近日，FDA发布了Apitoria Pharma Private Limited的483报告，其中提及有变更控制的“计划性偏差”，该公司最终因为变更评估不当导致批次不合格，但FDA引用的缺陷落点则是“未能制定并遵循书面程序来调查关键偏差或中间体及API批次不符合标准的情况”：

 

Failure to establish and follow written procedures for investigating critical deviations or the failure of intermediates and API batches to meet specifications. Specifically,

未能制定并遵循书面程序来调查关键偏差或中间体及API批次不符合标准的情况。具体而言：

 

Your firm’s change control request is inadequate and does not include risk evaluation and risk mitigation strategy. XX batch XX was manufactured following a planned deviation under Change Control Request CRF-UII-000286 (No. DE-UII-000018) for reduced batch size of approximately XX due to terminal batch of the campaign. Despite the reduced batch size, the process parameters and general process of established and validated for XX batch size were utilized that resulted in OOS for particle size. The change control request neglected the fact that the manufacturing process for batch size of XX had been previously validated which was more suitable for the subject batch.

 

贵公司的变更控制申请不充分，未包含风险评估和风险缓解策略。 批次XX按照变更控制申请 CRF-UII-000286下的计划性偏差（编号 DE-UII-000018）生产，因该批次为生产阶段的最后一批而按计划性偏差进行生产，批量约为XX 。尽管批量减小，但仍采用已验证批量的既定工艺参数和常规工艺，导致粒度不合格（OOS）。该变更控制申请忽略XX批量的生产工艺此前已验证且更适用于该批次的生产。

 

此外，该公司还涉及变更批次的批记录审核不完整，且未就此启动偏差调查的缺陷：

 

Failure of your quality unit to review and approve all appropriate quality - related documents. Specifically,

贵公司质量部门未能审核和批准所有质量相关文件。具体而言：

 

XX API (Lot# XX) has a change control (ID #CRF - UII - 000693) due the size reduction of this batch from reduced batch size XX instead of standard batch size xx and was approved on 16 July 2024. BPCR review check list for this batch was reviewed and verified by manufacturing andquality assurance on 27 July 2024. However, manufacturing and quality assurance personnel has signed the BPCR check list stating that any changed controls document was not initiated for this XX API (Lot# XX) and have attached to the final batch records. No quality assurance related deviation or investigation was initiated for not adequately reviewing quality documents.

某原料药（批号XX）有一项变更控制（编号 CRF - UII - 000693）：批量从标准批量缩小为XX，并于 2024 年 7 月 16 日获得批准。该批次的批生产控制记录（BPCR）审核检查表由生产部门和QA于2024年 7 月 27 日进行了审核和确认。然而，生产和质量保证人员在批生产控制记录（BPCR）检查表上签字，表明该原料药（批号XX）没有任何变更，然后随附在最终批记录中。对于未充分审核质量文件的情况，未启动与质量保证相关的偏差处理或调查。

来源：GMP办公室

关键词： FDA