无菌制剂的短缺给我们带来什么机会？

无菌注射剂生产FDA最关注的点 1. Aseptic Processing无菌工艺 2. CMOs/Knowledge Transfer CMOs/知识转移 3. Drug Shortages药品短缺 4. Environmental Monitoring环境监测 6. Metrics for Quality质量指标 7. Particulates/Visual Inspection颗粒物/目视检查 9. Training培训 无菌制剂的短缺给我们带来什么机会？ 齐鲁制药登上了CNN头条 美国短缺药品趋势分析 2 无菌制剂短缺主要原因是什么？ 3 FDA引入QbI理念来核查无菌制剂生产 4 对无菌生产厂家警告信案例分析 5 11/4/2024陈洪5 •CNN—The US Food and Drug Administrationis workingwith Chinese drugmaker Qilu Pharmaceutical to importthe cancer medication cisplatin to boost supply amid an ongoing shortage. •Cancer treatments are among the hardest-hit as the US faces a near-record number of drug shortages. As ofthe end of March, about two dozen chemotherapy drugs were in active shortage, the fifth most of any drugcategory, according to data from the University of Utah Drug Information Service. •Cisplatin and other platinum-based drugs are prescribed for 10% to 20% of all cancer patients, according totheNational Cancer Institute. Cisplatin has a cure rate of over 90% when used to treat testicular cancer. Italso treats bladder, cervical, ovarian, lung, gastric, breast, and head and neck cancers. 6 其他美国主流媒体 其他美国主流媒体 无菌制剂的短缺给我们带来什么机会？ 齐鲁制药登上了CNN头条 美国短缺药品趋势分析 2 无菌制剂短缺主要原因是什么？ 3 FDA引入QbI理念来核查无菌制剂生产 4 对无菌生产厂家警告信案例分析 FDA短缺品种 University of Utah Drug Information Service Teva 成功整改FDA警告信12/11/2009的注射剂工厂by 3/2012 无菌制剂的短缺给我们带来什么机会？ 齐鲁制药登上了CNN头条 美国短缺药品趋势分析 2 无菌制剂短缺主要原因是什么？ 3 FDA引入QbI理念来核查无菌制剂生产 4 对无菌生产厂家警告信案例分析 5 •Creating a shared understanding of the impact of drugshortages on patients and the contracting practices thatmay contribute to shortages; •Developing a rating system to incentivize drugmanufacturers to invest in quality management maturity fortheir facilities; and •Promoting sustainable private sector contracts (e.g., withpayers, purchasers, and group purchasing organizations)to make sure there is a reliable supply of medicallyimportant drugs. 21 无菌制剂的短缺给我们带来什么机会？ 齐鲁制药登上了CNN头条 美国短缺药品趋势分析 2 无菌制剂短缺主要原因是什么？ 3 FDA引入QbI理念来核查无菌制剂生产 4 对无菌生产厂家警告信案例分析 FDA STERILE DRUG PROCESS INSPECTIONS:168 Points to ConsiderFDA引入QbI理念来核查无菌制剂生产 文件范围 This program covers the manufacture and testing of all sterile drug products,including drugs that are sterilized by filtration or other means and asepticallyprocessed, and drug products that are terminally sterilized.该文件涵盖所有无菌药品的制造和测试，包括通过过滤或其他方式灭菌和无菌加工的药品，以及经过最终灭菌的药品。 The type of products covered by this program include sterile bulk drugs, ophthalmicdrugs, otic dosage forms, small volume parenteral (SVS) products for small moleculeand licensed biological therapeutic drug products, large volume parenteral (LVP)products, and any other drug products required to be sterile or labeled as sterile.该文件涵盖的产品类型包括无菌原料药、眼科药物、耳剂型、用于小分子和许可生物治疗药物产品的小容量肠外（SVS）产品、大容量注射（LVP）产品以及任何其他需要无菌或标记为无菌的药品。 Center for Biologics Evaluation and Research (CBER) regulated products andveterinary drug products are excluded from coverage under this program生物制品评估与研究中心（CBER）受管制的产品和兽药产品不包括在此计划的承保范围内 FDA QbI（question based Inspection）168个核查主要关注点27 一．MOISTHEATSTERILIZATION湿热灭菌 二．Dry Heat Sterilization / Depyrogenation干热灭菌\除热化 三．Aseptic Filling无菌灌装 四．Lyophilization冻干 五．Isolator Barrier Technology隔离屏障技术 六．Environmental Monitoring (Non-viable)环境的监控（非活粒子） 七．Environmental and Personnel Monitoring – Microbiology环境和员工监控-微生物 八．Biological Indicators生物标志。 Points to consider考虑要点 二，DRY HEAT STERILIZATION /DEPYROGENATION干热杀菌/去热原处理 •干热灭菌器主要用于注射药品玻璃容器的灭菌和去热原。烘箱和干热隧道都要使用。•烘箱是一个批处理过程，在循环结束时，手动将无菌小瓶从烤箱中取出，运输，然后手动装载到灌装线上。•干热隧道采用了一个连续的、综合的过程。在隧道中，小瓶在传送带上从清洗处理通过加热区，在加热区小瓶被灭菌和除热原，然后进入冷却区，然后直接进入灌装线的100级区域。•通常，公司会验证玻璃器皿的去热原作用，而不是灭菌循环。这是基于通常比微生物更难去除或变性的热原物质。经过去热原处理的组件保持无菌。 无菌制剂的短缺给我们带来什么机会？ 齐鲁制药登上了CNN头条 美国短缺药品趋势分析 2 无菌制剂短缺主要原因是什么？ 3 FDA引入QbI理念来核查无菌制剂生产 4 对无菌生产厂家警告信案例分析 为什么注射剂是FDA短缺药品的常客？ Injectable is a high risk product due to directly injectingto the blood stream Sterile injectable products are notoriously difficult toproduce, and the FDA has little tolerance for plant issues thatmight lead to contamination. FDA has found serious enough problems at Hospira，Mylan and Teva sterile injectables plants leading theyto suspend operations FDA drug shortage list updated weekly: almost 67% areinjectable 陈洪6/25/2009 Michael Jackson passed away by over dosed Propofol，•7/13-7/24/2009 FDA inspected飞行检查Teva located at19 Hughes, Irvine, California.•The inspection identified significant violations重大缺陷ofCGMP Regulations for Finished Pharmaceuticals•12/11/2009 warning letter issued•01/2010 started to shut down the production forremediation 483 Observation Letter FDA警告信1 1.Your firm's analysis of pooled samples from customer complaintvials of finished product (Lot#(b)(4)) revealed an endotoxinconcentration of (b)(4).Your firm failed to identify a root causeand failed to implement a corrective action.2.Your firm hasnot tested each lot of raw materialsused in themanufacture of Propofol Injectable Emulsion finished products todetermine the presence and levels of bacterial endotoxi