FDA 483表：印度Alkem Laboratories 20180411

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这个企业也有得拼了，不发warning letter就奇怪了！

FDA 483表：印度Alkem Laboratories 20180411

原创2018-04-13

JULIAJulia法规翻译

受检公司： Ltd

受检地址：167 Mahatma Gandhi Udyog Nagar Road Daman,Daman And Diu, 396210 India

受检身份：制剂生产商

FEI号：3006370524

检查员：June P Page (检查员) & Kellia NHicks (检查员) & Dipesh K Shah (国际程序办公室雇员)

检查日期：2018-03-19 至2018-03-27

签发日期：2018-03-27

发布日期：2018-04-11

OBSERVATION1 缺陷1

There is no quality control unit.

无质量部门。

Specifically, 具体来说，

• 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In addition,your firm failed to maintain and retain logbooks that are not obsolete or outdated.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。

OBSERVATION 2 缺陷 2

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

Specifically, 具体来说

• 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)        (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

• b)        (b)(4)-Reserve and Retain samples for February 2018
  
  
  

XX—2018年2月留样

• 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

• 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

• 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

• 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

• 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 Sample by Central  Quality Control (CQC) 中心QC接收样品日期	Product Name 产品名称	Batch Number 批号	Batch Release Date (T0) 批次放行日期（T0）	Market Intended for 销售市场
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 Documented T0时间未记录	Exhibit US 美国申报批
2017-12-11	(b)(4)	(b)(4)	Date for T0 not Documented T0时间未记录	Exhibit US 美国申报批
2017-12-11	(b)(4)	(b)(4)	Date for T0 not Documented T0时间未记录	Exhibit US 美国申报批
2018-02-13	(b)(4)	(b)(4)	Date for T0 not Documented T0时间未记录	Commercial US 美国商业批
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。

OBSERVATION 3 缺陷 3

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。

****THIS IS A REPEAT OBSERVATION****此为重复缺陷

Specifically, 具体来说

• 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（分钟）	Stop time (min)停止时间（分钟）
Inhibit Integration 抑制积分	(b)(4)	(b)(4)
Inhibit Integration抑制积分	(b)(4)	(b)(4)
Inhibit Integration抑制积分	(b)(4)	(b)(4)
Inhibit Integration抑制积分	(b)(4)	(b)(4)

Your QC Head agreed that known or unknown impurities will not be identified even if they are present 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。

OBSERVATION 4 缺陷 4

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

Specifically, 具体来说

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 所实施的分析	# of OOS not 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 物理描述	2
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)(4)	111

(2)      Twenty-three OOTs: 23个OOT

Analysis Conducted所实施的分析	# of OOT not 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)(4)	23

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。

OBSERVATION 5 缺陷 5

The written stability testing program is not followed.  

未遵守书面稳定性检测计划。

****THIS IS A REPEAT OBSERVATION****此为重复缺陷

Specifically, 具体来说

• 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”。

OBSERVATION 6 缺陷 6

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。

****THIS IS A REPEAT OBSERVATION****此为重复缺陷

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。

OBSERVATION 7 缺陷 7

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。

Specifically, 具体来说

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。

OBSERVATION 8 缺陷 8

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。

OBSERVATION 9 缺陷 9

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。

Specifically, 具体来说

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 合计	423

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 位置	Number of Equipment with that 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  total	96

OBSERVATION 10 缺陷 10

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。

OBSERVATION 11 缺陷 11

(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。

OBSERVATION 12 缺陷 12

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。

Specifically, 具体来说

• 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。

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。

DATES OF INSPECTION

2018-03-19至2018-03-24（周一至周六）2018-03-26至2018-03-27（周一至周二）

另外OMCL《计算机化系统验证指南--核心文件》中英文 下载链接

https://pan.baidu.com/s/1J6lHL6ARzgkt_8UaU2dNYQ

阅读原文

beiwei5du

OBSERVATION 6 的关于excel表格（spreadsheets）可以重点关注一下。

beiwei5du

有PLC是否必须都要密码保护？？？
红色字体如何理解（感觉是病句呢？？）？？？是PLC有报警功能，但是没有开启利用；还是PLC有报警记录，但没有评估其对产品的影响？？我个人认为是前者，大家怎么认为？？？


OBSERVATION 9 缺陷 9
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。
Specifically, 具体来说
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 合计	423

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 位置	Number of Equipment with that 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  total	96

beiwei5du

为何要验证呢？？？大家怎么认为这一条？？


OBSERVATION 10 缺陷 10
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。

beiwei5du

日常留样观察打开包装需要在可控的环境操作（比如洁净操作台内）
OBSERVATION 11 缺陷 11
(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 the Sample 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。

摩西擎仗劈红海

见过的最长的483了

hongweiwei000

beiwei5du 发表于 2018-4-13 17:23
有PLC是否必须都要密码保护？？？
红色字体如何理解（感觉是病句呢？？）？？？是PLC有报警功能，但是没有 ...

个人感觉这条的意思：这些PLC设备具有报警功能，但是未开启，企业应该评估一下这些设备没有开启报警是否会对生产过程造成影响

小金库

谢谢分享。