FDA于6月17日发布了对浙江华海药业有限公司的警告信，这次检查官是Justin A, Boyd，这个检查官对华海很熟，2018年和Peter E.Baker一起袭击华海的就是他。检查风格很细致，2025年1月16-24日在春节假期前夕，Justin A. Boyd和Jeffrey P.Raimondi再次来到华海进行为期一周半的检查，并签发了483缺陷表。尽管华海进行了整改答复，仍然收到FDA警告信。

该检查官检查后发483的比率高达75.19%，近期频繁检查国家：中国、印度。值得大家关注，文末有关于Justin A, Boyd的资料介绍。

华海警告信细节：

FDA检查人员在多台非专用设备表面（包括管道及相关阀门）发现残留物。FDA称脏污表面的气流可能导致药品受到污染。

检查期间对这些残留物进行检测，证实这些残留物含有多种活性成分。

该公司在回复中称交叉污染风险极低，理由包括留样药品的检测结果和交叉污染模拟实验。

FDA认为该公司的回复不充分。FDA认为污染通常不是均匀分布，留样检测和交叉污染模拟实验未能科学证明贵公司产品未受肉眼可见脏污设备的污染。此外，FDA认为调查未将微生物污染作为潜在风险因素进行评估。

检查人员在 ISO 5 级（A 级）区域的 HEPA 过滤器下方缝隙发现一块 2 厘米 ×126 厘米的非无菌胶带。该公司称自 2024 年 4 月起使用该胶带以方便清洁。

该公司的质量部门（QU）未被告知在无菌区域使用非无菌胶带，该胶带一直在无菌区域内未被注意到，直至 FDA 检查人员在检查中发现。

该公司称通过评估气流流型、清洁操作、环境监测结果（非活性和活性粒子）以及批次和培养基灌装回顾性审查，认为对产品无影响。

FDA认为该公司的回复是不充分的。该公司未回复对在灌装操作期间进行设施和设备改造时，质量部门（QU）在确保其适当性方面所起作用进行全面评估。FDA表示：该公司的回复中未明确洁净区改造是否无需质量部门批准，或质量部门是否按既定程序和时间定期对洁净区进行目视检查/巡检。

该公司的片剂压片拒收标准通过设定主压压力的上下限确定。该公司基于 “先前生产经验” 设定了拒收限和拒收率，但缺乏验证数据以确保该比率适用于生产持续符合标准的药品。FDA批评称：生产工艺的每个重要阶段必须经过适当设计。

该公司曾收到某批次产品溶出度测试不符合标准的投诉，该公司将其归因于主压压力值过高。

缺陷翻译如下：

The United States Food and Drug Administration (FDA) inspected your drug manufacturing facility, Zhejiang Huahai Pharmaceutical Co., Ltd., FEI 3003999190, at Xunqiao, Linhai, Zhejiang Province, from January 16 to 24, 2025.

FDA于2025年1月16日至24日检查了你们位于浙江省临海市浔桥的药品生产工厂浙江华海药业有限公司，编号FEI 3003999190。

 

This warning letter summarizes significant violations of Current Good Manufacturing Practice (CGMP) regulations for finished pharmaceuticals. See Title 21 Code of Federal Regulations (CFR), parts 210 and 211 (21 CFR parts 210 and 211).

本警告信总结了成品药品严重违反CGMP规定的情况。见21 CFR第210和211部分。

Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your drug products are adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), 21 U.S.C. 351(a)(2)(B).

由于你们的生产、加工、包装或保存的方法、设施或控制不符合CGMP，你们的药品根据FD&C Act第501(a)(2)(B)条，21 U.S.C. 351(a)(2)(B)条被认定为掺假。

We reviewed your February 14, 2025 response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence.

我们详细审查了你们2025年2月14日对FDA 483的回复，并确认收到了你们后续的回复。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在我们的检查中，我们的检查人员发现到的具体违规行为，包括但不限于以下情况。

During our inspection, our investigators observed specific violations including, but not limited to, the following.

在检查过程中，我们的检查人员发现了具体违规行为，包括但不限于以下内容。

1. Your firm failed to clean, maintain, and, as appropriate for the nature of the drug, sanitize and/or sterilize equipment and utensils at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements (21 CFR 211.67(a)).

贵公司未能按药品性质适当清洁、维护设备及器具，并在适当时间进行消毒和 / 或灭菌，以防止设备故障或污染导致药品安全性、特性、效价、质量或纯度超出官方或其他既定要求 (21 CFR 211.67(a))。

You manufacture prescription drug products used to treat various conditions such as (b)(4). Your cleaning procedures for your non-dedicated manufacturing equipment are inadequate. Our investigators observed residue on surfaces of several non-dedicated (b)(4), including (b)(4) ducts and associated valves, which had been documented in the cleaning records as having undergone product changeover cleaning. Your firm was also cited for unknown residue in the (b)(4) duct of a (b)(4) during a previous FDA inspection. Air flow over dirty surfaces can facilitate contamination of the drug being processed in an (b)(4). Additionally, your analytical testing during the inspection confirmed these residues contained multiple active ingredients. Furthermore, residues were observed on both product contact and non-contact surfaces of the (b)(4) equipment, which were previously indicated as clean.

贵公司生产用于治疗多种病症（如 (b)(4)）的处方药。贵公司非专用生产设备的清洁程序不充分。检查人员在多台非专用 (b)(4) 设备表面（包括 (b)(4) 管道及相关阀门）发现残留物，而清洁记录中却记载这些设备已完成更换产品清洁。在 FDA 此前的检查中，贵公司也曾因 (b)(4) 设备的 (b)(4) 管道内存在未知残留物被通报。脏污表面的气流可能导致 (b)(4) 中处理的药品受到污染。此外，检查期间的分析测试证实这些残留物含有多种活性成分。另外，在 (b)(4) 设备的产品接触和非接触表面均观察到残留物，而这些表面此前被标注为已清洁。

In your response, you state that there is minimal risk for cross-contamination. Your rationale includes the test results of reserve drug product samples, as well as cross-contamination simulation experiments. You also indicate that you have revised your cleaning procedures, and you explain that (b)(4) and (b)(4) equipment are now appropriately inspected to verify cleanliness, which is recorded in your cleaning records.

在回复中，贵公司称交叉污染风险极低，理由包括留样药品的检测结果和交叉污染模拟实验。贵公司还表示已修订清洁程序，并解释称目前已对 (b)(4) 和 (b)(4) 设备进行适当检查以确认洁净度，相关结果记录在清洁记录中。

Your response is inadequate. Your risk assessment, which included testing of reserve product samples and cross-contamination simulation experiments failed to scientifically demonstrate your products are free of contaminants from your visibly dirty equipment. Additionally, your investigation did not include an assessment for microbial contamination as a potential risk factor.

贵公司的回复不充分。你们的风险评估，包括留样检测和交叉污染模拟实验，未能科学证明贵公司产品未受肉眼可见脏污设备的污染。此外，调查未将微生物污染作为潜在风险因素进行评估。

Contamination is generally nonuniformly distributed. Data obtained from retrospectively testing a small proportion of a batch (e.g., retain samples) is limited in its ability to retrospectively assess the extent of contamination in other portions of a batch. The lowest or highest results obtained from testing a small sample size is unlikely to reveal the true range of minimum and maximum contamination levels that exist in a batch exposed to the contamination hazards identified at your firm. Consequently, the range of variability of contamination levels in batches produced by your firm remain characterized by substantial residual uncertainty.

污染通常不是均匀分布。通过对批次小部分样品（如留样）进行回顾性检测获得的数据，在评估批次其他部分污染程度时存在局限性。小样本检测的最低或最高结果，不太可能揭示贵公司存在污染风险的批次中实际存在的污染水平的最低和最高范围。因此，贵公司生产批次的污染水平变异性范围仍存在大量残留不确定性。

2. Your firm failed to perform operations within specifically defined areas of adequate size and to have separate or defined areas or such other control systems necessary to prevent contamination or mix-ups in aseptic processing areas (21 CFR 211.42(c)(10)).

贵公司未能在特定且面积足够的区域内开展操作，也未设置独立或界定的区域或其他必要控制系统，以防止无菌处理区域的污染或混淆 (21 CFR 211.42(c)(10))。

 

You also manufacture (b)(4) drug products used to treat various conditions including (b)(4). Our investigator observed a 2 cm x 126 cm piece of a non-sterile tape between (b)(4) below the HEPA filters and above the (b)(4) in an ISO 5 (Grade A) area. The (b)(4) were not securely fastened. One (b)(4) was hanging lower than the other (b)(4) and appeared to be missing a screw. Your firm stated that the tape was used to facilitate cleaning between the (b)(4) since April 2024. Your quality unit (QU) was not informed of the use of non-sterile tape in an aseptic area, and the tape remained in the classified area unnoticed until FDA investigators observed it during this inspection.

贵公司还生产用于治疗多种病症（包括 (b)(4)）的 (b)(4) 药品。检查人员在 ISO 5 级（A 级）区域的 HEPA 过滤器下方 (b)(4) 与 (b)(4) 上方之间，发现一块 2 厘米 ×126 厘米的非无菌胶带。(b)(4) 未牢固固定，其中一个 (b)(4) 悬挂高度低于另一个，且似乎缺少一颗螺丝。贵公司称自 2024 年 4 月起使用该胶带以方便 (b)(4) 之间的清洁。你们的质量部门（QU）未被告知在无菌区域使用非无菌胶带，该胶带一直在无菌区域内未被注意到，直至 FDA 检查人员在本次检查中发现。

In your response, you state that there is no impact to the product following an assessment of your airflow patterns, cleaning practices, environmental monitoring results (non-viable and viable particulates), and retrospective review of batches and media fills.

在回复中，贵公司称通过评估气流流型、清洁操作、环境监测结果（非活性和活性粒子）以及批次和培养基灌装回顾性审查，认为对产品无影响。

Your response is inadequate. Your response lacks a comprehensive evaluation of your QU’s role in assuring the suitability of the facility and equipment when modifications are made during filling operations. It is unclear in your response if modifications to classified areas are permitted without QU approval or if the QU regularly performs visual inspections of classified areas according to established procedure and timeframes. While your response states that the tape was used to facilitate cleaning by filling a gap between the (b)(4), your response did not address the FDA investigators’ observation that the (b)(4) were not properly and securely fastened.

贵公司的回复是不充分的。你们的回复对在灌装操作期间进行设施和设备改造时，质量部门（QU）在确保其适当性方面所起作用的全面评估有所欠缺。你们的回复中未明确洁净区改造是否无需质量部门批准，或质量部门是否按既定程序和时间定期对洁净区进行目视检查/巡检。尽管回复称胶带用于填补 (b)(4) 之间的间隙以方便清洁，但未回应 FDA 检查人员关于 (b)(4) 未正确牢固固定的观察结果。

3. Your firm failed to establish adequate written procedures for production and process control designed to assure that the drug products you manufacture have the identity, strength, quality, and purity they purport or are represented to possess (21 CFR 211.100(a)).

贵公司未能制定充分的生产和工艺控制书面程序，以确保所生产药品具有其宣称的特性、效价、质量和纯度 (21 CFR 211.100(a))。

Tablet compression rejections are established by setting the upper and lower limits of the main compression force. While your firm established reject limits and rates based on “prior manufacturing experience,” your firm lacks validation data for your U.S. marketed drug products to ensure the rates are suitable for producing drug products which consistently meet specifications. Of note, on at least one occasion, your firm received a complaint for a batch of product that failed specification for dissolution testing which you attributed to high main force compression value.

你公司的片剂压片拒收标准通过设定主压压力的上下限确定。尽管贵公司基于 “先前生产经验” 设定了拒收限和拒收率，但缺乏验证数据以确保该比率适用于生产持续符合标准的药品。值得注意的是，贵公司至少有一次收到某批次产品溶出度测试不符合标准的投诉，贵公司将其归因于主压压力值过高。

Process validation evaluates the soundness of design and state of control of a process throughout its lifecycle. Each significant stage of a manufacturing process must be designed appropriately and assure the quality of raw material inputs, in-process materials, and finished drugs. Process qualification studies include intensive monitoring and testing throughout each significant process stage to characterize intra-batch variation and evaluate batches to determine whether an initial state of control has been established.

工艺验证评估工艺设计的合理性及在整个生命周期中的受控状态。生产工艺的每个重要阶段必须经过适当设计，并确保原料输入、中间产品和成品的质量。工艺确认研究包括在每个重要工艺阶段进行密集监测和测试，以表征批内变异并评估批次，以确定是否已建立初始控制状态。

Successful process qualification studies are necessary before commercial distribution. Thereafter, ongoing vigilant oversight of process performance and product quality is necessary to ensure you maintain a stable manufacturing operation throughout the product lifecycle.

成功的工艺确认研究是商业分销前的必要条件。此后，必须对工艺性能和产品质量进行持续严格监测，以确保在产品整个生命周期中维持稳定的生产操作。

 

来源：Internet

关键词： 浙江华海药业有限公司 警告信