification as per SOP: GQA032
Handling of incident.” This practice is not being performed by the firm based on
two failures recorded on 2017-02-09 and 2017-12-27.
依 SOP#GQA053-00（化验室仪器系统的电子数据管理）第#3.9 步要求，“应对备份数
据进行评估以确认成功完成备份操作。如果备份失败，应依 SOP：GQA032 事故处理通过
事故通知进行调查。”公司对 2017-02-09 和 2017-12-27 所记录的 2 次失败均执行此规
范要求。
Procedures describing the handling of written and oral complaints related to API
materials are not followed. Specifically,
未执行与 API 原料有关的书面和口头投诉处理程序。具体如下：
A. Complaint #200262075 was received and initiated on 2017-10-09 for particle
size OOS ((b)(4) USP) for Batch#(b)(4). The conclusion of the complaint
investigation states that the firm “require sample from the customer to confirm
the particle size variation observed. ”However, the investigation did not reveal if
the firm received the requested sample from the customer and tested. A final
investigation report has not been issued.
2017-10-09 收到并启动关于批号 XXX 的粒径 OOS（XX USP 规格）投诉#200262075。
投诉调查结论说公司“要求客户提交样品以确认其所发现的粒径差异。”但是，调查并未
显示公司是否从客户处收到所要求的样品并进行检测。最终的调查报告尚未签发。
B. Complaint #200235463 was received on 2017-04-19 and initiated on 2017-04-
20 for (b)(4) Batches #(b)(4)and (b)(4) on 2017-04-19 due to the presence of a (b)
(4) bag found in the material. The conclusion of the complaint investigation states
that “SOP onPacking & Repacking shall be revised by including this
requirement. ”However, there was no CAPA reference number in the
investigation. At the time of the inspection, the SOP for Packing & Repacking has
not been update.
2017-04-19 收到，2017-04-20 启动 XX 产品 XX 批次，和 2017-04-19 启动 YY 批次由
于在物料中发现 XX 袋子的客户投诉#200235463。投诉调查的结论声称“应修订包装和重
新包装 SOP，加入此要求”。但是，在调查报告中并无 CAPA 索引号。在检查之时，包装
和重新包装的 SOP 仍未更新。
C. Complaint #200219745 was received and initiated on 2017-01-20 for (b)(4) Ph.
Eur Batch #(b)(4) due to OOS in Particle Size Results (b)(4). Per SOP #01-005/09
(Complaints) effectivedate 2016-04-11, if unable to meet the due date an
extension is to be requested with justification and approval. On (b)(4) a
justification for extension was written and approved by the QA Manager after the
due date (b)(4). The complaint investigation did not include a conclusion and
actions taken by the firm. Although the firm provided several follow-up responses
to the customer dated 2017-02-21 and 2017-05-09, there is no reference of these
actions in the preliminary complaint investigation report.
2017-01-20 收到并启动 XX 产品 EP 批次 XX 的粒径结果 XXOOS 投诉#200219745。依据
2016-04-11 生效的 SOP#01-005/09（投诉），如果到期未关闭，要提交延期申请说明
理由并获得批准。在 XX 到期日之后的 XX 日，提交了延期申请说明了理由并由 QA 经理批
准。投诉调查并未包括结论及公司要采取的措施。尽管公司在 2017-02-21 和 2017-05-09
给客户提供了几个后续回复，但在最初的投诉调查报告中并未引用这些措施。
D. Your Quality Unit failed to close complaint investigations within the allowable
timeframe and ajustification to extend the completion timeframe was neither
requested within the (b)(4) timeframe nor closed within the complaint
investigation completion timeframe. Specifically, your Quality Unit did not
request an extension to the following complaints within the (b)(4)
你们质量部门未能在允许的时间框架内关闭投诉调查，在 XX 时间框架内未提交理由申报
延期，也未关闭投诉调查。具体来说，你们的质量部门未对以下投诉申请延期：
CAPA No. Product Date OpenedDue date Closure date
CAPA 编号产品启动日期设定完成关闭日期
日
200262075 (b)(4)USP 2017-10-09 (b)(4) (b)(4)
200219745 (b)(4)Ph.Eur 2017-01-20 (b)(4) 2017-05-19
200269998 (b)(4) 2017-12-01 (b)(4) 2018-01-06
200235463 (b)(4) 2017-04-20 (b)(4) (b)(4)

Your firm’s Production Quality Reviews (PQRs) are deficient.
你公司的生产质量回顾（PQR）有缺陷。
A. 2017PQR for (b)(4) Capsules (review period January 2017-December 2017):
2017 年 XX 胶囊的 PQR（回顾期间 2017 年 1 月至 2017 年 12 月）
1. Does not address corrective and preventative actions implemented for out
of specification (OOS16-005) for (b)(4) content for (b)(4) Capsules (b)(4) mg,
Batch #(b)(4) .
并未说明 XX 胶囊 XX 批号 XX 含量 OOS（OOS16-005）所执行的纠正与预防措施
2. Is missing change control (EN/CCP/17/5036) for the installation of new
equipmentin the packing line (b)(4) inserting Machine, (b)(4) Machine, (b)(4)
Labeling Machine, (b)(4) Overprinting, Leaflet in Outserter Machine, and Torque
(Machines), which were qualified and installed in 2017.
缺失了在包装线 XX 安装新放置说明书的新设备，XX 机 XX 贴标机 XX 打印机和扭力机变
更控制（EN/CCP/17/5036），这些设备于 2017 年安装并确认。
3. In addition, your firm’s written procedure for product Quality Review
(SOP/CQO/3021), defines the product review period as a calendar year from
January to December. However, the 2017 PQR for (b)(4) covers a review period of
January 2016-December 2017. A Deviation was not provided.
此外，你公司书面产品质量回顾程序（OP/CQO/3021）定义了产品回顾时间段为从 1 月
至 12 月的自然年。但是，XX 产品的 2017 年 PQR 覆盖了自 2016 年 1 月-2017 年 12 月的
时间段。未能提供偏差。
B. Your firm’s PQR for (b)(4) Tablets does not address corrective and
preventative actions implemented for an out of specification (OOS) for the
following:
你公司的 XX 片剂 PQR 并未说明为以下 OOS 所实施的纠正和预防措施
1. OOS 17-002: Unknown impurity peaks were found in (b)(4) Tablets, Batch
(b)(4),dated 7 March 2017.
OOS17-002： 2017-3-7 在 XX 片剂批号 XX 检测中发现未知杂质峰
2. OOS 17-003: Sub-potent assay results for (b)(4) tablets, Batch #(b)(4) and
Batch #(b)(4) dated 17 March 2017.
OOS17-003： 2017-3-17 XX 片剂 XX 批次和 XX 批次含量结果不合格，
C. Your firm’s APQR for (b)(4) Capsules does not address corrective and
preventative actions implemented for an out of specification (OOS) for the
following:
你公司的 XX 胶囊 APQR 并未说明为以下 OOS 实施的纠正和预防措施
1. OOS 17-002: Unknown impurity peaks were found in (b)(4) Capsules, Batch
#(b)(4) dated 7 March 2017.
OOS17-002：2017-03-07 在 XX 胶囊 XX 批号中发现未知杂质峰
6. 印度 Glenmark 20180605
fully followed.
质量部门未全面执行适用职责和程序。
Your firm’s Quality Unit has no adequate oversight on the raw data pertaining
to production and QC laboratory. For example,
你公司的质量部门对生产和 QC 的原始数据并无足够的监管，例如：
1. On 05/15/2018, we observed torn balance printouts, shredded documents, torn
draft investigation reports, etc. Your firm’s interim investigations pertaining to
balance printouts confirmed that production employees dismantled printouts
pertaining to balance number EPD292 on05/15/2018 for the (b)(4) operation of
(b)(4) tablets (b)(4) mg, batch number (b)(4) ((b)(4) of lot-(b)(4)).
20180515 日，我们发现了撕毁的天平打印纸、碎掉的文件、撕毁的调查报告草稿等。你公
司的对天平打印件的临时调查确认是生产员工废弃的 20180515 日的 EPD292 天平在 XX
片剂 XXmg 的 XX 批号的 XX 操作的打印件。
Your firm’s production employees deviated from SOP CQA 061 “Data lifecycle
management” section 5.1.2 “Raw Data” and5.1.3. “Metadata (data about
data)” must be contemporaneously and accurately recorded by permanent
means.
你们公司的生产员工违背了 SOP CQA 061“数据生命周期管理”第 5.1.2 部分“原始数
据”和 5.1.3 部分“元数据（数据的数据）”必须以永久方式同步并准确记录的规定。
2. Your firm maintains a total of (b)(4)document destruction bins at various
locations throughout the facility and the documents gets shredded using a
shredder located in QA documentation cell and shredder area as per SOP
CM/QA050 “Procedure for disposal of GMP documents by shredding”. Your
SOP CM/QA050 per ANNEXURE-III allows shredding of investigations
reports(draft), records of supporting documents to change control, etc.
你们公司在整个工厂不同地方放了共 XX 文件销毁纸篓，文件碎纸则在 QA 文件中心和碎
纸区域按 SOPCM/QA050“GMP 文件碎纸处理程序”进行粉碎。你们的 SOP
CM/QA050 附录 III 允许对调查报告、变更控制支持性文件记录（草案）进行粉碎。
We observed entries for several investigations reports (draft) in your document
disposal records that were shredded per SOP CM/QA050.
我们发现几个调查报告（草案）录入了你们的文件处理记录，并依 SOP CM/QA050 被粉
碎。
3. On 05/21/2018, we observed that your firm has no control over the issuance of
qualification protocols and worksheets used for recording of equipment
qualification activities. The equipment qualification protocols and worksheets are
maintained on both production and QA computers and can be printed without
seeking an approval from the QA department as it was evident for Compression
ID: EPD264.
在 20180521 日，我们发现你们公司对确认方案和记录设备确认活动的工作表并无控制。
设备确认方案和工作表在生产和 QA 电脑上都有保存，可以不需要 QA 部门批准即行打印，
压缩机 IDEPD264 即为证据。
Your SOP CM/QA028 “Preparation and Approval of document” is deficient for
the control over issuance and control of qualification documents.
你们的 SOP CM/QA028“文件制订与批准”在确认文件的签发和控制方面有缺陷。

Written records of investigation of a drug complaint do not include the findings of the
investigation and follow-up.
药品投诉调查的书面记录中未包括调查结果及跟踪情况。
Investigation of complaints is deficient.
对投诉的调查是有缺陷的。
(a) Upon trending complaints from 2016, Iidentified that lots (b)(4) and (b)(4) of (b)(4)
Tablets had 5 associated complaints related to the category “Tablet Broken or Chipped”
On 13.04.16. batch (b)(4) “passed” 100% visual examination. I reviewed reports PRs
944122 and 986459 related to complaints for lot (b)(4) and did not observe a
comprehensive evaluation, including identifying the size of the chip or consideration of
formulation factors. This complaint type has been deemed a “Recurring Event/Trend”.
在 2016 年投诉的趋势分析中，我发现 XX 和 XX 批 XX 片剂有 5 个关联投诉，均与“片剂
破碎或缺损”类别有关。2016 年 4 月 13 日，XX 批“通过了”100%目视检查。我审核了报
告 PR944122 和 986459，该报告与 XX 批投诉有关，并未发现有一份全面的评估，包括
识别缺损大小或考虑配方因素。此投诉类别被认为是“反复发生的事件/趋势”。
I reviewed SOP MLLNSK-SOP-QA-GMP-0120 entitled “HANDLING OF
COMPLAINTS” with your firm’s General Manager – Quality Assurance. He specified
that (b)(4) or more complaints for the same lot was a threshold for investigating
“Major” of “Minor” complaints, in order to differentiate isolated events. On
09/08/2016, I observed multiple chipped tablets in a single (b)(4) tablet bottle of
retained (b)(4) Tablet lot (b)(4).
我与你们公司的 QA 总经理一起审核了 SOP MLLNSK-SOP-QA-GMP-0120，标题为
“投诉处理”。他指出同一批号的 XX 或更多投诉为对“轻微”投诉启动“重大”调查
的阈值，用以区别独立的事件。在 2016 年 9 月 8 日，我在 XX 片剂 XX 批号留样的一个
XX 片剂瓶中发现多个缺损片。
Your firm’s Head of OSD Site Operations –Nasik stated that your firm has opened a
comprehensive CAPA and made significant efforts to identify the source of the
broken and chipped tablets. However, the inspection was conducted in March 2015
and this CAPA was conducted in June 2016, when additional complaints related to
broken or chipped tablets were obtained. Additionally, these investigations are
deficient in not considering the aforementioned factors. Furthermore, this report
concludes that “As the compression observation ((b)(4)) and AQL observations are
within specifications, breakage of single tablet (in the reported complaint), cannot be
attributed toa process or product defect.”
你公司的 OSD 工厂运营负责人-Nashik 声称，你们公司已启动了全面 CAPA，做了巨
大努力识别出碎片和缺损片的来源。但是，检查是在 2015 年 3 月执行的，而此 CAPA
是在 2016 年 6 月收到更多与碎片或缺损片有关投诉时才执行的。另外，这些调查是有
缺陷的，因为它未考虑前述因素。还有，该报告得出结论说“由于压延缺陷 XX 和 AQL
缺陷均在标准内，因此（在所报告的投诉中）单个碎片不能归因于工艺或产品缺陷。
However, on 09/11/2016, I observed the (b)(4) of the filling line for (b)(4) Tablets,
where tablets had abrasions in the (b)(4). Additionally, I observed significantly
chipped tablets pass through the tablets(b)(4) occurrences are indicative of
deficiencies in your firm’s visual inspection, as well as ensuring drug product quality.
但是，在 2016 年 9 月 11 日，我察看了 XX 片的包装线的 XX，发现在 XX 上的片剂有
擦伤。另外，我还发现严重缺损片通过片剂 XX 发生是你们公司目视检查缺陷以及确保
药品质量的指征。
(b) (b)(4) tablet batch (b)(4) had two associated complaints.In one instance, no sample
was retrieved for analysis. In the complaint PR 632630, the complaint concludes that “As
some pieces match to form complete tablets” the incident is not related to your Nahik
facility (as all the piecesto the broken tablet were in the bottle therefore the issue is
unrelated to your manufacturing facility). Your firm’s General Manager – Quality
Assurance explained that as all fragments are contained within the bottle, therefore the
cause ofthe broken tablets is shipping. Your investigation into this matter failed to
consider other possible causes of the incidents, including the drug product formulationor
issues during manufacturing the may have led to the presence of broken tablets.
XX 片剂 XX 批有 2 个关联投诉。在一起投诉中，未能取回样品用于分析。在投诉
PR632630 中，投诉结论是“由于一些碎片拼起来形成完整的片子”，因此该事件与你们
Nashik 工厂并无关系（因为所有碎片均在瓶中，因此该问题与你们生产场所并无关系）。
你公司的 QA 总经理解释说因为所有碎片都在瓶内，因此碎片的原因是运输原因。你们对
此问题的调查未考虑其它可能的事件原因，包括药品配方或生产过程可能导致碎片出现的
问题。
THIS IS A REPEAT OBSERVATION FROM THEPREVIOUS INSPECTION
这是之前检查中的重复缺陷
8. 印度 Galaxy Surfactants 20180626

1. You failed to provide appropriate GMP and position specific training to personnel for
the particular operations that each employee performs as it relates to the employee’s
functions.
你们未给执行特定操作的员工提供与其职责相关的适当 GMP 培训和岗位特定培训
a) The operator responsible for the receiving of raw material was not given access to
the SOP that refers to the receipt of raw material in the warehouse. There spective
document, SOP#ST002-00 (Effective date 8/19/2017). Procedure for receiving of
materials, was not available to the operator in the warehouse.
负责接收原料的操作员在仓库里无法获取原料药接收 SOP，即文件 SOP#ST002-00（生
效日期 20170819）。操作员在仓库里拿不到物料接收程序文件。
b) Only 9 out of (b)(4) (include technical staff and the operators) employees at the firm
received cGMP training in 2017. However, SOP#QA011-00 (Effective date 8/12/2017).
Training and evaluation, section 4.1.3 states training frequency (b)(4) in a (b)(4). In
addition, firm also did not provide any refresher training as per section 4.1.33 of the SOP
that has a provision for refresher training (b)(4) in (b)(4).
XX 个员工（包括技术人员和操作人员）中只有 9 个在 2017 年接受了公司的 CGMP 培训。
但在 SOP#QA011-00（生效日期 20170819）“培训与评估”第 4.1.3 部分说明培训频次
为 XX。另外，公司亦未为每位新员工依 SOP 中 4.1.33 要求提供新进员工培训。
4. Your annual product review procedure is deficient suchthat:
你们的年度产品回顾程序存在缺陷，如：
a) You failed to conduct APR for your product (b)(4) for year 2016-2017.
你们未对 2016-2017 年度的产品 XX 进行年度回顾；
b) You did not include the stability data for 2016-2017 in the APR 2016-17. The 2016-
2017 APR for (b)(4) (Document # QA/M-3/APQR (b)(4) 16-17/00) contain only the
observations (not the actual data) with respect to the product specifications (complies
with specification) for the APIs that were manufactured in 2011 and 2012. Similarly, the
2016-2017 APR for (b)(4) Document # QA/M3/APQR (b)(4) 16-17/00) contains only the
observations (not the actual data) with respect to the product specifications (complies
with specification) for the API that was manufactured in 2011.
你们在 2016-2017 年度 APR 中未包括 2016-2017 稳定性数据。2016-2017 年的 XX 产品
APR（文件编号 QA/M-3/APQRXX 16-17/00）只有 2011 和 2012 年生产的 API 的关于药
品质量标准（符合质量标准）中的观察情况（不是实际数据）。类似情况，2016-2017 年
的 XX 产品 APR（文件编号 QA/M-3/APQRXX 16-17/00）只有 2011 年生产的 API 的关于
药品质量标准（符合质量标准）中的观察情况（不是实际数据）。

Observation3. There is a lack of quality oversight in the review of records and
proceduresfollowed in drug substance manufacture. Specifically, after deviation PR
176620(due to a bioburden excursion of the (b)(4) on 2 March 2017) was opened, an
unacceptably high level of bioburden ((b)(4) CFU/100mL) was (b)(4) detected on1 May
2017 (LIMS sample #974194) , on the same process equipment (X-165-01) used to
manufacture (b)(4) drug substance. The result (LIMS sample #974194) did not
automatically trigger a root cause investigation because the associated bioburden limit
was “report result”.
缺陷 3：对记录和原料药生产所遵守程序的审核中质量监管缺乏。具体来说，在偏差
PR176620（由于 20170302 生物负载超标）启动之后，20170501 发现用于生产 XX 原料
药的同一工艺设备（X-165-01）的生物负载水平高至不可接受（XXCFU/100ML）。该结
果（LIMS 样品#974194）未自动激活根本原因调查，因为相关的生物负载限度为“报告
结果”。
Observation4. Corrective actions do not include implementation of adequate procedures
to prevent similar deviations from recurring. Specifically, deviations PR 188727 and PR
189163 were opened because (b)(4) μm (b)(4) filter, item Master (IM) number 403350
(lot (b)(4)) failed to pass the (b)(4) integrity test. the root cause was determined to be a
defect in the filter’s manufacturing process. The filter vendor implemented corrective
actions to the filter manufacturing process inAugust 2017. The corrective actions
implemented after deviations PR 188727 and PR 189163 did not include establishing
appropriate procedures to prevent use of defective filters in the (b)(4) manufacturing
process.
缺陷 4：纠正措施未包括实施足够的程序来防止类似偏差的重复发生。具体来说，偏差
PR188727 和偏差 PR189163 由于 XXμmXX 过滤器，材料编号 403350（批号 XX）未通
过 XX 完整性测试而启动。根本原因确定为过滤器生产工艺有缺陷。该过滤器供应商于
2017 年 8 月对过滤器的生产工艺实施了纠正措施。在偏差 PR188727 和 PR189163 之后
实施的纠正措施不包括建立适当的程序防止在 XX 生产工艺中使用有缺陷的过滤器。
Aseptic processing areas are deficient regarding the system for monitoring
environmental conditions..
无菌加工区域的环境条件监测系统有缺陷。
Investigations for the below listed Out of Limits (OOL)for environmental monitoring in
Suite (b)(4), used in the manufacture of (b)(4) is incomplete.
下列用于 XX 生产的房间 XX 环境监测的 OOL 调查是不完整的：
OOL NO. Grade Type of Result Limit Product Activity
级别 monitoring 结果限度 manufacturing 操作
监测类型 (yes/No) 产品
生产（是/否）
M-EM/18/072 C Active air (b)(4) ≥(b)(4) No 否 Cleaning
sampling cfu/m3 cfu/m3 清洁
主动空气采样
M-EM/18/086 C Active air (b)(4) No 否 Cleaning
sampling cfu/m3 清洁
主动空气采样
M-EM/18/079 C (b)(4) (b)(4) ≥(b)(4) No 否 Cleaning
cfu/plate cfu/plate 清洁
M-EM/18/041 B Personnel (b)(4) ≥(b)(4) No 否 Cleaning and
monitoring cfu/plate cfu/plate Sanitization
人员监测清洁消毒
人员监测 (b)(4) 清洁消毒
cfu/plate
M-EM/18/0481 A Settle plate (b)(4) ≥(b)(4) No 否 Assembling
沉降碟 cfu/plate cfu/plate 装配
M-EM/18/068 B Surface (b)(4) ≥(b)(4) No 否 Cleaning and
表面微生物监测清洁消毒
The change control system to evaluate all changes that may affect the production and
control of intermediates or Active Pharmaceutical Ingredients (APIs) is not adequate.
Specifically,
评估所有可能影响原料药或中间体的生产和控制的变更控制系统不充分。具体来说
a) You do not always conduct a formal risk assessment for critical changes to evaluate
the potential impact of proposed changes on the quality of intermediates or APIs. Critical
Change Request PCRC-11025 was initiated November 27, 2011 and closed November
29, 2011, for the stated purpose of making changes to the (b)(4) manufacturing process
to (b)(4) the current (b)(4) ((b)(4)%- (b)(4)%) of the known isomer impurity (b)(4) in the
final API and (b)(4) batch yields (current batch yield (b)(4)- (b)(4) per batch).
你们未能对关键变更全部执行正式风险评估，以评价所拟变更对中间体 API 的潜在影响。

关键变更申请 PCRC-11025 于 20111127 启动，于 20111129 关闭。该变更声称其目的是对
XX 生产工艺进行变更使得 API 成品已知异构体杂质 XX 为 XX（XX%-XX%），并且收率
变更为 XX（当前收率为 XX-XX 每批）。
i) You did not conduct and document a formal risk assessment for Change
Request PCRC-11025 to evaluate the potential impact of proposed changes on the
quality of the intermediates or the final API for this critical change to your validated
manufacturing process prior to your quality unit approving the change. 你们未对变更申
请 PCRC-11025 执行正式风险评估并记录，以在质量部门批准该变更之前评价所拟的对
你们已验证工艺的关键变更对中间体或 API 成品的潜在影响。
ii) You hired an outside laboratory to conduct a small labscale research project.
Based on the results of a lab scale research project your initiated validation on a
commercial scale to change your validated manufacturing process without conducting
pilot scale or other small scale batches. Your Deputy Director of Manufacturing stated
you have commercial experience and since you only change the (b)(4) there was no
need to conduct pilot scale trial batches before instituting critical changes on a
commercial scale.
你们聘用外部实验室进行小规模实验室研究项目。基于实验室规模研究项目结果，你们启
动了商业规模的验证来变更你们已验证的生产工艺，而未进行中试规模或其它小型批次生
产。你们的生产副总声称你们具有商业化经验，并且因为你们只是改变了 XX，所以在对商
业规模进行关键变更之前不需要进行中试试验。
You initiated validation on a commercial scale without conducting a formal risk

assessment to evaluate the potential impact of changes to your validated manufacturing
process on the quality of intermediates and APIs. You do not have a quality agreement
with the outside laboratory you used to perform a lab scale research project requiring
(prior to initiating testing and reporting results): qualification of all instruments used to
conduct tests; validation of all software used with qualified instruments to conduct tests;
calibration of all applicable measurement devices against traceable standards prior to
use; use of official standards as appropriate; if applicable, establishing system suitability
prior to testing samples and processing data; and validation of all test methods used for
testing.
你们未执行正式风险评估评价改变你们已验证生产工艺对中间体和 API 质量的潜在影响就

启动了商业规模验证。你们与你们用来执行实验室规模研究项目的外部实验室没有签订质
量协议要求他们（在启动检测和报告结果之前）：确认所有检测用仪器、验证所有确认检
测用仪器的软件、使用前采用可追溯标准校正所有使用的测量仪器仪表、使用官方标准（适
当时），以及（适当明）在检测样品和处理数据之前确定系统适用性，以及验证所有检测
用方法。
b) You do not have an adequate change control system requiring scientific judgement
to determine what additional testing and validation studies are appropriate to justify
changes to a validated manufacturing process. You do not always have data to support
approval of changes to validated processes.
你们变更控制系统不充分，未要求进行科学判定以确定需要哪些附加检测和验证研究来论
证对验证过的生产工艺的变更。你们不是每次都有数据来支持对验证过的工艺的变更批准。
i) You did not identify specific parameters and specify acceptance criteria for those
parameters prior to implementing changes, as part of critical Change Request PCRC-
11025, to use to evaluate if the implemented changes (b)(4) the isomer (b)(4) of (b)(4)
and (b)(4) the batch yield. 你们未在实施（作为关键变更申请 PCRC-11025 的一部分）变
更之前识别特定的工艺参数及其可接受标准，使用这些标准评估所实施的变更 XX 能达成
异构体 XX 以及收率 XX。
ii) Additional testing requirements associated with critical changes are not always
based on sound scientific judgement. Change Request PCRC-11025 included changing
(b)(4) in your validated manufacturing process. Additional testing requirements
associated with these changes were limited to three validation batches and a
commitment to conduct additional testing on (b)(4) batches a (b)(4). 与关键变更有关的附
加测试要求并不都是基于科学合理的判定。变更申请 PCRC-11025 包括有更改你们验证过
的生产工艺中的 XX。对这些变更相关的附加测试要求仅限于 3 个验证批次，以及承诺会对
XX 批次执行附加检测的声明。
c) You do not have an adequate classification procedure for determining the level of
testing, validation, and documentation needed to justify changes to a validated process.
You do not consistently classify changes. You do not always increase testing, validation,
and the documentation required to justify changes to a validated process based on the
classification of a proposed change. Amendment to Drug Master File (b)(4) USP
(Process (b)(4)) DMF #(b)(4) dated December 10, 2013 indicates the amendment was
submitted for minor changes for drug substance manufacturing. Amendment to Drug
Master File(b)(4) USP (Process (b)(4)) DMF#(b)(4) contradicts your internal Change
Request PCRC-11025 which lists change control classification as critical change.
你们没有充分的分级程序来确定已验证工艺的变更进行论证时所需的检测、验证和文件程
度。你们对变更的分级不一致。你们并不是每次都根据所拟变更的分级来增加所需检测、验
证和文件以论证对已验证工艺的变更。对 DMFXX USP 的修订（工艺 XX） DMF#XX，日
期 20131210 显示修订是作为原料药生产的轻微变更提交的。对 DMFXXUSP（工艺
XX）DMF#XX 的修订与你们内部变更申请 PCRC-11025 是矛盾的，你们内部变更控制将
该变更分级为关键变更。
d) Written change control procedures should provide for the identification,

documentation, appropriate review, and approval of changes in raw materials,
specifications, analytical methods, facilities, support systems, equipment (including
computer hardware), processing steps, labeling and packaging materials, and computer
software. Any proposals for GMP relevant changes should be drafted, reviewed, and
approved by the appropriate organizational units and reviewed and approved by the
quality unit. Your quality unit does not always follow your written procedure for change
control. Your written procedure Change Control System SMP-018.05 effective December
30, 2017 section 5.3.6(3) specifies QA shall reject the change if the action cannot meet
predetermined expectations. Critical Change Request PCRC-11025 did not include
acceptance criteria with predetermined expectations. (b)(4) Product Development
Report-01 dated April 13, 2012 Table 8 includes (b)(4) isomer impurity (specification <(b)
(4)%) from three batches manufactured according to the validated manufacturing
process (results range from (b)(4)%- (b)(4)%) and Table10 includes (b)(4) isomer
impurity from the three validation batches manufactured using a different (b)(4) (results
range from (b)(4)%- (b)(4)%). The product development report is silent regarding
evaluation of the ability of the implemented changes to (b)(4) isomer (b)(4). (b)(4)
Product Development Report-01 did not compare the batch weights from batches
manufactured immediately before the change to the validated manufacturing process
and the first batches manufactured after implementing changes to the manufacturing
process.
书面变更控制程序应为原料、质量标准、分析方法、设施、支持系统、设备（包括计算机硬
件）、工艺步骤、标签和包材以及计算机软件变更提供识别、文件化、适当审核和批准。所有
对 GMP 相关变更的提议均应由适当的公司部门起草、审核和批准，并经过质量部门审核
和批准。你们的质量部门不能每次都遵守你们的书面变更控制程序。你们的书面程序变更控
制系统 SMP-018.05 生效日期 20171230 第 5.3.6（3）部分指明如果行动不能达成既定的
预期则应拒绝变更。关键变更申报 PCRC-11025 并未包括有预期接受标准。XX 产品研发报
告-01 日期 20120413 表 8 包括有根据已验证生产工艺生产的 3 批的 XX 异构杂质（质量标
准<XX%）（结果为 XX%-XX%），表 10 包括有使用不同 XX 生产的 3 个验证批次的 XX
异构杂质（结果在 XX%-XX%）。该产品研发报告对变更后 XX 异构的降低能力并未进行
评估。XX 产品研发报告-01 并未比较变更前后所生产批次的批重量。
Validation of production processes, cleaning procedures, analytical methods, and in-

process control test procedures are not always adequate. Specifically,
生产工艺、清洁程序、分析方法和中间控制检测方法的验证不完全充分。具体来说
a) Your manufacturing processes are not always capable of consistently producing final
products meeting all product quality specifications. Deviation No. DCB18-17017 was
initiated for OOS genotoxic impurity (b)(4) ppm (specification<(b)(4)ppm) in (b)(4) batch
(b)(4). Repeat test results included OOS results. As a corrective action you reprocessed
(b)(4) batch (b)(4) by (b)(4) the (b)(4) step in your manufacturing process. You did not
investigate corrective actions to your manufacturing process or to the manufacturing
batch record to improve product consistency and manufacturing reproducibility, and to
reduce the level of (b)(4) in the (b)(4) intermediate crude. You did notdevelop a prevent
action plan to prevent future OOS (b)(4) levels in the intermediate crude and final API.
你们的生产工艺没有能力保持持续生产出符合所有产品质量标准的成品。偏差编号
DCB18-17017 由于 XX 产品 XX 批号中 OOS 基因毒性杂质 XXppm 结果启动（标准
<XXppm）。重复检测结果包括有 OOS 结果。作为纠正措施你们对 XX 批号采用你们生产
工艺中的 XX 步骤进行了返工。你们并未调查生产工艺或生产批记录的纠正措施以改进产
品一致性和生产可重复性，降低 XX 中间体粗品中的 XX 水平。你们并未制订预防措施计划
来防止未来该中间体粗品和 API 成品中 OOSXX 水平。
Between December 16, 2016 and August 22, 2017 you initiated 17 OOS investigations
for (b)(4) impurity in (b)(4). Of the 17 OOS investigations initiated for (b)(4) impurity in (b)
(4) you attributed 13 OOS results to lab related errors, 5 OOS results to production
errors, and 2 OOS results to a combination of lab and production errors. You
reprocessed all 17(b)(4) batches you investigated for OOS (b)(4) impurity.
2016 年 12 月 16 日-2017 年 8 月 22 日期间，你们启动了 17 个 XX 中 XX 杂质的 OOS 调

查。在这 17 个 OOS 调查中，你们将 13 个 OOS 结果归因于化验室相关错误，5 个 OOS
结果归因于生产错误，2 个 OOS 结果归因于化验室与生产共同错误。你们将所有这 17 批
XX 杂质 OOS 调查的产品进行了返工。
b) Written validation protocols are not always adequate. 有的书面验证方案不充分。
i) Your process Validation Protocol for (b)(4) process(b)(4) Workshop (b)(4) CNVP-
11-075 and Process Validation Protocol for Crude(b)(4) Step (b)(4) PVC-18012(P) do not
include the specific parameters with acceptance criteria to establish your manufacturing
process is not only consistent and reproducible but able to fulfill the purpose for
changing your validated manufacturing process.
你们的 XX 车间 XX 工艺的工艺验证方案 XXCNVP-11-075 和 XX 粗品 XX 步骤工艺验证方

案 PVC-18012(P)未包括特定的工艺参数及其可接受标准用以建立你们的生产工艺不仅一
致可重复而且能达成改变你们已验证生产工艺的目的。
ii) Neither Process Validation Protocol for (b)(4) Process (b)(4) Workshop (b)(4)
CNVP-11-075 nor Process Validation Protocol for Crude (b)(4) Step (b)(4) PVC-18012
(P) specified the number of manufacturing batches to be manufactured as part of
validation of your manufacturing process or discussed the number of validation batches
to manufacture based on the complexity of the process or the magnitude of the process
change.
XX 车间 XX 工艺的工艺验证方案 XXCNVP-11-075 和 XX 粗品 XX 步骤的工艺验证方案

PVC-18012（P）均未指明要生产的批数，将其作为你们生产工艺验证的一部，亦未根据
工艺复杂性或工艺变更严重性讨论要生产的验证批数。
iii) Neither Process Validation Protocol for (b)(4) Process (b)(4) Workshop CNVP-
11-075 nor Process Validation Protocol for Crude (b)(4) Step (b)(4) PVC-18012(P)
included a sampling plan designed to demonstrate the consistency and reproducibility of
your manufacturing process through batch uniformity data.
XX 车间 XX 工艺的工艺验证方案 XXCNVP-11-075 和 XX 粗品 XX 步骤的工艺验证方案

PVC-18012（P）均未包括设计用以通过批均匀性数据证明你们生产工艺的一致性和可重
复性的取样计划。
c) You do not always initiate investigations during process validation. (b)(4) process
validation batch (b)(4) test results for Diastereo-isomer (b)(4)% ( specification <(b)(4)%)
were OOT (Out-of-Trend) compared to the other (b)(4) validation batches with Diasterio-
isomer results ranging from (b)(4)% to (b)(4)%. You did not initiate an investigation to
identify the CPP (s) (Critical Process Parameter), non-critical process parameter(s), raw
material(s), or other influences which could impact Diastereo-isomer results in an effort
to improve the quality and consistency of(b)(4) (the product from the (b)(4) synthesis
step in the manufacture of (b)(4)).
你们在工艺验证时不是每次都启动调查。XX 工艺验证批次 XX 的非对映异构体 XX 检测结

果为 XX%（标准<XX%），相比其它 XX 验证批非对映异构体（结果为 XX%-XX%））为
OOT 结果（超趋势）。你们并未启动调查来识别 CPP（关键工艺参数）、非关键工艺参数、
原料药或其它可能影响非对映异构结果的因素以努力提高质量和 XX（XX 生产中 XX 合成
步骤的产品）一致性。
d) You do not have sufficient data to demonstrate your in-house test methods, used for
Assay and Related Substance testing of (b)(4) are at least equivalent to USP
Monograph test methods. (b)(4) USP Method and In-house Method Qualification
Comparison Research Report VLDor-10-099(R) version 2 effective August 29, 2014
does not include data showing you tested known concentrations of (b)(4) and spiked (b)
(4) samples and then compared the results from your in-house test method with results
from tested known concentrations of (b)(4) and spiked (b)(4) samples using the USP
method to verify your in-house test results at least meet the acceptance criteria of the
USP methods.
你们没有足够的数据证明你们用于 XX 产品的含量和有关物质检测的内控检测方法至少等
同于 USP 各论检测方法。XX 的 USP 检测方法和内控检测方法确认对比研究报告 VLDor-
10-099（R）版本 2 生效日期 20140829 并不包括数据显示你们使用内控方法检测的已知
浓度 XX 与加标 XX 样品，与采用 USP 方法检测已知浓度 XX 和加标样品所得结果进行比
较，确认你们内控检测方法至少符合 USP 方法的可接受标准。
e) You do not have validated cleaning procedures. Cleaning procedures for (b)(4)-203-
1 and (b)(4) 204-3 in workshop (b)(4) used in the manufacture of crude (b)(4) are not
validated in that you do not have data to demonstrate the cleaning procedure is effective
following manufacture of (b)(4) consecutive batches. The most recent cleaning validation
study, CVD-18015(R), approved in July 2018, is based on (b)(4) consecutive batches.
The 2016 equipment use log for (b)(4)-203-1 shows (b)(4) consecutive batches were
manufactured before cleaning. Your Quality Assurance Director verbally confirmed no
rinse samples were analyzed following either of these cleanings.
你们的清洁方法未经验证。XX 车间 XX 粗品生产所用 XX-203-1 和 XX204-3 的清洁程序未

经过验证，你们没有数据证明在连续 XX 批次生产之后的清洁程序是有效的。最近的清洁
验证研究 CVD-18015（R）批准日期 201807，是基于 XX 个连续批次。2016 年设备 XX-
203-1 使用日志显示在清洁之前连续生产了 XX 批。你们的 QA 总监口头确认说在这些清洁
之后并没有检测淋洗样品。
The system for managing quality to ensure confidence that the API will meet its intended
specification for quality and purity is not adequate in that your quality unit lacks written
procedures and the authority and responsibility to ensure all critical deviations are
thoroughly investigated. Specifically,
管理质量以确保 API 符合其既定质量标准中质量和纯度可信度的体系不充分，因你们质量
部门缺少书面程序和权力及职责确保彻底调查所有关键偏差。具体来说
a) You released finished APIs manufactured from crude intermediates with OOS levels
of genotoxic impurities without conducting a thorough investigation. Deviation No.
DCB18017025 initiated December 13, 2017 and closed April 16, 2018 was initiated for
OOS (b)(4) impurity (b)(4) ppm (specification <(b)(4) ppm) in (b)(4) batch (b)(4). You
identified the root cause as an equipment failure which impacted intermediate crude (b)
(4) batch (b)(4) during (b)(4). You reprocess (b)(4) batch (b)(4) Intermediate crude(b)(4)
batch (b)(4) was also used in (b)(4) API final batch (b)(4). You did not reprocess batch
(b)(4) made from OOS intermediate crude (b)(4) batch (b)(4). You did not open an
investigation, or conduct additional testing on batch (b)(4). Your QA Director stated batch
(b)(4) met the product release specification for Related Substance (b)(4).
你们放行了使用 OOS 水平基因毒性杂质的中间体粗品所生产的 API 成品，而未进行彻底

调查。偏差 DCB18017025 于 20171213 启动，20180416 关闭，启动原因是 XX 产品 XX
批号 XX 杂质 OOS 结果 XXppm（标准<XXppm）。你们识别根本原因为设备故障影响了
XX 中 XX 产品 XX 批号的中间体粗品。你们将 XX 批 XX 中间体粗品返工，然后用于 XXAPI
成品的生产。你们并未返工采用 OOS 中间体粗品 XX 批次生产的 XX 批号。你们未启动调
查，或对 XX 批次进行附加检测。你们的 QA 总监声称批次 XX 的有关物质 XX 符合产品放
行标准。
b) Major Deviation DD (b)(4) 17003 was initiated August 2, 2017 and closed
September 11, 2017 for (b)(4) batch (b)(4) and (b)(4) with OOS results for unknown
impurity (specification<(b)(4)%). You confirmed OOS results for (b)(4) batches (b)(4)
single unknown impurity (b)(4)%, and (b)(4) single unknown impurity (b)(4)%.
主要偏差 DD XX 17003 于 20170802 启动，于 20170911 关闭，启动原因是 XX 批和 XX

批未知杂质 OOS 结果（标准<XX%）。你们确认了 XX 批 XX 单个未知杂质 OOS 结果 XX
%，以及 XX 单个未知杂质 XX%。
i. You did not identify a root cause for the single unknown impurity results in
batches (b)(4) and (b)(4). You stated the root cause was probably due to occasional
fluctuation in your manufacturing process. You did not attempt to identify this single
unknown impurity. You did not attempt to identify the source of fluctuations in your
manufacturing process for (b)(4).
你们未识别出 XX 批次和 XX 批次中单个未知杂质结果超标的根本原因。你们声称根本原因

可能是你们生产工艺的偶然波动。你们并未试图识别此单个未知杂质。你们并未试图找出你
们 XX 生产工艺波动的来源。
ii. You did not develop an adequate Corrective Action and Preventive Action
(CAPA) plan. The CAPA you listed on Deviation Investigation Report Form for Deviation
DD (b)(4) 17003 included: discarding both batches and following-up on the next (b)(4)
batches to see if a similar issue occurs. You did not review your manufacturing process
and manufacturing batch records to determine if your manufacturing process and
manufacturing batches records could be revised to reduce process variation. You did not
interview employees to determine if employees consistently and reproducibly follow your
manufacturing instructions.
你们未制订充分的 CAPA 计划。你们在偏差调查报告表 DD XX17003 中所列的 CAPA 包括
弃用这 2 批，跟踪下 XX 批查看是否有类似问题发生。你们并未回顾你们的生产工艺和批
生产记录以确定你们的生产工艺和批生产记录是否可进行修订以降低工艺波动。你们并未
与员工面谈以确定员工是否一致和重复地遵守你们的生产指令。
iii. You did not conduct a thorough risk assessment. Your risk assessment
consisted of answering (b)(4) generic questions: yes, no, or NA (Not Applicable).
Deviation DD (b)(4) 17003 investigation did not include documentation showing a more
thorough risk assessment was conducted by your risk management team. Your written
procedure for Quality Risk Management SMP-023.03 effective November 1, 2017
section 7.1.3 specifies a risk management team should be established when solving
major risk issues, and section 7.1.5 of the same procedure specifies to select different
tools according to the risk category. Quality Risk Management SMP-023.03 section 8.3
specifies allactivities should be defined and documented. Quality Risk Management
SMP-023.03 does not specify which risk management methods and tools to use in
association with specific deviation categories.
你们未进行深入的风险评估。你们的风险评估是由对 XX 个一般性问题的回答所组成的：
是、否或 NA（不适用）。偏差 DD XX 17003 调查并不包括显示由你们风险管理小组执行
更为深入风险评估的文件。你们的书面程序“质量风险管理”SMP-023.03 生效日期
20171101 第 7.1.3 部分说在解决主要风险问题时应组成一个风险管理小组，同一程序的
7.1.5 部分说要根据风险类别选择不同的工具。“质量风险管理”SMP-023.03 第 8.3 部分
说应定义并记录所有活动。“质量风险管理”SMP-023.03 并未说明对于特定的偏差分类
要使用何种风险管理方法和工具。
c) You do not always thoroughly document investigations. Your written procedure

Deviation Investigation Management System SMP-017.05 effective January 1, 2018
section 6.4.2 specifies the investigation should be well documented including the quality
risk assessment (the same specification as included in version SMP-17.04 effective May
30, 2016). Deviation Investigation Management System SMP-017.05 like SMP-017.04
does not specify which risk management methods and tools to use in association with
specific deviation categories.
你们未能记录所有调查。你们的书面程序“偏差调查管理体系”SMP-017.05 生效日期
20180101 第 6.4.2 部分说应好好记录所有调查包括质量风险评估（与 20180530 生效的版
本 SMP-017.04 中所包括的标准相同）。“偏差调查管理体系”SMP-017.05 像 SMP-
017.04 一样并说明对于特定的偏差类别要使用何种风险管理方法和工具。
d) You do not always thoroughly investigate deviations before closing the deviation.
Deviation DCB02-17002 was initiated October 10, 2017 and closed February 1, 2018 for
single unknown impurity (specification <(b)(4)%) (b)(4) intermediate (b)(4) batches (b)(4)
((b)(4)%) and (b)(4) ((b)(4)%). The Deviation Investigation Report states unspecified
impurity at RRT (Relative Retention Time) (b)(4) is an in process impurity observed in
other batches but at levels not more than (b)(4)%.You did not identify a root cause. Your
corrective action plan included: use LC-MS to identify the impurity, conduct further
investigations once the impurity is identified, and conduct a lab trial study to determine if
reprocessing removes the impurity. You did not develop a preventive action plan. You did
not identify the single unknown impurity. You reprocessed (b)(4) intermediate (b)(4)
batches (b)(4) and (b)(4) and assigned the reprocessed batches final API batch numbers
(b)(4) and (b)(4). You then closed the investigation without identifying the single
unknown impurity.
你们未在所有偏差关闭之前对其进行彻底调查。偏差 DCB02-17002 于 29171010 启动，于

20180201 关闭，启动原因是 XX 中间体未知杂质 XX 批（XX%）和 XX 批（XX%）（标
准<XX%）超标。偏差调查报告声称 RRT（相对保留时间）XX 的非特定杂质为在其它批准
中发现的过程杂质，但处于不超过 XX%的水平。你们并未找出根本原因。你们的纠正措施
计划包括：使用 LC-MS 识别杂质，在识别出杂质之后进行进一步调查，并且进行实验室
试验研究以确定返工是否能清除该杂质。你们并未制订预防措施计划。你们并未识别出该单
个未知杂质。你们返工了 XX 中间体 XX 批号 XX 和 XX，并为返工后的 API 成品批给定了
批号 XX 和 XX。然后你们没有识别出此单个未知杂质就关闭了此调查。
e) You do not always follow your written procedures. Returned Products Management
Procedure SMP-012.02 effective October 30, 2013 defines a quality-related issue as any
non-compliance to physical, chemical or microbiological feature. You classified Return
No. RC-18006 as not quality related for (b)(4) batches (b)(4) and (b)(4) returned for not
complying with customer PSD specifications, a physical feature. The Treatment Record
sectionand closure date on Return No. RC-18006 were left blank.
你们未能保持遵守你们的书面程序。“退货管理程序”SMP-012.02 生效日期 20131030 将

质量相关问题定义为不符合物理化学或微生物属性。你们将退货单 RC-18006 中 XX 批号
XX 和 XX 因不符合客户 PSD 标准（一个物理特性）退货分类为非质量相关问题。退货单
RC-18006 的处理记录部分和关闭日期还是空白的。
The quality unit doesnot always fulfill the responsibilities of the quality unit to release or
reject all APIs. Specifically, (b)(4) batch (b)(4) (b)(4) (designates the batch was (b)(4))
did not meet your customer’s specification for PSD (Particle Size Distribution (b)(4)-(b)
(4)um). The actual PDS values were not reported on the CoA (Certificate Analysis) for
the batch. The quality unit did not complete a Product Release Form rejecting the batch
for not meeting the customer’s PSD specification with instructions for handling the batch,
质量部门未能始终履行其放行或拒收所有 API 的职责。具体来说，XX 批次 XX 不符合你们

客户的 PSD（粒径分布 XX-XXum）质量标准。实际的 PSD 值在该批次 COA 上没有报告。
质量部门未完成产品放行单拒收该不符合客户 PSD 标准的批次以及下达该批次处理指令。
(b)(4) batch (b)(4) was (b)(4) a (b)(4) time and the batch number was changed to batch
(b)(4) ((b)(4) μm). The quality unit completed a Product Release Form and identified the
batch as released without further instructions for handling the batch. Yet (b)(4) batch (b)
(4) was (b)(4)a (b)(4) time. After (b)(4) batch (b)(4) was (b)(4) a (b)(4) time PSD results
were (b)(4) μm. The quality unit completed a Product Release Form releasing the batch
a second time.
XX 产品 XX 批号 XX 了时间然后该批号改为批号 XX（XXμm）。质量部门完整填写了产品
放行表认可放行该批次而无处理该批次的进一步指令。而 XX 批次 XX 是 XX 时长。在 XX 批
XX 被 XX 时长之后 PDS 结果为 XXμm。质量部门完整填写了产品放行单第二次放行了该
批次。
Written proceduresare not for the cleaning and maintenance of equipment, including
utensils, used in the manufacture, processing, packing or holding of a drug product.
用于药品生产、加工、包装和存贮的设备，包括工器具清洁和维保无书面程序。
A) You performed equipment cleaning verification activities for a specific number of

batches after you identified (b)(4) as ahigh risk product. During the cleaning verification
you did not perform analyses for the detergent residues nor did you perform bio-burden
testing. Your Deputy General Manager Quality Assurance stated that you are no longer
performing sampling and testing for equipment utilized in the manufacture of (b)(4) drug
products and are awaiting commercialization before completing cleaning validation
activities.
在识别了 XX 为高风险产品之后，你们为特定数量批次进行了设备清洁确认。在清洁确认
中，你们并未进行清洁剂残留检测，亦未进行生物负载检测。你们的 QA 副总经理声称你
们不再取样和检测用于 XX 药品生产的设备，准备等着在商业后完成清洁验证活动。
B) Your Vice President Operations stated that you did not conduct cleaning validation
activities for the (b)(4) used inside the capsule filling equipment to remove capsules and
(b)(4) and consequently ensure no risk of cross contamination between drug products.
你们的营运副总裁声称你们并未对 XX 所用的胶囊灌装设备内进行清洁验证，以清除胶囊
和 XX，因此无法确保防止产品之间的交叉污染风险。
The responsibilities and procedures applicable to the quality control unit are not in
writing.
质量部门适用的职责和程序未书面化。
Specifically, your Head of Operations, (b)(4) Solid Dosage and your Senior General
Manager, Quality Non-Sterile Manufacturing stated that you do not have procedures
inplace which require across batch trending of critical alarms raised during production
activities, such as those which occurred on capsule filling equipment ID HC-084 during
filling of batch (b)(4) of (b)(4) capsules USP (b)(4)mg on (b)(4) and again while we were
observing on 8/30/18.
具体来说，你们的 XX 固体制剂运营负责人和你们的非无菌生产质量高级总经理声称你们
并没有制订程序要求对生产活动中出现的关键报警进行批内趋势分析，如在胶囊灌装设备
IDHC-084 的 XX 胶囊批次灌装期间发现的情形，同样情况我们在 20180830 亦有发现。
The quality control unit lacks the responsibility and authority to approve and reject all in-
process materials and drug products.
质量部门缺乏批准和拒收所有中间体和制剂的责任和权力。
Specifically, you did not reject the three (b)(4) Tablets (b)(4)mg exhibit batches that failed
in-process (b)(4) sampling for (b)(4). Out of Specification Investigation No.283910,
282535, and 285929 approved 30/Jan/2018 shows exhibit batches (b)(4) and (b)(4)
failed RSD and mean of each location and batch (b)(4) failed RSD for (b)(4) sampling for
(b)(4). The results from these batches was submitted in support of drug application (b)
(4) Tablets. Additionally, these results were not submitted in one of the appropriate
Sections such as 3.2.P.2.3 (Process Development), 3.2.P.3.3 (Manufacturing Process
Descriptions), or 3.2.P.3.4 (Controls of Critical Process Parametersand Intermediates);
they were submitted in Section 3.2.P.3.5 (Process Validation and Evaluation).
具体来说，你们没有拒收中控 XX 样品不合格的 3 批 XX 片剂。20180130 批准的 OOS 调

查号 283910、282535 和 285929 显示申报批次 XX 和 XX 每个点的 RSD 和平均值均不合
格，批次 XX 的 XX 取样 RSD 不合格。这些批准的结果均提交给 FDA 用于支持 XX 片剂的
药品申报。另外，这些结果没有放在适当的部分如 3.2.P.2.3（工艺开发）、3.2.P.3.3（生产
工艺描述）或 3.2.P.3.4（关键工艺参数和中间体控制）中提交，而是放在了 3.2.P.3.5 部
分（工艺验证和评估）。
14. 印度 Lupin 20181105
Control procedures are not established which monitor the output and validate the
performance of those manufacturing processes that may be responsible for
causing variability in the characteristics of in-process material and the drug
product.
未建立控制程序监控输出，未验证可能导致中间体和制剂成品特性波动的生产工艺性
能。
a) Your process performance qualification (PPQ) study is deficient in that you did
not include the second exhibit batch for(b)(4) mg, lot# (b)(4) which failed (b)(4).
You rejected this batch and did not include it in your PPQ report.
你们的工艺性能确认（PPQ）研究有缺陷，其中未包括第二批申报批次，该批次 XX
不合格。你们拒收了该批，并未将其包括在你们的 PPQ 报告中。
During the inspection, you stated this batch was a product development batch
manufactured before exhibit batches and production process is recorded in PD
notebooks. WhenI asked for the production records and copies of the PD
notebooks, you stated that this batch was the first exhibit batch and failed (b)(4).
Review of your SAP records showed that this batch was the second exhibit batch,
then you admitted that this batch was the second exhibit batch which failed (b)(4)
and you rejected the batch.
在检查期间，你们声称该批次是研发批次，是在申报批之前生产的，其生产工艺记录
在 PD 笔记本上。当我索要生产记录和 PD 笔记本的副本时，你们声称该批次是申报批
次的第一批，XX 不合格。检查你们的 SAP 记录则显示该批次是第二个申报批次，然后
你们承认说该批确实是第二个申报批准，但因 XX 不合格而拒收了。
b) Additionally, after observing I out of (b)(4) failed the (B)(4) weight in exhibit
batch #(b)(4) instead of investigation and (b)(4) more data, you revised the
exhibit batch record and removed “(b)(4) weight measuring” requirement.
另外，你们在发现 XX 申报批中 XX 重量不合格时，你们并不是进行调查并查看更多数

据，而是修改了申报批次的记录，从中删除了“XX 称重”的要求。
Written procedures for cleaning and maintenance fail to include description in

sufficient detail of methods, equipment and materials used, description in
sufficient detail of the methods of disassembling and reassembling equipment as
necessary to assure proper cleaning and maintenance and instructions for
removal or obliteration of previous batch identification,
书面清洁和维护程序未包括对所用方法、设备与物料的详细描述、对设备拆卸与装配方
法的详细描述，不足以确保进行恰当的清洁与维护，以及指导清除或除去前一批次的
物料。
a) Cleaning validation and verification for rooms and equipment used for (b)(4)
filling, and (b)(4) of (b)(4) mg are deficient. You have not performed full cleaning
studies on dedicated equipment and cleaning validation on production room #(b)
(4) which is a multi-use room and is used for (b)(4) of (b)(4) as well as filling of
(b)(4) and other potent drug products such as (b)(4) solutions, (b)(4) drug
products, etc. to ensure preventing cross contamination and carry over.
XX 灌装与 XX 品种 XX mg 所用房间与设备清洁验证和定期确认有缺陷。你们对专用设
备进行了全面清洁研究，对共用生产房间 XX 进行了清洁验证以确保能防止交叉污染和
残留，该房间亦用于 XX 灌装和其它高活性药品如 XX 溶液、XX 药品等的生产。
You failedto provide a proper study and execution plan for validation and
verification ofthe cleaning. During the inspection you stated you conduct Type (b)
(4) cleaning, which is a (b)(4) for cleaning of equipment used in production of (b)
(4)mg since they are dedicated equipment. Later, you stated you perform Type (b)
(4) cleaning, which is a (b)(4) on production of (b)(4) mg even though they are
dedicated equipment. On Tuesday Oct. 16, 2018 (two days before inspection
closing day) you provided a series of data showing swab sample results for
different production equipment for (b)(4) and stated you have done a few studies
and determined the hold time for cleaned equipment.
你们未能提供一份适当的清洁验证与确认研究和执行计划。在检查期间，你们声称你们
执行了 X 类清洁，这是用于 XX mg 生产的设备的清洁程序，但它们是专用设备。后来，
你们声称说你们执行了 X 类清洁，而这类清洁是 XX mg 生产的设备清洁程序，亦是专
用设备。2018-10-16（检查结束之前 2 天），你们提供了一套数据显示不同生产设备
的 XX 擦拭取样结果，声称你们已进行了一些研究，并确定了清洁后设备的保持时间。
b) Your batch record for (b)(4) of (b)(4) is missing type of cleaning and cleaning
instructions on (b)(4) unit and there is no computer station inside the (b)(4) room
for the operator to access and retaining SOP electronically.
你们的 XX 与 XX 批记录里并没有 XX 单元的清洁类型与清洁指令，在 XX 房间里亦没

有计算机让操作人员可以获取电子 SOP。
Sampling procedures are deficient regarding sampling components from the top,
middle, and bottom of container
取样程序有缺陷，未规定要从容器的顶部、中间和底部取样。
Specifically, your sampling practice for removal of samples for APIs and (b)(4) is
deficient in that you do not collect samples from different locations of material
containers (top, middle and bottom). You use sampling (b)(4) for collecting
samples of APIs which come in different size containers (b)(4) and (b)(4) from
bags packed in a (b)(4) boxes.
具体来说，你们的 API 和 XX 取样操作是有缺陷的，你们没有从物料容器的不同位置采

集样品（上中下）。你们使用了 XX 取样用于采集 API 样品，这些 API 进厂时装在不同
尺寸容器 XX 和 X 箱里包装的袋子 XX 中。
15. 印度 Cipla 20181022
Written records of investigations into unexplained discrepancies do not always

include the conclusions and follow-up. Specifically,
对没有解释的差异的书面调查记录有时未包括结论和跟踪情况。具体来说，
A change to production instructions was implemented prior to completion of all

corrective action changes related with a deviation. Namely, as part of Deviation
DEV-1006-2017-00073 for (b)(4) Tablets, USP (b)(4)mg lot (b)(4) (AQL non-
compliance for minor defects), a Remedial Action item was initiated for the
revision to be “Inspection by Attributes for In-process Checks of (b)(4) Tablets”
form to modify defect type “Minor Spots” to “Minor spots (Other than (b)(4)
Spots)”.
对生产指令的修改在所有与偏差有关的纠正措施变更完成之前即已实施。换句话说，作
为 XX mg 的 XX 片剂 XX 批号偏差 DEV-1006-2017-00073（轻微偏差 AQL 不符合）
的一部分，启动了补救措施项目对“XX 片剂中控属性检查”表格进行修订，将“小
点”缺陷类型改为“小点（XX 点以外的点）”。
This Remedial Action was completed with revised form implemented on Nov.21,
2017, and before the approval of the concurrent proposal under Change Request
10006-P-18-00004 (initiated on January 10, 2018) for the change in the product
labeling (Pack Insert) for (b)(4) Tablets, USP to include “Due to inherent nature of
formulation, occasionally, (b)(4) spots may be present on tablet surface. This
does not affect efficacy of product”.
此补救措施完成并将修订后表格于 2017-11-21 开始实施，是在 USP 版本 XX 片剂生产

标签（包装说明书）变更增加“由于制剂内在原因，偶尔可能会在片剂表面出现 XX 点，
这并不影响药品效力”的变更申请（2018-01-10 启动）同步方案批准之前。

environmental conditions.
无菌处理区域在监测环境条件的系统方面存在缺陷。
a) You had several environmental monitoring results where you did not identify the
microorganism and continued to produce and distribute sterile drug products without
a complete investigation and corrective action taken.
您有几个环境监测结果没有识别微生物，并继续生产和分销无菌药品而未进行全面调
查并采取纠正措施。
Human Class
人药级别
(b)(4)A ISO 7 2 cfu (fungal) 5/21/2018
(b)(4)S ISO 7 1 cfu (fungi) 6/26/2018
(b)(4)S ISO 7 5 cfu (counted) 7/31/2018
(b)(4)S ISO 7 TNTC 太多无法计数 8/1/2018
(b)(4)S ISO 7 1 cfu ((b)(4)) 8/21/2018
Veterinary
兽药
(b)(4)S ISO 5 1 cfu 5/22/2018
(b)(4)S ISO 7 TNTC 5/29/2018
(b)(4)S ISO 7 1 cfu (fuzzy white) 8/21/2018
A：Air 空气
S：Surface 表面
b) Employees had positive results multiple times for fingertip testing after producing
sterile drug products. You did not identify the microorganism and continued to
produce and distribute sterile drug products without a complete investigation and
corrective action taken.
在生产无菌药品后，员工多次获得指尖测试的阳性结果。您未识别微生物并继续生产
和分发无菌药品而未进行全面调查并采取纠正措施。
Human Fingertip 人(药生产时)指尖

(b)(6) 3 cfu (L) 4/19/2018
7 cfu (Rt) 5/29/2018
3 cfu (L & Rt) 6/5/2018
1 cfu (L) asperg 6/25/2018
Veterinary Fingertip 兽药(生产时)指尖
(b)(6) 9 cfu (Rt) 7/19/2018
12 cfu (L) 7/12/2018
7 cfu (Rt) 7/12/2018
c) Your written procedure does not address how microorganisms can affect the sterile
drug product nor does it define the specific location of the sampling points.
您的书面程序没有说明微生物如何影响无菌药品，也没有确定采样点的具体位置。
d) You only monitor viable particulates (b)(4) and non-viable particulates every (b)(4).
您只能每隔 XX 监测活性颗粒 XX 和非活性粒子。
e) You do not have a qualified individual to read the (b)(4) plates for environmental
monitoring.
您没有合格的人员阅读环境监测的 XX 平板。

purporting to be sterile did not include adequate validation of the aseptic process.
设计以防止声称无菌的药品的微生物污染的程序不包括对无菌工艺的充分验证。
a) Media fills were not performed that closely simulate aseptic production operations
incorporating, as appropriate, worst-case activities and conditions that provide a
challenge to aseptic operations. You do not include the smallest or largest batch
size and different container types (vials).
a）没有进行密切模拟无菌生产操作的培养基灌装，酌情包括对无菌操作提出挑战的最差
情况活动和条件。您没有包括最小或最大批量大小和不同容器类型（小瓶）。
法规建议：针剂车间验证计划中的 MF，应对不同规格瓶子和批量进行评估，确定最差情
况并挑战。
b) Smoke studies have not been performed under dynamic conditions in ISO 5 areas.
The smoke study you performed during the inspection only included the hoods and
biosafety cabinets only demonstrated pulling drug product from a vial into a syringe.
b）烟雾测试未在 ISO 5 区域的动态条件下进行。您在检查期间进行的烟雾测试仅包括层

流罩和生物安全柜，仅展示了将药品从小瓶抽入注射器中。
c) (b)(4) testing performed on finished products is not (b)(4). In addition, the results of
(b)(4) testing for veterinary products is not documented.
c）对成品进行的 XX 测试不是 XX。此外，兽药产品的 XX 检测结果未记录在案。

Investigations of an unexplained discrepancy and a failure of a batch or any of its
components to meet any of its specifications did not extend to other batches of the same
drug product and other drug products that may have been associated with the specific
failure or discrepancy.
对不明原因的差异以及批次或任何成分未能满足任何质量标准要求的调查没有扩展到可能
与特定失败或差异相关的相同药品和其他药品的其他批次。
Specifically, your firm has documented 5 sterility failures since January 2016 to present.
具体而言，贵公司已记录了自 2016 年 1 月至今的 5 次无菌失败。
Date Product Lot Number Sterility Failure Date
Compounded 产品批号无菌失败日期
配制日期
11/1/17 Thymosin Alpha 1101201705 11/15/17
胸腺素 α
10/30/17 IGF-1 10301704 11/15/17
12/20/17 IGF-1 LR3 12201709 1/10/18
1/24/18 BPC-157 01241805 2/13/18
1/24/18 HCG-4000 01241804 2/13/18
Your firm does not evaluate other products that were produced in the same time-period
in which the sterility failure occurred. Per firm management, your firm performs a
cleaning after a sterility failure, however, there is no written documentation that this
additional cleaning of your ISO 5 and ISO 7 areas is performed.
贵公司未评估在无菌失败发生的同一时间段内生产的其他产品。根据公司管理层，您公司
会在无菌失败后进行清洁，然而，没有书面文件证明对 ISO 5 和 ISO 7 区域进行了额外清
洁。
purporting to be sterile are not established, written and followed.
没有建立、编写和遵循旨在防止声称无菌的药品微生物污染的程序。
a.) Your firm does not have any hold time studies for how long stoppers, vials and seals
(caps) can be stored after being (b)(4) prior to being used in sterile operations. On
8/21/18, we observed your pharmacy technician using the stoppers in sterile operations
while producing Thymosin Beta Injectable (lot# 0821201806), by placing the stoppers on
the vials with their gloved hands.
a）贵公司没有对塞子、瓶子和密封件（瓶盖）在用于无菌操作之前、xx 之后可以保存多久
进行任何保留时间研究。在 2018 年 8 月 21 日生产胸腺素 β 注射剂（批号 0821201806）
时，我们观察到您的制药技术人员在无菌操作中使用塞子，用戴手套的手将塞子放在小瓶
上。
b.) Media fills do not simulate your sterile operations process under normal operating
conditions. Your media fills are not performed under worst case aseptic processing
conditions, for example, your firm produces batches that consists of (b)(4) of vials during
normal sterile operations under the ISO 5 hood, whereas your media fill consists of only
(b)(4) vials being filled and does not incorporate any interventions that may occur during
sterile operations.
b）培养基灌装没有在正常操作条件下模拟无菌操作过程。您的培养基灌装没有在最差情况
的无菌加工条件下进行，例如，您公司在 ISO 5 层流罩下的正常无菌操作期间生产包含
XX 个瓶的批次，然而您的培养基灌装仅包含被灌装的 XX 个瓶，并且不包含在无菌操作
期间可能发生的任何干预。
c.) Your firm does not include the (b)(4) into the media fill program. No media fills are
performed on the (b)(4) process. For example, your firm produces the following two (b)
(4) products at your facility: Tesamorelin and HCG.
c）您公司未将 XX 包括在培养基灌装计划中。没有进行培养基灌装以模拟 XX 工艺。例如，
贵公司在您工厂生产以下两种 XX 产品：替莫瑞林和人绒毛膜促性腺激素（HCG）。
environmental conditions.
无菌加工区域在监测环境条件的系统方面存在缺陷。
a.) Specifically, your firm only conducts personnel monitoring every (b)(4) on each
individual that performs sterile operations. No other personnel monitoring is performed
besides this (b)(4) monitoring. Your firm does not document the time when personnel
monitoring is performed (i.e. before sterile operations, during sterile operations or after
sterile operations). Your firm 's personnel monitoring consists of finger tips only. No other
areas such as forehead, mask, or chest are monitored for the operators.
a）具体而言，贵公司只对每个执行无菌操作的人员每隔 XX 进行一次人员监控。除了此
XX 监测外，不进行其它人员监测。贵公司没有记录进行人员监测的时间（即无菌操作前、
无菌操作期间或无菌操作后）。贵公司的人员监测仅包括指尖。没有操作员的其他区域如前
额、面罩或胸部被监控。
b.) Your firm does not have alarms connected to your magnehelic gauges to monitor
pressure differentials during production. Furthermore, your firm only records the room
pressures in the aseptic processing areas (b)(4) and does not monitor the magnehelic
gauges during production.
b）你公司没有连接到压差表的警报，以监控生产过程中的压差。而且，贵公司仅在无菌加
工区域 XX 中记录房间压力，并且在生产过程中不监控压差表。
法规建议：压差表连接自动报警，在生产过程中监控压差，超标按偏差处理。
Routine calibration of equipment is not performed according to a written program
designed to assure proper performance.
设备的日常校准不是根据旨在确保正常性能的书面计划执行的。
a.) Specifically, your firm uses (b)(4) for sterile operations of all high-risk sterile products
(non-sterile to sterile products). The (b)(4) Temp pressure gauge (Serial Number: (b)(4))
used for performing the (b)(4) (post sterile operations) has never been calibrated. This
pressure gauge has been used since your firm began operations in January 2016. Also,
your firm does not receive a Certificate of Analysis for (b)(4) used for sterile operations.
a）具体而言，贵公司使用 XX 对所有高风险无菌产品（非无菌至无菌产品）进行无菌操
作。用于执行 XX（无菌后操作）的 XX 温度压力表（序列号：XX）从未被校准过。自贵公
司于 2016 年 1 月开始运营以来，该压力表已被使用。另外，贵公司未收到用于无菌操作的
XX 的分析证书。
b.) Equipment used in sterile operations are not on a calibration program to be calibrated
at any frequency. The following pieces of equipment have not been calibrated since your
firm began operations in January 2016: (b)(4) incubators, and (b)(4). Your (b)(4) scale
(model #: (b)(4); serial number: (b)(4)) used for weighing materials for sterile operations
is past due for calibration. On 8/21/18, we observed this scale had a due date sticker of
7/31/18.
b）无菌操作中使用的设备不在以任何频率被校准的校准计划上。自贵公司于 2016 年 1 月
开始运营以来，以下设备尚未校准：XX 培养箱和 XX。用于无菌操作称重物料的 XX 秤
（型号：XX；序列号：XX）超过预定校准日期。在 2018 年 8 月 21 日，我们观察到该秤
有一个预定日期为 2018 年 7 月 31 日的标签。
c.) The digital temperature recorder of your refrigerator (b)(4); model #(b)(4); serial #: (b)
(4)) used for storing finished drug product has never been calibrated. Your firm has been
using this refrigerator in your pharmacy since January 2016.
c）你用于储存成品药品的冰箱（XX；型号 XX；序列号：XX）的数字温度记录仪从未校
准过。自 2016 年 1 月以来，贵公司一直在您的药房使用该冰箱。
d.) Your firm has not qualified your (b)(4), (b)(4) and (b)(4) used for producing sterile
drugs at your facility.
d）贵公司未对你工厂用于生产无菌药物的 XX、XX 和 XX 进行确认。
The quality control unit lacks responsibility to approve and reject all procedures or
specifications impacting on the identity, strength, quality and purity of drug products.
质量管理部门没有责任批准和拒绝影响药品特性、强度、质量和纯度的所有程序或规范。
Specifically, your firm does not perform a visual examination of finished drug products
prior to dispensing and distribution. On 10/16/18, I observed the presence of particulates
in multiple bottles of Prednisolone and Gatifloxacin Ophthalmic Solution, Lot
09042018@2, BUD 12/03/18. (b)(4) bottles of Prednisolone and Gatifloxacin Ophthalmic
Solution, Lot 09042018@2 had already been dispensed and distributed.
具体而言，你公司在配药和分发之前没有对成品进行目视检查。在 2018 年 10 月 16 日，
我观察到多瓶泼尼松龙和加替沙星滴眼液（批号 09042018@2，BUD 12/03/18）中存在
微粒。XX 瓶泼尼松龙和加替沙星滴眼液（批号 09042018@2）已被分配和分发。
Your firm released drug product in which the strength differs from, or its purity or quality
falls below, that which it purports or is represented to possess.
你公司放行的药品剂量不同于，或其纯度或质量低于，其声称或代表拥有的药品。
A. Quality Related Event Report (QRE) dated 06/26/18: A complaint was received for
Rx# (b)(6) for particles floating in the injectable a few days after reconstitution for
AOD 9604 PF 6mg Injection, Lot 06182018@3, BUD 09/16/18. Your firm performed
an investigation confirming the presence of particles for multiple lots of AOD 9604
PF 6mg Injection. The probable root cause was identified as a problem with the
AOD powder, Lot (b)(4) used to produce the batches. Your firm failed to perform a
risk assessment assessing the impact and to take corrective actions, if indicated,
regarding the following AOD injectable batches using AOD powder, Lot (b)(4) that
were released and distributed: 01162018@14, 03192018@2, 05142018@4, and
06182018@3.
质量相关事件报告（QRE）日期 2018 年 6 月 26 日：收到对处方 Rx# xx 的投诉，
AOD 9604 PF 6mg 注射剂（批号 06182018@3，BUD 09/16/18）在复溶后几天内
有颗粒漂浮在注射液中。你公司进行了调查，确认多批 AOD 9604 PF 6mg 注射剂中
存在颗粒。可能的根本原因被确定为用于生产这些批次的 AOD 粉末（批号 XX）问题
你公司未能进行风险评估，评估影响并采取纠正措施，如果指出，涉及使用 AOD 粉
末（批号 XX）的下列被放行和分销的 AOD 注射剂批次：
01162018@14、03192018@2、05142018@4 和 06182018@3。
B. QRE dated 02/09/18: On 02/09/18, your firm identified a sterility failure for
Thymosin B4 PF 15MG Injectable, Lot 01312018@1, BUD 05/01/18. Your firm
failed to take appropriate corrective actions: to perform a risk assessment
assessing the impact on other batches produced from (b)(4) (date reported); and to
take corrective actions, if indicated, regarding the following batches produced in
your firm's ISO 5 sterile, non-hazardous room from (b)(4) :
QRE 日期 2018 年 2 月 9 日：在 2018 年 2 月 9 日，你公司确定了胸腺素 B4 PF
15MG 注射剂（批号 01312018@1，BUD 05/01/18）的无菌失败。你公司未采取适
当的纠正措施：进行风险评估，评估 XX（报告日期）对其它批次的影响；并采取纠
正措施，如果指出，涉及用 XX 在你公司的 ISO 5 无菌非危险室中生产的以下批次：
 Sermorelin PF 15mg Injectable, Lot 01312018@2, BUD 07/30/18
 舍莫瑞林 PF 15mg 注射剂，批号 01312018@2, BUD 07/30/18
 BPC-157 PF 10mg vial Injectable, Lot 01312018@3, BUD 05/01/18
 BPC-157 PF 10mg 瓶注射剂，批号 01312018@3, BUD 05/01/18
 Arginine HCL, 200mg/mL Injectable, Lot 02082018@13, BUD 03/25/18
 盐酸精氨酸 200mg/mL 注射剂，批号 02082018@13，BUD 03/25/18
 Leucine/Isoleucine/Valine 10mg/10mg/5mg/mL PF Injectable, Lot 02082018@4,
BUD 03/10/18
 亮氨酸/异亮氨酸/缬氨酸 10mg/10mg/5mg/mL PF 可注射，批号
02082018@4，BUD 03/10/18
 Dexpanthenol USP 250mg/mL Injectable, Lot 02082018@15, BUD 03/25/18
 右泛醇 USP 250mg/mL 注射剂，批号 02082018@15, BUD 03/25/18
 Ascorbic Acid Injection 500mg/mL Injectable, Lot 02082018@11, BUD 03/10/18
 抗坏血酸注射液 500mg/mL 注射剂，批号 02082018@11，BUD 03/10/18
 抗坏血酸注射液 500mg/mL 注射剂，批号 02072018@1，BUD 03/09/18
There is a failure to thoroughly review any unexplained discrepancy whether or not the
batch has been already distributed.
未彻底审核任何不明原因的差异，无论该批是否已经分销。
A. You initiated an investigation on 11/27/2017 emanating from mold contamination
results read on 11/18/2017 in your Grade A filling area. This event resulted in the
rejection of approximately (b)(4) batches of finished product manufactured on (b)(4)
filling line. This investigation is inadequate because you did not appropriately
identify the scope of the investigation, establish the root cause and implement
preventive actions or initiate the investigation in a timely period. You suspended
production activities on 12/8/2017 after three mold isolates were recovered in these
areas and to establish the root cause. You visually identified apparent dried product
residue on the underside of the lyophilization trayer bed / product path on
12/9/2017. You made no attempt to identify this residue. You sampled the area of
the residue which resulted in the recovery of 11 CFUs of mold on 12/15/2017. You
identified additional mold isolates near this affected area procured from apparent
product residue. You identified a potential source of contamination and sampled this
area without conducting a scientifically established sampling plan or worst-case
sample locations. You returned to manufacturing during late December 2017. You
identified inadequate cleaning as a cause for the apparent product residue on or
about 12/9/2017. You identified additional apparent product residue on
approximately 7/31/2018 at the same location it was identified on 12/9/2017.
A. 你在 2017 年 11 月 27 日启动了一个调查，产生于 2017 年 11 月 18 日在你的 A 级
灌装区发现霉菌污染结果。此事件导致拒绝约 XX 批在 XX 灌装线上制造的成品。由于
你没有适当确定调查范围、确定根本原因并实施预防措施或及时启动调查，因此调查
是不充分的。在这些区域恢复了三个霉菌分离株并确定根本原因后，你于 2017 年 12
月 8 日暂停了生产活动。你在 2017 年 12 月 9 日在冻干托盘床/产品路径的底面目视发
现明显的干燥产品残留物。你没有尝试识别该残留物。你对残留物区域进行了取样，结
果于 2017 年 12 月 15 日恢复了 11 CFU 的霉菌。你在此受影响区域附近发现了从表观
产品残留物中获得的额外霉菌分离物。你确定了潜在的污染源并对该区域进行了取样，
但没有进行科学确定的抽样计划或最差情况的样本位置。你于 2017 年 12 月下旬重新
投入生产。你确认不适当的清洁是导致 2017 年 12 月 9 日左右表观产品残留的原因。
你大约在 2018 年 7 月 31 日在 2017 年 12 月 9 日确认的同一地点发现了其他明显的产
品残留物。
B. You failed to adequately investigate approximately 9 previous events when an
unknown foreign material / gel was observed adhering to the High Efficiency
Particulate Air (HEPA) filter screens. The metal screens are a part of the ceiling in
all cleanrooms and are located approximately 4" - 8" from the face of the HEPA
filters. On 7/24/2018, we observed an apparent "gel" or other foreign material in the
(b)(4) line adhering to the HEPA filter screen, later identified as an approximately 3
mm x 3 mm "gel''. You failed to document the investigation contemporaneously as
well as who inspected the room. You did not immediately extend this investigation to
other areas even though this "gel" is used as a part of your HEPA filters. This gel is
used throughout your facility in cleanrooms as an integral part of your HEPA filters.
B. 当观察到未知异物/凝胶粘附在高效微粒空气（HEPA）过滤网上时，你未能充分调
查大约 9 次以前的事件。金属滤网是所有洁净室中天花板的一部分，距离 HEPA 过滤
器的表面大约 4 – 8 英寸。在 2018 年 7 月 24 日，我们在 XX 线观察到粘附在 HEPA 过
滤网上的明显“凝胶”或其他异物，后来被鉴定为大约 3mm×3mm 的“凝胶”。你没有
同时记录调查情况以及检查房间的人员。你没有立即将调查延伸至其他地区，即使这
个“凝胶”被用作你的 HEPA 过滤器的一部分。这种凝胶在你的整个工厂洁净室中用
作 HEPA 过滤器的组成部分。
C. You initiated an investigation on 9/26/2017 because of a potential data integrity
event associated with an in-process auditor per PR ID 2011571. The auditor
performed visual inspection operations affecting approximately (b)(4) lots
manufactured from 7/6/2015 through 9/22/2017. The investigation is inadequate
because you did not scientifically justify why you chose to analyze the retain data of
approximately (b)(4) lots. Additionally, you requested lot #81660LL be returned to
your control for further evaluation as it was distributed outside of your control.
C. 你在 2017 年 9 月 26 日启动了一个调查，因为根据 PR ID 2011571，与过程审计
员相关的潜在数据完整性事件。审计员执行了目视检查操作，影响了从 2015 年 7 月 6
日至 2017 年 9 月 22 日生产的大约 XX 批。该调查是不充分的，因为你没有科学地证
明为什么你选择分析大约 XX 批的保留数据。此外，你要求退回批次＃81660LL 以进
行进一步评估，因为它已被分销在你的控制之外。
D. You modified your validated parameters on approximately 5/19/2018 associated
with your (b)(4) stopper washing process. You have no documentation supporting
that you assessed the risk of this process change before it was implemented.
Specifically, you did not verify that modifying the pressure (b)(4) to (b)(4) pounds
per square inch or the use of a (b)(4) load versus a (b)(4) load, does not adversely
affect this process. Your Quality Site Director stated you would open an
investigation on 7/31/2018 to assess the risk of this event.
D. 你在大约 2018 年 5 月 19 日修改了与你的 XX 塞子清洗过程相关的已验证参数。你
没有任何文件支持你在其实施之前评估此工艺变更的风险。具体来说，你没有证明修
改压力 XX 至 XX 磅每平方英寸或使用 XX 负载替换 XX 负载不会对此工艺产生不利影
响。你的现场质量总监表示将于 2018 年 7 月 31 日开展调查，以评估此事件的风险。
E. You identified an activated Diphenhydramine Carpuject unit (critical defect)
during your retain examination on 12/20/2017 of lot #73525LL. You identified an
operator inappropriately re-incorporating ejected product back into your product
stream as a root cause. You modified your written procedures on approximately
3/30/2018 and implemented this preventive action on approximately 4/30/2018. You
did not perform any immediate action to prevent this reoccurrence in the interim.
E. 你在 2017 年 12 月 20 日对批次＃73525LL 的留样检查中发现了一个激活的苯海拉
明 Carpuject（注：一种注射器装置）单位（严重缺陷）。你发现操作员不恰当地将弹
出的产品重新合并到产品流中是根本原因。你大约在 2018 年 3 月 30 日修改了你的书
面程序，并大约在 2018 年 4 月 30 日实施了此预防措施。你没有立即执行任何操作来
防止在过渡期再次发生此类事件。
Repeat Observation from the 10/2017 and 6/2016
2017 年 10 月和 2016 年 6 月的重复缺陷
An NDA-Field Alert Report was not submitted within three working days of receipt of
information concerning a failure of one or more distributed batches of a drug to meet the
specifications established for it in the application.
NDA-现场警报报告未在收到有关药物的一个或多个分销批次的失败信息的 3 个工作日内
提交，以满足在申请中为其制定的标准。
A. On 11/27/2017, you opened an investigation initiated from mold recovered from a
settle plate on line (b)(4) in your grade A area. You visually observed apparent
product residue on the underside of the trayer bed. This product residue was
sampled and yielded 11 CFU s of mold. You made no documented attempt to
identify this residue nor how or when this residue was deposited. You identified
apparent product residue in this same area again, on 7/31/2018.
A. 在 2017 年 11 月 27 日，你开始调查从 A 级区 XX 处的沉降碟恢复的霉菌。你在托盘
床的底面目视发现明显的产品残留物。该产品残留物被取样，得到 11CFU 的霉菌。你
没有进行有记录的尝试识别该残留物，也不知道这些残留物是如何或何时沉积的。你
于 2018 年 7 月 31 日再次在同一区域发现了明显的产品残留物。
B. On 9/22/2017, you discovered information resulting in a potential data integrity
event associated with an in-process auditor per PR ID 2011571. The auditor
performed visual inspection operations affecting approximately (b)(4) lots
manufactured from 7/6/2015 through 9/22/2017.
B. 在 2017 年 9 月 22 日，你发现了导致潜在数据完整性事件的信息，根据 PR ID
2011571 与过程审计员相关。审计员执行了目视检查操作，影响了从 2015 年 7 月 6 日
至 2017 年 9 月 22 日生产的大约 XX 批。
C. On 10/9/2017, you discovered a cracked needle hub (critical A defect) while
performing a manufacturing quality audit of Morphine Sulfate Inj. USP, lot
#80740LL. You did not submit a Field Alert Report for this event until 2/5/2018.
C. 在 2017 年 10 月 9 日，你在对硫酸吗啡注射剂 USP（批号 80740LL）进行制造质
量审计时发现了一个有裂纹的针座（关键 A 缺陷）。你未在 2018 年 2 月 5 号之前提交
此事件的现场警报报告。
法规意见：按 21 CFR 314.81 规定，ANDA 也需要报告任何因产品原因或标签错误所

致用药差错、假劣药事件、细菌污染、重大的化学、物理或其他变化、产品变质、过期产
品。
Repeat Observation from 10/2017, 6/2016 and 8/2013

2017 年 10 月、2016 年 6 月和 2013 年 8 月的重复缺陷
Certificates of testing of containers are accepted in lieu of testing without establishing

the reliability of the supplier's test results through appropriate validation of the test
results at appropriate intervals.
接受容器测试证书代替测试，而未通过在适当的时间间隔对测试结果进行适当验证，确定
供应商测试结果的可靠性。
You have not performed a risk assessment or have performed one which is inadequate.
You have not fully qualified your vendor's Certificate of Conformance. Specifically, you
have not inspected incoming molded glass vials for (b)(4). This defect type is included
on your suppliers' Certificates of Conformance. You have no documented scientific
justification precluding you from testing for this defect.
你尚未进行风险评估或执行了不充分的风险评估。你还没有完全确认供应商的符合性证书。
具体而言，你没有检查进厂玻璃模制瓶的 XX。此缺陷类型包含在供应商的符合性证书中。
你没有文件化的科学证据，排除你对此缺陷进行测试。
Employees engaged in the manufacture, processing, packing, holding of a drug product

lack the training required to perform their assigned functions.
从事药品生产、加工、包装、保存的员工缺乏履行其指定职能所需的培训。
Your training is inadequate for the following:
你的培训在以下方面是不充分的：
A. Retain inspectors / operators are trained via the (b)(4) visual inspection training
program which requires qualification based using a (b)(4). You have no documented
scientific justification establishing why the (b)(4) is representative or worst case of
all primary container closure systems such as ampules (~1mL - 5 mL), amber vials,
100-mL vials, etc.
A. 留样检查员/操作员通过 XX 目视检查培训计划进行培训，该计划要求使用 XX 进行
资格确认。你没有文件化的科学证据证明为什么 XX 是所有主要容器封闭系统（如安
瓿(约 1mL－5mL)、琥珀色小瓶、100mL 瓶等）的代表或最差情况。
B. You do not trend time elapsed since last personnel training regarding visual
inspection processes. You have re-inspected approximately 300 of (b)(4) batches
manufactured since approximately 10/10/2017.
B. 自上次有关视觉检查过程的人员培训以来，你没有趋势化流逝的时间。自 2017 年
10 月 10 日左右以来，你已经重新检查了大约 300 个生产的 XX 批次。
C. You have no valid rationale for dismissing personnel training as a root cause for
your positive sterility test noted in Laboratory Investigation PR ID 1993529. You did
not trend to determine whether your analyst has previously performed positive
sterility test.
C. 你没有合理的理由否定人员培训作为实验室调查 PR ID 1993529 中记录的阳性无
菌测试的根本原因。你没有趋势分析以确定你的分析师之前是否进行了阳性无菌测试。
20. 印度 Dr. Reddy’s 20181114

There are no written procedures for production and process controls designed to
未设计生产和工艺控制书面程序用以确保药品具备其应有的鉴别、剂量、质量和纯度。
Your quality unit failed to implement adequate and reliable controls for ensuring
that distributed liquid injectable drug products or any of its components always
comply with the quality they represent to possess.
你们质量部门未能执行充分和可靠的控制用以确保所销售的注射液药品或及组份全部
符合其应有的质量。
All the following adverse incidents correspond to sterileliquid drug product lots
that were sealed (b)(4) in the sealing equipment PR-E007.
所有以下不良事件均对应的是无菌液体药品，这些药品均在封装设备 PR-E007 上密封。
In January 2018, your firm recalled one (1) lot of Docetaxel Injection USP
20mg/mL (USA market); Lot H7044; expiration date 05/2019, due to consumer
complaints related to critical sealing defect (i.e.seal and stopper comes off the
vial, making vial wide open and exposed). This critical defect was acknowledged
in each of the four (4) complaints reported for the affected lot.
2018 年 1 月，你公司召回了一批多西他赛注射液 USP 20mg/ml（美国市场）批号为
H7044，有效期 201805，原因是与关键密封缺陷有关的客户投诉（即密封和塞子脱出
西林瓶，瓶口大开，药液暴露）。此关键缺陷在受影响批次中 4 个投诉中均有提及。
First complaint was received on 10/20/2017. The complainant stated that “had
seven (7) vials of Docetaxel Injection USP 20mg/mL; Lot H7044 where the entire
top comes off when trying to administer the medication and the whole vial is wide
open, exposing the inside of the vial”. Your Quality Unit initiated a manufacturing
Investigation Report (IR) 200263810 on 10/21/2018. No Field Alert (FAR) was
submitted to the agency.
第一个投诉是在 20171020 收到的。投诉者声称“在准备用药时发现有 7 瓶多西他赛注
射液 USP 20mg/ml，批号为 H7044 顶部塞子完全脱出，整个瓶口大开，瓶内药品暴
露”。你们质量部门于 20181021 启动了生产调查报告 IR200263810，但没有向 FDA
提交 FAR。
IR 200263810 disclosed that all in-process controls are released testing for Lot
H7044 were as expected. However, based on the complaint nature, the
investigation identified (b)(4) major contributors for the confirmed critical sealing
defects (b)(4).
IR200263810 里说 H7044 批的所有中控检测均按要求放行。但是，根据投诉的性质，
调查识别出经确认的严重密封缺陷 XX 的 XX 主要原因。
None of the referenced sealing (b)(4) critical process parameters were validated
in the sealing equipment PR-E007 by the time the referenced complaint was
received.
在收到上述投诉时，在密封设备 PR-E007 上所用的关键工艺参数 XX 密封并未经过验
证。
As part of the manufacturing investigation IR 200263810, representative reserve
samples of (b)(4) lots were evaluated for (b)(4) seal removal. It was identified that
one (1) vial from (b)(4) lot of (b)(4) injection (Indian market); Lot (b)(4) and (b)(4)
Injection (Indian market); Lot(b)(4) showed also the critical sealing defect. As
corrections, your Quality Unit proposed the implementation of manual (b)(4)
functionality test during sealing activity and qualification of sealing (b)(4) critical
process parameters.
作为生产调查 IR 200263810 的一部分，对 XX 批次代表性留样进行了密封性脱除评估，
发现 XX 批 XX 注射液（印度市场）、XX 批和 XX 注射液（印度市场）、XX 批显示亦有
严重密封缺陷。作为纠正措施，你们质量部门提议在密封过程中实施手动 XX 功能性检
测，以及对密封 XX 关键工艺参数进行确认。
Second complaint for Docetaxel Injection USP 20mg/mL (USA market); Lot H7044
was received on 11/08/2018. The complainant stated “the whole top of the vials is
loose and when tried to pull the cap off, the whole metal part comes off
(aluminum seal)”. Your firm initiated the manufacturing IR 200266437 and
submitted a FAR to the agency on 11/09/2018. For the period from 10/20/2017
(first complaint was received) to 11/09/2017 (second complaint was received)
approximately (b)(4) vials of Docetaxel Injection USP 20,g/mL; Lot H7044 were
distributed into USA market. After the second complaint received for Lot H7044,
your Quality Unit determined to recall this lot.
第二起多西他赛注射液 USP20mg/ml（美国市场）投诉为批号 H7044，收到日期为
20181108。投诉者声称“整个西林瓶顶部松脱，当试图将盖拨出时，整个金属部分掉
了下来（铝盖）”。你公司启动了生产 IR200266437，并于 20181109 向 FDA 提交了
FAR 。从 20171021-20171109 （收到第二起投诉）期间约有 XX 瓶多西他赛注射液
USP20mg/ml 批号 H7044 销往美国市场。在收到 H7044 批的第二起投诉之后，你们质
量部门决定召回该批次。
In addition, 此外
Additional complaint was received on 12/26/2017 for (b)(4) Injection USP (b)
(4)mg/(b)(4)mL (USA market); Lot (b)(4) expiration date (b)(4). The complainant
reported two (2) observations:
XX 注射液 USP XXmg/xxml（美国市场）批号 XX 有效期 XX 亦收到一份投诉。投诉者
报告了 2 个问题：
* vial 1 - liquid leak found between the (b)(4) cap and the vial 第一瓶—在 XX 盖与
西林瓶之间发现液体泄漏
** vial 2 - (b)(4)seal came off from the vial where the (b)(4) cap remains on the
seal 第二瓶—XX 密封从西林瓶脱，而出 XX 盖与密封盖保持在一起
Manufacturing IR 200273645 was initiated and a FAR was submitted to the
agency on 12/28/2017. The IR 200273645 disclosed no discrepancy during the
manufacturing process of Lot (b)(4). All the in-process controls and released
testing for Lot (b)(4) were as expected. As part of the investigation, the reserve
samples of Lot (b)(4) were also inspected, and no loose seal or leakage was
observed. Your Quality Unit concluded that if seal on its place,the vial is integral.
No additional actions were considered.
20171228 启动了生产 IR 200273645，提交了 FAR。IR 200273645 发现在 XX 批次生
产工艺中并无偏差。XX 批次的所有中控和放行检测均满足要求。作为调查的一部分，亦
对 XX 批次的留样进行了检查，未发现密封松脱或泄漏。你们质量部门得出结论是如果
密封仍在原位，则西林瓶是完整的。未考虑采取进一步措施。
As corrections, your Quality Unit defined (b)(4) for removal of (b)(4) in alignment
with the supplier specification (06/2018); implemented (b)(4) functionality test
(02/2018), and carried out validation activities of the sealing (b)(4) critical process
parameters for (b)(4) vials (12/2017).
作为纠正措施，你们质量部门定义了根据供应商质量标准移除 XX（201806），执行
XX 功能性测试（ 201802 ），对 XX 瓶执行密封 XX 关键工艺参数的验证活动
（201712）。
The lack of qualifying the sealing critical parameters such as, (b)(4) do not ensure
that each sterile liquid drug products lot (b)(4) in (b)(4) equipment PR-E007 prior
to December 2017, is impacted by the defect of seal and (b)(4) stopper comes
off.
缺少对关键密封参数的确认，如 XX，导致不能确保 201712 之前在设备 PR-E007 上
生产的每个无菌液体药品批次不受到密封缺陷和 XX 塞子脱出的影响。
Repeat Observation from WL 320-16-02 & FDA-483 March 2017.
此为警告信 WL-320-16-02 和 2017 年 3 月 FDA-483 的重复缺陷。
purporting to be sterile are not established or followed. 未建立或未遵守设计用以防
止无菌药品微生物污染的程序。
Your control procedures SOP FTDQA007-02: dated on 02/28/2018 “Aseptic
Process Simulation (Media Fill)” and SOP FT07-QA-0022; dated on 07/03/2018;
version 2.0 “Handling of Interventions during routine production activity” were
found inadequate. Specifically, these control procedures do not require a periodic
simulation of new and highly critical intervention (corrective intervention)
observed during routine commercial process.
你们的控制程序 SOP FTDQA007-02 ，日期 20180228“ 无菌工艺模拟（培养基灌
装）”和 SOP FT07-QA-0022 ，日期 20180703，版本 2.0“常规生产活动中干扰处
理”不充分。具体来说，这些控制程序并未要求对日常商业工艺中发现的新的严重干扰
动作进行定期模拟（纠正性干预）。
A. For example, Incident Report (IR) 200241685 was initiated on 05/29/2017,
due to a new corrective intervention i.e. (b)(4). The intervention was performed on
05/27/2017 by two (2) operators in (b)(4) PR-E007 filling Line (b)(4) operation of
(b)(4) drug product (b)(4) Injection (b)(4) mg/vial; Lot (b)(4), expiration date (b)(4)
fill volume adjustment and filling operation were completed. The IR 200241685
identified a damage in the (b)(4) as the root cause for this new corrective
intervention.
例如，事件报告（ IR ） 200241685 于 20170529 因新的纠正干预而启动。干预于
20170527 由 2 名操作员在 XX PR-E007 灌装线生产 XX 药品 XX 注射液 XXmg/瓶批号
XX 有效期 XX 的 XX 过程中执行，对灌装体积进行了调整，灌装操作完成。
IR200241685 将 XX 的损坏作为根本原因，制订了新的纠正干预。
Same corrective intervention was also carried out on 07/04/2017, in (b)(4) PR-E-
007 filling Line (b)(4) operation of (b)(4) drug product (b)(4) Injection (b)(4)
mg/vial; Lot (b)(4) expiration date (b)(4). However, no incident report was initiated
to assess the impact of (b)(4) intervention over the aseptic filling operations for
Lot (b)(4). Moreover, no root cause was identified to prevent reoccurrence of
having a mechanical intervention in the (b)(4) while processing.
相同的纠正性干预亦在 20170704 在 XX PR-E007 灌装线 XX 药品 XX 注射液 XXmg/
瓶 XX 批号 XX 有效期的 XX 操作过程执行。但未启动事件报告来评估 XX 干预对 XX 批
号无菌灌装操作的影响。另外，未识别出根本原因防止生产过程中 XX 的机械性干预重
复发生。
(b)(4) corrective intervention was simulated during set-up process of (b)(4) PR-
E007 filling Line (b)(4) in two (2) successive media fill Lots (b)(4) (dated on
05/31/2017) and (b)(4) (dated on 06/07/2017). However, your firm simulated the
intervention during the set-up process of the fillingLine (b)(4) instead of
simulating it during aseptic filling process, which is where the worst condition is
represented. Moreover, there is no evidence in the media fill batch records (Lots
(b)(4) and (b)(4)), which demonstrate the corrective intervention was performed
by two (2) operators.
XX 纠正性干预在 PR-E007 灌装线 XX 装配期间进行了模拟，灌装了连续 2 批培养基批
号 XX（日期 20170531）和批号 XX（日期 20170607）。但是你们公司模拟的是装配
期间灌装线 XX 干预而不是模拟无菌灌装过程，没有呈现出最差情形。另外，培养基灌
装记录批号 XX 和 XX 没有证据证明纠正性干预是由 2 名操作员执行的。
Your Quality Unit failed to include (b)(4) intervention in the list of the corrective
and highly critical interventions that should be periodically simulated as part of
your media fill program.
你们质量部门未能在纠正性严重干预清单中包括 XX 干预，这些本应作为培养基灌装程
序的一部分进行定期模拟的。
Your firm has carried out approximately nine (9) media fill runs (b)(4) in aseptic
filling Line (b)(4) since the corrective action was observed on 07/04/2017.
自 20170704 年发现纠正措施后，你公司执行了 9 次培养基在无菌灌装线的模拟灌装。
Repeat Observation from WL 320-16-02.
此为 WL-320-16-02 的重复缺陷。
B. There is no assurance that your process simulation studies (media fills)
performed in the XXPR-E007 filling Lines XX are truly representative of the
conditions observed and/or that might occur during routine aseptic filling
operations of vials.
未能确保在 XX PR-E007 灌装线 XX 的培养基模拟灌装研究真实代表常规西林瓶无菌
灌装操作期间可能发生和/或发现的情形。
This is evidenced in that, although corrective and inherent operator’s
interventions are simulated during the media fills, the duration at which these
interventions are simulated is not established based on an historical and/or
retrospective evaluation.
有证据表明虽然在培养基灌装期间模拟了指定操作员的纠正性干预，但这些干预所模
拟的时间长度并不是根据历史和/或回顾性评估建立的。
Your current practice does not ensure the extension ofeach of the interventions is
accurately simulated during the aseptic-process (media fill) runs.
你们当前的做法并不能确保每个干预的程度准确在无菌灌装（培养基）中得到准确模
拟。
C. The control procedure SOP FT7QC247; dated on 05/29/2018;
“Microbiological Viable Monitoring Program” establishes the following rationale for
selecting the sample sites form icrobiological monitoring into the ISO 5 area of (b)
(4) PR-E007:
控制程序 SOP FT7QC247 日期 20180529“ 微生物监测程序 ” 建立了以下 XX PR-
E007 设备在 ISO5 环境中微生物监测取样点选择原则：
* Sites where activities that contribute spread of contamination 对导致污染传播的
活动地点
* Sites, which if contaminated, have adverse effect on product quality 受污染后对
产品质量有不良影响的地点
Per control procedure SOP FT7QC247, (b)(4) located in ISO5 area of (b)(4) PR-
E007 was selected for surface sampling monitoring. This location was selected to
ensure aseptic conditions of the filling (b)(4).
依据控制程序 SOP FT7QC247，XX PR-E007 所在 ISO 5 区域内 XX 点被选择用于表
面微生物取样监测。选择该点是为了确保灌装 XX 的无菌条件。
The control procedure SOP FT7QC247 was found inadequate, in that not requires
that surface sampling monitoring must (swab sampling method) must be collected
from the (b)(4) that was in use during the aseptic filling process.
控制程序 SOP FT7QC247 是不充分的，其中未要求表面微生物取样监测必须（擦拭
取样方法）从无菌灌装过程中所用的 XX 上采集。
For example, on 10/29/2018, I witnessed the aseptic filling process of (b)(4)
Injection (b)(4) mg/vial; Lot (b)(4). This lot was aseptically filled using the (b)(4)
located into (b)(4) PR-E007. However, the surface swab sampling collected by the
(b)(4) the filling process was carriedout in (b)(4) which does not truly represent
the worst surface sample site forfilling process of Lot (b)(4).
例如在 20181029，我亲眼看到 XX 注射液 XXmg/瓶批号 XX 的无菌灌装过程。该批准
采用 PR-E007 进行无菌灌装。但是，在灌装过程中的擦拭样品是在 XX 采集的，不能
真实代表批次 XX 灌装过程的最差表面样品位置。
D. Specifically, inadequate collection filters were used to confirm the retention of
(b)(4) during the (b)(4) filter validations. The microorganism retention study was
conducted to verify absolute retention of the test organisms on the (b)(4)um(b)(4)
product filters. The collection filter with pore size of (b)(4)um are placed (b)(4) to
the (b)(4) filters and used to validate the absolute retention of the test
microorganism, (b)(4). Due to the (b)(4) pore size of the collection filters, (b)(4)
that may have penetrated the (b)(4) um (b)(4) filters may not be detected by the
(b)(4) um collection filters, resulting infalse negative result. The (b)(4)um
collection filters were used during the(b)(4) filter validation studies for products
intended for U.S. market,including (b)(4) injection and (b)(4) injection.
具体来说，在 XX 过滤验证中用于确认 XX 截留的采集过滤器是不充分的。微生物截留
试验是用于确认 XXum 的 XX 产品过滤器上测试菌的绝对截留。实际验证使用的是孔径
为 XXum 的采集过滤器，放置在 XX 过滤器后，用于验证测试菌 XX 的绝对截留情况。
由于采集过滤器的孔径为 XX，XX 可能会穿透 XXum 的 XX 过滤器，XXum 的采集过
滤器可能就无法检出测试菌，导致假阴性结果。在美国市场产品包括 XX 注射液与 XX
注射液的 XX 过滤器验证研究过程中使用的是 XXum 采集过滤器。
Employees engaged in the manufacture and processing of drug product lack the
training and experience to perform their assigned functions.
生产和加工药品的员工缺乏与其工作有关的培训和经验。
A. The firm’s training program does not provide comprehensive trainings to
conduct the assigned job responsibilities. The trainings programs do not define
the requirements for the on-the-job trainings or the qualifications for technical
procedures, including operation/calibrationof dissolution apparatus, GC, pH
meter, Karl Fisher, etc. The self-conducted, SOP trainings are required for most
operations and there are no training assessments conducted to verify the training
effectiveness. Firm’s personnel showed insufficient knowledge of the written
procedures on the routine operations for the assigned job, resulting in numerous
incidences of atypical events.
公司的培训程序未提供全面的培训使员工能够执行指定工作职责。培训程序中未定义在
网培训的要求，亦没有技术程序包括溶出仪、GC、pH 计、卡尔费休仪等操作/校正资质
确认。大多操作是进行自学 SOP 培训，没有进行培训评估来确认培训效果。公司的人员
在日常操作中显示出对本职工作书面程序的知识不足，导致大量异常事件发生。
B. There are insufficient trainings provided for observed procedural or practical
deficiencies, identified from atypical incident events. Refresher trainings are not
always required or provided to all affected personnel, for the root causes
identified in the reoccurring a typicalevents. Repeated atypical events from
similar root causes have resulted in numerous aborted HPLC sequence runs.
During Jan-Oct 2018, I’ve identified at least 34 repeated atypical events, related
to insufficient handling of HPLC columns, 19 aborted sequence runs from
improper column conditioning and 15 events from poor column performance.
对于从异常事件中识别出或已发现的程序或实操缺陷给予培训不足。在重复发生异常事
件中识别根本原因后，未要求对所有受影响人员进行重新培训。由于同类根本原因引发
的重复异常事件导致大量 HPLC 序列中断运行。在 2018 年 1-8 月间，我已看到至少 34
例重复的异常事件均与 HPLC 柱子处理不充分有关，19 例因柱子平衡问题和 15 例因
柱效不良中断序列运行。
An (b)(4) Field Alert Report was not submitted within three working days of
receipt of information concerning afailure of one or more distributed batches of a
drug to meet the specifications established for it in the application. 在收到一批或
多批已销售药品不符合注册资料中既定标准时未在 3 个工作日内提交 FAR 。
On 10/20/2017, your Quality Unit received one (1) customer complaint related to
a critical sealing defect (i.e. (b)(4) observed in seven (7) vials of Docetaxel
Injection USP 20mg/mL (USA market); Lot H7044; expiration date 05/2019.
Manufacturing Investigation Report (IR) 200263810 was initiated and identified
(b)(4) major contributors for the confirmed critical sealing defects (b)(4)
Investigation IR 200263810 also disclosed that none ofthe referenced sealing (b)
(4) critical process parameters were validated in the(b)(4) PR-E007 filling Line (b)
(4) (sealing equipment) by the date (10/20/2017) the complaint for Lot H7044 was
received. (b)(4) PR-E007 was used during thesealing (b)(4) process of Lot
H7044.
20171020 ，你们质量部门收到 1 起严重密封缺陷（即批次 H7044 多西他赛 USP
20mg/ml （美国市场）注射剂效期 201805 有 7 瓶 XX ）客户投诉。生产调查报告
(IR)200263810 启动并识别 XX 为已确认严重密封缺陷的主要原因。调查还显示 XXPR-
E007 灌装线 XX（密封设备）截止 20171020 未进行关键工艺参数验证，而该产线用
于 H7044 投诉批次的密封。
Your Quality Unit did not submit a FAR to the agency until they received on
11/09/2017, a second complaint reporting the same critical sealing defect in lot
H7044.
直至 20171109 收到第二份相同缺陷相同批次投诉，你们质量部门才向 FDA 提交
FAR。
For the period from 10/20/2017 (first complaint was received) to 11/09/2017
(second complaint was received) approximately (b)(4) vials of Docetaxel Injection
USP 20mg/mL; Lot H7044 were distributed into USA market. Lot H7044 was
recalled.
在 20171020-20171109 期间，约 XX 瓶多西他赛注射液 USP 20mg/ml 批号 H7044 在
美国销售，目前该批次已召回。

Procedure for aseptic process (media fill) simulations, performed in the sterile API
manufacturing facility, are not adequate.
在无菌原料药生产设施中所实施的无菌工艺（培养基灌装）模拟程序不充分。
A. You do not continuously monitor environmental conditions via settle plates in
the aseptic (Grade A/B) manufacturing areas during the entire span of the aseptic
process simulation. Settle plate exposure is only performed for a (b)(4) period (b)
(4) in the Grade A/B areas, totaling(b)(4). A typical media fill simulation is
continuously performed over a (b)(4) from start to completion. You have not
provided any scientific rationale as to why settle plate exposure can be reduced to
(b)(4) and that unmonitored times during media fills are considered acceptable
and support evidence of aseptic environmental conditions during the entire media
fill campaign.
你们没有在整个无菌工艺模拟期间通过无菌（A/B 级）生产区域的沉降碟持续监测环境
条件。A/B 级沉降碟暴露时长只有 XX，总共 XX。一般的培养基模拟灌装应该从开始到
完成要持续进行监测。你们未提供科学理由证明沉降碟暴露时长可缩短至 XX，认为模
拟灌装中未监测的时长可以接受，以及整个培养基灌装过程的无菌环境条件的支持证据
B. According to your procedures, disinfection cleaning is to be performed (b)(4)
totaling (b)(4) disinfection cleanings in the Grade A/B area during normal
production. However, during media fill simulations, the disinfection cleaning
frequency is not challenged in a worst-case manner, where the number of
disinfection cleanings performed each day during a media fill simulation is
reduced, to further demonstrate and qualify operator aseptic technique.
根据你们的程序，在正常生产过程中 A/B 级要执行共 XX 消毒清洁。但是培养基模拟灌
装期间，消毒清洁频次并未经过最差情形挑战，即减少培养基模拟灌装期间的每天消毒
清洁的次数，进一步证明并确认操作员的无菌技术。
C. You do not collect (b)(4) filtration samples of the media fill compounding
solution (b)(4) for demonstration of bioburden load reduction after (b)(4) filtration
of the simulated API material during aseptic process simulations in the (b)(4)
building. Your firm has not scientific rationale or supporting data to demonstrate
equivalency of (b)(4) filtration assembly efficiency at your sterile API
manufacturing site, compared to the offsite filter validation study performed by
your third party vendor (b)(4).
你们未采集 XX 配制后溶液 XX 培养基灌装的过滤样品用以证明 XX 建筑物内无菌工艺
模拟中模拟 API 物料在 XX 过滤之后生物负载降低的结果。你公司没有科学合理性或支
持性数据来证明你们无菌 API 生产场地 XX 过滤的效率与你们第三方供应商 XX 所做的
离厂过滤验证研究的等同性。
D. Challenges are not consistently performed during media fill simulations for the
“Max. Permissible/Simulated time limits” listed in the “Batch Observations Sheet”
attached to the “Additional Attachment of BPR” (b)(4) of media fill simulation),
where the maximum allowable time limits are achieved or exceeded, in
accordance with a worst-case approach.
在培养基灌装模拟中所执行的培养基灌装“BPR 其它附件”所附“批缺陷表”中所列
的“最大允许/模拟时限”挑战不一致，根据最差情形方法应达到或超出最大允许时限。
Cleaning validations are inadequate for the equipment in the aseptic
manufacturing area.
无菌生产区内的设备清洁验证不充分。
A. The bioburden testing performed during cleaning validation study of aseptic
area does not utilized a (b)(4) for analysis of (b)(4) samples collected from the (b)
(4) in the aseptic manufacturing area. Your firm has not conducted a validation
study demonstrating that (b)(4) without the (b)(4) is capable of supporting
microbial growth in the presence of(b)(4) solutions collected from the (b)(4) in the
aseptic manufacturing area of the (b)(4) building.
在无菌区域清洁验证期间所执行的微生物负载测试中，无菌生产区内 XX 所采集的 XX
样品未使用 XX 进行分析。你公司未进行验证研究证明没有 XX 的 XX 在有 XX 建筑物中
无菌生产区域的 XX 中采集的 XX 溶液存在时能够支持微生物生长。
B. The determination of a maximum campaign time (b)(4) and maximum number of
batches which can be performed (b)(4) during a (b)(4) production campaign
(before campaign cleaning must be conducted) is not supported by the data and
results in the cleaning validation report for aseptic area-either by chemical testing
or microbiological testing conducted during the validation.
清洁验证报告中在验证期间对无菌区域的（化学检测和微生物检测）数据和结果不支
持最长生产周期时长 XX 和在一个 XX 生产周期内可生产 XX 的最多批次数量（之后必
须进行周期清洁）。
Systems for monitoring environmental conditions for Aseptic processing area are
deficient.
无菌工艺区域的环境监测系统有缺陷。
A. Your firm’s written procedure, CSB-095-09, “Gowning, Entry and Exit Procedure
for Grade A/Grade B Area”, with an effective date of 15 November 2018, is
deficient in addressing contact time of disinfectants for personnel hands during the
manufacturing of sterile products.
你公司 2018 年 11 月 15 日生效的书面程序 CSB-095-09“A/B 级区更衣和进出程序”
在无菌药品生产期间人员手部与消毒剂接触时长说明中有缺陷。
B. On 27 November 2018, I observed your firm’s employees conduct personnel
monitoring (PM) on themselves or others (via CCTV) who were engaged in aseptic
areas during the aseptic production of (b)(4)USP, Lot# (b)(4) sanitize their gloved
hands prior to conducting fingertip and gowning testing. The last fingertip failure is
dated 20 June 2016.
2018 年 11 月 27 日，我发现你公司在 XX USP 批号 XX 无菌生产过程中，无菌区内工
作的员工在对其自己和其它员工（通过集中监测摄像系统）执行人员监测（PM）时，
对其戴了手套的手进行消毒之后再进行手指和无菌服检测。最近的一次手指取样失败是
在 2016 年 6 月 20 日。
Investigations of an unexplained discrepancy are not extended to other batches of
the same drug product. for example, but are not limited to:
对非预期的不符合事件调查未延伸至相同药品的其它批次，例如但不仅限于：
MB-OOS-16-06, documents (b)(4) CFUs (acceptance limit = (b)(4)CFU), identified
as Verticillium aranearum (fungus), was found in area (b)(4) is located during the
routine settle plate air sampling during the aseptic production of (b)(4) (Sterile)
USP, lot #(b)(4) on 20 October 2016. However, your firm did not consider
evaluating sterile product produced in this area during the (b)(4) settle plate
incubation period. According to your firm’s (b)(4) Equipment Usage Log Book, the
following were produced for (b)(4) USP:
MB-OOS-16-06 记录了 20161020 日 XX（无菌）USP 批号 XX 无菌生产过程中常规
沉降碟空气取样时在 XX 区发现微生物 XX CFU（可接受标准=XXCFU），鉴别为黄萎
病菌（真菌）。但是你公司并未考虑评估在 XX 沉降碟培养期间在此区域生产的无菌药
品。根据你们公司的 XX 设备使用日志，期间生产的 XXUSP 药品如下：
Date API Lot Numbers Finished Product Lot Numbers

日期 API 批号制剂批号
2016-10-19 (b)(4) n/a
2016-10-20 (b)(4) n/a
2016-10-21 (b)(4) n/a
2016-10-22 (b)(4) n/a
2016-10-23 (b)(4) (b)(4)
2016-10-23 (b)(4) (b)(4)
2016-10-24 (b)(4) (b)(4)
Your firm’s Annual Product Quality Report (APQR) for (b)(4) (Sterile) USP, dated
July 2016-June 2017, documents an unidentified impurity was also found in lot
#(b)(4).
你公司覆盖 201607-201706 时间段的 XX（无菌）USP 产品年报（APQR）说在批号
XX 中亦发现未经鉴别的杂质。
Your firm’s QC Chemistry out-of-specification report, OOS(b)(4)16/MDP/FP/002,
dated 06 November 2016, did not consider the QC Microbiology OOS for fungus
for this same lot. Subsequently, the (b)(4) finished product, lot #(b)(4) and lot #(b)
(4) were released to the US Market.
你公司 20161106 的化学 OOS 报告 OOS（XX）16/MDP/FP/002 中未考虑相同批次中
QC 微生物真菌 OOS。随后，XX 成品批号 XX 和批号 XX 放行销往了美国市场。
Deviations are not always recorded per the firm’s written procedures.
未能总是按公司的书面程序记录偏差。
Specifically, your firm failed to document deviation(s) per your written procedure,
QCA-003-06, “Handling of Deviations”, for the following, but are not limited to:
具体来说，你公司未依据书面程序 QCA-003-06“偏差处理”的要求记录偏差，例如但
不仅限于以下：
A. Your firm received multiple out-of-specifications for environmental monitoring
and personnel monitoring.
你公司收到了多个环境监测和人员监测 OOS
According to your firm’s written procedures, QCD-320-05, “Investigation for Out of
Specification Results in Microbiological Tests” states if the counts observed are
very high indicating a major abnormality, it is recommended to stop filling and to
carry out the cleaning and (b)(4) of the area. However, your firm did not have any
documentation to support aseptic operations or the campaign was stopped and (b)
(4) occurred per your firm’s written procedures for the following microbial out-of-
specifications listed below:
根据你公司的书面程序 QCD-320-05“微生物检测中 OOS 结果调查”，如果发现计数
值非常高，显示出重大异常，则建议停止灌装，执行区域清洁和 XX。但是你公司在以
下微生物 OOS 时并未无任何文件记录支持无菌操作或生产周期停止，按公司书面程序
进行 XX：
- MB/OOS/16-01, documents (b)(4) CFU (action limit=(b)(4)CFU) was found during
a routine fingertip sampling on 16 June 2016, during the unloading of the (b)(4) in
the Grade –A/ISO 5 area, identified as Aspergillus sydowii (fungus).
- MB/OOS/16-01，记录 20160616 在 A 级区（ISO5 级）内 XX 放料过程中，常规手指
取样中发现微生物结果为 CFU（行动限=XXCFU），经鉴别为萨氏曲霉（真菌）
- MB/OOS/16-06, documents (b)(4) CFU (action limit=(b)(4)CFU) were found
during a routine settle plate (air) sampling on 20 October 2016, in the (b)(4)
Grade-A/ISO 5 area, identified as Verticillum araneaium (fungus). Your firm’s
Equipment Usage, Cleaning, and Maintenance Log for (b)(4) documents sterile (b)
(4) USP Lot number(s) (b)(4) were being produced during the (b)(4) settle plate
incubation period.
- MB-OOS/16-06 记录了 20161020 日 XX（无菌）USP 批号 XX 无菌生产过程中常规
沉降碟空气取样时在 XX 区发现微生物 XX CFU（可接受标准=XXCFU），鉴别为黄萎
病菌（真菌）。你公司的 XX 设备使用、清洁和维护日志记录显示在 XX 沉降碟培养期间
生产了无菌 XX USP 批号 XX。
In addition, the following Out-of-Trends (OOTs) did not follow the Preventative
Measure/ Corrective Action for cleaning as outlined on your firm’s Intimation
Report. Your firm’s Cleaning Sanitization, and Disinfection Record of Critical Areas
(Grade A & Grade B) only documents routine cleanings were performed.
此外，以下 OOT 并未按你公司报告中所列预防措施/纠正措施进行清洁。你公司的关键
区域（A 级和 B 级）区域的清洁消毒记录仅记录了所执行的日常清洁。
- OOT dated 10 May, 2018, documents thorough cleaning and disinfection of areas
were completed with (b)(4) solution followed by (b)(4) after an OOT was found for
Staphylococcus heamolyticus during routine settle plate sampling.
- OOT，日期 20180510，记录了在常规沉降碟取样中发现溶血葡萄球菌的 OOT 之后，
进行了 XX，然后用 XX 溶液进行了彻底清洁和消毒
- OOT dated, 17 May 2018, documents extensive cleaning, sanitization and
disinfection of areas were conducted with (b)(4) solution followed by (b)(4) after
an OOT was found for Staphylococcus epidermuis during routine settle plate
sampling.
- OOT，日期 20180517，记录了在常规沉降碟取样中发现溶血葡萄球菌的 OOT 之后，
进行了 XX，然后用 XX 溶液对区域进行了全面清洁和消毒
- OOT dated, 11 April 2017, documents thorough cleaning and sanitization shall be
performed with (b)(4) followed by (b)(4) after an OOT was found for Kocuria
rhizophila during routine settle plate sampling.
- OOT，日期 20170411，记录了在常规沉降碟取样中发现考克氏菌的 OOT 之后，进
行了 XX，之后应使用 XX 溶液对区域进行彻底清洁和消毒
B. Your firm’s Equipment Usage, Cleaning and Maintenance Log, (b)(4) 30/F1-00
for (b)(4) documents two (2) media fill lots of (b)(4) Lot #(b)(4) & Lot #(b)(4) were
manufactured on 06 September 2018 and 09 September 2018, respectively. (b)(4)
Lot#(b)(4) was produced prior to the production of (b)(4) Lot#(b)(4). However, a
product change over cleaning was not conducted prior to the production of (b)(4)
lot#(b)(4).
你公司的 XX 所用 XX30/F1-00 设备使用、清洁和维护日志记录 2018 年 9 月 6 日和 9 日
分别生产了 2 个培养基灌装批次 XX 批号#XX 和批号#XX。XX 批号#XX 生产在 XX 批号
#XX 之前。但是，在 XX 批号#XX 生产之前并示进行换产品清洁。
Equipment and Utensils are not cleaned at appropriate intervals to prevent
contamination that would alter the safety, identity, strength, quality or purity of the
Active Pharmaceutical Ingredients (APIs).
设备和工器具未以适当时间间隔进行清洁以防止可能改变 API 安全性、鉴别、剂量、质量
或纯度的污染。
Your firm failed to adequately validate the cleaning process of all manufacturing
equipment and utensils to ensure no build-up and carryover of impurities between
APIs manufactured using non-dedicated and dedicated equipment.
你公司未能对所有生产设备和工器具的清洁工艺进行充分验证，以确保使用非专用和
专用设备生产的 API 之间没有杂质累积和残留。
A. Your firm’s written procedure, QCD-320-05, “Investigation of Out of
Specification Results in Microbial Tests” states if the action limits for microbial
counts are in excess for (b)(4) in the critical area or aseptic processing areas,
filling will be stopped followed by thorough cleaning, disinfection, and (b)(4).
However, your firm did not conduct an evaluation to support the rationale for
choosing (b)(4).
你公司的书面程序 QCD-320-05“微生物检测中超标结果的调查”说如果关键区域或
无菌加工区域的 XX 微生物计数超出行动限，则要停止灌装，进行彻底清洁消毒和 XX。
但是，你公司并未进行验证来支持选择 XX 的合理性。
B. Your firm reduced the number of swab sampling locations from (b)(4) without
providing adequate scientific justification correlating the reduced sampling to
worst case scenario. For example but not limited to:
你公司减少了 XX 的擦拭取样点数量，但没有提供足够科学的论证将降低后的取样与最
差情形进行关联。例如但不仅限于：
1) (b)(4) USP and (b)(4) USP, Product changeover cleaning validation report:
CV/44/05/12, effective date:07/30/2014, was conducted by swab sampling from
multiple locations (i.e. (b)(4) locations to cover worst to clean areas). However, the
subsequent Product changeover cleaning validations reported for years July 2015
and May 2016 were conducted by collecting a swab sample from (b)(4) location.
Additionally, your firm has not evaluated the effectiveness of product changeover
and periodic equipment cleaning verification on a periodic basis.
XXUSP 和 XXUSP，产品更换清洁验证报告 CV/44/05/12，生效日期 20140730，从多
个位置（即 XX 位置以覆盖最差清洁区域）取擦拭样实施验证。但是，之后 2015 年 7 月
和 2016 年 5 月的产品更换清洁验证报告则是从 XX 位置采集擦拭样品实施验证。另外，
你公司并未评估更换产品和周期性进行设备定期清洁确认的有效性。
2) (b)(4) USP and (b)(4)USP, Product changeover cleaning validation report:
CV/05/05/09, effective date:12/25/2014 was conducted by swab sampling from
multiple locations (i.e. (b)(4) locations to cover worst to cleaning areas). However,
the subsequent Product changeover cleaning validation reported for year February
2016 and March 2016 were conducted by collecting swab sample from (b)(4)
location. Additionally, your firm has not evaluated the effectiveness of product
changeover and periodic equipment cleaning verification on a periodic basis.
XXUSP 和 XXUSP，产品更换清洁验证报告 CV/05/05/09，生效日期 20141225，从多
个位置（即 XX 位置以覆盖最差清洁区域）取擦拭样实施验证。但是，之后 2016 年 2 月
和 2016 年 3 月的产品更换清洁验证报告则是从 XX 位置采集擦拭样品实施验证。另外，
你公司并未评估更换产品和周期性进行设备定期清洁确认的有效性。
C. The selection of a (b)(4) swab sampling location for chemical analysis is not
based on worst to clean area and/or worst cases scenario. Additionally, your firm
deviated from SOP:CQA-081-03, Titled “CLENAING VALIDATION FOR DRUG
SUBSTANCES AND INTERMIDIATES” Effective date: 10/31/2018 Annexure A
depicting the swab sampling locations for (b)(4). The selection of a (b)(4) swab
sampling location during product changeover cleaning validation and upon routine
cleaning of equipment for product changeover is not based on worst to clean area
considering the complexity of equipment design and sizes.
化学分析的 XX 擦拭取样位置选择不是基于最差清洁区域和/或最差情形。另外，你公司
偏离了 SOP CQA-081-03“原料药和中间体清洁验证”生效日期 20181031 附录中 XX
的擦拭取样位置图。更换产品和日常设备清洁的清洁验证中 XX 擦拭取样点位置不是基
于最差清洁区域并考虑设备设计复杂性和尺寸而定的。
D. With regard to equipment cleaning validation, there is no evaluation of the
impact of continuous manufacturing on the carryover of related substances and
processing impurities. for example but are not limited to:
关于设备清洁验证，没有评估连续生产对有关物质和工艺杂质的残留影响，例如但不
仅限于：
Your firm’s SOP: MAM-014-07, Titled: “GENERAL GUIDELINE FOR CLEANING
OF EQUIPMENTS”, Effective date: 10/01/2018, per section: 5.5.1: “Periodic
cleaning shall be performed in NMT (b)(4) *****)”. However, your firm have not
evaluated the claim of periodic equipment cleaning for NMT (b)(4). Additionally,
the number of batches manufactured in between each periodic cleaning varied
significantly from equipment to equipment.
你公司的 SOP MAM-014-07“设备清洁通则”生效日期 20181001 第 5.5.1 章“应在
不少于 XX 内进行定期清洁”。但是你公司并未对不少于 XX 进行定期设备清洁的声明
进行评估。另外，在两次定期清洁之间所生产批次的数量因设备不同而大大不同。
E. Your firm has not evaluated the total number of batches in each campaign
during campaign manufacturing to ensure no build-up and carryover of impurities
between APIs manufactured using non-dedicated equipment. For example but not
limited to:
你公司未评估周期生产中每个周期所生产批次的总数，以确保使用非专用设备生产的
API 之间不会有杂质残留和累积。例如但不仅限于：
(b)(4)
F. There is no second person verification for the visual inspection of equipment
cleaning after batch to batch cleaning is performed. The cleaning logs were signed
under “Performed By” (after equipment cleaning) and “Reviewed By” (prior to
equipment usage) by the same person.
批间清洁之后没有第二人目视检查设备清洁情况。清洁日志中“清洁人”（设备清洁
后）和“检查人”（设备使用之前）是同一人签字。
The testing, review and trending of (b)(4) quality attributes of(b)(4) and (b)(4) are
not adequately performed.
XX 和 XX 的 XX 质量属性的检测、审核和趋势分析不充分。
A. According to your firm’s management, a potential exists for introduction of
additional (b)(4) when a (b)(4) or (b)(4) sample is collected for offline total organic
carbon (TOC) testing. Your firm has not conducted a study to show the extent of
influence (determination of a contamination factor) that the sampling, transport,
and testing have on the TOC levels of your (b)(4) and (b)(4) during offline TOC
testing, compared to an online TOC monitor which directly quantities the TOC
levels within the (b)(4) or (b)(4) loops. There is no supporting evidence to prove
that your offline TOC testing accurately assesses or reflects the intrinsic real value
TOC levels of the (b)(4) and (b)(4) at your site.
根据你公司的管理人员所称，在 XX 或 XX 样品采集检测离线 TOC 时，可能会有额外
XX。你公司未进行研究证明取样操作、运输和检测对 XX 和 XX 离线 TOC 水平影响的程
度（确定污染因素），与直接 XX 或 XX 循环管线上定量 TOC 水平的在线 TOC 监测进
行比较。没有支持性证据证明你们的离线 TOC 检测能准确评估或反映你场所内 XX 和
XX 的 TOC 内在真实值水平。
B. Your firm has not established TOC alert levels for the (b)(4) and (b)(4) in the (b)
(4) and (b)(4) buildings, where non sterile and sterile APIs are manufactured,
although you have established TOC alert levels for the (b)(4) in the (b)(4)
formulation building. Your firm has not provided adequate justification as to why
alert levels are selectively established for (b)(4) systems containing online
monitoring of TOC, but not for (b)(4) and (b)(4) which is assessed via offline TOC
testing.
虽然你们制订了 XX 制剂生产厂房内 XX 的 TOC 警戒水平，但你公司未制订非无菌和
无菌 API 生产用 XX 和 XX 厂房内 XX 和 XX 的 TOC 警戒限。你公司未提供充分的论证
说明你们为什么为装有在线 TOC 监测的 XX 系统有选择性地制订警戒限，却不为 XX
和 XX 制订，而只是使用离线 TOC 检测进行评估。
C. You do not adequately trend TOC levels for (b)(4) and (b)(4) in your (b)(4)
system trending reports, regardless of whether the TOC levels are assessed via
online monitoring or offline testing. As such, your firm does not conduct any out-of-
trend investigations for the (b)(4) or (b)(4) systems in the (b)(4) or (b)(4) buildings
when TOC values approach the action level threshold of (b)(4)ppb.
你们在 XX 系统趋势分析报告中未对 XX 和 XX 的 TOC 水平进行趋势分析，不管 TOC
水平是通过在线监测还是离线检测进行评估。例如，你公司在 TOC 值接近行动限
XXppb 时并未对 XX 或 XX 厂房内 XX 或 XX 系统进行 OOT 调查。
Supervisors and personnel responsible for the manufacturing, processing, and
testing of APIs and finished drug product lack the knowledge and adequate
training to perform their assigned duties in such a manner to assure APIs and drug
products have the safety, identity, strength, quality and purity they purport to
possess.
负责 API 和制剂生产、加工和检测的主管和员工缺乏知识和足够的培训执行其指定任务
以确保 API 和制剂具备其理应具有的安全性、鉴别、剂量、质量和纯度。
There is a lack of oversight by firm management, especially the QC and QA, and
Production departments, to ensure employees are performing their required job
functions as specified in your firm’s SOPs. The written exams for passing of
trainings are not adequate to demonstrate that your employees are knowledgeable
of the trainings/SOPs, and many of the personnel involved in providing information
during the inspection could not autonomously answer questions related to their
day to day job functions or activities in which they routinely participated. In many
instances during this inspection, employees and top management could not
directly answer basic questions when asked. Many employees, including the QC,
Production, and Validation Managers/Specialists, would directly read the
procedure from the document without being able to autonomously comment on
activities and operations in which they are described to be familiar with and
knowledgeable of. Additionally, firm personnel would provide data and evidence
which did not support the claims that could provide answers to specific questions
asked by the investigator.
缺乏公司管理人员监管，尤其是 QC 和 QA 和生产部门，无法确保员要按你们公司
SOP 所述履行其工作职责。通过书面培训考虑不足以证明你们员工了解培训内容
/SOP，许多在检查期间参与提供信息的人员不能自主回答被问到的与其日常工作职责
或其常规参与工作的问题。在本次检查中多次发生员工和高级管理人员不能直接回答基
本问题的疏不间亲中。许多员工，包括 QC、生产和验证经理/专员，会直接从文件上读
出程序，而不能自主地对其理应熟悉了解的活动和操作给出说明。另外，公司人员会提
供不能数据和证据证明其可以回答调查人员提出的具体问题。
During the inspection, we observed several instances where it appeared that
supervisors, specialists and personnel engaged in the activities related to the
manufacture, testing, and review of procedures, documents, methods and data
could not directly answer questions, or would hastily provide an answer without
consideration of the question which was asked.
在检查期间，我们发现几个实例，显示从事与生产、检测和审核程序、文件、方法和数据
的主管、专员和员工不能直接回复问题，或根本未考虑所问问题就冒失地给出答复。
- Your firm could not provide a scientific rationale as to why (b)(4) bioburden
samples were collected during production of sterile (b)(4) API. During the
inspection firm management conceded that the composition of the compounding
solvent (b)(4) was not capable of supporting microbial growth and the results for
bioburden sampling would always provide a negative result. However, no firm
personnel could provide an adequate explanation as to why the sample is
collected if the test does not provide meaningful results.
- 你公司未能提供科学理由解释为何在无菌 XXAPI 生产期间采集 XX 生物负载样品。在
检查期间，公司管理人员承认配制溶剂 XX 的组分可能无法支持微生物生长，生物负载
取样结果可能永远都是阴性结果。但是，公司无人能提供充分的解释说明既然检测并不
能提供有意义的结果为何还要采集样品。
- Your firm’s QC Manager could not directly explain why bioburden testing was
not performed during media fill simulations. The response he provided to justify
the lack of bioburden testing was that a filtration integrity test is performed, which
is an indicator of filter efficiency. We explained to him that a filter integrity test is
only an indicator of physical integrity of the filter, and cannoten umerate the
reduction of microbial load of non sterile production equipment on the
compounding solution.
- 你公司的 QC 经理不能直接解释为何不在培养基灌装模拟期间进行生物负载检测。他
对没进行生物负载检测所给出的回复是已执行了过滤完整性检测，而这只是过滤有效性
的指标。我们向他解释过滤器完整性检测只是过滤器的物理完整性指标，不能涵盖非无
菌生产设备对所配制溶液微生物负载的降低能力。
- Your firm’s Sr. Validation Manager provided us with cleaning validation
campaign data to support a maximum campaign time of (b)(4) and maximum
number of (b)(4) batches based on the evidence provided. Additionally, all of the
campaigns were not performed in a consistent (same number of (b)(4) and (b)(4)
batches) to justify a campaign length of (b)(4) and (b)(4) per the data compiled
and reported in the Cleaning Validation Report CV/03/07/05. Furthermore, it did
not appear that your firm’s Senior Validation Manager understood that a validation
requires three identical consecutive trials to be performed in a manner consistent
with the claims of (b)(4) manufactured for each campaign to be performed over (b)
(4).
- 你公司的高级验证经理向我们提交了清洁验证周期数据，用以支持 XX 的最长周期时
长，以及基于所提供证据证明的最多批数 XX 批。另外，根据清洁验证报告
CV/03/07/05 中所汇集和报告的数据，所有执行的周期并不一致（相同批数 XX 和
XX），无法论证 XX 和 XX 周期长度。还有，看起来你公司的高级验证经理并不了解验
证需要执行 3 次相同连续的试验，与每个周期生产批数的声明保持一致。
- When originally asked as to how the firm justified the campaign length of
maximum campaign time of (b)(4) and maximum number of (b)(4) batches before
campaign cleaning must be performed, the answer and evidence provided was a
theoretical extrapolation of the amount of time that a (b)(4) filtration assembly
effectiveness (b)(4) was assessed during the (b)(4) filter validation study
performed in 2003. Based on that time, it was theoretically determined that the
maximum number of batches which could be manufactured in (b)(4) was (b)(4)
batches based on the batch manufacturing time. However, we explained that the
filter assembly validation is to demonstrate a (b)(4) filtration effectiveness and not
applicable to a cleaning validation study, and that the campaign length and
number of batches was based on the data collected from the microbial and
chemical residue analyses of the (b)(4) samples from the (b)(4) (worst case
hardest to clean equipment).
- 在开始问到公司如何论证周期清洁之前所能生产的最多批次和周期时长时，公司回
答并提供的证据是 2003 年所做的 XX 过滤器验证研究中对 XX 过滤器有效性评估所得
时长的理论外推结果。根据该时长，理论上确定了在 XX 可生产的最多批次为基于批生
产时间的 XX 批数。但是我们解释了过滤器验证是为了证明 XX 过滤有效性，不适用于
清洁验证研究，生产周期的时长和批数应基于从 XX 的样品（最差情形最难清洁设备）
进行微生物和化学残留分析所采集的数据。
- Your firm’s QC Manager explained that offline TOC testing is not representative
of the intrinsic TOC content of the (b)(4) and (b)(4) within the (b)(4) circulation
loops. However, the results are reported in the (b)(4) and (b)(4) trending reports
and evaluated as meaningful. The QC laboratory personnel are performing the
offline TOC test in the QC laboratory without understanding of the influence that
offline sampling, transport and testing has on the reported results of OTC content
of (b)(4) and (b)(4). There is no evidence that the laboratory personnel understand
why they are performing the test, and why the results reported are not truly
indicative of the actual TOC content of (b)(4) and (b)(4).
- 你公司的 QC 经理解释说离线 TOC 检测不能代表 XX 循环系统中 XX 和 XX 的复杂
TOC 含量。但是，在 XX 和 XX 趋势分析报告中报告了这些结果，并被认为是有意义的。
QC 实验室人员在没有理解离线取样、样品传输和检测对所报告 XX 和 XX 的 TOC 含量
结果影响的情况下在 QC 实验室执行离线 TOC 检测。没有证据证明该实验室人员理解他
们为何要执行该检测，以及为何所报告结果不能真实反映 XX 和 XX 的实际 TOC 含量。
Additionally, the firm has a systemic problem with a lack of understanding
regarding protocol design, consideration of worst case conditions, and challenges
required to demonstrate operator aseptic techniques and why simulations are
designed to show that the aseptic environment is in a state of control during
stressed condition atypical from normal manufacturing conditions. Examples
include, but are not limited to:
另外，公司缺乏对方案设计、最差情形考量和证明操作人员无菌技能所需挑战的理解，
缺乏对为何模拟设计要展示无菌环境在异于正常生产条件的严酷条件中处于受控状态的
理解，这是一个系统性的问题。例子包括但不仅限于：
- Personnel disinfecting hands directly before performing personnel monitoring
after exit of the aseptic API manufacturing area.
- 员工在退出无菌 API 生产区域之后，进行人员监测之前进行手消毒
- Lack of understanding of the design of a master validation plan for challenges
and interventions performed during media fill simulations.
- 缺乏对验证主计划中在培养基灌装模拟中进行挑战和干扰的理解
- Lack of insight as to why routine disinfection of an aseptic area renders
environmental monitoring data essentially meaningless when the aseptic area is
routinely disinfected (b)(4) during a media fill campaign.
- 不理解为什么在培养基灌装过程中对无菌区进行常规消毒的话使得环境监测数据根
本失去意义
- Lack of understanding of the significance as to why (b)(4) samples for
bioburden testing are performed to demonstrate reduction of microbial load from
compounding solution contract with non sterile production equipment before it is
transferred into the aseptic area.
- 不理解为何生物负载检测的 XX 样品检测是为证明与非无菌生产设备接触的配制溶液
在其转移至无菌区域之前微生物负载降低能力情况的重要性
There is a failure to thoroughly review any unexplained discrepancy, the failure of
a batch, or any of its components to meet any of its specifications whether or not
the batch has been thoroughly distributed.
未能彻底审核所有未经解释的已放行或未放行产品的不符合情况、批次不合格或产品组
份不符合其质量标准。
A. Your firm documented eleven (11) complaints were received related to
particulate matter found in your firm’s sterile drug product, (b)(4) injection for (b)
(4) Gram, from 2016-2018. In 2018, seven (7) of these complaints were received
within a three (3) month time period for “(b)(4)flecks”, “(b)(4) matter”, “(b)(4)
flecks” observed in the product vial after(b)(4) for (b)(4) lots of (b)(4) (sterile)
Injection (b)(4) Gram. Our review of the complaints received in 2018, found (b)(4)
of the lots, related to six (6) of the complaints received, used (b)(4) Plug
(Stoppers), lot # (b)(4).
你公司在 2016-2018 年间记录了收到的 11 个投诉，均与在你们的无菌药品 XX 注射剂
中发现颗粒物有关。2018 年，在 3 个月内收到其中 7 份投诉，投诉原因为在药品瓶中
发现“XX 斑点”、“XX 物”、“XX 斑点”。我们审核了 2018 年收到的投诉，发现与
所收到的 6 起投诉有关的 XX 批使用了 XX 塞子（批号 XX）。
However, your firm’s investigations did not rule out the possibility these stoppers
maybe defected. For example, fragmentation testing was “Not applicable” on your
firm’s Certificate of Analysis for (b)(4) Plug (Stoppers) lot (b)(4). In addition, the
vendor’s Quality Certificate received by your firm did not conduct fragmentation
testing on this lot.
但是你们公司的调查并未排除这些塞子可能有缺陷的可能性。例如，你们公司 XX 塞子
的 COA 上面写的碎裂试验“不适用”。另外，你公司所收到的供应商的质量报告对该
批次并未进行碎裂试验检测。
Your firm has distributed (b)(4) vials of sterile drug product, (b)(4) Injection (b)
(4)Gram, to the U.S. Market.
你公司已将 XX 瓶该无菌药品 XX 注射剂销往美国，批号为 XX，共计 XX 瓶。
Batch No. Total Number of Vials Distributed to the US Market.
(b)(4)（以下列出了数据）
Similarly, on 24 August 2017, your firm received a complaint related to pieces of
(b)(4) stopper found in your firm’s sterile drug product, (b)(4) Injection for (b)(4)
Gram, lot #(b)(4) which used (b)(4) Plug (Stoppers), lot #(b)(4). Your firm did not
conduct any fragmentation testing during your investigation. During our review, we
found the same (b)(4) Plug (Stoppers) were used in the following batches,
resulting to the distribution of (b)(4) vials of (b)(4) (Sterile) Injection to the U.S.
Market.
类似地，2017 年 8 月 24 日，你公司收到在你公司的无菌药品 XX 注射剂中发现 XX 塞
子碎片的投诉，该批次使用了 XX 塞子（批号 XX）。你公司在你们调查中未进行碎裂试
验。在我们审核过程中，我们发现相同 XX 塞子被用于以下批准，导致 XX 瓶 XX（无
菌）注射液销往美国。
Batch No. Total number of Vials Distribute to the US Market.
(b)(4)（以下列出了批号和瓶数）
B. Market complaints are not investigated thoroughly. For example, since 2016,
the firm has received approximately 49 market complaints regarding product
thickening, and 14 market complaints regarding dose shortage for (b)(4)
suspension USP ((b)(4)mg/(b)(4)ml and (b)(4)mg/(b)(4)ml) for pediatric usage.
Details are as follows:
市场投诉未彻底调查。例如，自 2016 年起，公司已收到约 49 份关于儿科用混悬液
USP（XXmg/XXml 和 XXmg/XXml）产品变稠的市场投诉，14 份关于药量短少的投

诉。详细信息如下
Nature of complaint 投诉情况 2016 2017 2018
Increased viscosity/thickening/ clumpy/ unusable 2 45 2
during medication/ unable to measure dose after
(b)(4)
粘度增加/变稠/结块，在用药过程中不能使用/在 XX
后不能测量剂量
Short dose 药量短少 3 7 4
The firm identified that a specific lot (Vendor Lott#(b)(4)) of (b)(4) was causing the
increase of viscosity and lump formation in the (b)(4) suspension. Your resultant
medical assessment (dated: June 29, 2017) states that “Thickening of the
suspension can affect the pourability, as the suspension may not remain free
flowing and get changed to soft flowing mass”. Additionally, your Quality
Investigative team confirmed during the inspection that lump formation was found
“high” during the(b)(4) after (b)(4). Despite availability of this information, no
evaluation was conducted to ensure that the therapeutic effect (i.e. Assay per
dose) of the product remains consistent throughout the period of therapy.
公司识别出特定批次（供应商批号 XX）的 XX 导致了 XX 混悬液中粘度增加和形成结
块。你们得出的医学评估（日期 20170629）声称“混悬液变稠可能影响流动性，因为
混悬液不能保持自由流动，会变成软流动体”。另外，你们质量调查组在检查期间确认
在 XX 之后 XX 过程中结块情况很多。虽然有这些信息，但公司并未进行评估以确保该
药品在治疗期间保有其治疗效果（即每剂药品的含量）。
In addition, the complaints regarding shortage of doses were not investigated to
evaluate whether it was due to the thickened suspension as complaints reported
that it was difficult to measure doses.
此外，关于药量短少的投诉未进行调查，未评估是否源于投诉所报告的混悬液过稠而难
以测量药量。
Firm rejected (b)(4) number of batches (b)(4)mg/(b)(4)ml) manufactured utilizing
(b)(4) vendor lot (b)(4). However, no action was taken for batches distributed in
the U.S. market that were manufactured utilizing the same lot of (b)(4). The firm
distributed (b)(4) batches of (b)(4)mg/(b)(4)ml and (b)(4) batches of (b)(4)mg/(b)
(4)ml distributed to US market using the affected lot of (b)(4).
公司拒收了使用 XX 供应商批号 XX 生产的 XX 批 XXmg/XXml。但是对于使用相同批次
XX 生产的销往美国市场的批次并未采取措施。公司将采用受影响批次 XX 生产的 XX 批
XXmg/XXml 和 XX 批 XXmg/XXml 销往了美国。
Examples of (b)(4) suspension USP ((b)(4)mg/(b)(4)ml) batches include but are
not limited to:
XX 混悬液 USP（XXmg/XXml）批号包括但不仅限于：
（以下列出了批号、生产日期、有效期和放行瓶数）
Batch Number (b)(4)MFG Date EXP Date Qty. released (in bottles)
not limited to:
XX 混悬液 USP（XXmg/XXml）批号包括但不仅限于：
（以下列出了批号、生产日期、有效期和放行瓶数）
Batch Number (b)(4) MFG. Date: (b)(4) EXP Date: (b)(4) Qty. released. (in bottle)
(b)(4)
B. During dispensing of (b)(4) USNF (lot#(b)(4))for (b)(4) suspension USP (b)
(4)mg/(b)(4)ml, dead worms were reported as found between the primary package
and secondary package. Further investigation revealed the presence of dead
worms in three other bags of the same vendor lot. As a corrective action, the
remaining inventory of affected raw material lot was returned to the vendor.
However, (b)(4) suspension USP (b)(4)mg/ml (finished product batch #(b)(4)
expiration date June 2020), manufactured using the same raw material lot was
released to U.S. market. The justification provided as per the associated impact
assessment was “… current controls are adequate to detect the worm (if any) if
remains undetected during dispensing”. Thereview of manufacturing process
stated (b)(4). The decision taken by quality department to release the batch
without an evaluation through stratified sampling or visual inspection was found
deficient. For example, but not limitedto, the firm’s quality unit failed to provide an
evaluation supporting there was no contamination of this batch related to dead
worms, insects, and/or filth.
在 XX USNF（批号 XX）分料用于 XX 混悬液 USP XXmg/XXml 时，在内包和外包之
间发现有死虫子。进一步调查发现同一供应商批号中另 3 袋里也有死虫子。作为纠正措
施，受影响物料批号的剩余库存被退回给了供应商。但是使用相同原料批次生产的 XX
混悬液 USP XXmg/XXml（成品批号 XX 有效期 2020 年 6 月）却被放行至美国市场。
根据相关影响报告提供的论证是这样的“……如果在分料时未发现的话，当前控制不足
以发现虫子（如有）”。对生产工艺的审核声称 XX。质量部门未通过分层取样进行评估
或目视检查即做出放行该批次的决策是有问题的。例如但不仅限于公司的质量部门未提
供评估来支持与死虫子、昆虫和/或污物有关的该批准没有受到污染的说法。
C. Executed batch manufacturing record for (b)(4) suspension USP (b)(4)mg/(b)
(4)ml, batch #(b)(4) could not be reviewed by FDA investigators during the
inspection. This batch record was reported as missing. Finished product batch
#(b)(4) expiration date December 2019, was manufactured and released to U.S.
market despite unavailability of manufacturing batch record. There is no
assurance that critical processing parameters were maintained during critical
manufacturing stages. Additionally, no additional evaluation through stratified
sampling or an evaluation through stability testing of the batch was considered as
part of product released.
已执行的 XX 混悬液 USP XXmg/XXml 批号 XX 的批生产记录在检查期间无法提供给
FDA 调查人员审核。该批记录被报告丢失了。虽然没有生产批记录，但成品批次 XX（有
效期 2019 年 12 月）却被生产出来并放行至美国市场。公司不能确保在关键生产阶段保
存关键工艺参数。另外，在产品放行中亦未考虑通过分层取样进行更多评估，或通过该
批次的稳定性研究进行评估。
An (b)(4) Field Alert Report was not submitted within three working days of receipt
of information concerning a failure of one or more distributed batches of a drug to
meet the specifications established for it in the application.
未在收到一批或多批已在美国销售的药品不符合其申报资料中建立的标准相关信息之
后 3 个工作日内提交 XX 现场警示报告。
A. Your firm’s Regulatory Affairs department failed to issue a Field Alert Report
(FAR) after receiving multiple complaints for “pieces of (b)(4) stopper”, “(b)(4)
flecks”, “(b)(4) matter”, and “(b)(4)flecks” observed in the product vial after (b)(4)
of your sterile drug product,(b)(4) Injection, related to the following lots:
你公司的法规事务部门在收到多起在你们无菌药品、XX 注射剂药品瓶中发现“XX 塞子
碎片”、“XX 斑点”、“XX 物”和“XX 斑点”的投诉后未签发现场警示报告
（FAR）。相关批次如下：
Complaint Number Lot Number Expiration Date Qty. of vials

投诉编号批号有效期 produced 所生产小
瓶数
DPC-MA-028-18-0009 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0012 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0019 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0021 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0022 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0032 (b)(4) (b)(4) (b)(4)
DPC-MA-028-18-0008 (b)(4) (b)(4) (b)(4)
DPC-MA-028-17-0118 (b)(4) (b)(4) (b)(4)
B. Your firm received multiple complaints related to increased viscosity which was
unusable due to its “clumpy nature” for multiple lots of (b)(4) suspension USP ((b)
(4)mg/(b)(4)ml and (b)(4)mg/(b)(4)ml). On July 7, 2017, your quality unit identify
the root cause of these complaints were attributed to (b)(4) (vendor lot#(b)(4), a
(b)(4) used in the manufacturing process for (b)(4) suspension USP. During the
firm’s quality review for thee complaints, (b)(4) defective batches of (b)(4)
suspension USP ((b)(4)mg/(b)(4)ml) were identified, using (b)(4) (vendor lot#(b)
(4)) during manufacturing and subsequently released to US market.
你公司收到了多起粘度增加的投诉，多批 XX 混悬液 USP（XXmg/XXml 和
XXmg/XXml）由于“结块”而无法使用。20170707，你们质量部门将这些投诉的根本
原因归结为 XX（供应商批号 XX），这是用于 XX 混悬液 USP 生产工艺的一种 XX。在
公司对 3 个投诉进行质量回顾的过程中，发现在生产过程中使用了 XX（供应商批号
XX）的 XX 批次 XX 混悬液 USP 有缺陷，这些批次都放行到了美国市场。
A (b)(4) Field Alert Report was submitted to FDA for (b)(4) suspension USP (b)(4)
((b)(4)mg/(b)(4)ml).
你公司向 FDA 提交了 XX 混悬液 USP XX（XXmg/XXml）的 FAR。
Your firm rejected(b)(4) batches of (b)(4) suspension USP ((b)(4)mg/(b)(4)ml)
within inventory which were manufactured using the affected (b)(4) (vendor lot#(b)
(4)). As mentioned, your Quality Unit also identified this aforementioned affected
lot of (b)(4) was used during the manufacturing process of (b)(4) suspension
USP((b)(4) mg/(b)(4)ml). However, your Quality Unit failed to submit an (b)(4) field
alert report for (b)(4) suspension USP ((b)(4)mg/(b)(4)ml).
你公司拒收了库内 XX 批次 XX 混悬液 USP（XXmg/XXml），这些批次都是使用了受
影响 XX（供应商批号 XX）生产的。如上所述，你们质量部门还发现前述受影响批次
XX 用于 XX 混悬液 USP（XXmg/XXml）生产。但是你们质量部门并未提交 XX 混悬液
USP（XXmg/XXml）的 FAR。
not limited to:
XX 混悬液 USP（XXmg/XXml）批次例子包括但不仅限于：
Batch Number(b)(4) MFG. Date (b)(4) EXP Date (b)(4) Qty. released (in bottles)
批号 XX 生产日期 XX 有效期 XX 放行数量（瓶）
（此处信息被遮盖）
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
没有制订书面生产和工艺控制程序，设计用以确保药品生产具备其理应具备的鉴别、剂
量、质量和纯度。
Specifically, the (b)(4) Hold Time studies that you have conducted for products
marketed in the U.S are deficient. The batch sizes and the number of samples
used for the establishment of (b)(4) Hold time do not represent the commercial
batch size of the products and the handling of in-process containers during
storage of (b)(4).
具体来说，为美国销售的产品所做的 XX 保存时长研究有缺陷。用于建立 XX 存贮时长
的批量和样品数量不能代表该产品的商业批量，以及 XX 存贮过程中的中间容器处理。
Approximately (b)(4) and (b)(4) of (b)(4) was stored in simulated containers for
tablet/capsules and (b)(4) suspension products respectively and a composite
sample was tested for bulk hold time study. An evaluation of segregation potential
in the (b)(4) during storage was not conducted for products with relatively low
percentage of active content. Examples listed below include products
manufactured either by(b)(4) process and/or with relatively low amount of active
content with their respective hold time study summary (b)(4).
大约有 XX 和 XX 的 XX 分别存贮在片剂/胶囊和 XX 混悬药品模拟容器中，散装保存时
长研究时检测的是一个复合样品。存贮期间活性内容相对较低百分比的药品 XX 内的分
离可能性未进行评估。以下列出的包括了由 XX 工艺和/或采用相对较低数量活性含量所
生产产品，以及其对应的保存时长研究总结 XX。
Product Strength Qty. of API perBatch size Qty. used for Hold time period
name 剂量 batch in% 批量 (b)(4) hold available at (b)(4)
品名每批中 API 数 study 在 XX 可用保存时
据% XX 存贮研究长
所用数量
(b)(4) (b)(4)mg/(b)(4)ml (b)(4) (b)(4) (b)(4) (b)(4)
suspension
USP
（共 11 个产品/批次，具体信息被遮盖）
Since January 2016, approximately 25 investigations have been initiated for assay
failures for (b)(4) suspension products. For example, but are not limited to the
following OOS/OOT were observed for (b)(4) (b)(4) suspension (b)(4)mg/(b)(4)ml
and (b)(4) Suspension (b)(4)mg/(b)(4)ml which are related to assay and (b)(4)
Content Test.
自 2016 年 1 月以来，约有 25 个调查因 XX 混悬液药品含量不合格而启动。例如但不仅
限于以下 OOS/OOT 是关于 XX 混悬液含量和 XX 含量检测的。
Reviewed Period OOS OOT

审核时间段
June 2016-July 2017 8 11
June 2017-July 2018 5 17
In addition, a uniformity at the (b)(4) is not tested for products marketed in the US.
另外，未检测在美国销售的产品的 XX 均一性。
Written procedure are not established for evaluations conducted at least (b)(4) to
review records associated with a representative number of batches, whether
approved or rejected.
未建立书面程序至少 XX 进行评估，以回顾批准和拒收的具有代表数量的批次产品的记
录。
Specifically, the annual product review is deficient as uniformity of (b)(4) is not
reviewed. About (b)(4)% of the batches of (b)(4) suspension USP ((b)(4)mg/(b)
(4)ml) manufactured from 2016 to 2018 were failing on Assay test. An assignable
cause was not identified on majority of the failed assay tests as per the associated
OOS investigations. The firm never collects information about uniformity of active
ingredient in (b)(4) since 2009. Hence, an assessment of (b)(4) process is not
performed (b)(4) to evaluate the reason for consistent failure of assay of the
finished product. In addition, possible disturbances of (b)(4) during the storage
prior to the filling operation was not evaluated.
具体来说，年度产品回顾未对 XX 的均一性进行回顾，因此是有缺陷的。2016-2018 之
间大约有 XX%的 XX 混悬液 USP（XXmg/XXml）批次含量检测不合格。未根据相关的
OOS 调查找到大部分含量不合格的可归结原因。公司从未收集 2009 年以来 XX 中活性
成分均一性方面的资料。因此，未对 XX 工艺进行评估找出成品含量一直不合格的原因。
另外，未评估灌装操作之前存贮过程中 XX 扰动的可能性。
22. 印度 Lupin Limited 20190208

There is a failure to thoroughly review any unexplained discrepancy and 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.
未能彻底审核所有无合理解释的不符合情形，以及已销售和未销售药品及其组份不符合
其质量标准。
(A) Out of Specification (OOS) Investigation No. OOS/C/18/IN2/SS/012 was
initiated on 4 th July 2018 for Moxifloxacin Ophthalmic Solution USP 0.5% batch no.
H800393 at the 3-month stability time point (RT/Long Term: 25±2°C and (b)(4)
%RH). This batch is an (b)(4) stability batch that represented approximately (b)(4)
batches released to the U.S. market. The OOS failure during Related Substances
testing was initially categorized as an (b)(4) Impurity at (b)(4)% which exceeded
the specification limit of NMT (b)(4)%. During extensive follow-up investigations,
the impurity was re-categorized by the R&D group as (b)(4) formed due to(b)(4)
component present on the product label containing (b)(4). Furthermore, the R&D
group concluded that product label contributes to the generation of the (b)(4). A
detailed health-hazard assessment for the presence of (b)(4) in the product was
not conducted until 17 th January 2019 (during the current inspection). The health
hazard assessment acknowledged that (b)(4) is a strong irritant to the eyes. Other
deficiencies with the investigation include but are not limited to:
OOS 结果调查编号 OOS/C/18/IN2/SS/012 启动日期 20180704，批号 H800393 的莫
西沙星眼药水 USP0.5%在 3 个月稳定性时间点（RT/长期 25±2°C 和 XX%RH）检测不
合格。该批次是代表 XX 批次销往美国的 XX 稳定性批次。有关物质在检查期间发现
OOS 结果，最初归类为 XX 杂质超限度（NMT XX%），杂质结果为 XX%。在后续扩大
调查中，该杂质由 R&D 组重新归类为因标签中含有 XX 组份而形成的 XX。另外，R&D
组得出结论说产品标签导致了 XX 的生成。产品中出现 XX 的详细健康危害评估直到
20190117 才执行（在当前检查期间）。健康危害评估说 XX 对眼睛有较强刺激性。关于
调查的缺陷包括但不仅限于：
 Failure to re-train analysts who were involved in the purported mis-
identification of the impurity during the initial testing and subsequent
investigation.
 未对参与初始检测和后续调查中杂质错误鉴定的化验员进行重新培训
 The product labels utilized on the OOS batch (Label lot no. (b)(4)) were also
utilized in 3 other commercially released batches (H705563, H800616 and
H705562). The firm’s decision to analyze retention samples from these
three impacted batches and retention samples from all other market batches
on a quarterly basis is not scientifically justified. Additionally, the firm
deficiently limited the market action (i.e. recall) only to OOS batch H800393
while other impacted batches continued to remain in U.S. market until the
current inspection. (b)(4). An updated FAR was filed on 24 th January 2019.
There is no assurance that product label on the product bottles current in
the U.S. market (i.e. approximately (b)(4) batches) are free of (b)(4)
Presence of (b)(4) was never historically quantified through adequate
testing.
 OOS 批次（标签批号 XX）所用产品标签在其它 3 批商业放行批次（H705563,
H800616 和 H705562）中也有使用。公司决定对这 3 个受影响批次的留样，以
及所有其它销售批次的留样进行每季度分析的决策没有进行科学论证。另外，公
司的市场行动（即召回）仅限于 OOS 批次 H800393 而让其它受影响批次继续
留在美国市场上销售直至当前检查是有缺陷的。公司于 20190124 提交了一份经
过更新的 FAR。公司不能确保当前在美国市面上的药品（约 XX 批次）药瓶上的
产品标签不含有 XX。药品中是否含有 XX 从来未通过足够的检测得到定量结果。
 A CAPA (CAP-IO-153-18-0059) was initiated that included a directive to
develop an analytical test method for detecting presence of (b)(4) on the
product label. This task was not completed and instead, the CAPA was
closed by procuring labels without (b)(4) on the label. An in-house
verification test is unavailable to ensure that the new labels would continue
to remain free of (b)(4). In addition, you do not have any record available to
substantiate that the label supplier was audited during the investigation.
 公司启动了一份 CAPA（CAP-IO-153-18-0059），其中包括开发一个检测产品
标签中含有 XX 的分析方法的指令。该项任务并未完成，相反，该 CAPA 在采购
不含有 XX 的标签后就关闭了。没有内部验证测试用以确保新标签持续保持不含
有 XX。另外，在检查期间你们没有出示任何记录证明对标签供应商进行了现场
审核。
 The R&D evaluation demonstrated that (b)(4) contributes to the formation of
the (b)(4) during 7 days of exposure at RT conditions. The same evaluation
reported that (b)(4) was not detected in other batches. The R&D report is
silent as to why only the OOS batch was impacted while all other marketed
batches with the old label containing (b)(4) are not at risk for the said
impurity during the intended shelf life of the product (i.e. (b)(4)).
 在一个 7 天室温条件暴露试验中，R&D 评估证明 XX 对 XX 的形成有所贡献。相
同评估还报告了在其它批次中并未检出 XX。该 R&D 报告没有说明为何只有
OOS 批次受到影响，而其它采用了含有 XX 的旧标签的在售批次在产品的既定
货架期内（即 XX）没有所讨论杂质风险。
 The investigation does not record any attempt to procure retention samples
representing product labels utilized in marketed batches and no attempt was
made to quantify the amount of (b)(4) on the labels.
 该调查并未记录任何购买能代表在售批次中所用产品标签留样的努力，也没有记
录任何试图对标签上 XX 数量进行定量检测的工作。
 As of the current inspection, a formal analytical method re-validation has not
been performed to ensure that the current method can adequately detect
and quantify the (b)(4) in the finished product. A limit for (b)(4) has not been
established for the finished product. A non-validated test method is currently
being used to test the retention samples representing all (b)(4) batches on
the market as part of the on-going analysis.
 截至此次检查时，未正式重新验证分析方法以确保当前方法能充分检出并定量成
品中的 XX。公司尚未制订成品的 XX 限度。目前用来检测代表所有在售 XX 批次
留样作为持续分析一部分的方法未经验证。
 Your CAPA to evaluate retention samples through a protocol study every 3
months is not scientifically sound. There is no assurance that the label lots
used in the marketed batches uniformly contained the same level of (b)(4)
(and (b)(4)).
 你们的 CAPA 要求根据一份方案每 3 个月对留样进行评估不够科学合理。不能确
保在售批准所用的标准批次均匀含有相同水平的 XX（和 XX）。
 As a corrective action for the OOS Investigation, the product labels were
changed from labels containing (b)(4) (material code: (b)(4)) to labels
containing no (b)(4) (material code: (b)(4)). The current stability shelf life of
the product of (b)(4) was established utilizing the old product labels with
material code(b)(4). Approximately (b)(4) batches were released to the U.S.
market containing the revised product label with material code (b)(4). A
stability study for the product with the new labels was not conducted and
hence, the current shelf life of (b)(4) for the product (with the new product
labels) is not substantiated by any stability data.
 作为 OOS 调查的纠正措施，产品标准被从含有 XX（物料代码 XX）的标签改为
不含有 XX（物料代码 XX）的标准。XX 药品目前的稳定性货架期是采用物料代
码为 XX 的旧药品标签订立的。大约有 XX 批次含有修订后药品标签（物料代码
XX）的产品被放行至美国市场。采用新标签的药品未进行稳定性研究，因此目前
XX（使用新的药品标签）的货架期是没有任何稳定性数据支持的。
(B) Out of Specification (OOS) Investigation No. OOS/C/18/IN2/SS/016 for (b)(4)
Capsules USP (b)(4)mg was initiated on 23 rd July 2018 when OOS dissolution
results were obtained for batch #(b)(4) at the 3-month stability (Long Term:
25±2°C and 60±5%RH) time point. The OOS results obtained were as follows:
OOS 调查编号 OOS/C/18/IN2/SS/016 是关于胶囊 USP XXmg，2018 年 7 月 23 日
启动，OOS 结果为批号 XX 在 3 个月稳定性时间点溶出度。得到的 OOS 结果如下：

Time points Minimum (%) Maximum (%) Average (%) Specification
时间点最小最大平均标准
1 hour (b)(4) (b)(4) (b)(4) NMT (b)(4)%
2 hours (b)(4) (b)(4) (b)(4) (b)(4) to (b)(4)%
4 hours (b)(4) (b)(4) (b)(4) (b)(4) to (b)(4)%
8 hours (b)(4) (b)(4) (b)(4) NLT(b)(4)%
The resulting investigation was completed with an “invalid” decision on 18 th
September 2018. Independent review of the investigation by third party
consultants disagreed with the conclusions drawn from the investigation during
their 1 st and 2 nd review. The root cause identified as due to “addition of (b)(4)
quantity of (b)(4) solution and skipping the addition of (b)(4) solution during (b)(4)
dilution of samples at initial OOS analysis” continue to remain unsubstantiated.
This root cause is not conclusively proven in the resulting OOS investigation. The
most recent update to the investigation is currently pending review by third party
consultants. Additionally, approximately 6 months have lapsed since OOS
investigation was imitated. The firm has no procedural controls to ensure that
OOS investigations pertaining to stability samples are investigated and completed
in a timely manner. (b)(4) Capsules, (b)(4)mg with batch number (b)(4) is currently
in the U.S. market with an expiration date of February 2020.
调查以 20180918 决定“宣布无效”结束。第三方顾问在第 1 次和第 2 次对该调查进行
的独立审核中不同意该调查做出的上述结论。根本原因被识别为因为“在 OOS 检验中
样品 XX 稀释期间加标 XX 溶液和 XX 溶液加入 XX 数量”还是没有任何根据。OOS 调
查不能得出结论支持根本原因。对该调查最近的更新目前仍在第三方顾问审核中。另外
自 OOS 调查开始已过去了约 6 个月，公司没有程序控制来确保 OOS 调查针对稳定性
样品，并及时完成。有效期为 202002 的 XX 胶囊 XXmg 批号 XX 目前仍在美国市场销
售。
(C) Out of Specification (OOS) Investigation No. OOS/C/18/IN2/SS/016 for (b)(4)
Tablets (b)(4)mg, (b)(4)mg and (b)(4)mg was initiated on 26 th September 2018
when the Assay results from batches (b)(4), (b)(4) and (b)(4) at 3-month stability
testing (Long Term: 25±2°C and 60±5%RH) yielded OOS Assay results for the
(b)(4) and (b)(4) components. The resulting investigation attributed the root cause
to a malfunctioning sonicator. During hypothesis studies, batch (b)(4) was selected
for a study where the sample stock was prepared without sonication to prove
malfunctioning sonicator yielded OOS results. However, review of the hypothesis
study results for batch (b)(4) indicate that “no sonication study” (purportedly the
worst case) yielded results as follows:
OOS 调查编号 OOS/C/18/IN2/SS/016 是关于 XX 片剂 XXmg、XXmg 和 XXmg 在 3
个月稳定性测试中（长期 25±2°C and 60±5%RH）含量中 XX 和 XX 组份 OOS 结果，
于 20180926 启动。调查将根本原因归结为超声破碎仪故障。在假设性研究中，批次 XX
被选择用于研究，公司不使用超声制备了样品贮备液配制样品，用以证明超声破碎仪
故障会导致 OOS 结果。但是，对 XX 批次假设性研究结果的审核显示“不超声研究”
（认为是最差情形）得出结果如下：
(b)(4) (b)(4) (b)(4)
Initial OOS Results-Assay (b)(4) (b)(4) (b)(4)
初始 OOS 结果含量
Hypothesis study (no sonication)-Assay (b)(4) (b)(4) (b)(4)
假定性研究(不超声)—含量
Absolute % difference in Assay from initial 0.8% 25.4% 14%
OOS results
与初始 OOS 结果含量绝对差异%
The investigation is silent as to why the no sonication hypothesis study (i.e. worst
case) resulted in Assay values that were approximately 25.4% and 14% higher
(absolute difference) for the (b)(4) and (b)(4) components, respectively. The
investigation report indicates that the sonicator was functional during the analysis
but purportedly not at optimum working conditions. A sonicator performance
verification on 27 th September 2018 did not indicate that the sonicator was
completely in an on-working status. As such, the root cause due to extraction
issue as a result of a malfunctioning sonicator is not conclusively proven during
the investigation. These three batches continue to remain in the U.S. market as of
the current inspection. The three batches were PV batch from an alternate API
vendor for (b)(4).
调查没有讲为何不超声的假设性研究（即最差情形）得到的结果含量值比 XX 和 XX 成
分分别高出约 25.4%和 14%（绝对差异）。调查报告显示超声机在分析期间是工作的，
但不在最优的工作状态。2018 年 9 月 27 日的超声机性能确认并未显示超声机是完全不
能工作的状态。因此，在调查期间将超声机故障作为根本原因认为其引起萃取问题不能
得到证明。这三批截至此次检查仍继续在美国市场销售。这 3 批是一个替代 API 供应商
的 PV 批次。
(D) Out of Specification (OOS) Investigation No. OOS/C/18/IN2/FP/013 was
initiated on 28 th July 2017 for (b)(4) Capsules USP (b)(4)mg/(b)(4)mg where batch
(b)(4) was rejected due to Assay failure at (b)(4)% for (b)(4) against a specification
limit of (b)(4) to (b)(4)%. A 2 nd batch in the campaign (b)(4) was flagged as an Out
of Trend with an Acceptance Value of (b)(4) (for Content Uniformity). The following
deficiencies were noted with regards to this investigation:
OOS 调查编号 OOS/C/18/IN2/FP/013 启动日期 2017 年 7 月 28 日，是 XX 胶囊 USP
规格 XXmg/XXmg，该批次含量 XX 结果为 XX%不符合标准限度 XX-XX%。同一生产轮
次 XX 中的第 2 批被标为 OOT，其含量均一度在可接受范围内。关于此调查发现缺陷如
下：
 (b)(4) sampling during the investigation for batch (b)(4) indicated failing
results. However, no (b)(4) sampling of the 2 nd batch (b)(4) in the campaign
was considered.
 调查过程中对批次 XX 的 XX 取样得到不合格结果。但是，并未考虑对该生产轮次
中第 2 批 XX 取样。
 The 2 nd batch (b)(4) in the campaign was released and distributed to the
U.S. market on 14 th August 2017. Long Term impact (if any) on the batch
was not evaluated by placing to batch on stability.
 该生产轮次中第 2 批 XX 于 2017 年 8 月 14 日放行销售至美国市场。并未将该批
次放入稳定性试验计划中评估其长期影响性（如有）。
 A root cause of the Assay failure was never identified. Nevertheless, an
evaluation of the product’s validated status not considered.
 没有发现含量不合格的根本原因。但是，未考虑对产品验证状态进行评估。
Manufacturing investigation (Phase II) indicated that there was no difference in the
manufacturing processes among batches (b)(4) and (b)(4). There is no assurance
that the released 2 nd batch would consistently remain within its specification limits
during the intended shelf life of (b)(4) Batch (b)(4) is currently in the U.S. market
with an expiration date of (b)(4).
生产调查（第 II 阶段）显示批次 XX 与 XX 之间的生产工艺没有差异。无法确保所放行
的第 2 个批次在其指定的货架期内会持续保持在其质量标准范围内。批号 XX 当前仍在
美国市场上，有效期为 XX。
(E) Your firm has invalidated several Out-of-Specification (OOS) results obtained
during the testing of environmental monitoring as summarized below: You
attributed several of them to human error which raises concerns about the ability
of your laboratory personnel to properly conduct the required analytical testing.
For example:
你公司宣布在环境监测期间得到的几个 OOS 结果无效，总结如下。你们将其中几个归
结为人为错误，这使得我们担心你们实验室人员正确执行所需分析检测的能力。例如：
 OOS investigation, EMO/OOS/18-001 was initiated on 04/15/2018 for
routine air monitoring sampling activity (no filling) where the result for
Location #(b)(4) found exceeding the acceptance limits (b)(4) CFU
(Action/Level Limit (b)(4) CFU). Your firm attributed the root cause as
human error through a deficient investigation and interview where the
sampler lid might have not been properly sanitized before sampling in (b)(4)
((b)(4)). When interviewing the Analyst (Officer Micro) during the inspection
on 01/21/2019 using the same questions raised in the investigation report,
his response did not corroborate what is stated in the OOS investigation
report conducted by your firm. For example, in the OOS report he said for
Question 6 that “I have taken plates from PPM staging and loaded at (b)(4)
trolley. After loading, air sampling was performed as per sequence
mentioned below: (b)(4) again entered in Aseptic area and performed settle
plate exposer following the sequence as above in each step, I have
sanitized the hand while (b)(4)”, but in person on 01/21/2019 he said
“Firstly, sequence of (b)(4), it mentions in our SOP (QC2-128-13).” Your firm
invalidated the failing result through your interview process.
 OOS 调查 EMO/OOS/18-001 于 2018 年 4 月 15 日启动，在 XX 位置常规空气
监测取样活动中（未灌装）发现超出可接受标准 XXCFU（行动限 XXCFU）。你
们的调查和面谈都是有缺陷的，你们的取样品盖可能在 XX 取样之前未进行恰当
消毒，但你公司将根本原因归结为人为错误。在 20190121 检查期间与化验员
（微生物管理员）面谈时，我们提出了与调查期间所提的相同问题，化验员的回
答与你公司所做 OOS 调查报告中记载的不同。例如，在 OOS 报告中，他对问题
6 的回答是“我从 PPM 阶段取了碟子，放到 XX 推车上。放好后，按以下顺序执
行取样。再次进入无菌区，按上述各步骤打开沉降碟采样，我在 XX 时进行了手
消毒”。但在 20190121，他说的是“首先，按顺序 XX，在我们 SOP（QC2-
128-13）中有提及”。你们公司通过你们面谈过程将不合格结果宣布无效。
Written records of investigation of a drug complaint do not include the findings of
the investigation and the follow-up.
药品投诉调查书面记录未包括调查发现情况和跟踪情况。
Specifically, your complaint investigations are deficient. You have received several
repeated market complaints for (b)(4) Tablets USP ((b)(4)mg/(b)(4)mg, (b)(4)mg/
(b)(4)mg, and (b)(4)mg/(b)(4)mg) and (b)(4) Tablets (b)(4)mg) since 2011/2012 for
black spots, blackish greyish spots, and “mold” on the marketed finished products
in the U.S.A.. In all resulting investigations, you concluded the root cause as the
result of oil (or food grade lubricant used during the compression process) mixed
with fine product dust forming lumps and/or black spots, blackish greyish spots.
Despite the number of investigations summarized below, none of the
investigations conclusively provides any evidence that the lubricating oil when
adhered to the finished product results in finished products with black spots or
molded tablets. Additionally, a detailed health hazard evaluation (HHE) was not
performed until 24 th January 2019 (during the current inspection). However, the
HHE fails to provide assurance that the finished products contaminated with
potentially denatured lubricant oil are safe and effective for the consumers.
具体来说，你们对投诉的调查有缺陷。自 2011/2012 年起，你们收到了关于 XX 片剂
USP 规格（XXmg/XXmg、XXmg/XXmg 和 XXmg/XXmg 以及 XX 片剂 XXmg）几个重
复的市场投诉，投诉是关于美国销售的药品中发现黑点、黑灰点和“霉点”。在所有调
查中，你们将根本原因归结为油（或压片过程中所用食品级润滑剂）与细的成品粉形
成块和/或黑点、黑灰色点。下列总结的调查数量很多，但没有一个调查有证据证明润滑
油粘在成药上时会形成成药上的黑点或导致片剂长霉。另外，一直到 20190124（检查
期间）公司才执行了详细的健康危害评估（HHE）。但是，该 HHE 并不能确保受到可
能变性的润滑油污染的药品对消费者是安全有效的。
The following complaints have been recorded and investigated for the following
products since commercialization.
自商业化以来，公司记录并调查了以下产品投诉。
Product Complaints
(b)(4) Tablets USP ((b)(4)mg/(b)(4)mg, (b)(4)mg/(b)(4)mg 42 (since 2012)
and (b)(4)mg/(b)(4)mg)
(b)(4) Tablets ((b)(4)mg) 17 (since 2011)
Employees engaged in the manufacture, processing, packing and holding of a
从事药品生产、加工、包装和存贮的员工缺少完成其被指派工作所需的培训。
There is a lack of oversight by firm management, especially the QC, QA,
Warehousing, Production, and IT departments, to ensure employees are
performing their required job functions as specified in your firm’s SOPs. During the
inspection, we observed several instances where it appeared that top
management, general managers, supervisors, specialists, and personnel engaged
in the activities related to the manufacture, testing, holding and review of
procedures, documents, methods, and data could not autonomously answer
questions related to their day to day job functions or activities in which they
routinely participated or would hastily provide an answer without consideration of
the question which was asked. Many employees, including the QA, QC,
Warehousing, Production, and Validation Managers, would directly read the
procedure from the document without being able to autonomously comment on
activities and operations in which they are described to be familiar with and
knowledgeable of. Additionally, firm personnel would provide data and evidence
which did not support the claims that could provide answers to specific questions
asked by the investigators. For example:
缺乏公司高层监管，尤其是 QC、QA、仓库、生产和 IT 部门，无法确保员工按公司 SOP
履行其所需职责。在检查期间，我们发现几个例子，显示高级管理人员、总经理、主管、
专家和从事与生产、检验、存贮和审核程序、文件、方法与数据有关活动的人员不能自主
回答与其日常工作或日常参与活动有关的问题，或者匆忙回答问题却未对所问问题进行
考虑。许多员工，包括 QA、QC、仓管、生产和验证经理都是直接从文件上把程序读出来，
但不能自主对按规定熟悉理解的活动和操作进行说明。另外，公司人员提供的数据和证
据并不能证明他们能够回答调查人员所问的具体问题。例如：
A. Your firm’s Manager of IT, Deputy General Manager of Engineering, Sr.
Executive IT, Manager Validation/QA provided us with the following (b)(4)
and (b)(4) building management systems (BMS) validation documents for
the (b)(4) building and (b)(4) building (Sterile) in which they participated in
the validation studies and/or is part of their duties. However, when we
asked them why they did not follow the established/approved Validation
Master Plan (VMP)/Protocol for the validation such as issuing a system
release certificate and writing a validation summary report as part of the
validation deliverables. They could not answer and provide a justification.
你公司的 IT 经理、常务工程副总、资深 IT 执行专家、验证经理/QA 向我们提供了
厂房管理系统（BMS）验证文件，这是他们参与的验证研究，有些是他们的职
责的一部分。但是，当我们询问他们为何他们未遵守既定/批准的验证主计划
（VMP）/验证方案如签发系统放行证书并编制验证总结报告作为验证可交付物
的一部分时，他们不能回答，亦不能给出理由。
B. Document # VMP-003-INP-00 (Validation Master Plan Manufacturing
Software System at Lupin Limited, Pithampur) 08/02/2018 effective date.
文件# VMP-003-INP-00（鲁宾 pithampur 生产软件系统验证主计划）生效日期
20180802.
C. On 01/21/2019 during the walkthrough of the Analytical QC Laboratory, we
asked the Deputy General Manager (b)(4)-Quality Control who oversees
the QC Laboratories as part of his duties if he maintains a logbook for
every equipment in the lab. He stated yes they do. We then asked him to
provide us with the logbook for the ATAGO Refractometer RX-7000CX
(Asset #RM-03). He could not provide us with the request as he was
notified by one of his staff that they are currently using Electronic Logbook
(eLog) System V1.0.0. We asked him if the equipment is connected to a
data acquisition system. He could not provide us with an answer. We then
asked him how the information captured from the equipment is documented
into the e-log system. He could not answer the question. Then, both the
President of Technical Operations and the Managing Director asked him the
same question in a different way and local language. Still, he could not
answer the question. We asked him to show us how the review of entries in
the e-log is performed and if he could show us a document in the e-log
system where reviews have been performed. He tried to log in and could
not access the system. He finally stated he has no access toe-log. It took
approximately 45 minutes for him to answer these questions. During the
review of his training records, it revealed that he has been trained on the
SOP and is assigned a “Manager” role in the system. In addition, he is
overdue on the following SOPs:
在 20190121 我们在 QC 实验室检查时，我们询问常务总经理 XX—QC（监管
QC 实验室是他职责的一部分）实验室里是否每台仪器都有一本日志。他声称说
是的。然后我们问他能否给我们看 ATAGO 折光仪 RX-7000CX（资产编号#RM-
03）的日志。他拿不出来，因为有一个员工告诉他现在他们用的是电子日志
（eLog）系统 V1.0.0。我们问他仪器是否连接到数据采集系统。他不能作答。然
后我们问他仪器采集的信息是如何记录至电子日志系统的。他不能作答。然后，
技术运营总裁和管理总监用本地语言采用不同方式问了他同样的问题。他仍然不
能作答。我们让他展示给我们如何审核 eLog 里的记录，问他是否可以在 eLog
里面展示给我们一份已经过审核的文件。他试图登录却无法进入系统。最后他说
他没有 eLog 的登录权限。他花了大约 45 分钟回答上述这些问题。对他的培训记
录审核显示他接受过该 SOP 的培训，并在系统里被赋予“经理”身份。另外，
他的以下 SOP 培训已过期：
 CQA-106 (Production Planning and Tracking of Batches at Different
Manufacturing Stages)
 CQA-106（不同生产阶段的生产计划和批次追踪）
 CQA-110 (Reduced Testing, Rev.00, 10/19/18 effective date)
 CQA-110（减少测试，版本 00，生效日期 20181019）
 QC2-027 (Operation of (b)(4) Process, Rev. 01, 03/12/2018)
 QC2-027（XX 工艺的操作，版本 01，20180312）
 QC2-278 (Standard Management in SAP, Rev.00,10/23/2018)
 QC2-278（SAP 标准管理，版本 00，20181023）
D. On 01/21/2019 during the walkthrough of the Analytical QC Laboratory, we
asked the Manager of QC if he could explain the sample management
process (receiving of samples through issuing of samples to Analysts). I
asked him at least 3 times in different manner and rephrased the question.
He could not fully answer. Then, the Managing Director, President of
Technical Operations, and GM Quality asked in different manner including
local language. It took him nearly 40 minutes to explain the process. He
has been trained on SOP #SOP-UNIT2-QC2-178-07 (Sample Management
of QC Sample Ver.07) on 01/25/2018.
在 20190121 检查分析 QC 实验室时，我们询问 QC 经理他能否解说样品管理流
程（样品接受到将样品分发给化验员）。我以不同方式不同说法反复问了他至少
3 次，他不能完整作答。然后，管理总监、技术运营总裁和质量总经理用不同方
式包括当地语言询问他。他花了近 40 分钟才解释完该流程。他在 20180125 接受
过 SOP#SOP-UNIT2-QC2-178-07（QC 样品管理，版本 07）的培训。
E. On 01/21/2019 during the walkthrough of the Analytical QC Laboratory, we
asked Executive QC if he could tell us the dates when column #L19000563
was received in QC and issued for use. This column is used for (b)(4)
Solution (b)(4)%. He could not provide us with the requested information,
which is part of his duties to account for incoming laboratory equipment. It
took nearly half an hour with assistance of other personnel to access the
SAP system in order to provide us with the information. We then asked him
if he could tell us if the specific column has been used for testing (b)(4)
Solution (b)(4)%. He stated no. we then asked the Sr. Executive QC if he
could tell us if the column had been used. He provided us with the printout
from the e-column usage logbook showing it had been used for (b)(4)
injections.
在 20190121 检查分析 QC 实验室过程中，我们询问执行 QC 他能否告诉我们柱
子#L19000563 的 QC 接收日期以及发放使用日期。该柱子用于 XX 溶液 XX%的
检测。他不能给我们提供所索要的信息，这是他负责进入实验室仪器职责的一部
分。在其它人员帮助下，他花了近半小时才进入 SAP 系统，才得以给我们提供
该信息。然后我们问他能否告诉我们这支柱子是否曾用于 XX 溶液 XX%的检测。
他声称没有。然后我们询问资深执行 QC 是否能告诉我们该柱子可曾使用。他向
我们提供了柱子电子日志中的打印件，显示该柱子曾被用于 XX 进样。
F. On 01/23/2019, we asked the Manager of QC and the Officer IT if they
could access the Electronic Logbook (eLog) System V1.0.0 to show us the
user group’s roles and access level. The eLog is the data acquisition
software used by the firm to capture activities. They could not perform the
task which is part of their duties and warranted a conference call with your
CQA personnel and the vendor of the software.
20190123，我们询问 QC 经理和 IT 管理员是否可进入电子日志系统 V 1.0.0 给
我们展示用户组角色和权限级别。eLog 是该公司用于采集活动轨迹的数据采集
软件。他们无法执行该任务，而这是他们职责的一部分，他们要给你们 CQA 人
员和软件供应商打电话才能完成此任务。
G. On 01/24/2019, we asked the Sr. GM Corporate IT regarding the provided
list of “Administrators” for user creation form/e-Log Software System
Administration User List, how users (Administrators and Vendors) are
added, changed, and removed. He stated that he is knowledgeable of the
software and could not fully explain the process when he came into the
conference room. For example, we observed a username in this format
(firstnamelastname1) and when asked him how it is being created and why.
He stated that it is being done when the global directory already has a user
with similar name. We asked him to show us where that process is
described in their established SOPs. He stated it is not described. I
requested his training records and it revealed that the firm does not
maintain training records for his position.
20190124，我们询问资深 GM 公司 IT 要求提供创建用户表的“系统管理员”
清单/e-Log 软件系统管理用户清单，问他如何增加、修改和删除用户（管理员和
供应商）。他声称他知晓该软件，在进入会议室时不能完整解释该流程例如，我
们发现用户名是这种格式（名姓 1），问他是如何创建的以及原因。他声称这是
因为全球联系人目录里已经有了相同的用户名，所以这样创建。我们要他展示给
我们既定 SOP 中哪儿有说明这个流程。他声称没有表述在 SOP 中。我索要了他
的培训记录，然后发现公司并未保存他的职位的培训记录。
H. On 01/24/2019, we asked your Sr. GM Corporate IT to provide us with the
user creation form for one of the firm’s administrators. Your Sr. GM
Corporate IT and the Manager Site IT stated the requested form could not
be found. We then asked him to show us in the eLog software system when
the “Administrator” (b)(4) was removed from the system. he called on your
Officer, Site IT to show us (which is part of his job functions and has been
trained on the process) and it took him approximately 13 minutes(12.50pm-
1.03pm) to demonstrate when the vendor/administrator was removed from
the system although his training records revealed that he was trained on
the SOP #QC1-229-00 (User Management and Master Data Creation for
Electronic Usage Log System) on 07/20/2015 and Ver.01 on 10/03/2015.
20190124，我们询问你们的资深 GM 公司 IT 给我们提供公司的管理员之一的
用户创建表。你们的资深 GMP 公司 IT 和现场 IT 经理声称找不到所要表格。然后
我们要他给我们看电子日志软件系统中是何时删除“管理员”XX 的，他给你们
管理员打了电话，现场 IT 给我们展示了此信息（这是他的工作职责之一，并且
接受过该流程的培训），他花了近 13 分钟时间（下午 12.50-1.03）才展示何时
从系统中删除供应商/管事员，而他的培训记录显示他在 20150720 年接受
SOP#QC1-229-00（电子使用日志系统用户管理和主数据创建）培训，在
20151003 接受的 01 版培训。
I. Your firm does not maintain training records for the GM CQA position.
你们公司没有保存 GM CQA 岗位的培训记录。
J. On 01/16/2019, we asked an apprentice from Quality Control –
Microbiology how he collects (b)(4) samples for routine analysis. He
identified himself during the interview that he was responsible for collection
of (b)(4) samples for routine analysis from the (b)(4) production area. he
was unable to answer a Yes/No question (pertaining to the methodology of
(b)(4) sample collection from (b)(4) production block) when asked
repeatedly in English and in the local vernacular language.
20190116，我们询问 QC 微生物的一位实习员工他在日常分析中如何采集 XX
样品。他在面谈过程中表明自己的职责是在日常分析中从 XX 生产区域采集 XX
样品。我们反复地用英语和当地语言问他时，他都不能回答是否问题（关于从
XX 生产区采集 XX 样品的方法）。
三．实验室控制系统

OBSERVATION1 缺陷 1
There is no quality control unit. 无质量部门。
A. Your Quality Unit confirmed an out-of-specification for assay testing on (b)
(4)Tablets USP (b)(4)mg, Batch #(b)(4), and was signed by the Head of
Quality Control and the Head of Quality Assurance on 08 November 2017.
(b)(4) tablets of this product were distributed to the U.S., four (4) months
prior to (b)(4) product testing release (24 July 2017). The Certificate of
Analysis (COA) for this batch was approved on 13 November 2017. No
Recalls were initiated.
你们的质量部门确认了 XX 片剂 USP 规格 XX 批号含量检测的 OOS 结果并由 QC 和 QA 负
责人于 2017 年 11 月 8 日签字。该药品的 XX 片剂在 XX 药品检测旅行之前 4 个月（2017
年 7 月 24 日）即发往美国。该批次 COA 于 2017 年 11 月 13 日批准，未发起召回。
B. Your Quality Unit failed to track, trend, and investigate Invalid Analytical
Results for system suitability. As of 20 March 2018, your firm had 259
system suitability failures since 1 January 2018. Your firm’s QC Analyst
Reviewer and QC Assistant Manager stated the previous logbook for
January-Notification Record for Invalid Data, dated 11/12/17, was
destroyed. An Investigation into these failures was not initiated and no
corrective actions were taken to address these failures.
你们质量部门未能追踪系统适用性结果，对其进行趋势分析并调查无效的分析结果。截止
2018 年 3 月 20 日，你公司自 2018 年 1 月 1 日起已发生 259 起系统适用性失败。你公司
的 QC 化验员审核员和 QC 副经理说之前的登记本，无效数据 1 月通知记录，日期为
2017-11-12 已经销毁。你公司从未对这些失败进行调查，亦未采取纠正措施解决这些失
败问题。
In addition,your firm failed to maintain and retain logbooks that are not obsolete
or outdated. For example, once completed your firm destroys logbooks from the
following areas: (b)(4) block warehouse, Housekeeping (b)(4)-Block QC, (b)(4)-
Block QA,(b)(4)-Block Manufacturing, (b)(4)-Block, QC, Warehouse, and
Production-(b)(4)Block.
另外，你公司未维护和保存过期的登记本。例如，一旦完成，你公司即把以下区域的登记
本销毁：XX 车间仓库、库管 XX 车间 QC、XX 车间 QA、XX 车间生产、XX 车间、QC、仓库和
生产-XX 车间。
As recent as 2018, the destruction of logbook examples include, but are not
limited to: Notification Record for Invalid Data, Line Clearance Checklist,
Preventive Maintenance, Instrument Logbooks, training records, cleaning check
lists.
近至 2018 年，登记本的销毁例子包括但不仅限于：无效数据通知记录、清场检测清单、预
防性维护、仪器日志、培训记录、清洁检查清单。
C. Your firm failed to prioritize in-process, stability, and finished product
sample testing based on Quality. According to your firm’s QC Manager,
who is in charge of scheduling in-process and finished product sampling
for QC analysis, scheduling priority is driven by the needs of your firm’s
Head of Production. For example, but not limited to, (b)(4) Tablets (b)
(4)mg, Batch #(b)(4). Accordingto your firm’s Assistant Vice President of
QC, this sample was pulled on 15 July 2017. However, this sample was not
analyzed until 22 August 2017.
你公司未能基于质量对中控、稳定性和制剂样品检测进行优先排序。据你们公司负责中间体
和成品取样用于 QC 分析排程的 QC 经理说，先后顺序是根据你公司生产负责的要求来安
排的。例如但不仅限于，XX 片剂 XX 批号。据你公司 QC 副总说，该样品是在 2017-07-15
日取来的，但直到 2017-08-22 才分析。
D. Your firm’s QC department deleted two-thousand one hundred one
(2,101) files since 1 March 2018 on your network. These files names include,
but are not limited to:OOS, OOT, Incidents, Method Verification Reports,
chromatographs, calculations,and Stability Reports.
你公司的 QC 部门自 2018-03-01 起从你们网络上删除了 2101 个文件。这些文件名称包括
但不仅限于 OOS、OOT、事件、方法确认报告、色谱、计算和稳定性报告。
According to your Assistant Vice President of QC, your firm does not have any
written procedures addressing the deletion of files from your firm’s network. No
investigations were initiated for the deletion of these files.
据你们 QC 副总说，你公司没有任何书面程序说明从公司网络上删除文件的情况。对文件
删除亦从未启动调查。
The quality control unit lacks the responsibility and authority to approve and
reject all components, in process materials and drug products.
质量部门缺乏职责和授权来批准和拒收所有组份、中间体和成品。
****THIS IS A REPEAT OBSERVATION***此为重复缺陷
A. Your firm failed to conduct sample analysis in a timely manner for stability
samples, in-process samples, and finished product samples. No FARS or
recalls were initiated in the absence of timely results. For example, but are
notlimited to:
你公司未能及时检验稳定性样品、中间体样品和成品样品。在没有及时获得结果时没有启动
FARS 或召回，例如但不仅限于：
(1) As of 23 March 2018, your firm had (b)(4) pending samples for
analysis:
截止 2018-03-23，你公司有 XX 件样品待检：
a. a) (b)(4)– Late and untested stability batches for (b)(4)°C/75%RH
since January 2017.
XX-自 2017 年 1 月开始的 XX°C/75%RH 稳定性测试延迟未检
a. b) (b)(4)-Reserve and Retain samples for February 2018
XX—2018 年 2 月留样
a. c) (b)(4)-Late and back logged In-process samples since January
2017
XX—自 2017 年 1 月开始中间体样品延迟积压
a. d) (b)(4)-Late and back logged stability samples for (b)(4) pending
(b)(4)
XX—XX 稳定性样品延迟积压待 XX
a. e) (b)(4)-CQC(Central Quality Control/(b)(4) Quality Control) back
logged stability samples
XX—CQC（中心化验室/XX QC）稳定性样品积压
a. f) (b)(4)-Distributed batches of US marketed products that are
pending stability samples
XX—美国市场已销售批次未留稳定性样品
a. g) (b)(4)-Finished Products since September 2017
XX—自 2017 年 9 月以来的成品
(2) In addition, commercial batch, (b)(4) Tablets (b)(4)mg Batch #(b)(4), was
manufacture in November 2016. As of 19 March 2018, this batch is pending 2
month (2M) stability testing for storage condition 40±2°C/75±5%RH. On (b)(4)
tablets were dispatched to the US Market.
此外，XX 片剂 XX 批号的商业批次于 2016 年 11 月生产。截止 2018-03-19，该批次
40±2°C/75±5%RH 条件稳定性测试 2 个月时间点未检。该片剂于 XX 发往美国市场。
(3) Other examples of the former were found for other products as follows:
其它药品上述情形例子如下：
(b)(4)
B. A confirmed OOS, AM1/OOS/148/17, was found for (b)(4)mg tablets, Batch
#(b)(4)((b)(4) tablets) and Batch #(b)(4) ((b)(4) tablets) stability sample at
1M storage condition 40°C/75%RH for Related Substances. These batches
were manufactured in April 2017 and put on stability, Time zero (T0), on 19
June2017. 1 month (1M) testing began on 16 November 2017 (3 months
after T0 and 7months after manufacturing) and was not completed in the
Laboratory Information Management System (LIMS) as of 26 March 2018.
In addition, this batch is currently under investigation in your LIMS System.
This batch was distributed on (b)(4) to the US Market.
XX 片剂 XX 批号和 XX 批号 40°C/75%RH 条件稳定性样品 1 个月时间点检出有关物质
OOS 并确认，编号 AM1/OOS/148/17。这些批次生产日期为 2017 年 4 月，放稳定性时
间 T0 为 2017-06-19，1 个月时间点开始于 2017-11-16（T0 后 3 个月，生产后 7 个月），
并且截止 2018-03-26 在 LIMS 系统里仍未完成。此外，该批次目前正在你们 LIMS 系统调
查中。该批次已于 XX 日销往美国市场。
(1) Long term stability testing at 3 month (3M) Storage condition
25°C/60%RH for Batch #(b)(4) and Batch #(b)(4) were completed late for (b)(4)
mg tablets. These batches were manufactured in April 2017 and put on stability
T0, 19 June 2017. 3 months (3M) testing was started on 06 November 2017 (3
months after T0 and 7 months after manufacturing). Results of testing were not
reviewed and approved until 21 March 2018. Also stability testing at 3M storage
condition (b)(4) °C/75% for Batch #(b)(4), was completed late. 3M testing was
started on 06 November 2017 (3 months after T0 and 7 months after
manufacturing). Results of testing were not reviewed and approved until 21
March 2018.
XX 片剂的 XX 批号和 XX 批号 25°C/60%RH 长期稳定性试验 3 个月检测延迟完成。这些批
次于 2017 年 4 月生产，2017-06-19 放稳定性，3 个月检测时间点于 2017-11-06 开始
（T0 后 3 个月，生产后 7 个月）。检测结果直到 2018-03-21 仍未审核和批准。XX 批号 3
个月的 XX°C/75%稳定性检测也延迟完成。3 个月检测时间点开始于 2017-11-06（T0 后
3 个月，生产后 7 个月）。检测结果直到 2018-03-21 仍未审核和批准。
C. We observed inconsistent gaps in timeframes when samples were received
into your Central Quality Control (CQC) and the dates when a stability (b)
(4) occurred. During our assessment of the stability program, we found
Stability Samples of Exhibit Batches and Manufactured Batches are
documented as T0, the date samples are(b)(4). Below are some examples:
我们发现你们的 CQC 接收样品的时间与 XX 稳定性发生的时间不一致。在我们对你们稳定
性计划评估时，我们发现申报批次和生产批次的稳定性样品记录为 T0，取样时间为 XX，
以下为部分例子：
Date of Receipt of Product Batch Batch Release Date Market Intended
Sample by Central Name Number (T0) for
Quality Control 产品名称批号批次放行日期（T0）销售市场
(CQC)
中心 QC 接收样品日
期
2017-03-09 (b)(4) (b)(4) 2018-03-21 Commercial US
美国商业批
2018-01-04 (b)(4) (b)(4) 2018-03-05 Exhibit US
美国申报批
2017-12-11 (b)(4) (b)(4) Date for T0 not Exhibit US
Documented 美国申报批
T0 时间未记录
T0 时间未记录
T0 时间未记录
2018-02-13 (b)(4) (b)(4) Date for T0 not Commercial US
Documented 美国商业批
T0 时间未记录
2018-03-01 (b)(4) (b)(4) 2018-03-14 Commercial US
美国商业批
2018-01-22 (b)(4) (b)(4) 2018-02-01 Commercial US
美国商业批
D. In addition, on 24 March 2018, your firm’s QC Manager reviewed and
approved 130 samples (twice as many) pending in LIMS for stability
samples, in-process samples, and finished product samples during his daily
participation of this FDA inspection. Your QC Manager reported he spends
approximately (b)(4) per (b)(4)((b)(4) per analysis packet; totaling
approximately (b)(4) completed analytical reviews per (b)(4)).
此外，2018-03-24，你公司 QC 经理在参与本次 FDA 检查期间还审核和批准了 130 个
LIMS 系统里待审批的稳定性样品、中间体样品和成品样品（2 倍之多）。你们的 QC 经理
说他一般要花 XX 时间审核一个分析包，依 XX 总共完成 XX 个分析审核。
Laboratory control do not include the establishment of scientifically sound and
appropriate specifications, sampling plans and test procedures designed to
assure that drug products conform to appropriate standards of identity, strength,
quality and purity.
QC 无科学合理和恰当的质量标准、取样计划和检测程序，设计用以确保药品符合适当的
鉴别、剂量、质量和纯度标准。
A. Integration parameters are not established to ensure impurity peaks are
detected. Your Quality Unit failed to conduct an investigation where
unknown peaks were observed due to inhibiting integration. Unknown
peaks were observed in the following chromatographs where integration
was inhibited. For example, but are not limited to:
未建立积分参数以确保发现杂质峰。由于抑制积分，你们质量部门在发现未知峰时未进行
调查。在以下积分被抑制的色谱图中发现未知峰，例子包括但不限于：
During the (b)(4) test for (b)(4) by GC (ID: QC/260) sample set (b)(4), on 18
February 2017, we noted your firm inhibited integration in portions of the
chromatograms where impurities may be present. Processing Method ((b)(4),
Method ID: 19672) was used toprocess the sample for (b)(4), Batch #(b)(4), as
below:
在 2017-02-18，XX 的 GC（ID：QC/260）样品序列 XX 的 XX 检测中，我们注意到你公
司在杂质可能出现的部分抑制了积分。XX 产品 XX 批号样品处理使用了处理方法（XX，方
法 ID：19672），如下：
Function 功能 Start Time (min) 开始时间 Stop time (min)停止时间
（分钟）（分钟）
Inhibit Integration 抑制积 (b)(4) (b)(4)
分
分
分
分
Your QC Head agreed that known or unknown impurities will not be identified
even if they arepresent if integration of the peaks is inhibited for a particular time
frame. Your firm manufactured (b)(4) batches of (b)(4) mg Capsules ((b)(4) count
bottles) using (b)(4) USP, Batch #(b)(4); totaling the distribution of (b)(4) bottles
tothe US market. No Investigations were initiated.
你们的 QC 负责人认可如果在某个特定时间段的峰积分被抑制，已知或未知杂质即使出现
也无法发现。你公司使用了 XXUSP XX 批号生产了 XX 批次 XXmg 的 XX 胶囊（XX 瓶），
总共有 XX 瓶销往美国。未启动调查。
B. Your firm produced (b)(4) batches of (b)(4) products and (b)(4) batches of
(b)(4) in 2017. However, your firm conducts air samples (b)(4) to ensure
cross-contamination of these products do not occur in the (b)(4) Block ((b)
(4) and (b)(4) products). This sampling plan frequency is not representative
for the amount of(b)(4) and (b)(4) products manufactured at your firm.
你公司在 2017 年生产了 XX 批次 XX 产品和 XX 批次 XX 产品。你公司在 XX 车间取空气样
品以确保该车间这些产品没有交叉污染。这些取样计划频次不能代表你公司生产的 XX 和
XX 产品的数量。
The written stability testing program is not followed.
未遵守书面稳定性检测计划。
A. A. Your firm failed to initiate and approve a change control authorizing
the discontinuation of stability condition (b)(4) °C/75%. In the absence of
an approved change control, testing for this condition was halted resulting
in a back log of (b)(4)samples since January 2017. However, according to
your firm’s stability protocols, these conditions are to be tested from (b)
(4). The following products were distributed to the US Market, including
but are not limited to:
你公司未能启动和批准变更控制授权中止稳定性 XX°C/75%条件。在没有批准变更控制的
情况下，该条件的检测被中止，导致 XX 样品自 2017 年 1 月开始积压。但是，依据你公司
的稳定性方案，这些条件自 XX 需要进行检测。以下产品已销往美国市场，包括但不仅限
于：
 (b)(4) Tablets USP (b)(4) mg 片剂 USP 规格
 (b)(4) Tablets USP (b)(4) mg 片剂 USP 规格
 (b)(4) Capsules USP (b)(4) mg 胶囊 USP 规格
 On 23 March 2018, we observed, 45 comingled boxes of pending and
analyzed stability samples, stored in the “RH Room” without temperature
control or monitoring. Thereis no log book or tracking of these samples
and their location. For examples,(b)(4) Capsules USP (b)(4)mg, Batch #(b)
(4), was found in the “RH Room” pending for 25 °C/60% for 3M. The
batch was manufactured in February 2017. Testing was initiated on 27
October 2017 and is listed in LIMS as “Under Test”.
2018-03-23，我们发现 45 个混合的盒子装着待验稳定性样品，存贮在“RH 房间”，没
有温度控制和监测。这些样品及其位置没有登记本或追踪。例如，XX 胶囊 USP 规格 XX 批
号在“RH 房间”发现时 25 °C/60%条件待检 3 个月。该批次在 2017 年 2 月生产。2017-
10-27 开始检测，在 LIMS 中列为“检测中”。
Laboratory records do not include complete data derived from all tests,
examinations and assay necessary to assure compliance with established
specifications and standards. Electronic records are used, but they do not meet
requirements to ensure that they are trustworthy, reliable and generally
equivalent to paper records.
化验室记录未包括为确保符合既定规格和标准而进行的所有测试、检查和含量中生成的完
整数据。使用了电子记录，但它们不符合确保其可信度、可靠度和等同于纸质记录的要求。
Specifically, your firm failed to assure the accuracy and reliability for data
recorded which are derived or entered using non-validated and unprotected
excel spreadsheet that are not managed and controlled to ensure unauthorized
changes do not occur per your firm’s written procedures. No Deviations were
recorded and no investigations were initiated.
具体来说，你公司未能确保所记录数据的准确度和可靠性。这些数据使用了未经验证和未
受保护的 EXCEL 表格生成或录入，未依照你公司书面程序进行管理和控制以确保其不会
未经授权即被修改。未记录偏差，亦未启动调查。
A. During the inspection, we observed two (2) different QC lab analyst
demonstrate the ability to change calculation function in the excel spreadsheet
used for finished product testing for the following:
在检查期间，我们发现 2 个不同的 QC 化验员证明可以修改成品检测所用 EXCEL 表格中的
计算功能如下：
(1) On 22 March 2018, we observed your QC Analyst use an uncontrolled
excel spreadsheet to calculate the Average, Standard Deviation, and %RSD
values for (b)(4) Tablets, Batch #(b)(4) product release testing. The use of this
spreadsheet is not mentioned in any written procedure when conducting (b)(4)
Product Release Testing. In addition, this excel spreadsheet is not saved or
printed. Therefore, the QC Reviewer is unable to verify these calculations are
correct and the correct formula was used.
2018-03-22，我们发现你们 QC 化验员使用了一个未受控的 EXCEL 表格来计算 XX 片剂
XX 批号产品放行测试中的平均值、标准偏差和%RSD 值。在所有书面程序中均未提及实施
XX 产品放行测试中使用此表格。另外，该 EXCEL 表格并未保存或打印。因此，QC 审核员
无法核查这些计算是否正确，所用公式是否正确。
(2) On 23 March 2018, we observed the QC Reviewer use an uncontrolled
excel spreadsheet to verify the potency of (b)(4) working standard during the
Analytical Worksheet review for (b)(4) Tablets, Batch #(b)(4). The use of this
spreadsheet is not mentioned in any written procedure when conducting
Analytical Report reviews.
2018-03-23，我们发现该 QC 审核人员在审核 XX 片剂 XX 批号的分析工作表审核中使用
了未受控的 EXCEL 表格来核查 XX 工作标准的效价。在所有书面程序中均未提及在执行分
析报告审核时使用此表格。
B. On 19 March 2018, we observed your QC Manager’s use an excel
spreadsheet to track quality functions, such as stability samples. This document is
not maintained through document control and there is no protection from data
manipulation,overwriting, erasing of data, or audit trails.
2018-03-19，我们发现你们 QC 经理使用了一份 EXCEL 表格追踪质量函数，例如稳定性
样品。此文件并未通过文件控制进行维护，亦无数据篡改、改写、数据擦除或审核追踪保护。
C. On 19 March 2018, during the inspection, we observed two (2) (b)(4)
employees use an uncontrolled spreadsheet to calculate due dates used
during the manufacturing and packaging of drug products.
2018-03-19，在检查期间，我们发现 2 个 XX 员工使用了未受控表格来计算药品生产和
包装中所用的有效期。
(1) For example, but not limited to, the (b)(4) stage is to be completed
within (b)(4) initiating the compressed tablet stage. However, the dates used
to calculate these timeframes has not been validated. In addition, this
spreadsheet was no password protected.
例子包括但不限于，XX 步骤是在压片开始之后 XX 时间内完成。但是用于计算这些时间的
日期并未经过验证。此外这些表格亦无密码保护。
Established laboratory control mechanisms are not documented at the time of
performance.
实施既定的化验室控制机制时未记录。
A. During our inspection of the QC laboratory on 19 March 2018, we
observed your QC Analyst entering data electronically into an excel
spreadsheet, in the absence of raw data. This same data was also entered into the
9M Stability Study Logbook for (b)(4) Tablets (b)(4)mg, Batch #(b)(4),
manufactured April 2017 (2months late).
在我们对 QC 检查期间，2018-03-19，我们发现你们 QC 化验员将电子数据录入到一个
EXCEL 表格中，而没有原始数据。该相同的数据亦被录入生产日期为 2017 年 4 月的 XX 片
剂 XX 批号的 9 个月稳定性研究登记本（延迟 2 个月）。
B. On 23 March 2018, we observed a QC Executive reviewing an OOS/OOT
investigation for(b)(4) mg Tablets, Batch #(b)(4) where the stability and
scoring study were OOT. The employee had a pen for signing for the review,
but no checklist,paper, or workstation for recording errors. In the event of an
error the employee reported, they would notify the Section Head and Analyst, but
not document it.
2018-03-23，我们发现一位 QC 经理正审核一份 XX 片剂 XX 批号的 OOS/OOT 调查，该
稳定性和评估分研究为 OOT。该员工有一支钢笔用于审核签字，但并没有检查清单、纸或
工作站来记录错误。如果员工要报告错误，他就通知给分区领导和化验员，但并不记录。
C. On 23 March 2018, we observed an Analytical Worksheet for Raw
Materials for (b)(4), Batch #(b)(4), did not contain any data for the UV
conducted on 13 March 2018. The QC Analyst that conducted this analysis
stated he did not document these recordings on the Analytical Worksheet
because his data packet was removed by other Analysts without his knowledge.
2018-03-23，我们发现一个 XX 产品 XX 批号原料的分析记录，其中并无 2018-03-13 所
进行的 UV 检测数据。执行此检测的 QC 化验员声称他并未将这些记录在分析记录上，因
为他的数据包被别的化验员清除了，但他不知道。
D. On 22 March 2018, we observed a manufacturing employee entering
tablets weights non-contemporaneously during the manufacturing of (b)(4)
tablets USP (b)(4)mg, Batch # (b)(4) in the (b)(4) Block building.
2018-03-22，我们发现一位生产员工在 XX 车间生产 XX 片剂 USP 规格 XX 批号时不同步
地录入片剂重量。
Equipment and utensils are not (cleaned) at appropriate intervals to prevent that
would alter the safety, identity, strength,quality or purity of the drug product.
（译者注：cleaned 一词原文并无，明显缺失，依上下文加入）
设备和工器具没有恰当的（清洁）周期来防止改变药品的安全性、鉴别、剂量、质量或纯度。
Specifically, your QC Analyst failed to appropriately clean glassware used in assay
testing for (b)(4), Batch #(b)(4) and Batch #(b)(4). On 24 March 2018, we observed
your QC Analyst use the same (b)(4) on these two batches of (b)(4), without
cleaning. According to your Assistant General Manager QC, glassware is to be
cleaned (b)(4) batch in accordance to your firm’s written procedure, QC/QC/139,
“Cleaning of Laboratory Glassware”. In addition, your firm has not conducted a
cleaning validation for your laboratory equipment, which is non-dedicated.
具体来说，你们 QC 化验员未能恰当清洁 XX 产品 XX 批号和 XX 批号含量检测所用玻璃仪
器。2018-03-24，我们发现你们 QC 化验员使用了相同的 XX 检测 2 批 XX 而未进行清洁。
据你们 QC 副总所言，玻璃仪器依据你公司书面程序 QC/QC/139“化验室玻璃仪器清
洁”应进行清洁。另外，你公司并未对你化验室设备进行清洁验证，该设备并非专用。
2. 印度 Alembic Pharmaceuticals 20180410

OBSERVATION1 缺陷 1
There is a failure to thoroughly review any unexplained discrepancy and 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.
未能彻底审核所有非预期差异以及已销售和未销售成品批次及其组份不符合其标准的情况。
A. Specifically,your firm failed to take appropriate corrective and
preventative actions toreduce the high number of invalidations in a timely
manner when Out ofSpecification (OOS) results were observed as evidence
by the following: In2016, your firm reported 140 OOS results (raw material, in-
process and finishedproducts) for U.S. marketed drug products for Dissolution,
Assay, (b)(4),Content Uniformity and Related Substances. Your Quality Control
Unit (QCU)invalidated 131 of the 140 OOS results (94% invalidation rate) due to
analysterror (i.e. sample preparation), glass contamination, etc. in 2017, your
firmreported 129 OOS results and your QCU invalidated 117 (91% invalidation
rate). In2018 (January-March), your firm reported 30 OOS results and your
QCUinvalidated 19 (63% invalidation rate).
具体来说，你公司未能在发现 OOS 时采取适当的纠正和预防措施及时减少较高的 OOS
无效情形。证据如下：2016 年，公司报告美国销售药品 140 起 OOS 结果（原料、中间体
和成品），有溶出度、含量、XX、含量均一性和有关物质。你们质量部门（QCU）因化验员
错误（样品制备）、玻璃仪器污染等宣布其中 131 起 OOS 无效。2017 年，公司报告 126
起 OOS 结果，你们 QCU 宣布其中 117 起 OOS 无效（91%无效率）。2018 年（1-3 月）
公司报告 30 起 OOS 结果，你们 QCU 宣布其中 19 起无效（63%无效率）。
The followingexamples include, but are not limited to, OOS results that were
invalidated byyour firm’s QCU without scientific rationale and supporting
documentation:
以下例子包括但不限于你们公司 QCU 无科学合理性和支持性文件记录即宣布无效的 OOS
结果：
a. OOS#ALP/QA/OOS-8042: Opened on February 2, 2018 for high assay,
(b)(4)%(specification: (b)(4)%) for (b)(4) Tablets USP (b)(4)mg (stage: (b)(4)
tablets) batch #(b)(4) (mfg:12/17, exp: (b)(4)). Your firm attributed the
rootcause as a sample preparation error which is not supported since there-
injection, re-filled and re-diluted sample confirmed the high OOS result for assay.
In addition, your firm failed to evaluate the other (b)(4) Tablets USP (b)(4)mg
batch #(b)(4) that was prepared by the same analyst that your firm stated
conducted the sample preparation inadequately.
OOS#ALP/QA/OOS-8042：2018 年 2 月 2 日报告含量过高，USP 片剂 XXmg，批号
XX，生产日期 2017 年 12 月，有效期 XX。你公司将根本原因归结为样品制备错误，但并
无法支持该原因，因为重新进样、重新灌装和重新稀释的样品均确认了高含量的 OOS 结果
另外，你公司未评估该片剂由你们所称未充分制备好样品的同一化验员所制备样品的其它
批次。
b. OOS#ALP/QA/OOS-8027: Open on January 24, 2018 for an OOS
individual impurityresult of (b)(4)% (specification: NMT(b)(4)%) for the
Related Substances Testfor (b)(4) Capsules USP (b)(4)mg (stage: 6 month CRT
Stability) batch # (b)(4)(mfg.: 04/17, exp. (b)(4)). Your firm attributed the root
cause as glassware contamination (volumetric flask), stopper, or mortar and
pestle which is notsupported as glass contamination cannot be considered for
the failing results of all samples: T1 ((b)(4)%), T2((b)(4)%), re-injection ((b)(4)%),
re-filled ((b)(4)%) and re-centrifuged ((b)(4)%). Other root causes such as
contamination of the sample during collection or (b)(4) preparation was not
investigated.
OOS#ALP/QA/OOS-8027：2018 年 1 月 24 日报告 OOS，XX 胶囊 USP 规格 6 个月
CRT 稳定性（生产日期 2017 年 4 月，有效期 XX）有关物质检测单杂结果超标。你公司将
根本原因归结于玻璃仪器污染（容量瓶）、塞子或研钵和研杵，但并无法支持该原因，因
为不可能所有样品的不合格结果都是来自于玻璃仪器污染：T1（XX%）、T2（XX%）、重
新进样（XX%）、重新灌装（XX%）和重新离心（XX%）。未调查其它根本原因如样品在
采集过程或 XX 制备中被污染。
c. OOS #ALP/QA/OOS-8058:Open on February 22, 2018 for low assay, (b)
(4)% (specification: (b)(4) -(b)(4)%)for the (b)(4) for (b)(4) Tablets USP (b)(4)mg
(stage: (b)(4)) batch # (b)(4)(mfg.: 01/2018, exp. (b)(4)). Your firm attributed the
root cause as a sample preparation error (weighing of (b)(4) which resulted in
lower % assay). During therepeat analysis, your analyst was instructed to (b)(4)
and then weigh (thisaction deviated from the current Method: API/IT0269-00). In
addition, your firm’spreventative measure was to train analysts to verify the
physical appearance ofthe sample rather than evaluating the current method to
ensure the sample is (b)(4).
OOS#ALP/QA/OOS-8058：2018 年 2 月 22 日报告 XX 片剂 USP 规格 XXmg 含量偏低，
生产日期 2018 年 1 月，有效期 XX。你公司将根本原因归结于制品制备错误（XX 称重导
致含量低）。在重新检验过程中，你们要求化验员 XX 后再称重（该操作不同于当前的方
法 API/IT0269-00）。此外，你公司的预防措施是培训化验员核对样品的外观而不是评估
当前的方法来确保样品 XX。
d. OOS #ALP/QA/OOS-6491:Open on December 11, 2016 for high assay,
(b)(4)% (specification: (b)(4) -(b)(4)%)for validation Batch: (b)(4) Tablets USP
(b)(4)mg (stage: (b)(4) tablets) batch# (b)(4) (mfg.: 11/16, exp. (b)(4)). Your
firm attributed the root cause as adilution error (analyst wrongly used graduated
pipettes). In addition, yourfirm failed to evaluate the other (b)(4) tablets USP (b)
(4)mg batch #(b)(4) andbatch #(b)(4) that was prepared by the same analyst that
your firm statedconducted the sample preparation inadequately.
OOS#ALP/QA/OOS-6491：2016 年 12 月 1 日报告 XX 片剂 USP 规格验证批次含量过高，
生产日期 2016 年 11 月，有效期 XX。你公司将根本原因归结于稀释错误（化验员错误使
用了刻度吸管）。另外，你公司未评估其它 XX 片剂 USP 规格批号 XX 和批号 XX，该批次
亦由你公司声称未充分执行样品制备的同一化验员制备样品。
e. OOS #ALP/QA/OOS-6114:Open on April, 2016 for high assay, (b)(4)%
(specification: (b)(4) -(b)(4)%)for (b)(4) Tablets USP (b)(4)mg (stage: (b)(4)
tablets) batch # (b)(4) (mfg.: 04/16,exp. (b)(4)). Your firm attributed the root
cause as improper standard preparation, unknown error in sample preparation,
minor spillage of working standard while transferring it to a volumetric flask or air
entrapment in the detector or in mobile phase line at the time of injection. There
was noevidence of spillage by the analyst and there was no evidence of air
entrapment as the results were higher.
OOS#ALP/QA/OOS-6114：2016 年 4 月报告 OOS，XX 片剂 USP 规格含量过高，生产
日期 2016 年 4 月，有效期 XX。你公司将根本原因归结为对照品制备不当、样品制备未知
错误、工作标在转移至容量瓶时有些许洒出或进样时检测器或流动相线中有空气。然而并无
证据证明化验员洒出工作标，亦无证据证明空气进入，因为检测结果是偏高的。
B. Your firm’s Quality Unit failed to support the root cause through scientific
rational and supporting documentation for Production Deviation # APL/DC17017
during the packaging operations for (b)(4) Tablets USP (b)(4)mg batch #(b)(4)
(dated:April 16, 2017). The Deviation was initiated during in-process checks by
QA for(b)(4) failures. Your firm determined the root cause as the following:
correlation between the speed of the machine and sealing (b)(4) contribute to the
qualityof sealing, powder accumulation during longer packaging runs and
improper (b)(4) quality. Your firm failed to take appropriate corrective and
preventativeactions such as evaluating the potential requirement to change the
speed of the machine and sealing (b)(4) cycles per minute with a (b)(4) range
between (b)(4)to (b)(4) and the quality of (b)(4) received from the supplier.
你公司质量部门未能通过科学合理性和支持性文件来支持 XX 片剂 USP 规格包装操作中的
生产偏差# APL/DC17017 的根本原因（日期 2017 年 4 月 16 日）。该偏差是在 QA 对 XX
不合格进行中控检查时发起的。你公司认为根本原因如下：设备速度与密封 XX 之间的关
联对密封质量有影响，在长期包装过程中粉料累积以及 XX 质量不当。你公司并未采取适
当的纠正和预防措施，如评估改变设备速度和密封 XX 圈每分钟至 XX 范围的潜在要求，
以及评估从供应商处所接收的 XX 质量，
Employees are not given training in the particular operations they perform as part
of their function and written procedure required by current good manufacturing
practice regulations.
员工未接受作为其职能一部分而执行的特定操作和 CGMP 法规所要求的书面程序的培训。
Specifically, your firm’s SOP #ALP/QC/SOP032 (dated January 4, 2018) titled,
“Qualification of Analyst” is inadequate as Section 5.1.19 states, “re-
qualification of an analyst is to be done if (b)(4) consecutive OOS results are
observed due to human error”; therefore, your Quality Control Analysts’ are
not being properly qualified as evidenced by the following example: Analyst (b)
(4) was qualified for the Assay Analysis of (b)(4) Capsules (b)(4)mg (batch #(b)(4)
in (b)(4) on May 15, 2017. On June 10, 2017, analyst (b)(4) conducted the Assay
Analysis of (b)(4) Capsules (b)(4)mg (batch #(b)(4)) intended for the Canadian
market which resulted in an Out of Specification (OOS) result for low Assay
(invalidated due to analyst error). On November 25,2017, analyst (b)(4) conducted
the Assay Analysis of (b)(4) Tablets (b)(4)mg (batch #(b)(4)) intended for the U.S.
market which resulted in an OOS resultfor low Assay (invalidated due to analyst
error). On February 2, 2018, analyst (b)(4) conducted the Assay Analysis of (b)(4)
Tablets (b)(4)mg (batch #(b)(4)) intended for the U.S. market which resulted in an
OOS result for high Assay (invalidated due to analyst error).
具体来说，你公司 SOP #ALP/QC/SOP032（日期 2018 年 1 月 4 日）名为“化验员资格
认定”是不充分的。在其第 5.1.19 部分中有写“如果发现人为错误导致 XX 次连续 OOS 结
果，则该化验员应重新进行资格认定”；但你们 QC 化验员并未进行适当的资格认定，以
下例子即为证明：化验员 XX 被认定有资格进行 XX 胶囊 XXmg 的含量分析（批号
XX，2017 年 5 月 15 日）。2017 年 6 月 10 日，化验员 XX 执行了到加拿大市场的 XX 胶
囊 XXmg（批号 XX）的含量检测，结果为 OOS，含量偏低（因化验员错误宣布结果无
效）。2017 年 11 月 25 日，化验员 XX 执行美国市场的 XX 片剂的含量分析，结果为
OOS，含量偏低（因化验员错误宣布结果无效）。2018 年 2 月 2 日，化验员 XX 执行美国
市场的 XX 片剂的含量分析，结果为 OOS，含量偏高（因化验员错误宣布结果无效）
Analyst (b)(4) was observed conducting the Assay Analysis and Content
Uniformity Analysis for multiple U.S. marketed drug products (i.e, (b)(4) Tablets,
(b)(4) Tablets, (b)(4) Tablets and (b)(4) Capsules) for which she was not properly
trained on the test methods.
化验员 XX 被发现正在检测多个美国市场药品的含量和含量均一性（3 个片剂 1 个胶囊），
但其未接受这些检测方法的培训。
In addition, your firm failed to take appropriate corrective and preventative
actions to re-qualify the Analyst in a timely manner and instead allowed her to
conduct a total of (b)(4) analyses for assay and content uniformity involving (b)(4)
batches. She was re-qualified on March9, 2018.
此外，你公司未能采取适当的纠正与预防措施及时对化验员进行资格认定，而是允许她执
行总共 XX 次含量和含量均一性检测，涉及 XX 个批次。该化验员于 2018 年 3 月 9 日重新
进行了资格认定。

Laboratory controls do not include the establishment of scientifically sound and
appropriate test procedures designed to assure thatdrug products conform to
appropriate standards of identify, strength, quality and purity.
化验室控制未包括科学合理和恰当的检测程序文件，该程序是设计用以确保药品符合适当
的鉴别、剂量、质量和纯度标准。
The work conducted to validate the cleaning process of non-dedicated
manufacturing equipment (e.g. flexible hoses and (b)(4) sensor tip) located at
Drug Product Plant under validation report (BM/PDP/CVP/P001-01) was found
inadequate.
验证报告(BM/PDP/CVP/P001-01)中为验证非制剂车间专用生产设备（例如，可拆卸软
管和 XX 探头尖）的清洁工艺而执行的工作是不充分的。
Specifically, the validation studies conducted to justify the cleaning acceptance
criteria for (b)(4) with (b)(4) drug product failed to include the recovery studies
for the different surface material(e.g. (b)(4) and (b)(4) found in the manufacturing
train of (b)(4) drug product. therefore, there is no assurance the results obtained
for the collected samples during subject validation activities are accurate.
具体来说，所实施的为论证 XX 与 XX 药品清洁可接受标准的验证研究中未包括不同表面
材料（例如，XX 药品生产链上发现的 XX 和 XX）上的回收率研究。因此无法确保在验证
期间所采取样品而获得的结果是准确。
4. 印度 Cipla Limited 20180420

Testing programs are not adequately designed to assess the stability
characteristics of drug products.
测试计划设计不充分，无法评估药品的稳定性特性。
Specifically, test schedules established by stability protocols do not characterize
the degradation of products over their actual shelf-lives. Stability schedules are
based on the date of sample incubation rather than the date of manufacturing.
Section 2.6.2.6 of SOP 1035-L-0100, “STABILITYSTUDIES (LIMS)” (rev. 4.0,
eff.12JAN2018), states that “shelf life intervals and intervals after expiry are to be
calculated from the date of manufacturing and not the date of incubation”.
However, QC management stated that interim stability time points established by
the date of sample incubation per Section2.1.18: “Stability study should be
started in LIMS on the date of incubation”.
具体来说，稳定性研究方案中设定的检测计划并未确定产品在其实际货架期内的降解性。
稳定性计划是基于取样放置的日期计算的，而不是生产日期。SOP 1035-L-010 “稳定性
研究（LIMS）”（版本 4.0，生效日期 2018-1-12）0 第 2.6.2.6 部分中说“货架期和有
效期后的时间间隔应采用生产日期计算而不是放置在稳定性研究条件下的时间计算”。但
是，QC 管理人员说临时稳定性时间点是依据该 SOP 第 2.1.18 部分“稳定性研究在 LIMS
中应以样品放置时间开始计算”由样品放置时间确定的。
For example, Out-Of-Specification LC/OOS/PA/12/15/08 was initiated for the
failure of (b)(4)mg/ml solution Batch (b)(4) for high organic impurities, namely
Impurities (b)(4). The 21M long-termstability of Batch (b)(4) failed on (b)(4), as
anticipated by the extrapolation of impurity data from previous stability time
points. No apparent root cause was identified during laboratory investigation and
the OOS results were confirmed.
例如，编号为 LC/OOS/PA/12/15/08 的 OOS 为 XX 溶液批号 XX 有机杂质过高，即杂质
XX。XX 批号 21 个月长稳检测 XX 不合格，不符合之前稳定性杂质数据外推预测。在化验室
调查中未发现明显根本原因，OOS 结果被确认。
Batch (b)(4) was dispensed on 14JAN2014,compounded on 17JAN2014, sampled
for stability studies on 22JAN2014, tested,and finally released by QC on
05MAR2014. The stability samples of Batch (b)(4) were not charged into long-
term stability conditions until (b)(4).
XX 批号于 2014-1-14 分料，2014-1-17 配制，2014-1-22 取稳定性样品，2014-3-5 由
QC 检测并最终放行。XX 批的稳定性样品直到 XX 日才放入长期稳定性考察条件下。
As a result of a related investigation for the 12M long-term stability failure of (b)
(4)mg/ml (b)(4) solution Batch (b)(4) for high Impurity. LC/OOS/PA/03/15/05
(initiated March 2015), additional monthly time points were to be evaluated for
Batch (b)(4) from 17M thru end of shelf-lfe. The 21M stability sample was not
analyzed until (b)(4),coincidental with its (b)(4)M expiry, rather than the batch’s
actual 21M from date manufacture, September 2015. Since interim stability time
points are based on the date of sample incubation rather than the batch
manufacturing date, the 21M stability failure of Batch (b)(4) was not known until
(b)(4) months after the batch’s actual 21M on market.
XX 溶液批号 XX 的长期稳定性试验中在 12 个月时间点杂质过高，对应 OOS 编号
LC/OOS/PA/03/15/05（2015 年 3 月启动），相关调查确定要对 XX 批号自 17 个月开始
至货架期结束要增加月度检测时间点。21 个月的稳定性样品直到 XX 时间才检测，正好与
其 XX 个月的有效期相同，而不是该批号自生产日起计的实际 21 个月时间即 2015 年 9 月。
由于临时稳定性时间点是基于样品放置时间而不是批生产时间，21 个月的稳定性失败直
到该批次上市的第 21 个月之后，即 XX 个月才知道。
Scientifically sound and appropriate laboratory control mechanisms are not
established to assure that in-process materials or drug products conform to
appropriate standards of identity,strength, quality and purity.
未建立科学合理和恰当的化验室控制机制以确保中间体或成品符合恰当的鉴别、剂量、质量
和纯度标准。
Specifically,post-fertility testing (growth promotion testing) is performed
independentlyfor samples from the (b)(4) of media fills and documented on
Format1035-MM-011-INH/F2. The current version of SOP 1035-MM-011-INH,
“MICROBIOLOGICALPROCEDURES FOR MEDIA FILL” (rev. 3.0, eff. 30SEP2016),
consists of Annexure1035-MM-011-INH/A2, the specimen (or master) copy of
Form 1035-MM-011-INH/F2. Thiscurrent version of 1035-MM-011-INH/F2
consists of no requirement forverification of growth/no growth observed.
Observation of the growth promotionsamples is performed and documented by
a single analyst only with no direct,secondary verification. Lab Quality Assurance
verifies the informationdocumented by Quality Control only after completion of
the test. For example,
具体来说，从 XX 培养基灌装中取样做了独立的促进生长试验，记录在表格 1035-MM-
011-INH/F2 中。当前版本的 SOP 1035-MM-011-INH“培养基灌装微生物程序”（版本
号 3.0 生效日期 2016-9-30）中有一个附录 1035-MM-011-INH/A2，表格 1035-MM-
011-INH/F2 的样本（或母本）副件。当前这个版本的 1035-MM-011-INH/F2 不要求核
查对生长/无生长的观察。只有一名化验员观察和记录了促生长样品，没有第二人直接核查
化验室 QA 只是在检测完成之后对 QC 所记录的信息进行核对。例如：
A. There isno documentation of a 2nd analyst or supervisor verifying
theturbidity of (b)(4) post-fertility test samples from (b)(4) Line (b)(4) MediaFill
Batch (b)(4) as inspected on 27 and 29OCT2016.
没有文件记录 2016-10-27 和 2016-10-29 第 2 个化验员或主管核对 XX 生产线 XX 培养
基灌装批号 XX 促生长测试样品浊度的确认
B. There isno documentation of a 2nd microbiologist or supervisor verifying
theturbidity of (b)(4) post-fertility test samples from (b)(4) Line (b)(4) MediaFill
Batch (b)(4) as inspected on 22 and 25SEP2017.
没有文件记录 2017-09-25 和 2017-09-25 第 2 个微生物化验员或主管核对 XX 生产线 XX
培养基灌装批号 XX 促生长测试样品浊度的确认

Appropriate controls are not exercised over computer or related systems to
assure that change in master production and control records or other records are
instituted only by authorized personnel.
对计算机或相关系统未执行适当控制以确保主生产和检验记录或其它记录的变更只由经授
权的人员操作。
A. Your firm has a total of (b)(4) HPLCs and (b)(4) UPLCs used to analyze raw
material,finished product, and related substances for products marketed and
distributed to the US. The HPLCs and UPLCs use either Empower 3 or EZ CHROM
ELITE, while have audit trail capabilities. However, your firm could not provide
documentation these audit trails have been electronically reviewed by quality
personnel.
你公司共有 XX 台 HPLC 和 XX 台 UPLC 用于分析原料、成品和已在美国销售上市产品的有
关物质。HPLC 和 UPLC 要么使用了 EMPOWER3，要么用了 EZCHROM ELITE 系统，具
有审计追踪功能。但是，你们公司并未提交文件证明此审计追踪由质量人员进行了电子审
核。
B. Your firm’s Manager of Quality Assurance and Deputy Manager of QC
verified your firm did not conduct electronic data review for any analysis
performed in the QC Formulations Laboratory prior to August 2017.
你公司的 QA 经理和 QC 副经理证明你们公司在 2017 年 8 月前并未对任何 QC 制剂化验
室所做的分析进行电子数据审核。
Procedures for sampling of raw materials were not followed.
未遵守原料取样程序。
Specifically, on 05 February 2018, Iobserved the raw material, (b)(4) (Batch #(b)(4)
did not contain the appropriate number of sampled containers as written in your
firm’s written procedures forraw material sampling (SOP/CQO/3024).
具体来说，2018 年 2 月 05 日，我发现 XX 原料 XX 批号未按你公司书面程序“原料取样
SOP/CQO/3024”从适当数量容器中取样。
6. 瑞士 Akorn AG 20180503
The accuracy, sensitivity and reproducibility of test methods have not been
established and documented.
未建立并记录检验方法的准确度、灵敏度和重现性。
Specifically, the analytical test methods are not adequately transferred from the
validating laboratories to this firm to assure that drug product meet appropriate
standards of identity, strength,quality, and purity.
具体来说，检验方法从验证化验室转移至该公司时不充分，无法确保药品符合适当的鉴别、
剂量、质量和纯度标准。
The method transfers are incomplete because forced degradation studies were
not performed by the firm’s laboratory (receiving laboratory) to establish the
specificity of the method under actual conditions of use, accounting for
interlaboratory variances such as variance in detectors, instrumentation, and
analytical technique. These methods are used asstability-indicating procedures
and cannot be considered validated without sufficient testing to ensure that the
analyte of interest can be adequately resolved from impurities/degradants
formed throughout the lifetime of the product. These methods are used for
testing and releasing of in-process and finished products, e.g. (b)(4) gel, (b)(4)
gel.
方法转移不完整，因为该公司化验室（接收化验室）未做强降解研究以建立方法在实际使
用条件下的专属性，同时考虑化验室之间的差异如检测器、仪器和分析技术差异。这些方法
用作稳定性指示性方法，如果没有科学测试来确保受检物可以充分分辨产品生命周期中形
成的杂质/降解物，则不能认为其是经过验证的。这些方法用于中间体和成品的检测放行，
例如，XX 胶，XX 胶。
The written stability testing program isnot followed.
未执行书面和稳定性检测计划。
Specifically, the stability study protocol requirements are not fully followed. For
example the stability study for (b)(4)% is missing examination of samples for
“Minimum Fill Average, USP” at 3, 6, 9, and 18 months.
具体来说，未完全遵守稳定性试验方案要求。例如，XX%的稳定性研究在 3、6、9 和 18 个
月未检查样品“最小灌装平均值，USP”项目。
The accuracy, sensitivity, specificity and reproducibility of test methods have not
been established and documented.
未建立和记录检验方法的准确性、灵敏度、专属性和再现性。
Your firm’s QC laboratory has not validated analytical methods used in the
determination of active residue from equipment’s used for processing of the
following products:
你公司的 QC 未验证用于以下产品生产所用设备中活性残留检测的分析方法：
 (b)(4)Capsules USP (b)(4) mg & (b)(4) mg
 (b)(4)Tablets USP (b)(4) mg, (b)(4) mg & (b)(4) mg
 (b)(4)Tablets
 (b)(4)Tablets
 (b)(4)Capsules USP (b)(4) mg, and
 (b)(4)Tablets USP (b)(4) mg & (b)(4) mg
Your production unit has standalone non-dedicated manufacturing equipment
that in absences of using a non-validated analytical test method (swab analysis by
UPLC) for determining Type B equipment cleaning effectiveness creates a
potential for carryover of active residues remained on the equipment leading to
cross-contamination of the products manufactured using the same equipment.
你们生产部门有一台单机非专用生产设备，使用未经验证的分析方法（UPLC 擦拭样分
析）检测 B 类设备清洁效果，可能会使得设备中的活性残留带入使用相同设备的产品产生
交叉污染。
Your firm in justification stated that the firm was considering Assay by HPLC
method validation in substitution for equipment cleaning method by UPLC,
whereas, both the methods and their sample and standard preparations are
completely different, for example,
你公司在论证中说公司认为 HPLC 含量方法验证可替代 UPLC 设备清洁方法，但是，2 个
方法及其样品和标准制备是完全不同的，例如：
Assay by HPLC test method has tablets and/or capsules for the sample solution
preparation whereas cleaning testing method has swabbing stick(s) for the
sample solution preparation. The concentration of sample and standard solution
varies for both the test solutions.
HPLC 含量测试采用片剂和/或胶囊作为样品制备供试液，而清洁检测方法则是使用擦拭棉
签作为样品制备供试液。2 种样品和标准液的浓度也不一样。
appropriate sampling plans designed to assure that conform to appropriate
standards of identity, strength, quality and purity.
化验室控制未包括科学合理和适当的取样计划，设计用以确保符合适当的鉴别、剂量、质量
和纯度标准。
Your SOP CM/QA034 “Sampling Methodology” for (b)(4) is deficient in section
5.5 (b)(4) sample of (b)(4), subsection 5.5.2 indicates “The (b)(4) sample shall be
collected as (b)(4) gram unless and otherwise mentioned in the sampling (b)
(4)/process validation/ batch production record. (b)(4) bags/Glass Bottles with
stoppers shall be used for collecting the (b)(4) samples”. For example,
你们的 SOP CM/QA034 XX“取样方法学”的 5.5XX 部分 XX 的样品中 5.5.2 部分说“XX
样品就采集 XX 克，取样 XX/工艺验证/批生产记录另有要求者除外。应使用 XX 袋/具塞玻
璃瓶采集 XX 样品”是有缺陷的。例如：
 There is no mention of the sampling amount collected during unloading of
the (b)(4) from (b)(4) locations. IPQA employee responsible for sample
collection was unable to explain the sampling amount collected from each
location. Additionally, there is no weighting tape indicating the weight of
sample collected each time from different locations and the gross weight
to make it to (b)(4) gram.
 未提及在 XX 从 XX 位置放料时要采集的样品数量。负责样品采集的 IPQA 员工无法
解释从每个位置所采集的样品数量。另外，并没有重量条显示每次从不同位置所采
集的样品重量以及毛重积累至 XX 克。
 The sampling instructions mentioned in your process validation and batch
production records are deficient as there is mention of the glass bottle size
and (b)(4) instructions for the samples collected from (b)(4) locations.
 你们工艺验证和批生产记录中提到的取样指令是有缺陷的，因为其中提到玻璃瓶的
大小和从 XX 位置采集样品的 XX 指令。
SOPCM/QA034, section 5.5 is used for (b)(4) sampling of the following
products:
SOP CM/QA034 第 5.5 部分用于以下产品的 XX 取样：
 (b)(4)Tablets USP (b)(4) mg & (b)(4) mg, and
 (b)(4)Tablets USP (b)(4) mg
未能彻底回顾所有已销售和未销售批次中未经解释的差异。
 Your firm’s QC unit did not investigate in to the issues of API peak seen in
the blank injections during method validation for related substances by
HPLC method. Additionally, system suitability (precision) standard
injections((b)(4) ppm) peaks were not integrated (b)(4). The reintegration of
these peaks changed the area of standards by over (b)(4) i.e.30%.
 你公司的 QC 部门未调查 HPLC 有关物质方法验证期间空白样中看到的 API 峰问题。
另外，系统适用性（精密度）标准进样（XXppm）峰未积分 XX。这些峰重新积分
时改变的标准峰面积超过 XX 即 30%。
 In the past two years, your firm has initiated approximately sixteen (16)
Incident reports related to power outages in your QC laboratories which
occurred during testing of samples on HPLC and GC equipment. During
our review of the seincident reports, it was observed that
“chromatographers” who processes data and Analytical Quality
Assurance (AQA) reviewers who review processed data donot have the user
privilege “Verify Incomplete Data in Raw Data Files” in Empower 3. For
this reason, during the review of two such incidents during dissolution
testing for finished products, the investigation by your firm determined
that the interrupted sample injections were processed by
chromatographers and showed that the sample did not run. However,
during our review of electronic data in the QC laboratory, it was observed
that QC manager and the system administration have the user privilege to
“Verify Incomplete Data in Raw Data Files”. Subsequently, we requested
your manager to verify the incomplete data and reprocess the injection for
both sample sets (two different incidents) and discovered that the injected
samples did in fact run, the first incident with approximately (b)(4) minutes
out of (b)(4) minutes, and the second with approximately (b)(4) minutes out
of (b)(4) minutes, with both injections resulting in elution of the principal
peak. After reprocessing the incomplete data, your firm performed rate of
release calculations on the unreported processed injections, which
appeared to be within specification. However, this discrepancy in your
firm’s ability to review and investigate all electronic raw data is a
significant gap in your Data Integrity procedures and practices reviewed
during the current inspection.
 在过去 2 年中，你们公司启动了约 16 个事件报告，是与你们 QC 化验室在 HPLC
和 GCP 设备上样品检测期间的电力中断有关。在我们对这些事件报告的审核中，我
们发现处理数据的“色谱操作员”和审核处理后的数据的分析质量保证（AQA）
审核员不具备 EMPOWER3 系统内“核查原始数据文件中不完整数据”的用户权限。
由此，在成品溶出度检测的 2 次此类事件审核中，你们公司的调查认为被中断的进
样是由色谱操作员处理的，显示出样品并未运行。但是，在我们对 QC 的电子数据
进行审核时，我们发现 QC 经理和系统管理员具备“核查原始数据文件中不完整数
据”的用户权限。随后，我们要求你们经理核查了不完整数据，重新处理了 2 个样
品序列（2 个不同的事件）中的进样数据，发现所进样品事实上有运行过，第一次
事件中约运行了 XX 分钟（方法时长总 XX 分钟），第二次事件中约运行了 XX 分钟
（方法时长总 XX 分钟），2 次进样中均有主峰流出。在重新处理了不完整数据后，
你们公司对未报告的进样处理结果进行了放行计算，结果显示是质量标准范围内。
但是，在你们公司审核和调查所有电子原始数据的能力分歧使得你们数据完整性程
序的与当前检查中所审核的做法有重大差异。

The accuracy, sensitivity, specificity and reproducibility of test methods have not been
established and documented.
未建立并记录检验方法的准确性、灵敏度、专属性和再现性。
a) Analytical methods used to ensure the quality of drug products are not validated
prior to their transfer from your firm’s (b)(4) facility. For example, the following analytical
procedures were transferred to the Quality Control laboratory priorto completing method
validation:
用以确保药品质量的分析方法在从你们公司的 XX 场所转移过来之前未经验证。例如，以下
分析方法在方法验证完成之前被转移到了 QC 实验室：
Product Strength (b)(4) Analytical Test Method Date of Date of Method
name 剂量 No. 分析方法 Method Transfer from (b)(4)
品名 Validation 方 to Nashik
法验证日期方法转移从 XX 转移
至 Nashik 的日期
(b)(4) (b)(4) (b)(4) MVR-(b)(4)-BAY-006/00 2010-07-19 2010-07-29
tablets MVR-(b)(4)-AY-015/00 2012-11-21
USP MVR-(b)(4)-DS-014/00 2012-11-21
MVR-(b)(4)-RES-012/00 2012-11-12
MVR-(b)(4)-RS-016100 2012-11-30
(b)(4) (b)(4) (b)(4) MVR-(b)(4)-AY-001/00 2009-01-22 2007-11-05
tablets MVR-(b)(4)-DS-003/00 2009-04-09
MVR-(b)(4)-RS-002/00 2008-02-12
(b)(4) (b)(4) (b)(4) MVR-(b)(4)-DS-002/00 2015-05-11 2012-04-19
tablets MVR-(b)(4)- AY-003/00 2015-05-11 2012-05-23
MVR-(b)(4)-BAY-006/00 2015-06-11
Consistent with SOP GADS016-10 (“procedure for Transfer of Analytical methods”) and
examples above, your firm’s Quality Unit transferred methods prior to their validations for
the majority of recently submitted and approved (b)(4) submitted to Agency.
与 SOP GADS016-10（分析方法转移程序）和上述例子一致，你们公司的质量部门在最
近提交给 FDA 以及提交并获得批准的大多数药品中均在方法验证之前将方法进行了转移。
Furthermore, in multiple instances, your firm’s Quality Unit approved and undertook
analysis (i.e.,GMP testing) of drug products at the Nashik manufacturing facility prior to
ensuring the validity of the methods. Some examples are below. Your firm’s Head of
Global OSD Scientific Affairs, Product Development stated that it is common practice to
initiate testing of drug products prior to validation.
更有甚者，在多个案例中，你公司的质量部门在确保方法有效性之前就批准并在 Nashik
生产场所进行了药品分析。以下是一些例子。你公司的全球 OSD 科学事务/产品开发负责人
说在验证之前即开始对药品进行检测是常见做法。
Product name (b)(4) Analytical Test Method 分 Validation 验证 Date of First GMP
品名 No. 析方法 Testing 首次 GMP 检
测日期
(b)(4) capsules (b)(4) MTW-(b)(4)-004 2011-01-*14 2010-10-28
USP
(b)(4) capsules (b)(4) MVR-(b)(4)-AY-004/00 2014-03-25 2013-08-29
(b)(4) tablets (b)(4) MVR-(b)(4)-DS-002/01 2015-05-11 2014-09-25
b) I observed anomalies in the dating of various method transfers and method

validations as follows:
我发现在不同方法转移和方法验证中日期签署方面有以下异常情况：
I. The testing protocol to transfer the analytical method of (b)(4) capsules is dated
June of 2012 (document FPP (b)(4) 106R-00) with a method transfer date completed in
September 2012. However, the testing protocol to complete the analytical method
validation is dated February of 2013 (MVP-(b)(4)-AY-003/00) with a method validation
date of March 2014. According to these dates, the method was transferred from the (b)
(4) facility to the Nashik manufacturing facility prior to its validation or even validation
testing protocol. Stability testing submitted to Agency was performed prior to method
validation. Additionally, the submission batch (b)(4) was manufactured prior to validation.
XX 胶囊分析方法转移的检测方案签署日期为 2012 年 6 月（文件 FPP XX106R-00），而
方法转移完成日期为 2012 年 9 月。但是，完成分析方法验证的检测方案签署日期为 2013
年 2 月（MVP-XX-AY-003/00），而方法验证日期为 2014 年 3 月。根据这些日期，方法在
其验证之前即从 XX 场所转移至 Nashik 生产场所，甚至是在验证方案批准之前。提交给
FDA 的稳定性测试在是方法验证之前执行的。另外，申报批次 XX 在是验证之前生产的。
Additional, similar examples of such anomalous dating were observed with the testing
procedure for(b)(4) Tablets and (b)(4) Tablets.
此外，这种类似的反常批准日期例子在 XX 片剂和 XX 片剂的分析方法中也有看到。
II. Yourfirm’s Quality Unit prepared and approved method transfer protocols prior
tothe generation of approved STPs for the following drug products:
你公司的质量部门对以下药品在批准 STP 之前制订并批准了方法转移方法。
(b)(4) Tablets 片剂
(b)(4) Capsules USP 胶囊 USP
(b)(4) Tablets USP 片剂 USP
(b)(4) Tablets USP 片剂 USP
this practice is inconsistent with the prospective method validation approach described
by your firm in “Process Flow for Method Validation and Method Transfer”, which states
method validation precedes method transfer.
该种做法与你公司在“方法验证和方法转移流程图”中所述的检验方法预验证是不一致的，
其中要求在方法转移之前执行方法验证。
c) On September 7, 2016, your firm’s Head of Quality API & OSD – India stated that no
testing is performed at the (b)(4) located in (b)(4) once validation is completed. Similarly,
your firm’s Head of Regulatory Science OSD stated that the (b)(4) facility is solely for
method validation.
2016 年 9 月 7 日，你们公司的印度 API&OSD 质量负责人声称在验证完成之后在 XX 地的
XX 并未进行过检测。类似地，你们公司的法规科学 OSD 负责人说 XX 场所仅用作方法验
证。
However, a review of test injections performed on the (b)(4) Laboratory HPLCs
through the companywide server at Nashik revealed numerous instances of drug
product testing for the following products (the pages designation indicates the
number of pages obtained upon exporting injection history from the Empower 2
software –approximately 10 injections per page):
但是，对于在 Nashik XX 化验室 HPLC 公司服务器执行的检测进样情况审核发现有以下
的大量药品检测案例（页码表示 Empower2 软件中调出的进样历史的页数---每页约有
10 针）。
Product Pages
(b)(4) and (b)(4) tablets (b)(4)
(b)(4) tablets
(b)(4) and (b)(4) tablets
(b)(4) capsules
(b)(4) capsules
(b)(4)
(b)(4) tablets
(b)(4) tablets
The examples cited above are for the time period of July through August of 2016.
There is no documentation to support that any of the test methods used to analyze
these products are currently being revalidated (with the exception of (b)(4) and (b)(4)
Tablets), and no evidence was provided for drug product testing of these products at
the (b)(4) facility continuing despite a completed validation.
上述所引例子是 2016 年 7-8 月时间段的情况。没有文件记录支持用于分析这些产品的
任一检验方法当时经过了再验证（除 XX 和 XX 片剂以外），亦无证据被提交以证明在
XX 场所执行的这些产品的检测均完成了验证。
d) Validated laboratory methods do not provide consistent and reliable test results. For
example:
验证过的化验室方法并未提供可靠一致的检验结果。例如：
I. OOS investigation PR 808607 for assay of (b)(4) states “In order to avoid the
variability in the assay results, a CAPA (917679) was assigned to ADS ((b)(4)) to re-visit
the analytical method for assay test.” Your firm’s management stated that the report
refers to the assessment of suitability of the method for analytical testing. (b)(4) has
been tested approximately (b)(4) times (including for stability ) prior to this OOS.
OOS 调查 PR808607 是 XX 的含量，其中说“为了避免含量结果的波动，对 ADS XX 制
订了一项 CAPA（917679），对含量检验的分析方法进行再次检查”。你们公司的管理层
声称该报告指的是对分析方法的适用性进行评估。在此 OOS 发生之前 XX 已被检测了约
XX 次（包括稳定性）。
II. OOS investigation PR 859912 for (b)(4) content in (b)(4) and (b)(4) tablets
stated to “Discard first (b)(4)ml of (b)(4)”. Your firm’s General Manager – Quality Control
Compliance explained that the protocol lacked sufficient detail. This OOS investigation
states that the STEP will need to be updated to include this information. Prior to this
OOS, (b)(4) tests had been conducted utilizing this method and provided to FDA in
support of an (b)(4).
OOS 调查 PR859912 是 XX 和 XX 片剂的 XX 含量，其中说“舍弃 XX 的前 XX 毫升”。你
公司总经理—质量控制合规解释说方案缺乏足够的细节。此 OOS 调查中说要对步骤进行更
新，在其中包括此信息。在此 OOS 之前，已使用此方法实施过 XX 次检测，并将结果提交
给了 FDA 用于支持 XX。
III. OOS investigation PR 730461 for related substance testing of (b)(4) and (b)(4)
tablets determined that “results obtained by modified test preparation gives more
reproducible results compare to results obtained by test preparations as per current
STP.” Prior to PR 730461, (b)(4) samples of (b)(4) and (b)(4) tablets had been analyzed
for related substances.
OOS 调查 PR730461 是 XX 和 XX 片剂的有关物质检测，其中确定“相比于依据当前 STP
中样品制备所得结果，修改后的样品制备方法所得结果会得出更具重现性的结果”。在
PR730461 之前，已检验过 XX 和 XX 片剂的 XX 个样品的有关物质。
IV. OOS investigation PR 689665 for related substance in a sample of (b)(4)
Capsule concludes with a CAPA to “revise the product test procedures.” Prior to this
OOS, (b)(4) samples of (b)(4) and (b)(4) tablets had been analyzed for related
substances.
OOS 调查 PR689665 是 XX 胶囊一个样品的有关物质，其结论中有一个 CAPA 是“修订
产品检验方法”。在此 OOS 之前，已检验过 XX 和 XX 片剂的 XX 个样品的有关物质。
In 2016, 8 of 14 CAPAs resulting from incidence report are related to
implementing changes to sample preparation within the methods. As noted
above, several OOS results were attributed to failures to adequately prepare
samples for analytical testing. The variability in sample preparation has not been
assessed by the Quality Unit.
2016 年，14 个 CAPA 中有 8 个是来自于与方法中样品制备变更实施有关的事件报
告。自如以上所述，有几个 OOS 结果被归因于分析检测中样品制备失败，而质量部
门从未对样品制备的波动性进行过评估。
There is a failure to thoroughly review 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.
未彻底审核已销售或未销售的批次及其组份不符合其质量标准的情况。
Specifically, out of specification test resultsfor US marketed drug products were
invalidated without sound scientific justification. For example:
具体来说，销往美国的 OOS 检验结果在没有科学合理论证情况下即被宣布无效。例如：
(a) OOS report PR 801873 was opened for an out of specification result of (b)(4)% for
assay of (b)(4) and (b)(4) Tablets (18 month stability). The assay specification is (b)(4)-
(b)(4)%. Initially, “no apparent laboratory error was identified.” However, the report later
conversely concluded that “execution error could be spillage of sample.” However, the
assay of (b)(4) tested with the same sample that provided the OOS result yielded results
that were within specification. Nonetheless, this justification was used to invalidate the
initial failing results and utilize the passing retest results.
OOS 报告 PR801873 因 XX 和 XX 片剂的含量 XX%超标而启动（18 个月稳定性）。含量
标准为 XX-XX%。开始写的是“未识别出明显的化验室错误”。但是，报告后面反而得出
结论说“执行方面的错误可能是样品泼洒。”但是，采用 OOS 结果相同样品检测的 XX 含
量却在标准范围内。虽然如此，此论证仍被用于宣布初始不合格结果无效，并且采用了合
格的复测结果。
(b) .OOS report PR 879521 was opened for out of specification and out of tolerance
result for assay of (b)(4) and (b)(4) Tablets (12 month stability). The report initially
concluded “no obvious reason and probable cause identified for OOS/OOT results”. A
retest was performed and the results were within specification. The final conclusion was
that the root cause was laboratory error and the initial OOS results were invalidated.
OOS 报告 PR897521 因 XX 和 XX 片剂含量结果超标以及超出误差范围而启动（12 个月
稳定性）。报告开始得出结论说“未识别出该 OOS/OOT 结果的明显原因和可能原因”。
然后进行了复测，结果在标准范围内。最终的结论是根本原因为化验室错误，宣布初始
OOS 结果无效。
Note multiple OOS and OOT results were a part of this report.
注：本报告包括有多个 OOS 和 OOT 结果
(c) OOS report PR 908027 was opened for an initial out of specification for assay of (b)
(4) tablets (6 month stability) for a result of (b)(4) %. The specification is (b)(4)- (b)(4)%.
Although the report states that “The results of phase-I analysis does not conclude any
laboratory error during analysis”. The report then conversely concludes that the error
“probably could be due to spillage of sample solution.” this justification was used to
invalidate the initial failing results and the retest results were accepted as the final
reported test result.
OOS 报告 PR908027 因为 XX 片剂含量初检超标而启动（6 个月稳定性）。结果为 XX%，
标准为 XX-XX%。尽管报告中声称“第 I 阶段分析的结果并未得出结论说分析期间有任何
化验室错误。”报告后面却相反地得出结论说错误“可能是因为样品溶液洒出”。此论证被
用以宣布初始不合格结果无效，并且接受了复验结果作为最终报告的检测结果。
(d) OOS report PR 876239 was opened for out of specification and out of tolerance
results for assay of (b)(4) Tablets. The report indicates “no laboratory error was identified
for initial atypical result”. The report then conversely concludes “laboratory error”.
Nonetheless, the report concludes the root cause is laboratory error and the initial
results were invalidated and retest results were utilized.
OOS 报告 PR876239 因为 XX 片剂含量结果超标并且超出允许误差范围而启动。报告显示
“初始异常结果中并未识别出化验室错误”。报告后面却相反地得出结论说“化验室错
误”。报告结论中的根本原因是化验室错误，而初始结果被宣布无效，使用了复测结果。
(e) OOS report PR 915172 was opened for an out of specification result for (b)(4)
content of (b)(4) Tablets. The report confirms the OOS and failure to meet internal
specification. Yet the product was released for distribution. The report acknowledges the
product was “not complying with product releasespecification.”
OOS 报告 PR915172 因为 XX 片剂 XX 含量结果超标而启动。报告确认了 OOS 结果，该
批次不符合内部标准。但产品还是被放行销售。报告说该产品“不符合产品放行标准”。
Additional examples of deficient invalidation of failing results were observed. Moreover,
the aforementioned failures mostly relate to assay results. In 2016, assay data
accounted for approximately 54.5% of unconfirmed OOS results, but only approximately
24% confirmed OOS results. The majority of invalidated assay results are attributed to
sample preparation (mostly shaking of flasks); however, no CAPA or investigation has
been implemented to address or correct these issues.
还发现了其它一些宣布不合格结果无效的例子。另外，之前所提到的不合格大多数与含量
结果有关。在 2016 年，含量数据计占未确认 OOS 结果的约 54.5%，但仅有约 24%OOS
结果被确认。大多数被宣布无效的含量结果被归因于样品制备（大多数是容量并振摇），
但是却并未执行 CAPA 或调查来解决或纠正这些问题。
THIS IS A REPEAT OBSERVATION FROM THE PREVIOUS INSPECTION
这是上次检查的重复缺陷
Appropriate controls are not exercised over computers or related systems to assure that
changes in master production and control records or other records are instituted only by
authorized personnel.
计算机和相关系统未执行适当的控制以确保母版生产和检验记录或其它记录仅能由经授权
的人员修改。
Your firm has not ensured that analytical laboratory data is preserved.
你公司并未确保化验室分析数据的保存。
(a) In August 2016, two incidences of “DeletedResult Set” were observed by an
individual with “Reviewer” designation. These incidences were associated with assay of
(b)(4) batch (b)(4) and (b)(4) and (b)(4) Tablets identified (b)(4). No investigation or
CAPA was initiated for these two incidence by the Quality Unit. Your firm’s Assistant
General Manager – Producer (b)(4) indicated that a comprehensive assessment of audit
trail messages had not been assessed during validation of Empower 3.
2016 年 8 月，发现有 2 件“审核员”身份人员“删除结果序列”的事件。这些事件是关于
XX 片剂的 XX 批号的含量。这 2 起事件未由质量部门启动调查或 CAPA。你公司的副总经
理—生产 XX 说在 Empower 3 的验证期间未对审计追踪信息的全面评估进行评估。
(b) No investigation is conducted into identifying and solving the root cause of missing
data points –At the time of my inquiry during this inspection, there had been
approximately 160 incidents of “Project Integrity Failed” in your Empower 3 system audit
trail since the beginning of calendar year 2016. Your firm’s employees, including the
Deputy Manager – Quality Assurance, identified that these “Project Integrity Failed”
message are related to the incidences of “Oneor more injections are missing”. This
situation has led to this warning of missing injections in more than 115 incidents. In
multiple instances, this warning occurred multiple times throughout a run.
未对识别和解决数据点缺失根本原因进行调查—在此次检查期间当我们询问时，在你们的
Empower 3 系统审计追踪中从 2016 自然年起计有约 160 个“项目完整性失败”的事件。
你们公司的员工，包括 QA 副经理识别出这些“项目完整性失败”信息与“一个或多个进
样缺失”事件有关。此种情形已导致超过 115 个事件中进样缺失的报警。在多个事件中，此
报警在一个运行过程中发生多次。
For example, in the analysis of (b)(4) for (b)(4) and (b)(4) Tablets batch (b)(4) (June
20th 2016) this “Project Integrity Failed” rendered no chromatogram for the initial run
(only a “Data Incomplete” display) and there has been no investigation into this
incident or the fact there is no chromatogram.
例如，在 XX 片剂 XX 批号的 XX 分析中（2016 年 6 月 20 日），此“项目完整性失
败”是初始运行中无色谱图（只显示有一个“数据不完整”），并且对此事件或无色
谱图的事实并未调查。
In a number of other cases, an investigation was opened, but no root cause was
identified and no CAPA was opened to prevent recurrence of the “Project Integrity
Failed” messages.
在大量其它案例中，启动了调查，但未识别出根本原因，且未启动 CAPA 以防止“项
目完整性失败”信息的再次出现。
Additional examples of incidents and the corresponding conclusions are listed below
(these incidents are from 2016 alone):
以下列出了其它的事件例子以及相应的结论（这些事件只是 2016 年的）：
(b) PR 943693 – Describes a “Connection tochromatography system lost” event in the
analysis of (b)(4). The initial data acquired was invalidated due to the loss in
connectivity.
PR943693 – 描述了一个在 XX 检测过程中“与色谱色谱连接断开”事件。所获得的初始数
据由于连接失败而宣布无效。
(c) PR 947661 – Describes a “Connection to chromatography system lost” event in the
analysis of (b)(4) API. The initial data acquired was invalidated due to the loss in
connectivity.
PR947661 – 描述了一个 XX 原料药检测过程中“色谱系统断开连接”事件。所获得的初始
数据由于连接失败而宣布无效。
(d) PR 931672 – Describes a “instrument malfunction” during the run of (b)(4) Tablets.
The initial data acquired was invalidated due to the malfunction.
PR 931672 – 描述了一次 XX 片剂检测运行中“仪器故障”。所获得的初始数据由于故障
而宣布无效。
Additionally incidents PR 989728, 980190 and 989509 were related to “power loss”
of specific HPLCs during the acquisition of analytical data. The initial data acquired
was invalidated due to power loss.
其它的事件 PR 989728、980190 和 989509 与分析数据获取期间特定 HPLC 的“断
电”有关。所获得的初始数据由于断电而宣布无效。
(c) Within the Empower 3 messages center log from August 29 th, 2016 to September 5th
2016, I observed approximately 150 messages indicating “Possible data corruption or
modification of file” affecting 12 sequences. Moreover, during this same
period,connectivity to the system was lost on two occasions. No CAPA or investigation
has been opened to address these incidents of “Possible data corruption or modification
of file.” Data was lost, as it was not captured in a back-up system.
在 Empower 3 信息中心日志内，从 2016 年 8 月 29 日至 2018 年 9 月 5 日，我发现有约
150 条信息显示“数据可能损坏或文件可能修改”，其影响到 12 个序列。另外，在此相同
时间段内，有 2 次与系统连接断开。未启动 CAPA 或调查来解决此类“数据可能损坏或文
件可能修改”事件。由于数据并未被采集到备份系统中，因此数据就此丢失。
(d) I reviewed your firm’s “COMPUTER SYSTEM VALIDATION PLAN FOR WATERS
EMPOWER 3 CDS” dated 09/10/2015. On this report, under section 1.4 termed
“Assumptions” it is stated “Direct testing of the hardware, operating system software,
communication software, and network components is not included as these are indirectly
tested during validation testing.” These were reoccurrences of communication error
demonstrates observed throughout the inspection.
我审核了你们公司 2015 年 9 月 10 日的“WatersEmpower 3 CDS 计算机系统验证计划”。
在此报告中 1.4 部分中标题“假定”中说“由于在验证测试中采用的是间接测试，因此其
中并不包括对硬件、操作系统软件、通讯软件和网络部件的直接测试”。这些反复发生的通
讯错误证明了在整个检查过程中发现的情况。
9. 印度 Galaxy Surfactants 20180626

2. Your firm failed to validate the analytical methods required for the trace analysis of
API residue as part of the cleaning validation program. Specifically, there is not
validation report that confirms the sensitivity of <USP621> analytical method to detect
the established acceptable level of the residue or contaminants. The method’s attainable
recovery level is also not established.
你公司未验证作为清洁验证程序一部分的 API 残留痕量分析方法。具体来说，没有验证报
告确认<USP621>分析方法可检出既定可接受残留水平或污染物水平的灵敏度。方法的回
收率水平亦未建立。
3. Your firm failed to place on stability at least one batchof manufactured APIs to
monitor the stability characteristics of the API, and to test for appropriate storage
conditions and confirm expiry dates. Specifically in 2016, you did not confirm the stability
characteristics and storage conditions for a number of APIs including: (b)(4) Lot# (b)(4)
Lot# (b)(4) and(b)(4) Lot# (b)(4). These APIs were manufactured in 2016 and shipped to
US.
你公司未能放置至少一批所生产的 API 来监测 API 的稳定性特征，并针对适当的存贮条件
进行检测以确认有效期。具体来说，在 2016 年，你们未确认许多 API 的稳定性特性和存
贮条件，包括 XX 批号 XX 和 XX 批号 XX。这些 API 是在 2016 年生产并发至美国的。
10. 浙江华海 20180809

Failure to establish laboratory controls that include scientifically sound and appropriate
specifications, standard sampling plans, and test procedures designed to assure that
drug products conform to appropriate standards of identity, strength, quality and purity.
未建立化验室控制使其包括科学合理适当的质量标准、标准取样计划和检测方法用以确保
药品符合适当的鉴别、剂量、质量和纯度标准。
1. Assessments to establish environmental monitoring sampling points were not
comprehensive. For example, they did not evaluate expanded sampling points or
thoroughly evaluate common activities occurring in the clean room. Further, the
environmental monitoring procedures did not define sampling locations with description
diagrams to ensurere producible sampling.
设置环境监测取样点的评估不全面。例如，其中未评估增加取样点或彻底评估在洁净间通
常所发生的活动。另外，环境监测程序并未采用描述性图形来定义取样位置以确保取样具
有重复性。
2. Environmental monitoring media for air, surface, and personnel monitoring does not
contain any neutralizer for the disinfectants used in the clean room.
环境监测中空气、表面和人员监测用培养基并不含有任何洁净间所用消毒剂的中和剂。
3. During open door interventions, environmental monitoring is not performed. For
example, non-viable particle counts, active air monitoring, or settle plates is discontinued
during open door interventions.
在开门干预期间未执行环境监测。例如，尘埃粒子计数、主动取样监测，或沉降菌在开门干
预期间被中止了。
4. Monitoring of the unfiltered bulk compounded batch does not include evaluation for
endotoxin and the samples are collectedat least (b)(4) prior to the start of (b)(4).
对过滤前配制药液的监测没有内毒素项目，在 XX 开始之前至少取样 XX。
5. There is a lack of scientific rationale for the establishment of the parameters for the
RABS (b)(4) integrity test of(b)(4) pressure hold time between (b)(4) Pa and greater
than (b)(4) Pa drop in pressure.
对 RABS XX 完整性测试中 XX 帕和大于 XX 帕压降保压时长参数设定缺乏科学合理性。
6. Limits on reject type are not established inthe visual inspection procedures.
目检程序中未设定拒收类型的限度。

Appropriate controls are not implemented over Quality Control instruments to ensure the
integrity of analytical testing. Furthermore, anomalies in analytical testing are not
investigated.
未对 QC 仪器执行适当的控制以确保分析检测的完整性。另外，分析测试中的异常现象未
进行调查。
1. During a review of API testing assay testingis repeated in order to obtain
satisfactory/within specification results:
在对原料药检测的审核期间重复了含量测试以获取满意结果/合格结果。
Standard Operating Procedure (SOP) QC-024-5 requires that replicate samples subject
to analysis for assay to exhibit no more than (b)(4)% difference in result. This SOP was
utilized to engage in repeat analysis of API in instances of out-of-specification and out-
of-trend results without a corresponding investigation. Examples may be found below:
标准操作规程（SOP）QC-024-5 要求含量检测采用双样分析，双样结果差异应不得过
XX%。该 SOP 被利用来在 OOS 或 OOT 结果时重复 API 的分析，却不进行相应的调查。发
现的例子如下：
(a) (b)(4) batch (b)(4) exhibited a large differential between replicate sample results,
such that one injection yielded an out-of-specification. The initial failing injections were
not processed. Dueto this large differential, this batch of (b)(4) was retested without
conducting an investigation and passing results were reported.
XX 品种 XX 批次显示双样结果有较大差异，一针结果为 OOS。开始不合格的这针并未进
行数据处理。基于此较大差异，对该批次进行了复测，而未执行调查，然后报告了合格结
果。
(b) (b)(4) batch (b)(4) exhibited failing assay result for one of the replicate injections ((b)
(4)% against a specification of (b)(4)%). Due to a large differential in test results
between replicate injections for (b)(4) this batch was retested without conducting an
investigation and passing results were reported.
XX 产品 XX 批次两次进样中有一针得到含量结果不合格（结果为 XX%，标准为 XX%）。
由于两次平行进针检测结果差异较大，该批次进行了复测，而未进行调查，然后报告了合
格结果。
(c) The following batches exhibited out-of-trendresults, which were retested without an
investigation due to a greater than (b)(4)% differential in replicate assay injections:
以下批次得到结果为 OOT 结果，均未进行调查即以两次含量进样之间差异超过 XX%为由
进行复测：
i. (b)(4) batch (b)(4) 产品 XX 批号 XX
ii. (b)(4) batch (b)(4) 产品 XX 批号 XX
iii. (b)(4) batch (b)(4) 产品 XX 批号 XX
iv. (b)(4) batch (b)(4) 产品 XX 批号 XX
Further, due to this repeat testing as aresult of discrepancies in replicate assay values, I
reviewed repeat analytical testing for (b)(4) exhibited an increased rate of repeat testing.
The replicate samples from repeat testing conducted between September 2016 and
March 2017 for(b)(4) exhibited an average differential in assay results of approximately
(b)(4)% (with the acceptable range of the specification spanning (b)(4)%). The replicate
samples from repeat testing conducted between September 2016 and March 2017 for
(b)(4) exhibited an average differential in assay results ofapproximately (b)(4)% (with the
acceptable range of the specification spanning (b)(4)%). I asked your firm’s Quality
Control Director to explain how such routine, large differences in assay value of replicate
samples was consistent with assurance that the analytical method is effective and
released API indeed met specification. They did not provide a sustentative explanation.
鉴于两次含量测定值之间差异引发的重复检测情况，我审核了重复检测呈现增加趋势的
XX 的重复检测。2016 年 9 月至 2017 年 3 月之间所执行的重复检测结果双样间 XX 的含量
结果平均差异约为 XX%（标准可接受范围为 XX%）。2016 年 9 月至 2017 年 3 月之间所
执行的重复检测结果双样间 XX 的含量结果平均差异约为 XX%（标准可接受范围为 XX
%）。我询问了你们公司的 QC 主任要求解释为何如此常见，重复样本含量值的如此大差
异能持续确保分析方法的有效性，确保所放行的 API 实际是符合其质量标准的。他们并未
提供强有力的解释。
Note: this repeat testing encompassed subjecting the same API batch to repeat
testing without investigating the initial test results and the requirement for re-testing.
注：此重复检测指向相同 API 批次进行了重复检测，而未对初始检测结果和复测要求
进行调查。
2. Impurities occurring during analytical testing are not consistently
documented/quantitated.
在分析中出现的杂质未能全部记录/定量。
(a) Testing of (b)(4) content of (b)(4) batch(b)(4) by Liquid Chromatography-Mass
Spectrometry yielded an unidentified peak at an approximate retention time of (b)(4)
minute. Your firm explained this unknown peak as a “ghost peak” that appears from time
to time in chromatograms for undetermined reasons. This peak was substantially larger
than that of (b)(4) the subject of the testing. No investigation was conducted.
XX 产品 XX 批次的 XX 含量 LC-MS 检测中在 XX 分钟保留时间处出现了未知峰。你们公司
将此不明原因偶尔出现在色谱图的未知峰解释为“鬼峰”。该峰远远大于检测对象 XX。你
们未进行调查。
(b) Testing of (b)(4) content of (b)(4) batches(b)(4) (among others) by Liquid
Chromatography-Mass Spectrometry yielded an unidentified peak at an approximate
retention time of (b)(4) minute until the end of the chromatogram. This peak was
substantially larger than that of (b)(4) the subject of the testing. No investigation was
conducted.
XX 产品 XX 批次的 XX 含量 LC-MS 检测中在 XX 分钟保留时间处出现了未知峰并持续直
到运行结束。该峰远远大于检测对象 XX。你们未进行调查。
(c) Impurity testing of (b)(4) batches (b)(4) yielded a prominent, coalescing peak with
that of the primary (b)(4) peak. Nevertheless, the impurity was quantitated along with the
(b)(4) peak as desired API and no investigation was initiated.
XX 产品 XX 批次的杂质检测发现一个突起的峰与主峰 XX 重叠，而该杂质是与 XX 峰一起
进行定量计算作为目标 API，对此未启动调查。
Invalidation of out-of-specification results lacks adequate scientific justification.
宣布 OOS 结果无效时缺乏充分的科学论证。
a) Report OOS-CQC15067 relating to (b)(4) batch (b)(4) was reported “Unknown
impurity peak is appeared under unknown reason”. Your firm explained this unknown
peak as a “ghost peak” that appears from time to time in chromatograms for
undetermined reasons. Without an indication of the cause of the out-of-specification, an
attribution of “Lab error was made.”
报告 OOS-CQC15067 是 XX 产品批次 XX，报告“未知杂质峰出现，原因不明”。你们公
司将此未知峰解释为“鬼峰”，因未知原因偶尔出现在色谱图中。未指明 OOS 的原因，归
因于“实验室犯错”。
b) Report OOS-CQA16103 reported out-of-specification of residual solvents in (b)(4).
The Phase I laboratory investigation failed to identify a laboratory error. This
investigation attributed the failure to “Pollution” from the environment during sample
preparation.
报告 OOS-CQA16103 是 XX 中残留溶剂 OOS 结果。第一阶段实验室调查未能发现实验室
错误。该调查将不合格归因于样品制备过程中来自环境的“污染”。
c) Report OOS-CQC15103 due to a single impurity in (b)(4) batch (b)(4) ((b)(4)%
against a specification of no more than (b)(4)%). This was assigned as a “Lab error” due
to “possible” residue in the column. When inquiring about why this impurity specifically
eluted in the (b)(4) analytical test of the testing sequence, your firm again referenced a
“ghost peak”.
报告 OOS-CQC15103 是 XX 产品 XX 批次单杂（结果为 XX%，标准为不得过 XX%）。该
OOS 归因为因柱中“可能”有残留而发生的“实验室错误”。在询问为何在检测序列中的
XX 分析测试中会有洗出该特定杂质时，你们公司又将其归为“鬼峰”。

Observation 5. Sufficient controls to prevent unauthorized changes to data stored on
your firm’s HPLC and GC computer systems are inadequate. Specifically, on 25 April
2018, a Senior Scientist demonstrated that the time zone setting could be changed and
saved on the HPLC and GCsystems. No requirement of administrative privileges was
required to change the time zone of your firm’s (b)(4) HPLCs and (b)(4) GC system,
thereby allowing for the alteration of real-time records and data collection.
缺陷 5：防止未经授权修改你们公司的 HPLC 和 GC 计算机系统上所存贮的数据的控制是
不充分的。具体来说，20180425，一位高级实验员演示了可修改时区并保存在 HPLC 和
GC 系统上。修改你们公司的 XXHPLC 和 XXGC 系统的时区不需要有管理员权限，从而可
以修改实时记录和数据集。
13. 印度 Unichem Laboratories 20180910

2. Test procedures are not scientifically sound and appropriate to ensure that
raw materials, intermediates, APIs and labels and packaging material conform to
established standards of quality and/or purity.
检测方法不够科学合理亦不恰当，无法确保原料、中间体、API 和标签及包材符合既定
的质量和 /或纯度标准。
The review of the test results for the finished product testing of (b)(4) USP batch No. (b)
(4) Related Compound (b)(4) (USP limit NMT0.1%) did not correctly calculate and report
a peak matching the location (relative retention time) on the chromatogram for Related
Compound (b)(4). The peak matching Related Compound (b)(4) location in the sample
sets (b)(4) calculates to be approximately 0.3%, which would be Out Of Specification
(OOS). The required investigation and reconciliation by Quality Assurance was not
performed for this occurrence of an OOS event.
对 XX 成品 USP 批号 XX 有关物质 XX 检测结果（USP 限度 NMT0.1%）计算不正确，报
告的一个峰与有关物质 XX 的色谱图上位置相符合（相对保留时间）。对应样品 XX 的有关
物质 XX 位置的峰计算为约 0.3%，其实应为 OOS 结果。QA 要求对此 OOS 事件进行调查
和衡算但没有执行。
Further review of Unichem Laboratories Ltd. procedure PPQC141/00, confirmed the
company has a policy permitting any response attributed to a blank in HPLC analysis to
be (b)(4) without confirming the identity of the compound eluted, investigation, and
notification of QA when a possible OOS occurs.
进一步检查公司程序 PPQC141/00，确认该公司有政策允许在 HPLC 分析中将任何归为空
白而不需要确认洗出化合物是什么，当可能的 OOS 发生时要调查和通知 QA。
3. Laboratory controls were not followed and documented at the time of
performance.
未遵守实验室控制并同步记录。
Review of Unichem Laboratories Ltd. procedures for Media Preparation and Microbial
Limits testing do not provide for an assurance of GMP compliancein the following
examples:
公司的培养基制备和微生物限度检测程序不能确保 GMP 合规性，举例如下：
a. Media are not placed in a secure, quarantine state pending growth promotion before
being released for use in Microbial Limits testing of raw material, finished goods or
stability monitoring.
培养基在促生产试验进行中未放行用于原料、成品或稳定性监测的微生物限度测试之前未
放置在安全隔离状态
b. Microbial Limits testing procedures do not require the documentation of the specific
incubator used in the performance of testing of raw materials, finished goods or stability
monitoring.
微生物限度检测程序不要求记录原料、成品或稳定性监测执行时所用的具体培养箱
c. Microbial Limits testing procedures do not require the documentation of the specific
time test media are placed into or removed from the incubator used in the performance
of testing of raw materials, finished goods or stability monitoring.
微生物限度测试程序不要求记录培养基放进和取出用于原料、成品或稳定性监测检测所用
培养箱的具体时间
4. There was not record of stability samples stored in containers that simulate
the market container.
无记录显示稳定性样品是存贮在上市模拟包装中。
Review of the Unichem Laboratories Ltd. stability program records for Batch No. (b)(4)
and (b)(4) found that there was no traceability for the materials of construction of
containers used for the units created after the sample of the batch was delivered to the
lab. There also was no record of who and when aliquots were created in preparation for
stability storage.
审核公司 XX 批号和 XX 批号的稳定性试验记录，发现没有记录可追溯至样品送至实验室
后所使用的包装容器材质构造，亦没有记录下何人何时对稳定性制剂样品做的分样。

Failure to follow established and approved Standard Operating Procedures.
未遵守已制订且批准的 SOP。
SOP entitled: “ Procurement, receipt, storage, and handling of (b)(4) microbial cultures
and re-hydrating fluid”, Document Number:2261-SOP-QC-00090, Effective Date:
05/10/2018, Version 2.0, Section 6.0 (G) reads in parts: “*** (b)(4) received lot of (b)(4)
culture shall be checked for its purity, which is to be done by colony morphology and
characteristics, gram staining and microbial identification through (b)(4) as per SOP No.:
2261-SOP-QC-00121***”. However, all microbial cultures used for the growth promotion
test has not been verified for its purity.
题为“XX 微生物培养和补水液的采购、接收、存贮和处理”SOP，文件编号 2261-SOP-
QC-00090，生效日期 20180510，版本号 2.0，第 6.0（G）部分写道“……XX 培养基
XX 的接收批次应按 SOP 2261-SOP-QC-00121 采用菌落形态和特征、革兰氏染色和微生
物鉴别来检查纯度……”。但是，用于促生长试验的所有的微生物培养基均未确认其纯度。
Investigation invalidating an Out of Specification (OOS) during the real-time stability
studies is not scientifically justified.
调查宣布实时稳定性研究中的 OOS 结果没有经过科学论证。
For (b)(4), Lot number (b)(4), (b)(4), there was an Out of Specification (OOS) for
particulate matter at 183 days (real-time study). The OOS was invalidated and the
investigation reads in parts:” *** due to lack of cleanliness of the test tubes, aluminum
foil and the test environment***”.However, there is no history of cleaning in any of the
aforementioned areas, except for the environment, for real-time stability studies
performed on other (b)(4) batches. The investigation lacks any scientific rationale as to
why the aforementioned OOS related to real-time stability was invalidated.
对于 XX，批号 XX、XX，在 183 天（实时研究）时有一个颗粒物 OOS 结果。该 OOS 被宣
布无效，调查记录写道“……由于试管、铝箔和检测环境清洁度不够……”。但是，在上述
实施其它 XX 批次的实时稳定性研究的所有区域内除环境外并无清洁历史。调查在为何宣
布前述与实时稳定性 OOS 无效方面缺乏科学合理性。
Sampling plans, and test procedures are not always scientifically sound and appropriate
to ensure raw material, intermediates and APIs conform to established standards of
quality.
取样计划和检测方法并不全是科学合理并合适于确保原料、中间体和 API 符合既定的质量
标准。
a) You do not always have scientifically sound reasons for invalidating OOS results for
lab related reasons. This is a repeat observation. Complaint No. CC-16008 received
September 13, 2016 for (b)(4) batches (b)(4) ((b)(4)ppm (b)(4) impurity) and(b)(4) ((b)
(4)ppm (b)(4) impurity) failing to meet (b)(4) impurity specification <(b)(4)ppm identifies
the complaint as a quality complaint for product quality attribute. Your Vice President of
Analytical Operations stated a Single Quadrupole LC-MS is not as sensitive as a Triple
Quadrupole LC-MS and sometimes it gives false positive results. Your customer tested
(b)(4) batches (b)(4) and (b)(4) using a Triple Quadrupole LC-MS. You sent samples of
(b)(4) and (b)(4) to an outside laboratory to test using a Triple Quadrupole LC-MS. Your
customer provided you with their LC-MS test method. The outside laboratory used a
Triple Quadrupole LC-MS but did not follow the test method provided by your customer.
并不是所有因化验室相关原因宣布 OOS 无效均有科学有效的理由。此为重复缺陷。投诉

CC-16008 于 20160913 收到，原因是 XX 批次 XX（XX 杂质 XXppm）和 XX（XX 杂质
XXppm）不符合 XX 杂质标准<XXppm，该投诉为产品质量属性有关的质量投诉。你们的
分析运营副总裁声称单四极杆 LC-MS 不如三重四极杆 LC-MS 灵敏，有时单四极杆 LC-
MS 会得到假阳性结果。你们的客户使用的是三重四极杆 LC-MS 检测的 XX 批次 XX 和
XX，你们则将 XX 和 XX 样品送至一个外部实验室使用三重四极杆 LC-MS 检测。你们的客
户给你们提供了他们的 LC-MS 检测方法，而外部实验室使用了三重四极杆 LC-MS 但没有
按你们客户提供的方法进行检测。
You do not have a quality agreement with this outside laboratory requiring all equipment
used for testing is qualified, any software used with the instrument is validated, and the
test method used is validated prior to reporting results. You used results from this
outside laboratory for (b)(4) batches (b)(4) and (b)(4) to invalidate the OOS results
reported by your customer. After your customer returned (b)(4) batches (b)(4) and (b)(4)
you reprocessed the batches and assigned the reprocessed batches new batch
numbers (b)(4) and (b)(4) Finished API batches (b)(4) and (b)(4) were then sold to other
customers.
你们与该外部实验室没有质量协议要求所有用于检测的设备经过确认，要求所有仪器所用
的软件经过确认，并且在报告结果之前所有方法均经过验证。你们使用了此外部实验室的
XX 批次 XX 和 XX 的结果用以宣布你们客户报告的 OOS 结果无效。在你们的客户退回了
XX 批次 XX 和 XX 产品后，你们对这些批次进行了返工，对返工批次给定了新批号 XX 和
XX。成品批次 XX 和 XX 后来被卖给了其它客户。
b) You do not have scientifically sound sampling plans. 你们没有科学合理的取样计划
i) Sampling Procedure for API Raw Material QC-026-9 effective September 30,
2017 includes sampling instructions designed to obscure non-homogenous raw material
batches. As an example, section 5.6 specifies to sample the (b)(4) of (b)(4) compartment
in the tanker and (b)(4) thecompartment sample and then (b)(4) the (b)(4) samples from
(b)(4) the compartments. You do not have data establishing inter-batch and intra-batch
homogeneity for key starting material.
“API 原料取样程序”QC-026-9 生效日期 20170930 包括有取样指导，设计用以阻止不

均匀的原料批次。例如，第 5.6 部分说要在罐的 XX 取样，然后将 XX 中取的样 XX。你们没
有数据建立关键起始物料的批内和批间均匀性。
ii) Sampling procedures lack sufficient details describing how to collect samples to
ensure the sampling procedure is consistently and reproducibly followed. Sampling
Procedure for APIs QA-005-5 effective August 30, 2017 is silent regarding which drums
to sample or how to collect samples from the sampled drums.
取样程序对如何采集样品以确保能一致可重复地遵守取样程序描述不够详细。“API 取样
程序”QA-005-5 生效日期 20170830 未说明要从哪个桶取样或如何从桶中采集样品。
c) You do not have data to support reduced testing for genotoxic and other impurities.
during process validation for (b)(4) you committed to testing the final API validation
batches for elemental impurities and residual solvents, (b)(4). After the three (b)(4)
validation batches you test (b)(4) batches (b)(4) for elemental impurities and residual
solvents. During process validation for (b)(4) you tested the finished API validation
batches for potential genotoxic impurity (b)(4). After the validation batches you test (b)(4)
batches (b)(4) for potential genotoxic impurity (b)(4).
你们没有数据支持对基因毒性杂质和其它杂质降低检测频次。在 XX 工艺验证中，你们承
诺会检测 API 验证批次成品的元素杂质和残留溶剂 XX。在 3 个 XX 验证批次后，你们检测
了 XX 批次 XX 的元素杂质和残留溶剂。在 XX 工艺验证中，你们检测了验证批次的 API 成
品潜在基因毒性杂质 XX。在验证批次之后，你们检测了 XX 批次 XX 的潜在基因毒性杂质。
Your on-going testing program to monitor the stability characteristics of APIs to confirm
appropriate storage conditions and retest dates is not adequate. Specifically,
你们监测 API 稳定性特性以确认适当的存贮条件和复验期的持续检测计划不充分。具体来
说
a) You subjected (b)(4) API sample to conditions expected to cause degradation

(forced degradation). You did not conduct full product release testing on those forced
degradation samples, using validated test methods, to identify the specific product
release test(s) that are stability indicating. Instead you included forced degradation
samples in three HPLC test method validations for Related Substance, Assay and (b)(4)
impurity. Not all potential product degradants can be identified by HPLC test methods.
Product release tests for (b)(4) include tests for identification of Residual Solvents by
GC-FID. You did not test forced degradation samples for Residual Solvents by GC-FID.
你们将 XXAPI 样品放在产生降解（强降解）的条件下。你们并未对这些强降解样品使用验

证过的检测方法执行全面放行检测，以识别出具有稳定性指示性的特定产品放行测试。相
反，你们在 HPLC 有关物质、含量和 XX 杂质 3 个检测方法验证中包括了强降解样品。并不
是所有潜在产品降解物均可使用 HPLC 检测方法识别的。XX 产品放行检测包括采用 GC-
FD 鉴别残留溶剂的测试。你们并未采用 GC-FID 检测样品中的残留溶剂。
b) You do not always appropriately add stability study samples to your stability study
program. Deviation investigation DCB02-17002 was initiated for (b)(4) intermediate (b)
(4) batches (b)(4) signle unknown impurity (b)(4)% (specification <(b)(4)%) and (b)(4)
single unknown impurity (b)(4)%. You reprocessed the batches. You assigned the
following batch numbers to the finished APIs made from the aforementioned (b)(4)
intermediate (b)(4) batches: (b)(4) and (b)(4). You did not add batches (b)(4) and (b)(4)
your stability study program.
你们未能保持适当地将稳定性研究样品加入你们的稳定性研究计划。偏差调查 DCB02-
17002 启动原因为 XX 中间体 XX 批次单个未知杂质 XX%（标准<XX%）和 XX 单个未知
杂质 XX%。你们将这些批次进行了返工。你们将使用前述中间体 XX 批次所生产的 API 成
品给定了以下批号：XX 和 XX。你们未将批次 XX 和 XX 加入你们的稳定性研究计划。
appropriate test procedures designed to assure that drug products conform to
appropriate standards of identity, strength, quality and purity.
实验室控制未包括建立科学合理恰当的检测方法，设计用以确保药品符合适当的鉴别、剂
量、质量和纯度标准。
For example,electronic data for (b)(4) mg exhibit batch (b)(4) for 0-month stability shows:
dissolution at buffer stage L1 was conducted on 9/26/15 with results for the sampling
time point at 5 hours, to have a minimum of (b)(4)% release, a maximumof (b)(4)%
release and a mean of 47% release. The stability report STB4332 15 for the same batch
and time point shows you conducted an L2 test. Based on the data contained in the
report, the L2 was conducted with results to have a minimum of (b)(4)% release,
maximum of (b)(4)% release and a mean of 66% release. The chromatograms are
reflective of variability between the L1 and L2 stages. Similar variability was seen for (b)
(4), (b)(4) and (b)(4) for L1 and L2 results for time 0-month for accelerated and
intermediate stability repeat studies. You were unable to provide scientific justification for
this variability.
例如，XXmg 申报批次 XX 的 0 月稳定性试验电子数据显示 20150926 所测缓冲阶段 L1 溶

出度在 5 小时取样点最小溶出为 XX%，最大溶出为 XX%，平均为 47%溶出。同批次同时
间点的稳定性试验报告 STB4332 15 显示你们进行了 L2 测试。根据报告中的数据，L2 结
果为最低溶出 XX%，最高溶出 XX%，平均 66%。色谱图反映出 L1 与 L2 阶段有差异。类
似差异在 XX、XX 和 XX 的 L1 和 L2 在 0 月加速和中间体稳定性重复研究研究中均有发现。
你们未对此波动进行科学合理论证。
Procedure designed to prevent objectionable microorganisms in drug products not

required to be sterile are not followed.
未遵守设计用以防止非无菌制剂中致病菌的程序。
To date, no testing for burkholderia cepacia has been performed on 11 of the 12

productsidentified as having high (b)(4) content. On 3/14/17, you established Raw
Material Specification Report WT001-BCC to test (b)(4) utilized as a rawmaterial in the
manufacture of drug products for the presence of burkholderia cepacia complex. On
5/1/18, you identified 12 finished drug products as havinga high (b)(4) content. To date,
you have initiated testing for burkholderiacepacia on (b)(4) utilized to produce on product
–gel (b)(4)%.
截止检查日，未对 12 个被识别为具有高 XX 含量产品中的 11 个进行洋葱伯克霍尔德菌检

查。在 20170314，你们制订了原料质量标准报告 WT001-BCC 用以检测制剂生产用原料
XX 中的洋葱伯克霍尔德菌。在 20180501，你们识别出有 12 个制剂具有高 XX 含量。截止
检查日，你们仍未启动对用于生产产品 XX%的 XX 中的洋葱伯克霍尔德菌检测。
The written stability program for drug products does not include sample size based on
statistical criteria for each attribute examined to assure valid estimates of stability.
制剂的书面稳定性试验计划未包括根据统计学标准为所检测每个属性所订立的样品量以确
保稳定性的有效预期。
Specifically, on 8/28/18, we observed unused stability samples stored inside a

Styrofoam cooler, on top of a stool, located inside stability chamber QCC-380, 25
degrees 60% relative humidity. Your Senior General Manager, Quality Non-Sterile
Manufacturing, stated these were extra samples remaining from a completed stability
study for (b)(4) product coded as Protocol of (b)(4) tablets, (b)(4)mg strength and they
were being held in response to a request from the research and development site under
protocol number SP1550 in case additional testing is required.
具体来说，在 20180828，我们发现在 Styrofoam 冷柜里、凳上、25 度 60%RH 稳定性考察

箱 QCC-380 里存有未使用的稳定性样品。你们的非无菌生产质量高级总经理声称这些样品
是 XX 产品已完成的稳定性考察后剩下的多余样品，留着这些样品只是为了防止研发可能
会需要对 SP1550 方案进行额外检测。

未遵守书面稳定性试验计划。
Specifically, your stability data is not representative of the intended manufacturing

process for (b)(4) Tablets (b)(4)mg. Exhibit batches (b)(4) and (b)(4) failed in process (b)
(4) sampling for (b)(4). These batches were placed on stability and data from these
batches was submitted in support of drug application (b)(4) Tablets.
具体来说，你们的稳定性数据不能代表 XX 片剂将要使用的生产工艺。申报批准 XX 与 YY
中控 XX 取样不合格。这些批次被放在了稳定性中，其数据被提交给 FDA 用于支持 XX 药
品申报。
To date, your firm has manufactured (b)(4) feasibility/optimization batches on two

different compression machines after the three exhibit batches were manufactured. As
documented in Feasibility Trial Report of (b)(4) Tablets (b)(4)mg Report No.
FSTR/02/1217-00, your firm determined compressed tablets on (b)(4) Compression
Machine Model (b)(4) (ID MPDRCM02) will not yield acceptable (b)(4) results. Firm
management stated you intended to use (b)(4) Compression machine (b)(4) (ID
MPDRCM01) for commercial production of (b)(4) Tablets (b)(4)mg.
截止今日，在生产了 3 批申报批次之后，你公司已在 2 台不同压片机上生产了 XX 批可行

性/优化批次。正如 XX 片剂可行性试验报告（编号 FSTR/02/1217-00）所记录，你们公司
决定在 XX 型号（ID MPDRCM02）XX 压片机上压片不能得到可接受的 XX 结果。公司管
理人员声称你们要使用 XX 压片机（ID MPDRCM01）用于 XX 片剂的商业化生产。
18. 印度 Strides Pharma 20180926
The specifications for components, drug product containers or closures and labeling are
deficient in that they do not include a description of the testing to be performed.
组份、制剂容器或密闭器和标签的质量标准有缺陷，未包括对要执行的检测的描述。
The QC test method for incoming acceptance of bottles used for packaging of (b)(4)
Solution USP (b)(4)mEq/(b)(4)mL does not specify to examine the (b)(4) of the bottles.
QC 对 XX 溶液包装用瓶的进厂接收检测方法未指定要检查瓶子的 XX。
19. 印度 Lupin 20181105
Appropriate controls are not exercised over computers or related systems to

assure that changes in master production and control records or other records
are instituted only by authorized personnel.
未对计算机或相关系统采取适当的控制用以确保只有经授权的人员才可修改主生产和
检验记录或其它记录。
a) Control over the computerized system in QC laboratory is deficient. Your QC

laboratory Manager has permission to allow modification tothe sequences in
HPLC and GC systems. Your QC laboratory review does not review the
modification to the sequence after unlocking and change to the sequence. Your
QC reviewer even stated that they do not investigate modifications to
thesequences during normal review process and accepts the audit trail report as
“sequence modified”.
对 QC 实验室的计算机化系统控制有缺陷。你们的 QC 实验室经理有权限对 HPLC 和

GC 系统的序列进行修改。你们的 QC 实验室审核并不会审核解锁之后的序列修改及变
更。你们的 QC 审核员甚至声称他们在日常审核过程中并不会对序列修改进行调查，并
且会接受“序列已修改”的审计追踪报告。
You stated that the unlocking permissions should be approved by QA and are
kept in modified folder for that specific sequence. You failed to provide a copy of
a modified sequence which is approved by QA. When I asked for traceability of
the permissions you stated that the permission records are not traceable.
你们声称解锁权限要由 QA 批准，并保存在特定序列的修改后文件夹中。当我索要许可
追溯时，你们未能提供修改后由 QA 批准的序列副本，你们声称许可记录是不能追溯的
b) Your procedure (QCD-60, QCD61, and ITP-034) for control of computerized

systems does not have instruction modification control over sequences in HPLC
and GC and (b)(4) creation of folders standalone instrument such as FTIR, UV-
Vis, etc., and locking of the folders at the (b)(4).
你们的计算机化系统控制程序（ QCD-60、QCD61 和 ITP-034）中并没有修改 HPLC

和 GC 中序列的控制权修改指导，以及为单机版仪器如 FTIR、紫外-可见光等创建文件
夹和在 XX 锁定这些文件夹的指导。
Each batch of drug product required to be free of objectionable microorganisms is not

tested through appropriate laboratory testing.
没有通过适当的实验室测试对需要没有致病菌的每批药品进行测试。
Specifically, you do not conduct sterility testing on any finished sterile drug products.
具体而言，您不对任何成品无菌药品进行无菌检测。
Each batch of drug product purporting to be pyrogen-free is not laboratory tested to

determine conformance to such requirements.
声称无热原的每批药品未经实验室测试以确定是否符合此要求。
a) You do not have endotoxin analysis for any of the sterile stock solutions of veterinary
drug products you produce.
a）您没有对您生产的任何兽药产品的无菌储备溶液进行内毒素分析。
b) The endotoxin test method used for human sterile stock solution is not a compendial
method.
b）用于人体无菌储备溶液的内毒素检测方法不是药典方法。
c) You do not conduct any endotoxin testing for any finished sterile drug products
including intrathecal products that contain Morphine Sulfate, Bupivacaine, Fentanyl,
Clonidine, Baclofen or Hydromorphone.
c）您未对任何成品无菌药品进行任何内毒素检测，包括含有硫酸吗啡、布比卡因、芬太尼、
可乐定、巴氯芬或氢吗啡酮的鞘内产品。
Testing and release of drug product for distribution do not include appropriate laboratory
determination of satisfactory conformance to the identity and strength of each active
ingredient prior to release.
分销药品的测试和放行不包括适当的实验室测定，确定在放行之前每种活性成分的鉴别和
剂量的令人满意的符合性。
Specifically, you do not conduct any potency testing for finished sterile drug products.
具体而言，您未对成品无菌药品进行任何效力测试。

分销药品的检测和放行不包括适当的实验室测定，在放行之前确定每种活性成分的鉴别和
剂量的令人满意的符合性。
Specifically, your firm performs potency testing at various random intervals on products
produced. However, there is no set schedule or frequency for when potency testing will
be performed. Your firm's specification for potency is (b)(4)% to (b)(4)%. Your firm
released 3 products to patients with Out-of-Specification (OOS) potency results.
具体而言，贵公司对生产的产品在不同的随机间隔进行效力测试。然而，何时进行效力测
试没有设定的时间表或频率。贵公司的效力标准是 XX%－XX%。贵公司向患者放行了 3 次
有超标（OOS）效力结果的产品。
Product Lot BUD Sterile/ Date Test Test Released
产品 Number Date Non-Sterile Produced Date Result to patients
批号日期无菌/非无菌生产日期检测日期检测结果放行
Glutathione 12191702 90 Sterile 12/19/17 1/10/18 92.5% Yes –(b)(4)
200mg Injection Days 无菌 2/12/18 88.0% patient
谷胱甘肽注射液天是-XX 患者
DHEA 75 mg 09081701 180 Non-Sterile 9/8/17 9/20/17 86.1% Yes –(b)(4)
capsules Days 非无菌 patients
脱氢表雄酮胶囊天
Alprostadil/Papareri 11141713 60 Sterile 11/14/17 11/27/17 95.2% Yes –(b)(4)
ne/Phentolamine Days 无菌 12/26/17 83.2% patient
Injection 60mcg, 30 天
mg, 3 mg
前列地尔/罂粟碱/
酚妥拉明注射液
Furthermore, on potency results that are OOS your firm does not have a procedure in
place on how to handle these failed results. Also, your firm did not conduct an
investigation into each of these failed potency results that were released to patients.
此外，对于 OOS 效力结果，你公司没有关于如何处理这些失败结果的程序。并且，你公司
没有对放行给患者的这些失败的效力结果进行调查。
Drug product component testing is deficient in that at least one specific test to verify the
identity of each component is not performed.
药物产品成分测试的缺陷在于，未进行至少一种用于确认每种成分的身份的特定测试。
a.) Specifically, your firm does not perform any identity testing on incoming raw
materials.
a）具体而言，贵公司未对进厂原材料进行任何鉴别测试。
b.) Your firm receives raw materials and peptides from suppliers both domestically
and internationally. However, your firm has never audited any of these suppliers.
b）你公司接收来自国内和国际供应商的原材料和多肽。然而，你公司从未审计过任何这些
供应商。
There is no written testing program designed to assess the stability characteristics of
drug products.
没有专门设计用于评估药品稳定性特征的书面测试计划。
Specifically, there is no written stability program designed to assess the stability
characteristics of drug products. For example, Glutathione 200mg Injection (lot
12191702) was not within its BUD date with a 88.0% potency result on 2/12/18 and
Alprostadil/ Paparerine/Phentolamine Injection 60mcg, 30 mg, 3 mg (lot 11141713) was
not within its BUD date with a 83.2% potency result on 12/26/17.
具体而言，没有旨在评估药品稳定性特征的书面稳定性计划。例如，谷胱甘肽 200mg 注射
液（批号 12191702）不在其 BUD 日期内，2018 年 2 月 12 日效力为 88.0%，前列地尔/
罂粟碱/酚妥拉明注射液 60µg，30mg，3mg（批号 11141713）不在其 BUD 日期内，
2017 年 12 月 26 日效力为 83.2%。
Product Lot BUD Sterile/ Date Test Test Released
产品 Number Date Non-Sterile Produced Date Result to patients
批号日期无菌/非无菌生产日期检测日期检测结果放行
Glutathione 12191702 90 Sterile 12/19/17 1/10/18 92.5% Yes –(b)(4)
200mg Injection Days 2/12/18 88.0% patient
Alprostadil/Papareri 11141713 60 Sterile 11/14/17 11/27/17 95.2% Yes –(b)(4)
ne/Phentolamine Days 12/26/17 83.2% patient
Injection 60mcg, 30
mg, 3 mg
Each batch of drug product required to be free of objectionable microorganisms is not

tested through appropriate laboratory testing.
要求没有致病菌的每批药品没有通过适当的实验室测试进行测试。
Specifically, your firm does not perform sterility and endotoxin testing on batches of
sterile hazardous and non-hazardous drug products of (b)(4) vials/bottles or less.
Examples include, but are not limited to:
具体来说，您公司未对 XX 瓶或更少的无菌危险和非危险药品进行无菌和内毒素检测。示
例包括但不限于：
 抗坏血酸注射液 450mg/mL，批号 07202018@19，BUD 09/03/18
 Arginine HCL 200mg/mL Injectable, Lot 02082018@13, BUD 03/25/18
 精氨酸 HCL 200mg/mL 注射剂，批号 02082018@13，BUD 03/25/18
 Magnesium Sulfate 500mg/mL Injectable, Lot 08282018@2, BUD 10/12/18
硫酸镁 500mg/mL 注射剂，批号 08282018@2，BUD 10/12/18
分销药品的测试和放行不包括适当的实验室测定，在放行前确定每种活性成分的特性和强
度令人满意的符合性。
A. Your firm does not perform potency testing on all batches of sterile drug products
prior to release and distribution. Examples include, but are not limited to:
你公司未在放行和分销之前对所有批次的无菌药品进行效力测试。示例包括但不限于
 Ascorbic Acid 450mg/mL Injectable, Lot 07062018@2, BUD 08/20/18
 抗坏血酸 450mg/mL 注射剂，批号 07062018@2，BUD 08/20/18
 Magnesium Sulfate 500mg/mL, Lot 08282018@2, BUD 10/12/18
 硫酸镁 500mg/mL，批号 08282018@2，BUD 10/12/18
 Dexpanthenol USP 250mg/mL, Lot 02082018@15, BUD 03/25/18
 右泛醇 USP 250mg/mL，批号 02082018@15，BUD 03/25/18
 Sermorelin GHRP 6 GHRP 2 PF 6mg/3mg/3mg Injectable, Lot 08302018@13,
BUD 02/26/19
 舍莫瑞林/生长激素释放肽-6/生长激素释放肽-2 PF 6mg/3mg/3mg 注射剂，批号
08302018@13，BUD 02/26/19
B. Your firm released and distributed (b)(4) vials of Bremelanotide (PT141) 20mg
Injectable Lot 05312018@4, BUD 07/30/18, with super-potent results for
Bremelanotide of 114.3% (specification (b)(4) ).
你公司放行和分销了 XX 瓶的布美诺肽（PT141）20mg 注射剂（批号
05312018@4，BUD 07/30/18），布美诺肽的超高效结果为 114.3%（标准 XX）。
C. Your firm released and distributed (b)(4) vials of Sermorelin GHRP 6 GHRP 2 PF
6mg/3mg/3mg Injectable, Lot 05312018@3, BUD 11/27/18, with super-potent
results for GHRP-2 of 112.4% (specifications 90-110%) and GHRP-6 of 113.8%
GHRP-6 (specifications (b)(4) ).
你公司放行和分销了 XX 瓶舍莫瑞林/生长激素释放肽-6/生长激素释放肽-2 PF
6mg/3mg/3mg 注射剂（批号 05312018@3，BUD 11/27/18），生长激素释放肽-2
的超高效结果为 112.4%（标准 90-110%），生长激素释放肽-6 为 113.8%（标准
XX）。
Your firm released and distributed (b)(4) vials of Sermorelin GHRP 6 GHRP 2 PF
9mg/9mg/9mg Injectable, Lot 05242018@2, BUD 11/20/18, with super-potent results for
GHRP-6 of 111.3% (specifications (b)(4) ).
你公司放行和分销了 XX 瓶舍莫瑞林/生长激素释放肽-6/生长激素释放肽-2 PF
9mg/9mg/9mg 注射剂（批号 05242018@2，BUD 11/20/18），生长激素释放肽-6 的超高
效结果为 111.3%（标准 XX）。
There is no written testing program designed to assess the stability characteristics of

drug products.
没有设计用于评估药品稳定性特征的书面测试计划。
Specifically, your firm lacks written procedures for a continuous stability program; and
your firm does not perform stability testing for sterility or endotoxin on sterile hazardous
and non-hazardous drug products. For example, Stability/BUD study for Ascorbic Acid
450mg/mL Injectable, Lot 05012018@42 to extend the BUD from 45 days to 90 days did
not have sterility or endotoxin testing at the final test time point dated 07/27/18.
具体来说，你公司缺少一个连续稳定性程序的书面计划；并且你公司不对无菌危险和非危
险药品进行无菌或内毒素稳定性测试。例如，抗坏血酸 450mg/mL 注射剂（批号
05012018@42）的稳定性/BUD 研究将 BUD 从 45 天延长至 90 天，但在最终测试时间点
（2018 年 07 月 27 日）没有进行无菌或内毒素测试。
23. 印度 Dishman Carbogen Amcis Ltd.
2.) Laboratory investigations for OOS intermediate batches are not conducted,
2.）不进行中间体批次 OOS 的实验室调查。
Specifically, according to SOP BDQC-311 for OOS investigations (effective 07/16/2018),
OOS is to be conducted on "...all quantitative and qualitative tests of...intermediates..."
An investigation of an OOS impurity result in the (b)(4) intermediate, batch (b)(4) for (b)
(4) was not conducted.
具体而言，根据 OOS 调查 SOP BDQC-311（生效日期 2018 年 7 月 16 日），应对“……
中间体的……所有定量和定性检测……”进行 OOS 调查。但在 XX 中间体的一个杂质 OOS
结果的调查中，XX 的 XX 批没有进行调查。
24. 印度 Dr. Reddy’s 20181114

Investigations of a failure of a batch or any of its components to meet any of its
specifications did not extend to other batches of the same drug product that may
have been associated with the specific failure or discrepancy,
对药品批次或其组分不符合其质量标准的调查未延伸至其它批次可能与该失败或不符
合有关的相同药品。
Specifically, investigation into confirmed Out of Specification (OOS)results and
identified manufacturing equipment defects were not included and considered for
batch disposition of previously manufactured products, on the affected
manufacturing equipment. The Quality Unit did not expand the sampling and
teting program on the affected batches observed withlow or OOT assay results,
manufactured with known equipment defect.
具体来说，对已确认 OOS 结果和已识别的生产设备缺陷的调查未包括和考虑之前在受
影响生产设备上所生产药品的批处理。质量部门未延伸取样和检测计划至采用已知有缺
陷设备生产的含量较低或 OOT 含量的受影响批次。
(b)(4) Tablet, (b)(4)mg, batch # (b)(4) was rejected dueto a confirmed OOS (A.V.=
(b)(4), exceeding the A.V. value of (b)(4) for (b)(4) requirements for Uniformity of
Dose (UOD). This batch also yield low assay results (b)(4).
XX 片剂 XXmg，批号 XX 由于确认的 OOS 结果被拒收，A.V.=XX，超出剂量均一性要
求的 A.V.值（UOD）。该批次含量结果亦偏低。
The OOS investigation 310016050 was initiated on 31 Aug18, identified a defect
on the (b)(4) seal to the (b)(4) machine (b)(4) (PR-E648), resulting in poor (b)(4)
operations on the (b)(4). The seal leak resulted in the process control (HMI) to
run the (b)(4) to near (b)(4) to maintain the (b)(4) deviating from the typical (b)(4).
The OOS investigation identified low assay values on previously manufactured
batches of (b)(4) Tablet, manufactured on the same defective (b)(4) Machine (b)
(4) (PR-E648).(b)(4) Tablet batch numbers (b)(4) expiration date (b)(4) (b)(4)
expiration date (b)(4) and (b)(4) expiration date (b)(4) reported lower assay
results of(b)(4) respectively (assay specification limit = (b)(4)%).
OOS 调查 310016050 于 20180831 启动，发现 XX 设备（PR-E648）XX 密封有缺陷，
导致 XX 上操作 XX 不良。密封泄漏导致工艺控制（HMI）运行至近 XX，保持偏出常规
XX。OOS 调查发现之前在同一有缺陷 XX 设备（PR-E648）上所生产 XX 片剂的批次
含量值偏低。XX 片剂批次 XX 有效期 XX 有报告含量结果偏低，结果为 XX（含量标准
限度=XX%）。
During the manufacturing of the (b)(4) previously (b)(4) Tablet batches (b)(4) the
(b)(4) were operating near the (b)(4) indicating the same equipment defect. No
additional tests were performed to justify the release of the impacted batches,
manufactured on the equipment with known equipment defect. All (b)(4) impacted
batches of (b)(4) Tablets were released for distribution to USA market.
在之前 XX 片剂批次 XX 生产期间，XX 是在 XX 近处操作，其显示出相同的设备缺陷。
未进行附加检测来论证在同一已知有缺陷设备上所生产的受影响批次的放行。所有 XX
受影响批次 XX 片剂均已放行销售至美国市场。
对已销售或未销售的产品批次中未经解释的不符合情形未进行彻底审核。
Specifically, your Quality Unit failed to conduct a comprehensive evaluation and
implement appropriate and effective corrective and preventive actions to prevent
reoccurrence of aborted HPLC sequence events.
具体来说，你们的质量部门未能执行全面评估和实施适当的有效 CAPA 防止 HPLC 序
列中断事件重复发生。
During the period between 01 Jan 2018 to 15 Oct 2018, there were approximately
175 events identified as “repeated incidences” from QC, including at least 19
events due to column conditioning and 15 poor column performances that
resulted in aborted or invalid HPLC sequence runs. Based onyour assessment
and identified root causes, insufficient actions were taken by the Quality unit to
ensure the robustness and suitability of the analytical test procedures and the
equipment. Incident events with similar root causes were not thoroughly reviewed
for historical trends and corrective actions were not implemented to reduce the
occurrences of atypical events from similar root causes.
在 20180101-20181015 期间，有约 175 件 QC 事件被识别为“重复事件”，包括至
少 19 件柱平衡和 15 件柱效不良导致 HPLC 序列运行中断或无效。根据你们的评估和识
别出的根本原因，质量部门所采取的措施不足以确保分析方法和设备的稳健性和适用
性。类似根本原因的事件未进行彻底审核发现历史趋势，未实施纠正措施减少类似根本
原因的异常事件重复发生。
未遵守书面稳定性试验程序。
Specifically, your Quality unit failed to comply with the testing at pre-established
intervals in the stability protocol and as per the SOP# CQA-025-04,
“MANAGEMENT OF STABILITYSTUDIES” under section 5.7.16, requiring stability
samples analysis to be completed within (b)(4) from due date of withdrawal date.
The following are the recurrent deviations initiated due to the failure to comply
with the SOP requirement:
具体来说，你们质量部门未按稳定性方案中预先设定的时间间隔进行检测，未遵守
SOP#CQA-025-04“稳定性研究管理”第 5.7.16 部分中要求稳定性样品分析应在撤销
日到期日内 XX 日内完成检测。以下是由于不符合 SOP 要求启动的重复偏差：
a. DEV-MA-057-18-0003 initiated on May 12, 2018—included (b)(4) batches from
(b)(4) products.
DEV-MA-057-18-0003，20180512 启动，包括 XX 个产品 XX 个批次
b. DEV-MA-057-18-0002 initiated on February 6, 2018—included (b)(4) batches
from (b)(4) products.
c. DEV-MA-057-16-0013 initiated on May 4, 2016—included (b)(4) batch from (b)
(4) product.
d. DEV-MA-057-16-0010 initiated on March 19,2016—included (b)(4) batches from
(b)(4) products.
e. DEV-MA-057-16-0001 initiated on January 6,2016—included (b)(4) batches
from (b)(4) products.
Quality Assurance comments on the deviation # DEV-MA-057-18-0002 states that
the stability study and analysis was not completed because “… analysis of other
stability batches was planned and testing priority of other batches”. On December
1, 2018, the Quality Control Manager (KC) stated that the reason for the delay in
testing was because the Quality Control laboratory had focused on testing of
commercial batches. The following are some examples of the affected exhibit
batch samples for the US Market:
QA 对偏差# DEV-MA-057-18-0002 的建议是稳定性研究和分析未写完整，因为“…
…其它稳定性批次的分析已排好了计划，并且其它批次检测更为优先”。
20181201，QC 经理（KC）声称检测延迟的原因是 QC 实验室集中力量在商业批次的
检测。以下是受影响的美国申报批次样品的例子：
Product 产品 Batch Stability time point Number of OOS/OOT Reported on
批号稳定性时间点 days delayed the following tests
延误天数 OOS/OOT 报告项目
(b)(4) Capsules (b) (b)(4) 25°C /60%RH 42 Related substances
(4)mg -24 month 有关物质
(b)(4) suspension (b)(4) 40°C /75%RH 93 Assay 含量
USP (b)(4)mg/(b) 25°C /60%RH Related substances
(4)ml 30°C /65%RH 有关物质
-6 month (b)(4) content XX 含量
(b)(4) suspension (b)(4) 40°C /75%RH 93 Related substances
USP (b)(4)mg/(b) 25°C /60%RH 有关物质
(4)ml 30°C /65%RH
-6 month
(b)(4) suspension (b)(4) 40°C /75%RH 93 Assay
(4)ml 30°C /65%RH 含量、有关物质
-6 month
(4)ml 30°C /65%RH 含量、有关物质
-6 month
USP (b)(4)mg/(b) 25°C /60%RH 含量
(4)ml 30°C /65%RH
-6 month
(4)ml 30°C /65%RH
-6 month
(4)ml 30°C /65%RH
-6 month

Established laboratory control mechanisms are not documented at the time of
performance.
在实施检测时未记录既定的实验室控制方法。
A. There is no defined process regarding the issuance of Certificate of
Analyses (COAs) for (b)(4) analyses conducted in the QC Laboratories.
Per your VP of CQA, the QC Laboratories issue COAs for (b)(4) testing for
only regulatory submission. However, this statement is not described in
SOP #QC2-067-04 (Certificate of Analysis, 01/16/18 effective date). In
addition, we observed a folder labeled “12.12.18” located on the
Microbiology Laboratory’s PC drive filled with data was being shared
among the laboratory personnel. The approval dates on the COAs do not
match the approval date on the test data sheet and date of release. The
tested (b)(4) reflected on the COAs was then utilized to manufacture the
following US marketed products
没有规定在 QC 实验室对 XX 分析执行的 COA 签发流程。根据你们 CQA 的 VP
说法，QC 实验室的 XX 检测只为注册申报签发 COA。但是，此说法并未写在
SOP #QC2-067-04（COA，生效日期 20180116）中。另外，我们在微生物实
验室的 PC 驱动器中发现有一个名为“12.12.18”的文件夹，里面装满了共享
给实验室人员的数据。COA 上的批准日期与检测记录上的批准日期和放行日期
不符合。在 COA 上显示的检测 XX 被用来生产销往美国的药品。
（此处列出了 14 项原料的分析编号，取样日期，用于产品名称和批号）
B. There is no documented log for the equipment maintained by your firm
when (b)(4) (ID #QC2-PB-02) is cleaned. This (b)(4) is used for
transferring environmental media plates from the Microbiology Lab to the
aseptic facility ((b)(4)) and from the facility to the Microbiology Laboratory.
There is a label on the (b)(4) that states, “Surface sanitize the articles
using a (b)(4) unloading”. We observed your firm recorded several OOS
investigations for environmental monitoring including EMO/OOS/18-001
where the result for Location #(b)(4) was found exceeding the acceptance
limits (b)(4)CFU (Action/Level Limit (b)(4) CFU) related to (b)(4) within the
(b)(4) Block.
你们公司对 XX（ID #QC2-PB-02）清洁维护时没有记录在日志上。该 XX 用于
将环境监测用培养碟从微生物实验室送至无菌设施 XX，并从该设施送到微生
物实验室。在 XX 上有一个标签写着“采用 XX 卸载对器材进行表面灭菌”。我
们发现你们公司记录了几个环境监测的 OOS 调查，其中有一个是
EMO/OOS/18-001，发现在 XX 车间与 XX 有关的 XX 位置的结果超出可接受
限度 XXCFU（实际/限度 XX CFU）。
24. Lupin Limited 20190219

There is a failure to thoroughly review any unexplained discrepancy and 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.
未能彻底审核所有无合理解释的不符合情形，以及已销售和未销售药品及其组份不符合
其质量标准。
1. The firm’s procedure CQA-004-17 “Handling of out of Specification test results”
Section 5.1.12 (a) states – “Retesting shall be done by (b)(4) analysis following
the approved laboratory procedure preferably by original analyst from the portion
of sample available in the laboratory”. The procedure lacks statistical justification
to release the batch based on retest data.
公司的程序 CQA-004-17“OOS 结果处理”第 5.1.12(a)部分说“应由 XX 分析按照批
准的实验室程序（最好）由原化验员使用化验室现有样品的一部分执行复测”。该程序
缺少对基于复测数据放行批准的统计学论证。
a) OOS/C/18/GA/FP/042 was initiated on April 09,2018 to probe the failure in
assay for (b)(4) in (b)(4) and (b)(4) tablets USP (b)(4)mg/(b)(4)mg, Batch Nos. (b)
(4) ((b)(4)%) and (b)(4) ((b)(4)%) against a specification limit of (b)(4)% to (b)
(4)%. The initial samples of batch (b)(4) and (b)(4) prepared on April 06, 2018
were then reinjected, re-vialed and injected after re-dilution on April 09, 2018
without establishing system precision as part of hypothesis test. Based on passing
result obtained from re-dilution, root cause was identified as dilution error and (b)
(4) new sample was prepared on April 13, 2018. The results tabulated below do
not substantiate the area response obtained for standard and sample during
hypothesis and sample retest. Also, the impact of standard response on the assay
result was not evaluated. Approximately +4% bias was observed in the area
response between the initial ((b)(4)) VS fresh ((b)(4)) standard responses.
However, the sample response for initial preparation and (b)(4) confirmatory
preparation were consistent to the sample weights. The review of OOS by your
third-party consultant concluded that theroot cause determined was unsatisfactory,
however finally concurred with the firm’s investigation.
OOS/C/18/GA/FP/042 于 20180409 启动，用于调查 XX 片剂 2 个批号含量不合格
（检测结果 XX%标准限度 XX%）。20180409，公司重新进样、重新装瓶以及重新稀释
后进样了 2 批次在 20180406 的初始样品，但没有确立系统精度作为假设性测试的一

部分。根据重新稀释后得到的合格结果，公司将稀释错误作为根本原因，并于
20180413 重新制备了 XX 新样品。以下表格内的结果并不能支持假设性和样品复测中
得到的对照品和样品响应面积。另外公司亦未评估对照品响应对含量结果的影响。在初
始 VS 新制对照品响应中发现有+4%的响应面积偏倚。但是，初始检测的样品响应和
XX 确证性检测却与样品重量相对应。你们第三方顾问对 OOS 审核结论是不满意对根本

原因的确定，但最后还是同意了公司的调查。
Batch 批号 Hypothesis 假设
Initial Reinject Re-vial Re-dilute Fresh
assay% 重新进样重新分瓶重新稀释 preparation
初检新配
(b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
(b)(4) (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
(b)(4) (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
Standard weight (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
Standard response (b)(4) (b)(4) (b)(4) (b)(4) (b)(4) (+4%)
Sample weight (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
Batch (b)(4)
Sample weight (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
batch (b)(4)
Sample response (b)(4) (b)(4) (b)(4) (b)(4) (b)(4)
batch (b)(4)
These batch ((b)(4)and (b)(4)) were released to US market based on (b)(4)
confirmatory test.
根据 XX 确证检测结果，公司将这些批次（XX 和 XX）放行到了美国市场。
b) OOS/C/17/GA/FP/144 was initiated on December13, 2017 to probe the failure
in unknown impurity ((b)(4)%) at relative retention time (RRT) of (b)(4) for (b)(4)
Capsules, (b)(4)mg batch (b)(4) against a specification limit of (b)(4)%. On
reinjecting the same initial vialas part of hypothesis study, no peak was observed
at RRT (b)(4) however a new peak was observed at RRT (b)(4). Then, a fresh
sample preparation was injected anda peak was observed at RRT (b)(4) ( (b)
(4)%), however it was named as Impurity (b)(4) Per test procedure Impurity (b)(4)
elutes at RRT (b)(4). The molecular mass of impurity peak was identified at R&D
and based on the molecular mass the impurity was assumed to be coming from (b)
(4) and on injection of (b)(4) standard, the peak for (b)(4) eluted at RRT (b)(4).
The investigation concluded that the OOS for unknown impurity at RRT (b)(4) is
due to (b)(4) contamination attributing the failure to Analyst error whereas (b)(4)
peak elutes at RRT (b)(4).The batch was released to US market based on new (b)
(4) sample preparation made on 5 th March 2018 wherein no peak eluted at RRT
(b)(4) but a peak at RRT (b)(4) ((b)(4)%).
OOS/C/17/GA/FP/144 于 20171213 启动，原因是 XX 胶囊批次 XX 的 XX 相对保留时
间（RRT）的未知杂质超标（结果 XX%标准 XX%）。作为假设性研究的一部分，公司
重新进样相同小瓶样品溶液，在 RRT XX 处未发现峰，但在 RRT XX 处发现一个新的
峰。然后，公司重新进样了新配制的样品溶液，在 RRT XX 处发现一个峰（XX%），但
该峰被指认为杂质 XX。根据检测方法，杂质 XX 应在 RRTXX 流出。R&D 对杂质峰的分
子量进行了鉴定，根据分子量，该杂质被认定为来自 XX。在 XX 对照品进样中，XX 的
峰在 RRT XX 处流出。尽管 XX 峰在 RRT XX 处流出，但调查结论为 RRT XX 的未知杂
质 OOS 是由于 XX 污染，归因为化验员错误。基于 20180305 新配制样品检测结果，该
批次被放行至美国，但其实在 RRT XX 处没有峰流出，而在 RRT XX 处有一个峰。
2. The investigation (DEV-GO-276-18-0061) conducted on (b)(4) Tablets USP (b)
(4) (b)(4)mg, batch (b)(4) (Expiry July 2020) was found deficient. (b)(4) spots were
observed over the finished drug product during the AQL check performed (b)(4)
manual inspection. Based on the finding, the batch was manually inspected again,
and all together separated 224957 defective tablets out of (b)(4) tablets. The (b)
(4) batch yield inclusive of manufacturing loss ((b)(4)%)) did not meet the batch
record specification limit of (b)(4) to (b)(4)%. Your investigation concluded that the
(b)(4) spots were possibly from the (b)(4) due to improper (b)(4) at (b)(4) stage.
However, no qualitative test was performed to confirm that the spots were from the
(b)(4) to rule out other contaminants. The batch was released to US market.
调查 DEV-GO-276-18-0061 是一个片剂 USP 批号 XX 在目视检查 AQL 测试期间发现
成品上有 XX 斑。根据发现的问题，该批次被重新进行了人工检查，在 XX 片中分拣出
224957 片有缺陷。该批次收率（包括生产损耗）为 XX%不符合批记录所定标准（XX
%-XX%）。你们调查结论是 XX 斑点可能是因为 XX 步骤 XX 不当来自 XX。但是，你们
并没有进行定性检测以确认该斑点是来自 XX 从而排除其它污染物。该批次被放行到了
美国市场。
四．设施和设备系统

All processing lines and major equipment used during the production of a batch
of drug product is not properly identified at all times to indicate the phase of
processing of the batch. Electronic signatures based on are used, but they do not
meet the requirements of 21 CFRPart 11.
所有药品一个批次生产所用的生产线和主要设备未进行恰当识别以显示其批处理的阶段。
使用了电子签名，但不符合 21CFR 第 11 部分要求。
A. Your firm uses Programmable Logic Controllers (PLC) equipment during
the manufacturing of drug products, which require a password and user name
to operate. Your firm uses the following manufacturing PLC equipment that are
not password protected:
你公司在药品生产中使用了 PLC 设备，其需要一个密码和用户名来操作。你公司使用了以
下生产 PLC 设备，但无密码保护：
Location Number of Equipment with PLC
without Password Protection
位置有 PLC 但无密码保护的设备数据
(b)(4)-Block 322
(b)(4)-Block 6
(b)(4)-Block 95
Grand total 423
合计
B. In addition, on 22 March 2018, we observed a manufacturing employee
operating the (b)(4), Equipment ID AB/TM/23, in (b)(4)-Block. This equipment has
PLC capabilities with alarms. However, your firm does not assess alarms to verify
if the alarm affected manufacturing for the following equipment:
此外，2018-03-22，我们发现一位生产员工正在 XX 车间操作 XX，设备编号
AB/TM/23。该设备有报警功能的 PLC。但是你公司并未评估报警功能以核查受报警影响的
生产，此为设备有：
Location Number of Equipment with that
位置 does not utilize alarms 未使用报警
的设备数量
(b)(4)-Block 63
(b)(4)-Block 19
(b)(4)-Block 14
Grand 96
total
(b)(4) drug products were not tested forthe presence of (b)(4), when a reasonable
possibility existed that a (b)(4) drug product has been exposed to a cross-
contamination with (b)(4).
在 XX 药品存在被交叉污染的合理可能性时，未检查该药品中是否存在 XX。
Specifically, on 21 March 2018, we observed unsealed bottles and loose capsules
of (b)(4) in the Sample Storage Room in non-dedicated areas the General
Laboratory on the (b)(4) floor where other (b)(4) products are also stored. Your
firm’s QC Manager explained the bottles of (b)(4) are opened in order to obtain
a physical description. However, this analysis is conducted in an uncontrolled
environment in the Central QC Laboratory, where high traffic volume occurs for
sample analysis of all (b)(4) products.
具体来说，2018-03-21，我们在 XX 楼层 XX 一般化验室非专用区域的样品存贮间里发现
未封口的瓶子和未扣紧的胶囊，该房间里还存放着其它 XX 产品。你公司的 QC 经理解释说
XX 的瓶子打开是为了查看其物理性状。这样使得此种分析是在中心 QC 化验室的非受控环
境下进行，所有 XX 药品的样品分析都在该房间内，流通量很大。
The unsealed (b)(4) we observed in theSample Storage Room include, but are not
limited to the following:
注：下表数据均被覆盖，其中产品有 5 个胶囊，4 个混悬液，共 9 个产品中有 5 个 USP 产
品。
Building used in the manufacture, processing, packing or holding of drug
products are not maintained in a clean and sanitary condition and free of
infestation by rodents, birds insects, and other vermin.
用于生产、加工、包装或存贮药品的厂房未能维护其牌清洁卫生条件，以及使其免受啮齿动
物、虫鸟和其它害虫侵袭。
A. On 22 March 2018,your firm did not identify and investigate fungal growth
on the walls of the (b)(4) area as identified in work order dated 28 August
2016, From 01 July 2016-27 September 2016, according to General
Manager of Quality Assurance, (b)(4) batches of drug products were
manufactured using raw materials (e.g., API, excipients).
2018-03-22，你公司未识别和调查 2016-08-28 工作单中所发现的 XX 区域墙面上真菌滋
长。从 2017-07-01 至 2016-09-27，据 QA 总经理说，使用原料（如 API、辅料）生产了
XX 批药品。
We observed document titled “Compliance Charter -2016 Block (b)(4)” on a
computer station in the manufacturing area. That document states “Walls of (b)
(4) area became Spotted, dirty and observed with fungal growth.”
我们在生产区域一个计算机站上发现了标题为“合规—2016 车间 XX”的文件。该文件声
称“XX 区域的墙面长斑点，发现有真菌生长”。
B. In addition, your firm failed to establish, implement, and monitor a Pest
Control program and procedures inside Quality Control areas, such as, the
stability laboratory, where samples are kept and the Central and (b)(4)
laboratories where all samples are stored and analyzed. Flying insects,
including, but not limited to, mosquitos and gnats,were found too
numerous to count in the aforementioned areas.
此外，你公司未建立、执行和监测 QC 区域内虫害控制计划和程序，如保存样品的稳定性
实验室，和存贮与分析所有样品的中心和 XX 化验室。在上述区域中发现有不计其数的飞
虫，包括但不仅限于蚊子和蚊蚋。

Separate or defined areas to prevent contamination or mix-ups are deficient
regarding operations related to aseptic processing of drug products.
为防止制剂无菌工艺操作污染和混淆而分隔和界定的区域有缺陷。
Aseptic filling lines in Block (b)(4) and (b)(4) show poor design as follows:
XX 车间和 XX 车间的无菌灌装线设计不良，情况如下：
A. On 14 February 2018, I observed rough, cracked, and uneven (b)(4)
surfaces (with dislodged gaskets) used to create operational barriers
separating Grade Afilling areas in Block (b)(4) and (b)(4) from the surrounding
Grade B environment. These rough surfaces create difficult to clean surfaces in
the immediate vicinity of aseptic filling operations. The ceiling above the filling
equipment has channels surrounding each of the (b)(4) HEPA filters that are
approximately one inch wide by three inches deep that cannot be accessed with a
mop used during cleaning/sanitizing. There is extensive use of (b)(4) sealant
aroundall the HEPA filter units and various rough surfaces on the ceiling such as
mounting bolts for the filters that create a difficult-to-clean surface in the Grade
A environment.
2018-02-14 我发现 XX 车间和 XX 车间里用于建立操作屏障将 A 级灌装区与 B 级环境分
隔的 XX 表面粗糙不平（垫圈移位）。这些粗糙表面使得无菌灌装操作紧邻表面难以清洁。
灌装设备上方的天花板，每个 XX 高效过滤器（HEPA）有一些隧道包裹着，约 1 英寸宽 3
英寸深，在清洁/消毒过程中无法用抹布接触到。在 HEPA 过滤器周围使用了大量密封剂，
天花板上有大量粗糙表面，如过滤器铆钉上，这使得 A 级环境中存在难以清洁的表面。
B. Your air-flow visualization studies conducted in April 2017 show upward
flow of smoke ((b)(4)) from below waist level up towards the ceiling return
grates of Grade B areas immediately adjacent to Grade A areas. These Grade A
areas are used for loading a (b)(4) and filling sterile liquid product vials. Videos
identified with the following numbers are applicable: 188B and 190A, as well as
new videos (not serially numbered) created on 19 February 2018 during current
inspection.
你们于 2017 年 4 月所做的气流可视化研究显示从下面腰部高度向上到天花板的烟流
（XX）返回与 A 级区紧邻的 B 级区的格栅。这些 A 级区是用于装载 XX 和灌装无菌液体药
品西林瓶的。编号为 188B 和 190A（不是连续的编号）的视频，以及本次检查中 2018-
02-19 创建的新视频中显示出上述情况。
C. On 15 February 2018, I observed the aseptic filling operation for (b)(4)
injection batch #(b)(4). During this time and throughout the inspection, I
observed operators nearly constantly moving (b)(4) in the aseptic filling room (b)
(4) with their gloved hands (and gowned arms) as they moved about. However,
environmental monitoring does not include contact plates for the (b)(4) that
experience the greatest traffic during production and set-up activities. There isa
total of (b)(4) linear meters of (b)(4) in the (b)(4) room and separately (b)(4) linear
meters of (b)(4) installed in the Block (b)(4) aseptic filling room #(b)(4). There is
no scientific justification for omitting this sampling location.
2018-02-15 我查看了 XX 注射剂批号 XX 的无菌灌装操作。在此期间和整个检查期间，我
发现操作人员在无菌灌装间 XX 里用戴着手套的手（和着装的手臂）几乎不停地移动 XX。
但是，环境监测并没有包括在生产和装配过程中最大流通量的 XX 地方取接触碟样。XX 车
间的#XX 无菌灌装间内在 XX 房间里总共装有 XX 延米的 XX，分别装有 XX 延米的 XX。对
于忽略此取样点没有科学论证。

Procedures for the cleaning and maintenance of equipment are deficient
regarding inspection of the equipment for cleanliness immediately before use.
设备清洁和维护程序在使用前清洁度检查方面有缺陷。
A. Procedure #BM/EN/SOP/048-PM, version 004, titled “Visual Inspection
Machine Preventive Maintenance Procedure”, effective 31/10/2017 that is
used for finished Drug Product automated visual inspection is deficient for the
following reasons:
2017-10-31 生效的程序#BM/EN/SOP/048-PM 版本号 004，标题“目视检查设备维保
程序”用于制剂自动化目视检查因以下原因被认为有缺陷：
1. The light intensity (LUX) is not monitored or calibrated to ensure the
automated camera detection can be assured.
未监测或校正其照度（LUX）以确保自动摄像头检出问题。
2. The procedure calls for (b)(4) cleaning and preventive maintenance,
your firm has not established if (b)(4) PM is adequate or if more frequent
cleaning is needed depending on the equipment usage and number of
batches produced. The procedure states that when dust is found it is to be (b)(4)
away using a (b)(4) but the procedure does not define if the dust will be move to
other parts of the machine. The procedure calls for cleaning and preventive
maintenance to be completed by the engineering department, not by the
equipment operators.
程序要求进行 XX 清洁和维护，你公司未说明 XX 预防性维护是否充分，是否需要依据设
备使用情况和所生产批次数量而需要进行更频繁的清洁。程序说如果发现灰尘，则要使用
XX 将其除去，但程序中并未说是否灰尘会被弄到该设备的其它部分去。该程序要求由工程
部门来完成清洁和预防性维护工作，而不是由设备操作人员。
3. The proceduredoes not call for the tracking or trending of dirt, dust,
debris, or malfunctions of the machine. For example, deviation BM/DR-17/120 on
28/07/2017 was for a failed AQL for batch (b)(4). Your firm identified a possible
root cause of broken (b)(4) and that the machine had not been cleaned before
continuing the inspection of samples.
该程序并未要求对灰尘、粉尘、碎片或设备故障进行跟踪或趋势分析。例如，2017-07-28
的偏差 BM/DR-17/120 是 XX 批 AQL 失败。你们公司发现可能的根本原因为 XX 破碎，且
设备在继续检查样品之前未进行清洁。
Buildings used in the manufacturing, processing, packing of API finished
materials are not maintained in a good state of repair. Specifically,
API 成品生产、加工、包装所用厂房未能维护使其处于良好的维修状态。具体如下：
A. Ceiling area above the opening of (b)(4) -01 and (b)(4) #(b)(4)-17 used for
(b)(4) production is not maintained in a manner that will prevent foreign
object from falling inside the(b)(4) when opened. The ceiling needs repairs
and is cracked. In addition, there is a big hole in the ceiling above the
opening of (b)(4) #(b)(4)-06/01 used for (b)(4) production ( (b)(4) is the
Intermediate used for (b)(4) API for the US market).
XX 生产所用的 XX-01 和 XX-17 开口上方天花板未能良好维护使其可防止异物在 XX 打开
时掉入其中。天花板已开裂，需要修缮。另外，XX 生产（XX 是销往美国的 XX 原料药所用
中间体）所用的 XX-06/01 开口处上方天花板上还有一个大洞。
5. 瑞士 Akorn AG 20180503
regarding operations related to aseptic processing of drug products.
药品无菌工艺相关操作在区隔和界定区域以防止污染或混淆方面有缺陷。
Specifically, qualification for aseptic filling area, room (b)(4) (ISO class A and B), is
deficient in that the smoke study failure for the room is not identified and
investigated. This room currently is used for filling and packaging of drug
products which are commercially distributed.
具体来说，无菌灌装区域 XX 房间（ISO A 级和 B 级）的确认有缺陷，未发现该房间烟雾
实验失败亦未进行调查。该房间目前用于商业化销售药品的灌装和包装。
Procedures for the cleaning and maintenance of equipment are deficient
regarding sufficient detail of the methods, equipment,and materials used in the
cleaning and maintenance operation, and the methodsof disassembly and
reassembling equipment as necessary to assure proper cleaning and
maintenance.
设备清洁和维护程序未详细写明清洁和维护操作中所用的方法、设备和物料，亦未写明为
确保适当清洁和维护所需的拆卸方法和重新组装方法。
1. The efficacyof the (b)(4) system used for sanitization and elimination of
contaminants in the aseptic fill room is not evaluated for the hard to reach areas.
For example,your room qualification for aseptic fill room (b)(4) which includes the
filling machine (b)(4) (ID# A31) did not evaluate the penetration level and efficacy
ofthe (b)(4) inside the filling machine (b)(4).
用于无菌灌装间灭菌和清除污染所用的 XX 系统的有效性中未评估其难接触区域。例如，
你们无菌灌装 XX 房间的确认，包括灌装机 XX（ID#A31）未评估灌装机 XX 里的 XX 的穿
透水平和有效性。
2. The cleaning and disinfecting procedure does not include detailed cleaning
and disinfecting procedure when maintenance is conducted on the filling
machine.
清洁和灭菌程序未包括对灌装机进行维护后详细的清洁和灭菌程序。
assure that changes in master production and control records or other records
are instituted only by authorized personnel.
对计算机和相关系统未进行适当控制以确保对主生产和检验记录及其它记录的修改仅能由
经授权的人员执行。
Your firm’s manufacturing equipment are not21 CFR part 11 compliant. For
example,
你公司的生产设备不符合 21CFR 第 11 部分要求。例如
A) There are total (b)(4) standalone manufacturing equipment which are not
equipped with HMI/PLC/SCADA system. There is no time stamped audit trail, data
management, alarm management, archival and retrieval of records on these
standalone manufacturing equipment.
总共有 XX 台单机生产设备，未配备 HMI/PLC/SCADA 系统。这些单机生产设备没有带时
间戳的审计追踪、数据管理、报警管理、记录归档和检索。
These equipment includes but are not limited to (b)(4) and (b)(4) that are
operated at (b)(4) speed per manufacturing instructions given in BMRs. However,
there is no setting as (b)(4) on these equipment. Your production operator was
unable to explain and show the equipment operating speed. This information was
notclearly defined at the time of process validation that could significantly impact
the quality of products manufactured for the U.S. market.
这些设备包括但不仅限于 XX 和 XX，依据 BMR 中给定的生产指令在 XX 速度下操作。但是
在这些设备上并没有 XX 设置。你们的生产操作人员无法解释和展示设备的运行速度。此信
息在工艺验证时并未清楚界定，可能会严重影响为美国市场生产的产品质量。
B) Your firm’s total (b)(4) standalone production equipment has an inbuilt HMI
system but none of these equipment have time stamped audit trail, data
management, alarm management, archival and retrieval of records. These
equipment includes but are not limited to (b)(4)
你公司的共 XX 台单机生产设备有内置式 HMI 系统，但这些设备都没有带时间戳的审计追
踪、数据管理、报警管理、记录归档和检索。这些设备包括但不仅限于 XX。
C) Your firm’s total (b)(4) standalone production equipment has an inbuilt
SCADA systembut none of these equipment have time stamped audit trail, data
management, alarm management, archival and retrieval of records. These
equipment have capabilities for printing of audit trail report in real time for only
critical process parameters which is complied with the BMRs.
你公司的共 XX 台单机生产设备有内置式 SCADA 系统，但这些设备都没有带时间戳的审
计追踪、数据管理、报警管理、记录归档和检索。这些设备只能为关键工艺参数实时打印审
计追踪报告，然后汇整在 BMR 中。
Facilities and equipment are not maintained to ensure quality attributes of drug product.
设施设备的维护不能确保药品的质量属性。
a) On May 15, 2017, (b)(4) V-305 exhibited particulate matter and (b)(4) paint on the
inner face of the gasket to the(b)(4). Further, this gasket was fraying, and loose threads
were visible (b)(4). The gasket inside the (b)(4) had deteriorated such that the missing
portions could not be accounted for. The mass balance of this gasket could not be
accounted for. Further, this gasket was discolored brown. Finally, a portion of the interior
of this (b)(4) was discolored white. This (b)(4) was utilizedin the manufacture of (b)(4) lot
(b)(4) intended for the US market. This equipment was in the clean status.
2017 年 5 月 15 日，XX 设备 V-305 的 XX 垫圈内表面发现有颗粒物和 XX 涂料。另外，此
垫圈已磨损，松开的线头在 XX 处可见。XX 内的垫圈已老化，有一部分已缺失无法拼回。
该垫圈的质量已无法平衡。另外，此垫圈已变为棕色。最后，此 XX 的内部有一部分已变为
白色。此 XX 用于生产发往美国市场的 XX 产品 XX 批号。此设备为清洁状态。
b) On May 15 2017, (b)(4) J09-805 contained screws displaying a reddish-brown
discoloration consistent with rust (interior of the (b)(4)). This (b)(4) was utilized in the
manufacture of (b)(4) lot(b)(4) intended for the US market. This equipment was in the
clean status andis used in the (b)(4).
2017 年 5 月 15 日，XX 设备 J09-805 上的螺丝显出红褐色，与铁锈颜色相似（XX 的内
部）。该 XX 用于生产发往美国市场的 XX 产品 XX 批号。此设备处于清洁状态。
c) On May 15 2017, (b)(4) IX-501-2 exhibited particulate matter and blue paint on the
inner face of the gasket to the (b)(4). Particulate matter and paint were falling from the
(b)(4) upon opening the (b)(4). Further, this gasket was fraying, and loose threads were
visible (b)(4). The gasket inside the (b)(4) had deteriorated such that the missingportions
could not be accounted for. The mass balance of this gasket could not be accounted for.
Further, this gasket was discolored brown. Finally, the interior of this (b)(4) was
discolored brown. This (b)(4) was utilized in the manufacture of (b)(4) lot (b)(4) intended
for the US market. This equipment was in the clean status.
2017 年 5 月 15 日，XX 设备 IX-501-2 的 XX 垫圈内表面发现有颗粒物和蓝色涂料。颗粒物
和涂料在打开 XX 时从 XX 掉下。此外，该垫圈已磨损，松开的线头在 XX 处可见。XX 内的
垫圈已老化，有一部分已缺失无法拼回。该垫圈的质量已无法平衡。另外，此垫圈已变为棕
色。最后，此 XX 的内部有一部分已变为白色。此 XX 用于生产发往美国市场的 XX 产品 XX
批号。此设备处于清洁状态。
d) On May 15 2017, (b)(4) IX-501-1 exhibited what appeared to flaking of the surface to
the (b)(4). The gasket inside the(b)(4) had deteriorated such that portions of the gasket
were missing and threads of the gasket were fraying. The mass balance of this gasket
could not be accounted for. This (b)(4) was utilized in the manufacture of (b)(4) lot(b)(4)
intended for the US market. This equipment was in the clean status.
2017 年 5 月 15 日，XX 设备 IX-501-1 表面貌似正在掉皮掉到 XX。XX 内的垫圈已老化，
有一部分已缺失无法拼回。该垫圈的质量已无法平衡。另外，此垫圈已变为棕色。最后，此
XX 的内部有一部分已变为白色。此 XX 用于生产发往美国市场的 XX 产品 XX 批号。此设备
处于清洁状态。
e) On May 15 2017, the (b)(4) W02-802-2 exhibited white particulate facing the interior
of the (b)(4) that appeared to originate from the gasket to the (b)(4). Further, this (b)(4)
appeared heavily scratched. This (b)(4) was utilized in the manufacture (b)(4) lot (b)(4)
intended for the US market. This equipment was in the clean status and is used in the
(b)(4).
2017 年 5 月 15 日，XX 设备 W02-802-2 的 XX 内发现有白色的颗粒，貌似是来自 XX 的
垫圈。另外，此垫圈已严重刮伤。此 XX 的内部有一部分已变为白色。此 XX 用于生产发往
美国市场的 XX 产品 XX 批号。此设备处于清洁状态并用于 XX。
f) On May 16 2017, (b)(4) III-319 exhibited whatappeared to white particulate matter in
the interior of the (b)(4). The gaske tinside the (b)(4) had deteriorated such that portions
of the gasket were missing and threads of the gasket were fraying. The mass balance of
this gasket could not be accounted for. This (b)(4) was utilized in the manufacture of (b)
(4) lot (b)(4) intended for the US market. This equipment was in the clean status.
2017 年 5 月 16 日，XX 设备 III-319 的 XX 内发现有白色的颗粒物。XX 内的垫圈已老化，
有一部分已缺失，垫圈线头已松开。该垫圈的质量已无法平衡。此 XX 用于生产发往美国市
场的 XX 产品 XX 批号。此设备为清洁状态。
For the aforementioned Observation, the following complaints pertaining to your firm’s
API were noted:
对于上述问题，有记录到以下对你们公司 API 的投诉：
i. CC-16006 addressing (b)(4) particles, (b)(4) color, yellow rust in (b)(4) batch (b)
(4) 某批次中发现颗粒物、XX 颜色、黄色锈
ii. CD-15004 reporting “black metallic particles”in (b)(4) batch (b)(4) 某批次报告
“黑色金属颗粒物”
iii. CD-15003 addressing “mixed fragment (b)(4)”in (b)(4) batch (b)(4) 某批次中发
现“混合碎片 XX”
iv. CD-15006 stating “black particles were foundin (b)(4) batch (b)(4) 某批次中发现
“黑色颗粒物”
v. CD-15001 reporting “That (b)(4) particles is(b)(4)”. The affected product is (b)(4)
报告 XX 颗粒物是 XX。受影响产品为 XX。

Observation1. There is an unacceptably high number of mold recoveries in the classified
rooms used for manufacture of (b)(4) bulk drug substance. Specifically, mold recoveries
in ISO-8 classified rooms ranged from 6 to 46 during 2017, and one mold was recovered
in the ISO-7 manufacturing area during 2017. The mold recoveries have been trending
upward since 2015.
缺陷 1：用于生产 XX 散装原料药的洁净区内霉菌回收数字高得不可接受。具体来说，ISO-
8 洁净级别房间在 2017 年霉菌回收在 6-46，2017 年在 ISO-7 级生产区回收到一个霉菌。
自 2015 年以来霉菌回收持续趋高。
Cleaning procedures do not contain sufficient details to enable operators to clean each
type of equipment in a reproducible and effective manner. Specifically, your cleaning
procedures are inadequate in that three of the three (b)(4) examined during the
inspection contained visible residue or apparent foreign material. (b)(4) 102-1 contained
apparent white particulate matter and what appeared to be a red-colored metallic
particle. (b)(4) 102-2 contained apparent white residue.(b)(4) II-250 also contained
apparent white residue along the length of the (b)(4).,
清洁程序不够详细，无法让操作工以可重复和有效方式清洁每种设备。具体来说，你们有
3 个设备清洁程序不够充分，在检查期间发现有可见残留或明显的异物。XX102-1 有明显
的白色颗粒物和貌似红色金属颗粒，XX102-2 有明显白色残留，XXII-250 亦有明显的 XX
长的白色残留。
Equipment used in themanufacture of intermediates and APIs should be of appropriate

design andadequate size, and suitably located for its intended use, cleaning,
andmaintenance. This is a repeat observation. Specifically,
用于中间体和 API 生产的设备应具备适当的设计，有足够的尺寸，并适当安装以符合其既
定用途、清洁和维护。此为重复缺陷。具体来说
a) You do not maintain equipment in a good state of repair. Theend of the (b)(4)
consists of (b)(4) different colored unidentified materials:(b)(4). Your Engineering
Supervisor stated the (b)(4) material is the (b)(4)repair material and the (b)(4) material is
the (b)(4) of the same repairmaterial. Only a small portion of the (b)(4) covered the
repaired area. Thedurability of the (b)(4) in the absence of the (b)(4) is unknown. The (b)
(4)material is unknown.
你们未将设备保持在良好的维修状态。XX 的尾端包括 XX 不同颜色未经识别的物料 XX。你
们工程主管声称 XX 材料是 XX 维修材料，并且 XX 材料是相同维修材料的 XX。只有小部
分 XX 覆盖在维修后的区域。没有 XX 时 XX 的耐用性是未知的。XX 物料是未知的。
b) You do not have adequate lighting in (b)(4) to inspect (b)(4) after cleaning to ensure
no visible residue remains.
你们在 XX 没有充足的照明检查清洁后的 XX 以确保没有可见残留。
c) You do nothave an adequate (b)(4) sealing machines to seal (b)(4) API (b)(4) bags.
(b)(4) sealing machines (b)(4)-811 does not have sufficient controls for pressure and
time to ensure proper sealing. You do not conduct leak tests to check bag seals prior to
final product approval and release.
你们没有足够 XX 的封口机用以密封 XX API 的 XX 袋。XX 封口机 XX-911 没有足够的压力

和时长控制确保进行适当的密封。你们并未在成品批准放行之前进行泄漏测试检查袋子密
封情况。
Schedules and procedures for preventive maintenance of equipment are not adequate
or do not exist. Specifically,
设备预防性维保计划和程序不充分或不存在。具体来说
a) You do not have a written procedure describing how to conduct a (b)(4) test to verify
the integrity of the interior surface of the (b)(4) in your manufacturing workshops. (b)(4)
are used in the manufacture of crude (b)(4) in workshops (b)(4) and (b)(4).
你们没有书面程序描述如何进行 XX 测试以确定你们生产车间的 XX 内表面的完整性。XX

用于 XX 车间 XX 和 XX 的粗品生产。
b) You do not have a written procedure describing how to perform repairs to the interior
surfaces of (b)(4). Repairs to interior surfaces of (b)(4) are made by your employees
without written instructions for how to make those repairs.
你们没有书面程序描述如何对 XX 内表面进行维修。XX 内表面的维修是由你们员工执行的

但没有书面程序指导如何进行这些维修。
c) You do not have a record showing a (b)(4) test was performed immediately following
a repair to the (b)(4) of the (b)(4) in (b)(4)II-250. (b)(4)II-250 is used in themanufacture of
crude (b)(4).
你们没有记录显示在 XX 粗品生产所用 XXII-250 里的 XX 维修之后立即进行了 XX 检测。
Substances associated with the operation of equipment, such as lubricants, heating
fluids or coolants are not always food grade lubricants and oils. Specifically, you use (b)
(4) in all of your (b)(4) reactors in Workshop (b)(4). You do not test (b)(4) prior to release
for use for (b)(4) a potential toxic contaminant. Rather than preventing potential finished
API contamination from (B)(4) by testing (b)(4) for (B)(4) prior to approval and release,
your QA Director stated you periodically monitor your finished product APIs for (B)(4)
contamination,
与设备操作有关的物质如润滑剂、导热油或冷却剂并不都是食品级润滑剂或润滑油。具体来
说，你们在 XX 车间所有 XX 反应釜上使用了 XX。你们在放行其使用之前未对 XX 检测可
能的毒性污染物。你们未在批准和放行 XX 之前检查 XX 防止 API 成品受到可能的 XX 污染，
你们 QA 总监声称你们定期检查你们的 API 成品中的 XX 污染情况。
10. 美国 Johnson Memorial Cancer Center
You did not make adequate product evaluation and take remedial action where
actionable microbial contamination was found to be present in the ISO 5 classified
aseptic processing area during aseptic production.
如果在无菌生产过程中发现 ISO 5 分类无菌加工区域存在可操作的微生物污染，则未进行

充分的产品评估并采取补救措施。
Specifically, The firm produces chemotherapeutic drugs and other sterile prescription
drug products for injection. The following actionable environmental excursions were
repo1ted recovered in the ISO 5 classified aseptic processing areas. The firm failed to
adequately assess, investigate or perform corrective actions regarding these excursions.
具体而言，该公司生产用于注射的化学治疗药品和其他无菌处方药品。在 ISO 5 分类的无菌加工区域中回收了以下可操作的环境偏移。该公司未能对这些短
途旅行进行充分的评估，调查或采取纠正措施。
Date Location Recovery Total number Microbiological Identification

Reported 位置 Type of colonies 微生物鉴别
报告日期类型菌落总数
5/8/18 Biological Safety Air 1 Penicillium spp.1 (mold)、
Cabinet (ISO 5) 空气青霉属（霉菌）
生物安全柜
7/25/18 Laminar Air Flow Air 1 Cryptococcus spp.2 (mold)
Hood (ISO 5) 空气隐球菌属（霉菌）
8/30/18 Laminar Air Flow Air 2 Bacillus cereus
Hood (ISO 5) 空气蜡状芽孢杆菌
8/30/18 Laminar Air Flow Surface 3 1 Bacillus cereus, 2 Unidentified
Hood (ISO 5) 表面 Gram+ Sporeforming Rods
层流罩 1 个蜡状芽孢杆菌、2 个不明革兰
氏阳性孢子形成杆菌
1
The firm's contract laboratory identified these genera of fungi are known to have strains
which may produce mycotoxins under the proper conditions.
1
该公司的合同实验室发现，这些真菌属是已知具有可在适当条件下产生霉菌毒素的菌株。
2
The firm's contract laboratory identified this microorganism as potentially highly
pathogenic for immunocompromised patients.
2
该公司的合同实验室发现这种微生物对免疫功能低下的患者具有潜在的高致病性。
You did not make adequate product evaluation and take remedial action where
actionable microbial contamination was found to be present in an area adjacent to the
ISO 5 classified aseptic processing area during aseptic production.
在无菌生产过程中，如果发现可操作的微生物污染存在于 ISO 5 级无菌加工区域附近，您

没有进行适当的产品评估并采取补救措施。
Specifically, The following actionable environmental excursions were reported recovered

in the surrounding and supporting ISO 7 classified areas adjacent to the aseptic
processing areas. The firm failed to adequately assess, investigate or perform corrective
actions regarding these excursions.
具体而言，以下可操作的环境偏移被报告在与无菌加工区域相邻的周围和辅助 ISO 7 级区
域中被发现。该公司未能对这些偏移进行充分的评估、调查或采取纠正措施。

报告日期类型菌落数
5/8/18 Anteroom (ISO 7) Air 1 Aspergillus fumigatus1 (mold)
前室空气烟曲霉（霉菌）
6/27/18 Non-Hazardous Drug Air 1 Cladosporium spp.1 (mold)
Buffer Room (ISO 7) 空气枝孢菌属（霉菌）
非危害药缓冲室
6/27/18 Non-Hazardous Drug Air 1 Epicoccum spp. (mold)
Buffer Room (ISO 7) 空气附球菌属（霉菌）
8/30/18 Non-Hazardous Drug Surface 6 4 Bacillus cereus, 2 Unidentified
Buffer Room (ISO 7) 表面 Gram+ Sporeforming Rods
非危害药缓冲室 4 个蜡状芽孢杆菌、2 个不明革兰
8/30/18 Anteroom (ISO 7) Surface 2 1 Bacillus cereus, 1 Unidentified
前室表面 Gram+ Sporeforming Rods
1 个蜡状芽孢杆菌、1 个不明革兰
8/30/18 Anteroom Sink (ISO 7) Surface 4 3 Bacillus cereus, 1 Unidentified
前室水槽表面 Gram+ Sporeforming Rods
3 个蜡状芽孢杆菌、1 个不明革兰
1
1
该公司的合同实验室确定这些真菌属是已知具有可在适当条件下产生霉菌毒素的菌株。
The following actionable environmental excursions were reported recovered in the

surrounding and supporting ISO 7 classified areas during the current inspection.
在当前的检查中，以下可操作的环境偏移被报告在周围和辅助 ISO 7 级区域中被发现。

报告日期类型菌落数
10/3/18 Anteroom (ISO 7) Air 1 Cladosporium spp.1 (mold)
前室空气枝孢菌属（霉菌）
10/3/18 Anteroom (ISO 7) Air 1 sterile hyaline mould (mold)
前室空气不育透明霉（霉菌）
10/10/18 Anteroom (ISO 7) Air 1 Mucor spp.1, 3 (mold)
前室空气毛霉菌属（霉菌）
10/10/18 Anteroom (ISO 7) Air 1 Mucor spp.1, 3 (mold)
前室空气毛霉菌属（霉菌）
1
1
该公司的合同实验室发现，这些真菌属是已知具有可在适当条件下产生霉菌毒素的菌株。
3
The firm's contract laboratory identified this microorganism can cause life-threatening
disease in diabetics, burn patients, and immunocompromised patients.
3
该公司的合同实验室发现，这种微生物可以在糖尿病患者、烧伤患者和免疫功能低下的患
者中引起危及生命的疾病。
Environmental excursions including mold recoveries in the ISO 7 classified areas were
also noted during the 2014 FDA inspection.
在 2014 年 FDA 检查期间，也记录了包括在 ISO 7 级区域发现霉菌之类的环境偏移。
Your facility design allowed the influx of poor quality air into a higher classified area.
您的设施设计允许劣质空气流入更高级区域。
The firm failed to maintain proper room classification and environmental control of
supporting areas in which ISO 5 classified aseptic processing equipment is located and
sterile production occurs. The firm's air handling unit (AHU) was offline from 05/15/18 to
05/18/18, 6/01/18 to 6/04/18, and for approximately 10 hours on 06/06/18. This resulted
in elevated temperatures and relative humidity levels, and loss of differential pressures
for surrounding buffer and ante areas, for each of the offline time periods. Production
activities were not always suspended during these offline timeframes. For example, on
6/01/18, the firm continued to produce (b)(4) chemotherapeutic drug products for
injection, inside the ISO 5 Biological Safety Cabinet, even though there was a lack of
adequate HEPA filtered airflow to the surrounding buffer and ante areas to maintain an
adequate room cleanliness classification.
该公司未能对支持区域进行适当的房间分级和环境控制，ISO 5 级的无菌加工设备位于此
区域，并进行无菌生产。该公司的空气处理单元（AHU）于 2018 年 5 月 15 日至 05 月 18
日、2018 年 6 月 1 日至 6 月 4 日离线，并于 2018 年 6 月 6 日离线约 10 小时。对于每个离
线时间段，这导致温度和相对湿度升高，以及周围缓冲和前室区域的压差减少。在这些离
线时间范围内，生产活动并不总是暂停。例如，在 2018 年 6 月 1 月，该公司继续在 ISO 5
生物安全柜内生产 XX 注射用化疗药品，即使没有足够的 HEPA 过滤气流到周围缓冲和前
室区域以保持足够的房间清洁度分级。
You had inadequate HEPA filter coverage and airflow over the area to which sterile
product was exposed.
在无菌产品暴露的区域内，HEPA 过滤器覆盖的范围和气流不足。
Specifically, The firm's air pattern analysis and media fills are deficient for the following
reasons:
具体而言，由于以下原因，该公司的空气模型分析和培养基灌装不充分：
1) The firm conducted an air pattern analysis (smoke study) on 02/22/18 and
08/15/18 for the ISO 5 Biological Safety Cabinet (BSC) utilized for the production of
chemotherapeutic drug products and the ISO 5 Laminar Flow Hood (LFH) utilized for
the production of non-hazardous drug products. The aforementioned smoke studies
were inadequate as the studies did not include the transfer of starting components
and materials into the ISO 5 classified areas. In addition, the firm's smoke studies for
the BSC failed to simulate the most complex product to produce, which was identified
as (b)(4).
1）该公司于 2018 年 2 月 22 日和 2018 年 8 月 15 日对用于化疗药品生产的 ISO 5 生物

安全柜（BSC）和用于生产非危害药品的 ISO 5 层流罩（LFH）进行了空气模型分析
（烟雾试验）。上述烟雾试验不充分，因为试验不包括将起始成分和材料转移到 ISO 5
级区域。此外，该公司对 BSC 的烟雾试验未能模拟生产的最复杂产品（确定为 XX）。
2) The firm performs media fills on an (b)(4) basis. Media fills are not performed on
site and do not represent actual production operations. The firm failed to evaluate
and provide justification for this practice.
2）公司在 XX 的基础上进行培养基灌装。培养基灌装不在现场执行，并不代表实际的
生产操作。该公司未能对此做法进行评估并提供理由。
Buildings used in the manufacture, processing, packing or holding of drug products are
not maintained in a clean and sanitary condition.
用于制造、加工、包装或保存药品的建筑物不能保持清洁卫生状态。
a) I observed a brownish residue on top of the return air vent in the human clean room
(ISO 7) where the laminar flow hoods and biosafety cabinet are located, and aseptic
operations occur.
a）我在人洁净室（ISO 7）的回风口顶部观察到褐色残留物，层流罩和生物安全柜位于
此处，并进行无菌操作。
法规建议：回风口需要注意定期清洁，需要有 SOP 和记录。特别是固体车间。
b) The seam on the floors for all rooms in the classified area is raised and not smooth.
b）分级区域内所有房间的地板上的接缝都是凸起和不光滑的。
c) All the (b)(4) are scratched and cloudy in appearance.
c）所有 XX 的外观都是划痕和混浊的。

Aseptic processing areas are deficient regarding systems for maintaining any equipment
used to control the aseptic conditions.
无菌加工区域在维护用于控制无菌条件的任何设备的系统方面存在缺陷。
a.) Specifically, smoke studies are conducted every (b)(4) by a third-party. Your firm's
smoke studies were performed on (b)(4). Prior to November 2017 your firm did not
perform smoke studies. Your firm does not perform smoke studies under dynamic
conditions. We reviewed your firm's smoke studies and they were brief and had no
description of what action was being performed. Furthermore, while viewing these
smoke studies, it was difficult to see smoke on various occasions.
a）具体而言，烟雾测试由第三方每隔 XX 进行一次。你公司的烟雾测试是在 XX 进行的。在
2017 年 11 月之前，你公司没有进行烟雾测试。你公司未在动态条件下进行烟雾测试。我们
审查了你公司的烟雾测试，它们简短且没有说明正在进行的动作。此外，在观看这些烟雾
测试时，很难在各种场合看到烟雾。
b.) Also, your firm does not include the (b)(4) process in your smoke studies. Your firm
(b)(4) two products, Tesamorelin and HCG using a (b)(4) located inside the ISO 5 hood.
The process includes (b)(4) vials, (b)(4) vials from the (b)(4) and (b)(4) vial (b)(4) from
the (b)(4).
b）另外，你公司未将 XX 工艺包括在您的烟雾测试中。你公司 XX 两种产品：替莫瑞林和
HCG，使用置于 ISO 5 层流罩内的 XX。该工艺包括 XX 瓶子、来自 XX 的 XX 瓶子和来自
XX 的 XX 瓶子。
Your smoke studies are performed under static conditions and do not incorporate the (b)
(4) process nor any dynamic conditions to evaluate the efficiency of your HEPA airflow.
您的烟雾测试是在静态条件下进行的，并未包含 XX 工艺或任何动态条件来评估 HEPA 气
流的效率。
13. 西班牙 Gadea Biopharma S.L. 20181204
The information stated in the submitted drug application is not exactly as is on

site. Specifically, drug application (b)(4) states that the firm is ready for inspection
and identified as having functions, responsibilities, and operations including
primary packaging and vial labeling. On site observation revealed no labeling
equipment and currently site has no capability to perform labeling operations for
vial.
在所提交的药品申报资料中的信息与现场情况有差异。具体来说，药品申报资料 XX 中
声称公司已准备好接受现场检查，并说已具备相关功能、职责和操作条件包括内包和西
林瓶贴标，但在现场发现并没有贴标设备，目前工厂并没有能力对西林瓶进行贴标操
作。
Labeling equipment is no qualified in preparation for commercialization of drug

product. Specifically, one of the responsible functions described in the drug
application (b)(4) is labeling and labeling machine is in placed to perform labeling
operation for (b)(4) but is not currently qualified.
贴标设备还未针对商业化药品生产进行确认。具体来说，药品申报资料 XX 中说该工厂
负责的操作之一是贴标，XX 贴标设备放在现场，但还未进行确认。
The flow of components, drug product containers, closures and in-process materials
though the building is not designed to prevent contamination.
成分、药品容器、密封件和过程中物料在建筑物中的流动没有被设计以防止污染。
A. The environment in which sterile, non-hazardous drug products are produced does
not meet the standards of an ISO 5 environment due to the following:
由于以下原因，生产无菌非危险的药品的环境不符合 ISO 5 环境标准：
 HEPA filters do not cover the entire room. HEPA 过滤器不能覆盖整个房间。
 There is no full assessment of the room's pressure differentials.
没有全面评估房间的压差。法规建议：对洁净区压差进行风险评估
 Smoke studies were not performed throughout the entire room.
烟雾研究没有遍布整个房间。
 There is a non-classified (b)(4) from the ISO 8 Prep room to the ISO 5 sterile
environment. 有一个从 ISO 8 准备室到 ISO 5 无菌环境的未分类 XX。
On 10/18/18 10/19/18, I observed the transfer of partially stoppered Bremelanotide, Lot
10192018@4, from the stainless-steel compounding table to the (b)(4) in the ISO 5
sterile, non-hazardous room. I observed the (b)(4) is partially located under a light fixture
that does not have a HEPA filter.
在 2018 年 10 月 19 日，我观察到半加塞的布美诺肽（批号 10192018@4）从不锈钢配料
桌转移到 ISO 5 无菌非危险室中的 XX。我观察到 XX 部分位于没有 HEPA 过滤器的灯具下
面。
Equipment and utensils are not maintained at appropriate intervals to prevent

malfunctions that would alter the safety, identity, strength, quality or purity of the drug
product.
设备和器具未在适当的时间间隔维护，以防止可能改变药品安全性、特性、强度、质量或纯
度的故障。
Specifically, the validation of your firm's (b)(4) and (b)(4) lack temperature mapping to
ensure the required internal temperatures are reached and maintained throughout batch
for the required runtime.
具体来说，你公司的 XX 和 XX 的验证缺乏温度分布研究，以确保达到所需的内部温度并
在整个批次中维持所需的运行时间。
Aseptic processing areas are deficient regarding the system for cleaning and disinfecting
the room and equipment to produce aseptic conditions.
无菌处理区域在用于清洁和消毒房间和设备以产生无菌条件的系统方面存在缺陷。
A. On 7/23/2018, during the (b)(4) setup on (b)(4) fill line, (b)(4) were observed un-
extended with occluded surfaces. (b)(4) fill line was being setup to produce
Glatiramer Acetate Injection 20mg lot 911253F.
A. 在 2018 年 7 月 23 日，在 XX 灌装线 XX 准备期间，观察到 XX 有遮盖表面未延伸。
XX 灌装线正在准备以生产醋酸格拉替雷注射剂 20mg 批号 911253F。
B. The following hazardous products are manufactured at the facility:
Hydroxyprogesterone Caproate; (b)(4); Fentanyl Citrate; Dexmedetomidine HCL;
Liraglutide. All the hormones and steroids manufactured at the facility utilize the
same general cleaning room, Room 657. Room 657 is adjacent to (b)(4) Room 655
which opens to general corridor 436. While conducting your risk assessment, you
failed to consider the following:
B. 以下危险产品在工厂生产：己酸羟孕酮、XX、枸橼酸芬太尼、盐酸右美托咪定、利拉
鲁肽。该设施生产的所有激素和类固醇都使用相同的一般清洁室 657。657 室与 XX 室
655 相邻，通向一般走廊 436。在进行风险评估时，你没有考虑以下：
1. Room 657 and 655 are both under positive pressure. While cleaning of
equipment used to manufacture Hazardous material in Room 657 there is a
likelihood the (b)(4) could become contaminated with hazardous material. The
contaminated (b)(4) room could allow contamination to escape into the general
corridor.
1. 657 室和 655 室都处于正压。当在 657 室清洗用于生产危险材料的设备时，XX
可能会被有害物质污染。被污染的 XX 房间可能让污染物逃逸到一般走廊。
2. Inadvertent release of the hazardous material can't be promptly detected as
on 26th July 2018 since your current action alarms were set with a delay of (b)
(4) ((b)(4)). Changes in the airflow would not be promptly detected.
2. 由于你当前的动作警报设置为延迟 XX，因此无法在 2018 年 7 月 26 日立即检
测到无意释放的危险物质。不会立即检测到气流变化。
Equipment used in the manufacture, processing, packing or holding of drug products is

not of appropriate design to facilitate operations for its intended use.
用于制造、加工、包装或保存药品的设备未适当设计，不便于其预定用途的操作。
Your (b)(4) equipment which processes plungers and stoppers for your sterile drug
products has not been performed adequately. You have not scientifically supported this
process reduces particulate matter to an acceptable level. Your Process Qualification
Report states this washing equipment should effectively remove particulates to an
acceptable level. However, data used in this evaluation exhibit no reduction in
particulates greater than (b)(4) microns in size and a reduction of one particulate from
the approximate (b)(4) micron sized particles.
为你的无菌药品处理柱塞和塞子的 XX 设备尚未适当工作。你没有科学支持这一过程将颗
粒物质降低到可接受的水平。你的工艺确认报告指出，该洗涤设备应有效地将颗粒去除到
可接受的水平。然而，在该评估中使用的数据表明尺寸大于 XX µm 的颗粒没有减少，并且
尺寸约 XX µm 的颗粒减少一个颗粒。
16. 印度 Dr. Reddy’s 20181114

environmental conditions. 无菌加工区的环境条件监测系统有缺陷。
The control procedure SOP FTDQA004-00; dated on 09/14/2017; “Air flow
Visualization for Clean Rooms/Zones” establishes/requires:
控制程序 SOP FTDQA004-00，日期 20170914“洁净间/区气体流型可视研究”要求：
*Section 6.3.18.1 – The study is to evaluate the impact of all the production
interventions performed by human, machine during routine operation on air flow
pattern demonstrated at operation.
第 6.3.18.1—研究用于评估动态中所有人为和设备的生产干预在日常操作中对气体流
型的影响。
*Section 6.3.18.20 – Interventions: all the aseptic manipulations and interventions
shall be captured during the dynamic smoke study i.e. inherent interventions that
occur during operational conditions and corrective interventions that may occur
when machinery is not operating.
第 6.3.18.20—干预：在动态发烟试验中要捕获所有无菌操作和干预，即在操作条件下
发生的必要干预和设备运行问题时可能发生的纠正性干预。
Nonetheless, your air flow pattern study conducted during filling equipment
assembly and process for (b)(4) PR-E007, and documented in the DVD,
Doc.FT7APRPQP235-11(A) “Air Flow Visualization Study, Vial Line (b)(4) Block
(b)(4) injection” dated 01/11/2017, utilized to ensure unidirectional airflow during
manufacture of aseptically filled drug products, is deficient inthat do not
demonstrate how the air flow pattern of the ISO-5 area of the (b)(4) PR-E007 vial
filling Line (b)(4) is affected by a new corrective intervention (b)(4) position from
(b)(4) to (b)(4) or vice versa”.
但是你们用于确保无菌灌装药品生产期间的单向流，在灌装设备 XXPR-E007 装配和
运行期间所做的气体流型试验，记录在 DVD 文件号 FT7APRPQP235-11(A)“气体流
型发烟试验，西林瓶线 XX 注射剂”日期 20170111，是有缺陷的，它未能演示新的纠
正性干预 XX 位置从 XX 至 XX 以及反向操作会如何影响 XX PR-E007 西林瓶灌装线
XX 的 ISO-5 区域气体流型。
Per media fill run DVD; Lot (b)(4) (dated on 05/31/2017) the corrective
intervention was performed by two (2) operators. One of the operator was in the
(b)(4) of the filling Line (b)(4) and the other operator was in the (b)(4) of the filling
Line (b)(4) Both operators simultaneously carried out the intervention in the ISO-5
area of the (b)(4) PR-E007 vial filling Line (b)(4).
在培养基灌装运行 DVD 中，批号 XX（日期 20170531），纠正性干预是由 2 名操作员
实施的。一名操作员在灌装线 XX 的 XX，另一名操作员在灌装线 XX 的 XX。2 名操作员
同步执行 ISO-5 区域对 XX PR-E007 西林瓶灌装线的干预。
Repeat Observation from FDA-483 March 2017.
此为 2017 年 3 月 FDA-483 的重复缺陷。

assure that changes in master production and control records or other records are
instituted only by authorized personnel.
未对计算机或相关系统执行适当控制以确保主生产和检验记录或其它记录只能授权人员
修改。
The Electronic Logbook (eLog) System V1.0.0 is used for Instrument, Equipment,
Area Operation and Cleaning usage log for Production, Warehouse, and Quality
Control departments of Lupin Limited. The eLog is not directly connected to
respective equipment.
电子日志(eLog)系统 V1.0.0 被用于鲁宾公司的生产、仓管和 QC 部分仪器、设备、区间
操作和清洁使用日志。eLog 未直接接入对应设备。
A. Your firm including your Sr. GM Corporate IT cannot assure us that access
to the system is adequately controlled. There is no guidance provided for
Vendor Administrator to eLog. On 01/23/2019, your Officer Site IT stated
during the interview process that all (b)(4) employees he selected from the
eLog system directory (as part of his job functions) are active employees
of Lupin Limited. When asked for supporting documentation of the Lupin
“Administrators” and the vendor “Administrator” to corroborate histhe
statement, he stated on 01/24/019 that only 10 of the (b)(4) two individuals
of the (b)(4) (2 (b)(4)) (assigned as Administrators) previously reported are
as Lupin Limited’s personnel are in fact vendors. The firm could not
distinguish between vendor administrator and Lupin Site IT Administrator
from eLog system (Administrators).
你公司包括你们资深 GMP 公司 IT 不能确保系统访问充分受控。没有为供应商
管理员提供 eLog 指南。20190123，面谈期间你们的现场 IT 管理员声称他从
eLog 系统目录中挑选（是他的工作职责的一部分）的所有 XX 员工均为鲁宾公
司在职员工。当询问鲁宾“管理员”和供应商“管理员”支持性文件来佐证其
说法时，他在 20190124 声称之前报告为鲁宾公司员工的 10 人中有 2 人其实
是供应商（指定为管理员）。公司从 eLog 系统（管理员）上不能区分供应商管
理员与鲁宾现场 IT 管理员。
B. SOP #QC2-229-01 (User Management and Master Data Creation for
Electronic Usage Log System, 10/16/15 effective date) and version 00 do
not define the following roles for the system (Administrator, QA Manager,
and Vendor). In addition, most the practices performed by your users and
described by your Corporate IT CQA and Site IT personnel are not defined
in the SOP. For example, raising “Incident Ticket” when users are being
added is not described in the SOP.
SOP#QC2-229-01（电子使用日志系统用户管理和主数据创建，生效日期
2151016）和版本 00 中未定义系统的以下身份（管理员、QA 经理和供应商）。
另外，你们用户所做的和你们公司 IT CQA 和现场 IT 人员所描述的大部分操作
在该 SOP 中均未定义。例如，增加用户时提交“事件工票”在 SOP 里就没有
描述。
C. The review of the audit trail for Electronic Logbook (eLog) System Version
1.0.0. in Unit 2 revealed that the “Reviewer” role has more (full) rights to
the system than the “Administrator” and the system is managed by QC.
对 2 厂电子日志（eLog）系统版本 1.0.0 的审计追踪的审核发现“审核员”身
份比“管理员”有更多系统权限，并且该系统由 QC 管理。
Equipment used in the manufacture, processing, packing or holding of drug
products is not of appropriate design to facilitate operations for its intended use.
用于生产、加工、包装或存贮药品的设备设计不当，不便于其既定用途的操作。
A. The qualification of your firm’s (b)(4) Systems instrument Software version
07.01 lacks data to fully support it was validated following the re-
installation in December 2018. The (b)(4) Systems ((b)(4)) is used to
perform microbial identification in the Microbiology Laboratory. The
existing software file was corrupted and the analyst and reviewer were
unable to access the software. Per your vendor’s recommendation,
Software 07.01 needed to be re-installed for (b)(4) (microbial identification
system).Your initiated change control #CCP-IO-115-18-0040 on
11/21/2018 to revalidate the software and stated that (b)(4) system shall
be used for routine identification only after firm successful performed IQ,
OQ and PQ of the re-installed software version 07.01. You did not initiate
a validation protocol including the deliverables for the revalidation and did
not issue a summary report to summarize whether the system has been
validated, complied, and released for use. Since re-installation this
equipment has been used approximately (b)(4) times for (b)(4)
environmental samples where US marketed products are manufactured
((b)(4) and (b)(4) Blocks).
你公司的 XX 仪器软件系统版本 07.01 的确认缺少数据全面支持其在 2018 年
12 月重新安装之后曾进行过验证。XX 系统用于微生物实验室进行微生物鉴别。
现有软件文件已损坏，化验员和审核员都不能进入软件。根据你们供应商的建
议，XX（微生物鉴别系统）需要重新安装软件 07.01 版。你们于 20181121 启
动了变更控制#CCP-IO-115-18-0040，重新验证了该软件，声称只有在成功实
施软件 07.01 重新安装的 IQ、OQ 和 PQ 之后才可用于日常鉴别。你们并未启动
验证方案，包括重新验证的可交付物，亦未签发报告总结该系统是否已经过验
证、汇总和放行用于使用。自从重新安装以来，该设备已用于约 XX 次 XX（美
国市场药品生产车间）环境样本检测。
B. Your firm utilizes Electronic Logbook (eLog) System Version 1.0.0. in Unit
2 facility to document the all activities including results of analytical data
for laboratory equipment and production. Your firm processed Change
Control #CCP-IO-135-14-0009 to implement Logbook System Version
1.0.0 in Unit 2. Your firm did not execute a validation protocol including a
validation summary report for the software Electronic Logbook System
Version 1.0.0.
你公司在 2 厂设施内使用电子日志（eLog）系统版本 1.0.0 记录所有活动，包
括实验室仪器分析数据结果和生产数据。你公司实施了变更控制#CCP-IO-135-
14-0009 在 2 厂内执行日志系统版本 1.0.0.你公司并未执行电子日志系统软件
版本 1.0.0 的验证方案，包括验证报告。
五．包装和贴签

Label access is not controlled.
标签未受控。
Specifically, the label storage room that contains printed packaging materials for
(b)(4) Capsules and (b)(4) Tables was observed to be unlocked by your firm’s
Corporate Quality Manager during a walkthrough of production on 12 February
2018.
具体来说，标签存贮间有 XX 胶囊和 XX 片剂的打印包材，2018 年 2 月 12 日在生产部检
查时发现你们公司质量经理没有锁门。
Employees engaged in the manufacture,processing, packing, and holding of a
生产、加工、包装和保存药品的员工缺乏执行其指定职责所需的培训。
Specifically, your firm failed to conductcGMP training for (b)(4) of (b)(4) selected
employees performing Quality related functions, such as, production, quality
control, and quality assurancein 2016.
具体来说，你公司在 2016 年未向 XX 所选履行质量相关职责的员工如生产、QC 和 QA 执
行 CGMP 培训。

Labeling materials issued for a batch were not carefully examined for identity and
conformity to the labeling specified in the master or batch production records.
没有仔细检查为批（生产）发放的标签材料的身份和是否符合主或批生产记录中指定的标
签。
Specifically, on 9/11/18, we observed (b)(4) vials of Tesamorelin 1 mg subcutaneous
injection (batch 07161804; BUD Date 07/12) stored in the refrigerator in your pha rmacy.
The Beyond Use Date (BUD) on each of the (b)(4) Tesamorelin vial labels of this lot
contained an incorrect one-year BUD date, while the correct BUD date for Tesamorelin
is 180 days.
具体而言，在 2018 年 9 月 11 日，我们观察到 XX 瓶替莫瑞林 1 mg 皮下注射剂（批次
07161804；BUD 日期 07/12）储存在药房的冰箱中。每瓶该批 XX 替莫瑞林瓶标签上的超
越使用日期（BUD）包含不正确的一年 BUD 日期，而替莫瑞林的正确 BUD 日期为 180 天。
（译注：根据 USP<797>药物调剂－无菌制剂，药师在调剂重新包装药品时，应根据生产企业和药典
凡例提供的信息确定适宜的使用期限 BUD，在此日期后药品将不能使用。）
Your firm began using a new computer program called (b)(4)((b)(4)) on or about 7/6/18
for printing labels to be affixed to finished product vials. When this issue was brought to
your management's attention, your firm conducted an investigation which identified that
any Tesamorelin product produced and shipped between 7/6/18 to 9/11/18 contains the
incorrect one year BUD date, due to an installation error of the new computer program.
贵公司于 2018 年 7 月 6 日或左右开始使用名为 XX（XX）的新计算机程序来打印贴在成
品瓶上的标签。当这个问题引起管理层的注意时，贵公司进行了调查，发现在 2018 年 7 月
6 日至 2018 年 9 月 11 日之间生产和运输的任何替莫瑞林产品包含不正确的一年 BUD 日
期，由于新计算机程序的安装错误。

There are no established written procedures for handling labeling and packing
operations. For examples,
未制订书面的贴标处理和包装操作程序，例如：
A. Procedures describing in sufficient detail the controls employed for the

issuance of labeling are not written.
没有书面程序详细描述标签发控制。
B. Written procedures describing in sufficient detail the receipt, identification,

storage, handling, sampling, examination and testing of labeling and packaging
materials.
没有书面程序详细描述标签和包材接收、鉴别、存贮、取样、检查和测试。
C. Procedures designed to assure that correct labels, labeling and packaging

materials are used for drug products are not written.
没有书面程序用以确保使用正确的标签和包材。
六．物料系统
1. 英国 Dr. Reddy’s 20170926

Manually managed materials in the warehouse are not separated during storage.
仓库的人工管理物料在存贮时未曾分开。
 The Retain Samples of various materialssuch as (b)(4) are stored in freezers
identified as Quarantine and Approved along with finished material that are
Quarantine or Approved.
 不同物料的留样如 XX 存贮在冰柜里，标识为待验和批准，与待验或批准的成品物
料放在一起。
 (b)(4) API labeled “Reprocess” was storedalong with “Approved”
material in the (b)(4) refrigerator since 21 Oct 2016.
 XX 原料药标识为“返工”，自 2016-10-21 起就与“批准”的物料一起放在 XX 冰
箱里。
 Additionally, raw materials of (b)(4) used for the production of (b)(4) API
was stored in the Quarantine area since 6 April 2016. There are no allocated
timeframes for storage of Quarantine materials.
 另外，用于 XX 原料药生产的 XX 的原料自 2016-04-06 起就存放在待验区。待验物
料没有重新放置的时间限制。
regarding operations related to the quarantine storage of API finished material
prior to release. Specifically,
原料药成品在放行之前的待验存贮操作中防止污染或混淆的独立区域或指定区域有缺陷。
具体如下：
(b)(4) drums of (b)(4) finished API Batch #(b)(4) with quarantine labels were
observed inside the (b)(4) Room (Packaging/Cleanroom) on 2018-03-05 and were
manufactured on 2018-01-07. The firm packaged (b)(4) more batches of (b)(4)
(Batch # (b)(4)) in that room on (b)(4) while this quarantine batch remained in
that room and a line clearance was performed. No explanation was provided for
why these (b)(4) drums remained in the room nearly two months after
manufacturing.
2018-03-05 日发现 XX 间（包装/洁净间）里 XX 原料药成品 XX 批号的 XX 桶贴有待验标
签，生产日期为 2018-01-07。公司于 XX 日在该房间包装了 XX 产品 XX 批号，但该时上
述待验批号仍在该房间内，并且还做了清场。公司并未解释为何这 XX 桶在生产之后近 2
个月仍放在房间内。

There was a failure to handle and store components at all times in a manner to
prevent contamination.
未能在所有时间以防止污染的方式处理和存贮组份。
Specifically, during the inspection, several active ingredients and raw materials
were discovered as stored in (b)(4) containers that are either kept open or partially
closed. On November 26, 2018, we observed (b)(4) USP, lot #(b)(4) quantity-(b)
(4)kg, weighed for (b)(4) suspension USP (b)(4)mg/(b)(4)ml, batch #(b)(4) and (b)
(4) USNF, lot #(b)(4) weighed for (b)(4) suspension USP (b)(4)mg/(b)(4)ml,
batch#(b)(4) stored in the “Dispensed Material Storage Room”. However, the
covers of these containers were found as partially open. In addition, presence of
(b)(4) over the outer surface of in-process containers was also discovered during
the current inspection.
具体来说，在检查期间发现有几个活性成分和原料存贮在 XX 容器中，容器打开着或部
分密闭。20181126，我们发现 XX USP 批号#XX 有 XXkg，称重了用于 XX 混悬液 USP
XXmg/ml，批号 XX 和 XX 的 USNF，批号 XX 称重用于 XX 混悬液 USP
XXmg/XXml，批号 XX，存贮在“已分物料存贮间”内。但是，这些容器的盖子部分打
开。另外，此次检查在中间体容器的外表面上发现有 XX。
七．其它
The certificate of Analysis from the drug application does not match the raw data
from the analytical test records and specification sheet. Specifically, drug
application (b)(4) the related substance impurities results provided in the CAO
approved on 10/21/2016 for the batches (b)(4) submitted to the agency does not
match the reported results on raw data on the specification sheet for all the
corresponding batches.
药品申报资料中的 COA 与检验记录和质量标准中的原始数据不一致。具体来说，药品

申报资料 XX 中，提交给 FDA 的 XX 批 XX 于 20161021 批准的 COA 中有关物质杂质
结果与所有对应批次的原始数据中报告结果并不一致：
a) For batch (b)(4) the related substance HPLC (%w/w) COA submitted in the
application did not match the Analytical Development Specification
申报资料中提交的 XX 批次有关物质 HPLC（%W/W）COA 与分析开发标准不一致
b) For batch (b)(4) the related substance HPLC (%w/w) COA submitted in the
c) For batch (b)(4) the related substance HPLC (%w/w) COA submitted in the
Original records of analysis submitted in the drug application was not available.
Specifically, the original COA record for (b)(4) for batches (B)(4) were not
available. Specifically,
在药品申报资料中提交的分析数据没有原始记录。具体来说，没有 XX 批次 XX 的原始
COA 记录。具体如下：
a) The original copy of the COA record approved on10/21/2016 submitted in the
application for the batches (b)(4) was not available.
在申报资料中提交的 XX 批次于 20161021 批准的 COA 没有原始件
b) The original copy of the COA record approved on10/21/2016 submitted in the
c) The original copy of the COA record approved on10/21/2016 submitted in the
There is no established written procedure in the event of change in the version of

the Certificate of Analysis.
没有制订书面程序规定 COA 版本修订的处理方式。
Specifically, controls and procedures to track change history for the certificates of
analysis (CoA), which document whether a drug meets specifications, to prevent
unauthorized changes to a CoA after quality unit approval is deficient. For
example,具体来说，跟踪 COA（其记录药物是否符合质量标准）的变更历史，以防止
在质量部门批准之后对 COA 未经授权的变更，的控制和程序是有缺陷的。例如：
A (b)(4) Batch (b)(4) three version of COA approved on 10/21/2016, 03/31/2017,

10/15/2018 were found without providing any unique identification number on the
documents.
XX 批次有 3 个版本的 COA，批准日期分别为 20161021、20170331 和 20181015，在

文件上没有任何唯一编号。
B. (b)(4) Batch (b)(4) three version of COA approved on 10/21/2016, 03/31/2017,

documents.

C. (b)(4) Batch (b)(4) three version of COA approved on 10/21/2016, 03/31/2017,

documents.


2018年FDA 483表缺陷之六大系统分类

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2018年FDA 483表缺陷之六大系统分类

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2018 年 FDA 483 表中缺陷项

1. 印度 Alkem Laboratories 20180411

2. 印度 Sun Pharmaceutical 20180306

3. 印度 Alembic Pharmaceuticals 20180410

5. 马来西亚 Biocon Sdn Bhd 20180312

7. 印度 Cipla Limited 20180420

8. 印度 Suven Life Sciences Limited 20180424

9. 印度 Mylan Laboratories Limited, (Nashik FDF) 20180626

10. 浙江华海 20180809

验证“非灭菌方法转移物料至 B 级区的有效性确认”中未评估灌装机 XX 部件从其非洁净

11. 美国 Cook Pharmica 20180910

12. 印度 Unichem Laboratories 20180910

13. 印度 Liva Pharmaceuticals 20180910

14. 浙江华海川南一分厂 20180920

2018 年 7 月 25 日，在 XX 车间 XX 粗品 XX 批次生产中看到有一个生产人员正在批生产记

15. 印度 Sun Pharmaceutical 20180910

Specifically, there is no line clearance required during intervention activities performed

具体来说，生产操作人员进行干预之后不要求进行清场。在 20180830，我们发现 USP 级

HC-084 灌装机也用于生产 XX 产品的鉴定批次，亦用于 XX 产品的商业化生产。

16. 印度 Strides Pharma 20180926

A．XX 溶液和 YY 溶液生产所用制剂灌装设备的清洁程序未写明传输泵的清洁操作。该传

B．在清洁后，在 XX 溶液与 YY 溶液生产共用生产罐中发现有残留清液。

17. 印度 Cipla 20181022

所拟 XX 片剂商业化生产的主批记录版本 01 中没有提供关于从你们的 IPC（中间体容

在您工厂的洁净室和/或 ISO 5 级无菌加工区域中未使用杀孢子剂。

具体而言，在 2018 年 9 月 10 日我们观察到您的 ISO 5 无菌加工区域的每日清洁在不使用

ISO 5 级无菌加工区域难以清洁设备或表面。具体而言，ISO-5 无菌处理区域的背面不具有

ISO 5 classified areas were not certified under dynamic conditions.

具体而言，在 ISO 5 层流罩中进行的烟雾测试并未在代表您的无菌加工实践的动态条件下

19. 美国 Johnson Memorial Cancer Center

具体而言，由于以下原因，该公司对 ISO 5 生物安全柜和 ISO 5 层流罩的清洁不充分：

○ 公司日常使用非无菌抹布 XX 以无菌 XX（杀孢子消毒剂）和无菌 XX 清洁所有

具体而言，在 ISO 5 分类无菌加工区域内工作期间，在无菌药品的生产过程中观察到不良

1）在 2018 年 10 月 1 日，观察到一名操作员在公司的 ISO 5 层流罩（LFH）中生产

3) On 10/2/18. an operator was observed producing several chemotherapeutic drugs

在 2018 年 10 月 2 日。观察到一名操作员在该公司的 ISO 5 生物安全柜（BSC）中生产

20. 美国 Med Shop Total Care Inc.

Clothing of personnel engaged in the manufacturing, processing, packing and holding of

Specifically, your formulation worksheets do not include specific instructions. For

21. 美国 Tailor Made Compounding, LLC

21. 美国 Promise Pharmacy, LLC

Procedures designed to prevent microbiological contamination of drug products

22. 印度 Dishman Carbogen Amcis Ltd.

1.) Blending of in-specification with out-of-specification (OOS) intermediate batches is

23. 美国 Hospira Inc. A Pfizer Company 20180612

Procedures designed to prevent microbiological contamination of drug products

B. On 7/24/2018, I observed 100-mL vials of lyophilized Vancomycin semi-

24. 印度 Dr. Reddy’s 20181114

25. 印度 Lupin Limited (Unit I) 20181204

装操作中的目视检查标准。以下总结了 2016 年以来与目视缺陷和异物有关的投诉：

Nature of complaint 投诉情况 2016 2017 2018

26. Lupin Limited 20190219

1. 印度 Alkem Laboratories 20180411

2. 英国 Dr. Reddy’s 20170926

3. 马来西亚 Biocon Sdn Bhd 20180312

5. 印度 Suven Life Sciences Limited 20180424

7. 印度 Mylan Laboratories Limited, (Nashik FDF) 20180626

8. 印度 Galaxy Surfactants 20180626

9. 美国 Cook Pharmica 20180910

11. 浙江华海川南一分厂 20180920

你们未能对关键变更全部执行正式风险评估，以评价所拟变更对中间体 API 的潜在影响。

You initiated validation on a commercial scale without conducting a formal risk

你们未执行正式风险评估评价改变你们已验证生产工艺对中间体和 API 质量的潜在影响就

b）烟雾测试未在 ISO 5 区域的动态条件下进行。您在检查期间进行的烟雾测试仅包括层

c）对成品进行的 XX 测试不是 XX。此外，兽药产品的 XX 检测结果未记录在案。