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FDA-483报告解读

2025-10-03 05:30:15 责编:小OO

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1 FDA 483 for Hospira Rocky Mount 2013

检查期: 02/12/2013-03/01/2013

To: Zena G. Kaufman, Senior Vice President, Global Quality

Hospira, Inc.

Hwy. 301N. +4285 North Wesleyan Blvd.

Rocky Mount, NC 27804

Sterile Pharmaceutical Manufacturer

FDA 检察官:

Penny H. McCarver, Investigator

Thomas J. Arista, Investigator

Jason F. Chancey, Investigator

Tammara A. Stephens, Investigator

Viviana Matta, Investigator

Observation 1

There are no written procedures for production and process controls designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess.

生产规程和艺制的书面管理规程缺失

Specifically,

A. The “Aseptic Media Fill Run” Document #B6100_0051 establishes that, “This procedure will document the minimum

requirements for performance of aseptic process simulations at Rocky Mount aseptic solution manufacturing.” And, “The purpose of the media fill simulation is to: demonstrate the capability of the aseptic process to produce sterile drug products. Qualify aseptic processing personnel. Comply with Current Good Manufatcuring Practice Requirements.” The following observations pertain to the media fill operations and aseptic process:

“ 养灌装操作规程”是在Rocky Mount 厂行无菌艺模拟验证的本操作规程，养灌装实验的的是了确认生产无菌产品的无菌艺，确认无菌艺操作人员并符合CGMP 要求但是审场发缺陷

1. There are xxx and xxx different finished drug products in various container sizes (e.g, 10ml to 100ml) that include a

XXXX overlay that are produced in the xxx and xxx manufacturing buildings. However, as confirmed by the Quality Operations Director and the Production Services Officer, they did not perform anaerobic media fills with anaerobic conditions;

场包装规格的产品的生产，据总和生产管的确认并未在氧条件行氧养灌装实验确认

点评点评属于型的没按照自的操作规程行操作的象，考虑到特指明的养灌装实验要求氧

，很能是厂没结合自的产品特性行相关的验证作理论的问发生，体了厂的人员和QA 管的力养灌装实验在无菌艺验证中是非常要的一个节，也是生产艺并能符合无菌的关键， FDA 将做第一条缺陷列来

2 回复意见回复意见针对个件本身行整改，然对QA 人员行，确保厂他的产品没类似的缺陷对将来系统的的问提解决方案或是新的SOP

2. We observed some of the routine aseptic filling operations in the SVP manufacturing rooms xxxxx which included

observing fill room operators performing a number of reoccurring manual interventions e.g., remove glass vials from line, adjustment of fill equipment, access the fill line via access panels. The Production Services Officer and Production Supervisor confirmed that the media fill runs do not include executing the same number of reoccurring manual interventions and for the same length of time as performed during routine filling operations.

场看到无菌操作中复的人预操作, 例如从生产线移除玻璃西林瓶，调整灌装备，通过入操作面板入灌装生产线生产管确认在养灌装验证阶段并没考虑些人预的操作和频次

点评点评

类问挑战的是养灌装验证的效性问，理论考虑最差的情况最多多少次人预，别是什类别的人预，体的人预操作的规程是什？些都需要在养灌装验证阶段结合产品生产艺，备状，施状作的班次行定由于备稳定会带来大的人预项和人预的频次，也是产备和口备最大的别实内无菌GMP 检查的过程中没格的来执行个操作检查力度，如果真的检查，内的生产线备和验证结果本都会因个缺陷被决

回复意见回复意见养灌装验证方案必须结合实的生产产品艺特和备生产线的体实情况行修并完善相关的操作SOP ，管理SOP ，避免类似的问在体系内次发生

3. The manual interventions include “Replace fill pump”, “Replace solution tubing (includes from needle to pump and

pump to manifold)”, “Replace bladder and Stopper head”. One of the fill room operators confirmed that he has performed the intervention during routine filling operations. However, regarding the aforementioned manual interventions he has not performed a similar activity during the media fill simulation process;

人预操作包括更换灌装泵，替换溶液管道包括从注射器到泵的管道和泵到转器的管道，替换袋和塞头灌装操作间的操作确认他在实操作中做了些人预操作，但是并没在养灌装验证中行些操作

点评

点评只是更体的列举了例作证据

4. During routine aseptic filling operations, the XXXX filtered production solutions are transferred from the second floor

with the use of a transfer hose (e.g., xxxx) that is manually placed through a XXXXXX (fill lines xxxxxx and xxxxxx (fill lines xxxxxx that xxxxxx. The solution transfer hose is subsequently connected manually to a corresponding transfer hose xxxxxxx in the aseptic fill room. (Note: the manual connection is performed adjacent to the capping station in an uncontrolled unclassified manufacturing.) With respect to media fill operations, the aforementioned manual operations are not performed in a similar manner. Rather, the microbial growth media if prepared and transferred into the fill room via the use of XXXX.

在常无菌灌装操作中，人操作的管被用于从楼转移到无菌灌装间，人连接管的操作是在未的域行的，的操作在养灌装实验中没被模拟

点评点评只是更体的列举了例作证据

5. The “Media fill procedure for vials” (production batch record) describes to “Fill the units aseptically per SOPs,

XXXXXX if required”, which references the document “B5350_0993” (SOP). However, as confirmed by the Quality Operations Director and the Production Service Officer, the document is silent with respect to a description and/or providing the language regarding how to aseptically fill the units;

西林瓶养灌装操作生产批记录中述到如果需要参考XXXX SOP 行无菌灌装，中的SOP

3 是指 B5350_0993 个文件，但是个文件中并没相关的操作述和规定

点评点评文件的管理缺失

a. During routine filling operations, the fill room operators record the manual interventions that they perform and

document the events on the production batch records. However, during media fill room operators do not perform a similar manner of record keeping and frequency of documentation. Rather, the Core Monitor captures the manual interventions and documents the events in the media fill records.

在常的灌装操作中，操作在生产批记录中对人预行了记录但是在养灌装验证中，操作并没做类似的记录更确的说是视仪在养灌装验证中记录了些人预的行

点评点评到人忽略的问，从头到看来是厂忽视了养灌装验证的一些本要求，人实知道需要记录一些信息，但是在养灌装验证中意的忽略了些操作和记录更一来说的管理体系潜在的问，很容易人产生联想能他们知道灌装验证的结果好，才忽略的也就到作假了 FDA 然会明确说你作假，但是会收集证据去引导大家想的策略或是思路是值得做场审的人参考和借鉴的

B. The “Aseptic Media Fill Run” document #B6100_0051 establishes the acceptance criteria. Specifically, the “Target

value for all media fills is zero positive units. Any (1) position unit requires an investigation, requirements for alert/action levels of contaminated units for a single media fill trial comply with the guidance in the Aseptic Processing Guideline and the XXXXX Department on the number of units filled the Alert and Action levels range from XXXX, respectively. Furthermore, “Should a media fill reach the action level, the media fill has failed and an immediate review of pertinent records will be made relating to product manufactured on that line between the current and last successful media fill for that fill line.” The following table contains a brief summary of the media fills.

无菌养灌装操作文件#B6100_0051中接标准的规定，明确指标是养灌装西林瓶染菌率 0. 任何染菌都需要行调查单一养灌装实验的染菌警线和行动线的定要求必须和无菌艺指南法规的要求相一规定了如果养灌装实验的结果达到了行动线，那实验就失了必须立行一生产线前到次养灌装实验的时间段之间的相关的产品的生产记录的审表格汇总了养灌装实验的本情况

Media Fills

Fill Line File date Filled Vials Defect Vial Assignable cause for discarded vials 12-034-MR

XXXX 2/20/12 6357 1652 Not specified 12-086-MR

XXXX 7/25/12 10675 382 Not specified 12-0-MR

XXXX 7/30/12 10653 334 Not specified 12-090-MR

XXXX 8/1/2012 12002 1826 Not specified 12-149-MR

XXXX 10/29/2012 10736 622 Not specified 12-151-MR

XXXX 10/31/2012 10190 63 Not specified 11-003-MR

XXXX 1/5/11 70 114 Not specified 12-082-MR XXXX 7/12/12 11673 242 Not specified

1. The Production Services Officer confirmed that media filled vials are removed and/or discarded during routine filling

operations. However, there are no records to document the total number of filled vials that are removed during the media fill operations and there is no record to documents an assignable cause for the removal of the media filled vials. 生产管确认养灌装瓶在常灌装测试中被遗的情况，但是场并没被遗的总数记录，也没记录什遗

4 2. The media fill batch record list a “Defect Categories” which is referenced to corresponding document #B6100_0051

(SOP). However, as confirmed by the Quality Operations Director, the document is silent with respect to a reference or language that addresses defect categories for the filled vials.

养灌装批生产记录中缺陷类别一栏参考SOP 是#B6100_0051 ，但是个文件中并没的规定和类

3. Fill volume samples are documented as rejects in the defect category for “cap/seal” and not included in the number of

units to be incubated in the batch record. The batch record establishes “Fill volume testing will not be destructive testing since all filled units are required to be retained. Fill volume units will be placed on the scale to obtain a gross weight and placed in a separate tray on the inside of the filling suite to be incubated as non-integral units at the end of filling.”; nonetheless, all units listed under the “Defect Categories” are not included in the “Number of units to be incubated” and there is no evidence to demonstrate all the units were incubated and evaluated.

灌装体的检测品被记录盖/密封合格品，也没包括在必须行养的数中批生产记录中写到灌装体测试会行破坏性的测试因的品必须保留灌装体品在放置到一个的托盘内在灌装结束作非完整性的品行养但是在缺陷类别的记录中都没记录被养的品数，没记录证明的品都被养和评估

点评点评综合来看结合A 的缺陷来看，的确证实了们之前的假无菌灌装实验大的合格，厂也没对的合格行合理的调查和预的措施，而是放任度 FDA 了证明的实施收集了大的数据去证实

回复意见回复意见最简单而是最效的回复就是认之前的养验证试验做的完善，没考虑到合格的时间的调查个肯定是到全部新验证，相关操作规程体人员的了然由于的面很广，能会体的产品召回，个层面需要小心

C. Regarding the aforementioned observations, the media fill data documents that the company is not able to substantiate

that they met their aseptic media fill established acceptance criteria, which is used to support, for example, “the minimum requirements for performance of aseptic processing simulations at Rocky Mount aseptic solution manufacturing”; “demonstrate the capability of the aseptic process to produce sterile drug products” and “Qualify aseptic processing personnel”;

据之前的述，养灌装实验的数据反证了公能符合无菌养灌装实验的标准要求，而个标准是用来支持信息的，例如无菌艺最少模拟验证次数，无菌产品的无菌艺生产能力确认无菌艺操作人员

点评

点评较犀利的指了养灌装实验失会被疑的系统缺陷，也提了多个方面的结论因被翻

D. The media filled vials are inspected for turbidity and visible particulates following the initial 7 day and final 14 day

incubation periods. However, the Biological Quality (BQ) Supervisor confirmed that there is no specific document that describes the requisite traininig for the individuals who perform the visual inspection of media filled vials. Some of the training would include, but not necessarily limited to, for example, visuals aids for turbid and non-turbid liquid media and examples of vials containing particulates.

养灌装西林瓶被要求在养的最初7 和续的14 内检查澄清度和见物然生物管确认没门的文件体要求相关的检测人员必须行的内容包括( 限于)澄清度差和好的品对照，含物的品实例

1. Microbial growth promotion tests are performed for microbial growth medium that is used for the aseptic media fill

process. The “Growth Promotion Testing” document #B6131_0033 establishes, for example, “For the growth

5 promotion to be valid, the inoculums level must be XXXX microorganisms”, which requires the use of microbiological positive controls. As confirmed by a Laboratory Analyst-I and BQA Supervisor, the rehydration of the microbial positive controls uses the manufacturer’s reconstitution instructions. However, the BQA Supervisor and the Quality Operations Director confirmed that the manufacturer’s instruction have not been officially vetted and in conformance with the Quality System.

微生物促生长实验使用了促生长养，个养被用于养灌装实验促生长测试的SOP# B6131_0033规定了了确保促生长实验效，接种微生物必须是XXX 微生物来行微生物性对照场析人员和管都确认微生物性对照的复采用的是供商的操作手方法实验室管和总认供商的手并没过式的审程序，也和公的体系符合

点评点评提示了个细节，一个是标准检查品的照片是的很好的资料另一个细节就是供商的说明书和指导方法如果没过公 QA 的审批准，也是你操作的依据尤是一个点，内的少企也会类似的问

Observation 2

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile are not established, written, and followed.

微生物污染的规程缺失够或没格遵

Specifically,

A. The V alidation Change Request (VCR) 9799, dated 12/1/10 concerns the establishment of a unidirectional airflow zone

above the XXX, Line XXX (room XXX capper operation via the installation of XXXX self-contained, HEPA filtered air recirculation units and associated laminar flow curtains. The VCR concludes, “…the combines system (HEPA recirculation units and associated laminar curtains) has proven capable of meeting the requirements of QPO.29.002, Microbiological and Environmental Control of Aseptic Process Operations Procedure , and has proven capable of maintaining an ISO Class 5 HEPA air supply until the product’s final cap seal has been applied.” However, these is no non-viable particulate monitoring performed to assure that the laminar flow curtained area is “capable of maintaining an ISO Class 5 HEPA air supply until the product’s final cap seal has been applied.” In addition;

某一生产线盖生产某产品之前的层流空气系统 HEPA 回流风和层流帘虽然在更申请验证的结论写着符合ISO-5 别的要求，但是没粒度数据的支持证明符合要求

1. The aforementioned corporate procedure “defines the minimum control limits and monitoring requirements for all

Hospira manufacturing environments involved with sterile parenterals products produced by aseptic processing.” The following 30ml tear top vial type finished products are aseptically filled and capped with the use of the XXXXX Capper;

1. Acetylcysteine 20% Solution, USP, List #3308-04-13

2. 2% Chloroprocaine T Hydrochloride Injection USP, List #4169-04-86

3. 3% Chloroprocaine T Hydrochloride Injection USP, List#4170-04-86

4. Bupivacaine HCl 0.25% EPI 1:200,000, list #9042-04-17

5. Bupivacaine HCl 0.25% EPI 1:200,000, list #9042-04-87

6. Bupivacaine HCl 0.5% EPI 1:200,000, list #9045-04-17

7. Bupivacaine HCl 0.5% EPI 1:200,000, list #9045-04-87

However, during the capping process, the aforementioned finished products are not maintained within an ISO-5

6 environment in that they are exposed to an unclassified manufacturing environment in room XXX.

列举了大 30ml 规格卡口西林瓶产品在生产线行盖操作，但是没相关的境数据的支持

点评点评要针对的是生产境的没实的数据支持

B. All materials, fill room equipment parts and utensils that are used for the manufacturing operations that are not subject

to a sterilization process are decontaminated via a XXX process in the XXXXXX #RMFJ-0477 XXX feet, room XXXX). The following provide a brief summary of observations;

生产用物料，灌装间备和器没行灭菌艺处理就被使用，例子如

1. The Engineer (Engineer-I) explained some of the key XXXX process parameters, e.g., XXXXXX. The process

parameters were evaluated during the XXX Cycle development and ultimately used to establish the XXXX process. The Engineer-I confirmed that there exists no record of the cycle development studies to support the current XXXX process;

某程师解释到一些的灭菌艺关键艺参数在开发阶段被评估过并最终用于建立些备施的灭菌艺但是没记录支持些参数的建立过程

2. The manufacture’s cycle development guide defines the validation process to include XXXX study, XXXXX

distribution with XXXXX and a challenge with XXXXX. For example, a XXXXX most be determined to establish the present sterilant concentration.” And the XXXX via the use of XXX “are useful for assuring homogenous XXX patterns”. The Engineer-I confirmed that they have no performed a XXXX profile or a XXXX evaluation via an XXXXX evaluation for the XXXXX;

公的灭菌周期开发指南定了验证艺涵盖XXX 实验，用XXX 做的实验 XXX 的挑战实验例如，XXXX 被用于建立的微生物污染物浓度但是程师确认他们实并没按照指南的要求去做

3. The XXX process validation includes the use of XXX monitoring probes positioned at defined locations, each with

a corresponding XXX on the XXXX. However, as previously noted, there exists no xxxxx evaluation to assure a homogenous XXXXX distribution within the XXXX which will identify and establish the worst case xxxx challenge locations of the XXXXX load configurations, which will in turn assists to assure that all materials are appropriately decontaminated prior to being transfer into the manufacturing controlled and classified areas;

XXX 艺验证中包括了使用探头在确认的地方的测试，但是因之前并没确认备的均一性，也没确认最差的点的置，的验证并能确保的物料都被效的灭菌处理了

4. The XXXX process validations included evaluations with various material load configurations on the XXXX.

Regarding routine production operations, the QA Project Specialist confirmed, excluding the language noted in the aforementioned procedures, they do not have any specific load configurations for the XXXXX.

验证中包括了对物料载的评估，实操作规程中并没特的载放置的规定和要求

5. There is no record to document that the routine production load configuration do not exceed the validated load

configurations established via the XXXX process;

常生产的载放置是超验证的规程要求并没记录的支持

6. The “Aseptic Sterilization Operations and Procedures” document #B5340_2023, and XXXX Work Order”

document #W530_342, establish the routine production operations, for example, “Do no stack items or allow other items to remain in contact with each other” and “Items loaded into the XXXX most be loaded in a configuration that allows no contact with other items or cart”, respectively. The aforementioned standard procedures are silent with respect to defining and establishing the routine load configurations.

7 无菌操作规程文件#B5340_2023和 XXX 生产指文件#W530_342都提到在常生产中允许堆器使相互接触和在XXX 中的器放置必须符合规定来相互接触但是对于常的灭菌载操作中的细节没明确的规定

7. The Engineer-1 confirmed that the is no xxxxxx profile performed or a XXXX for the XXX Line XXXX

production XXXXX), the XXXXX and the XXXXXX that is used for Sterility Tests.

程师确认对行无菌测试的的器和没行对的无菌确认

点评

点评要针对的是生产中用的，器和备施的灭菌符合自身规程的规定，也没细节的无菌确认述，也没按照相关的内部要求做好相关的记录

C. For fill line XXXX, we observed non-viable particulate (NVP) monitoring that is performed in close proximity to the aseptic filling zone. However, NVP measurements are not taken from other ISO-5 areas (e.g., XXXXX) during the aseptic filling process.

在XXX 灌装生产线，们看到在临无菌灌装域做粒度的，但是无菌灌装期间的他的ISO-5 域就没粒度了

点评点评是做的没做，的错误实在 QA 的管也很问

D. The “Aseptic Gowning and Technique Procedure”, document #B5350_0996, establishes the “proper aseptic techniques” when engaged in the aseptic filling operations, which includes to “move slowly and avoid excessive body movements”. However, we observed fill room personnel movements and production activities being performed in fill lines XXXX that were inconsistent with the established standard operation procedure.

无菌域的人员走动和操作书面的规定一

点评点评在无菌操作中人员的一举一动都是关键，也是的错误

E. Senior Purchasing Agent explained that all of the gowning attire (e.g., personnel scrubs, clean room gowning/coverall, over shoe covers and goggles) used by personnel that enter into the manufacturing areas have an established minimum and maximum life of a garment, that is in terms of the number of laundry cycles. For example, the clean room gowning/coverall and overshoe covers have a life cycle of XXXXX laundry cycles, respectfully. The Senior Purchasing Agent confirmed that there is no standard procedure that defines and establishes the minimum and maximum life of a garment. In addition,

无菌作服的体最少和最多的使用灭菌操作频次没书面规程规定另外，

1. There exists no record to document the life cycle of the aforementioned gowning attire, which would assure that the

garments and personnel attire are fit for use.

无菌作服的使用也没记录，能确保用性

点评点评无菌服的潜在合性也被提了，FDA 划把的能的污染源都说一遍

F. “Smoke Profile for Air Flow Pattern(s) & Curtain Lengths” document #B7100_0003 establishes that the, “Smoke profiling helps determine the effectiveness of the unidirectional air flow, (commonly known as laminar air flow) within the ISO-5 curtained areas of that cleanroom itself.” The air flow pattern evaluations include “the smoke profile is done in the operational mode or dynamically” and “the smoke should move down and away from product when introduced at or above product heights. There should be no turbulent flow of air in the critical process areas.” The corporate “Facility Qualification Procedure” document #QVO.19.021, establishes the smoke test, “Evaluates the HV AC systems under

空气流模式和风帘长度的烟雾实验文件#B7100_0003提到烟雾实验用于确认ISO-5 别的风帘域空气流的状层流状空气流模式评估包括动条件的烟雾实验和烟雾必须在产品生产高度流动原理或是向流动，在关键艺域得乱流集团的施确认规程文件#QVO.19.021规定烟雾实验用于评估空调系统在静和动都符合层流特性面汇总了实们看到的厂空气流状

1.For fill room XXX the evaluations did not include an assessment of the air flow from the HEPA filters that are

positioned over the ISO-5 XXX to assure that the air flow from the ISO-7 surrounding area does not adversely affect the ISO-5 area (Note: the distance between the ceiling (HEPA) and the XXXX partition is approximately 3 feet);

在灌装间XXX的空气流评估没包括从高效过滤器到ISO-5操作的空气流周边是ISO-7 别，距离达到3英尺

2.For fill room XXXX the evaluations did not include an assessment to determine the affects of the air flow when

opening and closing the xxxxx to assure that “the smoke should move down and away from product when introduced at or above product heights”;

没评估关门和开门期间灌装间气流的状确认气流会到利影响

3.For fill rooms XXXX the simulations of a replacement and/or removal of filling equipment e.g., “Replace fill

pump”, “Replace solution tubing (includes from needle to pump to manifold)”, “Replace bladder and Stopper head”, the evaluations did not include the routine movements and personnel activities that are commonly performed during routine production operations;

灌装间模拟灌装备的移动和更换，例如更换灌装泵，更换灌装管道和替换袋和塞子，的更换评估没考虑到常的备移动和人员的操作

4.There has been no assessment performed to determine and assure that the air flow from the ISO-7 area does not

enter into the ISO-5 when personnel are performing the various personnel activities next to or when accessing the ISO-5 areas e.g., adjusting the fill equipment/needles, glass vial in feed area in rooms XXX and XXXX (approximately XXXXX, respectively), and when accessing the ISO-5 via the XXXXX (room XXX) from the ISO-7 surrounding environment;

没评估操作人员在个域行操作的时候，ISO-7 域空气流入ISO-5 域的情况

5.There are a number of instances when the air flow pattern video did not demonstrate that “the smoke should move

down and away from product when introduced at or above product heights. There should be no turbulent flow of air in the critical process areas.” For example, for line XXX during the XXXX). (Please note that the aforementioned simulations and approximate video time stamps are not intended to be an all inclusive or exhaustive list of examples);

的烟雾实验录证明多个域空气流并能符合预期的要求

6.The various pieces of fill room equipment and materials used during routine production operations are transferred

from the ISO-8 manufacturing support rooms and into the ISO-7 manufacturing areas (surround the ISO-7 critical zones) with the use of XXXX. There has been no assessment of the air flow patterns to assure that the air flow of the ISO-7 AND ISO-5 areas are not compromised when opening and closing the room doors;

常生产操作中，少灌装间备和物料被用XXX从ISO-8的域转移到ISO-7的制域，但是没任何的开门关门的确认来保证ISO-7和ISO-5 域的空气流影响

9 7. The aforementioned procedure establishes to “allow enough smoke to be introduced to the area to observe the air

pattern to the approximate exit of the unidirectional air flow area. If a question arises, introduce additional smoke until the air pattern is determined.” However, the air flow pattern videos for three individual evaluations (approximately 1 minute each) for fill line XXX (xxxx bldg.) XXX documents no visible or distinctly visible smoke;

操作规程也提到如果需要的情况考虑做额外的烟雾实验来确保空气流效确认但是灌装线XXX 的次评估烟雾实验都只别持续了1 钟时间，记录中并没记录明显的烟雾状

点评

点评烟雾实验要的是空气流和差，也是本的境的要求从 7个缺陷项来看，跨域的层流状，人员操作对气流的影响，域之间联通对气流的影响，烟雾实验录的本要求录的评估都做了全面的论，本按照个思路大家就对如何审和考察烟雾实验了一个本的思路和尺度很惜，hospira 个厂各个节都做的好！

G. The microbiology department responsibilities include for example, the implementation of the Environmental

Monitoring (EM) program and establishment of the microbial alert and action levels for the manufacturing areas (e.g., ISO-5, ISO-7 and ISO-8) and for personnel monitoring. The Biological Quality Supervisor confirmed that they have not performed an evaluation of the air flow pattern evaluations, which for example would assist to determine the appropriate EM site selections for passive and active sampling, the manufacturing areas and personnel activities that may present a greater degree of microbiological challenge to ultimately assure that the EM program appropriately captures all critical monitoring areas.

微生物部门的职责包括境建立生产域的微生物警告线和行动线人员的，但是生物学管确认他们并没行空气流模式的评估显然的评估利于确认境的被动和动点，并能确认制域和人员活动多大程度给境带来微生物的挑战，确保境能效的涵盖关键的域

点评点评挑战的是相关部门能职的问，到系统的效性了

Observation 3

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed. (This is a repeat observation)

Specifically,

制部门的职责和规程没书面规范，而也没完全按照执行是一个复的缺陷

特别是，

A. The firm’s Quality unit has failed to evaluate all standard operating procedures/standard test methods to assure they are

in compliance with cGMPs, accurately reflect current practices, and do not conflict with other procedures.

部门没评估的行SOP 来确保它们符合cGMP 要求和准确的反实的操作方法，也没确保和他程序没矛盾

For example:

例如

1. SOPs WGTSGLVQC, “TS Glass Vial Quality Control Chart”, WGTSPLVQC, “TS Plastic Vial Quality Control

Chart”, WGASGLVQC, “Aseptic Glass Vial Quality Control Chart”. WGASVIALQC and “Aseptic Vial Quality Control Chart” describing in-process checks of defects have an accept/restrict level of XXX for crimping defects. When crimping defects met or exceeded the “restrict” level there was no requirement to conduct an investigation or to evaluate product since the last acceptable in-process check. This practice which had been effect since 2006 was only identified by the firm in January 2013 due to several complaints received for uncrimped vials.

10 SOP WGTSGLVQC, TS 玻璃小瓶制， WGTSPLVQC, TS 塑料小瓶制， WGASGLVQC, 无菌玻璃小瓶制， WGASVIALQC 无菌小瓶制述了中缺陷检查对于XXX 的盖缺陷一个接 /限定水盖缺陷到达或者超过限定水时，没要求对次接的中检查之的产品行调查或者评估方法从2006 开始就执行，但是在2013 1 因收到几个关于没盖的小瓶的投诉才被公明确

2. Thirteen (13) Standard Test Methods describing how to perform sterility testing based on various container

configurations of aseptically filled and terminally sterilized products state if outgrowth occurs “a retest must be performed.” This language is misleading and contradicts the required investigation that must occur as described in Standard Laboratory Practice 94. M-001 “Sterility Testing, Effective 8-23-12”.

13个标准检测方法述了怎据无菌灌装和最终灭菌产品的包装形行无菌检测些方法规定如发生细菌生长必须行复测表述使人误解，而标准实验室方法94. M-001 无菌检测 2012 8 23 执行规定的需要行调查相互矛盾

点评点评对于盖合格率超范围和包材无菌检测的要求必须和书面规程规定的保持一，并需要体的处理方式的书面述规范

B. Employee practices do not consistently align with written procedures and are not assessed for their impact upon

manufacturing efficiency and/or product quality. Examples include:

员操作没持续地和书面程序一，并没评估它们对于生产效率和/或者产品的影响例如

1. There is no written procedure or means of tracking for Flex Manufacturing Area employee’s practice of storing

plastic films for use in the fabrication of 500ml and 100ml bags for XXX in the Flex Area Airlock (Room XXX). 在Flex 生产域，对于储用于在Flex 域气锁 XXX 间内制 XXX500ml 和100ml 袋子的塑料薄片的员操作，没书面程序或者追溯方法

2. There are no written procedures for Flex Manufacturing Area employees’ practice of using XXX and XXX at

multiple points on and in the XXXX machines that place 500ml and 1000ml bags into overwraps to prevent jams and possible damage to overwrap pouches and/or bags.

对于Flex 生产域员在多点使用XXX 和XXX ，并在XXX 备中将500ml 和1000ml 袋子制作外包装挤和对于外包装小袋或者袋子的能破损的操作，没书面程序

3. There are no written procedures for SVP Manufacturing Area employees’ practice of securing a XXX to the

stoppering machine with XXXX so as to reduce the incidence of line stoppages.

对于SVP 生产域员在塞机固定XXX XXXX 降生产线停发生率的操作，没书面程序

点评点评调的是任何无菌域的操作和行都必须书面规程的规定

Observation 4

Drug product production and control records, are not approved by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed.

Specifically,

在批次放行和发前，药品生产和检验记录没被部门批准，确保符合建立和批准的书面程序特别是，

A. Five hundred forty-three (543) non-viable particulate test results obtained during the production of both aseptically

11 filled and terminally sterilized products were invalidated without the required Biological Quality Supervisor approval from 2011 to 2013. SOP B6134_0007 “The Rocky Mount Facility Environmental Quality Program, Effective, 12-11-12” states that a supervisor signature is required within that shift for approval of invalid results. The invalid results were not entered into the XXXXX), only the passing retest. The Biological Quality Manager stated that the Biological Quality staff was told to stop invalidating data in this manner “around the third week of September.” There have been 2 more instances of data invalidation since. No procedures have been updated to address this invalidation practice. The Remediation Manager identified that a protocol was approved on 1/30/13 to detail the review of 2011 and 2012 XXXX logbooks for documentation errors. In addition, the protocol needs revision to address the invalidated data and assess the impact that each individual case may or may not have on marketed product.

从2011 到2013 ，在无菌灌装和最终灭菌产品的生产中， 543个非活性微粒检测结果是无效的，但是没要求生物管的批准 SOP B6134_0007 “落山厂境规程, 2012 12 11 执行”规定需要班管的签来批准无效的结果些无效的结果没登记入XXXXX ，只是通过复测生物理声生物员大在9 的第周被告知停无效数据的种处理方式在之，发了2个无效数据的实例没程序被升，来规定无效数据的处理方法纠偏理解释一个方案在2013 1 30 被批准，用细规定对于2011和2012 的XXXX 文件错误的复外，方案需要修无效数据，并评估个个案对于产品是影响

B. Discussions with the Biological Quality Supervisor revealed that in some instances, the alarms were stopped prior

to completion of the sample. Therefore, measurements for both XXXX size particles are not recorded. A measurement that was stopped on line XXX during simulated water run on 2/28/12 stated that an operator was inside the line. When asked whether it is normal to stop a measurement because someone is in the line, the Biological Quality Supervisor stated that they are not trained to do this. Another instance of the alarm being aborted during an activity occurred on 2/11/2012 when a measurement was stopped and invalidated because of a tank change.

通过生物管的论发在一些情况，在完操作前警被中因，对于XXX 大小的微粒检测没被记录一个在2012 2 28 在线XXX 模拟水行过程中的检测被停了，并解释一个操作员时在生产线询问因某人在生产线而停检测是常象时，生物管回答对于种情况他们没被过另一个活动发生时警被中的实例是，在2012 2 11 ，因一个储罐的更换一个检测被停和无效了

点评点评

要针对无菌制剂产品放行前相关的境指标和记录必须审，操作过程中的常引发的警等QA 都必须行的调查和处理，评估对相关产品的潜在影响

Observation 5

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. (This is a repeat observation) Specifically,

对于任何无解释的偏差产品或组的合格，公没行彻的审 ( 是一个复的缺陷

A. Investigation with PR ID #80622 was created on 05/04/12 to address three separate events associated with product

complaints for Bacteriostatic Water for Injection, USP. In the first event, associated with Lot #08-368-DK, the reporter revealed 93 particulate defects (9 specks, 6 fibers and 78 loose glass). In the second event, associated with lot #17-103-DK, the reporter revealed 54 particulate defects (1 speck, 2 fibers, 51 loose glass). In the third event, lot #17-104-DK, the reporter revealed 58 particulate defects (55 loose glass, 2 speck and 1 fiber). All lots related to the aforementioned events were manufactured in line XXXX. A potential root cause for the glass particulate was

12 identified to be needle to vial strikes; as a result, needle offset and dive settings were established for the affected line.

在2012 5 4 创建了一个调查，编 PR ID#80622 调查包含了个注射用水抑菌剂产品投诉相关的件第一个件，批 #08-368-DK ，告人发了93个缺陷 9个色点，6个纤维和78个脱落玻璃微粒第个件，批 #17-103-DK ，告人发了54个微粒相关的缺陷 1个色点，2个纤维和51个脱落玻璃微粒第个件，批 #17-104-DK ，告人发了58个微粒相关的缺陷 55个脱落玻璃微粒，2个色点，1个纤维些投诉相关的批都是在生产线XXX 生产的玻璃微粒的一个潜在原因被确定针对于玻璃小瓶的撞，因，对于条影响的生产线，新定了针的偏移和降参数

1. Engineering failed to conduct an engineering study, as established in the investigation report, to establish

acceptable needle offset and dive settings.

对于在调查告中建立的接的针的偏移和降参数范围，程部门没行程学研究

2. The investigation fails to address the impact needle offset and dive settings to any other products or lines.

调查没说明针的偏移和降定对于他产品或者生产线的影响

3. In addition, the firm failed to address the failure of the firm’s visual inspection process to identify these

numerous particulate defects.

外，公没解释说明公检过程没发些明显微粒缺陷的原因

点评点评任何调查都必须体的数据行支持，如果到备的行参数或是定参数的调整，需要人员的科学解释 FDA 提到了延伸调查，他生产线的类似的置是问，是在调查过程中容易忘记的关键点

B. Investigation with PR ID#68090 was created on 02/03/12 to address white particulate, “with a very thin fiber like”

appearance, observe inside Epinephrine Inj. Solution with lot #14-071-DK. The white particulate was identified to be silicone. The investigation report established XXXX may exhibit signs of unadhered silicone” and “these units are not classified as defects”; as a result, the investigation was cancelled.

在2012 3 2 ，创建了一个调查，编 PR ID #68090 调查包含了白色微粒，在肾腺素注射剂中发了一个非常细的类纤维，溶液的批是#14-071-DK ，白色微粒被确定是硅建立的调查XXX 说明它是非粘硅的信，并些能被类缺陷因，调查被

C. During media fill with fill date 01 AUG 2012, fill line XXX and lot #12-090-MR, 27 vials were identified as

having a “glass” cosmetic defect (glass particulates); nonetheless, an investigation to identify the root cause of these events and prevent occurrence during routine operations was not initiated as confirmed by the Quality Operation Director.

在2012 8 1 的养灌装过程中，灌装线XXX 和批 #12-090-MR ，27个西林瓶被确定玻璃表面缺陷玻璃微粒然而，一个确定些件的本原因的调查和在常操作中预次发生的措施没被营总建立和确认

Observation 6

Aseptic processing areas are deficient regarding the system for monitoring environmental conditions.

无菌操作域的境系统缺陷，

Specifically,

特别是

A.In October 2012, Biological Quality Manager identified that “Gram positive rods in XXX increased to 25% from

0%”. The XXX trend report for XXX 2012 states “Gram positive (spores), Gram negative rods, and molds (objectionable organisms) occur more abundantly than expected for properly functioning clean room.” For example in the XXX aseptic core the microbial bioburden consisted of the following: 48% Gram positive spore forming rods, 31% Gram positive cocci, 9% Gram positive non-spore forming rods, 6% mold, 5% Gram negative rods, and 1% yeast. The small volume parenteral terminally sterilized classified area had bioburden consisting of 27% Gram positive spore-forming rods, 23% mold, 18% Gram negative rods, 18% Gram positive cocci, 8% non-spore forming rods, and 6% yeast. Review of the XXX trend reports form XXXX 2012 to XXXX 2012 remained similar. The report states that the “vast majority of microbial contamination is human borne in adequately functioning clean rooms.” Subsequently, on October 31, 2012 Production Services Manager opened CA-PA PR ID 105693 in order to create a focus team to review the current Rocky Mount Cleaning and Disinfectant Program to identify graps, standardize cleaning procedures, and implement continuous improvements around cleaning, sanitization, and disinfection in the ISO classified areas. Although more than 3 months have passed, no focus team has been established.

在2012 10 ，生物理确认在XXX中的革兰氏性杆菌从0%增到25% XXX的2012 XXX趋势告说明对于几个能洁净室，革兰氏性孢子，革兰氏性杆菌和霉菌病菌的产生数预期的更多例如在XXX的无菌操作心域，微生物的生物负载组如 48%的产芽孢革兰性杆菌，31%革兰氏性球菌，9%非产芽孢革兰性杆菌，6%的霉菌，5%革兰氏性杆菌和1%酵母菌小容注射剂最终灭菌制的生物负载的组 27%的产芽孢革兰性杆菌，23%的霉菌，18%革兰氏性杆菌，18%革兰氏性球菌，8%非产芽孢革兰性杆菌和6%酵母菌复了从XXXX2012到XXXX2012的XXX趋势告，结果类似告说明在大多数的能洁净间，要的微生物污染是人员带入的因，在2012 10 31 ，了创建一个小组复行的落山清洁和灭菌城用确定差距标准清洁程序，并对ISO 域的清洁毒和灭菌执行持续的改，生产服理创建了一个CAPA PR ID 105693 管批准超过3个了，没建立小组

B.The microbial action limits for purified water used in the production of aseptic and TS products have not been

evaluated to determine if they are appropriate for the Rocky Mount facility based on historical data, resulting in a large spread between the alert and action limits. For example, the alert limit in XXX small volume parenterals is XXXXX and the action limit is XXXXX.

用于生产无菌和TS产品的纯水的微生物行动限没据历数据行评估用确定它们是用于落山厂，于警示限和行动限之间很大的范围例如，XXX小容注射剂的警示限是XXXXX，而行动限是XXXXX

C.Procedures do not define how data must be presented in the XXXX trend reports generated by Biological Quality.

Corporate SOP QPO.29.002 “Microbiological and Environmental Control of Aseptic Process Operations Procedure, Effective: 11-20-09” states that normal operating trends of all ISO Class 5 environments must be reviewed XXX. A standard operating procedure describing how the data must be evaluated and presented is necessary to assure that negative trends are discussed during the management review meeting. For example, the XXX 2012 trend data presented during management review on 7/5/12 presented that there were “no negative trends in XXX.” However, review of the XXXX trend report indicated that there was a negative trend for non-viable air particles on aseptic critical site Line XXX. This information was not discussed during management review because of the format in which the trend information was presented.

没程序规定哪些数据必须在生物部门创建的XXX趋势告中包括公 SOP QPO.29.002 无菌艺操作程序的微生物和境制 2009 11 20 执行规定 ISO 第5 域的常操作趋势需要复 XXX 需要一个标准操作程序述些数据必须怎评估和呈，确保负面趋势在管理层回顾

会中得到论例如，在2012 7 15 的管理层回顾会中，XXX2012趋势数据行了展示，呈的是对于XXX ，没负面趋势然而，在复的XXXX 趋势告中提，对于无菌关键生产线XXX 的粒度负面趋势因趋势信息呈格式的原因，信息没在管理层回顾会中被论

D. There were 5 instances of Gram negative rods (objectionable organisms) recovered form the aseptic core within the

ISO Class 5/EU Grade A area of the XXX and filling lines during 2011 and 2012. Review of associated Exception Reports PR ID 67333, PR ID 107671, PR ID 102686, PR ID 51460, and PR ID71321 investigating the recoveries revealed the following deficiencies:

五个实例，在2011 和2012 ，在XXX 的ISO 5/A 和灌装线的无菌心域，检测到革兰氏性杆菌病菌复了用调查检测情况的相关符告PR ID 67333, PR ID 107671, PR ID 102686, PR ID 51460和 PR ID71321，发了缺陷

1. The investigations failed to adequately evaluate a possible route of contamination. Each investigation describes

the type of organism and its usual source. However, they do not explore how the organisms entered the

controlled environment. PR 107671 suggested the most probable root cause as being “attributed to water

condensation from outside of the XXXX settling onto the sterile plate during fill machine set-up activities.”

During discussion, the Biological Quality Manager and Biological Quality Supervisor agreed that the

likelihood of this occurring from XXX materials is 0%. The investigation was approved by Quality.

调查没充地评估能的污染途径个调查述了微生物的类别和通常的来源然而，没探究

些微生物是怎入制域的 PR 107671建的最能的本原因是因于在灌装机开启作

时，在XXXX 外部的冷凝水落到了无菌养皿在论中，生物理和生物管意了

情况发生在XXX 物料的能性 0%

2. The interviews conducted as part of the investigations were poor in that they only involved the BQ technicians

responsible for taking the environmental samples. No interviews were conducted with the line operators whom

are in the aseptic environmental longer periods of time and are more likely to witness any unusual events.

Additionally, the interviews were conducted approximately 2 months after the occurrence.

作调查一部的面对面论做的很差，只负责境品的生物术员对于长期在无

菌境内并更能睹非常时间的生产线操作员，没行面对面论外，面对面论是在

件发生 2个才行的

3. The investigations include environmental data for the aseptic area that is reviewed for trends. However, there is

no procedure that defines the search criteria for trending. No evaluation of environmental monitoring data for

the support areas within the aseptic core were conducted during the investigations. The BQ Manager agreed

that this process needs improvement.

调查包含了对于无菌域境数据的趋势复然而没程序规定趋势的调查标准对于在无菌心

内的支持性域的境数据，没行评估生物理意流程需要改

点评点评个方面的缺陷实好提供了如何做调查的确的思路和方向，用作们将来自的

施发生问的调查思路

E. There exist no established procedures to define the evaluation process when establishing sample site rationales for

environmental monitoring of ISO classified areas. The sample sites for locations within the ISO Class 5/EU Grade

A area were established without review of the smoke studies. Biological Quality Supervisor who established the sample site locations did no review this material. The Biological Quality Manager added that she was in the process of training him on how to review smoke studies.

没建立程序定在建立ISO 制域的境点原理时的评估流程在ISO 5 / A 内建立的

Observation 7

Equipment for adequate control over air pressure, humidity, and temperature is not provided when appropriate for the manufacture, processing, packing or holding of a drug product.

制生产包装或放无菌产品的境差湿度和温度的备合

Specifically,

A.The XXXXX is a computer based automated system that is used to provide control and monitoring of both CGMP

and non-CGMP system throughout the XXX and XXX facilities. Examples of CGMP functionality at this plant include Differential Air Pressure (ΔP) monitoring and alarming in the Aseptic/TS cores and HV AC systems.

Regarding the XXXX measure points, the Senior Maintenance Supervisor confirmed that XXX measurement points monitor CGMP “important” parameters. The following provide a brief summary of observations;

自动系统用于无菌关键域和HV AC系统的差和警制，但是在问

1.The XXXX is accessed remotely by designated and approved Level 1 (administrative privileges) individuals

that include a XXXX contractor. The Level-1 privileges include for example, configure items, adjustments, resets and override capability, analysis, and trending report. However, there is no record to document that the XXXX contractors and the individual who has remote access privileges for the XXX computer system have taken the requisite CGMP training modules;

算机系统程问权限Level 1的授权人员包括来自于包商授权人员，别的权限涵盖参数析和趋势告的置，调整，启和覆盖但是对些人员没相的CGMP 记录

2.Regarding the aforementioned access by the XXXX contractor with Level 1 access privileges, there is no

standard procedure that establishes a periodic review (e.g., Quality Assurance oversight) of the remotely accessed computer data related events e.g., configure items, adjustments, resets and override capability, analysis, and trending reports;

也没建立相的SOP规定QA定期地审授权人员程问算机数据的相关件情况

3.The Senior Maintenance Supervisor confirmed that in the last nine months there have been approximately

4,000 and 3,800 alarmed events that have occurred in the XXX and XXX buildings. However, there is no record to document that the XXX alarms are reviewed on a periodic base to assure that the alarmed events do not document a negative trend for the XXX measurement points;

高维管确认，在最的9个 XXX 和XXX建筑楼的洁净别 4000和3800次警发生但是没建立相关记录定期审些警情况，并确认没良的趋势发生

4.The XXX will provide an audio and visual alarm to alert the production and engineering staff of the air

pressure alarm when the differential air pressure exceeds the established upper and lower levels between the aseptic fill rooms and the surrounding manufacturing areas. An alarm text message is printed out in a production office. However, the computer print out does not include the actual air pressure measurement that generated the alarm event. The Senior Maintenance Supervisor confirmed that the actual air pressure measurements can be printed out and the information can be provided, that is, if the Manufacturing Quality (MQ) personnel specifically request a print out;

超标警打印信息没包括实的差数据无菌灌装间相对于外部，而实是打印来的

5. In the absence of an air pressure alarm print out, the Senior Maintenance Supervisor and the MQ personnel do

not periodically review the air pressure measurements to assure that the differential air pressures do not present

a negative or outward drift from the established upper or lower air pressure levels.

因没打印来体的差超标警情况，高维管和生产人员无法行定期地审，来确认在良的差趋势超限的趋势

B. The Senior Maintenance Supervisor confirmed that there are no As Built engineering diagrams for the Air

Condition (AC) XXX. The XXXX units provide high quality HEPA filter air for the fill rooms XXXX (ISO-5 and ISO-7) aseptic filling rooms and for the ISO-7 and ISO-8 manufacturing support areas leading to the aseptic fill rooms, respectively. And, the simplified block Air Flow Diagrams K-RM-5-M101c and K-RM-5-M101a for AC-1 and AC-2, respectively, that illustrate the air systems are not current or up-dated.

没对空调系统的程示简易的空气流向示意方框说明空调系统是前最新的或先的

点评点评

一方面无菌间理念和水足，特别是用于无菌关键域差的算机系统在权限管理警记录和审，趋势析方面在较大足，特别是多次警的情况，合的纠和预措施才对则检查官也会着放，见个公的保证意识很薄弱也很被动

Observation 8

Aseptic processing areas are deficient regarding humidity controls.

无菌生产的湿度制缺陷

Specifically,

Review of the temperature and humidity monthly measurements from 2010 to present for all controlled ISO5 to ISO8 aseptic processing environments in XXX and XXX revealed that relative humidity readings repeatedly exceeded the specification of XXXX% RH (relative humidity) with excursions ranging from XXXX-99%. “Humidity is only controlled in rooms having specific product parameters that require control”…”All other rooms will be controlled and monitored for personnel comfort only” as stated in SOP S7100_1002” Room Temperature and Humidity Testing Effective: 10/29/2012.” This approach to temperature and humidity control has not been evaluated with regard to impact on controlling the propagation of microorganisms.

从2010 到在的相对湿度数据显示，无菌生产域反复相对湿度超标 XXXX-99% 的问而按照SOP 规定只是对产品要求的间才制，他的间只是提供人体舒的境但是对的温湿度制方式会会利于制微生物滋生方面的影响，没行合的评估

The Failure Mode and Effect Analysis performed regarding temperature and humidity as described in SOP7100_0255 “Rocky Mount Engineering (P/M) Preventative Maintenance Program, Effective; 09/28/2012” was performed and identified that this task has a priority ranking XXXX. This is documented on Maintenance Work Order Forms identified as “Task No: RM XXX” and “Task No: RMxxxx.” Priority XXX “task(s) have major affect on safety, product, quality or process.” The Quality Operations Director stated that the actual FMEA matrix was discarded as part of Hospria’s corporate record retention policy.

而据SOP 和维作指单显示关温湿度的FMEA 风评估是优先等，意味着对全产品或艺大影响但行总说实的FMEA 风告 201 的作废了

点评点评足见公对于无菌风来源的意识非常淡薄无菌域最担心的就是微生物滋生，而微生物的滋生关键因素是必要的水和一定的温度湿度制对于无菌域是很关键的 FMEA 告保的时间短了，也许本没做

Observation 9

Testing and release of drug product for distribution do not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release.

产品放行前没合的QC 检测来确保产品是符合最终标准的

Specifically,

A. The XXX is the XXX used to perform sterility test on aseptically filled finished products. Review of the last

performance qualification entitled “2011 Periodic Performance Qualification (PPQ), Biological Quality Laboratory XXXXX revealed the following deficiencies:

1. The study does not include a documented rationale for the placement of XXXX within the XXXXX. Additionally,

there were no air distribution studies performed to demonstrate adequate distribution of XXX throughout the XXXX and visualize the hardest to reach areas within the XXXX.

用于无菌测试的施— 是超净没行空气流型研究

2. Performance qualifications for the unit are performed every XXXX years. The rationale for this timeframe is not

documented. Aside from normal preventative maintenance performed by the BQ technicians, no periodic review is performed between qualifications. Validation stated that as a part of the periodic review which is currently on schedule for approximately every XXX years, they look back at the environmental trending data in a report provided by the BQ laboratory. However, the report that is provided by the BQ laboratory is not based on a protocol detailing what information must be included and in what format. Therefore, all negative trends may not be revealed during the periodic review.

超净性能确认 XXX 行一次，但是没合理的依据预性维确认没到定期的审微生物实验室提供的验证告显示并没按照方案的要求行告因的良趋势能无法在定期审时被发

点评点评微生物实验室的无菌检测条件保证性足，检测靠性被疑很多公忽略了微生物实验室的检查风，认检查官会去或者懂

B. SOP 6131_0013 “Procedures for Testing Positive Isolates Found in Sterile Products, Effective: 11/21/2005” describes

procedures that may result in a false negative being reported during a sterility test positive investigation by instructing the following:

据SOP 的关述，能导无菌检测性结果调查时，假性结果的告

1. The subculture incubation period is only XXXX. This could preclude the proliferation of slower growing organisms.

次养时间足，能假性结果-生长较慢的微生物没充的繁殖而被排除

2. The subculture procedure for XXXX ) only requires anaerobic incubation. XXX also supports the growth of

organisms with reduced oxygen requirements that may be excluded if aerobic incubation is not performed as well. 次养程序对于XXX 只是在氧条件行，没行氧条件的养在氧条件也能会生长

点评点评如何术避免假性是问的

Observation 10

Written specifications for laboratory controls do not include a description of the testing procedures used.

18 标准没包含使用的析程序

Specifically,

During the incubation of anaerobic environmental monitoring samples the anaerobic indicator is being used incorrectly. The appropriate use is not detailed in SOP B6117_4013 “Operation and Use of the XXXX Water Baths, XXX Anaerobic System XXXX Pipet Washer, XXXX Sealing Machine, and the XXX of XXXX Glassware, Effective 10-08-02.” Since no positive control is incubated concurrently with the samples, there is no assurance that anaerobic conditions are achieved.

氧指示剂的使用方法确，在对 SOP 中也没体的述而氧养时也没行的性对照制，将无法保证氧条件的效性

点评点评微生物检测，特别是无菌检测，避免假性或假性情况的很要的手段就是性对照性对照包括养和境背景的，然养的促生长试验

Observation 11

Laboratory records do not include complete data derived from all tests, examinations and assay necessary to assure compliance with established specifications and standards. (This is a repeat observation)

QC 检测记录没包含完整的数据

Specifically,

A. The 2011-2013 XXX logbooks used to adhere non-viable air raw data to bound worksheets were reviewed.

Requirements for this documentation are described in SOP “The Rocky Mount Facility Environmental Quality Program, Effective, 12-11-12.” The following documentation errors and omissions were revealed:

1. The non-viable particulate test results are incompletely entered into the XXXX logbook, incorrectly documenting

whether a retest was or was not performed. In many instances, “No retest” is selected when in fact there was a retest attached to the form.

非活性微粒测试结果没在logbook 完整地记录，也没确记录是是复测的结果很多时候实是复测的但是选择的是是复测的

2. Omission of the term “invalid” on the invalidated over alert and/or over action results.

超过警限或者行动限的结果没注明无效

3. Details describing why the measurement is invalid are not properly documented on the form.

测试结果无效的理由在记录中没体的述

4. Signature missing from the BQ technician and/or the reviewer showing that no review was performed at all.

没微生物人员和复人员的签说明本没被审

点评点评记录都乱来，QC 都谨，见检察官火大了，除了必要的，就是常的审督没执行到

B. The raw data generated from the semi-automated thickness tester used to measure the thickness of perimeter seals on

fabricated 500ml and 1000ml bags used as container closure systems for injectable drugs can be overwritten with new data without explanation and the original data is erased from the computer’s memory upon being overridden. For example, the first three pages of the “FLEX FAB SEAL THICKNESS REPORT” for bags fabricated for list number

7983-04-49, 0.9% Sodium Chloride Injection, USP, lot 26-806-FW recorded that 17 out of 48, 16 out of 47, and 12 out of 48 measurements were overridden.

半自动厚度测试仪打印原始数据在数据覆盖的问但没合的解释，而原始数据也没保在算机中

点评点评足见常审督到，偏差怕，怕的是发生了没合的调查评估并制定相的纠预措施避免次发生

Observation 12

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process.

无菌生产用产品预微生物污染的程序中没涵盖充的无菌艺验证

Specifically,

A. The periodic performance qualification protocols for the XXXX used to terminally sterilize 500ml and 1000ml drug

products do not require that biological indicator D-values be comparable to those previously used to qualify the terminal sterilization process. Written procedure 90.M-0330, “D-values Associated with Microorganisms used for Sterilization Validation”, effective 7/20/12, allows for the stipulated biological indicator organism, XXXX to processes D-values ranging from XXXX.

用于终端灭菌的产品的备XXX 周期性性能确认方案没要求对于生物指示剂的D-value 值和之前的确认行对

B. There is no written procedure requiring that sporulation counts of the biological indicator organisms used to validate the

performance of the XXXX are compared against each other and against scientifically justified specifications prior to heat shock processing, after heath shock processing, and with the positive controls. Personnel at this facility currently utilize a non-proceduralized requirement that the post-heat shock sporulation counts must be within XXX% of the pre-heat shock counts.

没建立相关的程序要求热激处理前，对用于性能确认的生物指示剂中的孢子数行相互对和合的标准对，并行性对照前只是采用非程序的要求规定热激处理前的孢子数在XXX% 内

点评

点评只是合格是够的，必要的横向和纵向对才更好地避免潜在风

Observation 13

Rejected in-process materials are not identified and controlled under a quarantine system to prevent their use in manufacturing or processing operations for which they are unsuitable.

合格的物料没行必要的识别和隔离制，被错误地用于生产中

Specifically, potentially defective 500ml and 1000ml bags fabricated onsite and used as drug product container closure systems are not appropriately bracketed upon discovery of one or more defective units during routine in-process testing for seal integrity conducted on the final set of XXX bags on each shelf of approximately XXX bags.

A failing in-process test results in XXX random sets of XXX bags being sampled from the implicated shelf. If any of bags from the XXX random sets fails the additional in-process testing, all of the bags on the shelf are rejected. If all of the bags from the XXX random sets of XXX bags pass the additional in-process testing, all of the bags on the shelf are accepted. There are no assurances that all of the defective units fabricated before and after the failing unit are appropriately bracketed and/or specifically identified.

潜在缺陷的包装袋并没行合的隔离在发合格的包装时，并没保证将前的缺陷包装行必要的隔离或者识别

点评点评过程更要，因检测竟是一个很的概率测试只表被测试的品没问，只过程保证了才能确保被的品表整批的

Observation 14

Aseptic processing area are deficient regarding the system for cleaning and disinfecting the room and equipment to produce aseptic conditions.

无菌生产的间和备清洁和毒缺陷

Specifically,

A. The validation study to evaluate sanitizers used on surfaces within the aseptic core entitled, “Microbial Evaluation of

Germicidal Effectiveness XXXXXX on Bacterial Microorganisms, Protocol #RM BQ12.043” is inadequate in that: 无菌关键域的表面灭菌验证评估在缺陷

1. Critical surface that the aseptic filling rooms are constructed of XXXX were not evaluated. Regarding the grade of

stainless steel that is used for the aseptic filling lines in XXX and XXX, the Engineering Services Manager stated that “it could not be determined.”

XXX 材用于建无菌灌装间关键表面的合性没评估程术理能确定用于无菌灌装生产线的锈钢材别

2. XXX failed when challenged with XXX isolate and Rocky Mount isolate #H201214BQ on the wall XXXX)

surface with XXXX reductions, respectively. Although the acceptance criteria of XXXX were not met, Production Services Manager concluded that the result “rounds to a XXXX reduction, therefore it meets the acceptance criteria.” The study was approved by Quality Operation Director designee and the Biological Quality Manager.

毒挑战性试验的结果符合既定的标准，但是生产术理认在少的趋势而作了符合接标准的结论，并最终行理和生物理都批准了

3. There is no documented scientific rationale detailing the surface selection evaluation. The Lead Director for

Manufacturing Science and Technology confirmed that XXXX were used in the previous corporate efficacy studies because they were considered to be worst case surfaces that were more difficult to clean than XXXXX. However, Rocky Mount did not evaluate either the XXXXX. Additionally, the corporate studies did not evaluate isolate from the Rocky Mount site.

没科学的依据来细说明和评估选择的用于毒验证的表面的科学性

点评点评没行必要是确认或者是科学的评估，最终会导面的作一文值 DQ 的高度决定了最终的，何况无菌产品的风那大

B. While viewing the set-up of aseptic filling line XXX for the filling on 1% Lidocaine Lot#26-416-DK, List#4279, a

white residue was observed on the stainless steel filling cabinet, around a hose leading from a trough beneath the filling zone, on the floor immediately beneath the filling cabinet, on the floor beneath the XXX system, in between the XXXX particle counters and the stoppering machine. The room was cleaned the morning prior to set-up on 2/20/13 with a start time of 0036 hours and a completion time of 0245. According to SOP 5000_0001 “Hospira Rocky Mount Cleaning and Disinfection Program”, Effective: 13-01-28, the area is inspected “to ensure that all equipment is clean and that no

remained in several locations in the ISO5 and ISO7 areas, the records indicate that the cleaning was verified by the Line Coordinator as acceptable.

场发无菌灌装生产线多处在白色的产品留，说明是清洁足，但是记录显示场察员给了 acceptable 的结论

点评点评除了清洁本身的到，相关的过程督形虚

Observation 15

Employees engaged in the manufacture and processing of a drug product lack with training required to perform their assigned functions.

药品生产人员缺足够的 :

Specifically, Small V olume Parenteral filling area operators do not recognize ab errant conditions.

特别是小容注射剂罐装域人员并没能发常情况

For example:例如

A. Filling nozzle XXX on the filler located in Line XXX was observed to be misaligned which resulted in product solution

spilling over the edge of the respective vials being filled. This, in turn, resulted in product solution pooling in a catch basin beneath the vial conveyor system and forming puddles on the floor and an indention in a wall as the conveyor system transported spilled product solution from the filling machine to the capping machine on 2/17/13. Line XXX was filling list number 4778, Lot 26-292-DK, Ciprofloxacin Injection, 400mg/40ml.

在生产线XXX 灌装机的灌装嘴没放置准确在相关产品灌装过程中产溶液溢，式因个问了产品溶液在西林瓶转系统部汇集，并形地板的污水传系统将溢的产品溶液从灌装机传到盖机的时候就在地板形污水和墙形印痕生产线在13 2 17 灌装序列是4778，批是26-292-DK ，产品是400mg/40ml 规格的沙注射液

B. The tubing connecting a pump to the fill nozzle XXX on the filler located in Line XXX was observed to be pulling tight

upon each filling cycle on 2/17/13. Line XXXX was filling list number 4778, Lot 26-292-DK, Ciprofloxacin Injection, 400mg/40ml.

一个生产线的灌装嘴和泵之间的管道链接在次灌装周期内都被拉紧实行常，但是员没发和处理

C. Filling nozzle XXX on the filler located in Line XXX was observed to be misaligned which resulted in product solution

spilling over the edge of the respective vials being filled. This, in turn, resulted in product solution pooling in a catch basin beneath the vial conveyor system and a puddle formed on the floor as the conveyor system transported spilled product solution from the filling machine to the capping machine on 2/17/13. Line XXX was filling list number 4276, Lot 26-229-DK, 1% Lidocaine HCl Injection.

在生产线XXX 灌装机的灌装嘴没放置准确在相关产品灌装过程中产溶液溢，式因个问了产品溶液在西林瓶转系统部汇集，并形地板的污水传系统将溢的产品溶液从灌装机传到盖机的时候就在地板形污水和墙形印痕生产线在13 2 17 灌装序列是4276，批是26-229-DK ，产品是1%规格的利多卡因注射液

点评点评直接挑战了员的缺陷，因在生产线的类似域检察官发了类似的缺陷，但是操作没发也没做任何补救措施回复类问很麻烦，必须彻调查是类似的问在，并要解释如何确保自到的原因是真的本原因，要考察相关的生产线是类似的问，类似的岗员是好的

Laboratory controls do not include the establishment of scientifically sound and appropriate sampling plans and test procedures designed to assure that in-process materials and drug products conform to appropriate standards of identity, strength, quality and purity.

实验室制并没建立过科学论证的方案和测试方法来保证中间体和药品能满足相的鉴别，含，纯度标准

A.Deficiencies related to the manual 100% visual inspection of in-process drug products and finished drug products

include:

中间体和品100%人检相关的足:

1.Personnel engaged in the manual 100% visual inspection of in-process drug products and finished drugs products

are not qualified to detect defects successfully at the rate at which the products are presented to them for inspection.

For example, personnel assigned to perform manual 100% visual inspection of 500ml and 1000ml bags of drug products in the Flex Manufacturing Area are qualified, in part, to perform the inspections after passing a seeded defect qualification in which they have XXX minutes to inspect and identify defects in XXX bags. Inspection rates for specific work stations include:

中品的检测试人员资没过足够确认，无法对于检需要的产品的呈度例如在Flex制域对500ml和1000ml规格的产品行测的人员必须通过在定时间内检查指定数合格包装的测试项但是发多个作站点度超过了确认要求

a.Personnel in the Flex Manufacturing Area fabrication room inspect approximately XXX bags per minute.

Flex制域的备料度是钟XXX包

b.Personnel in the Flex Manufacturing Area filling room inspect approximately XXX bags per minute.

Flex制域的灌装度是钟XXX包

c.Personnel in the Flex Manufacturing Area overwrap room inspect up to approximately XXX bags per minute.

Flex制域的外包度是钟XXX包

d.Personnel in the Flex Manufacturing Area XXXX loading space and pack-off inspect up to approximately

XXX bags per minute.

Flex制域的装卸度是钟XXX包

2.The defect kits used to qualify personnel assigned to perform manual 100% visual inspection of 500ml and 1000ml

bags of drug products in the Flex Manufacturing Area include at least one defective unit that is identified with large “X”’s across both the front and back panels.

用于检测试人员的500ml和100ml 品输液袋的瑕疵品都预先用前行了明显的标识无法模拟实生产情况行盲测

3.An assessment of the manual 100% visual inspection process for 500ml and 1000ml bags of drug products

manufactured in the Flex Manufacturing Area written by a third party consultant between 6/23/11 and 6/22/12 concluded that it is not suitable to detect defects in the bags as reported in PR41875 which reads, in part: “…this is not a 100% inspection process and the manufacturing line (speed, product orientation, configuration) does not allow for inspection of all of the bags.”

一份由第方咨询人员对检项评估的告指 … 能够行检并生产线度，产品置，配置也无法满足对内袋行检测的要求…

4. Quality defects, including critical quality defects, with high levels of detectability are not consistently being

identified and rejected from in-process materials. Examples of end user complaints reporting units of 500ml and 1000ml bags of drug products possessing defects that are readily identifiable include, but are not limited to:

瑕疵需要高度关注的关键瑕疵没能够稳定的通过内识别并剔除例如一些用户投诉述了对500ml 和1000ml 输液袋的明显的瑕疵

a. Compliant 1234277 in which a 500ml bag of list number 07953-04-44, lot 95-618-FW, Lactated Ringers

Solution Injection, USP, was reported and confirmed by Hospira to contain a pinhole leak resulting in the bag

leaking into the overwrap.

投诉1234277 述了一袋500ml 输液产品乳酸林格注射液，序列 07953-04-44，批 95-618-FW

发针孔状泄露并泄露到外部塑料包装 Hospira 确认述情况

b. Compliant 1376716 in which a 1000ml bag of list number 07953-04-49, lot 17-929-FW, Lactated Ringers

Solution Injection, USP, was reported to contain a melted administration port resulting in the healthcare

provider electing to select another bag for use.

投诉1376716 述了一袋1000ml 输液产品乳酸林格注射液，序列 07953-04-49，批 17-925-FW 发给药口热熔形无法使用，导人员使用了另外一袋产品

c. Complaints 1434281 and 1435294 in which two 500ml bags of list number 07922-13-44, lot 01-815-FW,

Dextrose 5% Injection, XXXXX were reported to be missing the white port cover and/or z-port (administration

port) resulting in the solutions contained within the bags to spill out as the healthcare providers were preparing

to administer the drugs to patients.

投诉1434281 和1435294，述了人员配2袋500ml 输液产品 5%葡萄糖注射液，序列 07922-13-44，批 01-815-FW 时发输液袋白色口和Z 口给药口盖遗失

d. Compliant 1508549 in which a 1000ml bag of list number 07926-04-49, lot 19-612-FW, 5% Dextrose and 0.45%

Saline Chloride Injection, USP, was reported to be leaking from the filling port cover resulting in the product

solution leaking into the overwrap.

投诉1508549，述了一袋1000lm 产品 5%葡萄糖和0.45%生理水注射液，序列 07926-04-49，批

19-612-FW 输液袋罐装口泄露导药液泄露到外部塑料包装

B. Hospira personnel were unable to locate the scientific justifications for in-process specifications for 500ml and 1000ml

polyvinylchloride (PVC) bags (e.g., XXXX test, XXXX integrity tests, etc.) fabricated onsite and used as container closure systems for sterile drug products. Additionally, these in-process specifications are not subject to periodic review to assess whether they are appropriate.

Hospira 人员无法提供用于无菌产品的500ml 和1000ml PVC 袋内标准的科学论证并内标准没过周期性审评估是用

点评点评对于中间体和品的人检测符合生产的实，从而导的相关投诉调查没追究本原因，没建立合的CAPA 体系避免类似问的反复发生 FDA 引申了对于内包材用性的疑因到品的规格，的QC 制失误是被认是关键性的缺陷

Observation 17

Written production and process control procedures are not followed in the execution of production and process control functions.

的生产和艺规程和实的生产和制情况符合

Specifically, written procedures related to the manufacture of sterile drug products may contain conflicting instructions. For example, written procedure MPRM_1500, “Periodic performance Qualification for the XXXXX”, effective 2/14/12, establishes the maximum time that 500ml bags can remain in the XXX section as xxxxx which corresponds with the validated maximum XXXXX whereas instruction 3.43 of written procedure BFCF_STER_OPER00.EW1, xxxxx-Routine Operation of The XXXXX”, effective 8/27/12, allows 500ml bags to remain in the XXXX section for up to XXX minutes which exceeds the validated maximum F 0 XXXX.

无菌产品生产规程包含矛盾的条款，例如规程MPRM_1500 周期性XXX 性能确认确认了最长保留时间 XXX ，而另一份文件 BFCF_STER_OPER00.EW1 XXX 常操作中的保留时间超了述规程验证的时间

点评点评对于无菌验证的参数必须和实生产操作保持一是本的要求

Observation 18

Equipment used in the manufacture, processing, packing or holding of drug products is not of appropriate design to facilitate operations for its intended use.

用于生产制包装和储药产品的备合理能用用途

Specifically, 例如

A. All XXXX machines used to place 500ml and 1000ml bags into overwrap pouches are not suitable for use without

significant ad hoc modification by area personnel. Examples of modifications include:

将500ml 和1000ml 规格产品放入到透明包装小袋的机器没过场人员的特改装来合用途，例如

1. Adhesive tape is used to secure a XXXXX to prevent jams and possible damage to the bags.

用于确保XXXXX 全，塞紧的胶带能破坏包装袋

2. Adhesive tape is used independently and also to XXXX prevent jams and possible damage to the bags.

使用也 XXXX 塞紧的胶带能破坏包装袋

3. Adhesive tape is used to secure stacks of XXXXX to prevent jams and possible damage to the bags.

用于确保XXXX 堆放全塞紧的胶带能破坏包装袋

B. The metal guard plate shielding the XXXXXX on Line XXX was observed to be held in place by two pieces of bent

tubing wedges beneath it and a metal spring bowed across it. The bent tubing and spring held the plate in place and prevent excessive line stoppages do to displacement of the metal guard plate.

在生产线XXX 用于保 XXXX 的金属板是用块曲管装楔从面固定的，中间一个金属簧曲管和簧固定了金属板，阻了生产线停时金属板的更换

C. A stainless steel panel situated between the XXXX separating the filling zone Class 5 area from the surrounding Class 7

prevents inspection of critical operating equipment and operations by Manufacturing and Manufacturing Quality personnel in an area where products are filled aseptically.

用于割ISO5 灌装域和周边ISO7 域的锈钢面板妨碍了对关键行备的检查，也妨碍了操作和制人员在无菌灌装域的操作

点评点评类的缺陷和实操作的方便性体了备的并没考虑实操作人员的方便性，在体的方案提来理一线操作人员参审评对于使用的备合性对生产能带来的影响，一些操作人员是最发言权的

Observation 19

Equipment and utensils are not cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions and contamination that would alter the safety, identity, strength, quality or purity of the drug product.

备器没在合间隔行清洗维和毒，能故障和污染发生，能导对药产品的带来负面影响

Specifically, 例如

A. Substantial amounts of debris that were too numerous to count were observed on metal plates located immediately

beneath the conveyor belts supplying 500ml and 1000ml bags to the XXXX machines used to place the bags into overwrap pouches. The edges of the metal plates are located above the areas where the overwrap pouches are opened to receive the 500ml and 1000ml bags.

将500ml 和1000ml 袋传到XXXX 机器的传带方的金属板大的金属脱落物，金属板的边沿就于透明包装小袋开口和接收500ml 和1000ml 袋的置能会物脱落到包装袋中

B. Tank XXX in the Small V olume Parenterals area was observed to be leaking from the main valve on the bottom of the

tank on 2/12/13. It was holding bulk solution for List 4283, Lot 26-340-DK, Lidocaine 4% HCl Injection, USP.

小剂注射剂域的储罐XXXX 部阀门泄漏 2013 2 12 检查场，个储罐的内容物是批 26-340-DK 的4%利多卡因酸注射液

C. Tank XXX in the Small V olume Parenterals area was observed to be leaking from XXXX connection on tubing

connected to the main valve on the bottom of the tank on 2/12/13. It was holding bulk solution for List 4921, Lot 26-156-DK, Epinephrine Injection, USP. This is an aseptically filled product.

小剂注射剂域的储罐XXX 部阀门和连接管道之间泄漏 2013 2 12 检查场，个储罐的内容物是批 26-156-DK 的肾腺素注射液，产品是无菌灌装产品

D. A large gasket in the Tank XXX manway in the Small V olume Parenterals area was observed to be degrading

(delaminating at the edges and pieces were missing) following clean in place activities on 2/12/13.

小剂注射剂域的储罐XXX 人孔处的大垫片在清洗的时破损象垫片边缘破损脱落

E. There are no preventative maintenance activities for dipsticks used in the Small V olume Parenterals Solutions Area to

measure the volume of solutions during formulation activities in bulk solution tanks. Tank XXXX dipstick G3439 was observed to be bent at an approximate 5º angle slightly below the handle during an inspection of the Small V olume Parenterals Solutions Area on 2/12/13.

小剂注射剂溶液域内的用于在储罐内配方溶液体的液管没预维措施在2013 2 12 场检查的时候发储罐XXXX 的液管G3439在手柄端 5度角的轻度弯曲

F. The thermal paper used in the XXX non-viable particle counter is not decontaminated prior to use within the aseptic

core. Once inside the core and placed in use, the unit and all of the required supplies can remain there for up to one month according to SOP B6134_0131 “XXXX Electronic Particle Counter Operation, Calibration, Maintenance and Usage, Effective: 12-10-22.” The Biological Quality Supervisor confirmed that the thermal paper is not subject to cleaning and sanitization process to preclude the ingress of non-viable and viable particles.

XXXX 粒度数仪使用的热敏纸在无菌心域使用前没任何的毒措施一备被入无菌心域被使用，相关的件和备本身据SOP B6134_0131 “XXXXX 电子粒数器行，校验，维和使用规程，12-10-22生效”就要使用一个生物管确认的域粒度和微生物的清洗毒清洗方法并用于热敏纸

点评点评施备的维和清洁状是对产品潜在的污染和影响是非备考的关键点那些

26 属性的非心的备，尤是一些配液储罐，因结构简单而被忽视任何在洁净域使用的备如提到的粒度检测仪都需要考虑的毒措施

Observation 20

Buildings used in the manufacturing and processing of a drug product are not maintained in a good state of repair. 生产制制剂产品的厂建筑没维好

Specifically, 例如

A. Thick strips of a caulking material were observed around the edges of ceiling tiles located in the Flex Northside Filling

Area (Room XXX) and the Flex Southside Filling Area (Room XXX) where 500ml and 1000ml bags of injectable pharmaceuticals are filled and sealed.

Flex 部灌装域间XXX 和Flex 南部灌装域间XXX 的顶部边缘大嵌缝材料厚条，些域就是500ml 和1000ml 袋灌封的域

B. Caulking material around multiple ceiling tiles was observed to be cracking and degrading in the Flex Northside Filling

Area (Room XXX) where 500ml and 1000ml bags are filled and sealed. At least one ceiling tile was observed to have displaced slightly upwards into the interstitial space above on 2/13/13.

建筑物花板周边的嵌缝材料多处破损，在2013 2 13 的检查场少看到一处花板轻度翘起

C. A brick, metal beams, and large metal cogs were among the objects used to weigh down ceiling tiles as observed from

the interstitial space directly above the Flex filling areas on 2/13/13.

砖头金属块和大的金属齿被用于将面提到的翘起的屋顶去

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