夜雨聆风2026年7月27日，FDA公布一则483缺陷报告。
检查对象：Novel Laboratories, Inc. d.b.a Lupin（卢平制药）
检查日期：2026 年 4 月 13 日 至 2026 年 4 月 17 日
检查员：Anthony J Donato、Daniel T Lee
OBSERVATION 1
Investigations of an unexplained discrepancy and a failure of a batch or any of its components to meet any of its specifications did not extend to other batches of the same drug product.
针对无法解释的偏差以及批次或其组分不符合质量标准情况开展调查时，未将调查范围延伸至同一药品的其他批次。
Specifically,
具体如下：
During the investigation (LAB-00433) initiated on February 6, 2026, for an out-of-specification (OOS) (b)(4) result obtained for (b)(4), USP, Receiving Lot # (b)(4) (Retest Date: (b)(4)), you determined that the root cause was the aging of the (b)(4) material, which decreases (b)(4) over time. (b)(4) Lot # (b)(4) was subsequently rejected. However, this same (b)(4) lot had previously been used while meeting in-house (b)(4) limits at the time of use to manufacture the following finished product batches that were released to the market:
2026 年 2 月 6 日启动调查（LAB-00433），针对 (b)(4)（USP 标准，接收批号 (b)(4)，复测日期：(b)(4)）出现的超标（OOS）(b)(4) 结果开展调查，贵司判定根本原因为 (b)(4) 物料老化，该物料的 (b)(4) 指标会随时间下降。批号 (b)(4) 的 (b)(4) 物料随后被拒收。但是，该同一批 (b)(4) 物料此前投入使用时符合企业内部 (b)(4) 限度标准，并用于生产以下已放行上市的成品批次：
Bulk Batch (b)(4) → Filling Batch (b)(4) → (b)(4) Batch (b)(4) ((b)(4) ; Manufacture Date: (b)(4) ; Expiry Date: (b)(4))
原液批次 (b)(4) → 灌装批次 (b)(4) → (b)(4) 批次 (b)(4)（(b)(4)；生产日期：(b)(4)；有效期至：(b)(4)）
Bulk Batch (b)(4) → Filling Batch (b)(4) → (b)(4) Batch (b)(4) ((b)(4) ; Manufacture Date: (b)(4) ; Expiry Date: (b)(4))
原液批次 (b)(4) → 灌装批次 (b)(4) → (b)(4) 批次 (b)(4)（(b)(4)；生产日期：(b)(4)；有效期至：(b)(4)）
The investigation concluded that the associated drug product batches were not impacted because the (b)(4) material met in-house (b)(4) limits at the time of use and the finished product batches passed drug product specifications at release. However, the investigation was not extended to evaluate the potential impact on the stability of finished product batches (b)(4) and (b)(4). Specifically, you did not place these batches on a stability program or conduct additional stability testing to assess whether the known aging behavior of (b)(4) Lot # (b)(4), which you had identified as causing a progressive and measurable decrease in (b)(4) over time could affect the (b)(4) of the finished product over its shelf life.
调查结论认为相关药品批次未受影响，理由为该 (b)(4) 物料投入使用时满足企业内部 (b)(4) 限度，并且成品批次放行时符合药品质量标准。但本次调查未进一步评估该情况对成品批次 (b)(4) 与 (b)(4) 稳定性的潜在影响。具体而言，贵司未将上述批次纳入稳定性研究方案，也未开展额外稳定性试验，用以评估已确认的批号 (b)(4) 的 (b)(4) 物料老化特性（该特性会造成 (b)(4) 指标随时间推移持续、可检测地下降）是否会在有效期内影响成品的 (b)(4) 指标。
Your own investigation data (LAB-00380, Phase II) established that (b)(4) has a positive correlation with (b)(4) bulk (b)(4), and that (b)(4) continues to decrease with aging. Despite this knowledge, no additional stability monitoring was initiated for (b)(4) Batches (b)(4) and (b)(4) to ensure that the finished product would remain within specification throughout its shelf life.
贵司自有调查数据（LAB-00380，第二阶段）证实，(b)(4) 指标与 (b)(4) 原液的 (b)(4) 指标呈正相关，且 (b)(4) 指标会随老化持续下降。尽管掌握该信息，贵司仍未针对 (b)(4) 批次 (b)(4) 与 (b)(4) 启动额外稳定性监测，无法确保成品在整个有效期内持续符合质量标准。
OBSERVATION 2
The number of containers to be sampled and amount of material taken from each container is not based upon appropriate criteria.
待取样容器数量以及从每个容器中取样的物料量，未依据恰当标准制定。
Specifically,
具体如下：
The number of containers to be sampled and the amount of material to be taken from each container for (b)(4) and (b)(4) testing of high-risk components is not based upon appropriate criteria.
针对高风险组分开展 (b)(4) 与 (b)(4) 检测时，待取样容器数量以及每个容器的取样量，未依据恰当标准制定。
Specifically, your sampling procedure (SOP No. NL-QA-017.12) does not include a written scientific or statistical rationale for the amount of sample collected from each container for (b)(4) testing of high-risk drug components. You collect approximately (b)(4) per container; however, there is no documented justification establishing that this quantity is appropriate relative to container size or sufficient to perform all required testing, including repeat testing. Additionally, your written procedure does not establish criteria requiring that each individual container of each lot of high-risk drug
具体而言，贵司取样规程（SOP 编号 NL-QA-017.12）中，未针对高风险药品组分 (b)(4) 检测的单容器取样量提供书面科学依据或统计学依据。贵司每个容器取样约 (b)(4)；但无文件论证该取样量相对于容器规格是否合适，以及是否足以完成全部所需检测（包含复测）。此外，书面规程未制定标准，未要求高风险药品每一批次的每一个独立容器
OBSERVATION 3
The responsibilities and procedures applicable to the quality control unit are not fully followed.
质量控制部门适用的职责与规程未得到全面遵守。
Specifically,
具体如下：
Excel spreadsheets used to perform GMP calculations, including system suitability assessments and analytical result calculations for HPLC analyses, were observed to be unvalidated and executed outside of your validated (b)(4) system. Specifically, the following spreadsheets were observed in use:
现场发现，用于 GMP 计算（包括 HPLC 分析的系统适用性评估与分析结果计算）的 Excel 电子表格未经过验证，且在贵司经验证的 (b)(4) 系统外部运行。现场正在使用的电子表格包括：
(b)(4) SysSuit.xlsx — HPLC system suitability for (b)(4)
(b)(4) SysSuit.xlsx — (b)(4) 项目 HPLC 系统适用性计算
(b)(4) SysSuit.xlsx — HPLC system suitability for (b)(4) analysis
(b)(4) SysSuit.xlsx — (b)(4) 分析 HPLC 系统适用性计算
(b)(4)_BU_Calc.xlsx — (b)(4) bulk calculation
(b)(4)_BU_Calc.xlsx — (b)(4) 原液计算
(b)(4)_ASCU_Calculation.xlsx — Assay/content uniformity calculation
(b)(4)_ASCU_Calculation.xlsx — 含量 / 含量均匀度计算
(b)(4)_AS_Calc.xlsx — (b)(4) assay calculation
(b)(4)_AS_Calc.xlsx — (b)(4) 含量计算
(b)(4)_ASCU_Calculation.xlsx — Content uniformity calculation
(b)(4)_ASCU_Calculation.xlsx — 含量均匀度计算
(b)(4) Disso calc.xlsx — Dissolution calculation
(b)(4) Disso calc.xlsx — 溶出度计算
(b)(4) CU By (b)(4).xlsx — Content uniformity calculation
(b)(4) CU By (b)(4).xlsx — 含量均匀度计算
(b)(4) BU Calc.xlsx — Bulk calculation
(b)(4) BU Calc.xlsx — 原液计算
(b)(4) As Calc.xlsx — Assay calculation
(b)(4) As Calc.xlsx — 含量计算
(b)(4) Calculation.xlsx — Assay calculation
(b)(4) Calculation.xlsx — 含量计算
(b)(4)_Calc.xlsx — (b)(4) calculation
(b)(4)_Calc.xlsx — (b)(4) 计算
(b)(4)_Calc.xlsx — (b)(4) calculation
(b)(4)_Calc.xlsx — (b)(4) 计算
(b)(4)_DS_Calculation.xlsx — Dissolution calculation
(b)(4)_DS_Calculation.xlsx — 溶出度计算
(b)(4)_Calc.xlsx — Content uniformity calculation
(b)(4)_Calc.xlsx — 含量均匀度计算
(b)(4)_DS_Calculation.xlsx — Dissolution calculation
(b)(4)_DS_Calculation.xlsx — 溶出度计算
(b)(4)_calculation.xlsx — Assay calculation
(b)(4)_calculation.xlsx — 含量计算
(b)(4)_Calcn.xlsx — (b)(4) calculation
(b)(4)_Calcn.xlsx — (b)(4) 计算
(b)(4)_BU_Calculation.xlsx — Bulk uniformity calculation
(b)(4)_BU_Calculation.xlsx — 原液均匀度计算
(b)(4)_Calc.xlsx — Impurity calculation
(b)(4)_Calc.xlsx — 杂质计算
(b)(4) Calculation.xlsx — (b)(4) impurity calculation
(b)(4) Calculation.xlsx — (b)(4) 杂质计算
(b)(4)_DV.xlsx — Deliverable volume calculation
(b)(4)_DV.xlsx — 可递送体积计算
(b)(4) .xlsx — (b)(4) calculation
(b)(4).xlsx — (b)(4) 计算
These spreadsheets were observed to lack the identification numbering convention ((b)(4)), version control, cell protection, audit trail functionality, and electronic signature controls required by your own procedures. No evidence was observed that these spreadsheets were imported into or executed within the (b)(4) validated environment. No evidence of a second-person review or QA data reviewer sign-off was observed for the data contained within these spreadsheets.
现场发现，上述电子表格未按照贵司规程要求设置唯一编号规则 ((b)(4))、版本控制、单元格保护、审计追踪功能以及电子签名管控。无证据证明这些电子表格导入至 (b)(4) 验证环境或在该环境内运行。未发现表格内数据经过第二人复核，或由 QA 数据审核人员签字确认。
Applicable Firm Procedures:
适用企业规程：
SOP NL-VA-007.3, Preparation, Protection, and Qualification of Excel Calculation Sheets, Section 6.4.2: "Users must use validated excel templates from (b)(4) only. System will not record audit trails if they are executed outside (b)(4)."
SOP NL-VA-007.3《Excel 计算表格的编制、保护与确认》6.4.2 节：“用户仅可使用来自 (b)(4) 的经验证 Excel 模板。若在 (b)(4) 外部运行，系统将无法记录审计追踪。”
SOP NL-VA-007.3, Section 6.1.2: Requires assignment of a unique identification number ((b)(4)) to all GMP Excel calculation sheets.
SOP NL-VA-007.3 第 6.1.2 节：要求为所有 GMP Excel 计算表格分配唯一编号 ((b)(4))。
SOP NL-IT-011.0, Data Integrity, Section 7.10: "All the electronic recording documents including excel spread sheets along with the formulas shall be validated and any changes thereafter shall follow change management process."
SOP NL-IT-011.0《数据完整性》7.10 节：“所有电子记录文件（包括 Excel 表格及其公式）均需经过验证，后续任何变更均应遵循变更管理流程。”
SOP NL-QA-075.0, Review of Laboratory Documentation, Section 6.3.1.7: "When using Microsoft Excel spreadsheets for calculations, data reviewers must verify all the entries and calculations manually if the Excel spreadsheet validation is not performed. If the Excel spreadsheet is validated, all the input entries and one model calculation must be verified."
SOP NL-QA-075.0《实验室文件审核》6.3.1.7 节：“使用 Microsoft Excel 电子表格开展计算时，若 Excel 表格未经验证，数据审核人员必须人工复核所有录入内容与计算过程。若 Excel 表格已验证，则必须复核全部录入数据以及一组典型计算。”
