Followers of FDA warning letters and Form 483s will have noticed that over the last 12 – 18 months, there have been increasing mention of data integrity issues around manufacturing data, often as a result of outdated equipment and practices, such as:

FDA 警告信和 483 表发现,在过去 12 到 18 个月中,生产数据相关的数据完整性问题越来越多,这通常是由于老旧的设备和做法引起的,例如:

• No backup of data from the SCADA system

  SCADA系统数据没有备份

• No logs of alarm messages for in-process excursions for critical manufacturing operations

  对于关键生产操作,没有用于记录生产过程漂移报警消息的日志

• No tracking or trending of process alarms

  过程报警没有跟踪或趋势分析

• Personnel were able to, and did, change process limits to values outside those specified in the batch recipe

  操作人员具备将工艺限度更改超出批处理配方范围的权限,且确实这样做了。

• Process parameters in batch records jar with the values recorded by the programmable logic controller (PLC) of manufacturing machine.

  批记录中记录的工艺参数与设备PLC上的数据相矛盾。

• Standalone manufacturing equipment not equipped with HMI/PLC/SCADA system. There is no time stamped audit trail, data management, alarm management, archival and retrieval of records on these standalone manufacturing equipment.”

  单机版生产设备未配备 HMI/PLC/SCADA 系统。这些单机版生产设备上没有带时间戳的审计最终、数据管理、报警管理、记录存档和检索。

典型的警告信如下:

印度Indoco Remedies Limited (PlantI)

While multiple batch records of (b)(4) mg tablet included handwritten values routinely within process parameters, the values recorded by the programmable logic controller (PLC) of your compression machine were frequently outside your established process parameters. For example, (b)(4) mg batch (b)(4) had compression force valuesh and written (b)(4) in the batch record ranging from (b)(4) (your limit was (b)(4)).

虽然多批XX片剂生产记录中有手写值均在工艺参数范围内,但你们压片机PLC所记录的值频繁超出你们设定的工艺参数。例如,批记录中手写的XX片剂的压力值为XX(你们的限度为XX)。

However, the PLC data recorded individual values ranging from (b)(4) for the same time period. In addition to compression force values, handwritten values for filling depth and automatic weight control (AWC) did not accurately reflect the values within the PLC data.

同一时间段内PLC数据所记录单值从XX至XX。除了压力值外,自动重量控制(AWC)和充填高度的手写值亦不能准确反映PLC数据中的值。

An inspection conducted by the (b)(4) in March 2018 found similar discrepancies between the compression force values in batch records and PLC data.

2018年3月由XX执行的检查中发现类似缺陷,看到批记录中和PLC中的压力值有差异。

Your response acknowledged discrepancies including missing data, “mis-matched data,” non-contemporaneous entries, and other inconsistencies in your batch records. It also acknowledged inadequate procedures for compression machine setup and adjustments during operations intended to maintain process control, and a lack of documentation of these critical activities.

你们的回复提及这些情况,包括数据缺失、“不匹配的数据”、未同步录入和其它批记录中的不一致情况,还承认用于的压片机设置和运行过程中为维持工艺控制而进行调整的程序不够充分,并缺乏对这些关键动作的文件记录。

Your response is insufficient. The integrity of all data within your manufacturing records is called into question by the actions of your staff involved in compression operations. You did not commit to perform a comprehensive retrospective evaluation of the integrity of data throughout your manufacturing operation. You also did not adequately address how you will ensure that AWC is consistently maintained and documented throughout compression by providing detailed procedures for setup and changing of parameters during a batch, and address how all associated parameters will be controlled.

你们的回复是不充分的。你们生产记录中所有数据的完整性因为你们压片操作员工的行为而引起质疑。你们未承诺对整个生产操作中的数据完整性进行全面回顾性评估,亦未充分说明你们将如何通过提供详细的参数设置和参数修改程序以确保自动重量控制(AWC)在整个压片过程中得到一致的保持和记录,亦未说明如何对所有相关参数进行控制。

It is essential that you use appropriate continuous process controls to promptly respond to variation in your process, and prevent sporadic loss of control during processing. Additionally, you did not sufficiently detail your batch record changes for each strength of (b)(4) tablets.

使用适当的连续工艺控制以对你们工艺波动进行快速响应,防止生产过程中偶发性失控是非常有必要的。另外你们亦未足够详细地说明你们对每个规格的XX片剂的批记录修改情况。

In response to this letter, provide: 

回复此函,请提交:

Procedures that establish use of appropriate AWC and other control procedures in your compression operation. This includes but is not limited to detailed procedures for batch setup and subsequent adjustments for AWC; identification of all parameters that can impact consistency of compression; and complete documentation of all batch production activities.

建立适当AWC和其它压片操作控制程序,其中包括但不仅限于AWC的批设置和后续调整详细程序、识别出所有可能影响压片一致性的参数,以及所有批生产活动的完整记录。

Your d master production and control batch records for drug products that fully document each manufacturing operation. Also submit your most recent executed batch production and control record with full machine printouts for each strength of your (b)(4)     tablet drug product.

修订后可以完整记录每个生产操作的药品主生产和控制记录以。亦请提交你们最近执行的批生产和控制记录,包括你们XX片剂每个规格的完整设备打印件。

An independent review of all your process parameters for the manufacture of your (b)(4) dosage form drug products to ensure adequacy of ranges, setup parameters, and in-process monitoring for detecting variation in your process.

一份对你们XX剂型药品生产的所有工艺参数的独立审核,以确保范围、设置参数和过程监测足以发现生产过程的波动。

A data-driven and scientifically sound program that identifies and controls variability, to ensure production and packaging processes consistently meet appropriate manufacturing standards and parameters. This includes, but is not limited to, evaluating suitability of equipment for its intended use, ensuring quality of input materials, and determining the capability and reliability of each manufacturing process step and control.

由数据支持的发现和控制波动的科学合理程序,以确保生产和包装过程能一直符合适当的生产标准和参数。其中包括但不仅限于评估设备是否适合其既定用途、确保输入物料的质量,以及确定每个生产工艺步骤和控制的能力与可靠性。

Your corrective action and preventive action (CAPA) plan as requested in the Data Integrity Remediation section of this letter below. As one facet of the comprehensive CAPA plan, an independent reviewer(s) should provide a thorough retrospective assessment of  manufacturing data validity since February 1, 2016, and perform thorough interviews of production staff (both operators and supervisors). This assessment should augment the internal investigation that you have performed and include but not be limited to an independent review of the integrity of (b)(4) in-process checks (b)(4) and disintegration testing, and evaluate any missing compression operation data. The retrospective assessment should fully determine the degree to which this in-process testing data has information gaps (whether due to omissions or lost data), personnel sign-offs occurred at times where staff were not present, and to what extent current data can be relied upon for     this product and other products.

本函以下数据完整性补救措施部分中要求的CAPA计划。作为CAPA计划的一部分,应由一位独立审核人员提交一份对2016年2月以来的生产数据有效性的彻底回顾性评估,并对生产员工进行深入面谈(操作员和主管)。此项评估应在你们之前已执行调查的基础上进行扩展,包括但不仅限于对中控检查XX和崩解试验完整性的独立审核,以及对所有缺失压片操作数据的评估。回顾性评估应全面确定该中控测试数据资料缺失的程度(是否由于疏忽或数据丢失)、员工不在场时的签名情况,以及该产品和其它产品当前数据可依赖的程度。

印度Sun Pharmaceutical Industries Ltd.

You lacked audit trails or other sufficient controls to facilitate traceability of the individuals who access each of the programmable logic controller (PLC) levels or Man-Machine Interface (MMI) equipment. You had no way to verify that individuals have not changed, adjusted, or modified equipment operation parameters.

你们缺乏审计追踪或其他充分的控制,以方便跟踪每个访问可编程逻辑控制器 (PLC) 或人机接口 (MMI) 设备的个人。你们无从确认个人是否未更改、调整或修改设备操作参数。

Access to production equipment used in parenteral manufacturing and solid (b)(4) dosage forms used a password shared by four or five individuals to gain access to each individual piece of equipment and access level. During our inspection, your Executive Production and QA manager confirmed that the password was shared. Neither your operators nor your supervisors had individual passwords.

使用四五个人共享的密码,访问无菌和固体制剂产品生产设备,获取每一个设备和接入级别。在我们检查期间,你们的生产经理和 QA 经理承认密码是共享的。你们的操作人员和主管都没有单独的密码。 

During our inspection, firm officials also confirmed that you had not established or documented a control program to describe the roles and responsibilities of production equipment system administrators. There was also no record documenting the individuals who have access to the production equipment or the manner in which individual personnel access production equipment.

在我们的检查中,公司官员还确认你们没有建立或制订控制程序来描述生产设备系统管理员的角色和职责。也没有记录写明有权限访问生产设备的人员或人员访问生产设备的方式。 

In your response, you indicated that you have performed a comprehensive review of the PLCs and manufacturing equipment associated with the production of parenteral and solid (b)(4) dosage forms to assess your access controls and traceability to individual operators. You suggested that traceability to the individual operator could be determined through a hybrid system using the batch manufacturing record and equipment logbook. However, because you used shared login credentials that did not permit identification of a specific person using the shared login, you have not shown how your hybrid system could link specific actions to a specific operator.

在你们的回复中,你们表示对与无菌和固体剂型相关的 PLC 和生产设备进行了全面审查,以评估权限控制和人员的可追溯性。你们表示,对于操作人员的追溯性可以通过使用批生产记录和设备日志的混合系统来确定。但是,由于你们使用共享的登录凭据,无法识别使用共享登录的具体人员,因此你们没有办法证明你们的混合系统如何将特定操作链接到集体的操作人员。 

In your response, you also stated that you will conduct a retrospective risk assessment to evaluate the effects of your deficient computerized system controls on the quality of the products manufactured using this automated equipment. However, you did not indicated the timeframe for your review, your criteria for evaluating the effects of these deficiencies on your products, or any actions needed for products within expiry.

在答复中,你们还表示,你们将进行回顾性风险评估,以评估你们计算机系统控制不足对使用此自动化设备生产的产品质量的影响。但是,你们没有说明审核的时间范围、评估这些缺陷对产品影响的标准,以及对效期内产品需要采取的任何措施。

Finally, in your response, you indicated that you planned to (b)(4). Your response is inadequate because you did not indicate what controls you will implement in the interim to assure that only authorized personnel change your production or other records.

最后,在答复中,你们表示计划 (b)(4)。你们的回复是不充分的,因为你们没有说明在此过渡期间将实施哪些控制措施,以确保只有经过授权的人员才可更改生产或其他记录。

In response to the letter, provide your retrospective review and risk assessment of lots manufactured using equipment with shared passwords. Explain how you will identify which operators or personnel performed and recorded specific activities, your criteria for evaluating how manufacturing and quality of your products has been affected by your deficient controls, and any actions needed to assure the quality, safety, and efficacy of products within expiry.

回复此函,请对使用带有共享密码的设备所生产的批次进行回顾性审核和风险评估。说明你们将如何确定哪些操作人员或个人执行并记录了哪些活动,用于评估产品的生产和质量如何受到的控制不足的影响的标准,以及为确保效期内产品的质量、安全性和有效性需要采取的措施。