ANNEX 3 Manufacture of RadioPharmaceuticals WZH 20060905
分析三联、四联药物方案治疗胃溃疡的临床效果
系统医学 2023 年 12 月第 8 卷第 24期分析三联、四联药物方案治疗胃溃疡的临床效果王昌盛1，陈兰2，廖小红21.广东药科大学附属第一医院药学部，广东广州510062；2.广东三九脑科医院药剂科，广东广州510510[摘要]目的探讨胃溃疡患者选择四联药物治疗后的临床效果。
方法选取2022年1月—2023年8月广东药科大学附属第一医院收治的76例胃溃疡患者为研究对象，依据投掷硬币法分组，参照组（38例）选择三联药物治疗，研究组（38例）选择四联药物治疗，比较两组治疗总有效率、胃灼痛评分、胃溃疡面积、上腹疼痛评分、临床症状改善时间。
结果研究组治疗总有效率为97.37%，明显高于参照组，差异有统计学意义（χ2= 6.176，P<0.05）。
治疗后，研究组胃灼痛评分、胃溃疡面积、上腹疼痛评分、临床症状改善时间均低于参照组，差异有统计学意义（P均<0.05）。
结论同三联药物比较，胃溃疡患者接受四联药物治疗，可显著提升临床效果，有效改善疾病症状，可促进胃溃疡患者的良好预后。
[关键词]胃溃疡；三联药物；四联药物；疗效[中图分类号]R573 [文献标识码]A [文章编号]2096-1782（2023）12(b)-0175-03 Clinical Effect of Triple and Quadruple Drug Regimens in the Treatment of Gastric UlcerWANG Changsheng1, CHEN Lan2, LIAO Xiaohong21.Department of Pharmacy, the First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, Guang⁃dong Province, 510062 China;2.Department of Pharmacy, Guangdong Sanjiu Brain Hospital, Guangzhou, Guangdong Province, 510510 China[Abstract] Objective To investigate the clinical effect of quadruple drug therapy in patients with gastric ulcer. Methods Seventy-six patients with gastric ulcer admitted to the First Affiliated Hospital of Guangdong Pharmaceuti⁃cal University from January 2022 to August 2023 were selected as the research object and divided into groups ac⁃cording to coin tossing method. The reference group (38 cases) received triple drug therapy, and the study group (38 cases) received quadruple drug therapy. The total effective rate, the score of heartburn pain, the area of gastric ulcer, the score of upper abdominal pain and the improvement time of clinical symptoms were compared between the two groups. Results The total effective rate of the study group was 97.37%, which was significantly higher than that of the reference group, and the difference was statistically significant (χ2=6.176, P<0.05). After treatment, the score of heartburn pain, the area of gastric ulcer, the score of upper abdominal pain and the improvement time of clinical symptoms in the study group were lower than those in the reference group, and the differences were statistically sig⁃nificant (all P<0.05). Conclusion Compared with triple drug, quadruple drug treatment for gastric ulcer patients can significantly improve the clinical effect, effectively improve the disease symptoms, and promote the good prognosis of patients with gastric ulcer.[Key words] Gastric ulcer; Triple drug; Quadruple drugs; Curative effect对于胃溃疡疾病而言，其属于一种胃肠道高发病[1-2]。
紫外光谱法监测阿司匹林合成体系中的阿司匹林和水杨酸
第28卷,第4期光 谱 实 验 室Vol.28,No.4 2011年7月Chinese J ournal of Sp ectroscop y L abor atory July,2011紫外光谱法监测阿司匹林合成体系中的阿司匹林和水杨酸张小玲 粟晖 姚志湘 兰月来(广西工学院生物与化学工程系 广西柳州市城中区东环大道268号 545006)摘 要 建立一种同时快速定量分析阿司匹林合成体系中阿司匹林和水杨酸的方法。
通过均匀设计构造样本并采集其紫外光谱,结合偏最小二乘法(P LS)建立同时测定混合体系中阿司匹林和水杨酸的校正模型,阿司匹林和水杨酸模型的校正均方根误差分别为1.708 g/mL和0.435 g/m L。
该模型用于预测氨基磺酸催化合成过程中阿司匹林和水杨酸含量,二组分回收率在93.48%—108.37%之间,相对标准偏差(R SD)分别为3.45%和4.80%。
结果表明,紫外光谱法结合P LS模型实现氨基磺酸催化合成阿司匹林过程的实时监测是可行的。
关键词 阿司匹林;水杨酸;紫外光谱法;偏最小二乘法中图分类号:O657.32 文献标识码:A 文章编号:1004-8138(2011)04-1911-051 引言阿司匹林,即乙酰水杨酸,是一种常用的解热镇痛和抗风湿类药。
阿司匹林由水杨酸和乙酸酐或乙酰氯催化反应制得。
氨基磺酸催化合成阿司匹林经济环保、产品收率高、反应时间短[1],但依靠某一固定时刻来判断反应终点,存在一定的误差。
目前,需要一种可实现实时或接近实时的方法保证合成阿司匹林的质量。
乙酰水杨酸易水解成水杨酸,2005版《中国药典》[2]以中性乙醇为溶剂、酚酞为指示剂,用NaOH滴定其含量,步骤繁琐,误差较大。
高效液相法[3]测量结果精确度高,但分析时间较长。
王桂梅[4]提出近红外光谱法实时监控阿司匹林的合成过程,设备费用高。
拉曼光谱法可实现阿司匹林过程的监测,但背景干扰大,易受光学系统参数影响[5]。
WHO_TRS_996_annex09翻译
Annex9组织机构进行体内生物等效性研究指南背景2014年的一场非正式讨论会上，在世界卫生组织（WHO）药学准备工作规范专家委员会的第49次会议，讨论产生关于可能修正组织机构进行体内生物等效性研究指南（WHO技术报告系列，No. 937, Annex9, 2006）。
WHO药学准备工作规范专家委员会同意，鉴于新的事态发展，将会准备一条修正法案。
新的指南不仅考虑多来源指南的修订，并会考虑创造良好数据管理下的新的指南。
法案也会考虑自从2006年评价和稽查BE试验领域的经验。
在稽查者们重复发现相同问题的领域，新的指南将会提供阐述，增补的细节也已加入生物分析。
指南也会更加注重项目安全性和数据完整性。
在第一版工作文件的基础上，第二版结合了很多的意见和反馈，有来自于公众、WHO资格预审团队(PQT)的意见，也有来自于2015年举行的关于数据管理、生物等效性、GMP、药品稽查的讨论会。
WHO/PQT建立于2001年，是为了保障采购的药用产品满足WHO关于质量、安全性、有效性的规范和标准(http://www.who.int/prequal/)。
特别的是，要求报送的产品档案所有必要的内容经评估都是可接受的，成品药（FPP）以及API的生产地点满足WHO的GMP要求。
由于报送WHO/PQT的产品通常是多来源的（仿制的），一般通过在比如合同研究组织CRO（也叫做临床研究机构）进行的BE试验来证明治疗等价性。
对于资格预审的产品至关重要的是，除了上述的要求，申办方BE试验使用的CRO公司要满足WHO的药物临床试验质量管理规范GCP，考虑优良实验室规范GLP和质量控制（QC）305实验室管理规范来保证数据的完整性和可追溯性。
除此之外，如果存在当地的法律法规，CRO应该得到各自国家药品局的认可。
如果国家规定需要，BE试验应该获得国家监督管理局的授权。
因此报送资格预审的产品涉及到BE试验中执行和分析的，需要保证满足WHO相关的规范和标准，以便为WHO的稽查做准备。
氨基酸分析仪测定复方甘草酸苷注射液中甘氨酸的含量
相应的位置上，显相同黄色斑点”为宜。
此外，现行质量标准中，金银花和金果榄的薄层鉴别均采用三氯甲烷作为提取溶剂,而射干的展开剂也使用到了三氯甲烷,从降低试剂毒性出发，考虑将三氯甲烷更换为二氯甲烷,对薄层鉴别方法进行改进,实验结果表明可以进行替代。
TLC主要用于中药材、中药成方制剂中有效成分的快速分离与定性分析4〕。
虽然随着检验技术的发展，许多检测方法在定量和定性方面比TLC更具优势，但正是因为技术的日新月异，作为检验工作者，更应该熟知每门技术的优缺点，通过人整合技术，物尽其用4S〕。
本研究通过对小儿咽扁颗粒TLC的分析和优化，充分展现了TLC在定性鉴别中的优势，它不仅设备简单、分离速度快，而且可以同时分离多种样品且色谱图色彩鲜艳，结果直观，便于鉴别。
参考文献〔2国国家药典委员会编・中国药典(224版一部))S〕.北京：中国医药科技出版社952：541944〔2〕刘朋朋・桔梗质量标准研究〔D〕.北京：中国中医药科学院中药研究所,2027.4〕向金莲，王伟，任飞宇•薄层色谱技术在中药检验中的应用4〕.中国医药指南,224,2(4)：237W38〔4〕邓哲,荆文光，刘安.薄层色谱在当前中药质量标准中的应用探讨4〕.中国实验方剂学杂志922,25(7)：291A06.4〕王秀芹，林彤，江英桥.薄层色谱法标准化操作要点及实例分析〔〕•中成药92492(7):255-259.氨基酸分析仪测定复方甘草酸苷注射液中甘氨酸的含量张黎莉（福州市食品药品检验所，福建福州350007）摘要：目的探究和建立用氨基酸分析仪测定复方甘草酸苷注射液中甘氨酸的含量的方法，完善复方甘草酸苷注射液中甘氨酸含量的监测体系。
方法本实验采用氨基酸分析仪法，色谱柱:PEEK材料安玛西亚色谱填料填装色谱柱;检测波长：577am；显色剂：茚三酮缓冲液;进样量: 12jxL；流速：55mL/6；流动相:缓冲液系统。
甘氨酸经离子交换色谱和茚三酮柱后衍生化，根据外标法进行测定。
不对称催化亲电氟化反应研究进展
不对称催化亲电氟化反应研究进展汪忠华;巫辅龙;吴范宏【摘要】在有机氟化学领域中,α-氟代羰基化合物具有特异的生物活性,在有机合成中也可以作为合成砌块,其合成方法学的研究是目前研究的热点和难点之一.不对称亲电氟代反应是直接构建α-氟代羰基骨架的有效方法,主要用到的催化剂包括钌、铜、钪为催化中心的金属催化剂和奎宁、手性有机磷酸为主的有机小分子催化剂.介绍了最近催化对映体选择性亲电氟化反应领域研究情况.【期刊名称】《上海应用技术学院学报（自然科学版）》【年(卷),期】2015(015)001【总页数】10页(P9-18)【关键词】不对称催化;对映体选择性亲电氟化反应;金属催化剂;有机催化剂【作者】汪忠华;巫辅龙;吴范宏【作者单位】上海应用技术学院化学与环境工程学院,上海 201418;上海应用技术学院化学与环境工程学院,上海 201418;上海应用技术学院化学与环境工程学院,上海 201418【正文语种】中文【中图分类】O622氟元素是地球上第十三大丰富的元素，但自然界中的含氟天然产物却很少，这可能是由于氟原子的强电负性和低的亲核性导致的.氟原子的引入，能诱导化合物的物理化学和生物特性，如生物活性、新陈代谢的稳定和药动力学的特性发生显著改变.氟原子的大小介于氢原子和氧原子之间［1］，C—F键长也相似地介于C—H和C—O键之间，但C—F键能在三者中最强.因此，当分子中氢原子被氟原子取代后，其空间大小并不会有显著变化，但分子的电子云分布、偶极矩、脂溶性、稳定性等都有明显改变.分子中引入氟的方法很多，不对称催化亲电氟化反应是其中之一，它是制备手性α-氟代羰基化合物的一种有效途径，α-氟代羰基结构常常在药物分子中出现.氟红霉素（Flurithromycin）是法玛西亚公司（Pharmacia）开发的一种新型大环内酯类呼吸道感染的主要致病菌肺炎链球菌抗生素［2］.氟林卡那（Flindokalner，MaxiPost）是百时美施贵宝公司（Bristol Myers Squibb）开发的一种大钾离子通道开放剂［3］.氟红霉素和氟林卡那的结构式见图1.不对称催化亲电氟化反应主要通过手性催化剂作用，亲电氟代试剂作用于底物羰基的邻位并引入氟原子而完成.2000年，Hintermann等［4-5］报道了第一个对映选择性催化氟化反应，使用氟化试剂Selectfluor和催化量为5 mol%的手性四价钛配合物，对不同取代基的β-酮酸酯进行了对映选择性氟化反应研究，对映体选择性最好的为82%.2005年，Enders等［6］报道了第一例以（S）-脯氨酸衍生物为手性有机催化剂，Selectfluor为氟化试剂诱导的对映选择性氟化反应，研究了醛、酮的不对称氟化反应，但对映体过量率并不理想，只有34%，之后发现，氟化试剂的选择性对反应非常重要，同时必须抑制氟化产物的烯醇化.同样，2005年，Beeson等［7］研究发现了一种普遍能够对醛类衍生物氟代后得到很高的对映体选择性（ee值）的有机催化剂咪唑烷酮化合物.在23°C反应中N-氟代双苯磺酰胺（NFSI）为氟化试剂，催化量为2.5 mol%的咪唑烷酮化合物为有机催化剂，氟代后也能得到很高的ee值，可达到98%.随后，Mauro等［8］以NFSI为氟化试剂，采用不同手性催化剂对直链脂肪醛的不对称氟化反应进行了系统研究，筛选出高效催化剂咪唑烷酮化合物并应用于含有不同取代基的脂肪醛的氟化，得到较高对映选择性的α-氟代醛衍生物（86%～96%ee）.Steiner等［9］同样也在2005年报道了对于不是很稳定的咪唑烷酮化合物催化生成苯乙醛，也能够以高收率和高对映体选择率得到相应的氟化产物，进而将醛基还原，可制备更稳定的、高光学纯度的2-氟代醇衍生物.在不对称亲电氟代反应中，常用的亲电氟代试剂有Selectfluor、氟代吡啶、NFSI 等［10-18］，具体结构如图2所示.所用催化剂主要包括钌、铜、钪为催化中心的金属催化剂和奎宁、手性磷酸为主的有机小分子催化剂.本文报道自2009年以来，金属催化剂、有机金属催化剂和有机小分子催化剂对α-羰基化合物不对称亲电氟代反应的研究进展.1.1 钌为催化中心在有关文献报道中，有效的氟代试剂大多只有3种，分别为Selectfluor，N-fluoropyridinium和N-fluorobenzenesulfonimide（NFSI）.2009年，Martin 等［19］报道了以Ag HF2为氟代试剂，钌为催化剂的2-烷基苯基乙醛不对称氧化α-氟化反应如图3所示.反应过程中氟化试剂Ag HF22.4倍物质的量，催化剂［RuCl2（PNNP）］SbF6量为5 mol%，1，2-二氯乙烷为溶剂，反应温度为60°C，反应时间为24 h，对不同α-位上的苯基乙醛进行了研究，不同苯乙醛衍生物经过氟代反应后最高的收率可达35%，ee值为27%，见表1.R的取代基位阻变大后，相应的产率和ee值也会变小，表明产物的反应受位阻的影响.虽然在反应过程中产率和ee值都比较低，但新氟化试剂的研究为今后研究和发展提供了更广阔的空间.1.2 铜为催化中心2009年，Assalit等［20］报道了以Cu（OTf）2与胺手性配体形成的复合物为催化剂，酮酯化合物在二氯甲烷中经NFSI作用的不对称亲电氟代反应（见图4），得到相对应产物6a、6b和6c的ee值和较好的收率，不同配体4和5b对应的产物产率和ee值分别为75%（9%ee）和78%（17%ee）、77%（27%ee）和60%（32%ee）、54%（18%ee）和55%（27%ee）.手性配体5b和化合物4相比，不同反应底物6a、6b和6c对应产物的收率影响不大，但手性配体5b得到对应产物的ee值明显高于化合物4，这很可能取决于配体的空间位阻，如表2、图5所示.除此之外，研究还发现，当以化合物5a为配体，化合物6b为反应底物时，氟化试剂NFSI与Selectfluor和N，N-difluoro-2，2’-bipyridinium bis-（tetrafluoroborate）相比，具有反应时间短和收率高的优势（分别对应的收率和时间为64%迅速反应，63%反应3 d和13 d后仍无反应），如表2所示.对不同金属催化剂的考察发现，二价铜的催化效果优于其他金属催化试剂（收率为77%，27%ee），如表3所示.1.3 钪为催化剂的氟化反应2012年，Li等［21］以一步法直接在吲哚酮五元环的N原子相对的C3位置上引入氟原子，完成氟代亲电反应，如图6所示.在反应过程中，Li等以NFSI（1.2 mol）作为氟化试剂，5 mol%～10 mol%的9-Sc（OTf）3（见图6）为催化剂，120 mol%Na2CO3为碱，CHCl3为溶剂，得到的收率最高达98%和99%ee.还研究了以化合物9为配体（见图7）的不同金属（如：Ni（ClO4）2· 6H2O、Mg（OTf）2、（OTf）3和La（OTf）3）催化剂对反应收率和ee的影响，结果表明，反应收率和ee普遍偏低.在5种金属催化剂中钪的催化效果最好，9f为配体时ee值最高可以到达88%（见图8和表4）.这也同样体现出了不同金属配体化合物的几何构型的差异对对映体选择性的影响［22］.当改变配体取代基的空间位阻后，发现小位阻的配体反而得到的ee有所下降（取代基位阻大小：9b＞9c＞9d＞9e，对应的ee值分别为87%、75%、50%和13%，见表4）.化合物12为Bristol Meyer Squibb为治疗中风研发的氟化羟吲哚［23］，其合成须经过3步反应.但在Li的报道中提出了一种一步合成化合物12（Maxipost）的方法，还对化合物12的合成进行了条件优化，以81%的收率和96%的ee值得到化合物12，如图9所示.2.1 奎宁生物碱为催化剂奎宁生物碱是一种作为不对称亲电氟代反应的主要催化剂，这主要是由于奎宁生物碱具有高效的催化效果.但在反应过程中，奎宁生物碱必须先和氟化试剂结合，才能和氟代底物发生反应得到较好的对映体选择性［24］，如图10和表5所示.通过X-ray对DHQB的结构分析如图11所示，研究者认为晶体结构表现出来的DHQB其中的一部分（右下方）和另一部分（左上方）相比空间位阻比较大，故左上方部分能够容易地诱导来自氟试剂的一个氟原子.这样空间结构就像口袋一样，处在DHQB之间，能够形成对对映体选择性氟化转变的有利手性环境.金鸡纳碱DHQB和Selectfluor组合的氟代反应机理大致如图12所示.在过去大部分以奎宁生物碱为催化剂的亲电氟化反应中，使用的氟化试剂普遍为Selectfluor、N-fluoropyridinium和NFSI.2011年，Yasui等［25］报道了一种新的氟化试剂N-Fluoro-（3，5-di-tertbutyl-4-methoxy）benzenesulfonimide（NFBSI），如图13所示.NFBSI与NFSI相比位阻大大增加，但是当NFSBSI和NFSI在相同的反应条件下反应时，能够提高对映体的选择性，增加幅度可高达18%，比如：1.2倍物质的量的氟化试剂NFSI和NFBSI分别与硅醚衍生物15a和15b在10 mol%的奎宁生物碱催化剂，6.0倍物质的量的K2CO3，乙腈为溶剂，反应温度为0°C到室温，反应时间为2 d的情况下明显可见，NFBSF为氟化试剂对应的对映体的选择性明显高于NFSI，分别为70%ee和52%ee（16a），58% ee和40%ee（16b），高于18%（见图14），主要是由于NFBSI的空间位阻的增大，大大增加了其对对映体的选择性.2.2 手性磷酸为催化剂Hamashima等［26-29］以手性有机磷化合物为催化剂，开发了由羟基架桥的手性复核Pd（μ-OH）配合物17a（见图15），从而实现手性金属磷催化剂与氟化试剂发生氟化反应.Phipps等［30］在2013年报道了纯粹的以（S-3，3’-双-2，4，4-三环己基-苯基）-［1，1’］-联萘-3，3’-二氧磷酸（（S）-TCYP）为催化剂（见图16）也能够实现不对称亲电氟化反应（见图17），并且对映体选择性非常高，为今后的研究工作提供更好的研究思路和方法，尽可能摆脱有机金属配体对氟化反应的依赖.在反应过程中加入碳酸钠可以加快反应速率，得到较高的对映体选择性.氟化试剂与碳酸钠反应能够形成具有活性的Selectfluor碳酸盐，该盐离子有可能诱导氟原子转移.之后，Wu等［31］也在2013年报道了以（S-3，3’-双-2，4，4-三异丙基-苯基）-［1，1’］-联萘-3，3’-二氧磷酸（（S）-TRIP）和（R）-6，6’-二（2，4，6-三异丙基苯）-1，1’-螺二茚-7，7’-二氧磷酸（（R）-STRIP）为催化剂（见图18）的不对称氟化反应.报道中，以烯烃化合物20a和20b为底物（见图18和表6），Selectfluor（1.35 equiv.）为氟化试剂，Na2CO3（1.45 equiv.）为碱，催化剂为TRIP（10%mol），反应温度为10°C，经过18 h反应后，也可以得到很好的ee值，最高可达90%ee（见表6）.由表6可见，不同溶剂和不同催化试剂对相同反应底物经过不对称氟化反应后得到的对映体也不尽相同.为此，通过以（R）-STRIP为催化剂改变酰胺衍生物氟代反应底物的结构作为研究，在甲苯为溶剂，Selectfluor（1.35 equiv.）为氟代试剂，Na2CO3（1.45 equiv.）为碱，室温反应18 h后，也可得到较好的对映体选择性的产物24，如图19和表7所示.当改变R取代基时，对映体的选择性也会发生明显变化.当烷甲基数目增大，从1个甲基变成3个（序号1～3）时，空间位阻明显增大，相应地，对映体选择性也从30%ee优化到75%ee.其原因主要是空间位阻增大，当位阻增大时，空间位阻的效应明显大于电子效应（t-Bu＞i-Pr＞Me）.当R取代基为二氟甲基时，对映体选择性为30%ee（序号5），这与甲基取代时一样，主要原因可能是氟原子构型和其空间旋转的共同作用，从而减小空间位阻.由表6（序号5、6）可知，氟原子的增加，对映体选择性就会明显增加（氟原子的取代数目由2个变成3个对应的对映体选择性分别为30%ee和82%ee）.通过对比可以看到R为3个Cl取代基团的对映体选择性（93%ee）明显高于3个F原子的取代对映体选择性（82%ee），故空间位阻的影响明显大于吸电子效应（见表7，序号6、7）.从某种意义上，新的有机小分子作为不对称亲电氟化反应的催化剂的发现为今后研究提供了更加宽广的思路，摆脱金属有机配体作为催化剂的思维.对映体选择性氟化反应仍然是研究的热门领域，这必将引起对不对称催化亲电氟代反应的关注和研究，从而不断促进氟化反应的发展和创新.特别是现今医药行业对含氟药物日益扩大需求，因此，合成具有生物活性新的氟代产物和研究其药用价值将具有更加重大的意义.【相关文献】［1］ Hagan D O.Understanding organofluorine chemistry. An introduction to the C—F bond［J］.Chem Soc Rev，2008，37（2）：308-319.［2］ Grassi G G，Alesina R，Bersani C，et al.In vitro activity of flurithromycin，a novel macrolide antibiotic［J］.Chemioterapia，1986，5（3）：177-184.［3］ Young B L，Cooks R G，Madden M C，et al.Chiral purity assay for Flindokalner using tandem mass spectrometry：Method development，validation，and benchmarking ［J］.J Pharmaceut Biomed Ana，2007，43（5）：1602-1608.［4］ Hintermann L，Togni A.Catalytic enantioselective fluorination ofβ-ketoesters ［J］.Angew Chem Int Ed，2000，39（23）：4359-4362.［5］ Hintermann L，Perseghini M，Togni A，et al.Titanium-catalyze stereoselective geminal heterodihalogenation ofβ-ketoesters［J］.Org Lett，2003，5（10）：1709-1712. ［6］ Enders D，Hüttl M R M.Direct organocatalytic alpha-fluorination of aldehydes and ketones［J］.Synlett，2005，6：991-993.［7］ Beeson T D，Mac Millan D W C.Enantioselective organocatalyticα-fluorination of aldehydes［J］.J Am Chem Soc，2005，127（24）：8826-8828.［8］ Mauro Marigo，Doris Fielenbach，Ala Braunton，et al.Enantioselective formationof stereogenic carbonfluorine centers by a simple catalytic method［J］.Angew Chem Int Ed，2005，44：3703-3706.［9］ Steiner D D，Mase N，Barbas C F.Direct asymmetric α-fluorination of aldehydes ［J］.Angew Chem Int Ed，2005，44：3706-3710.［10］Pihko P M.Enantioselectiveα-fluorination of carbonyl compounds：Organocatalysis or metal catalysis［J］. Angew Chem Int Ed，2006，45（4）：544-547. ［11］ Hamashima Y，Sodeoka M.Enantioselective fluorination reactions catalyzed by chiral palladium complexes［J］.Synlett，2006，10：1467-1478.［12］ Prakash G K S，Beier P.Construction of asymmetric fluorinated carbon centers ［J］.Angew Chem Int Ed，2006，45（14）：2172-2174.［13］ Bobbio C，Gouverneur V.Catalytic asymmetric fluorinations［J］.Org Biomol Chem，2006，4（11）：2065-2075.［14］ Shibata N，Ishimaru T，Nakamura S，et al.New approaches to enantioselective fluorination：Cinchona alkaloids combinations and chiral ligands？／metal complexes ［J］.Fluorine Chem，2007，128（5）：469-483.［15］ Brunet V A，O’Hagan D.Catalytic asymmetric fluorination comes of age［J］.Angew Chem Int Ed，2008，47（7）：1179-1182.［16］ Ma J A，Cahard D.Update 1 of：Asymmetric fluorination，trifluoromethylation，and perfluoroalkylation reactions［J］.Chem Rev，2008，108（9）：1-43.［17］ Furuya T，Kuttruff C A，Ritter T，et al.Carbon-fluorine bond formation［J］.Drug Discov Devel，2008，11（6）：803-819.［18］ Ueda M，Kano T，Maruoka anocatalyzed direct asymmetricα-halogenationof carbonyl compounds［J］.Org Biomol Chem，2009，7（10）：2005-2012.［19］ Martin A，Antonio T，Antonio M.Asymmetric oxidativeα-fluorination of 2-alkylphenylacetaldehydes with Ag HF2and ruthenium／PNNP catalysts［J］.Science Direct，Journal of Fluorine Chemistry，2009，130（8）：702-707.［20］ Assalit A，Billard T，Chambert S，et al.2，2’-Bipyridine-3，3’-dicarboxylic carbohydrate esters and amides.Synthesis and preliminary evaluation as ligands in Cu（II）-catalysed enantioselective electrophilic fluorination［J］.Tetrahedron：Asymmetry，2009，20（5）：593-601.［21］ Li Jun，Cai Yunfei，Chen Weiliang，et al.Highly enantioselective fluorination of unprotected 3-substituted oxindoles：One-step synthesis of BMS 204352（MaxiPost）［J］.J Org Chem，2012，77（20）：9148-9155.［22］姜永莉，刘兆鹏.对映选择性亲电氟化反应研究进展［J］.有机化学，2009，29（9）：1362-1370.［23］ Hewawasam P，Gribkoff V K，Pendri Y，et al.The synthesis and characterization of BMS-204352（Maxi-Post）and related 3-fluorooxindoles as openers of maxi-K potassium channels［J］.Bioorg Med Chem Lett，2002，12（7）：1023-1026.［24］ Shibata N，Suzuki E，Asahi T，et al.Enantioselective fluorination mediated by cinchona alkaloid derivatives／Selectfluor combinations：Reaction scope and structural information for N-fluorocinchona alkaloids［J］.J Am Chem Soc，2001，123（29）：7001-7009.［25］ Yasui H，Yamamoto T，Ishimaru T，et al.N-Fluoro-（3，5-di-tert-butyl-4-methoxy）benzenesulfonimide（NFBSI）：A sterically demanding electrophilic fluorinating reagent for enantioselective fluorination［J］. Journal of Fluorine Chemistry，2011，132（3）：222-225.［26］ Hamashima Y，Yagi K，Takano H，et al.An efficient enantioselective fluorination of variousβ-ketoesters catalyzed by chiral palladium complexes［J］.J Am Chem Soc，2002，124（49）：14530-14531.［27］ Hamashima Y，Suzuki T，Takano H，et al.Catalytic enantioselective fluorination of oxindoles［J］.J Am Chem Soc，2005，127（29）：10164-10165.［28］ Hamashima Y，Suzuki T，Shimura Y，et al.An efficient catalytic enantioselective fluorination ofβ-ketophosphonates using chiral palladium complexes［J］. Tetrahedron Lett，2005，9（46）：1447-1450.［29］ Suzuki T，Goto T，Hamashima Y，et al.Enantioselective fluorination of tert-butoxycarbonyl lactones and lactams catalyzed by chiral Pd（II）-bisphosphine complexes［J］.J Org Chem，2007，72（1）：246-250.［30］ Phipps R J，Toste F D.Chiral anion phase-transfer catalysis applied to the direct enantioselective fluorinative dearomatization of phenols［J］.J Am Chem Soc，2013，135（4）：1268-1271.［31］ Wu J，Wang Yiming，Drljevic A，et al.A combination of directing groups and chiral anion phase-transfer catalysis for enantioselective fluorination of alkenes［J］.Proc Natl Acad Sci，2013，110（34）：13729-13733.。
欧盟化妆品26种过敏香料目录
ANNEX 3 INCI NAMES FOR 26 SUBSTANCES ADDED TO ANNEX III OF THE COSMETICS DIRECTIVE Annex III reference67 68 69 70 71 72 73 74 75 76 77 78 79Directive DescriptionAmyl Cinnamal Benzyl Alcohol Cinnamyl Alcohol Citral Eugenol Hydroxy-citronellal Isoeugenol Amylcin-namyl Alcohol Benzyl Salicylate Cinnamal Coumarin Geraniol Hydroxymethylpentylcyclohexenecar boxaldehyde Anisyl Alcohol Benzyl Cinnamate Farnesol 2-(4-tert-butylbenzyl) Propionaldehyde Linalool Benzyl Benzoate Citronellol Hexyl cinnam-aldehyde d-Limonene1, 2INCI NameAmyl Cinnamal Benzyl Alcohol1 1CAS N°122-40-7 100-51-6 104-54-1 5392-40-5 97-53-0 107-75-5 97-54-1 101-85-9 118-58-1 104-55-2 91-64-5 106-24-1 31906-04-4EINECS N°204-541-5 202-859-9 203-212-3 226-394-6 202-589-1 203-518-7 202-590-7 202-982-8 204-262-9 203-213-9 202-086-7 203-377-1 250-863-4Cinnamyl Alcohol1 Citral Eugenol1 Hydroxycitronellal Isoeugenol1 Amylcinnamyl Alcohol Benzyl Salicylate1 Cinnamal1 1Coumarin1 GeraniolHydroxyisohexyl 3-Cyclohexene Carboxaldehyde Anise Alcohol1 Benzyl Cinnamate Farnesol1 180 81 82 83 84 85 86 87 88 89 90105-13-5 103-41-3 4602-84-0 80-54-6 78-70-61203-273-6 203-109-3 225-004-1 201-289-8 201-134-4 204-402-9 203-375-0 202-983-3 227-813-5 203-836-6 204-846-3Butylphenyl Methylpropional Linalool1 Benzyl Benzoate Citronellol1120-51-4 106-22-9 101-86-0 5989-27-5 111-12-65Hexyl Cinnamal Limonene1, 2Methyl heptin carbonate 3-Methyl-4-(2,6,6-tri-methyl2-cyclohexen-1-yl)-3-buten2-one Oak Moss extract Treemoss extract Notes 1. 2.Methyl 2-Octynoate Alpha-Isomethyl Ionone127-51-591 92Evernia Prunastri 4 Evernia Furfuracea 490028-68-5 90028-67-4289-861-3 289-860-8These ingredients are also found in some natural essential oils and extracts. DL-Limonene is a mixture of the D and L isomers. If used in the cosmetic product, strictly speaking the relative proportions of the isomers would have to be worked out to determine whether the concentration requires d-Limonene to be labelled under its new INCI name 24‘Limonene’. In practice, because of the technical difficulty of the analysis, the total level of both isomers will be used to establish whether the threshold is exceeded and labelling is required. 3. The Directive specifies the restrictions for each ingredient as: The presence of the substance must be indicated in the list of ingredients referred to in Article 6(1)(g) when its concentration exceeds: - 0.001 % in leave-on products - 0.01 % in rinse-off products This applies if these ingredients are present in the product for any reason – not just as constituents of fragrances. 4. Evernia Prunastri: as listed in 1996 inventory, we expect this to change to Evernia Prunastri extract in a future update. Evernia Furfuracea: for consistency we have used the format that would have appeared in the 1996 inventory. We expect this to change to Evernia Furfuracea extract in a future update. Alpha-Isomethyl Ionone is the name which appears in the current CTFA On-line listing of the INCI name for 3-Methyl-4-(2,6,6-tri-methyl-2-cyclohexen-1-yl)-3-buten-2-one. Previous hard copy listings omitted ‘iso’ from the name.5.25。
Annex3-TRS992- non
75Annex 3Guidelines on good manufacturing practices: validation, Appendix 7: non‑sterile process validation 1BackgroundThe appendices of the Supplementary guidelines on good manufacturing practices: validation currently comprise the following:Appendix 1. Validation of heating, ventilation and air‑conditioning systems Appendix 2. Validation of water systems for pharmaceutical useAppendix 3. Cleaning validationAppendix 4. Analytical method validationAppendix 5. Validation of computerized systemsAppendix 6. Qualification of systems and equipmentAppendix 7. Non‑sterile process validation – revised text reproduced inthis Annex 1. Background and scope 762. Glossary 763. Introduction 784. Process design 805. Process qualification 816. Continued process verification 837. Change management 84References 851 Supplementary guidelines on good manufacturing practices: validation. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 4 (WHO Technical Report Series, No. 937).76W H O T e c h n i c a l R e p o r t S e r i e s N o . 992, 2015WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth report1. Background and scopeFurther to the Supplementary guidelines on good manufacturing practices: validation , as published in the World Health Organization (WHO) Technical Report Series, No. 937 (1), additional guidelines to support current approaches to good manufacturing practices (GMP) are published here. These guidelines are intended to further support the concept of process validation linked to quality risk management (QRM) and quality by design principles as described by WHO and the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). These guidelines allow for different approaches to process validation. The principles described are mainly applicable to non‑sterile finished pharmaceutical dosage forms. Similar approaches may be applicable to active pharmaceutical ingredients (APIs) and sterile products. (See also recommendations in WHO Technical Report Series, No. 957, Annex 2 (2) and WHO Technical Report Series, No. 961, Annex 6 (3).)A risk‑based and life‑cycle approach to validation is recommended.Thorough knowledge of product and process development studies; previous manufacturing experience; and QRM principles are essential in all approaches to process validation, as the focus is now on the life‑cycle approach. The life‑cycle approach links product and process development, validation of the commercial manufacturing process and maintaining the process in a state of control during routine commercial production.The use of process analytical technology (PAT), which may include in‑line, online and/or at‑line controls and monitoring, is recommended to ensure that a process is in a state of control during manufacture.2. Glossary The definitions given below apply to the terms used in these guidelines. They may have different meanings in other contexts.at-line. Measurement where the sample is removed, isolated from, and analysed in close proximity to the process stream.concurrent validation. Validation carried out during routine production of products intended for sale in exceptional circumstances when data from replicate production runs are unavailable because only a limited number of batches have been produced, batches are produced infrequently or batches are produced by a validated process that has been modified. Individual batches may be evaluated and released before completion of the validation exercise, based on thorough monitoring and testing of the batches.Annex 377control strategy. A planned set of controls, derived from current product and process understanding that assures process performance and product quality. The controls can include parameters and attributes related to API and finished pharmaceutical product materials and components, facility and equipment operating conditions, in‑process controls, finished product specifications and the associated methods and frequency of monitoring and control.continued process verification. Documented scientific evidence that the process remains in a state of control during commercial manufacture.critical process parameter. A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored and/or controlled to ensure the process produces the desired quality.critical quality attribute. A physical, chemical, biological or microbiological property or characteristic of materials or products that should be within an appropriate limit, range or distribution to ensure the desired product quality.in-line. Measurement where the sample is not removed from the process stream: can be invasive or non‑invasive.life cycle. All phases in the life of a product from the initial development through marketing until the product’s discontinuation (ICH Q8 (4)).matrix approach or bracketing. Bracketing is the assessment of a single parameter or variable by identifying the edge(s) of the range of conditions for the parameter or variable and assessing these during validation to span the possible range of that parameter or variable. For example, bracketing can be applied to process parameters, multiple pieces of identical equipment and/or different size considerations for the same product. The rationale for using this strategy should be justified, documented and approved.Matrixing involves the assessment of the effect of more than one parameter or variable by using a multidimensional matrix to identify the “worst‑case” or “extreme” conditions for a combination of parameters or variables. These conditions are used during validation of the process, rather than validating all possible combinations. Matrixing is typically used when there are significant similarities between products in a product family (e.g. the same product with different strengths in the manufacturing stage or different products with a similar container‑closure in the packaging stage). The rationale for using this strategy should be justified, documented and approved.The use of a matrix approach or bracketing design would not be considered appropriate if it is not possible to demonstrate that the extremes are limited to the batches, products, strengths, container sizes or fills. For those excluded from the exercise there should be no risk to process capability.online. Measurement where the sample is diverted from the manufacturing process, and may be returned to the process stream.pharmaceut cal qual ty system. Management system to direct andcontrol a pharmaceutical company with regard to quality.78W H O T e c h n i c a l R e p o r t S e r i e s N o . 992, 2015WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth reportprocess qualification. Process qualification combines the actual facility, utilities, equipment (each now qualified) and the trained personnel with the commercial manufacturing process, control procedures and components to produce commercial batches; confirms the process design and demonstrates that the commercial manufacturing process performs as expected.process vali dati on. The collection and evaluation of data, from the process design stage through to commercial production, which establishes scientific evidence that a process is capable of continuously delivering the finished pharmaceutical product meeting its predetermined specifications and quality attributes.quali ty target product profile (QTPP). A prospectively documented summary of the quality characteristics of a finished pharmaceutical product (FPP) that ideally will be achieved to ensure the desired quality, taking into account safety and efficacy of the FPP . The QTPP forms the basis of design for the development of the product and typically would include:–intended use in clinical setting, route of administration, dosage form, delivery systems;–dosage strength(s);–container‑closure system;–therapeutic moiety release or delivery and attributes affecting pharmacokinetic characteristics (e.g. dissolution, aerodynamic performance) appropriate to the FPP dosage form being developed;–FPP quality criteria (e.g. sterility, purity, stability and drug release) appropriate for the intended marketed product.real-time release testing. The ability to evaluate and ensure the quality of in‑process and/or final product based on process data, which typically include a valid combination of measured material attributes and process controls.state of control. A condition in which the set of controls consistently provides assurance of continued process performance and product quality.3. Introduction Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process. The validation should be carried out in accordance with GMP and data should be held at the manufacturing location whenever possible and should be available for inspection.Process validation is associated with the collection and evaluation of data throughout the life cycle of a product – from the process design stage throughAnnex 379to commercial production – and provides scientific evidence that a process is capable of consistently delivering a quality product.A risk assessment approach should be followed to determine the scope and extent to which process(es) and starting material variability may affect product quality. The critical steps and critical process parameters should be identified, justified and documented and based on relevant studies carried out during the design stage and on process knowledge, according to the stages of the product life cycle. During process validation and qualification, the critical process parameters should be monitored.It may be helpful to use a flow diagram depicting all the operations and controls in the process to be validated. When applying QRM to a given operation, the steps preceding and following that operation should also be considered. Amendments to the flow diagram may be made where appropriate, and should be recorded as part of the validation documentation.Manufacturers should ensure that the principles of process validation described in these guidelines are implemented. These cover the phases of validation during process design, scale‑up, qualification of premises, utilities and equipment and process performance qualification, and continuous process verification to ensure that the process remains in a state of control.The objectives of process validation include ensuring that:–the process design is evaluated to show that the process is reproducible, reliable and robust;–the commercial manufacturing process is defined, monitored and controlled;–assurance is gained on a continuous basis to show that the process remains in a state of control.The validation should cover all manufactured strengths of a product and the extent of validation at each manufacturing site should be based on risk assessment. A matrix approach or bracketing may be acceptable and should also be based on appropriate risk assessment.There are various approaches to process validation which include: traditional process validation (consisting of prospective and concurrent validation); process design followed by process qualification and continued process verification; or a combination of traditional process validation and the new approach described in these guidelines. Historical data should be evaluated in cases where there have been changes to the process.Manufacturers should plan to implement the new approach to process validation, which covers process design, process qualification and continued process verification throughout the product life cycle.Figure A3.1 shows the phases in the new approach to process validation.80W H O T e c h n i c a l R e p o r t S e r i e s N o . 992, 2015WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth reportFigure A3.1Phases of process validationCQA, critical quality attribute; CPPs, critical process parameters.4. Process designUnder the life‑cycle approach, the focus of validation is shifted from commercial‑scale batches to development. Product development activities provide key inputs to the process design stage, such as the intended dosage form, the quality attributes and a general manufacturing pathway. Laboratory or pilot‑scale models designed to be representative of the commercial process can be used to estimate variability.Process design should normally cover design of experiments, process development, the manufacture of products for use in clinical trials, pilot‑scale batches and technology transfer. Process design should be verified during product development.Process design should cover aspects for the selection of materials, expected production variation, selection of production technology/process and qualification of the unitary processes that form the manufacturing process as a whole, selection of in‑process controls, tests, inspection and its suitability for the control strategy.Annex 381As part of the process validation life cycle some process validation studies may be conducted on pilot‑scale batches (corresponding to at least 10% or 100 000 units, whichever is the greater) of the production scale. Where the batch size is smaller and/or where the process is tailored to the geometry and capacity of specific equipment, it may be necessary to provide production‑scale validation data.Process qualification and continued process verification should always be linked to process design and be referenced to those specific batches used in studies critical to the development of the product, for example, the batch(es) used for pivotal clinical assessments (biobatch(es)), e.g. bioequivalence testing in the case of multisource products) and toxicological studies. The number of batches included in the process design stage of validation should be appropriate and sufficient to include (but not be limited to) the expected variations in starting materials, and confirm the suitability of the equipment and manufacturing technology. A statistically‑based design of experiment approach can be helpful during this stage. Processes and results should be appropriately documented.A development report and/or a technology transfer document, formally reviewed and approved by research and development personnel, and formally accepted by manufacturing, engineering and quality personnel, should be prepared. Such a document may include information such as QTPP , desired clinical performance, bills of materials, approved suppliers, finished product specifications and test methods, in‑process testing specifications, equipment recommendations, master batch production records, master batch packaging records, stability reports, critical quality attributes, critical process parameters, batch comparisons, data on formulation batches, stability batches, clinical/biobatches and scale‑up batches. These documents should be readily available to the manufacturing site.The goal is to design a suitable process for routine commercial manufacturing that can consistently deliver a product that meets its required quality attributes.5. Process qualificationPersonnel, premises, utilities, support systems and equipment should be appropriately qualified before manufacturing processes are validated. Materials, environmental controls, measuring systems, apparatus and methods should be considered during validation. The stages of qualification of equipment may include design, installation, operation and performance of equipment (for more details see (WHO Technical Report Series, No. 937, Annex 4 (1)).Traditionally, three batches have been considered the normal andacceptable number for process validation; however, the number of batches should82W H O T e c h n i c a l R e p o r t S e r i e s N o . 992, 2015WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth reportbe justified and based on a risk assessment that includes, for example, variability of results from the process design stage, variability of materials, product history, where the product is being transferred from and where it will be produced. Manufacturers should define the stage at which the process is considered to be validated and the basis on which that decision was made. The decision should include a justification for the number of batches used based on the complexity and expected variability of the process and critical quality attributes (C QAs). Successful completion of process performance qualification stage of the life cycle is required for commercial distribution.A risk assessment should be performed for the change from scale‑up to commercial batch size. Process qualification should confirm that scale‑up in batch size did not adversely affect the characteristics of the product and that a process that operates within the predefined specified parameters consistently produces a product which meets all its CQAs and control strategy requirements.The process should be verified on commercial‑scale batches prior to marketing of the product.Extensive in‑line and/or online and/or at‑line controls may be used to monitor process performance and product quality in a timely manner. Results on relevant quality attributes of incoming materials or components, in‑process material and finished products should be collected. This should include the verification of attributes, parameters and end‑points and assessment of CQA and critical process parameter (CPP) trends. Process analytical technology applications and multivariate statistical process control can be used.Manufacturers are encouraged to implement the new validation approach to ensure that processes are of known and acceptable capability. As full implementation of this approach may take time, the traditional approach of prospective validation and concurrent validation (used infrequently and restricted to the scenarios described in section 2) may be acceptable in the interim. A combination of elements of the traditional process validation approach and the new continuous process verification approach may be considered appropriate, subject to appropriate controls being in place, based on scientific justification and risk management principles.Validation should be done in accordance with process validation protocols. A written protocol is essential for this stage of process validation. The protocol should include or reference at least the following elements: –the manufacturing conditions including operating parameters, processing limits and component (raw material) inputs; –the data to be collected and when and how they will be evaluated; –the type of testing or monitoring to be performed (in‑process, release, characterization) and acceptance criteria for each significant processing step;Annex 383–the scientifically justified sampling plan, including sampling points, number of samples and the frequency of sampling for each unit operation and attribute;–the number of batches for which additional monitoring is proposed; –status of the validation of analytical methods used in measuring the process, in‑process materials and the product;– a description of the statistical models or tools used;–review and approval of the protocol by appropriate departments and the quality unit;– a description of the process;–details of the equipment and/or facilities to be used (including measuring or recording equipment) together with its calibration status;–the variables to be monitored with appropriate justification;–the samples to be taken – who, where, when, how, how many and how much (sample size);–the product performance characteristics or attributes to be monitored, together with the test methods;–the acceptable limits;–personnel responsibilities;–details of methods for recording and evaluating results, including statistical analysis.Data should be collected and reviewed against predetermined acceptance criteria and fully documented in process validation reports. The report should reflect the validation protocol. A dual protocol report can be used; however, such reports must be designed to ensure clarity and sufficient space for recording of results. The outcome should confirm that the acceptance criteria have been met. Any deviations (including abandoned studies) should be explained and justified.The planned commercial production and control records, which contain the operational limits and overall strategy for process control, should be carried forward to the next phase for confirmation.6. Continued process verificationManufacturers should monitor product quality of commercial batches after completion of process design and process qualification. This will provide evidence that a state of control is maintained throughout the product life cycle.The scope and extent of process verification will be influenced by anumber of factors including:84W H O T e c h n i c a l R e p o r t S e r i e s N o . 992, 2015WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-ninth report–prior development and knowledge of the manufacturing of similar products and/or processes;–the extent of process understanding gained from development studies and commercial manufacturing experience;–the complexity of the product and/or manufacturing process;–the level of process automation and analytical technologies used;–for legacy products, with reference to the product life‑cycle process robustness and manufacturing history since the point of commercialization, as appropriate.Manufacturers should describe the appropriateness and feasibility of the verification strategy (in the protocol) including the process parameters and material attributes that will be monitored as well as the validated analytical methods that will be employed.Manufacturers should define:–the type of testing or monitoring to be performed;–the acceptance criteria to be applied;–how the data will be evaluated and the actions to be taken.Any statistical models or tools used should be described. If continuous processing is employed, the stage at which the commercial process is considered to be validated should be stated based on the complexity of the process, expected variability and manufacturing experience of the company.Periods of enhanced sampling and monitoring may help to increase process understanding as part of continuous improvement. Information on process trends, such as the quality of incoming materials or components, in‑process and finished product results and non‑conformances should be collected and assessed to verify the validity of the original process validation or to identify changes required to the control strategy.The scope of continued process verification should be reviewed periodically and modified if appropriate throughout the product life cycle.7. Change management Manufacturers should follow change control procedures when changes are planned to existing systems or processes. The change control procedure and records should ensure that all aspects are thoroughly documented and approved, including regulatory approval where appropriate (variation).Annex 385Sufficient data should be generated to demonstrate that the revised process will result in a product of the desired quality, consistent with approved specifications.Validation should be considered when changes to production and/or control procedures are planned. Based on risk assessment, changes that may require revalidation could include (but are not limited to):–changes in the master formula, methods, starting material manufacturer, starting material manufacturing process, excipient manufacturer, excipient manufacturing process;–changes in the equipment or instruments (e.g. addition of automatic detection systems);–changes associated with equipment calibrations and the preventive maintenance carried out, which may impact the process;–production area and support system changes (e.g. rearrangement of areas or a new water‑treatment method);–changes in the manufacturing process (e.g. mixing times, drying temperatures);–transfer of processes to another site;–unexpected changes (e.g. those observed during self‑inspection or during routine analysis of process trend data);–changes to standard operating procedures;–changes to cleaning and hygiene programmes.Depending upon the nature of the change being proposed the change control process should consider whether existing approved specifications will be adequate to control the product subsequent to the implementation of the change.References1. Supplementary guidelines on good manufacturing practices: validation. In: WHO ExpertCommittee on Specifications for Pharmaceutical Preparations: fortieth report. Geneva: World Health Organization; 2006: Annex 4 (WHO Technical Report Series, No. 937).2. WHO good manufacturing practices for active pharmaceutical ingredients. In: WHO ExpertCommittee on Specifications for Pharmaceutical Preparations: forty-fourth report. Geneva: World Health Organization; 2010: Annex 2 (WHO Technical Report Series, No. 957).3. WHO good manufacturing practices for sterile pharmaceutical products. In: WHO ExpertCommittee on Specifications for Pharmaceutical Preparations: forty-fifth report. Geneva: World Health Organization; 2011: Annex 6 (WHO Technical Report Series, No. 961).4. ICH harmonised tripartite guideline, pharmaceutical development Q8(R2), Current Step 4 version,dated August 2009 (/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf, accessed 15 January 2014).86W H O T e c h n i c a l R e p o r t S e r i e s N o . 986, 2014WHO Expert Committee on Specifications for Pharmaceutical Preparations Forty-eighth reportFurther readingGuideline on process validation. London: Committee for Medicinal Products for Human Use (CHMP), Committee for Medicinal Products for Veterinary Use (CVMP); 2012 (EMA/CHMP/CVMP/QWP/70278/2012-Rev1) (http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/04/WC500125399.pdf, accessed 15 January 2015).Guidance for industry. Process validation: general principles and practices. Silver Spring (MD): US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER), Center for Veterinary Medicine (CVM); 2011 (Current Good Manufacturing Practices (CGMP) Revision 1).ICH harmonised tripartite guideline, quality risk management, Q9, Current Step 4 version, dated 9 November 2005.ICH harmonised tripartite guideline, pharmaceutical quality system, Q10, Current Step 4 version, dated 4 June 2008 (/products/guidelines/quality/article/quality-guidelines.html, accessed 15 January 2014).Quality assurance of pharmaceuticals. WHO guidelines, related guidance and GXP training materials. Geneva: World Health Organization; 2014 (CD-ROM).WHO good manufacturing practices: main principles for pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-eighth report. Geneva: World Health Organization; 2014: Annex 2 (WHO Technical Report Series, No. 986 (http://www.who.int/medicines/areas/quality_safety/quality_assurance/GMPPharmaceuticalProductsMainPrinciplesTRS961Annex3.pdf, accessed 15 January 2015).WHO guidelines on quality risk management. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations: forty-seventh report. Geneva: World Health Organization; 2013: Annex 2 (WHO Technical Report Series, No. 981).。
电喷雾解吸电离串联质谱法快速检测果蔬表面残留有机磷农药
电喷雾解吸电离串联质谱法快速检测果蔬表面残留有机磷农药薛岚;苏海峰【摘要】在不需要样品制备、预处理的前提下，将电喷雾解吸串联质谱法用于果蔬表面残留的乙酰甲胺磷、甲拌磷、乐果、乙嘧硫磷、乙硫磷和亚胺硫磷等6种有机磷农药的直接快速检测。
在串联质谱中，选择电喷雾离子源，用甲醇作雾化溶剂；以碰撞诱导解离反应正离子检测模式进行定性和定量检测。
确定了上述6种有机磷农药的碎片特征峰（m／z）分别为206，261，252，293，407，318。
结果表明：6种有机磷农药分子的裂解规律与其分子结构相吻合，排除了检测结果的假阳性。
方法的检出限（3S/N）在5．0×10^-10～1．0×10^-8g·cm^-2之间。
以1．0×10^-8g·cm^-2的6种有机磷农药溶液进样，平行测定8次，测定值的相对标准偏差在1．6％～6．5％之间。
%Desorption electrospray ionization-tandem mass spectrometry （DESI-MS/MS） was applied to the rapid determination of residual amounts of 6 organophosphorus pesticides （OPP＇s）, i. e. , acephate, thimet, rogor, etrimfos, ethion and phosemet, on surface of fruits and vegetables, without sample preparation and pretreatment. In the MS/MS analysis, ESI was used as ion ization source with methanol as the electrospray solvent, and positive electrospray ionization as well as collision induced dissociation reaction monitoring mode was taken for qualitative and quantitative analysis. The characteristic peaks of the fragments of 6 organophosphorous pesticides with （m/z）206, 261, 230, 293, 407, 340 respectively were confirmed. It was found that the fragmentation regularity of molecules of the 6 OPP＇s were in coincidence with their molecular structures, and the possibility of arisingfalse positiveness of the results of detection was thus eliminated. Values of detection limit （3S/N）found were in the range of 5.0×10^-10～1.0×10^-8g·cm^-2. Precision of the method was tested with sample introduction of 1.0×10^-8g·cm^-2 of mixture of the 6OPP＇s for 8 determinations, values of RSD＇s found were in the range of 1.6%- 6.5%.【期刊名称】《理化检验-化学分册》【年(卷),期】2011(047)010【总页数】5页(P1218-1221,1232)【关键词】电喷雾解吸;串联质谱;有机磷农药;果蔬【作者】薛岚;苏海峰【作者单位】宁德师范学院化学与环境科学系,宁德352100;厦门大学化学化工学院,厦门361005【正文语种】中文【中图分类】O657.63有机磷是我国目前使用量很大的农药之一，有机磷农药杀虫活性高，应用范围广，但对人畜有急性毒性作用，因此，它是食品安全检测中的一个重要项目。
三元生物塔格糖技术
三元生物塔格糖技术英文回答：Tripartite Biotic System (TBS) Targeting Glycomics.The Tripartite Biotic System (TBS) is a novel approach to glycomics research that integrates three distinct biological systems:Microbiota: The complex community of microorganisms that inhabit the human body.Host: The human organism itself.Environment: The external factors that influence the relationship between the microbiota and the host.The TBS approach recognizes that the microbiota plays a crucial role in the development, function, and regulation of the host's glycome, which is the collection of allglycans (carbohydrates) in the body.By studying the interactions between the microbiota, host, and environment, TBS aims to:Unravel the mechanisms by which the microbiota influences the host's glycome.Explore the potential for manipulating the microbiota to modulate glycomic pathways.Identify new diagnostic and therapeutic targets for glycan-related diseases.Several research projects have utilized the TBS approach to investigate the role of the microbiota in glycomic processes. For example, one study found that the gut microbiota of obese mice exhibited alterations in the expression of genes involved in glycan synthesis and degradation.Another study demonstrated that probiotics (beneficialbacteria) could modulate the host's glycome, reducing inflammation and improving glucose tolerance. Thesefindings highlight the potential of TBS to advance our understanding of glycomics and develop novel therapies for glycan-related diseases.中文回答：三元生物塔格糖技术。
靶向Annexin A3短发夹环RNA干扰载体的构建及鉴定
ｃｒｅｔ『ｏ ｃｕ ｉｎ ｋ ｒｏｉ ｅｐｅｓｏ ｅ ｔｒ ｆｉ ＮＡ ｔｒｅｉｇａ ｎ ｘｎＡ３ｇ ｎ ａ ｕ ｃｓｆｌ ｏ ｓ ｕ ｔｄ ｏｒｃ．Ｃ ｎ ｌｓ １ ｏ Ｅｕ ａｙ ｔ ｘ ｒｉｎｖｃｏ Ｒ ｇｔ ｅ ｉ ｅ ｅｗ ｓｓｃ ｅｓ ｌ ｃｎ ｔ ｃｅ ． ｃ ｏｓ ａ ｎ ｎ ｕｙ ｒ
达 栽体 。
关 键 词 Ａ ｎｘ ３ｐｉＮ — Ｈｌｅ； Ｎ ｎｅｉＡ ；ｓ Ａ ｈ ｎｏ Ｒ Ａ干扰 ； ｎ Ｒ 真核 表 达 栽体 中图分 类 号 Ｑ ８ 文 献标 识码 Ａ ７２ 文 章编 号 ０ １— ６ ２０ ）７ ０ １５ ０ ５ ７ ６ １（０ ８１— ７４ — ２ １
Ｋｅ ｙｗｏｒ Ａｎ ｘｎ Ａ３ ｐ ｉ ｄｓ ｎｅ ｉ ； ｓＲＮＡ－ Ｈ ｌ ｅ ； ｉ ｈ ｎ ｏ ｓＲＮＡ ： ｋ ｒ ｏｉ ｘ ｅ ｓｏ ｅ ｔｒ Ｅｕ ａ ｙ ｔｃｅ ｐｒｓ ｉｎｖ ｃｏ
近年 来 ， 三氯 乙烯 （ｒ ｈｏ ｅ ｙ ｎ ，Ｃ 引 起 的 中 由 Ｔｉ ｌ ｏｔ ｌ ｅＴ Ｅ） ｃ ｒ ｈｅ
Ｔ ｅｃ ｎ ｔ ｃｅ ｓＲ ｈ ｏ ｓｒ ｔ ｄｐ ｉ ＮＡ ｌｓ ｄｄ ｇ ｓｅ ｉ ｅ １ｗ ｓｌ ｅ ｉ ｄ Ｔｈ ｑ ｅ ｃｎ ｓ ｌ ｃ ｎ ｒ ｄｔａ ｅｓ ｑ ｅ ｃ ｆ ｎ ｅ ｅ ａ ｍｅ ｔ ａ ｕ ｐａ ｍｉ ｉｅ ｔ ｄｗ ｔ Ａｓ ａ ｎ ａ ｚ ． ｅ ｅ ｕ ｎ ｉ ｇｒ ｕｔ ｏ ｆ ｍｅ ｔ ｈ ｕ ｎ ｅｏ ｓ ｒ ｄｆ ｇ ｎ ｓ ｈ ｉ ｒ ｅ ｓ ｅ ｉ ｈ ｔ ｅ ｉ ｔ ｒ Ｗ
席 ， 建军卜， 振强２ 梅 黄海燕 仁荣 ２ 刘 吴 ， 邢秀 ，
（． １深圳市疾病预 防控 制中心毒理研究室 ， 广东 深圳 ５ ８２ ； ． 南理工大学生物科学 与工程学院 ， １０ ０ ２ 华 广东 广州 ５ ８ ４ １６０）
膜联蛋白A3在恶性肿瘤中的研究进展
•662•医学研究生学报2019年6月第32卷第6期J Med Pos仰a,Vol.32,No.6,June,2019综述膜联蛋白A3在恶性肿瘤中的研究进展王娇娇，闫克敏综述，肖海娟审校［摘要］膜联蛋白A3(ANXA3)是膜联蛋白(Annexin)超家族中非常重要且研究较少的一员。
既往研究表明.Annexin A3参与了多种细胞过程，但对其功能的研究尚有不足。
研究证实Annexin A3的异常表达与多种恶性肿瘤密切相关，在肿瘤的发生发展、迁移、侵袭及抗药性等方面发挥重要作用，有望成为恶性肿瘤一个新的治疗靶点。
文章就Annexin A3在恶性肿瘤中的作用进行综述。
［关键词］Annexin A3;恶性肿瘤;转移;化疗耐药［中图分类号］R73［文献标志码］A［文章编号］1008-8199(2019)06-0662-06［DOI］10.16571/ki.1008-8199.2019.06.021Research progresses of Annexin A3in malignant tumorsWANG Jiao-jiao1,YAN Ke-min1reviewing,XIAO Hai-juan2checking(1.First School of Clinical Medicine,Shaanxi University of Chinese Medicine,Xianyang712046,Shaanxi,China;2.State Key Laboratory of Cancer Biology,Xijing Hospital of Digestive Diseases,Air Force Medical University,Xi'an 710032,Shaanxi,China)［Abstract］Annexin A3(ANXA3),is a crucial member of the membrane associated protein superfamily,whose function research is still insufficient.Previous researches have confirmed that Annexin A3is involved in a variety of cellular processes,but its function is still unclear.Accumulating evidences suggested that Annexin A3is closely related to various malignant tumors,and plays an important role in tumor development,metastasis,invasion and drug resistance.Therefore,Annexin A3is expected to be a new therapeutic target for malignant tumors.This article provided an overview about the role of Annexin A3in malignant tumors.［Key words］Annexin A3;malignant tumor;metastasis;drug resistance0引言膜联蛋白（Annexin）是一类由Ca2+参与调节的酸性磷脂和膜结合蛋白，主要在细胞内表达，约占细胞总蛋白量的1%~2%o Annexin家族共有5类，分别为A、B、C、D和E,脊椎（哺乳）动物的膜联蛋白属于A类。
细胞中的微型氧气探测器
细胞中的微型氧气探测器作者：陶诗秀来源：《下一代英才》2020年第04期想象一下，你参加了一场100米赛跑，在全力冲刺后浑身汗如雨，嘴巴大口大口地呼吸，渴望能补充身体消耗的氧气。
为什么我们的身体能够知道运动后需要加快呼吸呢？这一切都得归功于体内的微型氧气探测器——缺氧诱导因子。
缺氧诱导因子的发现，要感谢三位科学家：美国哈佛医学院的威廉·凯林、美国约翰霍普金斯政策研究所的格雷格·塞门萨和英国研究癌症的彼得·雷克里夫。
他们揭露了细胞怎么透过稳定缺氧诱导因子适应缺氧环境的神祕面纱，也因此获得2019年诺贝尔生理医学奖的殊荣。
关掉警报窒息癌细胞在癌症中，很多恶化的细胞都会产生大量缺氧诱导因子，让癌细胞能够适应肿瘤中的低氧环境。
在不清楚这个机制以前，人们多半只能以手术切除，或是副作用强烈的化疗来治疗癌症。
但现在我们可以尝试抑制癌细胞中的缺氧诱导因子，既能让癌细胞“窒息”，又不影响到正常细胞。
这重大的发现，获得了诺贝尔奖。
警报超载启动机制与此同时，研究罕见遗传疾病林道症候群的凯林发现，在细胞中，有一种VHL蛋白平时会与缺氧诱导因子结合，让缺氧诱导因子被分解掉，而不会累积在细胞中。
但是当VHL蛋白出现异常时，就无法协助分解缺氧诱导因子，这时细胞中大量累积的缺氧诱导因子就会使得细胞异常增生，进而容易形成癌症。
凯林的研究拼凑起缺氧诱导因子的故事：在正常氧气充足的环境中，细胞中的PHDs酵素会利用氧气当材料，帮缺氧诱导因子贴上标签，让VHL蛋白能够认得缺氧诱导因子，进而协助移除。
但是当细胞缺乏氧氣时，PHDs酵素就没有原料可以帮缺氧诱导因子贴上标签，使得VHL 蛋白不认得缺氧诱导因子，也就没办法协助移除。
这时，在细胞中大量累积的缺氧诱导因子会与DNA产生反应，启动抵抗恶劣环境的基因功能，帮助细胞渡过难关。
当身体因为激烈运动进入缺氧状态时，肾脏会刺激骨髓制造更多红血球，提高血液携带氧气的能力。
欧盟发布激素替代疗法第三版核心药品特性概要
欧盟发布激素替代疗法第三版核心药品特性概要
佚名
【期刊名称】《中医药国际参考》
【年(卷),期】2010(000)009
【摘要】欧盟于近期发布第三版激素替代疗法（雌激素单用或雌激素与孕激素联用，HRT）核心药品特性概要的修订信息。
【总页数】2页(P6-7)
【正文语种】中文
【中图分类】R459.1
【相关文献】
1.欧盟纳米安全集群发布2012年概要 [J],
2.欧盟发布GCP规定以及临床药品方面的规定 [J], 郑晶心(摘)
3.EMEA发布含哌甲酯类药品在欧盟的安全使用建议 [J],
4.EMEA发布含哌甲酯类药品在欧盟的安全使用建议 [J],
5.欧盟更新激素替代疗法第三版核心药品特性概要 [J],
因版权原因，仅展示原文概要，查看原文内容请购买。
微粒体三酰甘油转运蛋白研究进展
微粒体三酰甘油转运蛋白研究进展
张彩虹;刘宏峰
【期刊名称】《国际检验医学杂志》
【年(卷),期】2017(038)010
【总页数】3页(P1384-1386)
【作者】张彩虹;刘宏峰
【作者单位】山东省淄博市中心医院检验科 255036;山东省淄博市中心医院检验科 255036
【正文语种】中文
【相关文献】
1.微粒体甘油三酯转运蛋白的研究进展 [J], 徐闯;刘彩霞;董凤仙;王哲;姜玉富;夏成;魏明竞
2.微粒体甘油三酯转运蛋白MTP研究进展 [J], 叶健强;蒋立;王继文
3.微粒体甘油三脂转运蛋白MTP的研究进展 [J], 叶健强;王继文
4.微粒体甘油三酯转运蛋白研究进展 [J], 陈仕均;唐海蓉
5.微粒体甘油三酯转运蛋白MTP的研究进展 [J], 叶健强;蒋立;王继文
因版权原因，仅展示原文概要，查看原文内容请购买。
原研药物在临床中的应用价值
65
65
60
58.7
临床有效率(%)Βιβλιοθήκη 555045
40
原研亚胺培南/西司他丁
仿制亚胺培南/西司他丁
一项国外2007年6月至2008年9月纳入600例对比使用，原研与仿制亚胺培南/西司他丁治疗感染性疾病 的临床疗效，安全性比较比较
Piyasirisilp S, et al.J Med Assoc Thai. 2010 Jan;93 Suppl 1:S117-25.
Data on file.MSD
FDA关于仿制药的警告
• FDA的警告信促使美国对南新公司在 印度生产的多个仿制药和原料药发出 了禁令，警告信指出，南新印度工厂 的记录保存规范有问题，预防污染的 措施也未经过验证
• 在2006年6月的警告信中，FDA称 Paonta Sahib工厂的稳定性试验有 偏差
C. Chu et al. European Journal of Internal Medicine 22 (2011) e45–e49
临床医生选择药物的需求：临床数据需可靠严谨
临床医生的需求：
选择药物时，需要全方面了解药物多方面的临床数据
仿制药的劣势：
与原研药相比，仿制药可能不能有效传递可靠医学信息
目录
• 原研药与仿制药生产质量的区别 • 原研药与仿制药临床疗效的区别
– 生物等效性与临床等效性的区别 – 亚胺培南(泰能®)与仿制药的相关临床研究比较
• 原研药与仿制药药物经济学的区别 • 泰能®是全球抗生素市场的领导品牌
原研药和仿制药一样吗？
仿制药一般只进行生物等效性研究
• 尽管在各国政策推荐促进仿制药的使用和
15.Iijima H, et al. Yakugaku Zasshi. 2004 Jun;124(6)：341-7.
盐酸普萘洛尔的化学合成进展
Ｈｉｓａｓｈｉ Ｔａｋａｈａｓｈｉ 等［３７］研究发现 ３－ （芳氧基）－ ２－ 氧－ １－ １ 丙基衍生物的不对称氢化作用能够高效合 成盐酸普萘洛尔。该反应分四部分完成，每步的产 率分别为 ９１％、６２％、５１％、９８％，得到的盐酸普萘洛 尔粗产物光学纯度为 ９０．８％ ｅ．ｅ，为了提高光学纯度，
基 ） － ２ － 丙 醇 盐 酸 盐 ， 英 文 名 Ｈｙｄｒｏｃｈｌｏｒｉｄｅ 起颅内出血［２１］等。
Ｐｒｏｐｒａｎｏｌｏｌ，ＣＡＳ 登录号：３１８－ ９８－ ９。白色或乳白色
口服盐酸普萘洛尔后胃肠吸收率约 ９０％，１～１．
结晶性粉末，无臭，味微甜后苦，熔点 ９６℃，盐酸盐 ５ｈ 谢丹红．心得安的临床应用进展［Ｊ］．临床荟萃，１９９４，９ （１２）：５５６－ ５５８．
［５］ 向继洲．药理学［Ｍ］．北京：科学出版社 ［６］ 闫升光．普萘洛尔和心血管疾病［Ｊ］．中国疗养医学， ２００１，１０（４）：１２－ １３． ［７］ 吕群．缓解甲亢症状可用普萘洛尔［Ｊ］．健康报，２００３－ ０２－ ２０． ［８］ 吴瑞蛟，孙金红，等．普萘洛尔对急性心肌梗死患者的 镇痛作用［Ｊ］．潍坊医学院学报，２００５，２７（３）：１３５． ［９］ 张建玉，蔡晓玲．普萘洛尔的临床应用新进展［Ｊ］．医药 导报，１９９８，２（１７）１：５９－ ６０． ［１０］ 杨桂琴，江霞，等．小剂量静脉滴注普萘洛尔用于麻 醉中窦速的临床治疗观察［Ｊ］．中国医药药学杂志，１９９６，１６（７）： ３００． ［１１］ 李维．临床内科杂志［Ｊ］，１９９０，７（６）：４１． ［１２］ 林传水．心得安治疗多动腿综合症 ５ 例［Ｊ］．综合临床 医学，１９９０，６（２）：９６． ［１３］ 陈伟家，翁辉廉．普萘洛尔在精神科的新用途［Ｊ］．广 东药学，１９９５（３）１３－ １４． ［１４］ 金正淑．中国神经精神杂志［Ｊ］，１９８８，１４（５）：３１８． ［１５］ Ｌｅｂｒｅｃ Ｄ．ｅｔ ａｌ．Ｅｎｇ．［Ｊ］Ｍｅｄ， １９８１，３０５：１３７１． ［１６］ 刘德午．国外医学（合成药、生化药制剂分册）［Ｊ］， １９９０，１１（１）：５１． ［１７］ 信长茅．河北医药［Ｊ］，１９８９，１１（５）：２９０． ［１８］ 林桦． 谈盐酸普萘洛尔的服用禁忌 ［Ｊ］． 海峡药学， １９９９，１１（４）：８４． ［１９］ 池晨．临床应用普萘洛尔的注意事项［Ｊ］．中国药物与 临床，２００４，２（４）：２－ １３９． ［２０］ 李小鹰，叶平．最新心血管用药［Ｍ］．北京：人民军医 出版社，１９９３．１６１． ［２１］ 汪晓阳．维德临床用药手册［Ｍ］．北京：中信出版社， １９９７．５３５． ［２２］ Ｃｈａｎｇｅ Ｓ．Ｆ，ｅｔ ａｌ． Ｐｈａｒｍ Ｉｎｔ［Ｊ］，１９８４，５（１２）：２８７－ ２８８． ［２３］ Ｐａｒｒ ＧＤ，ｅｔ ａｌ． Ｌｉｂｉｄ［Ｊ］， １９８３，４（８）：２０２－ ２１０． ［２４］ 平井真一郎．武田研究所报．１９８２，４１（３－ ４）：２４６－ ２５０． ［２５］ 国家食品药品监督管理局药品审评中心，四川美康 医药软件研究开发有限公司．ＭＣＤＥＸ 药物临床信息参考［Ｍ］． 成都：四川科学技术出版社．２００４． ［２６］ Ｈｕｓｓａｉｎ Ａ．Ａ．Ｉｎｔｒａｎａｓａｌ ｄｒｕｇ ｄｅｌｉｖｅｒｙ ［Ｊ］．Ａｄｖ Ｄｒｕｇ
美国奈文全面解析
美国奈文全面解析美国奈文是美国酶科学公司的明星产品,是一款高端复合酶制剂。
酶是新陈代谢、生命运行不可缺少的催化剂，正因为有了酶的存在，身体每个角落都有条不紊的运转着，如果某一种酶缺失了，身体就会出现相应的问题。
补充身体缺失的酶，不仅可以消除出现的问题，还能强化身体的免疫系统，更关键的是复合酶对身体而言是非常安全的。
美国奈文成分分析：蛋白水解酶 Protease Thera-blend TM活性高达350,000HUT, 可以溶解血管内的血栓、斑块，同时维持人体免疫系统健康。
过氧化氢酶 Catalase兼具抗氧化及组织修复的能力，清除对人体有害的自由基，延长细胞生命周期与活力。
纳豆复合酶 Nattokinase blend w/ NSK-SD®荣获三项美国专利，有效溶解纤维蛋白，调节血液黏稠度，维持正常血液循环。
舍雷肽酶Serratiopeptidase 专一的纤维蛋白溶解效能，通过溶解纤维蛋白，修复受损组织，维持血管健康。
美国奈文优势分析：科学配比——高效吸收美国耐文革命性的将蛋白水解酶、过氧化氢酶、纳豆复合酶、舍雷肽酶等多种酶完美配比，吸收更高效。
原料优选——选自全球绿色原产地美国酶科学公司与全球几十处原材料供应地合作，原材料选自全球优选的绿色产地，确保产品品质。
缓控释技术——食用无负担，吸收更好24小时缓控释技术，每天只需食用1至2粒，24小时均匀释放，与人体吸收频率一致，达到更好的吸收。
每天1至2粒，空腹服用，没有压力。
强耐酸碱性——保证高活性，效果更佳美国耐文先进的包埋技术，能够让酶在pH2.0-12.0的强酸碱环境下保持高活性，在经过胃酸（pH1.5左右）后仍能保持350, 000 HUT活性，高活性是高效果的前提。
美国原装进口——海关全程监管美国耐文只在美国本土生产、包装，运输至中国保税仓库，由中国海关全程监管整个流程，确保原装品质。
专为国人设计——更贴心美国耐文专门针对中国人体质，调整了配方比例，更加符合国人特点，只在中国大陆销售。
- 1、下载文档前请自行甄别文档内容的完整性，平台不提供额外的编辑、内容补充、找答案等附加服务。
- 2、"仅部分预览"的文档,不可在线预览部分如存在完整性等问题,可反馈申请退款(可完整预览的文档不适用该条件!)。
- 3、如文档侵犯您的权益，请联系客服反馈,我们会尽快为您处理(人工客服工作时间：9:00-18:30)。
ANNEX 3 附件3MANUFACTURE OF RADIOPHARMACEUTICALS放射性药品的生产Principle 原则The manufacturing and handling of radiopharmaceuticals is potentially hazardous. The level of risk depends in particular upon the types of radiation emitted and the half-lives of the radioactive isotopes. Particular attention must be paid to the prevention of crosscontamination, to the retention of radionuclide contaminants, and to waste disposal. Special consideration may be necessary with reference to the small batch sizes made frequently for many radiopharmaceuticals. Due to their short half-life, some radiopharmaceuticals are released before completion of certain Quality Control tests. In this case, the continuous assessment of the effectiveness of the Quality Assurance system becomes very important.放射性药品的生产和处理存在着潜在的危险，危险的程度取决于放射线的种类和放射性同位素的半衰期。
特别要注意防止交叉污染、放射性物质的残留和废物的处理，尤其在进行小批量多个产品的放射性药品的生产时要特别注意。
由于有的产品的半衰期特别短，他们会在完成质量控制检测前产品已被放行，这种情况下，对质量保证系统持续地进行有效性的评估是非常重要的。
NoteManufacture must comply with the requirements of EURATOM Directives laying down the basic standards for the health protection of the general public and workers against the dangers of ionising radiation, as well as complying with other relevant national requirements.注：生产必须符合EURATOM的要求，EURATOM 规定了公众和生产人员的基本健康保护标准，防止离子放射的危险，同时也要符合其他的相关国家的要求。
Personnel 人员1. All personnel (including those concerned with cleaning and maintenance) employed in areas where radioactive products are manufactured should receive additional training specific to this class of products. In particular, they should be given detailed information and appropriate training on radiation protection.所有在放射性产品的生产区域工作的人员（包括有关的维护和清洁人员）要进行关于这类产品的培训，特别是他们要接受放射保护方面的培训和有关这方面的详细信息。
Premises and equipment厂房和设备2. Radioactive products should be stored, processed, packaged and controlled in dedicated and self-contained facilities. The equipment used for manufacturing operations should be reserved exclusively for radiopharmaceuticals.放射性产品要采用专用的和独立的设备进行生产、包装、储存和控制。
生产用的所有设备要单独保存和专用。
3. In order to contain the radioactive particles, it may be necessary for the air pressure to be lower where products are exposed than in surrounding areas. However, it is still necessaryto protect the product from environmental contamination.为控制放射性粉尘微粒，产品暴露的生产区与周围环境空气要保持相对负压，同时要保证产品不被周围环境污染。
4. For sterile products the working zone where products or containers may be exposed should comply with the environmental requirements described in the Supplement on Sterile Products. This may be achieved by the provision within the work station of a laminar flow of HEPA-filtered air and by fitting air-locks to entry ports. Total containment work stations may provide these requirements. They should be in an environment conforming to at least grade D.对无菌产品，产品和容器暴露的生产区要符合无菌制剂生产对环境的要求，可以通过在工作区安装带有高效过滤器的层流装置和在出入口安装气闸室的方法来达到这个要求，一个完整的密封工作站可以符合这个要求，内部环境至少达到D级。
5. Air extracted from areas where radioactive products are handled should not be re circulated; air outlets should be designed to avoid possible environmental contamination by radioactive particles and gases. There should be a system to prevent air entering the clean area through extract ducts e.g. when the extract fan is not operating.放射性产品处理工作区排放的空气不能循环；排风口的设计要避免放射性尘埃粒子和气体对环境的污染。
要有防止空气倒灌进入洁净区的设施，如在排气煽停止运转时。
Production 生产6. Production of different radioactive products in the same work stations and at the same time should be avoided in order to minimise the risk of cross-contamination or mix-up.要避免在同一个工作站同时生产不同的放射性产品，防止交叉污染和混药的风险。
7. Process validation, in-process controls and monitoring of process parameters and environment, assume particular importance in cases where it is necessary to take the decision to release or reject a batch or a product before all tests are completed.工艺验证、过程控制、对工艺参数和环境的监控，在产品的放行、判断不合格、或检验完成之前放行时，都特别重要。
Quality control 质量控制8. When products have to be dispatched before all tests are completed, this does not obviate the need for a formal recorded decision to be taken by the Qualified Person on the conformity of the batch. In this case there should be a written procedure detailing all production and Quality Control data which should be considered before the batch is dispatched. A procedure should also describe the measures to be taken by the Qualified Person if unsatisfactory test results are obtained after dispatch.当产品要在检验完成之前发货时，也要进行由合格的人员对产品的质量符合性做有记录的判定。
在这种情况下，要有一个书面的规程来规定所有需要在产品放行前考虑的产品生产和质量控制的数据。
还要有一个规程来规定如果发货后又发现检验结果不符合时，由合格的人员采取的措施。