冻干胶塞水分测定方法及影响因素的研究

摘要 目的：比较并探讨冻干胶塞水分的测定方法,考察影响胶塞水分的因素。方法：通过比较不同检测方法的检测原理、取样方式、干燥方式,统一采用卡式炉-库仑法测定70批冻干胶塞样品中水分,并考察胶塞处理过程与储存环境对水分的影响。结果：该方法属于库仑滴定法,灵敏度和准确性较高;与干燥失重法相比,更具有专属性;与ISO方法进行配对T检验和回归分析,结果具有一致性。结论：该方法采用250℃条件下的永停滴定法,取样方式不受胶塞部位和切割方式的影响,能简便快速的测得胶塞中的水分。     

硅化程度对冻干胶塞跳塞的影响

目的确定最佳硅化条件,增加半加塞的稳定性。方法采用正交试验法调整硅油的加入量、硅化温度及硅化时间。结果最佳试验条件是硅油加入量、硅化温度及硅化时间均在各个二水平时,胶塞的上机率达到98％以上。结论采用各个因子的二水平进行洗塞,可以增加半加塞的稳定性,减少跳塞,提高生产效率,降低生产成本。     

影响冻干胶塞跳塞问题的常规因素

各种不同剂型的药物,有不同的生产工艺。不同的剂型、不同的生产工艺,对包装物有不同的要求。药物冻干制剂的冻干工艺,是将配制的药物溶液,在冰冻状态下通过低压升华和解吸附的方法,使制品内水分减到使其在长时间内无法维持生物学或化学反应的水平。为满足冻干剂型和冻干工艺要求而设计制造的丁基胶塞,通常称之为冻干胶塞。冻干制剂的包装加塞过程分两步完成:半加塞和全压塞。半加塞的稳定性及跳塞情况直接影响生产效率,本文就影响冻干胶塞半加塞稳定性和跳塞的各种因素以及解决办法加以分析探讨。1冻干瓶塞的尺寸尺寸标准中,一类是适应药厂…     

血液制品生产工艺验证实践的探讨

工艺验证是药品生产验证的重中之重。本文根据生产工艺验证的实践经验,从工艺验证的介入时间、验证策略、验证风险管理和验证执行等方面总结了血液制品工艺验证的一些心得体会。     

人凝血因子Ⅷ血液制品中的病毒灭活与验证

目的 研究人凝血因子Ⅷ制备过程中S/D病毒灭活法和80℃、72 h干热灭活法的病毒灭活工艺的灭活效果。方法 经过S/D法及80℃、72 h干热法双重处理灭活病毒,并通过加入指示病毒(PRV、Sindbis、HIV、EMCV、PPV)验证病毒灭活效果。结果 上述工艺可有效灭活脂包膜和非脂包膜病毒。最终制品中TNBP残余量小于1/10万(10 ppm)、吐温-80(Tween-80)残余量小于1/万(100 ppm),符合安全标准,人凝血因子Ⅷ的生物活性及其他各项指标未发现明显变化。结论 可以作为人凝血因子Ⅷ实验过程中的病毒灭活方法。     

冻干甲型肝炎减毒活疫苗三氯甲烷残留量检测方法的建立及验证

目的  建立准确可靠检测冻干甲型肝炎减毒活疫苗中三氯甲烷残留量的方法。方法  采用顶空气相色谱进行三氯甲烷残留量检测,用外标法计算三氯甲烷含量。对方法的专属性、线性、范围、准确度、精密度、定量限和耐用性进行验证。结果  三氯甲烷峰5次进样峰面积的相对标准偏差小于5%,且与其他峰分离度大于1.5。阳性对照溶液在相应保留时间处可见三氯甲烷峰,阴性对照溶液无三氯甲烷峰。三氯甲烷的浓度在10~1 000 ng/ml范围内与峰面积成线性关系。浓度为600 ng/ml的供试品溶液回收率在91.3%~99.0%之间,含量相对标准偏差均小于4%。定量限浓度为0.022 g/ml。结论  建立的三氯甲烷残留量检测方法具有良好的专属性、线性、范围、准确度、精密度和耐用性,符合定量检测的需求。     

线粒体示踪体系的建立及验证

目的 通过构建稳定表达线粒体荧光报告系统的牙髓干细胞（DPSC）建立线粒体示踪体系,并采用该示踪体系研究间充质干细胞（MSC）向辐射损伤细胞输送线粒体。方法 (1)构建质粒pSIN-EF1α-COX8A-DsRed2（简称COX8A-DsRed2）,并进行基因测序和PCR鉴定;COX8A-DsRed2用293T细胞包装获得慢病毒（Lv-COX8A-DsRed2）并感染DPSC,采用荧光显微镜观测红色荧光蛋白DsRed2在DPSC线粒体的稳定表达（DPSC-COX8A-DsRed2）。(2)在DPSC-COX8A-DsRed2中使用荧光染色法观察DsRed2荧光蛋白与线粒体膜受体线粒体外膜转位酶20(TOMM20)和线粒体示踪试剂MitoTracker Green的共定位。(3)采用10 Gy X射线照射大鼠小肠隐窝上皮细胞系IEC-6建立细胞辐射损伤模型,并使用5(6)-羧基二乙酸荧光素N-琥珀酰亚胺酯（CFSE）荧光染料标记IEC-6细胞;于照射后,立即加入DPSCCOX8A-DsRed2,继续培养24 h,荧光显微镜观察DPSC-COX8A-DsRed2能否向辐照受损细胞递送线粒体...     

临床试验质量管理量化测评体系的建立与验证

目的 建立和验证临床试验质量管理量化测评体系。方法 参考国内外指南,结合本院实践对质量问题进行分类、分级与评分,建立测评体系。用相关性与配对符号秩检验分析重测信度与测试员间可信度。结果 用本院临床试验项目验证该体系,同一测试员间隔2周重复判定质量问题,分类的相关系数为0.643～1.000,质量评分、重要和一般级别为0.895以上。不同测试员对分类判定的相关系数为0.616～1.000,质量评分、重要和一般级别为0.828以上。所有判定结果间无显著差异（P> 0.05）。严重级别的信度虽不高,但不影响整体判定。结论 本研究建立了可信度高的量化测评体系,可为临床试验质量管理提供标准化方法。     

冻干工艺和设备验证的研究

验证工作对制药企业药品生产的无菌保证至关重要,而灭菌验证尤为重要.本文采用文献法和案例法,运用V-模型阐述了我国在确认验证方面存在的不足,为完善我国制药企业在冻干工艺和设备方面的验证提出了建议和对策.     

总胆红素测定试剂盒行业标准的建立和实验验证

目的建立总胆红素测定试剂盒(钒酸盐氧化法)行业标准,并进行实验验证。方法选择不同生产厂家钒酸盐氧化法的总胆红素测定试剂盒,按照行业标准规定,对线性范围、准确度、精密度、稳定性等项目进行验证。结果不同试剂盒的各项指标均符合拟定的行业标准。结论总胆红素测定试剂盒(钒酸盐氧化法)行业标准制定合理、可操作性强。该标准的制定有助于统一总胆红素测定试剂盒(钒酸盐氧化法)的质量标准,为其生产、检验及流通等领域的监管提供依据。     

Determination of the moisture content of bromobutyl rubber stoppers as a function of processing: implications for the stability of lyophilized products

The purpose of the present study is to apply and contrast several analytical techniques to understand the change in moisture content of 20 mm diameter bromobutyl rubber stoppers as a function of typical stopper processing conditions. Three separate methods were examined and Karl-Fischer titration and techniques based on capacitance measurements at a thin-film sensor were found to provide comparable results. Stopper moisture levels were examined in stoppers: (i) as received from the manufacturer, (ii) following steam sterilization, (iii) as a function of various drying cycles, and (iv) during simulated hold conditions prior to use. Finally, the transfer of moisture from stopper to an actual product is examined on storage and general agreement observed between stopper drying conditions and cake moisture levels.     

Effect of stopper processing conditions on moisture content and ramifications for lyophilized products: comparison of "low" and "high" moisture uptake stoppers

The purpose of this study was to evaluate the effect of processing and storage on the moisture content of two commercially available, 13-mm lyophilization stoppers designated as low moisture (LM) and high moisture (HM) uptake stoppers. The stopper moisture studies included the effect of steam sterilization time, drying time and temperature, equilibrium moisture content, lyophilization and moisture transfer from stopper to a model-lactose lyophilized cake. Results indicated that both stoppers absorbed significant amounts of moisture during sterilization and that the HM stopper absorbed significantly more water than the LM stopper. LM and HM stoppers required approximately 2 and 8 h drying at 105 degrees C, respectively, to achieve final moisture content of not more than 0.5 mg/stopper. Following drying, stopper moisture levels equilibrated rapidly to ambient storage conditions. The apparent equilibrium moisture level was approximately 7 times higher in the HM versus LM stopper. Freeze-drying had minimal effect on the moisture content of dried stoppers. Finally, moisture transfer from the stopper to the lyophilized product is dependent on the initial stopper water content and storage temperature. To better quantify the ramifications of stopper moisture, projections of moisture uptake over the shelf life of a drug product were calculated based on the product-contact surface area of stoppers. Attention to stopper storage conditions prior to use, in addition to processing steps, are necessary to minimize stability issues especially in low-fill, mass lyophilized products.     

建立医院药品不良反应监测系统及工作体会

20世纪以来,世界上发生过很多起重大药害事件,导致成千上万人的致死致残,如1960年震惊世界的"反应停(Thalidomide)事件"和20世纪末发生的"苯丙醇胺事件".     

Practical formulation and process development of freeze-dried products

Freeze-drying science and technology continues to evolve and increase in importance because of the emergence of biotechnology drugs that are too unstable to be commercially available as ready-to-use solutions. As more new drug compounds need to be developed as freeze-dried products, this mini-review article provides practical guidance and commentary on the latest literature articles on formulation and process development of freeze-dried products. This article contains a table that provides the quantitative formulations of all commercial freeze-dried protein pharmaceutical products through 2004.     

The use of near-infrared spectroscopy in the efficient prediction of a specification for the residual moisture content of a freeze-dried product

The purpose of this study is to improve the efficiency in the search for a suitable specification for the residual moisture content in a freeze-dried product. A near-infrared spectroscopic (NIRS) method was developed for the measurement of the residual moisture content. Samples with a wide range of residual moisture contents were stored for two months at 8, 50, and 60°C. Because of the non-destructive character of the NIRS method initially the residual moisture content and, subsequently, the content of the active ingredient could be measured in the same sample vials after storage. Plots of the residual moisture content against the content of the active ingredient were made for storage at 50 and 60°C. For this only 69 samples were needed in the stability study for the assay determination while traditionally a five-fold of samples is needed because of the high intra-batch variability of the residual moisture content. The plots at 50 and 60°C were combined with the Arrhenius relationship between degradation rate constant and temperature. The maximal allowable residual moisture content was calculated for product shelf-lives of 2 and 3 years and storage temperatures of 20, 25, and 30°C, respectively.     

某院药物相关问题分类系统的建立及初步验证

目的 对现有药物相关问题分类系统进行改进,在此基础上建立某院药物相关问题分类系统,为更好地监控药物相关问题,促进患者用药安全及节省医疗费用提供帮助.方法 在对公开发表的DRPs分类系统进行分析汇总的基础上,选择一相对较完善的系统,结合某院的实际情况,建立适合某院的药物相关问题分类系统,并进行初步验证.结果 建立的新系统...     

胶塞可挥发性物质的迁移及其对头孢曲松钠的可能影响

目的研究来源于胶塞的可挥发性物质向头孢曲松钠的迁移,并对这些可挥发性物质与头孢曲松钠的可能影响进行分析。方法应用气相色谱方法对澄清度不合格注射用头孢曲松钠及所用胶塞的可挥发性物质进行测定。结果在头孢曲松钠样品中可测得来源于胶塞的较高沸点可挥发性物质,而较低沸点可挥发性物质及C13H23Br未在头孢曲松钠样品中测得。结论来源于胶塞的高沸点可挥发性物质能够迁移进入头孢曲松钠,并被头孢曲松钠吸附,部分物质能与头孢曲松钠发生进一步的作用。     

Establishment and effect of the drug safety management monitoring system

Early detection and early treatment of adverse drug reactions have recently become more important. It is natural that physicians should treat adverse drug reactions carefully, but it is also important to establish a system for their early systematic detection and treatment. Therefore, by comparing current data with that preserved in our clinical laboratory's data management registry and identifying values significantly different from earlier values, we established a screening system for any condition which may have a possible relationship with drugs and feeds back the results to the physician(s) in charge (drug safety management monitoring system). The effectiveness of the system was then evaluated. The subjects were outpatients who visited the Diabetes Endocrine Metabolism Center of our hospital during a six-month period. Cases where the possibility of a relationship between abnormal changes of laboratory data and drugs was not ruled out were reported to the attending physician using a drug safety monitoring report form. In 14 of 34 cases reported, a relationship with drugs could not be ruled out. Two of these 14 cases were reported to the Ministry of Health, Labour and Welfare because they were serious. Therefore, it was concluded that this system was useful for early detection of adverse reactions.