近日，FDA 发布了以岭万洲国际制药有限公司的警告信，缺陷涉及交叉污染和质量体系运行不善，如下：

多产品共线的某带管道的生产设备上的某个部件，未能确保防止药粉末回流污染正在生产的其他产品（这个缺陷很常见，很多设备如包衣机、沸腾干燥机、流化床等都可能存在这个问题）。

FDA现场对该管道进行擦拭取样，检测到包括多种API残留物。随后该公司回复称已启动对留样的检测，以排查是否存在交叉污染。对此FDA并不接受，FDA表示：污染通常并非均匀分布。通过对批次中一小部分样品进行回顾性检测（例如，检测留样中是否存在其他活性成分残留），在回顾性评估交叉污染程度方面存在局限性。

设备管道的连接处密封件已老化，现场使用胶带进行覆盖已批准的清洁SOP程序未包含如清洁设备风管的说明，包括拆卸和洁净度目视检查的指导。进而，FDA提出该公司质量部门未能充分履行质量职能并确保质量监督。该公司在回复中指出，设备的设计不利于清洁，并表示，正在更新清洁程序，要求进行拆卸和清洁后检查。

缺陷翻译如下：
During our inspection, our investigator observed specific violations including, but not limited to, the following.在我们的检查过程中，我们的调查人员发现了特定的违规行为，包括但不限于以下内容。
1. Your firm failed to use equipment in the manufacture, processing, packing, or holding of drug products that is of appropriate design, adequate size, and suitably located to facilitate operations for its intended use and for its cleaning and maintenance (21 CFR 211.63).贵公司在药品生产、加工、包装或存储过程中，未使用设计适当、尺寸合适且位置合理的设备，以使其便于按预期用途操作及清洁维护（21 CFR 211.63 ）。
Your non-dedicated manufacturing equipment was not designed and maintained appropriately to prevent potential cross-contamination of drug products.贵公司的非专用生产设备在设计和维护上存在缺陷，未能有效防止药品的潜在交叉污染。
For example, (b)(4) were not designed and maintained to ensure that the (b)(4) consistently closes tightly, to prevent backflow of bulk drug powder into the (b)(4) duct. Residues were observed in the (b)(4) duct of (b)(4).例如，（b)(4）的设计和维护未能确保（b)(4）持续紧密闭合，以防止原料药粉末回流到（b)(4）管道中。在（b)(4）的（b)(4）管道中观察到了残留物。
Numerous drug substance residues, including (b)(4), were recovered upon swabbing of (b)(4). Your (b)(4), are used to manufacture multiple drug products, including (b)(4) therapeutics such as (b)(4).通过对（b)(4）进行擦拭取样，检测到包括（b)(4）在内的多种API残留物。贵公司的（b)(4）设备用于生产多种药品，包括（b)(4）治疗药物（如（b)(4)）
In addition, junctions on the (b)(4) duct had degraded seals and were covered with tape.此外，（b)(4）管道的连接处密封件已老化，使用胶带进行了覆盖。
In your response, you state you will replace the (b)(4) on (b)(4) to prohibit backflow into the (b)(4) ducting and replace the (b)(4) ducting on (b)(4) for ease of cleaning and sanitization. You further state you are identifying all batches of U.S. product within expiry from these (b)(4) and have initiated testing reserve samples for possible cross-contamination.在贵公司的回复中，贵方称将更换（b)(4) 上的（b)(4)，以防止回流至（b)(4) 管道，并更换（b)(4) 上的（b)(4) 管道以便于清洁和消毒。贵方进一步表示，正在识别这些（b)(4) 生产的所有在有效期内的产品批次，并已启动对留样的检测，以排查是否存在交叉污染。
Your response is inadequate. Your assessment is limited to testing reserve samples of each finished drug product only for the presence of the preceding drug substance processed on the same non-dedicated equipment, instead of testing each reserve sample for all drug substances processed on the equipment. You do not adequately address how you intend to maintain this equipment to ensure the integrity of the seals.贵公司的回复不充分。贵方的评估仅限于检测每种成品药的留样是否含有在同一非专用设备上处理过的前一种原料药，而非针对该设备处理过的所有原料药对每个留样进行检测。此外，贵方未充分说明打算如何维护该设备以确保密封件的完整性。
Equipment used in pharmaceutical manufacturing operations should be designed to protect drug products from contamination. Air flow over dirty surfaces can cause contamination of the drug being processed in a (b)(4). Robust design, cleaning, and maintenance of this and other equipment are critical to prevent cross-contamination.药品生产操作中使用的设备设计应能保护药品免受污染。污染表面的气流可能导致（b)(4）中正在加工的药品受到污染。对此类设备及其他设备进行可靠的设计、清洁和维护，对防止交叉污染至关重要。
Contamination is generally not uniformly distributed. Data obtained from retrospectively testing a small proportion of a batch (e.g., reserve samples for the presence of previous active ingredient) 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 level that exists 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.污染通常并非均匀分布。通过对批次中一小部分样品进行回顾性检测（例如，检测留样中是否存在其他活性成分残留）所获得的数据，在回顾性评估批次其他部分的污染程度方面存在局限性。从少量样本检测中获得的最低或最高结果，不太可能揭示出在贵公司所发现的污染风险下，批次中实际存在的最低和最高污染水平的真实范围。因此，贵公司生产批次中污染水平的变异范围仍存在大量的残留不确定性。
Because of the limitations of retrospective testing in gaining a representative understanding of the entire lot, testing reserve samples alone is insufficient to determine the scope of the contamination issues and mitigate the associated risks. Further evaluation and scientific rationale are needed in your firm’s risk assessment to reflect the nature of cross-contamination events and determine the degree of cross-contamination risk that may be posed to portion of marketed batches.由于回顾性检测在全面了解整个批次的代表性方面存在局限性，仅检测留样不足以确定污染问题的范围并降低相关风险。贵公司的风险评估需要进一步的评估和科学依据，以反映交叉污染事件的性质，并确定已上市批次可能面临的交叉污染风险程度。
In response to this letter, provide the following:收到本函后，请提供以下内容：

Your corrective action and preventive action (CAPA) plan to implement routine, vigilant operations management oversight of facilities and equipment. This plan should ensure, among other things, prompt detection of equipment/facilities performance issues, effective execution of repairs, adherence to appropriate preventive maintenance schedules, timely technological upgrades to the equipment/facility infrastructure, and improved systems for ongoing management review.

你们的CAPA计划以实施设施和设备的日常、严密的运行管理监督。该计划应确保（除其他事项外）及时发现设备 / 设施性能问题、有效执行维修工作、遵守适当的预防性维护计划、及时对设备 / 设施基础设施进行技术升级，以及完善持续管理评审体系。

A comprehensive retrospective risk assessment that addresses all possible cross-contamination, including but not limited to, highly potent substances such as (b)(4).

开展全面回顾性风险评估，涵盖所有可能的交叉污染情况，包括但不限于（b)(4) 等高活性物质。

A comprehensive risk assessment from analysis of adverse drug events for all affected drug products. Any side effects possibly attributable to cross-contamination with (b)(4) should be reported.

通过分析所有受影响药品的不良事件开展综合风险评估。任何可能归因于（b)(4) 交叉污染的副作用均应进行报告。

A detailed CAPA plan to implement segregation of highly potent substances such as (b)(4) from equipment shared with other drug products.

制定详细的 CAPA 计划，确保将（b)(4) 等高活性物质与其他药品共用的设备进行隔离。

2. Your firm’s quality control unit failed to exercise its responsibility to ensure drug products manufactured are in compliance with CGMP, and meet established specifications for identity, strength, quality, and purity (21 CFR 211.22).贵公司质量控制部门未能履行其职责，以确保所生产的药品符合现行药品生产质量管理规范（CGMP），并满足既定的鉴别、规格、质量和纯度标准（ 21 CFR 211.22 ）。
Your quality unit (QU) failed to adequately implement the facility’s quality function and ensure quality oversight. For example:贵公司质量部门（QU）未能充分履行工厂的质量职能并确保质量监督。例如：
You failed to have an adequate procedure to clean (b)(4). Your approved procedure did not include sufficient directions to clean the (b)(4) ducts, including directions on disassembly and visual inspection for cleanliness. Thus, you failed to identify visible residue with the possibility of cross-contaminated drug products being released to the market.贵公司未能制定充分的（b)(4）清洁程序。已批准的程序未包含清洁（b)(4）管道的充分说明，包括拆卸和清洁度目视检查的指导。因此，贵公司未能识别可见残留物，导致可能存在交叉污染的药品被投放市场。
In your response you identify (b)(4), was not designed to facilitate appropriate cleaning. You acknowledge this resulted in residual drug substances inside the (b)(4) duct of your (b)(4). You indicate that you are updating your cleaning procedures to require disassembly and post cleaning inspection.在贵公司的回复中指出，（b)(4) 的设计不利于进行适当的清洁。贵公司承认，这导致（b)(4) 设备的（b)(4) 管道内残留药物物质。贵公司表示，正在更新清洁程序，要求进行拆卸和清洁后检查。
Your response is inadequate. You do not provide a written approved procedure that would ensure adequate disassembly and cleaning of the (b)(4) duct. And you fail to provide evidence you have implemented CAPA measures ensuring QU oversight of cross-contamination risks from highly potent substances, such as (b)(4), on shared equipment.贵公司的回复不充分。一是贵公司未提供书面批准的程序以确保（b)(4）管道的充分拆卸和清洁。二是贵公司未能提供证据证明已实施纠正与预防措施（CAPA），以确保质量部门（QU）对（b)(4) 等高活性物质在共用设备上的交叉污染风险进行监督。
You also manufacture (b)(4), a highly potent drug on the same shared equipment. (b)(4) is a hazardous drug that can cause (b)(4) if administered outside of its therapeutic range.贵公司还在同一共用设备上生产（b)(4)—— 一种高活性药物。（b)(4) 属于危险药物，若在治疗范围外使用可能导致（b)(4)
In response to this letter, provide:针对本函，请提供：
A comprehensive, independent assessment and remediation plan to ensure your QU is given the authority and resources to effectively function. The assessment should also include, but not be limited to:一项全面、独立的评估及整改计划，以确保贵公司质量部门（QU）被赋予有效履行职能的权限和资源。该评估应至少包括但不限于以下内容：

A determination of whether procedures used by your firm are robust and appropriate.

公司所用程序是否健全且适当的判定。

Provisions for QU oversight throughout your operations to evaluate adherence to appropriate practices.

质量部门（QU）在整个运营过程中的监督条款，以评估对相关规范操作的遵守情况。

A complete and final review of each batch and its related information before the QU disposition decision.在质量部门做出放行决定前，对每一批次产品及其相关信息的完整最终审核。

Oversight and approval of investigations and discharging of all other QU duties to ensure identity, strength, quality, and purity of all products.

对调查的监督和批准，以及履行质量部门的所有其他职责，以确保所有产品的鉴别、规格、质量和纯度符合要求。

A comprehensive, independent retrospective assessment of your cleaning effectiveness to evaluate the scope of cross-contamination hazards. Include the identity of residues, other manufacturing equipment that may have been improperly cleaned, and an assessment whether cross-contaminated products may have been released for distribution. The assessment should identify any inadequacies of cleaning procedures and practices, and encompass each piece of manufacturing equipment used to manufacture more than one product.

对清洁有效性进行全面、独立的回顾性评估，以评估交叉污染风险的范围。评估内容应包括残留物的特性、可能未被正确清洁的其他生产设备，以及对可能已放行销售的交叉污染产品的评估。该评估需识别清洁程序和操作中的任何不足，并涵盖用于生产多种产品的每一台生产设备。

A CAPA plan, based on the retrospective assessment of your cleaning program, that includes appropriate remediations to your cleaning processes and practices, and timelines for completion. Provide a detailed summary of vulnerabilities in your process for lifecycle management of equipment cleaning. Describe improvements to your cleaning program, including enhancements to cleaning effectiveness; improved ongoing verification of proper cleaning execution for all products and equipment; and all other needed remediations.

根据清洁程序回顾性评估制定纠正与预防措施（CAPA）计划，内容包括对清洁流程和操作的适当整改措施及完成时间表。提供设备清洁生命周期管理流程中漏洞的详细总结。描述清洁程序的改进方案，包括提高清洁有效性的措施；加强对所有产品和设备清洁执行情况的持续验证；以及所有其他必要的整改措施。

A comprehensive assessment of your overall system for investigating deviations, discrepancies, complaints, out-of-specification results, and failures. Provide a detailed action plan to remediate this system. Your action plan should include, but not be limited to, significant improvements in investigation competencies, scope determination, root cause evaluation, CAPA effectiveness, QU oversight, and written procedures. Address how your firm will ensure all phases of investigations are appropriately conducted.

对贵公司用于调查偏差、差异、投诉、超标结果和故障的整体系统进行全面评估。提供详细的整改行动计划以完善该系统。您的行动计划应包括但不限于以下方面的重大改进：调查能力、范围确定、根本原因评估、纠正与预防措施（CAPA）有效性、质量部门（QU）监督以及书面程序。阐述贵公司将如何确保调查的所有阶段均得到适当执行。

A complete assessment of all investigations where unknown impurities or unknown peaks were detected in marketed product and a determination if these are associated with potential cross-contamination events.

对上市产品中检测到未知杂质或未知峰的所有调查进行全面评估，并判定这些情况是否与潜在的交叉污染事件相关。

 

 

来源：Internet

关键词： FDA 交叉污染