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IVF实验室及相关重要区域的空气质量控制

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  • 1. Sandro C. Esteves, MD, PhD Director, ANDROFERT Andrology & Human Reproduction Clinic Campinas, BRAZIL IVF实验室及相关重要区域的 空气质量控制 TQM Summit, CHINA 2014
  • 2. 目录 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 2 2014 March ANDROFERT 空气质量对IVF的重要性 监管机构: 要求 我们是如何实施AQC 我们的经验
  • 3. ANDROFERT 空气质量在IVF的重要性 动物/实验性研究证据 Study Population Method Outcome Little and Mirkes, 1990 In vitro cultured rat embryos Protein and DNA analysis High levels of acrolein associated with embryotoxicity Cohen et al, 1997 Analytical measurement procedure Air sampling and VOC determination in human IVF labs Higher levels of VOC in HEPA- filtered lab ambient air and incubators compared with outside ambient air Hall et al, 1998 Analytical measurement procedure and bioassay Air sampling and VOC determination in human IVF laboratories; acrolein bioassay using 2-cell mouse embryos Increased levels of VOC in ambient air. Reduction in aldehyde levels by air filtration using carbon-activated and permanganate. In vitro mouse embryo development, implantation and post-implantation outcome inversely correlated with acrolein levels Worrillow et al, 2002 Analytical measurement procedure Design of a high velocity air control system and laboratory with VOC air filtration IVF laboratory and procedure rooms qualified as class 100 areas. No VOCs found above >0.1 parts per billion
  • 4. ANDROFERT 空气质量在IVF的重要性 人类观察性研究证据 Study Population Method Outcome Mayer et al, 1999 RCT of infertile IVF couples Embryo culture in incubators with and without VOC filtration Higher PRs when embryos were cultured in incubators with VOC filters Racowsky et al, 1999 Infertile IVF couples, observational IVF and embryo culture in labs and incubators with and without VOC filtration Reduction in miscarriage in cycles performed in labs and incubators with carbon-activated filters Boone et al, 1999 Infertile IVF couples, observational Construction of cleanrooms for IVF activities Reduction in air particles associated with an increase in the number of high-quality embryos Worrillow et al, 2002 Infertile IVF couples, observational IVF in clean rooms with VOC filtration. Outside and inside ambient air monitored for 2 years Seasonal correlation between temperature/humidity of outside ambient air serving the IVF air system and VOC levels with impact on IR Knaggs et al, 2007 Infertile IVF couples, observational IVF lab redesigned to meet the EU directive Implantation and pregnancy rates increased after the move into the cleanroom
  • 5. 空气质量对IVF的重要性-人类实验的观察研究 CPR Miscarriage rate 36.9% 23.0% 47.1% 15.0% Severe Male Factor Infertility (N=399) Standard IVF lab P=0.01 P=0.03 Esteves et al. Fertil Steril 2004 Esteves et al. Fertil Steril 2006 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 5 2014 March ANDROFERT
  • 6. 空气质量对IVF的重要性 ANDROFERT ü 无空气过滤的IVF实验室存在高浓度VOC ü 空气过滤系统可有效地过滤颗粒物和VOC ü 鼠胚发育与VOC呈负相关 ü 安装空气过滤系统的IVF实验室可帮助临床获得更好的 结局( 妊娠率、种植率和流产率) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 6 2014 March ANDROFERT
  • 7. 监管机构的要求 ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 7 2014 March ANDROFERT
  • 8. Region (directive) European Union (EU directive 2004/23/EC; 2006/86/EC) Brazil (Anvisa RDC33/2006; RDC23/2011) Particle filtration Equivalent to GMP Grade A air quality in the critical areas with a background environment at least equivalent to Grade D (exceptions apply) At least equivalent to ISO class 5 (NBR/ ISO 14644–1) in the critical areas Microbial contaminatio n Microbial colony counts equivalent to those of Grade A as defined in the current GMP guide with a background environment at least equivalent to Grade D Microbiological monitoring required; specifications not defined Volatile organic compounds filtration Not required Ventilation systems should be equipped with filters imbedded with activated charcoal ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 8 2014 March ANDROFERT
  • 9. 当科学研究发现了可能的风险,即使还 没有达成科学共识; 我们也有社会责任来保护公众健康免受 暴露于有害物质的风险。 预防原则 *Convention on Biological Diversity, UN 1992; Ratified by 192 countries and the EU, except USA, Andorra and South Sudan ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 9 2014 March ANDROFERT
  • 10. 污染 任何可能会影响最终产品质量的不良的材 料或物质 1. 尘埃 清洁剂残留物、衣物纤维、皮屑(短 时悬浮粒子),1至100µm 2. 微生物 病毒,孢子,细菌,(长时悬浮粒子) , 1 至 8µm 污染物是由实验室人员,流程,家具和 设备所产生的 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 10 2014 March ANDROFERT
  • 11. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 11 2014 March ANDROFERT
  • 12. 污染物 3. 室内挥发性有机化合物VOC 任何可挥发的并与室内空气发生反应的化 合物 产生亚微颗粒和有害副产物(甲苯、苯、 醇类、酮类、醛类、制冷气体) 香烟烟雾、汽车尾气、清洁剂、润滑剂、 染料、家具、橡胶、塑料、树脂、合成 纤维、尼龙、碎料板、胶合板 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 12 2014 March ANDROFERT
  • 13. 生殖实验室VOC含量 Indoor air Personnel Material and Equipment Cell, tissue and fluids 5-fold increase in VOC Anderson et al. 1997 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 14 2014 March ANDROFERT
  • 14. 通常病人看到是…
  • 15. …AND NOT WHAT IS BEHIND THE DOORS!
  • 16. 我们是如何实施AQC ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 17 2014 March ANDROFERT
  • 17. 规划和构造 现场湿式作业 低VOC材料 表面和涂层 照明设备 平装和封闭式 弓形接合 不锈钢和铝材 (无VOC) 家具,门,窗,排气口,工 作站 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 18 2014 March ANDROFERT
  • 18. 空气处理通风系统 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 19 2014 March ANDROFERT
  • 19. 如何避免对配子和胚胎的污染 细菌和其他污染物能自行吸附 在尘埃颗粒上。所以减少尘埃 颗粒可以改善空气质量 粉尘(粗)过滤器: >10µ 细微粉尘过滤器: 1<10µ 高效空气净化器 : 0,3µ = 99,97% 加压流动空气并通过一系列过滤器以便更高效去 除空气中的微粒 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 20 2014 March ANDROFERT
  • 20. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 21 2014 March ANDROFERT Particle size/m3 of air: ISO 14.644-1   0.3 µM   0.5 µM   1 µM   5 µM   ISO 1   ISO 2   10   4   ISO 3   102   35   8   ISO 4   1,020   352   83   IVF  lab   ISO 5   10,200   3,520   832   29   ISO 6   102,000   35,200   8,320   293   OR   ISO 7   352,000   83,200   2,930   Transfer   ISO 8   3,520,000   832,000   29,300   ISO 9   35,200,000   8,320,000   293,000   洁净室分级
  • 21. VOCs是比HEPA过滤器的有效孔 径小100-1000倍的化合物 碳颗粒之间的云离域电子充当电子 胶水去除化学污染物 高锰酸钾可通过氧化降解 醇类和酮类化合物 如何避免对配子和胚胎的污染 使用正空气加压强制空气流动并通过一系列 的含有活性炭和高锰酸钾的过滤器去除VOCs ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 22 2014 March ANDROFERT
  • 22. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 23 2014 March ANDROFERT
  • 23. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 24 2014 March ANDROFERT
  • 24. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 25 2014 March ANDROFERT
  • 25. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 26 2014 March ANDROFERT
  • 26. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 27 2014 March ANDROFERT
  • 27. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 28 2014 March ANDROFERT
  • 28. 如何监测 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 29 2014 March ANDROFERT
  • 29. 监测指标 仪器 气体体积流量 温差式风速仪 气体交换率 温差式风速仪 大气-室内气压差 微风速仪、辐射热测定器 HEPA过滤器完整性 烟雾发生器 尘埃粒子计数 电子微粒计数仪 还原能力 烟雾发生器 光照水平 照度计 噪音水平 分贝计 温湿度 温度计、湿度计 Third-part certification company (CCL, Brazil); semi-annually IEST 006.2 standards ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 30 2014 March ANDROFERT
  • 30. ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 31 2014 March ANDROFERT
  • 31. VOCs检测 活性碳寿命估计 四氯化碳活性法 应用Tenax TA吸附剂和2,4二硝基苯 的活性取样 苏玛罐 热解析 气相色谱法 (Limits < 2 µg/m3) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 32 2014 March ANDROFERT
  • 32. 沉降培养皿 霉菌和血琼脂培养皿 表面采样 拭子和接触培养皿 手套印迹 培养箱,工作站,空气,地板,墙壁 菌落形成单位(CFU) 沉降培养皿 (直径90mm) CFU/4 小时 接触培养皿 (直径55mm) CFU/皿 手套印迹 CFU/手套 <3 <3 <3 微生物检测 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 33 2014 March ANDROFERT
  • 33. Esteves & Bento. RBM Online 2013 ü 经核准通过标准 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 34 2014 March ANDROFERT
  • 34. 我们的收获 ANDROFERT ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 35 2014 March ANDROFERT
  • 35. 空气质控 & IVF 结局 2,315个病人; 14,660 个胚胎 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% Before After  2002-­‐ 2004 After  2005-­‐ 2007 After  2008-­‐ 2010 TQE  D3  (%) Miscarriage  (%) LBR  fresh  (%) ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 36 2014 March ANDROFERT
  • 36. 平均每个病人可多获得一个胚胎 用于移植或冷冻 空气质控 & IVF 结局 2,315 patients; 14,660 embryos ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 37 2014 March ANDROFERT
  • 37. IVF累计妊娠率 Esteves, 38 ANDROFERT, Referral Center for Male Reproduction ET #3 (FET) 49 ET #2 (FET) 239 ET #1 (fresh) 822 50.5% +18.8% +25.0%Female  Age  ≤38   ANDROFERT 332/822 63/239 17/49
  • 38. 结论 (1) 动物和人类研究显示空气质量(颗粒物和VOC)与胚胎 体外发育有关 监管机构已出台IVF实验室与空气质量有关的具体指南和 要求 我们建立了IVF洁净室技术(胚胎学和男科学实验室, 手术室,胚胎移植室)并显示了它的可行性 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 39 2014 March ANDROFERT
  • 39. 结论 (2) 7年间,我们的ART技术在洁净室环境下进展良好 洁净室技术的费用: 仪器: 150,000美元 运作: 15,000美元/年 过滤器,洁净室器具/材料/保养,认证 每个病人增加的费用: 130美元/周期 ANDROFERT androfert.com.br ANDROLOGY AND HUMAN REPRODUCTION CLINIC - REFERRAL CENTER FOR MALE REPRODUCTION SC ESTEVES, 40 2014 March ANDROFERT
  • 40. ThankYou obrigado

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