FDA483：看到撕毁的GMP文件和记录

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2024年9月17日，FDA发布了一篇在9月6日给Granules India Ltd.的483，一共出了6个发现项，包括设施维护、设备清洁、质量控制和生产过程中存在的多个问题。

以下是课代表对报告中观察项的总结：

观察项1：设施和设备系统

• 设备和器皿清洁不当，可能影响药品的安全、身份、强度、质量和纯度。

• 特定设备自安装以来未进行适当清洁，存在潜在的细菌、真菌和霉菌生长。

• APUs的HEPA过滤器损坏，可能无法有效过滤颗粒物。

• 防止交叉污染的措施不足，存在潜在的药品活性成分交叉污染风险。

• 预防性维护程序存在缺陷，如仅更换HEPA过滤器而不理解其目的。

• 处理设备的清洁不充分，如压片设备在清洁后仍有可见粉末。

观察项2：质量系统

• 未彻底审查OOS和OOT调查，以及批次或其任何组件未达到规格的情况。

• OOS和OOT调查不彻底，未对超标批次进行适当处理。

• 质量控制部门未能充分监督GMP文件的控制和管理，发现有大量GMP文件被撕毁并作为废料处理。

观察项3：质量控制部门的责任和程序

• 质量控制部门未能确保药品生产和测试的质量、纯度、特性和强度。

• 缺乏对GMP文件的书面规定和遵守，包括分析天平和其他测试设备的打印输出。

观察项4：生产系统

• 从特定物料中提取的过程未充分评估，以确保物料在进一步加工前的质量。

• 批次记录中物料的处理和记录不足，如未记录谁执行了目视检查以及物料如何加入批次。

• 市场投诉未充分调查，如未对可能导致质量问题的工艺步骤进行评估。

观察项5：生产过程中的控制

• 未遵循书面程序进行过程中控制，如未对片剂的两面进行计数和检查。

• 过程中检测发现超标读数时，未进行适当的偏差处理。

观察项6：设施和设备的维护

• 建筑和设施未得到适当维护，如APUs和AHUs覆盖着粉末和灰尘，水箱生锈。

• 高压清洗设备放置在积水中，可能导致微生物、酵母菌和霉菌生长。

• 设备和表面潮湿、漏水和腐蚀

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基础信息

FEI：3004097901

公司名称：Granules India Limited

被检查机构类型：Drug Product Manufacturer

调查员信息：

Pratik S. Upadhyay

Joseph A. Piechocki

483正文

QUALITY SYSTEM

OBSERVATION 2

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.

Specifically, your investigations pertaining to Out of Specification (0OS) and Out of Trend (00T) investigations are not thoroughly investigated and the CAPA taken is inadequate to determine the risk to the drug products sold into the US market. For example,

A. Your OOS and OOT Investigations for Process Validation (PV) batch # (b)(4) '3rd batch of PV) are not thoroughly investigated for Product: (b)(4) mg and (b)(4) mg Tablets (b)(4) For example, the following investigations relating to this PV are found deficient:

1.OOS Investigation, number: 00s/049/2 1, date of initiation: 30-Mar-2021, Issue: 0OS result reported for (b)(4) test by (b)(4) Results (b)(4) % Limit: NLT (b)(4) % and NMI (b)(4) %, and for (b)(4) %RSD  (b)(4) %, Limit: NMT (b)(4) %, Stage: In-process control test, Final classification: Valid OOS

2.OOS Investigation number: 00S/052/2 1. date of initiation: 8,Apr-2021, Issue QQS result reported for Assay by (b)(4) test: (b)(4) %, Limit: NLT (b)(4) %and NMT%,Stage: (b)(4) Tablets at in-process control test, Final classification: Valid QOS

3. 00T Investigation number: 00T/041/21, date of initiation: 09-Apr-2021, Issue: 0OT result reported for (b)(4) test with average of (b)(4) %，Trend limit: Above (b)(4) %,Stage: (b)(4) 

Tablets at in-process control test, Final classification: Valid OOT

4.OOT Investigation number: 00T/018/23, date of initiation: 08-Mar-2023 Issue OOT result reported for (b)(4) test by HPLC for vessel  (b)(4)% for (b)(4) Trend limit: for individual results above (b)(4) %,Stage: Long term stability(250760yoKH)at 18 month, Final classification: Valid OOT

For the failing batch#(3rd batch of PV) at in-process control tests relating to (b)(4) by (b)(4) and Assay by (b)(4) tests, your firm did not reject the batch as you rejected batch # (b)(4)  1^st PV batch) for the similar test failure. Your batches # (b)(4) 1^st PV hatch post rejection (b)(4) and (b)(4) 2nd PV batch) also failed the first set of (b)(4) samples for (b)(4) by (b)(4) test for (b)(4) content indicating a systemic problem with the manufacturing of (b)(4) mg and (b)(4)  (b)(4) mg Tablets (b)(4) 

Further,your in-process specification for (b)(4) mg and (b)(4) mg Tablets (b)(4) Product code: (b)(4) Specification, No,: (b)(4) ersion: 03.Effective date: 20-Feb-2020 is inadequate,Per this specification, (b)(4) test shall be performed for exhibit and validation batches,If  (b)(4) test results do not meet to the specification limits, (b)(4) shall be released for compression by proposing (b)(4) sampling at compression stage”, There was no justification provided,for this provision to bypass failing test results at (b)(4) stage and continuing to use the failing (b)(4) batch# (b)(4) "in the manufacturing. Also, there was no justification provided for how, text of (b)(4) tablets (b)(4) tablets at post compression) would be representative of the entire batch size of (b)(4) tablets).As such, your test results at compression stage for (b)(4) tablets failed for Assay by (b)(4) test (00S/052/21-Valid OOS).

Moreover, your firm, dispatched the failing batch # (b)(4) (3rd PV batch) along with batches # (b)(4) 1st PV batch) and  (b)(4) (2nd PV batch) into the US market on (b)(4) Subsequently,your firm added (b)(4) more batches as batches # (b)(4) to the same process validation report number:GGP/PVR/TT/MFG/012-A-21,approval dated: (b)(4) and concluded the process validation based on the manufacturing and testing outcome of (b)(4) batches of which batch# (b)(4) 3rd PV batch) confirmed OOS and OOT test results, You manufactured tota (b)(4) patches and dispatched them into the US market between (b)(4) About (b)(4) out of (b)(4) batches distributed in the US market are still within the product shelf life.

Lastly, the evaluation of market complaint revealed lack of efficacy complaint received for batch # (b)(4) PV batch)for which the complaint investigation was limited to only (b)(4) trend evaluation for the similar complaints and not to the entire shelf life of (b)(4) 

B. Your OOT Investigation relating to unknown/unspecified impurities are deficient, For example,

1.OOT Investigation number: OOT/069/21, Products (b)(4) Tablets USP (b)(4) mg and (b)(4) mg, Batch numbers (b)(4) 

Results: (b)(4) %

Specification: (b)(4) %, Trend limit: No (b)(4) % of the specification limit.

2.OOT Investigation number: 00T/071/21, Products: (b)(4) Tablets USP (b)(4) mg,Batch numbers: (b)(4)

Results: (b)(4) %

Specification: NMT(b)(4) %, , Trend limit: NMT (b)(4) % of the specification limit.

3.OOT Investigation number: 00T/072/21, Products: (b)(4) Tablets USP (b)(4) mg,Batch numbers: (b)(4) 

Results: (b)(4) %

Specification: NMT(b)(4) %, , Trend limit: NMT (b)(4) % of the specification limit.

4.OOT Investigation number: 00T/077/21, Products: (b)(4) Tablets USP (b)(4) mg,Batch numbers: (b)(4)

4.OOT 调查编号：00T/077/21，产品：(b)(4) 片剂 USP (b)(4) mg，批号：(b)(4)

Results: (b)(4) %

Specification: NMT(b)(4) %, , Trend limit: NMT (b)(4) % of the specification limit.

Your firm concluded the above OO'T investigations for batches tested at release based on identifying the unknown peak found in their finished product at about (b)(4).This unknown peak was present in APl lots that were used in manufacturing these batches from one of your APl suppliers, This impurity peak was identified as “Related Compound (b)(4) by your APl supplier for which your firm established “Control Strategy and Action (b)(4) Plan" meng;ghing in your investigation that “Decision taken go not to use **** source APl lois in the manufacturing of (b)(4) Tablets UISP (Product codes:  (b)(4) If needed, **** APl lots to be tested against drug product test method #(b)(4) through a proper communication and shall be used if the unknown impurity levels below (b)(4) %”. However, your firm did not follow this “Control Strategy and Action Plan" and released the batches # (b)(4) listed under each OOT investigations) into the US market.

Further, you (b)(4) only (b)(4) batches (b)(4) out of (b)(4) on long term stability which does not ensure the product performance for the remaining (b)(4) batch (b)(4) throughout the product shelf life until (b)(4).There is a potential that “Related Compound (b)(4) may have increased over the period of shelf life.

C, (This is a repeat observation from the January 2023 inspection)

Your Deviation investigation number: DEV-GGP-23-0224, date initiated: 08-Sep-2023, Issue: OOS value was reported for swab sample analysis for equipment name: (b)(4) Blister Packaging Machine, equipment number (b)(4) GCW/PP/027.swab location: Product (b)(4) Cleaning Verification for (b)(4) active swab analyses test result: (b)(4) PPM, Acceptance limit: NMT (b)(4) PPM.

Upon observing the failing test result during (b)(4) cleaning verification, your firm did not extend the impact of equipment cleaning practices on the potential risk for cross-contamination to the previous products that were (b)(4) packaged using non-dedicated (b)(4) Blister Packaging Machine. Along with (b)(4) this blister packaging equipment was largely used for (b)(4) drug products packaging.

D. Your OOT Investigation number: OOT/124/22, Products (b)(4) Tablets USP (b)(4) mg (b)(4) mg (b)(4) mg.Batch numbers and stability timepoint: (b)(4) (25°C/60%RH -24 month), (b)(4) (259C/60%RH-36 month). and (b)(4) (25°C/60%RH-24 month), Test:Organic Impurity by (b)(4) test.Issue: Related Compound Impurity (b)(4) 't retention time (RT) about (b)(4) was OOT, Manufactured in Module (b)(4) Block.

Results: (b)(4) %

Limit: NMT (b)(4) %

OOT Status: Invalid

Your firm invalidated the OO'T results based on assumption of the most probable root cause could be due to glassware contamination without proving through testing that how Related Compound Impurity (b)(4) could be present in the glassware to the significant level to reach to the level of OOT.

OBSERVATION 3

The responsibilities and procedures applicable to the quality control unit are not in writing and fully followed.Specifically,

Your Quality Unit lacks oversight on the control and management of GMP documents that are critical in ensuring drug products manufactured and tested at your site are safe and effective. For example, at the initiation of this inspection on 26-Aug-2024, we observed three (3) trucks full of scrap materials leaving from your facility at around8: 19 am. The inspection of scrap materials from these trucks revealed presence of large number of torn pieces of GMP documents such as analytical balance printouts, worksheets with handwritten documentation in “blue color indelible ball-point ink pen" which were signed and dated along with large number of uncontrolled papers torn into pieces and crumpled having manufacturing and testing information, Similarly, during the walk through inspection of your QC laboratory, we observed cleaning personnel removing a large black color scrap bag from the area. The evaluation of this scrap bag revealed a large number of tor and few intact pieces of analytical balance printouts pH meter printouts, and some printouts similar to Karl Fisher (b)(4) test equipment. We also observed many tor pieces of uncontrolled white papers with GMP information documented in blue indelible ball-point ink pen pertaining to testing activities. Per your SOP No: GIL-CQA-028, Titled: “Good Documentation Practices”Version: 03, Section: 5 .37 “blue indelible ball-point ink pen" is used for recording of GMP documentation.

We also observed handwritten documentation in “green color indelible ball-point ink pen" on large number of uncontrolled papers torn into pieces and crumpled having manufacturing and testing information. Per your SOP No.: GGQA 057, Titled: “Responsibilities of Quality Assurance", Version: 04, Section: 5.3.4 “The QA personnel shall use the green color indelible ball-point pen at applicable areas of work i.e. manual issuance of documents,IPQA related activities involved logbooks, formats, labels, BPR entries, approval of COA, certificate of compliance release and approval of executed batch records/analytical records”

There is also a lack of Quality Unit oversight on employee practices of documenting GMP data on uncontrolled white paper and later disposing of these papers by tearing into pieces inside scrap bags. Among multiple sections violated by destroying GMP documents, section 5.1.4 of SOP No: GIL-CQA-012, Titled: “Data Integrity"Effective date: 30-Aug-2022 refers to ALCOA+ principle to ensure integrity of data and Good Documentation Practices.

Upon putting together some of the torn pieces of documents with the help of your employees, your Quality Unit management stated the torn pieces belonged to original record, raw data and metadata pertaining to QC and manufacturing units and these documents should not have been destroyed. For example, but not limited:

1.Material Name: (b)(4) Tablets (b)(4) mg (b)(4) Batch Number:)A R.Number: (b)(4) Specification Number  (b)(4) STP Number: (b)(4) 

The completed and signed off Raw Data Worksheets pertaining to Description, Identification of (b)(4) by (b)(4) tests were torn into pieces by the Analyst. These torn Raw Data Worksheets were collected from one of the scrap material trucks at the initiation of inspection on 26-Sep-2024.

2.Product Name: (b)(4) Batch Number: (b)(4) A.R.Number: (b)(4) Specification Number: (b)(4) STP Number: (b)(4) Worksheet Number (Raw Data Sheet):GGRDSMSC001.

Analytical weight printouts (2) for Sartorius Balance ID: QC-284 were torn into pieces by the Analyst. The evaluation of some of the torn pieces revealed the weighing activities pertaining to (b)(4) Analysis tests.The weights on the torn printouts and those found affixed inside your worksheets depicted different weights on the torn balance printouts. These torn balance printouts were collected from a scrap bag from Q(laboratory that your cleaning personnel tried to remove from the OC laboratory during the walkthrough inspection on 26-Sep-2024.

Sartorius 天平（编号：QC-284）的分析重量打印件（2 份）被分析员撕成碎片。被撕碎的打印纸上的砝码和贴在工作表内的砝码在被撕碎的天平打印纸上显示的砝码不同。这些被撕毁的天平打印纸是从 Q（实验室）的一个废料袋中收集的，在 2024 年 9 月 26 日的现场检查中，贵公司的清洁人员试图将其从OC实验室中拿走。

OBSERVATION 5

Written procedures are not followed that describe the in-process controls to be conducted on appropriate samples of in-process materials of each batch.

Specifically,

A.During the in-process sampling and testing for (b)(4) Tablets USP (b)(4) mg Batch (b)(4) the following discrepancies were observed for the sample collected on 27Aug2024 at 10:54 AM:

1.According to the batch production record, the operator is to inspect both faces of (b)(4) tablets from the (b)(4) of the compression equipment for tablet description verification. We observed and your operator verbally confirmed that they did not count the tablets nor did they look at both sides before documenting the tablet verification results and transferring to the (b)(4) in-process sample container.

2.The operator is to perform a weight check of (b)(4) tablets from (b)(4) the compression equipment.We observed and your operator verbally confirmed that the weight check utilized (b)(4) tablets collected and stored within the (b)(4) in-process sample container, and the samples were not discreetly tested from (b)(4) the compression equipment.

B.During the in-process testing for (b)(4) Tablets USP (b)(4) mg Batch (b)(4) on 27-Aug-2024,we observed one tablet obtained a (b)(4) reading of (b)(4) which did not pass the in-process limit of (b)(4) of (b)(4) According to procedure GFMF009, “In-process Checks and Log Book Entries During Manufacturing Stages", a deviation is to be opened in the event of a parameter found out of the specified limit given. However, a note was added to the printout and the sample was reanalyzed with no investigation with no investigation conducted.

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