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Johnson Hou
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Shanghai, Shanghai, China
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May 19, 2023 (posted via ProZ.com):  Just completed a IPO-related translation+editing job, Chinese to English, 28,000 words, for a China company to be listed on HK stock exchange ...more »
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English to Chinese: Nexium becomes no. 1 best-selling PPI worldwidea
Source text - English
Nexium has achieved world number one status in the Proton Pump Inhibitor market* - a remarkable success story in just five years since launch. But the story has just begun. Here we look at the advantages and future opportunities for Nexium. Just a month ago, CEO Sir Tom McKillop commented: "The whole pharmaceutical industry is full of admiration for what has been achieved with Nexium. Many CEOs tell me what a fantastic job XXX has done with the product, and indeed how we have set the benchmark in developing a therapeutic area with Nexium." CEO designate Dave Brennan added:"You take a look at what we've accomplished with this product, and I think it silences a lot of the critics. We¡¯ve been able to do it because it is a better product, and we¡¯ve been able to demonstrate that to patients and to customers in marketplaces around the world." With 26.6 percent of the PPI market value worldwide, Nexium beat the closest competitor lansoprazole for the first time in October *, despite being launched in fewer markets. Eight years ago, XXX ¡¯s best-known product ¨C Losec ¨C was the biggest-selling prescription drug in the world. The company was very much a pioneer in the GI field and Losec was a first-in-class drug, the first proton pump inhibitor (PPI) for treating acid-related diseases. But despite its success, there were still unmet patient needs ¨C and there were still symptom breakthroughs." So the company was very much committed to finding a better product and we explored hundreds of different compounds to find an alternative," said Nexium VP Peter Wallich. "In the end ¨C and completely unexpectedly ¨C we found that one of the isomers of Losec showed completely different characteristics to the other, demonstrating increased bioavailability, decreased inter-individual variability and better acid control, and a greater potential than Losec for patient benefits." "We concentrated on areas of greatest need and there was a huge marketing effort with a very consistent brand position ¨C demonstrating better efficacy for many patients and meeting patient needs. A range of studies against our competitors ¨C and against Losec ¨C established that Nexium was the most effective PPI in the world, offering distinct clinical improvements for many patients over all other PPIs on the market," said Peter. "We had been looking for a drug that was better than Losec ¨C and we found it in Nexium. Nexium is now regarded as the gold standard in PPI therapy." Said Sir Tom: "This isn't some kind of mirage, or a bit of mythology, or marketing skill alone. Success begins with the product. It begins with the quality of the clinical studies that we've conducted; the strength of evidence, and then followed, of course, by the professionalism of the sales and marketing. Becoming number one is a huge achievement and a tribute to everyone in the company who has been associated with the product. This is a $4.5billion a year product within five years of launch ¨C the most successfully launched product ever in the history of the industry ¨C still growing at 20% a year ¨C fantastic!" Dave Brennan said: "It is important to remember how much of a difference this product makes for patients. It makes a difference to people¡¯s lives and allows them to return to doing things that they might not have been able to do in their lives for a long time." Nexium was first launched in Sweden in August 2000 and is now available in over 100 markets. Gaining approval for its use in the healing and prevention of ulcers associated with NSAID (non-steroidal anti-inflammatory drug) therapy was particularly significant at a time when some COX-2 painkillers ¨C with their promise of reducing GI ulcers ¨C were questioned by regulatory authorities because of CV side-effects. ¡°It put Nexium in a good position,¡± said Peter. Many patients treated with COX-2s or NSAIDs have GI symptoms and risk of ulcer due to these medicines and consequently are prescribed Nexium. The biggest success for Nexium has been its effectiveness in treating GERD ¨C gastroesophageal reflux disease. Some 20% of adults in the western world suffer from GERD and its associated heartburn pain. For the future, to build on its current status as world number one PPI, the company is concentrating on developing the market for GERD treatment ¨C and investigating Nexium¡¯s use in other related areas. "If you look at what we've accomplished with Nexium in the first five years, it really gives us an ambitious target for the future of this product. Getting to be number one is a tremendous accomplishment, and we now need to distance ourselves from number two. We want to be number one by a long shot and I think the sky¡¯s the limit. This is still a big market; there are still opportunities for us to grow within the market, and what we need to do is think about broadening our leadership position so that we can truly realise the full potential of this product in the marketplace." Said Dave Brennan. 		Translation - Chinese
耐信成为全球最畅销的质子泵抑制剂 耐信已在质子泵抑制剂 (PPI) 市场上获得了全球第一的地位*，这是耐信自投放市场以来整整五年内一个极为成功的创举。 但是这只是一个开头，接下来让我们来看看耐信的优势和发展前景如何。 一个月前，XXX 公司首席执行官麦奇洛爵士 (Tom McKillop) 发表评论指出：“整个制药行业都对耐信所取得的成功羡慕不已， 许多CEO告诉我说XXX 在耐信方面所做的工作简直是太神奇了。的确，我们在开发耐信的治疗领域方面已建立了一个具有重要意义的里程碑。” XXX 现任首席执行官 Dave Brennan 补充道：“大家都可以看到我们在这一产品上所取得的成功，我想它足以使许多批评销声匿迹。 我们之所以能取得这么好的成绩，是因为耐信是一款非常出色的产品，我们也已经向全球市场上的患者和客户证明了这一点。” 虽然耐信投放的市场不多，但是它却拥有26.6 %的全球 PPI 市场份额，并在十月份首次击败了最具竞争力的药物兰索拉唑 (lansoprazole)*。 八年前，XXX 最有名的产品――洛赛克是全球最畅销的处方药。 当时的阿斯利康公司在胃肠道治疗领域一直处于领先地位，洛赛克是一种极好的药物，是治疗酸性相关疾病的首选质子泵抑制剂（PPI）。 洛赛克虽然有其成功之处，但我们仍然未能满足某些患者的需求，而且仍然需要在改善患者的症状方面有所突破。耐信副总裁 Peter Wallich 表示：“所以我们一直致力于开发一种更好的产品，并通过研究上千种不同的化合物来寻求洛赛克的替代产品。”。 “完全出乎意料的是：最后我们在洛赛克的众多同分异构体中发现了一个特性与其它完全不同的药物。在患者受益方面与洛赛克相比，这种药物具有更高的生物利用度、更低的个体间变异度、更好的酸性控制能力和更高的潜力。” Peter 补充道：“我们把重点放在需求最大的领域。虽然在一个巨大的市场上维持一个品牌的长久地位需要付出艰辛的努力，但我们所做的一切证明：对于许多患者来说，这种药物具有更好的疗效并能满足他们的需求。“针对我们的竞争对手和洛赛克所做的一系列研究表明：耐信是世界上最有效的质子泵抑制剂，与市场上的所有其它质子泵抑制剂相比，它能为许多患者带来特别明显的临床改善。我们一直在寻找一种比洛赛克更好的药物，现在我们终于有所发现，它就是耐信。目前，耐信被认为是质子泵抑制剂治疗的黄金标准。” 麦奇络爵士指出：“耐信的成功不是什么海市蜃楼，不是什么传奇神话，也不是单纯的市场技巧。 它的成功源自于产品本身， 源自于我们所进行临床研究的质量和证据的有力性，当然接下来就是销售和市场上的专业性。 成为世界第一是一项巨大的成就，而且对与该产品有关的公司里的每个人来说也是一种奖励。 该产品在投放市场的短短五年里就达到了每年 45 亿美元的销售业绩，成为了业界历史上最成功的产品。同时它仍然以每年 20% 的速度增长，简直是太不可思议了！” Dave Brennan 指出：“需要重点指出的是，该产品为患者带来了极大的变化。 它使人们的生活产生了变化，使他们能够重新做以前在生活中很长时间都不能做的事情。” 耐信在 2000 年 7 月首次在瑞典投放市场，现在已在100多个市场上销售。 当一些声称可以减少胃肠道溃疡的 COX-2（环氧化酶 2）止痛药因为心血管 (CV) 副作用而受到监管部门的质疑时，耐信在治疗和预防NSAID（非甾体抗炎药）治疗所引起的溃疡方面的使用而得到了认可，因而立刻成为了人们关注的焦点。 Peter 接着说道：“这使得耐信处于一种十分有利的地位”。 许多使用 COX-2 或 NSAID 的患者都有胃肠道症状以及因使用这些药物而引起溃疡的危险性，因此人们都开始使用耐信。 耐信最大的成功是在治疗GERD――胃食管返流疾病方面特别有效，而西方国家有20%的成年人都患有胃食管返流疾病以及与之相关的胃灼热痛。 对于将来，为了巩固目前耐信作为世界一号 PPI 的地位，XXX 公司正集中于开发 GERD 治疗市场，并在调查耐信在其它相关领域的应用。 Dave Brennan 补充道：“如果你看到我们在过去五年所取得的成就，你肯定会对耐信的前景充满希望，同时它也确实给我们带来了极大的信心。 成为世界第一是一项巨大的成就，我们现在需要努力去永远保持第一。 我们希望能在长时间内保持这个第一，“海阔凭鱼跃，天高任鸟飞”，我想我们必定会大有作为。 这是一个巨大的市场，在这个市场里我们仍然有很多机会去发展，我们需要做的是思考如何扩大我们的领导地位，这样我们才能真正挖掘出该产品在市场上的所有潜力。”
English to Chinese: MassTrak™ Systems
Source text - English
XXX Corporation, incorporating XXX Technologies, has over 40 years history of developing innovative HPLC, mass spectrometry, software, chemistry and support services. XXX can now provide clinical research laboratories with complete solutions that can improve the accuracy and precision of your assays, and increase productivity. MassTrak™ Systems bring the power of tandem mass spectrometry in a robust, easy-to-use, cost-effective package. These systems bring new levels of sample throughput, sensitivity, specificity and flexibility for therapeutic drug monitoring, toxicology and many other applications. For clinical research laboratories, MassTrak™ Systems provide: • Fast Speed of Analysis Enable high sample throughput and rapid turnaround of time-sensitive samples • Improved Specificity Eliminate cross-reactivity problems associated with immunoassays, providing excellent accuracy and precision for therapeutic drug monitoring and clinical biomarker analysis • Increased Sensitivity Give reliable results at low ng/mL levels, especially important for emerging drug therapies • Enhanced Flexibility Provide the capability to analyze a wide range of compounds on the same system • Robust Tandem MS Methods Ensure the quality and reliability of analysis MassTrak™ Systems for LC/MS/MS Set New Standards for Clinical Research Applications Many of the assays performed in research laboratories involve the identification and quantification of chemical species in complex biological matrices. Today¡¯s clinical chemists demand more accurate and cost-effective analytical tools that can be easily integrated into current laboratory practices. LC/MS/MS is ideally suited to many clinical research applications as the selectivity of the technique enables individual analytes to be quantified confidently. MassTrak™ Systems integrate HPLC, chemistries, mass spectrometry, software and support services for clinical research facilities worldwide. Single vendor support is also available through XXX dedicated clinical team. LC/MS/MS Applications MassTrak™ Systems are offered for therapeutic drug monitoring and drugs of abuse analysis including both confirmation and systematic toxicological analysis. These systems include a HPLC, a mass spectrometer and a data application manager, and are routinely used in clinical research laboratories worldwide for the following applications: Therapeutic Drug Monitoring • Cyclosporin A • Tacrolimus • Sirolimus • Everolimus • Mycophenolic Acid • Tobramycin Inborn Errors of Metabolism • Amino Acid Disorders • Fatty Acid Oxidation Defects • Organic Acidemias Clinical Biomarkers • Homocysteine • Methylmalonic Acid • Vitamin D • Steroid analysis • Catecholamines and Metanephrines Clinical and Forensic Toxicology • Amphetamines • Opiates • GHB • Cannabis and Metabolites • Cocaine • Benzodiazepines XXX MassTrak™ Systems Applications Inlet Instrumentation MS Instrumentation Applications Managers Therapeutic Drug Monitoring Alliance® HT 2795 Quattro micro™ QuanLynx™ Drugs of Abuse: Confirmation/Quantification Alliance® HT 2795 Quattro micro™ TargetLynx™ Drugs of Abuse: Systematic Toxicological Analysis Alliance® 2695 ZQ™ ChromaLynx™ 		Translation - Chinese
XXX 公司有40多年的历史，随着与XXX 公司质谱技术的强强联合，已经具备研发最先进的高效液相色谱法(HPLC)、质谱分析法、软件分析法、化学分析法的能力，并能够提供相应的服务。目前XXX 公司能够为临床研究实验室提供完备的解决方案，从而可以提高其测量的精确度和精密度，并提高其生产力。 MassTrakＴＭ系统的串联质谱技术具备功能强大、使用便利、成本高效益化等一系列优点。这些系统能为治疗药物监测、毒理学以及其它许多应用提供高水准的样品处理能力、灵敏度、特异性和灵活性。 MassTrakＴＭ系统可为临床研究实验室提供： •快速分析能力 具备高效的样品处理能力和时间敏感性样品迅速周转的能力 •高效特异性 可消除与免疫测定相关的交叉反应现象，为治疗药物监测和临床生物标记分析提供极高的精确度和精密度。 •高度灵敏性 可以在低ng/mL水平提供可靠的分析结果，这对于新研发的药物治疗方法尤为重要。 •高度灵活性 为同一系统中的大量复合物提供分析的能力 •功能强大的串联质谱法 确保分析的质量和可靠性 符合临床研究应用新标准的LC／MS／MS设备的MassTrakＴＭ系统 研究实验室进行的许多分析包括复合生物学基质中化学种类 的鉴定和定量分析。当今的临床化学家要求有更精确且成本高效益化的分 析仪器能够与目前实验室的实际工作有效地结合起来。 因为可以选择不同的技术对个体分析物进行可靠的定量分析，所以ＬＣ／ＭＳ／ＭＳ设备是很多临床 研究应用的理想选择。该设备的MassTrakＴＭ系统融高效液相色谱法(HPLC)、化学分析法、质谱分析法、软 件分析法为一体，并能为全球的临床研究设施提供支持服务。沃特斯公司也有专业的临床队伍可为零售商提供支持。 LC／MS／MS应用 MassTrakＴＭ系统可用于治疗药物的监测和滥用药物的分析，其中包括药物的确认和 系统毒理学分析。这些系统包括一台高效液相色谱仪、一台质谱仪和一台资 料应用管理器，可进行全球临床研究实验室的下列 常规应用： 治疗药物监测 环孢霉素A 先天性代谢缺陷 临床生物标记 临床和法医毒理学 •他克莫司（Tacrolimus） •氨基酸病（Amino Acid Disorders） 高半胱胺酸(Homocysteine) •苯异丙胺(Amphetamines) •西罗莫司（Sirolimus） •脂肪酸氧化缺陷（Fatty Acid Oxidation Defects） •甲基丙二酸(Methylmalonic Acid) •鸦片(Opiates) •依维莫司（Everolimus） •有机酸酸血症（Organic Acidemias） •维生素Ｄ(Vitamin D) •γ-羟基丁酸盐(GHB) •依维莫司（Everolimus） •类固醇分析(Steroid analysis) •大麻及其代谢产物(Cannabis and Metabolites) •霉酚酸（Mycophenolic Acid） •儿茶酚胺类和甲氧基肾上腺素(Catecholamines and Metanephrines) •可卡因(Cocaine) •妥布霉素（Tobramycin） •苯二氮卓类(Benzodiazepines) 沃特斯MassTrakＴＭ系统 应用 入口仪器 质谱仪仪器 应用管理器 治疗药物监测 Alliance® HT 2795 Quattro micro™ QuanLynx™ 滥用药物：确认与定量分析 Alliance® HT 2795 Quattro micro™ TargetLynx™ 滥用药物：系统毒理学分析 Alliance® 2695 ZQ™ ChromaLynx™
Chinese to English: A Phase Ⅲ, Randomized, Double-Blind Controlled, Multi-Center Clinical Trial of Rh-Endostatin (YH-16) + NP Regimen in 493 patients with Non-Small-Cell Lung Cancer (NSCLC)
Source text - Chinese
讨 论
目前晚期非小细胞肺癌的化疗已经进入一个平台期[9-11]，尽管化疗方案已进入第三代，但患者的生存受益仍然有限，因此寻找新的治疗手段和方法以期提高疗效。自1971年Folkman提出肿瘤血管生成的理论以来，把抗肿瘤新生血管生成作为治疗肿瘤侵袭和转移的一个重要研究领域。很多临床研究说明，肺癌病人内皮抑制素的水平和临床又无淋巴结转移相关[12]。实验研究表明，重组血管内皮抑制素对小鼠Lewis肺癌有稳定的抑制效应[13]。近年来许多研究表明，抗血管生成治疗与化疗药联合应用有可能提高疗效，带来生存受益。最令人鼓舞的是抗VEGF单抗bevacizumab（Avastin）联合化疗治疗813例初治的大肠癌患者[14]，与单纯化疗比较，中位生存期、中位TTP和总有效率都有提高。因此，抗血管生成药物与化疗联用成为目前研究的热点。
1．临床疗效分析
我们对493例III/IV期非小细胞肺癌患者使用NP＋YH-16和NP方案进行了III期、双盲、随机对照研究，在可评价疗效的486例患者中，NP＋YH-16和NP的总有效率分别为35.40％和19.51%，P＜0.01；总临床受益率为73.29％和 64.02%，P＜0.05；总的中位TTP为6.25月和3.59月， P＜0.001。
Le Chevalier T 等报告NP方案较长春花碱酰胺+顺铂治疗晚期非小细胞肺癌可使患者获得明显的生存受益，从而确立了NP方案作为治疗晚期NSCLC的标准治疗方案[15]。西南肿瘤协作组（SWOG）进行的III期随机研究表明，NP方案治疗晚期非小细胞肺癌的有效率是26％，无进展生存时间是4月，总的生存时间是8月，一年的生存率是36％[16]。国内孙燕，张湘茹等进行III期随机研究报告， NP方案治疗晚期NSCLC的有效率是42.0%－47.6% ，中位缓解期是3.3月，中位生存时间是8.5月[17，18]。
我们的研究中，NP方案的疗效和国外随机研究结果相似，总有效率分别为19.51%和26％，中位TTP分别为3.59月和4月。我们报告的NP方案的有效率较国内报告的有效率偏低，但中位的TTP相似，分别为3.59月和3.3月。这可能与本研究是大型的III期随机研究，并进行了严格的疗效确认有关。本研究中观察到的NP联合YH-16总有效率和中位TTP均显著优于目前NP方案国内外的疗效。表明NP方案联合YH-16能提高晚期非小细胞肺癌的总有效率和延长总的中位TTP。
一线治疗（初治）NP＋YH-16和NP的有效率分别为40.00％和23.93%，P＜0.01；临床受益率为76.52％和64.96％，P＜0.05；中位TTP 6.61月和3.65月，P＜0.001。
复习文献，TAX326研究中以泰素蒂联合铂类和NP方案作为一线治疗治疗晚期非小细胞肺癌，NP方案的有效率24.5%,中位肿瘤进展时间是3.1个月，中位生存时间为10.1个月，1年和2年生存率分别为41％和14％[19]。我们观察到NP方案的有效率为23.93%与TAX326报道的NP方案的结果非常接近，YH-16联合NP方案的有效率较NP方案提高16%,并且中位TTP也延长2.9个月，虽然目前尚未观察到中位生存时间和1年生存率，但目前的资料已经表明YH-16＋NP作为一线治疗中效果优于NP方案。考虑两种完全不同作用机制的药有协同作用。
国际上著名的ECOG1594研究表明，一线治疗采用第三代的化疗方案（紫衫醇＋顺铂，紫衫醇＋卡铂，健择＋顺铂，多烯紫衫醇＋顺铂），四组的疗效均在20％左右，将四组患者的有效人数相加，总的有效率为19％，总的中位TTP为3.6个月，中位生存期7.9个月，1年和2年生存率分别为33％和11％。值得注意的是ECOG1594研究是一个大型的III期随机研究总共入组了1207例患者，虽然其报告的有效率偏低，但却代表目前晚期非小细胞肺癌的化疗现状[19]。在我们的研究中，所有疗效的判定均是经过独立的专家评审委员会进行确认, 我们观察到的NP方案的有效率和中位TTP与目前常用的第三代化疗方案的有效率和中位TTP相似，我们的研究中，作为一线治疗NP＋YH-16较NP方案的有效率明显提高（40.00％和23.93%，P＜0.01），中位TTP明显延长（6.61月和3.65月， P＜0.001），YH-16＋NP方案可能优于目前的第三代化疗方案，但尚需进一步研究证实。
二线治疗（复治）NP＋YH-16和NP的有效率分别为23.91%和8.51%，P＜0.05；
临床受益率65.22％和61.70％， P＞0.05；中位TTP 5.72和3.16月， P＜0.001。
目前对于非小细胞肺癌的二线标准治疗是多烯紫衫醇单药，有效率10％左右,中位生存期6个月左右，1年生存率20％左右[21]。二线治疗使用的单药还包括异环磷酰胺、Alimita等，但疗效均低于10％[20，21]。二线治疗选择使用单药的原因主要是考虑了患者以往化疗情况、重要脏器功能以及患者的耐受情况。本研究中，二线治疗患者的选择是既往未用过NP或用过NP方案有效且停药达6个月以上。本组资料中单用NP方案治疗的有效率和目前国外二线治疗报道的结果相似，尽管NP＋YH-16较单用NP方案在临床受益率上没有统计学意义（65.22％和61.70％， P＞0.05），但联合YH-16后有效率提高15.4%（23.91%和8.51%，P＜0.05），中位TTP也有明显延长（5.72和3.16月， P＜0.001）,表明YH-16在复治患者中与NP同样有协同作用，疗效优于NP方案并可使患者的生存受益，YH-16与化疗联合可能会改变目前NSCLC二线治疗使用单药的现状。
晚期NSCLC治疗作用是以缓解症状、延长生存期为目的的，因此提高生存质量作用显得较为重要[24，25]，也是确定任何一个新的治疗的价值所在。本研究中，NP+YH-16组与NP组疗后QOL评分比较，有明显提高（P=0.0155）。
2． 影响疗效因素的分析
我们对可能影响NSCLC患者预后的因素包括病理类型、临床分期、PS、既往治疗情况、性别、年龄等情况也进行了分析。对这些因素进行分层分析表明，在既往治疗初治或复治、病理类型鳞癌或腺癌、PS 0－1，性别、年龄≥40岁的情况下，治疗组与对照组的有效率和中位TTP都有统计学差异（P＜0.05）。在IV期的患者中，治疗组与对照组的疗效有统计学差异（P＜0.05），而无论临床分期如何，治疗组与对照组的中位TTP均有统计学差异（P＜0.05)。
本研究中PS≥ 2的患者并未从治疗中受益，原因可能归于这些患者通常有进行性的脏器功能减退和多种并发症。ECOG1594表明，PS 2的晚期非小细胞肺癌患者不能耐受铂类的化疗（包括紫衫＋顺铂、紫衫＋卡铂、泰素蒂＋顺铂、健择＋顺铂）。许多大型的随机研究[25-26]表明，从NP方案中主要受益的是PS 0-1的患者。
目前对于功能状态良好的患者联合化疗是标准的治疗模式。然而，对于老年晚期非小细胞肺癌的患者支持使用联合化疗的临床资料还很有限。大型III期临床随机试验的亚组分析表明[27-28]，功能状态良好的老年患者也能像年轻患者一样接受联合化疗。我们的研究表明对于年龄≥40岁（包括年龄大于60岁），治疗组与对照组的有效率和中位TTP均有统计学差异（P＜0.05)。在年龄＞60岁亚组中，治疗组与对照组临床受益率比较有统计学差异（P＜0.05)。表明YH-16联合NP治疗老年患者可以带来生存方面的裨益。
对可能影响疗效的因素（治疗分组、性别、既往治疗、临床分期、转移灶数目、基础疾患或合并症、年龄、身体状况评分、体重指数、病程）进行多因素logistic回归分析表明，治疗分组、性别、既往治疗、身体状况评分和体重指数是影响疗效的因素，其贡献的P值分别为0.0006、0.0178、0.0032、0.0116和0.0248。
文献报道，影响化疗疗效的因素主要包括患者的功能状态（PS）和疾病的程度[20]。影响的预后因素包括有无体重下降、性别、LDH水平、有无肝或骨转移。本组均为局部晚期或播散性NSCLC患者，其中在影响疗效的因素中以治疗分组（P		Translation - English
Discussion
Presently, the chemotherapy of advanced non-small cell lung cancer (NSCLC) has come into a plateau stage [9-11] . Though the chemotherapy regimen has developed into third generation, the survival benefits of patients are still limited, so we need to look for new therapeutic tools and methods to increase efficacy. Since the theory of tumor angiogenesis was proposed by Folkman in 1971, the anti-angiogenesis of tumor has been made as one important research field for treating invasion and metastasis of tumor. Many clinical researches show that the level of endostatin in patients with lung cancer is related to the clinical lymph node metastasis [12]. Experimental researches show that the reorganization of endostatin has stable depression effect for the Lewis lung cancer of mice [13] Recently, many researches show that the combined therapy of anti-angiogenesis and chemotherapy drugs may increase efficacy and bring about survival benefit. What is most encouraging is that the median survival time, median TTP and total efficacy rate of 831 cases of initial treatment with carcinoma of large intestine who received combined chemotherapy of anti-VEGF and Bevacizumab£¨Avastin£©were increased in comparison with the simple chemotherapy. Hence, the combination of anti-angiogenesis drugs and chemotherapy is the focus of research presently.
1. Analysis of Clinical Efficacy
We conducted a phase III, double-blinded, randomized control study of the NP+YH-16 and NP regimens in 493 cases with NSCLC at the III/IV stage. Of the 486 cases with evaluable efficacy, the total efficacy rates in the NP+YH-16 and NP groups were 35.40£¥ and 19.51% (P
Chinese to English: Overview of Production Methods of Rabies Vaccine for Human Use
Source text - Chinese
一、人用狂犬病疫苗生产方法概述
本品系用狂犬病毒固定毒接种原代地鼠肾细胞，培养后，收获病毒液，经病毒灭活、浓缩、纯化，以PBS稀释，加入人血白蛋白制成。用于预防狂犬病。
1 基本要求
生产、检定用设施、原料及辅料、水、器具、动物等应符合《中华人民共和国药典》2005年版三部“凡例”要求。
2 生产
2.1生产用细胞
生产用细胞为原代地鼠肾细胞或连续传代不超过5代的地鼠肾细胞。
2.1.1细胞管理及检定
应符合《中华人民共和国药典》2005年版三部《生物制品生产用动物细胞基质制备及检定规程》的有关规定。
2.1.2细胞制备
选用12~14日龄健康地鼠，无菌取肾，剪碎，经胰蛋白酶消化、分散细胞，接种培养瓶，用含0.4%水解乳蛋白的E氏平衡盐溶液加入8%~10%的灭活小牛血清进行培养。同一生产周期、用同一批原材料、同一方法制作的原液为一批。
2.2毒种
2.2.1名称及来源
生产用毒种为狂犬病病毒固定毒aG株。
2.2.2种子批的建立
应符合《中华人民共和国药典》2005年版三部《生物制品生产检定用菌种、毒种管理规程》的规定。
原始种子批系从中检所购入，代次为4aG2。主种子批代次为4aG3，工作种子批代次为4aG4。
2.2.3种子批的检定
主种子批应进行如下全面检定，工作种子批应至少进行2.2.3.1~2.2.3.5项检定。
2.2.3.1鉴别试验
以小鼠脑内中和试验，鉴定毒种的特异性。中和指数应不低于500。
2.2.3.2病毒滴定
取毒种作10倍系列稀释，每个稀释度脑内接种体重11~13g小鼠至少6只，病毒滴度应为8.0 ~9.5LgLD50/ml。
2.2.3.3无菌检查
依法检查（《中华人民共和国药典》2005年版三部附录ⅫA），应符合规定。
2.2.3.4支原体检查
依法检查(《中华人民共和国药典》2005年版三部附录ⅫB)，应符合规定。
2.2.3.5病毒外源因子检查
依法检查(《中华人民共和国药典》2005年版三部附录ⅫC)，应符合规定。
2.2.3.6免疫原性检查
将主种子批毒种直接灭活，制备成原疫苗，腹腔注射体重为12~14g小鼠，每只0.5ml。1周后重复接种1次。第一次免疫后的第14天，用10倍系列稀释（10-5、10-6、10-7、10-8）的CVS病毒脑内攻击每只0.03ml，每个稀释度10只小鼠。同时用同样体重未免疫的小鼠，用10倍系列稀释（10-2、10-3、10-4、10-5）的CVS病毒脑内攻击作对照，每个稀释度10只小鼠，每只0.03ml。保护指数应不低于200。
2.2.4毒种保存
冻干毒种应置-20℃以下保存，液体工作种子批毒种置-60℃以下保存应不超过2年。
2.3原液制备
2.3.1细胞制备
按2.1.2项进行。
2.3.2培养液
用含0.4%水解乳蛋白的E氏平衡盐溶液加入8%~10%的灭活小牛血清，调PH7.0~7.2培养细胞。小牛血清的质量标准应符合《中华人民共和国药典》2005年版三部(附录ⅩⅢD)规定。
2.3.3对照细胞外源因子检查
依法检查(《中华人民共和国药典》2005年版三部附录ⅫC)，应符合规定。
2.3.4病毒接种、培养
将狂犬病毒毒种上清液与细胞悬液以混种于细胞培养瓶中，狂犬病毒毒种接种量：0.01～0.1MOI(或4.5～5.5 LgLD50/ml),于36.5℃±1℃培养68~76小时，使细胞培养成致密单层，然后弃去培养液，用生理盐水冲洗去除小牛血清，加入含0.2%人血白蛋白的199维持液继续置34℃±1℃培养6~7天。
2.3.5病毒收获
培养结束，收获病毒液。
2.3.6 病毒单一收获液检定
按3.1 项进行。
2.3.7 病毒灭活
病毒收获液中加入1/5000甲醛溶液，在26℃±1℃条件下灭活96±1小时，每天摇动2次，即为灭活病毒液。
2.3.8 病毒灭活验证试验
病毒灭活后立即取样做病毒灭活验证试验，按3.1.4项进行。
2.3.9 灭活病毒液浓缩、纯化
2.3.9.1合并及超滤、浓缩
同一批生产的病毒收获液，经分子量为300KD的超滤膜超滤浓缩60倍±10倍，取样测定蛋白质含量，蛋白质含量应为25mg/ ml- 40mg/ ml，浓缩后杂蛋白去除率不低于82%。
2.3.9.2 纯化
经浓缩并检定合格后的病毒液，以Sepharose 4FF凝胶柱层析方法纯化，每次上样量是柱内凝胶体积的5~10%，以PH值7.6、浓度0.01M的PBS洗脱，用OD280紫外监测，收集第一峰，取样测定蛋白质含量，蛋白质含量应为150μg/ ml-300μg/ ml，纯化后杂蛋白去除率不低于99%。纯化后加入人血白蛋白作稳定剂，同时加入硫柳汞作防腐剂，即为疫苗原液，纯化原液中人血白蛋白含量为0.4%，硫柳汞含量为0.0025%。
2.4 原液检定
按3.2项进行。
2.5 半成品制备
2.5.1 配制
根据测定的蛋白质含量和测定的抗原含量配制半成品，按半成品中蛋白质含量为60μg/剂进行配制。配制时再加入人血白蛋白、硫柳汞，即为半成品，半成品中人血白蛋白含量为2%，硫柳汞终浓度为0.003%。
2.5.2 半成品检定
按3.3项进行
2.6　成品制备
2.6.1分批
应符合《中华人民共和国药典》2005年版三部《生物制品分批规程》有关规定。
2.6.2分装
应符合《中华人民共和国药典》2005年版三部《生物制品分装、冻干规程》的有关规定。
2.6.3规格
每瓶为1.0ml，每次人用剂量为1.0ml，狂犬病疫苗效价应不低于2.5IU。
2. 6.4包装
应符合《中华人民共和国药典》2005年版三部《生物制品包装规程》的有关规定。
3.检定
3.1病毒单一收获液的检定
3.1.1病毒滴定
按2.2.3.2项进行，滴度应为6.0 ~8.0LgLD50/ml。
3.1.2无菌检查
依法检查（《中华人民共和国药典》2005年版三部附录ⅫA），应符合规定。
3.1.3支原体检查
依法检查（《中华人民共和国药典》2005年版三部附录ⅫB），应符合规定。
3.1.4灭活验证试验
采用动物法，将病毒灭活后的原液脑内接种体重为11~13g小鼠20只，每只0.03ml，观察14天，应全部健存（3天内死亡的不计）。
3.2原液检定
3.2.1无菌检查
依法检查（《中华人民共和国药典》2005年版三部附录ⅫA），应符合规定。
3.2.2蛋白质含量测定
取纯化后未加入人血白蛋白的原液，依法测定，应为50~82μg/剂，见《中华人民共和国药典》2005年版三部（附录ⅥB第二法）。
3.2.3抗原含量
取纯化后未加入人血白蛋白的原液，用酶联免疫法测定抗原含量，应不低于10IU/ml。
3.2.4牛血清白蛋白残留量
采用酶联免疫法，牛血清白蛋白残留量应不高于50ng/剂。
3.3半成品检定
无菌检查
依法检查（《中华人民共和国药典》2005年版三部附录ⅫA），应符合规定。
3.4成品检定
3.4.1鉴别试验
按3.4.4项进行，应符合规定。效价测定不合格时， 鉴别试验不成立。
3.4.2外观
无色澄明液体。
3.4.3化学检定
3.4.3.1PH值
应为7.2~8.0（《中华人民共和国药典》2005年版三部附录ⅤA）。
3.4.3.2硫柳汞含量
应为0.01 ~0.06mg/ml（《中华人民共和国药典》2005年版三部附录ⅦB）。
3.4.3.3游离甲醛含量
应不高于0.05mg/ml(《中华人民共和国药典》2005年版三部附录ⅥL)。
3.4.4效价测定
放行标准应不低于4.0IU/剂，有效期内效价应不低于2.5IU/剂。效价试验同时检测2组动物，以计算均值作为结果（《中华人民共和国药典》2005年版三部附录ⅪA）。
3.4.5热稳定性试验
出厂前进行热稳定性试验。37℃放置2周后按3.4.4项进行效价测定，应不低于2.5IU/剂。
3.4.6无菌检查
依法检查(《中华人民共和国药典》2005年版三部附录ⅫA)，应符合规定。
3.4.7异常毒性检查
依法检查(《中华人民共和国药典》2005年版三部附录ⅫF)，应符合规定。
3.4.8细菌内毒素检查
应不高于100EU/剂(《中华人民共和国药典》2005年版三部附录ⅫE凝胶限量试验)。
4 保存、运输及有效期
于2~8℃避光保存和运输。自效价测定合格之日起，有效期为12个月。
二、我公司直接负责技术及监控药品生产的人员共有十名，名系如下：
序号 姓 名 资 历 岗 位 职 务
杨光林 四川大学，生物学专业本科，
相关工作经验四十年 生产总监
于淑萍 中央党校，生物制品专业专科，
相关工作经验三十八年 生产管理部 经 理
李 鹏 中国人民解放军军需大学，生物制品专业本科，相关工作经验十六年 疫苗车间 主 任
王会娟 保定市卫生学校，医士专业中专，
相关工作经验十年 疫苗车间 配液组
组 长
郭书会 河北经贸大学，市场营销专业专科，
本行业工作经验八年 疫苗车间 细胞组
组 长
王小龙 保定市经济管理干部学校，机电专业中专，本行业工作经验七年 疫苗车间 浓缩组
副组长
纪广辉 河北大学，生物学专业专科，
相关工作经验十年 分包装车间 主 任
王正江 保定市地区卫生学校，医士专业中专，相关工作经验八年
相关工作经验八年 分包装车间 分装组
组 长
汪鹏飞 河北职工大学，财政金融专业专科，
本行业工作经验五年 分包装车间 包装组
组 长
朱革娜 保定求实医学院，医士专业中专，
相关工作经验八年 分包装车间 物检组
组 长

三、仪器设备
序号 生产药品过程中所用的仪器设备 GMP投诉
纯化水机 是 否√
多效蒸馏水机 是 否√
纯蒸汽发生器
紫外线消毒器
板式换热器
传递窗
机动门脉动真空灭菌器
电热自动消毒烘箱
配液罐
废液罐
真空泵
空气压缩机
吸附式干燥塔
冷冻式干燥器
超净工作台
移动百级层流罩
洗瓶机
冲洗台
搅拌器
细胞培养床
柱式滤器
超滤浓缩系统
柱式层析系统
蠕动泵
离心机
水浴灭活箱
无油式移动空压机
完整性检测仪
电子天平
酸度计
超声波洗瓶机
杀菌干燥机
灌装机
磁力搅拌器
轧盖机
灯检台
不干胶贴标机
喷码机
封包机
自动烘手器
免接触感应式手消毒器
冷库系统
恒温室系统
四、生产商每一个班次的生产能力：
⑴半成品生产周期较长，无法计算每个班次的产量。按投料量计算，每批可生产28000~30000人份。
⑵分装及包装每个班次可生产18000~20000人份。
五、负责质量控制的人员名系如下：
序号 姓 名 资 历 岗 位 职 务
张灵敏 河北大学，微生物专业本科，
相关工作经验十六年 质量保证部 经 理
于红艳 河北科技大学，精细化工专业本科，
相关工作经验四年 QC 主 管
赵昕欣 河北科技大学，微生物制药专业专科，相关工作经验八年
相关工作经验八年 理化实验
组 长
李秀云 石家庄长安医学专修学院，医学检验专业专科，相关工作经验十年 动物实验
组 长
屈立斌 河北大学，生物学专业本科，
相关工作经验一年
王永权 中国医科大学，实验动物专业专科，
相关工作经验一年
刘宏伟 廊坊市卫生学校，社区医学专业中专，相关工作经验两年
相关工作经验两年
卢开朗 湖北药检高等专科学校，药物制剂专业专科，相关工作经验五年 QA 主 管
杨国松 河北大学，生物技术专业本科，
相关工作经验两年
黄 玲 河北科技师范学院，生物技术专业本科，相关工作经验一年
孙雪南 西北大学，微生物专业研究生，
相关工作经验五年
朱丽宁 河北工业大学，生物工程专业本科，相关工作经验两年
六、用于对活性原料与最终产品进行质量控制的设备
序号 设 备 名 称
生化培养箱
电热隔水培养箱
二氧化碳培养箱
离心机
电热恒温水浴箱
电热恒温水浴锅
微型震荡器
数字酸度计
数字电导率仪
可见分光光度计
尘埃粒子计数器
紫外可见分光光度计
完整性检测仪
电热鼓风干燥箱
循环水真空泵
电冰箱
液氮罐
洁净工作台
台式灭菌器
一级反渗透
电蒸馏

七、水处理设备的说明
水处理部分主要由纯化水系统、注射用水系统组成。根据生产的需要，各车间分别配有独立的水处理设备。
1、 纯化水系统
根据车间生产对纯化水的需求量，我公司的主要生产车间分别使用了如下规格型号的纯化水机，如下表：

车间名称 纯化水机型号 产水量 组 成 功 用
疫苗车间 4t/h 二级反渗透+EDI 产水为多效蒸馏水机提供原料水，提供洗涮用水
分包装车间 2t/h 二级反渗透 产水为多效蒸馏水机提供原料水，提供洗涮用水
实验动物房 0.5t/h 二级反渗透 提供洗涮用水及为实验动物提供饮用水
质量保证部 100l/h 一级反渗透 为实验室提供洗涮用水

纯化水机是以当今世界是最先进与成熟的反渗透膜分离工艺为基础，结合最新的电去离子除盐(EDI)技术设计制造，这种新型的水质净化技术既可制备高品质的纯化水，又能降低运行成本；该系统采用了先进自动化控制技术，使水处理系统的操作变的更加简单，运行更加稳定，而且设备运行，无化学废水排放，也符合当今的环保要求。整个系统采用了先进的在线仪表监控、人机对话界面使设备的操作与水质得到了更好的保障。
其工作过程如下：
原水 原水箱 多介质过滤器 精密过滤器 一级反渗透

二级反渗透 EDI电去离子装置 纯水罐
其中的原水预处理系统由原水供水、原水箱、原水泵、多介质过滤器、精密过滤器五部分组成，能够有效滤除水中的悬浮及胶状性物质，精密过滤器滤除5μm以上的颗粒，从而保证了高压泵及膜在高压水流作用下免受机械损伤。
反渗透脱盐系统，采用美国海得能公司生产的ESPA2(一级)超低压膜和CPA3(二级)低压高脱盐复合膜组成，它具有超低的运行压力(较常规低压复合膜的运行压力降低了25%-40%)，具有更高的水通量(在大通量时有着与其他复合膜相同的脱盐率)，具有更宽的水质适应范围和压力适应范围等优点。
电去离子 (EDI)技术应用电再生离子交换去离子工艺，取代传统的需要酸、碱再生的混合离子交换树脂去离子工艺(DI)。EDI技术与反渗透膜分离技术相结合可连续不断的制取高纯水。
为了充分保证水质，我们还在纯化水管道上加装了紫外线杀菌装置。另外，为了保证管道的清洁，还规定的定期的纯蒸汽在线消毒。
所有纯化水系统所生产的纯水经质检部门检验，其各项指标都远远高于国家对纯化水水质的要求。
2、 注射用水系统
根据车间生产的需要，各主要生产车间都配备了相应的注射用水生产设备，以满足生产的需要。主要生产设备如下表：

车间名称 设备名称 型 号 产水量 作 用
疫苗车间 多效蒸馏水机 2t/h 产水为洗涮及配液提供用水
分包装车间 多效蒸馏水机 1t/h 产水为洗涮及分装线提供冲洗用水
质量保证部 电蒸馏机 30l/h 为实验室提供实验用水

注射用水系统，由多效蒸馏水机、注射用水罐及316L管道所组成。我公司采用的是由吉林省华通制药设备有限公司生产的五效蒸馏水机，该种设备目前在国内处于领先水平，它以前面所讲到的纯化水机所制的纯化水为进料水，用工业蒸汽加热，生产出的蒸馏水，质量稳定、纯度高、无热原、电导率lus/cm，符合中国药典2000年版“注射用水”的要求。注射用水罐，采用夹层蒸汽保温，保证注射用水80℃保存，65℃循环，保证工艺用水的质量。整个注射用水管道全部采用符合要求的316L不锈钢材料，阀门采用隔膜阀，避免了注射用水与外部的直接接触。另外整个管路系统都根据要求可以进行在线蒸汽消毒，从而保证了注射用水的品质。
八、环境控制处理
1、 厂房内部环境的控制
由于主要生产环节是在厂房内完成的，所以厂房内部环境控制的好坏，将主要决定着最终产品质量的好坏。为了达到控制的目的，我们主要在以下几方面采取措施。
1) 在厂房建设装修时，我们要求厂房内墙面要平整、光滑、不积尘、防潮，门窗要求密封耐用，防火、防虫、防微生物细菌滋生；地面要耐磨不起尘，易清扫及易识别分区。针对以上要求，车间主体外墙为100mm厚阻燃型彩钢夹芯板，内隔断采用50mm厚白色阻燃型彩钢夹芯板，在洁净区采用PVC地面，并以不同的颜色区别不同的级别区，其他位置则采用环氧自流平地面。墙壁与房顶和地面的交界为弧形，便于清洁。窗户、天棚及进入室内的管道、风口、灯具等也严格密封。
2) 为了控制外界污染物的进入，厂房内设有相应的缓冲间，并且人、物流根据生产工艺严格区分，物料的存放和传递也采取了相应的消毒与隔离措施，如通过带有紫外线灭菌功能并可以互锁的传递窗等。并且每天严格执行对车间整体的臭氧灭菌消毒。在厂房的进出口，安放了灭蝇灯和挡鼠板，可以防止昆虫和其他动物进入厂房。
3) 对于一个生物制药企业来说，厂房洁净度控制的好坏是最能直接影响产品质量的关键。根据生产工艺要求及GMP要求，我们严格控制车间运行参数为：
① 十万级区域室内设计温度:18~28℃,万级区域室内设计温度:20~24℃;
② 十万级区域室内设计湿度:50%~65%,万级区域室内设计湿度:45%~60%;
③ 洁净区与普通区最小压差为10pa，洁净区间压差最小为5pa。
为了达到以上的设计参数，我们在厂房内按不同的洁净区域设有多套空调系统，每个空调系统设有新风段、预热段、混合段、表冷挡水段、加热段、风机段、均风段和加湿送风段，从而达到空调系统在PLC的控制下自动实现温度、湿度、风量的控制。送入洁净房间的风将经过新风过滤器、初效过滤器、中效过滤器，并最终经过高效过滤器进入房间。对于新风过滤器、初效过滤器、中效过滤器和高效过滤器的清洗与更换周期我们也严格的进行了规定，从而更进一步保证房间的洁净度。
对于直接暴露在空气中的半成品或成品，我们也采取了相应的措施，将其放置于万级条件下的局部百级中进行保护。
4) 为了防止带毒的物品或污染物流出室外，给外界环境或人员带来危害，我们设置了多套灭菌、消毒处理设施。对于生产中的带毒废液，我们有专门的废液回收罐，通过真空等动力可以在人员不与废液直接接触的情况下将其集中到废液罐，然后通过高压灭菌后排出室外。最终留入污水池，加入次氯酸钠排入市政污水管网。
对于带毒的物品，我们有机动门脉动真空灭菌器和干烤箱对装置和衣物进行灭菌。保证物品不再对环境造成二次污染。
5) 我们还保证工作间内的照度及噪声等，从而为从业人员创造一个舒适的工作环境，保证工作质量，防止出现差错。
2、 厂区环境的控制
我公司现主要的生产车间及配套建筑有疫苗车间、分包装车间、库房（包含汽车库）、办公与质检研发楼、实验动物房、变电站、泵房消防水池换热站、污水处理站、绿化设施和地下管网等。其布置原则为：
① 本着实用、经济、美观的设计原则，充分满足生产工艺和运输要求，满足防火、卫生和安全要求，严格执行现行中华人民共和国有关规范、规定及药品生产质量管理规范；
② 尽量避免厂区、生产车间内的人流和货流的交叉；
③ 厂区内的相关设施，使用功能和建筑物进行必要的组合并分区集中布置，在便于管理的同时避免各区之间的相互影响和干扰；
④ 厂区绿化与周围环境协调。
公司现在所在的燕郊经济开发区，整体环境空气清新湿润，无任何污染。地下给水、排水、供电、供暖、供汽、电讯等公用工程配套设施完善。公司绿化面积35，000㎡，建筑覆盖率21.3%，绿地率54.6%（以上所属数据为公司一期建设技术经济指标）。
总体来说，我公司从车间内部到厂区都对环境的控制采取了极其严格的控制措施，可以最大限度的保证产品的质量。



九、由国家食品药品监督管理局颁发的生物制品批签发合格证
十、公司及各部门车间的照片
1、公司厂区
2、疫苗车间
洁净走廊/细胞培养温室
3、分包装车间/分装流水线
4、实验动物室
5、库房
十一、含有佐剂（氢氧化铝）的疫苗，在其注射部位偶有硬结或炎症等副反应发生，故不适宜皮下注射。不含有佐剂（氢氧化铝）的疫苗可采用肌内与皮下两种注射方式。福尔博人用狂犬病疫苗为无佐剂疫苗，但2005年版《中华人民共和国药典》中仍沿用以前肌内注射的方法，为与2005年版《中华人民共和国药典》保持一致，福尔博人用狂犬病疫苗仍采用肌内注射的方式。		Translation - English
¢ñ. Overview of Production Methods of Rabies Vaccine for Human Use
This product is prepared for the use of rabies prevention by means of vaccinating the primary hamster kidney cell (PHKC) against the fixed strain of rabies virus, collecting the virus liquid after cell culture, diluting it with PBS (phosphate buffered saline) after inactivation, concentration and purification of virus and adding the human serum albumin.
1. Basic requirements
The facilities, raw & ancillary materials, water, appliances and animals etc used for production, examination and determination should comply with the requirements of Tripartite ¡°General Notes¡± of the 2005 Edition Pharmacopoeia of the People's Republic of China (abbreviated as the Chinese Pharmacopoeia 2005, Ch.P.2005).
2. Production
2.1 Cells used for production
The cells used for production are primary hamster kidney cells or hamster kidney cells with no more than five serial passages.
2.1.1 Cell management and assay
It should comply with relevant regulations of the Specifications for Preparation and Assay of Animal Cell Matrixes Used for the Manufacturing of Biological Products of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China.
2.1.2 Cell preparation
Select the healthy hamsters with 12~14 days of age to take kidneys from them with aseptic manipulation, shear the kidneys into pieces, disperse the cells after trypsinization and add 8%~10% inactivated calf serum with Earle's Balanced Salt Solution (EBSS) containing 0.4% lactoalbumin hydrolysate into the inoculated culture bottle. The stock solutions prepared with same production cycle, same batch of raw materials and same method are made as a batch.
2.2 Virus seed
2.2.1 Name and source
The virus seed used for production is the fixed strain (aG) of rabies virus.
2.2.2 Establishment of seed lot
It should comply with relevant regulations of the Specifications for Management of Bacterial Spawns and Viruses Used for the Manufacturing and Assay of Biological Products of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China.
The original seed lots are purchased from the National Institute for the Control of Pharmaceutical and Biological Products (NICPBP) with the generation number of 4aG2. The generation number of master seed lot is 4aG3 and that of working seed lot is 4aG4.
2.2.3 Assay of seed lot
The master seed lot should be given the following full assay and the working seed lot should be given the assay of 2.2.3.1~2.2.3.5 items at least.
2.2.3.1 Identification test
The specificity of virus seed should be identified with the intracerebral neutralization test of mice and the neutralization index should be no less than 500.
2.2.3.2 Titration of virus
The virus seed is given 10 times of serial dilution and the mice weighing 11~13g with intracerebral inoculation should be no less than 6 at each dilution. The virus titer should be 8.0 ~9.5LgLD50/ml.
2.2.3.3 Sterility test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
2.2.3.4 Mycoplasma test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üB of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
2.2.3.5 Test of exogenous factors of virus
It should be examined in compliance with relevant laws and regulations (Appendix ¢üC of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
2.2.3.6 Immunogenicity test
The virus seed of master seed lot is inactivated directly and made into original vaccine which is injected in the abdominal cavity of mice weighing 12~14g, 0.5ml for each. Each mouse is given a second inoculation after 1 week. In the 14th day after the first immunization, the mice are given the intracerebral attack with the CVS virus in the form of 10 times of serial dilution (10-5, 10-6, 10-7and 10-8), 0.3ml for each mouse and ten mice at each dilution. Meanwhile the non-immune mice with same weight, as a control, are given the intracerebral attack with the CVS virus in the form of 10 times of serial dilution (10-2, 10-3, 10-4and 10-5), 0.3ml for each mouse and ten mice at each dilution. The protection index should be no less than 200.
2.2.4 Storage of virus seed
The freeze-dried virus seed should be stored at the temperature of less than -20¡æ, and the virus seed of liquid working seed lot should stored in the temperature of less than -60¡æ for no more than 2 years.
2.3 Preparation of stock solution
2.3.1 Cell preparation
It should be carried out according to Item 2.1.2.
2.3.2 Culture solution
The Earle's Balanced Salt Solution (EBSS) containing 0.4% lactoalbumin hydrolysate is added into the 8%~10% inactivated calf serum and the PH value is adjusted to 7.0~7.2 to carry out the cell culture. The quality standard of calf serum should comply with the regulations of tripartite structure (Appendix ¢ú¢óD) of the 2005 Edition Pharmacopoeia of the People's Republic of China.
2.3.3 Test of exogenous factors of control cell
It should be examined in compliance with relevant laws and regulations (Appendix ¢üC of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
2.3.4 Inoculation and culture of virus
Mix the supernatant liquid and cell suspension of rabies virus seed in the cell culture bottle. Carry out the cell culture of rabies virus seed with the inoculum size of 0.01¡«0.1MOI (or 4.5¡«5.5 LgLD50/ml) for 68~76 hours at the temperature of 36.5¡æ¡À1¡æ to make the cultured cell form dense monolayer, then remove the culture solution and use the physiological saline to wash it to remove calf serum, add the ¡°199¡± main medium containing human serum albumin in it and continue to place it at the temperature of 34¡æ¡À1¡æ to carry out the cell culture for 6~7 days.
2.3.5 Virus harvest
The virus liquid should be harvested after the completion of culture.
2.3.6 Assay of single harvest fluid of virus
It should be carried out according to Item 3.1.
2.3.7 Inactivation of virus
Add the 1/5000 formaldehyde solution in the harvest liquid of virus, inactive it in the conditions of 26¡æ¡À1¡æ for 96¡À1 hours and shake it twice every day, thus it¡¯ll be inactivated virus liquid.
2.3.8 Verification test of virus inactivation
According to Item 3.1.4, the virus should be taken a sample immediately after inactivation to perform the verification test of virus inactivation.
2.3.9 Concentration and purification of inactivated virus liquid
2.3.9.1 Combination, ultra-filtration and concentration
The harvest liquid of virus produced in the same batch is concentrated by 60¡À10 times through the ultra-filtration of ultra-filtration membrane with the molecular of 300KD, and is taken a sample to measure the protein content which should be 25mg/ ml- 40mg/ ml. The removal rate of hybridprotein after concentration should be no less than 82%.
2.3.9.2 Purification
Carry out the purification for the concentrated virus liquid with the method of Sepharose 4FF gel column chromatography after the assay is approved. Notice that the quantity of sample should be 5~10% of the gel volume in column every time. Elute it with the PBS with the PH value of 7.6 and the concentration of 0.01M, perform the monitoring with the ultraviolet rays of OD280, collect the first peak and take a sample from it to measure the protein content which should be 150¦Ìg/ ml-300¦Ìg/ ml. The removal rate of hybridprotein after purification should be no less than 99%. Add the human serum albumin into it as stabilizing agent after purification and add the thimerosal into it as antiseptic at the same time, thus it¡¯ll be the stock solution of vaccine. The content of human serum albumin is 0.4% and the thimerosal content is 0.0025% in the purified stock solution.
2.4 Assay of stock solution
It should be carried out according to Item 3.2.
2.5 Preparation of semi-finished products
2.5.1 Preparation
According to the measured protein content and antigenic content, the semi-finished products are prepared by adopting the protein content in semi-finished products as 60¦Ìg/dose. The stock solution will be made into semi-finished product after added with human serum albumin and thimerosal again. The content of human serum albumin is 2% and the thimerosal content is 0.003% in the semi-finished product.
2.5.2 Assay of semi-finished products
It should be carried out according to Item 3.3.
2.6 Preparation of finished products
2.6.1 Batch separation
It should comply with relevant regulations of the Specifications for Batch Separation of Biological Products of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China.
2.6.2 Sub-package
It should comply with relevant regulations of the Specifications for Sub-package and Freeze-drying of Biological Products of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China.
2.6.3 Specifications
1.0ml each bottle and 1.0ml of dose for human use each time. The titer of rabies vaccine should be no less than 2.5IU.
2.6.4 Package
It should comply with relevant regulations of the Specifications for Package of Biological Products of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China.
3. Assay
3.1 Assay of single harvest liquid of virus
3.1.1 Titration of virus
It should be carried out according to Item 2.2.3.2 and the titer should be 6.0 ~8.0LgLD50/ml.
3.1.2 Sterility test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.1.3 Mycoplasma test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üB of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.1.4 Verification test of inactivation
Use animal methods to carry out the intracerebral inoculation in 20 mice weighing 11~13g with inactivated stock solution, 0.03ml for each mouse. All the mice should still exist after 14 days of observation (not include the mice died within 3 days).
3.2 Assay of stock solution
3.2.1 Sterility test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.2.2 Measurement of protein content
Select the stock solution that is not added with human serum albumin after purification and carry out the measurement according to relevant laws and regulations. The protein content should be 50~82¦Ìg/dose, see tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China (Clause 2 of Appendix ¢öB).
3.2.3 Antigenic content
Select the stock solution that is not added with human serum albumin after purification and measure the antigenic content with the method of euzymelinked immunosorbent assay. The antigenic content should be no less than 10IU/ml.
3.2.4 Residual volume of bovine serum albumin
The residual volume of bovine serum albumin is measured with the method of euzymelinked immunosorbent assay, and it should be no more than 50ng/dose.
3.3 Assay of semi-finished products
Sterility test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4 Assay of finished products
3.4.1 Identification test
According to Item 3.4.4, it should be carried out in compliance with relevant regulations. The identification test will be untenable if the titer measurement is not qualified.
3.4.2 Appearance
Colorless and transparent liquid
3.4.3 Chemical assay
3.4.3.1 PH value
It should be 7.2~8.0 (Appendix ¢õA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.3.2 Thiomersal content
It should be 0.01 ~0.06mg/ml (Appendix ¢÷B of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.3.3 Content of free formaldehyde
It should be no more than 0.05mg/ml (Appendix ¢öL of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.4 Titer measurement
According to released standards, the titer should be no less than 4.0IU/dose and the titer within validity period should be no less than 2.5IU/dose. Two groups of animals will be measured for the titer test and the calculated mean is made as its result (Appendix ¢ûA of tripartite structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.5 Thermal stability test
The product should be given the thermal stability test before delivery. It should be carried out the titer measurement according to Item 3.4.4 after being placed at the temperature of 37¡æ for two weeks, and its titer should be no less than 2.5IU/dose.
3.4.6 Sterility test
It should be examined in compliance with relevant laws and regulations (Appendix ¢üA of Tripartite Structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.7 Examination of abnormal toxicity
It should be examined in compliance with relevant laws and regulations (Appendix ¢üF of Tripartite Structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
3.4.8 Examination of bacterial endotoxin
The bacterial endotoxin should be no more than 100EU/dose (Gel Limit Test in the Appendix ¢üE of Tripartite Structure of the 2005 Edition Pharmacopoeia of the People's Republic of China).
4. Storage, transportation and validity duration
It should be stored and transported away from light at the temperature of 2~8¡æ. The validity duration is 12 months since the date that the titer measurement is qualified.
¢ò. There are totally 10 persons who are directly responsible for the technology and monitoring of drug production in our company, and their names are listed as the following:
No.
Name
Seniority
Position
Title

Yang Guanglin
Si Chuang University, University graduate in Biology.
14 years¡¯ experience in relevant work.
Chief Product Officer

Yu Shuping
Party School of the CPC Central
Committee, junior college graduate in Biological Products.38 years¡¯ experience in relevant work.

Department of Production Management
Manager

Li Peng
Munitions University of the PLA, junior college graduate in Biological Products. 16 years¡¯ experience in relevant work.
Vaccine workshop
Director

Wang Huijuan
Baoding Urban Health School, specialized secondary school graduate in Medical Assisstant.10 years¡¯ experience in relevant work.
Vaccine workshop
Team leader of liquor distribution group

Guo Shuhui
Hebei University of Economics and Trade, junior college graduate in Marketing & Sales. 8 years¡¯ experience in this field.
Vaccine workshop
Team leader of cell group

Wang Xiaolong
Baoding Urban School of Economic Management, specialized secondary school graduate in Mechanical and Electrical Engineering. 7 years¡¯ experience in this field.
Vaccine workshop
Assisstant team leader of concentration group

Ji Guanghui
Hebei University, junior college graduate in Biology.10 years¡¯ experience in relevant work.
Sub-package workshop
Director

Wang Zhengjiang
Regional Health School of Baoding City, specialized secondary school graduate in Medical Assistant. 8 years¡¯ experience in relevant work.
Sub-package workshop
Team leader of sub-package group

Wang Pengfei
Hebei Engineering Vocational College, junior college graduate in Finance & Economics. 5 years¡¯ experience in this field.
Sub-package workshop
Team leader of package group

Zhu Gena
Baoding Urban Qiushi Medical College, specialized secondary school graduate in Medical Assistant. 8 years¡¯ experience in relevant work.
Sub-package workshop
Team leader of product inspection group


¢ó. Instruments and Equipments
No.
Instruments and equipments used during the course of pharmaceutical production
Complains about GMP

Water purifier
Yes
No¡Ì

Multi-effect water distiller
Yes
No¡Ì

Pure steam generator

Ultraviolet sterilizer

Plate heat exchanger

Delivery window

Power-driven pulsing vacuum sterilizer

Electrothermal automatic sterilizing oven

Liquid mixing tanker

Waste liquid tank

Vaccum pump

Air compressor

Adsorption-type drying tower

Refrigerant type dryer

Superclean bench

Mobile 100-grade laminar flow device

Bottle washer

Scouring table

Blender

Cell culture table

Collumn type filter

Ultra-filtration system

Collumn type chromatographic system

Peristaltic pump

Centrifuge

Water-bath inactivation box

Oilless mobile air compressor

Intergrity detection apparatus

Electronic balance

Acidometer

Ultrasonic bottle washer

Sterilizing drier

Filling machine

Magnetic stirring apparatus

Capper

Light-examination table

Pressure-sensitive labeling machine

Code-printing Machine

Bag closing machine

Automatic hand blower

Non-touching induction hand sterilizer

Cold storage system

Thermostatic chamber system

¢ô. Production capacity of manufactory at each work shift:
¢Å Because the production cycle of semi-finished product is relatively long, it has no way to calculate the output at each work shift. If the output is calculated in terms of feeding quantity, 28000~30000 units per person can be produced at each batch.
(2) For sub-package and package, 18000~20000 units per person can be produced at each work shift.
¢õ. The persons responsible for quality control are listed as the following:
No.
Name
Seniority
Position
Title

Zhang Lingmin
Hebei University, university graduate in Microbiology. 16 years¡¯ experience in relevant work.
QA
Manager

Yu Hongyan
Hebei University of Science & Technology, university graduate in Fine Chemical Industry. 4 years¡¯ experience in relevant work.
QC Supervisor

Zhao Yixin
Hebei University of Science & Technology, junior college graduate in Microbiology & Pharmaceutical. 8 years¡¯ experience in relevant work.

Team leader of physics & chemistry group

Li Xiuyun
Chang¡¯an Medical College of Shi Jiazhuang City, junior college graduate in Medical Laboratory Science.10 years¡¯ experience in relevant work.
Team leader of animal experiment group

Qu Libin
Hebei University, university graduate in Biology. 1 year¡¯s experience in relevant work.

Wang Yongquan
China Medical University, junior college graduate in Experimental Zoology. 1 year¡¯s experience in relevant work.

Liu Hongwei
Langfang Urban Health School, specialized secondary school graduate in Community Medicine.2 years¡¯ experience in relevant work.

Lu Kailang
Hubei Junior College of Pharmaceutical Inspection, junior college graduate in Pharmaceutical Preparation. 5 years¡¯ experience in relevant work
QA Supervisor

Yang Guosong
Hebei University, university graduate in Biotechnology.2 years¡¯ experience in relevant work.

Huang Ling
Hebei Vocation-technical Teachers College, university graduate in Biotechnology. 1 year¡¯s experience in relevant work.

Sun Xuenan
Xibei University, junior college graduate in Microbiology. 5 years¡¯ experience in relevant work.

Zhu Lining
Hebei University of Science & Technology, university graduate in Bioengineering. 2 years¡¯ experience in relevant work.

¢ö. Equipments used in the quality control on activated raw materials and final productsNo.
Names of Equiments

Biochemical incubator

Electrothermal water-insulation incubator

CO2 incubator

Centrifuge

Electrothermal thermostatic waterbath box

Electrothermal thermostatic waterbath pan

Minitype shaker

Digital acidometer

Digital electric conductivity analyzer

Visible spectrophotometer

Dust particle counter

Ultraviolet-visible spectrophotometer

Intergrity detection apparatus

Electrothermal air-blasting drying cabinet

Circulating-water vacumm pump

Refrigerator

Liquid nitrogen container

Clean bench

Desktop sterilizer

Primary reverse osmosis (RO) equipment

Electrical distillating apparatus


¢÷. Instructions of water treatment equipments
The water treatment part is mainly consisted of purified water system and water-for-injection system. According to the requirements of production, each workshop is equipped with separate water treatment equipments.
1. Purified water system
According to the demand of production workshop for purified water, the water purifiers with the following specifications are used in main production workshops of our company, as is listed in the following table:

Workshop nmae
Type of water purifier
Water output
Structure
Functions

Vaccine workshop
4t/h Secondary reverse osmosis+EDI
Provide ingredient water for multi-effect water distiller and provide water for washing and swilling

Sub-package workshop
2t/h Secondary reverse osmosis
Provide ingredient water for multi-effect water distiller and provide water for washing and swilling

Experimental animal room
0.5t/h Secondary reverse osmosis
Provide water for washing and swilling, and provide drinking water for experimental animals

QA Department
100l/h Primary reverse osmosis
Provide water for washing and swilling in the laboratory


The water purifier is designed and manufactured based on the most advanced and matured separation process of reverse osmosis membrane in today¡¯s world in combination with the latest electro-deionization (EDI) desalination technology. The new water purification technology not only can produce high-quality purified water, but also can reduce operation cost. With the adoption of advanced automatic control technologies, this system further simplifies the operation of water treatment system and makes its running more stable, and there is no discharge of chemical wastewater during the course of running of the equipment, which also conforms to the requirements of environmental protection nowadays. The whole system provides higher security on the operation of equipments and water quality by adopting the advanced online instrumentation control and man-machine dialog interface.
Its working flow is shown as the following:
Raw water- Raw water box -Multi-media filter -Precise filter -Primary reverse osmosis

Secondary reverse osmosis- EDI deionizer- Purified water tank
The raw water pre-treatment system in it is consisted of raw water supply, raw water box, raw water pump, multi-media filter and precise filter, which can effectively filter off suspending and gelatinous substances in the water. The precise filter can filter off particles with the diameter of over 5¦Ìm, thus it can protect the high-pressure pump and membrane from mechanical damage under the effect of high-pressure water flow.
By adopting the ultra-low pressure RO membrane ESPA2 (primary) and low-pressure high-desalination compound membrane CPA3 (secondary) which are produced by American Hydranautics Company, the RO desalination system has the features of extremely low operating pressure (which is decreased by 25%-40% in comparison with common the operating pressure of low-pressure compound membrane), higher water flux (its desalinization ratio is same as that of other compound membranes in large water flux) and wider water quality range and pressure quality range etc.
The electro-deionization (EDI) technology adopts the deionization process of electro-regeneration ion exchange and takes the place of traditional deionization (DI) process of mixed ion-exchange resin which needs the regeneration of acid and base. The combination of EDI technology and RO membrane separation technology can continuously produce highly purified water.
In order to ensure the water quality, we also install ultraviolet sterilizing equipments on the purified-water pipeline. In addition, we also specify that the pipeline should be given regular online pure-steam sterilization so as to ensure the clean of pipeline.
All indexes of purified water produced in all of our purified water systems are much higher than the national requirements on the purified water quality after the inspection of quality supervision authorities.
2. Water-for-injection system
In order to satisfy the requirements of production workshops, all the main workshops are equipped with corresponding production equipments of water for injection. The main production equipments are listed as the following:

Workshop nmae
Equipment name
Type
Water output
Functions

Vaccine workshop
Multi-effect water distiller
2t/h Provide water for washing, swilling and liquid distribution

Sub-package workshop
Multi-effect water distiller
1t/h Provide water for washing, swilling and sub-package line

QA Department
Electrical distiller
30l/h Provide water for experiments in the laboratory


The water-for-injection system is consisted of multi-effect water distiller, water-for-injection tank and 316L pipeline. Our company adopts the five-effect water distiller produced by Jilin Watertown Pharmaceutical Equipment Co., Ltd, and this kind of equipment takes the leading position presently in China. The distilled water, which is produced by the equipment by means of taking the purified water produced by the above-mentioned water distiller as feeding water and heating with industrial steam, has the features of stable quality, high purity, pyrogen free and lus/cm of conductivity, so it can meet the requirements of ¡°water for injection" in the China Pharmacopeias 2000. The water-for-injection can ensure that the water for injection is stored at the temperature of 80¡æ and circulated at the temperature of 65¡æ and can ensure the quality of process water by adopting the intercalated-bed steam incubation. The qualified 316L stainless steel materials and diaphragm valve are adopted for the whole water-for-injection pipeline, so it can prevent the water for injection from direct contact with outer environment. In addition, the whole pipeline system can be given online steam sterilization according to relevant requirements, which can ensure the quality of water for injection.

¢ø. Measures of Environmental Control
1. Internal environment control of factory buildings
Because the main production links are completed in the factory buildings, the quality of final products will mainly depend on the internal environment control of factory buildings. In order to reach the goal of environmental control, we mainly take the measures in the following aspects:
1) When the factory buildings are constructed and decorated, we demand that the wall surfaces should be even, smooth, dust-proof and damp-proof, the doors and windows should be durable, fire-proof, mothproof, microbe-proof and bacterium-proof, and the floor should be durable, dust-proof and easy to sweep and identify different areas in the factory buildings. In accordance with above requirements, the external wall is made with 100mm heat-insulation colored-steel sandwich plate, the internal partition is made with 50mm white heat-insulation colored-steel sandwich plate, and the PVC floor is adopted for the clean area by differentiating the areas at different levels with different colors, and the spreading epoxy floor is adopted for other places in the workshops.
2) In order to control the ingression of external pollutants, the corresponding buffer rooms is established in the factory buildings, people and material flow are discriminated strictly according to production process, and corresponding sterilization and insulation measures are taken for the storage and transmission of materials, e.g. delivery window that has the functions of ultraviolet disinfection and interlocking. In addition, the ozone sterilization is carried out strictly in the whole workshop every day. The fly-killer lamp and mouse-resistance plate are placed in the entrances of factory buildings so as to prevent insects and other animals from entering the factory buildings.
3) As far as a biopharmaceutical enterprise is concerned, the effectiveness of purity control in the factory buildings is the most important factor that influences the product quality. According to the requirements of production process and GMP, the operation parameters of workshops which will be controlled strictly are:
¢Ù Interior design temperature in areas with the air cleanliness level of 100,000: 18~28¡æ, Interior design temperature in areas with the air cleanliness level of 10,000: 20~24¡æ;
¢ÚInterior design humidity in areas with the air cleanliness level of 100,000: 50%~65%, Interior design humidity in areas with the air cleanliness level of 10,000: 45%~60%;
¢Û Minimum differential pressure between clear area and common area: 10pa, Minimum differential pressure between clear areas: 5pa.
In order to reach the standards of above design parameters, we set up multiple suits of air conditioning systems in different clean areas of factory buildings and set up the fresh air section, preheating section, mixing section, cooling-coil water-resistant section, heating section, air blower section, even air supply section and wet air supply section in each air conditioning system, so the automatic control of air conditioning system on temperature, humidity and air volume are achieved under the control of PLC. The wind entering clean rooms will pass through the fresh air filter, primary filter, secondary filter and high-efficiency filter finally to access the rooms. We also give strict regulations on the cleaning and replacement cycle of fresh air filter, primary filter, secondary filter and high-efficiency filter, thus the air cleanliness of rooms are furthermore ensured.
For the semi-finished products or finished products directly exposed to air, we also take corresponding measures to place them in local areas with the air cleanliness level of 100 under the conditions of the air cleanliness level of 10,000.
4) In order to prevent poisonous matters or pollutants from discharging outside of rooms to bring about harm to external environment or people, we set up multiple suits of sterilization facilities. For the poisonous waste liquids produced during the course of production, we can collect them in specialized waste liquid tanks through motive force such as vacuum under the conditions that persons don¡¯t contact with waste liquids directly, and then discharge them outside of rooms after high-pressure sterilization. The waste liquids run into the sewage tank finally, and are discharged into municipal sewage pipeline network after added with sodium hypochlorite.
For poisonous matters, we can use power-driven pulsing vacuum sterilizer and hot air oven to carry out sterilization on equipments and clothes. It can be ensured that the poisonous matters don¡¯t cause the secondary pollution of environment.
5) We can also ensure the effective control on the illumination and noise etc in working rooms to create a comfort working conditions for personnel, ensure the quality of working and prevent the occurrence of mistakes.
2. Environmental control of the factory
The main production workshops and supporting buildings of our company include vaccine workshop, sub-package workshop, storehouse (including garage), office, quality check and research buildings, experimental animal room, transformer substation, pump house, fire-fighting pool, heat exchange station, sewage treatment station, greening facilities and underground pipeline network etc. Their allocation principle is:
¢Ù In accordance with the design principle of practicality, economy and beauty, it should fully satisfy the requirements of production process and transportation and the requirements of fire prevention, health and security, and the relevant present specifications and regulations of PRC as well as Good Manufacturing Practice and Quality Control of Drug should be carried out strictly;
¢Ú The crowds and freight flow in the factory area and workshops should be avoided from crossing as far as possible;
¢Û The functions and buildings of relevant facilities in the factory area should be given necessary combinations and centralized allocation in different zones, and should be avoided from interaction and interference among each zone for the convenience of management.
¢Ü The greening in the factory area should be harmonious with surrounding environment.
As far as the overall environment of Yanjiao Economic Development Zone where our company locates presently is concerned, the atmosphere is fresh and moist and there is no pollution, the supporting facilities of utilities such as underground water supply, drainage, power supply, heating supply, gas supply and telecomm nation are complete. The greening area of our company is 35,000©O with the buildings¡¯ coverage rate of 21.3% and green space rate of 54.6% (the above data are the technical and economical indexes of first-stage construction of our company).
As a whole, our company takes extremely strict measures on environmental control from the interior of workshop to factory area, so the product quality can be ensured at the greatest degree.



¢ù. Certificate for the Release of Biological Products issued by State Food and Drug Administration
¢ú. Photos of our company and workshops of each department
1. Factory area of our company
2. Vaccine workshop
Clean passage/cell culture greenhouse
3. Sub-package workshop/sub-package line
4. Experimental animal room
5. Storehouse
¢û. The vaccine containing adjuvant (aluminum hydroxide) is unsuitable to be given subcutaneous injection because the adverse reactions such as induration or inflammation can take place in the injection sites sometimes. The two kinds of intramuscular and subcutaneous injection methods can be adopted for the vaccines not containing adjuvant (aluminum hydroxide). The ¡°Forewell Biophram¡± Rabies Vaccine for Human use doesn¡¯t contain adjuvant, and is still used with the method of intramuscular injection in order to keep in line with the 2005 Edition Pharmacopoeia of the People's Republic of China which continues to adopt the previous intramuscular injection method.

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