富马酸泰诺福韦酯与工业设计
纯化水制备系统功能设计说明资料
1. 弓I言 (4)1.1 目的 (4)1.2 范围 (4)1.3 合同状况 (4)1.4 缩写定义 (4)1.5 其他相关的文件 (4)2. 概述 (5)2.1 项目背景 (5)2.2 过程控制 (6)2.2.1. 预处理 (6)2.2.2. 终端处理 (7)关键控制参数 (8)自控系统描述 (8)自控系统配置示意图 (9)3. 系统过程控制 (9)1. 原水储罐 (10)2. 多介质过滤器 (11)2.2.1. 多介质过滤器操作流程图 (12)2.2.2. 压力控制回路 (12)2.2.3. 温度控制回路 (12)2.2.4. 多介质过滤器的输入及输出 (13)2.2.5. 多介质过滤器报警 (13)3. 活性碳过滤器 (15)3.5.6 活性碳过滤器操作流程图 (15)3.5.7 多介质与活性碳过滤器消毒流程图 (16)3.5.8 温度控制回路 (17)3.5.9 活性碳过滤器的输入及输出...................................................... 仃3.5.10 活性碳过滤器报警 (17)4. 软水机 (19)4. 软水机操作流程图 (20)3.5.11 软水机消毒流程图 (21)5. 软水机的输入及输出 (22)6. 软水机报警 (22)RO 及EDI (23)一级RO运行流程图 (25)—级RO及EDI运行流程图 (26)流量控制回路 (27)pH控制回路 (27)RO及EDI输入及输出 (28)RO 及EDI 报警 (28)纯水制备系统整体操作 (29)4. 密码 (29)5. 电气配置 (29)6. 数据 (29)6.1 访问数据 (30)6.2 数据容量、延时、存档详细信息 (30)7. 电气安全特点 (30)8. 界面 (30)8.1 用户界面 (30)8.2 装置界面 (30)9. 系统可利用性 (30)9.1 发生故障时的可利用性 (30)9.2 运行寿命 (30)引言 1.1目的功能设计规范是定义用户功能需求的关键文件，需要满足用户需求，本文件详细描述纯化水系统的功能设计规范。
质量源于设计--辉瑞药物研发案例--童成博士
Glyoxal Addn T: Target Addn 2-15C; Rxn 15-30C; Demonstrated Range 0-35C
Glyoxal Addn Rate: 30-90 minutes
Deagglomeration/Milling
Quality Attributes
CP-XXXXXX Quality CP-XXXXXX Reslurry (CP-XXYXYX nmt 0.5% Unpsecified Individual nmt 0.1% Total nmt 1.0%
实现市场要求
CPP范围扩展 正在实施的变更（CBE） CBE-0 -修正过的工艺描述 或预先申请 -变更证实
-修正过的工艺描述 -更新的批次记录 -一批次常期稳定性 -变更论证 -溶出度曲线
增加产量/降低 成本
药品测试方法: 预先申请
使用近红外（NIR）， -NIR 方法总结 取代KF -各种方法间的相关数据 -NIR 方法验证
Steps 5 & 6
Process Parameters
Toluene Vol: Target 7 L/kg; Range 5-14 NaOH Quantity Target 3.1 Meq; Range 1.1-4.5 Reaction T: 33-50 C Rxn T: Target 3-4 hr Range 3 hr – 5 d Darco KB-B: Target 5%; Range 0-20%
产品知识空间
F o rm u la tio n & P ro c ess D evelo p m en t P re b le n d in g a n d M illin g D ry Gran u latio n an d M illin g L u b ric a tio n a n d C o m p re ssio n F ilm -C o atin g
新突破｜西得乐破解乳品PET瓶回收难题
第46卷 第16期·60·CHINA RUBBER/PLASTICS TECHNOLOGY AND EQUIPMENT （PLASTICS ）橡塑技术与装备（塑料）全球流行并为我们所熟知，但是早在危机发生以前，PPE 就一直在保护医护人员免受一系列健康和安全风险的困扰。
而眼前比以往任何时候都更加重要的是，我们要确保PPE 的高质量以保护医护人员，索尔维的抗氧剂产品组合在这里起着关键作用。
“ 索尔维的稳定技术为聚合物提供了医疗行业所需的耐用性和可加工性，以确保最终产品的高质量，” 索尔维聚合物添加剂集团全球营销经理Sophie Poelmans 解释道。
（1）安全网：聚合物纤维的抗氧剂个人防护装备如手术帽、靴子、手术服和面罩，能够保护医护人员免受各种健康和安全风险。
为了开发有效的PPE ，厂商采用了纺黏纤维，它在加工过程中能保持稳定，其微纤结构能在无纺布中形成细小孔径。
用于聚烯烃和其它聚合物的抗氧剂可以减少纤维加工过程中的断裂以保持其稳定性，有助于纤维间形成更小微孔而达到更佳的过滤性能，而这对于医疗用品是必需的。
索尔维的无菌医疗用途的抗氧剂产品着眼于改善聚合物材料的稳定性，保证稳定的聚合物熔体黏度，以满足PPE 生产厂家不断发展的需求。
抗氧剂对于聚合物材料是一种有用的添加剂，用于减少降解和维持高效生产。
这些聚合物添加剂对于医疗用品也是必需的，能够使聚合物保持稳定和有效透气以改善产品的可靠性，从而防止通过病毒、细菌和真菌造成的医院感染。
抗氧剂有助于聚合物在加工过程(挤出，纺丝，热黏合等)中保持熔体稳定，如果没有使用这些高性能的抗氧剂，纤维的加工会变得十分困难，会影响纤维的尺寸，旦数和黏合，降解效应会导致医疗装备不合格。
（2）稳定一致：聚烯烃抗氧剂纺黏纤维为诸如手术面罩，帽子和手术服等医疗用品带来了独有的益处，而在抗氧剂的帮助下能进一步提高加工稳定性和纤维质量。
在此应用中纤维是非织造，通过黏合形成网状结构。
富马酸泰诺福韦酯片说明书(英文)
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use VIREAD safely and effectively. See full prescribing informationfor VIREAD.VIREAD® (tenofovir disoproxil fumarate) tabletsInitial U.S. Approval: 2001WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OFHEPATITISSee full prescribing information for complete boxed warning. • Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use ofnucleoside analogs, including VIREAD. (5.1)• Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic functionshould be monitored closely in these patients. Ifappropriate, resumption of anti-hepatitis B therapy may bewarranted. (5.2)---------------------------RECENT MAJOR CHANGES--------------------------- Indications and Usage (1.2) 10/2010 Dosage and Administration (2.1, 2.2, 2.3) 10/2010 Warnings and PrecautionsNew Onset or Worsening Renal Impairment (5.3) 10/2009Decreases in Bone Mineral Density (5.6) 03/2010----------------------------INDICATIONS AND USAGE--------------------------- VIREAD is a nucleotide analog HIV-1 reverse transcriptase inhibitor and an HBV reverse transcriptase inhibitor.VIREAD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older. (1)VIREAD is indicated for the treatment of chronic hepatitis B in adults. (1)---------------------------DOSAGE AND ADMINISTRATION-------------------- • Recommended dose for the treatment of HIV-1 or chronic hepatitis B in adults: 300 mg once daily taken orally withoutregard to food. (2.1)• Recommended dose for the treatment of HIV-1 in pediatric patients (≥12 years of age and ≥35 kg): 300 mg once daily taken orally without regard to food. (2.2)• Dose recommended in renal impairment in adults:Creatinine clearance 30-49 mL/min: 300 mg every 48 hours.(2.3)Creatinine clearance 10-29 mL/min: 300 mg every 72 to 96 hours.(2.3)Hemodialysis: 300 mg every 7 days or after approximately 12hours of dialysis. (2.3)-----------------------DOSAGE FORMS AND STRENGTHS-------------------- Tablets: 300 mg. (3)--------------------------------CONTRAINDICATIONS------------------------------ None. (4)--------------------------WARNINGS AND PRECAUTIONS--------------------- • New onset or worsening renal impairment: Can include acute renal failure and Fanconi syndrome. Assess creatinine clearance (CrCl) before initiating treatment with VIREAD. Monitor CrCl and serum phosphorus in patients at risk. Avoid administeringVIREAD with concurrent or recent use of nephrotoxic drugs. (5.3) • Coadministration with Other Products: Do not use with other tenofovir-containing products (e.g., ATRIPLA and TRUVADA). Do not administer in combination with HEPSERA. (5.4) • HIV testing: HIV antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. VIREAD should only be used as part of an appropriate antiretroviralcombination regimen in HIV-infected patients with or without HBV coinfection. (5.5)• Decreases in bone mineral density (BMD): Observed in HIV-infected patients. Consider assessment of BMD in patients with a history of pathologic fracture or other risk factors for osteoporosis or bone loss. (5.6)• Redistribution/accumulation of body fat: Observed in HIV-infected patients receiving antiretroviral combination therapy. (5.7)• Immune reconstitution syndrome: Observed in HIV-infected patients. May necessitate further evaluation and treatment. (5.8)• Triple nucleoside-only regimens: Early virologic failure has been reported in HIV-infected patients. Monitor carefully and considertreatment modification. (5.9)-----------------------------ADVERSE REACTIONS--------------------------------In HIV-infected subjects: Most common adverse reactions (incidence ≥10%, Grades 2 - 4) are rash, diarrhea, headache, pain, depression, asthenia, and nausea. (6)In HBV-infected subjects with compensated liver disease: most common adverse reaction (all grades) was nausea (9%). (6)In HBV-infected subjects with decompensated liver disease: most common adverse reactions (incidence ≥10%, all grades) were abdominal pain, nausea, insomnia, pruritus, vomiting, dizziness, and pyrexia. (6)To report SUSPECTED ADVERSE REACTIONS, contact Gilead Sciences, Inc. at 1-800-GILEAD-5 or FDA at 1-800-FDA-1088 or /medwatch------------------------------DRUG INTERACTIONS--------------------------------• Didanosine:Coadministration increases didanosineconcentrations. Use with caution and monitor for evidence ofdidanosine toxicity (e.g., pancreatitis, neuropathy). Considerdose reductions or discontinuations of didanosine if warranted.(7.1)• Atazanavir:Coadministration decreases atazanavirconcentrations and increases tenofovir concentrations. Useatazanavir with VIREAD only with additional ritonavir; monitor for evidence of tenofovir toxicity. (7.2)• Lopinavir/ritonavir:Coadministration increases tenofovir concentrations. Monitor for evidence of tenofovir toxicity. (7.3)----------------------------USE IN SPECIFIC POPULATIONS-------------------• Pregnancy: There is a registry available. Enroll patients by calling 1-800-258-4263.• Nursing mothers: Women infected with HIV should be instructed not to breast feed. (8.3)• Safety and efficacy not established in patients less than 12 years of age. (8.4)See 17 for PATIENT COUNSELING INFORMATION and FDA-Approved Patient LabelingRevised: October 2010 FULL PRESCRIBING INFORMATION: CONTENTS*WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT EXACERBATION OF HEPATITIS1 INDICATIONS AND USAGE1.1 HIV-1 Infection1.2 Chronic Hepatitis B2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in Adults2.2 Recommended Dose in Pediatric Patients (≥12 Years ofAge and ≥35 kg)2.3 Dose Adjustment for Renal Impairment in Adults3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with Steatosis5.2 Exacerbation of Hepatitis after Discontinuation ofTreatment5.3 New Onset or Worsening Renal Impairment5.4 Coadministration with Other Products5.5 Patients Coinfected with HIV-1 and HBV5.6 Decreases in Bone Mineral Density5.7 Fat Redistribution5.8 Immune Reconstitution Syndrome5.9 Early Virologic Failure6 ADVERSE REACTIONS6.1 Adverse Reactions from Clinical Trials Experience6.2 Postmarketing Experience7 DRUG INTERACTIONS7.1 Didanosine7.2 Atazanavir7.3 Lopinavir/Ritonavir7.4 Drugs Affecting Renal Function8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use8.6 Patients with Impaired Renal Function10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics12.4 Microbiology13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility13.2 Animal Toxicology and/or Pharmacology14 CLINICAL STUDIES14.1 Clinical Efficacy in Patients with HIV-1 Infection14.2 Clinical Efficacy in Patients with Chronic Hepatitis B16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION AND FDAAPPROVED PATIENT LABELING* Sections or subsections omitted from the full prescribing information are not listedFULL PRESCRIBING INFORMATIONWARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITHSTEATOSIS and POST TREATMENT EXACERBATION OF HEPATITISLactic acidosis and severe hepatomegaly with steatosis, including fatalcases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals [See Warnings and Precautions (5.1)].Severe acute exacerbations of hepatitis have been reported in HBV-infected patients who have discontinued anti-hepatitis B therapy, including VIREAD. Hepatic function should be monitored closely with both clinical andlaboratory follow-up for at least several months in patients who discontinueanti-hepatitis B therapy, including VIREAD. If appropriate, resumption ofanti-hepatitis B therapy may be warranted [See Warnings and Precautions(5.2)].1 INDICATIONS AND USAGEInfection1.1 HIV-1VIREAD® is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age and older.The following points should be considered when initiating therapy with VIREAD for the treatment of HIV-1 infection:• VIREAD should not be used in combination with TRUVADA® or ATRIPLA® [See Warnings and Precautions (5.4)].1.2 Chronic Hepatitis BVIREAD is indicated for the treatment of chronic hepatitis B in adults.The following points should be considered when initiating therapy with VIREAD for the treatment of HBV infection:• This indication is based primarily on data from treatment of subjects who were nucleoside-treatment-naïve and a smaller number of subjects who had previously received lamivudine or adefovir dipivoxil. Subjects were adults with HBeAgpositive and HBeAg-negative chronic hepatitis B with compensated liver disease [See Clinical Studies (14.2)].• VIREAD was evaluated in a limited number of subjects with chronic hepatitis B and decompensated liver disease. [See Adverse Reactions (6.1), Clinical Studies(14.2)]• The numbers of subjects in clinical trials who had lamivudine- or adefovirassociated substitutions at baseline were too small to reach conclusions ofefficacy [See Microbiology (12.4), Clinical Studies (14.2)].2 DOSAGE AND ADMINISTRATION2.1 Recommended Dose in AdultsFor the treatment of HIV-1 or chronic hepatitis B: The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.In the treatment of chronic hepatitis B, the optimal duration of treatment is unknown.2.2 Recommended Dose in Pediatric Patients (≥12 Years of Age and ≥35 kg) For the treatment of HIV-1 in pediatric patients 12 years of age and older with body weight ≥35 kg (≥77 lb): The dose is one 300 mg VIREAD tablet once daily taken orally, without regard to food.2.3 Dose Adjustment for Renal Impairment in AdultsSignificantly increased drug exposures occurred when VIREAD was administered to subjects with moderate to severe renal impairment [See Clinical Pharmacology (12.3)]. Therefore, the dosing interval of VIREAD should be adjusted in patients with baseline creatinine clearance <50 mL/min using the recommendations in Table 1. These dosing interval recommendations are based on modeling of single-dose pharmacokinetic data in non-HIV and non-HBV infected subjects with varying degrees of renal impairment, including end-stage renal disease requiring hemodialysis. The safety and effectiveness of these dosing interval adjustment recommendations have not been clinically evaluated in patients with moderate or severe renal impairment, therefore clinical response to treatment and renal function should be closely monitored in these patients [See Warnings and Precautions (5.3)].No dose adjustment is necessary for patients with mild renal impairment (creatinine clearance 50–80 mL/min). Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients with mild renal impairment [See Warnings and Precautions (5.3)].Table 1 Dosage Adjustment for Patients with Altered Creatinine ClearanceCreatinine Clearance(mL/min)aHemodialysis Patients≥50 30–49 10–29Recommended 300 mg Dosing Interval Every 24hoursEvery 48hoursEvery 72 to96 hoursEvery 7 days or after a total ofapproximately 12 hours ofdialysis ba. Calculated using ideal (lean) body weight.b. Generally once weekly assuming three hemodialysis sessions a week of approximately 4 hours duration.VIREAD should be administered following completion of dialysis.The pharmacokinetics of tenofovir have not been evaluated in non-hemodialysis patients with creatinine clearance <10 mL/min; therefore, no dosing recommendation is available for these patients.No data are available to make dose recommendations in pediatric patients 12 years of age and older with renal impairment.3 DOSAGE FORMS AND STRENGTHSVIREAD is available as tablets. Each tablet contains 300 mg of tenofovir disoproxil fumarate, which is equivalent to 245 mg of tenofovir disoproxil. The tablets are almond-shaped, light blue, film-coated, and debossed with “GILEAD” and “4331” on one side and with “300” on the other side.4 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Lactic Acidosis/Severe Hepatomegaly with SteatosisLactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including VIREAD, in combination with other antiretrovirals. A majority of these cases have been in women. Obesity and prolonged nucleoside exposure may be risk factors. Particular caution should be exercised when administering nucleoside analogs to any patient with known risk factors for liver disease; however, cases have also been reported in patients with no known risk factors. Treatment with VIREAD should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity (which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations).5.2 Exacerbation of Hepatitis after Discontinuation of Treatment Discontinuation of anti-HBV therapy, including VIREAD, may be associated with severe acute exacerbations of hepatitis. Patients infected with HBV who discontinue VIREAD should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment. If appropriate, resumption of anti-hepatitis B therapy may be warranted.5.3 New Onset or Worsening Renal ImpairmentTenofovir is principally eliminated by the kidney. Renal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of VIREAD [See Adverse Reactions (6.2)].It is recommended that creatinine clearance be calculated in all patients prior to initiating therapy and as clinically appropriate during therapy with VIREAD. Routine monitoring of calculated creatinine clearance and serum phosphorus should be performed in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving HEPSERA®.Dosing interval adjustment of VIREAD and close monitoring of renal function are recommended in all patients with creatinine clearance <50 mL/min [See Dosage and Administration (2.3)]. No safety or efficacy data are available in patients with renal impairment who received VIREAD using these dosing guidelines, so the potential benefit of VIREAD therapy should be assessed against the potential risk of renal toxicity.VIREAD should be avoided with concurrent or recent use of a nephrotoxic agent.5.4 Coadministration with Other ProductsVIREAD should not be used in combination with the fixed-dose combination products TRUVADA or ATRIPLA since tenofovir disoproxil fumarate is a component of these products.VIREAD should not be administered in combination with HEPSERA (adefovir dipivoxil) [See Drug Interactions (7.4)].Coinfected with HIV-1 and HBV5.5 PatientsDue to the risk of development of HIV-1 resistance, VIREAD should only be used in HIV-1 and HBV coinfected patients as part of an appropriate antiretroviral combination regimen.HIV-1 antibody testing should be offered to all HBV-infected patients before initiating therapy with VIREAD. It is also recommended that all patients with HIV-1 be tested for the presence of chronic hepatitis B before initiating treatment with VIREAD.5.6 Decreases in Bone Mineral DensityAssessment of bone mineral density (BMD) should be considered for adults and pediatric patients 12 years of age and older who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation may be beneficial for all patients. If bone abnormalities are suspected then appropriate consultation should be obtained.In HIV-1 infected adult subjects treated with VIREAD in Study 903 through 144 weeks, decreases from baseline in BMD were seen at the lumbar spine and hip in both arms of the study. At Week 144, there was a significantly greater mean percentage decrease from baseline in BMD at the lumbar spine in subjects receiving VIREAD + lamivudine + efavirenz (-2.2% ± 3.9) compared with subjects receiving stavudine + lamivudine + efavirenz (-1.0% ± 4.6). Changes in BMD at the hip were similar between the two treatment groups (-2.8% ± 3.5 in the VIREAD group vs. -2.4% ± 4.5 in the stavudine group). In both groups, the majority of the reduction in BMD occurred in the first 24–48 weeks of the study and this reduction was sustained through Week 144. Twenty-eightpercent of VIREAD-treated subjects vs. 21% of the stavudine-treated subjects lost at least 5% of BMD at the spine or 7% of BMD at the hip. Clinically relevant fractures (excluding fingers and toes) were reported in 4 subjects in the VIREAD group and 6 subjects in the stavudine group. In addition, there were significant increases in biochemical markers of bone metabolism (serum bone-specific alkaline phosphatase, serum osteocalcin, serum C-telopeptide, and urinary N-telopeptide) in the VIREAD group relative to the stavudine group, suggesting increased bone turnover. Serum parathyroid hormone levels and 1,25 Vitamin D levels were also higher in the VIREAD group. Except for bone specific alkaline phosphatase, these changes resulted in values that remained within the normal range.In a clinical study of HIV-1 infected pediatric subjects 12 years of age and older (Study 321), bone effects were similar to adult subjects. Under normal circumstances BMD increases rapidly in this age group. In this study, the mean rate of bone gain was less in the VIREAD-treated group compared to the placebo group. Six VIREAD treated subjects and one placebo treated subject had significant (>4%) lumbar spine BMD loss in 48 weeks. Among 28 subjects receiving 96 weeks of VIREAD, Z-scores declined by -0.341 for lumbar spine and -0.458 for total body. Skeletal growth (height) appeared to be unaffected. Markers of bone turnover in VIREAD-treated pediatric subjects 12 years of age and older suggest increased bone turnover, consistent with the effects observed in adults.The effects of VIREAD-associated changes in BMD and biochemical markers on long-term bone health and future fracture risk are unknown.Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of VIREAD [See Adverse Reactions (6.2)].The bone effects of VIREAD have not been studied in patients with chronic HBV infection.Redistribution5.7 FatIn HIV-infected patients redistribution/accumulation of body fat including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and "cushingoid appearance" have been observed in patients receiving combination antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established. 5.8 Immune Reconstitution SyndromeImmune reconstitution syndrome has been reported in HIV-infected patients treated with combination antiretroviral therapy, including VIREAD. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections [such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia (PCP), or tuberculosis], which may necessitate further evaluation and treatment.5.9 Early Virologic FailureClinical studies in HIV-infected subjects have demonstrated that certain regimens that only contain three nucleoside reverse transcriptase inhibitors (NRTI) are generally less effective than triple drug regimens containing two NRTIs in combination with either a non-nucleoside reverse transcriptase inhibitor or a HIV-1 protease inhibitor. In particular, early virological failure and high rates of resistance substitutions have been reported. Triple nucleoside regimens should therefore be used with caution. Patients on a therapy utilizing a triple nucleoside-only regimen should be carefully monitored and considered for treatment modification.6 ADVERSEREACTIONSThe following adverse reactions are discussed in other sections of the labeling:• Lactic Acidosis/Severe Hepatomegaly with Steatosis [See Boxed Warning, Warnings and Precautions (5.1)].• Severe Acute Exacerbation of Hepatitis [See Boxed Warning, Warnings and Precautions (5.2)].• New Onset or Worsening Renal Impairment [See Warnings and Precautions (5.3)]. • Decreases in Bone Mineral Density [See Warnings and Precautions (5.6)].• Immune Reconstitution Syndrome [See Warnings and Precautions (5.8)].6.1 Adverse Reactions from Clinical Trials ExperienceBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.Clinical Trials in Adult Patients with HIV-1 InfectionMore than 12,000 subjects have been treated with VIREAD alone or in combination with other antiretroviral medicinal products for periods of 28 days to 215 weeks in clinical trials and expanded access studies. A total of 1,544 subjects have received VIREAD 300 mg once daily in clinical trials; over 11,000 subjects have received VIREAD in expanded access studies.The most common adverse reactions (incidence ≥10%, Grades 2–4) identified from any of the 3 large controlled clinical trials include rash, diarrhea, headache, pain, depression, asthenia, and nausea.Treatment-Naïve PatientsStudy 903 - Treatment-Emergent Adverse Reactions: The most common adverse reactions seen in a double-blind comparative controlled study in which 600 treatment-naïve subjects received VIREAD (N=299) or stavudine (N=301) in combination with lamivudine and efavirenz for 144 weeks (Study 903) were mild to moderate gastrointestinal events and dizziness.Mild adverse reactions (Grade 1) were common with a similar incidence in both arms, and included dizziness, diarrhea, and nausea. Selected treatment-emergent moderate to severe adverse reactions are summarized in Table 2.Table 2Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 903 (0–144 Weeks)VIREAD + 3TC + EFVd4T + 3TC + EFV N=299 N=301 Body as a WholeHeadache Pain Fever Abdominal pain Back painAsthenia 14%13% 8% 7% 9% 6% 17% 12% 7% 12% 8% 7% Digestive SystemDiarrhea Nausea Dyspepsia Vomiting 11% 8% 4% 5% 13% 9% 5% 9% Metabolic Disorders Lipodystrophy b1% 8%Musculoskeletal Arthralgia Myalgia 5% 3% 7% 5% Nervous SystemDepression InsomniaDizziness Peripheral neuropathy cAnxiety 11%5% 3% 1% 6% 10% 8% 6% 5%6% Respiratory Pneumonia 5% 5% Skin and Appendages Rash event d18% 12%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. Lipodystrophy represents a variety of investigator-described adverse events not a protocol-defined syndrome.c. Peripheral neuropathy includes peripheral neuritis and neuropathy.d. Rash event includes rash, pruritus, maculopapular rash, urticaria, vesiculobullous rash, and pustular rash.Laboratory Abnormalities: With the exception of fasting cholesterol and fastingtriglyceride elevations that were more common in the stavudine group (40% and 9%)compared with VIREAD (19% and 1%) respectively, laboratory abnormalities observedin this study occurred with similar frequency in the VIREAD and stavudine treatmentarms. A summary of Grade 3 and 4 laboratory abnormalities is provided in Table 3.Table 3 Grade 3/4 Laboratory Abnormalities Reported in ≥1% of VIREAD-TreatedSubjects in Study 903 (0–144 Weeks)VIREAD + 3TC + EFV d4T + 3TC + EFVN=299 N=301Any ≥ Grade 3 Laboratory Abnormality 36% 42%Fasting Cholesterol (>240 mg/dL) 19% 40%Creatine Kinase (M: >990 U/L; F: >845 U/L) 12% 12%Serum Amylase (>175 U/L) 9% 8%AST (M: >180 U/L; F: >170 U/L) 5% 7%ALT (M: >215 U/L; F: >170 U/L) 4% 5%Hematuria (>100 RBC/HPF) 7% 7%Neutrophils (<750/mm3) 3%1% Fasting Triglycerides (>750 mg/dL) 1% 9%Study 934 - Treatment Emergent Adverse Reactions: In Study 934, 511 antiretroviralnaïve subjects received either VIREAD + EMTRIVA® administered in combination withefavirenz (N=257) or zidovudine/lamivudine administered in combination with efavirenz(N=254). Adverse reactions observed in this study were generally consistent with thoseseen in previous studies in treatment-experienced or treatment-naïve subjects(Table 4).Table 4Selected Treatment-Emergent Adverse Reactions a (Grades 2–4) Reported in≥5% in Any Treatment Group in Study 934 (0–144 Weeks) VIREAD b + FTC + EFV AZT/3TC + EFVN=257 N=254 Gastrointestinal Disorder Diarrhea Nausea Vomiting9% 9% 2% 5% 7% 5% General Disorders and Administration Site Condition Fatigue9% 8% Infections and Infestations SinusitisUpper respiratory tract infectionsNasopharyngitis 8% 8%5% 4% 5%3% Nervous System Disorders Headache Dizziness 6% 8% 5% 7%Psychiatric Disorders Depression Insomnia9% 5% 7% 7% Skin and Subcutaneous TissueDisorders Rash eventc7%9%a. Frequencies of adverse reactions are based on all treatment-emergent adverse events, regardless of relationshipto study drug.b. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz. c. Rash event includes rash, exfoliative rash, rash generalized, rash macular, rash maculopapular, rash pruritic, andrash vesicular. Laboratory Abnormalities: Laboratory abnormalities observed in this study were generally consistent with those seen in previous studies (Table 5).Table 5 Significant Laboratory Abnormalities Reported in ≥1% of Subjects in AnyTreatment Group in Study 934 (0–144 Weeks)VIREAD a + FTC + EFV AZT/3TC + EFVN=257 N=254Any ≥ Grade 3 Laboratory Abnormality 30% 26%Fasting Cholesterol (>240 mg/dL) 22% 24%Creatine Kinase (M: >990 U/L; F: >845 U/L) 9% 7%Serum Amylase (>175 U/L) 8% 4%Alkaline Phosphatase (>550 U/L) 1% 0%AST (M: >180 U/L; F: >170 U/L) 3% 3%ALT (M: >215 U/L; F: >170 U/L) 2% 3%Hemoglobin (<8.0 mg/dL) 0% 4%Hyperglycemia (>250 mg/dL) 2% 1%Hematuria (>75 RBC/HPF) 3% 2%Glycosuria (≥3+) <1% 1%Neutrophils (<750/mm3) 3%5% Fasting Triglycerides (>750 mg/dL) 4% 2%a. From Weeks 96 to 144 of the study, subjects received TRUVADA with efavirenz in place of VIREAD + EMTRIVAwith efavirenz.Treatment-Experienced PatientsTreatment-Emergent Adverse Reactions: The adverse reactions seen in treatmentexperienced subjects were generally consistent with those seen in treatment naïvesubjects including mild to moderate gastrointestinal events, such as nausea, diarrhea,vomiting, and flatulence. Less than 1% of subjects discontinued participation in theclinical studies due to gastrointestinal adverse reactions (Study 907).A summary of moderate to severe, treatment-emergent adverse reactions that occurredduring the first 48 weeks of Study 907 is provided in Table 6.。
泰诺福韦的合成工艺研究
泰诺福韦的合成工艺研究王志刚;聂静;王治国【摘要】泰诺福韦是制备抗病毒药物泰诺福韦酯富马酸盐的关键中间体，以腺嘌呤和（ R）－1，2－亚丙基碳酸酯为原料，经开环缩合、取代和水解3步反应制得泰诺福韦。
反应过程用高效液相色谱仪（ HPLC ）进行监测，探讨了反应的最佳工艺：①开环缩合的最佳反应温度为145℃，最佳反应时间为5．5 h；②以叔丁醇镁为碱，取代反应的最佳反应时间为10 h；③采用廉价的三甲基氯硅烷和溴化钠进行水解，最佳反应时间为24 h。
在最优化的条件下总收率达到49．6％。
%Tenofovir is the key intermediate for the antiviral drug tenofovir disoproxil fumarate .Tenofovir is synthesized by adenine and propyl carbonate through ring -opening condensation , substitution reaction and hydrolysis reaction .The process of reaction is monitored by using High Performance Liquid Chromatography ( HPLC) .The optimal reaction conditions are discussed:①The best synthesis condition of ring -opening condensation is at 145 ℃ for 5.5 h.②The best reaction time of substitution reaction is 10 h with magnesium tert-butoxide as alkali .③The best reaction time of hydrolysis reaction is 24 h using cheap trimethylchlorosi-lane and sodium bromide.The overall yield of 49.6 % is obtained under optimal conditions.【期刊名称】《湖北理工学院学报》【年(卷),期】2015(000)005【总页数】4页(P46-49)【关键词】泰诺福韦;合成;工艺【作者】王志刚;聂静;王治国【作者单位】湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003;湖北理工学院化学与化工学院，湖北黄石435003; 湖北理工学院矿区环境污染控制与修复湖北省重点实验室，湖北黄石435003【正文语种】中文【中图分类】O626Key words：tenofovir;synthesis;process泰诺福韦(Tenofovir)，化学名是R-9-(2-磷酸甲氧基丙基)腺嘌呤，CAS号：147127-20-6，是抗病毒药物泰诺福韦酯的关键中间体。
年产16000吨L-天门冬氨酸建设项目环境影响报告表
础上编制完成了该项目环境影响报告书。 在报告书编写过程中得到了烟台市环保局、龙口市环保局、相关专家以及建 设单位的大力支持和协助，在此一并表示衷心的感谢。 由于水平所限，书中不足之处难免，敬请专家、领导批评指正。 项目组 2017 年 3 月
年产 16000 吨 L-天门冬氨酸建设项目
总论
第 1 章 总论
1-1
年产 16000 吨 L-天门冬氨酸建设项目
总论
号)； （5） 《国务院关于印发节能减排综合性工作方案的通知》 （国发[2007]15 号） ； （6） 《关于进一步加强危险废物和医疗废物监管工作的意见》 （环发 [2011]19 号） ； （7） 《关于实施〈环境空气质量标准〉 (GB3095-2012) 的通知》 ( 环发 [2012]11 号)； （8） 《环境保护部关于进一步加强环境影响评价管理防范环境风险的通 知》(环发[2012]77 号)； （9） 《关于切实加强风险防范严格环境影响评价管理的通知》 ( 环发 [2012]98 号)； （10） 《危险废物转移联单管理办法》 （国家环境保护总局令 第 5 号） ； （11） 《关于执行大气污染物特别排放限值的公告》 （环境保护部公告 2013 年 第 14 号） ； （12） 《关于印发<建设项目环境影响评价政府信息公开指南>（试行）的 通知》 （环办[2013]103 号） ； （13） 《关于切实加强环境影响评价监督管理工作的通知》(环办[2013]104 号)； （14） 《 关 于 发 布 < 一 般 工 业 固 体 废 物 贮 存 、 处 置 场 污 染 控 制 标 准 > （GB18599- 2001）等 3 项国家污染物控制标准修改单的公告》 （环境保护部公告 2013 年 第 36 号） ； （15） 《关于加强企业环境信用体系建设的指导意见》 （环发[2015]161 号） ； （16） 《关于印发<建设项目环境影响评价信息公开机制方案>的通知 《 （环 发[2015]162 号） ； （17） 《关于发布 < 环境保护部审批环境影响评价文件的建设项目目录 （2015 年本）>的公告》 （环保部公告 2015 年第 17 号） ； （18） 《工业和信息化部关于促进化工园区规范发展的指导意见》 （工信部 原[2015]433 号） ； （19） 《环境保护公众参与办法》 （环境保护部令 2015 年第 35 号） ；
年产800吨富马酸单乙酯的车间工艺设计
毕业论文课程设计说明书题目：年产800吨富马酸单乙酯的车间工艺设计姓名：学号：班级：指导老师：成绩：应用化学专业课程设计任务书1．设计原始数据年产量；800吨年工作日：280天生产工艺原理：以马来酸酐、乙醇为原料，氯化铝为催化剂，生产制备富马酸单乙酯。
反应温度：醇解60℃，异构化回流温度。
反应时间：醇解2小时，异构化2小时，反应完毕后,用甲苯结晶、冷却、过滤、烘干称量,计算收率。
其中富马酸单乙酯产率为80%。
其它工艺参数通过查资料自己确定。
2．物料规格原料与产物规格（纯度）马来酸酐98.0%乙醇99.5%氯化铝98.0%甲苯98%3．工艺计算物料衡算热量衡算设备计算4．编制设计说明书设计说明书的内容：一、总论（1）概述所设计产品的性能、用途和在国民经济中或对人民生活的重要性；该产品的市场需求，该产品的生产方法及特点。
（2）文献通过查阅国内外期刊文献，简述该产品的生产试验概况，国内外的生产现状和发展趋势。
（1000字以上）（3）项目来源由教师指定的课题（4）设计产品所需的主要材料的规格、来源以及水、电、汽的供应情况、结合设计地区供应情况加以说明。
二、生产流程和生产方案的确定根据查阅文献或实际调查所掌握的情况，或依据科学试验报告或小试结果进行放大设计，分析各种生产方法及其特点。
简要叙述自己设计所选定的生产方法的依据和特点。
画出一个简单流程图。
三、工艺计算包括物料衡算与能量衡算，计算结果汇总于物料衡算表和热量衡算表中，并将计算基准转换为生产能力的基准，包括时间基准和单位产品基准。
四、主要设备的工艺计算和设备选型根据设计任务工作量的大小，对反应釜进行工艺计算并进行选型。
并根据生产能力，按物料衡算和热量衡算的结果，对其它设备都作为辅助设备进行选型。
如泵、压缩机、换热器、槽罐等。
五、原材料、动力消耗定额六、车间成本估算七、环境保护及安全措施八、设计的体会和收获九、参考文献十、附工程图纸（1）带控制点的工艺流程图（2）主要设备装配图参考书《化工设计手册》（上、下册），国家医药管理局上海医药设计院编《精细化工反应器及车间工艺设计》（左识之主编），华东理工大学出版社《化工制图》《工程制图》（化工）《化工工艺设计概论》学生签名：目录第一章概述 (1)1.1 产品介绍 (1)1.2 原料介绍 (1)第二章生产方法的选择和流程设计 (4)2.1 工艺流程说明及操作步骤 (4)2.2 富马酸单乙酯生产流程框图[5-7] (4)第三章物料衡算及能量衡算 (5)3.1 物料衡算 (6)3.2 能量衡算[8] (7)3.2.1 热量平衡式 (7)3.2.2 热量衡算 (7)第四章设备计算和选型 (10)4.1 反应釜的结构和材质 (10)4.2 反应釜中物质的平均密度ρm的计算 (10)4.3 反应釜的计算和选型[9-10] (10)第五章投资估算和成本估算 (13)5.1 原料消耗量[11-12] (13)5.2 车间水、电、水蒸气的消耗量M (13)第六章环境保护措施 (16)6.1 环境保护 (16)6.2 安全措施 (16)第七章结论 (19)第八章主要设备装配图 (20)8.1 反应釜结构图（见附页） (20)8.2 富马酸单乙酯生产工艺流程图（见附页） (20)第九章心得体会 (21)第十章参考文献 (23)第一章概述1.1 产品介绍富马酸酯是一类重要的有机合成中间体和新型的化学防霉剂，具有低毒、高效、使用不受 pH 值局限、无残留等优点[1]。