新政策法规下品质本年度回望年报规章制度及加工工艺变更管理重中之重培圳：药品研发质量管理体系创建第二届质量控制高峰论坛邀您一同参加（800/位包括二天午饭）北京站2020版中国药典有关讲解与各处难题实践活动剖析昨天，FDA在官方网站公布了对迈兰（Mylan）试验室有限责任公司的警告信，该警告信因亚硝胺杂质造成，有关NDMA/NDEA杂质，欧盟国家先前发布消息规定全部有机化学药品生产企业在6月内进行风险性评（点一下文本连接：EMA提议药品生产企业采用流程防止在用药物中的亚硝胺（EMA / 511347/2019））估，近期，国家食药监局也刚开始规定一部分公司进行自纠自查自查了，提议造成关心！警告信缺点包含：生产工艺流程评定无法包含亚硝胺等杂质污染。应用收购溶剂，但无法操纵收购溶剂产生的污染和交差污染风险性NDEA检验結果规范程度40倍，但仍下结论是不容易造成NDEA的明显水准。欠缺纪录哪家储存罐用以储放哪家溶剂的文档。尽管该企业坚持不懈觉得现行标准加工工艺中沒有将会造成亚硝胺杂质，但在內部溶剂回收的使用性能确定汇报发觉溶剂中带有NDMA（高过检测限）和 NDEA （高过规范限）。虽然服务承诺了事后将应用新鮮溶剂，但沒有表明在海关放行用以生产制造以前检测NDMA/NDEA等杂质。查验全过程发觉，某非专用型被贴上已清洗标识。殊不知，若用无绒布擦洗带槽内表层时，观查到残余。接着检测发觉是残余的缬沙坦 API。对于，该企业根据对举报和OOS调研的回望，判断对产品品质的危害不大。该企业强调，全部生产制造的缬沙坦批号和别的药物都历经"外地人杂质"的检测，沒有汇报不过关。FDA表达这类回应不是充足的。交差污染的遍布不可以假设是匀称的，光靠检测不能够缓解观查到的污染伤害。FDA着重强调应留意药物生产制造实际操作中好几个最烂状况的组成标准，如毒副作用较高的药物、药力较高的药物、在清洗溶剂中溶解性较低的药物、具备使其无法清洗的特点的药物、较难清洗的部位、清洗前的较大维持時间。该警告信汉语翻译以下：Dear Ms. Bresch:The U.S. Food and Drug Administration (FDA) inspected your drug manufacturing facility, Mylan Laboratories Limited, Unit 8, FEI 3002785310, at G. Chodavaram Village, Vizianagaram, Andhra Pradesh, India, from May 27 to June 5, 2019.FDA于2019年5月27日至6月5日查验了大家在印尼安得拉邦维齐亚纳加拉姆的G.Chodavaram村的药物加工厂，Mylan试验室有限责任公司，8模块，FEI 3002785310。This warning letter summarizes significant deviations from current good manufacturing practice (CGMP) for active pharmaceutical ingredients (API).此警告信小结了与特异性药物成份（API）违背CGMP的重特大误差。Because your methods, facilities, or controls for manufacturing, processing, packing, or holding do not conform to CGMP, your API 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).因为大家生产制造、生产加工、包裝或储存的方式 、设备或操纵不符CGMP，大家的API 依据FD&C Act，21 U.S.C. 351（a）（2）（B）被判定为造假。We reviewed your June 26, 2019, response to our Form FDA 483 in detail and acknowledge receipt of your subsequent correspondence. Your response is inadequate because it did not provide sufficient detail or evidence of corrective actions to bring your operations into compliance with CGMP.人们详尽审阅了大家2019年6月26日对人们FDA 483表的回应，并确定接到了大家接着的信函。大家的回应不是充足的，由于它沒有出示充足的关键点或改正对策直接证据，令其大家的实际操作合乎 CGMP。During our inspection, our investigators observed specific deviations including, but not limited to, the following.在人们的查验全过程中，人们的检查员发觉的实际误差，包括下列：1. Failure to have adequate written procedures for the receipt, identification, testing and handling of raw materials.无法创建用以原辅材料接受、评定、检测和解决的适度的书面形式程序流程。Your procedures for receiving, identifying, testing, and handling raw materials were inadequate to ensure suitability of materials used in manufacturing, including preventing contamination and cross-contamination with (b)(4) impurities such as (b)(4) and (b)(4). Your firm had not anticipated the presence of (b)(4) impurities based on your assessment of the API manufacturing process.大家用以原材料接受、评定、检测和解决的程序流程不能够保证生产制造中应用了适度的原材料，包含避免污染和与 （b）（4） 杂质的交差污染，比如 （b）（4） 和 （b）（4） 杂质。依据大家对API生产工艺流程的评定，贵司沒有想到存有 （b）（4） 杂质。By December 2018, you recalled all your valsartan API batches after tests determined that the majority of batches contained NDEA contamination at levels above the limit. Your investigation dated November 21, 2018, with addendum dated January 1, 2019, concluded that NDEA contamination originated from recovered (b)(4)solvents. Your investigation into nitrosamine contamination also found that another recovered solvent, (b)(4), contained NDEA at levels of 3.38 ppm, more than 40 times your limit of 0.08 ppm. Without adequate scientific justification, you concluded that the recovered (b)(4) solvent containing high levels of NDEA would not result in significant levels of NDEA in your API.直至2018年12月，在检测明确大部分批号带有超出程度水准的 NDEA 污染后，大家招回了全部缬沙坦 API 批号。大家在 2018 年 11 月 21 日的调研及其 2019 年 1 月 1 日的填补中下结论，NDEA 污染物自收购的 （b）（4） 溶剂。大家对亚硝胺污染的调研还发觉，另一种收购的溶剂（b）（4）带有3.38ppm的NDEA，超出0.08ppm程度的40倍。在沒有充足的科学论证的状况下，大家的依据是，收购的（b）（4）溶剂带有高浓的NDEA不容易造成API中NDEA的明显水准。In addition, your firm found low levels of NDMA in your valsartan API. Your investigation concluded this nitrosamine impurity was introduced via contaminated (b)(4) recovered solvents. Notably, you stated in a Field Alert Report (FAR) submitted to FDA on September 13, 2019, that one likely root cause of the nitrosamine contamination found in rejected batches of valsartan API was recovered (b)(4) solvent containing NDMA at levels as high as 0.629 ppm.除此之外，贵司还要缬沙坦API 中发觉了适度性的 NDMA。大家的调研下结论，这类亚硝胺杂质是根据受污染的（b）（4）收购溶剂引进的。特别注意的是，大家在2019年9月13日递交给 FDA的当场报警汇报（FAR）中强调，在已拒批 缬沙坦API 中发觉的亚硝胺污染的一个将会来源于被收购（b）（4） 溶剂，其浓度值达到 0.629 ppm。Your firm used recovered solvents such as (b)(4) and (b)(4) from multiple external contract manufacturers, including (b)(4). In January 2019 you restricted the procurement of all valsartan-related materials from (b)(4)and in March 2019, you removed (b)(4) from your approved manufacturing list. FDA placed (b)(4) on Import Alert 66-40 on (b)(4), and issued Warning Letter (b)(4) on (b)(4), due to CGMP deficiencies involving inadequate solvent recovery operations resulting in nitrosamine impurity contamination of solvents supplied to their customers.贵司应用从好几个外界合同书制造商（包含（b
