Effect of rolling process on microstructures and mechanical properties of AZ31B alloy sheets
高科技对食物带来的影响英语作文
高科技对食物带来的影响英语作文High-Tech Advancements and their Impact on FoodThe rapid advancements in technology have had a profound impact on various aspects of our lives, and the food industry is no exception. From the way we produce, process, and distribute food to the way we consume it, the influence of high-tech innovations is undeniable. In this essay, we will explore the multifaceted ways in which high-tech advancements have transformed the food landscape.One of the most significant ways in which technology has impacted the food industry is through precision farming. The advent of precision agriculture has revolutionized the way crops are grown and managed. Precision farming utilizes GPS technology, sensors, and data analytics to provide farmers with detailed information about their fields, enabling them to optimize the use of resources such as water, fertilizers, and pesticides. This not only leads to increased crop yields but also reduces the environmental impact of agricultural practices. Additionally, the use of drones and robotic systems in farming has streamlined tasks such as crop monitoring, spraying, and harvesting, making the entire process more efficient and cost-effective.Another area where high-tech advancements have had a significant impact is in food processing and preservation. The development of advanced food processing techniques, such as high-pressure processing, pulsed electric field processing, and microwave processing, has allowed for the creation of safer, more nutritious, and longer-lasting food products. These technologies can effectively eliminate harmful bacteria and pathogens while preserving the natural flavor and nutritional content of the food. Furthermore, the use of advanced packaging materials and intelligent packaging systems has extended the shelf life of food, reducing waste and ensuring food safety.The impact of high-tech advancements on the food supply chain is equally remarkable. The integration of blockchain technology, Internet of Things (IoT), and cloud computing has transformed the way food is tracked, traced, and distributed. These technologies enable real-time monitoring of food shipments, allowing for the early detection of potential issues and the implementation of corrective measures. This increased transparency and traceability in the supply chain have enhanced food safety, reduced waste, and improved the overall efficiency of the food distribution network.The rise of e-commerce and online food delivery platforms has also been a significant outcome of high-tech advancements in the foodindustry. Consumers can now access a wide range of food products and restaurant meals with just a few clicks, and the integration of AI-powered recommendation systems and personalized offerings has further enhanced the customer experience. Moreover, the use of advanced logistics and delivery optimization algorithms has enabled faster and more reliable food delivery, catering to the growing demand for convenience and immediacy.The impact of high-tech advancements on food consumption and dietary habits is equally noteworthy. The proliferation of mobile apps and wearable devices has made it easier for consumers to track their dietary intake, monitor their nutritional needs, and make informed choices about the food they consume. Additionally, the rise of smart kitchen appliances, such as connected ovens, refrigerators, and food processors, has enabled greater automation and personalization in meal preparation, making it more convenient for individuals to maintain a healthy and balanced diet.Furthermore, the integration of high-tech solutions in the food industry has also fostered the development of innovative food products and alternative protein sources. From 3D-printed food and lab-grown meat to plant-based and insect-based proteins, these novel food technologies have the potential to address the growing global demand for food while reducing the environmental impact of traditional food production methods.However, the widespread adoption of high-tech advancements in the food industry has also raised concerns and challenges. Issues such as data privacy, cybersecurity, and the potential displacement of traditional food production methods have sparked debates and discussions among stakeholders. It is crucial that the implementation of these technologies be accompanied by robust regulatory frameworks and ethical considerations to ensure the long-term sustainability and inclusivity of the food system.In conclusion, the impact of high-tech advancements on the food industry is multifaceted and far-reaching. From precision farming and advanced food processing to e-commerce and smart kitchen appliances, these innovations have transformed the way we produce, distribute, and consume food. While the benefits of these advancements are undeniable, it is essential to address the potential challenges and ensure that the implementation of high-tech solutions in the food industry is guided by principles of sustainability, inclusivity, and ethical considerations. As we continue to navigate the rapidly evolving landscape of food and technology, it is crucial that we remain vigilant and adaptable, embracing the opportunities presented by high-tech advancements while mitigating their potential risks.。
FIDIC银皮书(中英文对照)
CONTENTS目录1General Provisions一般规定 (5)1.1Definitions定义 (5)1。
2Interpretation解释 (10)1.3Communications通信交流 (11)1。
4Law and Language法律和语言 (12)1。
5Priority of Document文件优先次序 (12)1。
6Contract Agreement合同协议书 (12)1。
7Assignment权益转让 (13)1.8Care and Supply of Document文件的照管和提供 (13)1.9Confidentiality保密性 (14)1.10Emplo yer’s Use of Contractor’s Documents雇主使用承包商文件 (14)1。
11Contractor’s Use of Employer’s Documents承包商使用雇主文件 (15)1。
12Confidential Details保密事项 (15)1。
13Compliance with Laws遵守法律 (15)1.14Joint and Several Liability共同的和各自的责任 (16)2The Employer雇主 (16)2.1Right of Access to the Site现场进入权 (16)2。
2Permits, Licences or Approves许可、执照或批准 (17)2.3Employer’s personnel雇主人员 (18)2。
4Employer’s Financial Arrangements雇主的资金安排 (18)2。
5Employer's Claims雇主的索赔 (18)3The Employer’s Administration雇主的管理 (19)3.1The Employer’s Representative雇主代表 (19)3。
综合管理试题及答案英语
综合管理试题及答案英语一、选择题（每题2分，共20分）1. The correct spelling of the word "management" is:A) manegmentB) manegmentC) managemnetD) management答案：D2. Which of the following is not a function of management?A) PlanningB) OrganizingC) LeadingD) Innovating答案：D3. The process of setting goals and deciding on actions to achieve these goals is known as:A) OrganizingB) LeadingC) ControllingD) Planning答案：D4. Who is considered the father of scientific management?A) Henry FordB) Frederick Winslow TaylorC) Peter DruckerD) Max Weber答案：B5. What is the term used to describe the process of making things happen in an organization?A) MotivationB) CoordinationC) ExecutionD) Delegation答案：C6. In management, "span of control" refers to:A) The number of employees a manager can effectively manageB) The number of products a company producesC) The number of departments in an organizationD) The number of years a manager has been in their position答案：A7. Which of the following is a characteristic of an effective team?A) Clear communicationB) Lack of trustC) Poor leadershipD) Conflict avoidance答案：A8. What is the process of making decisions in an organization?A) PlanningB) OrganizingC) LeadingD) Decision-making答案：D9. The management concept that emphasizes the importance of employee satisfaction and motivation is known as:A) Scientific managementB) Administrative managementC) Human relations movementD) Systems theory答案：C10. In the context of management, "feedback" is:A) Information about the results of a decision or actionB) The process of setting goalsC) The process of organizing resourcesD) The process of motivating employees答案：A二、填空题（每题2分，共20分）1. The four main functions of management are planning, organizing, leading, and ________.答案：controlling2. The management theory that focuses on the importance ofthe social and psychological aspects of work is known as the________ theory.答案：human relations3. A management style that involves providing employees with the freedom to make decisions is known as ________ leadership. 答案：autonomous4. The process of ensuring that activities are carried out as planned is called ________.答案：monitoring5. The management principle that states that managers should focus on the most important tasks is known as the ________ principle.答案：80/206. A management technique that involves breaking down a large task into smaller, more manageable parts is known as ________. 答案：task analysis7. The process of identifying the causes of a problem and determining the best course of action to solve it is called________.答案：problem-solving8. The management concept that suggests that organizations should be structured in a way that reflects their goals and objectives is known as ________.答案：organizational design9. The process of measuring the performance of anorganization against its goals is called ________.答案：performance evaluation10. The management theory that suggests that organizations should be viewed as a whole, with each part interacting with the others, is known as ________ theory.答案：systems三、简答题（每题10分，共40分）1. Explain the difference between leadership and management.答案：Leadership is about inspiring and motivating a team to achieve a common goal, while management involves planning, organizing, and coordinating the efforts of a team to accomplish tasks efficiently.2. What is the significance of delegation in management?答案：Delegation is significant in management as it empowers employees, improves productivity, and allows managers tofocus on strategic tasks. It also helps in developing theskills of subordinates and fostering a sense ofresponsibility.3. Describe the role of communication in effective management. 答案：Effective communication is crucial in management as it ensures that information is accurately and timely conveyed, facilitates collaboration among team members, and helps in resolving conflicts. It also aids in setting clearexpectations and feedback mechanisms.4. How can a manager ensure ethical behavior in an organization?答案：A manager can ensure ethical behavior by setting a good example, establishing clear ethical guidelines, providing training on ethical practices, encouraging open communication, and implementing a system for reporting unethical behavior without fear of retaliation.。
苏格兰 围术期预防的抗菌药物使用
KEY TO EVIDENCE STATEMENTS AND GRADES OF RECOMMENDATIONS
LEVELS OF EVIDENCE 1++ 1+ 12++ 2+ 23 4 High quality meta-analyses, systematic reviews of RCTs, or RCTs with a very low risk of bias Well conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias Meta-analyses, systematic reviews, or RCTs with a high risk of bias High quality systematic reviews of case control or cohort studies High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal Well conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal Non-analytic studies, eg case reports, case series Expert opinion
涟漪效应英语作文
涟漪效应英语作文The Ripple Effect: How Small Actions Can Create Lasting ChangeThe world we live in is a complex and interconnected web, where the actions of one individual can have far-reaching consequences. This phenomenon, known as the Ripple Effect, is a powerful concept that has the potential to transform our lives and the world around us. At its core, the Ripple Effect suggests that even the smallest of actions, when set in motion, can create a domino effect that extends far beyond our initial intentions.To truly understand the Ripple Effect, we must first recognize that every decision we make, every word we utter, and every deed we perform has the potential to create a chain reaction. Imagine dropping a pebble into a still pond – the initial impact creates a small ripple that gradually expands outward, touching the entire surface of the water. In much the same way, our individual actions, no matter how insignificant they may seem, can have a profound impact on the people and environments around us.One of the most remarkable aspects of the Ripple Effect is its ability to transcend time and space. A kind word spoken to a stranger today may inspire them to pay that kindness forward, creating a ripple that continues to spread long after the initial interaction. Similarly, a small act of environmental stewardship, such as recycling or planting a tree, can have a lasting impact on the health of our planet, benefiting generations to come.The Ripple Effect is not limited to the personal or local level; it can also be observed on a global scale. The outbreak of a pandemic, for example, has demonstrated the interconnectedness of our world in a profound way. As the virus spread rapidly across borders, it disrupted economies, strained healthcare systems, and changed the way we live our lives. Yet, in the midst of this global crisis, we have also witnessed the power of the Ripple Effect in action – individuals and communities coming together to support one another, scientists collaborating to develop life-saving vaccines, and governments working to coordinate international responses.The Ripple Effect is not just a theoretical concept; it is a tangible force that shapes the world we live in. By understanding and harnessing the power of the Ripple Effect, we can become agents of positive change, empowered to make a difference in the lives of those around us.One of the most inspiring examples of the Ripple Effect in action is the story of Rosa Parks. In 1955, when Rosa Parks refused to give up her seat on a segregated bus in Montgomery, Alabama, her simple act of defiance sparked a movement that would ultimately lead to the desegregation of public transportation and the broader civil rights movement in the United States. Her courageous stand, which seemed like a small act at the time, set in motion a chain of events that transformed the course of history.Similarly, the story of Greta Thunberg, the young Swedish environmental activist, demonstrates the power of the Ripple Effect on a global scale. Thunberg's decision to skip school and protest outside the Swedish parliament to demand action on climate change has inspired millions of people around the world to join the fight against the climate crisis. Her ripple has grown into a global movement, with young people taking to the streets and demanding that their leaders take decisive action to protect the planet.The Ripple Effect is not limited to individual actions; it can also be observed in the collective efforts of communities and organizations. The rise of social media, for instance, has amplified the power of the Ripple Effect, enabling individuals to connect, share ideas, and mobilize for change on an unprecedented scale. The #MeToo movement, which began with a single tweet, has grown into a global reckoning with sexual harassment and gender-based violence,empowering survivors to speak out and hold perpetrators accountable.As we navigate the complexities of the modern world, it is essential that we embrace the Ripple Effect and recognize the profound impact that our actions can have. By cultivating a mindset of compassion, empathy, and environmental stewardship, we can become the catalysts for positive change, creating ripples that will continue to spread long after we are gone.In conclusion, the Ripple Effect is a powerful concept that underscores the interconnectedness of our world and the profound impact that even the smallest of actions can have. Whether it's a kind word, an act of environmental stewardship, or a bold stand for social justice, each of us has the ability to set in motion a chain of events that can transform lives and shape the world around us. By embracing the Ripple Effect and using it as a guiding principle in our lives, we can become agents of change, empowered to make a lasting difference in the world.。
fluent 湍流模型
10.10.1 湍流选项湍流模型可用的不同的选项在10.3到10.7节已经详细的介绍过了。
这里将提供这些选项的用法。
如果你选择的是Spalart-Allmaras 模型，下列选项是有用的：● Vorticity-based production （基于漩涡的产出）● Strain/vorticity-based production （基于应变/漩涡的产出）● Viscous heating （对耦合算法总是激活）如果你选择的是标准的ε-k 模型或是可实行的ε-k 模型，下列选项是有用的： ● Viscous heating （对耦合算法总是激活）● Inclusion of buoyancy effects on ε（包含浮力对ε的影响）如果你选择的是RNG ε-k 模型，下列选项是有用的：● Differential viscosity model （微分粘性模型）● Swirl modification （涡动修正）● Viscous heating （对耦合算法总是激活）● Inclusion of buoyancy effects on ε（包含浮力对ε的影响）如果你选择的是标准的ω-k 模型，下列选项是有用的：● Transitional flows● Shear flow corrections● Viscous heating （对耦合算法总是激活）如果你选择的是剪切-应力传输ω-k 模型，下列选项是有用的：● Transitional flows （过渡流）● Viscous heating （对耦合算法总是激活）如果你选择的是雷诺应力模型（RSM ），下列选项是有用的：● Wall reflection effects on Reynolds stresses （壁面反射对雷诺应力的影响） ● Wall boundary conditions for the Reynolds stresses from the k equation （雷诺应力的壁面边界条件来自k 方程）● Quadratic pressure-strain model （二次的压力－应变模型）● Viscous heating （对耦合算法总是激活）● Inclusion of buoyancy effects on ε（包含浮力对ε的影响）如果你选择的是增强壁面处理（对ω-k 模型和雷诺应力模型可用），下列选项是有用的：● Pressure gradient effects （压力梯度的影响）● Thermal effects （热影响）如果你选择的是大漩涡模拟（LES ），下列选项是有用的：● Smagorinsky-Lilly model for the subgrid-scale viscosity● RNG model for the subgrid-scale viscosity● Viscous heating （对耦合算法总是激活）10．2．4 The Spalart-Allmaras 模型Spalart-Allmaras模型是设计用于航空领域的，主要是墙壁束缚流动。
混合实验仪（Mixolab）评价筛选优质饺子粉
秦毛毛，王雯斐，刘艳喜，等. 混合实验仪（Mixolab ）评价筛选优质饺子粉[J]. 食品工业科技，2023，44（20）：257−264. doi:10.13386/j.issn1002-0306.2022110185QIN Maomao, WANG Wenfei, LIU Yanxi, et al. Evaluation and Screening of High-quality Dumpling Flour by Mixolab[J]. Science and Technology of Food Industry, 2023, 44(20): 257−264. (in Chinese with English abstract). doi: 10.13386/j.issn1002-0306.2022110185· 包装与机械 ·混合实验仪（Mixolab ）评价筛选优质饺子粉秦毛毛1，王雯斐1，刘艳喜1，常 阳1，周正富1，雷振生1,2，吴政卿1,*（1.河南省作物分子育种研究院，河南郑州 450002；2.河南省农业科学院小麦研究所/小麦国家工程实验室，河南郑州 450002）摘 要：利用混合实验仪对优质饺子粉进行评价筛选研究，旨在为达成饺子专用粉高效在线配粉提供理论支撑。
本研究以市场上现有的30种饺子粉为研究对象，通过分析面粉的白度、湿面筋含量、流变学特性、糊化特性等理化指标和饺子皮感官评分，比较不同饺子粉品质差异性，运用聚类分析将上述面粉进行等级分类。
结合混合实验仪软件的内置功能Chopin+标准协议对优类饺子粉进行测定并制作目标剖面图。
利用该剖面图实现了郑麦136、郑麦366和新麦26等3种基础粉的饺子皮配粉应用。
结果表明，30种饺子粉品质性状的变异系数大小依次为：形成时间>稳定时间>粉质质量指数>弱化度>面筋指数>衰减值>最低粘度>峰值粘度>湿面筋含量>糊化温度>吸水率>白度>峰值时间>感官评分，其中形成时间的变异系数最大，为68.59，感官评分变异系数最小，为0.11。
软件工程_东北大学中国大学mooc课后章节答案期末考试题库2023年
软件工程_东北大学中国大学mooc课后章节答案期末考试题库2023年1._______ is a discipline whose aim is the production of fault-free software,delivered on time and within budget, that satisfies the client's needs._______是一个学科，其目标是生产出满足客户的需求的、未超出预算的、按时交付的、没有错误的软件。
答案:2.The relationship between whole-class and part-classes is called ______.整体和部分类之间的关系被称为______。
答案:aggregation3.The relationship between super-class and subclasses is called ______.超类和子类之间的关系称为______。
答案:inheritance4.The strategy of inheritance is to use inheritance wherever _______.继承的策略是在_______的情况下使用继承。
答案:appropriate5._____is to encapsulate the attributes and operations in an object, and hides theinternal details of an object as possible. _____是为了在一个对象中封装属性和操作，并尽可能隐藏对象的内部细节。
Data encapsulation6.Two modules are ________ coupled if they have write access to global data.如果两个模块对全局数据具有写访问权限，则是________耦合。
科技发展增加失业率的英语作文
科技发展增加失业率的英语作文Title: The Impact of Technological Advancements on Unemployment RatesIn the ever-accelerating march of technological progress, the landscape of industries and labor markets is undergoing profound transformation. While innovations have undeniably brought about remarkable advancements in productivity, efficiency, and convenience, they have also sparked concerns over their potential impact on employment levels, particularly with regard to increasing unemployment rates. This essay delves into the ways in which technological development contributes to job displacement and explores the complex interplay between technological progress and unemployment.At the heart of the debate lies the phenomenon of automation, which refers to the substitution of human labor with machines or software capable of performing tasks more efficiently andcost-effectively. The advent of robotics, artificial intelligence (AI), and machine learning technologies has enabled businesses to automate a wide range of jobs previously performed by humans, from assembly line work and data entry to more sophisticated rolesin customer service, accounting, and even professional services. As companies adopt these advanced systems, they often experience reduced operational costs, increased output, and improved accuracy, leading to higher profit margins. However, this process of automation can result in significant job losses, particularly forlow-skilled workers who are more susceptible to replacement by machines.Moreover, digitization and the rise of e-commerce have reshaped traditional business models, rendering some occupations obsolete and pressuring others to adapt rapidly. Brick-and-mortar retailers, for instance, have faced stiff competition from online marketplaces, leading to store closures and job cuts in sales and retail management. Similarly, the advent of digital platforms and mobile applications has disrupted industries such as transportation (ride-hailing apps replacing conventional taxi services) and hospitality (online vacation rentals challenging traditional hotels). These shifts, while creating new opportunities in the tech sector and related fields, often entail net job losses in the affected industries, contributing to the upward trend in unemployment rates.Technological advancements have also facilitated globalization and outsourcing, further compounding the issue of unemployment. The ease of communication and data transfer enabled by modern technology allows companies to relocate production facilities to regions with lower labor costs or to subcontract work to remote teams, thus reducing domestic employment opportunities. While this practice may enhance corporate profitability, it can lead to job losses in developed countries, particularly in sectors such as manufacturing and IT services.However, it is crucial to acknowledge that technological progress is not solely a job destroyer; it also creates new employment avenues and transforms existing roles. The growth of the digital economy has spawned entirely new industries, such as cybersecurity, data analytics, and renewable energy, which offer abundant job prospects for those with the appropriate skills. Furthermore, while certain tasks may be automated, human expertise remains indispensable in areas that require creativity, empathy, problem-solving, and strategic decision-making.Nonetheless, the benefits of these emerging job opportunities are often offset by the fact that they tend to be concentrated in urban areas and require specialized knowledge and skills that manydisplaced workers lack. This exacerbates regional disparities and widens the skills gap, leaving many unemployed individuals struggling to re-enter the workforce. To mitigate these negative effects, proactive policy measures and educational initiatives are needed to facilitate reskilling and upskilling programs, ensuring that the workforce is equipped to adapt to the evolving demands of the job market.In conclusion, the relationship between technological development and unemployment is a nuanced and complex one. While technological advancements undoubtedly drive productivity and economic growth, they also contribute to job displacement, particularly for low-skilled workers, and exacerbate structural unemployment due to skill mismatches. Addressing this challenge necessitates a multi-faceted approach involving investment in education and training, the promotion of inclusive innovation policies, and the implementation of social safety nets to support those affected by technological change. By striking a balance between harnessing the benefits of technology and safeguarding the welfare of the workforce, societies can ensure that technological progress ultimately serves as a catalyst for sustainable, inclusive economic development rather than a harbinger of widespread unemployment.。
哈工大博士学位论文模板
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LATEX TEMPLATE FOR MASTER/DOCTOR THESIS/DISSERTATION OF HARBIN INSTITUTE OF TECHNOLOGY
Candidate: Supervisor: Academic Degree Applied for: Specialty: Affiliation: Date of Defense: Degree-Conferring-Institution:
Development and Characterization of a Cell Culture Manufacturing Process Using Quality
Development and Characterizationof a Cell Culture Manufacturing ProcessUsing Quality by Design (QbD)PrinciplesDaniel M.Marasco,Jinxin Gao,Kristi Griffiths,Christopher Froggatt,Tongtong Wang and Gan WeiAbstract The principles of quality by design (QbD)have been applied in cell culture manufacturing process development and characterization in the biotech industry.Here we share our approach and practice in developing and char-acterizing a cell culture manufacturing process using QbD principles for establishing a process control strategy.Process development and character-ization start with critical quality attribute identification,followed by process parameter and incoming raw material risk assessment,design of experiment,and process parameter classification,and conclude with a design space con-struction.Finally,a rational process control strategy is established and documented.Keywords Cell culture process characterization ÁCell culture process develop-ment ÁCell culture process scale-up ÁControl strategy ÁCritical quality attribute ÁDesign space ÁQuality by design ÁRisk assessment AbbreviationsQbDQuality by design QTPPQuality target product profile CQACritical quality attributes DOEDesign of experiment CPMControl point matrix FMEA Failure modes and effects analysisD.M.Marasco (&)ÁJ.Gao ÁK.Griffiths ÁC.Froggatt ÁT.Wang ÁG.WeiBioproduct Research and Development,Lilly Research Laboratories,Eli Lilly and Company,Indianapolis,IN 46285,USAe-mail:marasco_daniel_m@Adv Biochem Eng Biotechnol (2014)139:93–121DOI:10.1007/10_2013_217ÓSpringer-Verlag Berlin Heidelberg 2013Published Online:5July 201394 D.M.Marasco et al. Contents1Introduction (94)2Development and Characterization of Cell Culture Manufacturing Process for Establishing a Process Control Strategy (96)2.1Construct CQA(s)Control Points Matrix (96)2.2Initial Process Parameter Risk Assessment (98)2.3Risk Mitigation/Initial Process Characterization Experiments (101)2.4Final Characterization Experiment (106)2.5FMEA Process Parameter Risk Assessment (106)2.6Classification of Process Parameters (108)2.7Process Excursion Studies (110)2.8Construction of the Design Space/Operating Space (110)2.9Cell Culture Process Control Strategy (110)3Case Study (111)3.1Construct CQA(s)Control Points Matrix (111)3.2Initial Process Parameter Risk Assessment (111)3.3Scale-Down Model (112)3.4Initial Process Characterization Experiments (112)3.5Final Process Characterization Experiment (115)3.6FMEA Process Parameter Risk Assessment (116)3.7Process Excursion Study (116)3.8Classification of Process Parameters (117)3.9Construction of Design Space (117)References (121)1IntroductionThe quality by design(QbD)concepts embodied in the International Conference on Harmonization(ICH)guidelines Q8(R2),Q9,Q10,and Q11have been applied to cell culture manufacturing process development and characterization[1–4].The January2011revised FDA Guidance for Industry,Process Validation:General Principles and Practices,integrates QbD principles into process validation prac-tices[5].These guidance documents outline the application of QbD principles in the lifecycle of a product from process design,process definition,and process characterization to process validation and continued process verification.The expectation from regulatory agencies is that quality is designed or built into the product and its manufacturing process and quality cannot be adequately assured by testing[5].The benefit of QbD is twofold:one is to provide a high level of assurance for product quality through lifecycle management of the product;the other is the potential forflexibility in the reporting responsibilities for movements within a registered design space[1].The implementation of QbD principles means product characteristics are designed and fully understood and their linkage to patient safety and clinical efficacy is established,the interaction between critical product quality attributes and its manufacturing process are fully characterized,and control strategyDevelopment and Characterization of a Cell Culture Manufacturing Process95including design space is established to ensure that the manufacturing process is capable of consistently producing the product with the desired quality attributes [6,7].Figure1presents our approach in applying QbD principles to developing and characterizing a cell culture manufacturing process for establishing a process control strategy.Development of a cell culture manufacturing process control strategy starts from identifying drug substance critical quality attributes based on the quality target product profile(QTTP).Critical quality attributes(CQAs)are identified through risk assessment that evaluates severity based on impact on patient safety and/or clinical efficacy[8].The list of CQA(s)evolves during the development lifecycle.Then,a matrix is created to describe the interaction between critical quality attributes and process unit operations based on previous process development work,platform knowledge,literature information,andfirst principles.This control point matrix (CPM)visually indicates the origin,growth,reduction,or clearance of the quality attributes over the entire drug substance manufacturing process and demonstrates the process control points for each critical quality attribute.96 D.M.Marasco et al.Using the CPM as a guide,initial process parameter risk assessments are per-formed to evaluate the impact of process parameters and incoming raw materials systematically,within common cause variability,on critical product quality attributes.Process parameters are selected based on risk assessment for empirical evaluation using design of experiments(DOE)utilizing a qualified scale-down model.The purpose of the initial characterization study is to link process parameters to critical quality attributes.A resolution III or IV,fractional factional DOE is conducted depending on the number of parameters to be evaluated.Pro-cess parameters having statistically significant impact on CQA(s)are selected for further study using response surface DOE.The functional relationships between these process parameters and CQA(s)are fully characterized.A secondary risk assessment,failure mode and effects analysis(FMEA),is performed during technology transfer to the commercial manufacturing site.Risks identified during the FMEA are further reduced or mitigated through process excursion and/or process challenge studies.Process parameters are classified as critical or noncritical postprocess charac-terization studies.The classification is performed based on risk assessment and experimental results from process characterization studies.Based on risk assess-ments conducted throughout the development lifecycle,those process parameters assessed as not likely to affect CQAs are classified as noncritical.For process parameters evaluated in characterization studies,if a parameter is both statistically significant and practically significant in affecting CQA(s),it is classified as critical. Otherwise,it is classified as noncritical.A design space/operating space is constructed post parameter classification.Per ICH Q8,design space is the multidimensional combination and interaction of input variables(e.g.,material attributes)and process parameters that have been dem-onstrated to provide assurance of quality.A cell culture process control strategy is established and documented based on information generated through risk assessments and process characterization studies during the development lifecycle.The establishment of analytical control strategy and microbiological control strategy is beyond the scope of this chapter.In the next sections,we describe our practices for process parameter risk assessments,CQA-driven process characterization by design of experiment,pro-cess parameter classification,design space/operating space construction,and process control strategy establishment.2Development and Characterization of Cell Culture Manufacturing Process for Establishing a ProcessControl StrategyThe process development lifecycle consists of process design,process definition, process characterization,process validation,and continued process verification.Development and Characterization of a Cell Culture Manufacturing Process97Table1Control points matrix describing the probable quality attribute control pointsCritical quality attribute Analytical method Unit operation influencing CQA(s)12345…N CQA#1OCQA#2OCQA#3O:XCQA#4O l X; CQA#5O X;O Origin of attribute at this unit operation:Growth of attribute at this unit operation;Reduction of attribute at this unit operationl Potential for growth or reduction of attribute at this unit operationX Significant reduction/clearance of attribute at this unit operationAfter definition of an initial baseline process,characterization studies are initiated to understand fully the impact of process parameters and incoming raw material attributes,within common cause variability,on critical quality attributes.Process characterization starts with risk assessment.The intention of the initial risk assessment is systematically to evaluate the potential risk of process parameters and incoming raw material attributes from each unit operation,within common cause variability,on critical quality attributes.A cause and effect methodology is utilized in the initial risk assessment.2.1Construct CQA(s)Control Points MatrixPrior to initializing process characterization,sufficient information should be available to describe,or reasonably estimate,the relationship between the unit operations and critical quality attributes.In order to facilitate the initial cause-and-effect risk assessment,a unit operation-based,control points matrix(CPM),is created to describe the probable control points(one or many)for each critical quality attribute.The matrix should include the most likely origin,growth, reduction,or clearance of the critical quality attributes across the entire drug substance manufacturing process.An example of a unit operation-based control point matrix is displayed in Table1.The control points matrix is used to guide the process parameter risk assessment by allowing unit operation characterization studies to focus only on the relevant critical quality attributes that are significantly influenced by the purpose or design intent of the unit operation.The control points matrix is updated as additional information becomes available.2.2Initial Process Parameter Risk AssessmentInitial process parameter risk assessments are based on process knowledge,that is, a combination of practical experience and theoretical understanding.The process parameter risk assessment is performed iteratively throughout the development lifecycle to prioritize development efforts.Depending upon an organization’s experience and relative level of comfort conducting these risk assessments,they may be performed by a subject matter expert,or by a cross-functional team.Per ICH Q6,the degree of rigor and formality of quality risk management should reflect available knowledge and be commensurate with the complexity and/or criticality of the issue to be addressed.The initial process parameter risk assessment is performed in four basic steps: (1)identify output,(2)identify input process parameters,(3)evaluate the probablerisks,and(4)rank the process parameters by riskscore.The results from the risk assessment guide and prioritize the experimental program used to characterize each unit operation of the cell culture manufacturing process.2.2.1Identification of OutputsCritical quality attributes are the main output analyzed in the initial process parameter risk assessment.Process performance indicators may also be considered.2.2.2Identification of Input Process ParametersThe inputs,or process parameters,are identified based on the operational knowledge and mechanistic understanding of each unit operation in the manu-facturing process.A cause and effect diagram is a useful tool to organize and group process parameters systematically by function.The cause-and-effect diagram is constructed by placing the output(i.e.,product and process attributes of interest)at the right side of the diagram,with the potential design factors(i.e.,process parameters and incoming raw material attributes,e.g.,concentration accuracy)on a series of branches and subbranches extending from the output axis.The process parameters can be grouped by function or process step to ensure no process parameters are overlooked.98 D.M.Marasco et al.The level of branching can be moderated to facilitate efficient communica-tion to ensure the level of detail is appropriate.An example cause-and-effect diagram describing a typical production bioreactor process is given in Fig.2[9].2.2.3Risk AnalysisAfter identifying the relevant process outputs (CQAs)and process inputs (process parameters)for each unit operation,the risks of common cause variability in the input parameters that may affect the output parameters are assessed.The risk analysis is based on first principles,literature information,platform knowledge,manufacturing experience,scientific judgment of the subject matter experts,and molecule-specific empirical knowledge.The process parameters can be classified into two groups:those that have the potential to affect critical quality attributes and those that do not.Process parameters that do not have the potential to affect critical quality attributes may be assigned a low risk score.Typically,low-risk process parameters are not formally studied in laboratory models or designed experiments and are classifiedas Development and Characterization of a Cell Culture Manufacturing Process 99100 D.M.Marasco et al.noncritical with appropriate rationales.The remaining process parameters are classified as high risk,thus,they may have the potential to affect critical quality attributes and require additional evaluation to better understand,reduce,or miti-gate risks.The process parameter risk assessment follows the logic diagram pre-sented in Fig.3.The initial process parameter risk assessment is an integral part of the development of a control strategy;therefore,this assessment should be ade-quately documented.2.2.4Raw Material Risk AssessmentThe risks of variability inherent to the cell culture raw materials used to manu-facture drug substances on CQA(s)are evaluated in the development lifecycle.The raw material components are analyzed to assess the intrinsic risk(use of the correct raw materials)and the extrinsic risk(lot-to-lot variability)on CQA(s)and other quality attributes.The assessment includes the risks introduced from a quality,technical,and procurement perspective.The initial risk assessment occurs prior to the manufacture of pivotal clinical materials,and is reassessed as the process evolves.For example,technology transfer and/or changes in the process or supply chain may initiate a reassessment.The evaluation of raw material risk utilizes a series of weighted risk elements based on their criticality to the product or process,and the risk to the patient.Each raw material is assigned a three-tiered risk score(low=1,medium=3,or high=5)for each risk element using a combination of platform knowledge, manufacturing experience,opinions of the subject matter experts,and molecule-Development and Characterization of a Cell Culture Manufacturing Process101 specific empirical knowledge.The summation of the individual risk scores mul-tiplied by the risk element weight is calculated for each component.These values are used to rank the relative risks for each raw material component.As an example,the risk elements,and their respective weights,are described in table.Description of risk elementsWeight=5•Variability has the potential to affect the drug substance quality attributes•Ability of raw material to introduce bioburden,endotoxin,viral contaminates•Known issues with raw materialWeight=3•Molecular complexity•Potential to affect process performanceWeight=1•Experience with vendor•Manufactured for pharmaceutical industry2.3Risk Mitigation/Initial Process CharacterizationExperimentsFollowing the identification of high-risk process parameters and raw materials,an experimental program is designed to characterize and mitigate the risks of iden-tified process parameters on critical quality attributes within common cause variability.2.3.1Experimental StrategyThe experimental program is designed to characterize the manufacturing process to ensure consistent robust manufacturing capability.The high-risk process parameters are studied in a series of designed experiments intended to understand and mitigate potential risks further.Scale-independent process parameters are explored using a laboratory scale-down model.Scale-dependent parameters may be studied using intermediate or at-scale bioreactors.The experimental program is typically initialized utilizing a highly leveraged design of experiments of a resolution sufficient to identify the main effects and some quadratic effects.Depending upon the number of relevant process parameters identified in the risk assessment process,a single or a series of screening exper-iments can be planned.Multivariate fractional factorial design of experiments of resolution III or IV run using one or several blocks are common.Based on the output from the screening experiment,additional studies may be performed to102 D.M.Marasco et al. characterize parameters further that have a statistically and practically significant effect on critical quality attributes.Prior to designing experiments,the high-risk process parameters should be examined while acknowledging that not all process parameters are independent of each other(i.e.,medium strength and medium osmolality).Potential correlations should be identified and taken into consideration.2.3.2Process Parameter Range of InterestDuring cell culture manufacturing process characterization studies,the target setpoints of process parameters are determined based on process design and def-inition experimentation;process parameter ranges selected are intended to eval-uate the impact of common cause variability in operations on critical quality mon cause variability is defined as the expected level of variability experienced during normal unit operations in a manufacturing environment when executed according to the batch record instructions.The range of interest is determined from the current understanding of the at-scale control capability using a combination of operational variability,or the variance from target setpoints,and the measurement uncertainty of the device(s) that record the process measurement.Theoperationalvariabilityisameasureofperformancederived fromsampling unit operations in the clinical manufacturing or commercial manufacturing facilities.The range encompassing common cause variability is chosen so that the probability of the parameter values being within the range of the target setpoints±operational vari-ability is at least0.995(or99.5%).Generally,six times the operational variability is selectedtoensurethatthevaluesofagivenprocessparameterwillfallwithinthisrange irrespective of the underlying distribution[10].The measurement uncertainty characterizes the dispersion of the values that could be reasonably attributed to the measurement.The measurement uncertainty is designed to reduce the false acceptance rate and is selected to ensure95%of the recorded measurements fall within the desired range.The measurement uncer-tainty is derived from either the measurement system design specification or historic calibration performance[11].The summation of operational variability(containing99.5%of the observed values)and measurement uncertainty(containing95%of the recorded measure-ments)defines the recommended minimum range of interest used to characterize the process,as displayed in Fig.4.2.3.3Laboratory Scale Models for Process CharacterizationIn most scenarios,performing process characterization studies at the manufac-turing scale is not practically feasible due to the cost of operation,and limited availability of large-scale bioreactors.Therefore,laboratory scale models are usedto perform process characterization experiments that define acceptable process ranges and establish predictive relationships between the scale-independent pro-cess parameters and critical product quality attributes.This approach is in align-ment with ICH guidance [4];small–scale models can be developed and used to support process development studies.The development of a model should account for scale effects and be representative of the proposed commercial process.A scientifically justified model can enable a prediction of product quality,and can be used to support the extrapolation of operating conditions across multiple scales and equipment.The cell culture manufacturing process includes a series of shake flasks and conventional stirred-tank or disposable bioreactors to manufacture the unprocessed bulk drug substance.The culture expansion steps have a limited potential for impact on critical quality attributes due to negligible accumulation of product;therefore the focus of the scale-down model is typically on the production bio-reactor unit operation.The bioreactor configuration has five primary control loops intended to measure and control culture temperature,dissolved oxygen,culture pH,agitation rate,and vessel pressure by manipulating caustic and acidic pH control loops,air,oxygen,and carbon dioxide gas flow rates,vessel jacket heat exchanger,and the agitator drive.An example P&ID (piping and instrumentation diagram)is provided in Fig.5.The cell culture process parameters can be separated into two groups including scale-dependent and scale-independent parameters.The operating conditions for scale-independent parameters (i.e.,temperature,pH,dissolved oxygen concen-tration)are conserved across different scales.The scale-dependent parameters (i.e.,agitation rate,gas flow rates,nutrient addition volume)are adjusted to conform to the scaling strategy employed.The scale-dependent parameters included in a bioreactor system are driven by gas–liquid and liquid–liquid mixing with the associated mass and heat transport phenomena.Mixing systems do not scale proportionally in all dimensions;therefore a basis for scaling up mixing unit operations must be chosen by bal-ancing the characteristics that are important to the process under consideration.Scaling strategies are typically based on a combination of geometric similarity,kinematic similarity,dynamic similarity,and/or power per unit volume input.TargetVariability6σr 2σmu2σmu 6σrTypically two of the four methods are selected,allowing the other characteristics to change.Bioreactor unit operations used for mammalian cell culture processes are usually scaled up by conserving the power per unit volume with geometrically similar vessels.When scaling up on the basis of geometric similarity and constant power per unit volume,the relative agitator tip speed and the bulk mixing time increase.Increasing the agitator tip speed may increase the risk of shear damage to the cells;however,prior experiments have demonstrated that the risk of damage is minimal over the normal operating range of interest.Increasing the bulk mixing time will result in an increased risk of vessel heterogeneity which could affect the product’s critical quality attributes and process performance.Equipment design and addi-tional experiments should be considered if there is a high risk of vessel hetero-geneity affecting culture performance or critical quality attributes.In cell culture processes the proper scaling of gas flow rates to control dissolved carbon dioxide and dissolved oxygen levels is not trivial.As the process is scaled up,the mass transport of oxygen increases with vessel volume leading to a decreased volumetric flow rate of oxygen necessary to meet the culture demand.The resulting decrease in volumetric flow rate reduces the capability to remove carbon dioxide.An air balance is required in the sparger line to provide a sufficient volumetric flow for carbon dioxide removal.In addition,the medium chemistry and the profile of metabolic by-products (i.e.,lactate concentration)may lead to a feedforward control strategy based on the interaction between dissolvedoxygen Fig.5Example bioreactor piping and instrumentation diagramand pH control loops.In our system,the gas sparger configuration may be spec-ified so that the amount of gasflow needed to maintain the dissolved oxygen control is the amount of gas needed for carbon dioxide removal.The carbon dioxide management in the at-scale and intermediate-scale bioreactors may be determined through process models that simultaneously solve the chemistry equilibrium and mass transfer equations through the course of the run assuming that the oxygen uptake rate and significant metabolic by-products are defined by the process conditions.The models are used to define a target airflow rate that allows for carbon dioxide off-gassing.The interaction between multiple scale-dependent control loops presents additional challenges when scaling down cell culture processes to the laboratory bench scale.The power per unit volume is difficult to determine as the standard vessel geometry is modified to accommodate the reduced scale.In addition,the ratio between culture volume and surface area in contact with the head space increases,influencing the mass transfer rates for gases.As a result controlling the pCO2concentration at the laboratory scale is difficult to model.Additional experiments may be performed to understand the risks better that elevated carbon dioxide levels have on culture performance and/or product critical quality attributes.The capabilities of the laboratory scale models are monitored throughout the development lifecycle and the risk,whether the scale-down models are repre-sentative of at-scale processes,is analyzed as sufficient large-scale information becomes available.The laboratory-scale models are analyzed by comparing results between the scale-down and at-scale processes for outcomes including critical quality attributes,other product quality attributes,and process performance indicators.The scale comparison data for quality attributes are explored using statistical methods.The data from bioreactors run at process targets in the scale-down model (from process characterization and process design and definition studies)are compared to the data generated from at-scale clinical material manufacturing campaigns.An equivalence test(two-one-sided t test,TOST)with a predefined practical difference is used to test for equivalency between critical and other product quality attributes[12].A practical difference threshold should be sufficient to support the claims,or intended use of the scale-down model.Based on these criteria,the suitability of the scale-down model relative to the at-scale process can be assessed.The process performance indicators are also explored qualitatively by exam-ining the process trends over parisons are made relative to the direc-tionality and closeness of the time-series data.If the performance of the scale-down model is not equivalent,additional analysis should be performed to determine if the process characterization results are sufficient to construct an adequate control strategy.If not,additional work should be performed to develop a better model,or generate additional data to mitigate risks.。
AZ 不机性发展者系列说明书
D A T A S HE E TAZ® Developer,400K, and 421KInorganic DevelopersDescriptionAZ® inorganic developers are either sodium- or potassium-based developers. Most are buffered to maintain a uniform pH and to provide maximum developer bath life and process stability.These developers are odorless aqueous alkaline solutions that are compatible with batch and in-line development processes. AZ developers are defi ned by a product name and, as applicable, a dilution inparts of developer concentrate to parts of deionized water, e.g., AZ® 400K developer 1:4. AZ® Developer and AZ 400K developer are supplied as concentrates or prediluted. AZ® 421K developer is prediluted.Key Characteristics• A Z Developer: Sodium-based buffered developer that provides optimal process control while minimizing the attack on aluminum surfaces.• A Z 400K developer: Potassium-based buffered developer that provides optimal process control while minimizing con-tamination risks by using the less mobile potassium ion. Provides high throughput and contrast, particularly for thick fi lm AZ®9200 and P4000 series photoresists.• A Z 421K developer: Potassium-based unbuffered developer that provides high throughput and contrast, particularly for thicker fi lm AZ P4000 series photoresists.Features• B road range of developers provides numerous options from which to obtain wide process latitude, high contrast, and superior production throughput.• E xcellent batch-to-batch consistency from tight productspecifi cation control.ProcessingDevelopers typically have a limited range of useful dilutions. Highly concentrated dilutions have high sensitivity and allow faster photo-speeds, but they are limited by high dark fi lm losses and reduced contrast. The more dilute concentrations enable high contrast and provide greater selectivity between the exposed and unexposed resist. These require longer development times or increased exposure energy. They also have greater sensitivity to the effects of standing waves from monochromatic exposure.• A ll the high contrast and high sensitivity formulations of AZ inorganic developers are suitable for a 60 to 120 second batch immersion development at 20 to 25°C. High sensitivity dilutions and/or longer development times are recommended for dyed photoresists. While inorganic developers are not as sensitive to temperature changes as metal-ion-free developers, temperature control of ± 1°C is recommended to maintain a stable process. Mild agitation is recommended to achieve uniform development.• I n-line development applications require short development times because of equipment throughput constraints. High sensitivity developer formulations are recommended. A wide variety of spray, stream, and puddle combinations can be used. Typical processes follow.Typical Develop ProcessSpray-PuddleWet Wafer in Water Spray 0 - 5 sec, 100 - 200 rpmSpray Developer 5 - 15 sec, 100 - 200 rpmStop Wafer and Continue Spray to Set up Puddle 0 - 2 sec, 0 rpmPuddle Develop 10 - 30 sec, 0 rpmStream on Rinse 5 - 10 sec, 100 rpmSpin Dry 5 - 10 sec, 4000 rpmSpray OnlyWet Wafer in Water Spray 0 - 5 sec, 100 - 200 rpmSpray Developer 30 - 40 sec, 100 - 200 rpmOverlap Rinse and Developer Sprays 0 - 5 sec, 100 - 200 rpmStream on Rinse 5 - 10 sec, 100 - 200 rpmSpin Dry 5 - 10 sec, 4000 rpmNote: Contaminating inorganic developer baths or lines with tetramethylammonium hydroxide (TMAH) based metal-ion-free developers, even at the parts-per-million level, seriously affects the photospeed of the inorganic developer process. Use caution when changing developing equipment from a metal-ion-free to an inorganic process.Developer bath life is dependent on the amount of carbon dioxide absorbed from the air and on the amount of dissolved photoresist. Replenish the developer periodically, perhaps once a shift or when developer activity is reduced.Typical recommendations for high sensitivity and high contrast dilutions follow.Developer High Sensitivity* High Contrast*AZ® Developer 2:1 1:1AZ® 400K Developer 1:3 1:4*developer:DI waterSpecifi cationsDeveloper: Normality (R1) Normality (R2) Color Chloride Liquid Particle(ppm) Count(#/ml > 0.5 μm)AZ® Developer 0.460 ± 0.010 0.6.00 ± 0.005 25 max. 120 max. AZ® Developer 1:1 0.230 ± 0.005 0.3000 ± 0.0025 15 max. 120 max. AZ® Developer 2:1 0.307 ± 0.005 0.400 ± 0.003 25 max. 120 max. AZ® Developer 3:2 0.276 ± 0.004 0.360 ± 0.003 15 max. 120 max. AZ® 400K Developer 0.482 ± 0.005 1.390 ± 0.005 25 max. 2.0 max. 100 max. AZ® 400K Developer 1:3 0.120 ± 0.001 0.348 ± 0.001 15 max. 2.0 max. 100 max. AZ® 400K Developer 1:4 0.0960 ± 0.0005 0.2780 ± 0.0005 15 max. 1.5 max. 75 max. AZ® 400K Developer 1:5 0.080 ± 0.001 0.232 ± 0.001 15 max. 2.0 max. 100 max. AZ® 421K Developer 0.210 ± 0.001 15 max. 2.0 max. 100 max. Specifi cations are subject to revision. Contact your AZ account manager for additional information.North America:Somerville, NJ, USA (908) 429-3500 Europe:Wiesbaden, Germany 49 (611) 962-6867Far East:Shanghai, China 86-21-64851000 x 323Tsuen Wan, N.T. Hong Kong (852) 24081913Tokyo, Japan 81-3-5977-7938Seoul, Korea 82-2-510-8613Selangor Darul Ehsan, Malaysia 603 5101 2888Singapore 65 5630288Taipei, Taiwan 886-2-2516-3268AZ® Developer, 400K, and421K Inorganic DevelopersEquipment CompatibilityAZ® inorganic developers are compatible with most commercially available wafer and photomask processing equipment. Recommended materials of construction include stainless steel, PTFE, polypropylene, and high density polyethylene.StorageKeep in sealed original containers. Protect from sunlight. Store in a cool, dry place. Empty container may contain harmful residue.Handling Precautions/First AidRefer to the current Material Safety Data Sheet (MSDS) for detailed information prior to handling.The information contained herein is, to the best of our knowledge, true and accurate, but all recommendations or suggestions are made without guarantee because the conditions of use are beyond our control. There is no implied warranty of merchantability or fitness for purpose of the product or products described here. In submitting this information, no liability is assumed or license or other rights expressed or implied given with respect to any existing or pending patent, patent application, or trademarks. The observance of all regulations and patents is the responsibility of the user. AZ and the AZ logo are registered trademarks of AZ Electronic Materials. © 2005 AZ Electronic Materials. 1/05。
中文-PDA TR60 工艺验证：生命周期方法
4.1.2 Installation............................................... 29 4.1.3 Qualification Plan..................................... 2CTION...................................................1
1.1 Purpose and Scope......................................... 1 1.2 Background.................................................... 1
4.2 Process Performance Qualification .............. 31 4.2.1 PPQ Readiness........................................ 31
4.3 Design Strategy for Process Performance Qualification (PPQ)........................................ 33
4.1.3.1 Test Functions and Acceptance Criteria............................ 30
4.1.4 Maintaining Systems in a State of Control ...................................... 30
英语作文-集成电路设计行业中的行业热点与前沿技术
英语作文-集成电路设计行业中的行业热点与前沿技术In the rapidly evolving landscape of the integrated circuit (IC) design industry, numerous trends and cutting-edge technologies continue to shape its trajectory. From advancements in process technology to novel design methodologies, the industry is witnessing a wave of innovation that promises to redefine the possibilities of electronic systems. This article explores some of the key industry hotspots and frontiers in IC design.1. Advanced Process Nodes:。
One of the perennial focal points in IC design is the race towards smaller process nodes. Shrinking transistor dimensions enable higher transistor density, lower power consumption, and increased performance. Leading semiconductor companies are investing heavily in pushing the boundaries of process technology, with nodes like 7nm, 5nm, and beyond becoming the new battlegrounds for competitiveness. These advancements not only pose technical challenges but also necessitate innovative design strategies to harness the full potential of the latest process nodes.2. System-on-Chip (SoC) Integration:。
Emulsions乳剂
Section 10EmulsionsBy Drs. Pardeep K. Gupta, Clyde M. Ofner and Roger L. SchnaareTable of Contents Emulsions (1)Table of Contents (1)Introduction and Background (3)Definitions (3)Types of Emulsions (3)Formation of an Emulsion (4)Determination of Emulsion Type (4)Miscibility or Dilution Test (4)Staining or Dye Test (4)Electrical Conductivity Test (4)Physical State of Emulsions (5)Pharmaceutical Application of Emulsions (5)Formulations (6)Typical Ingredients (6)Drug (6)Oil Phase (6)Aqueous Phase (6)Thickening Agents (6)Sweeteners (6)Preservative (6)Buffer (7)Flavor (7)Color (7)Sequestering Agents (7)Humectants (7)Antioxidants (7)Emulsifiers (7)Guidelines (7)Type of Emulsion Desired (7)Toxicity (8)Method of Preparation (8)Typical Formulas (8)Cod Liver Oil Emulsion (polysaccharide emulsifier) (8)Protective Lotion (divalent soap emulsifier) (8)Benzoyl Benzoate Emulsion (emulsifying wax emulsifier) (8)Barrier Cream (soap emulsifier) (9)Cold Cream (soap emulsifier) (9)All Purpose Cream (synthetic surfactant emulsifier) (9)Emulsifiers (10)Natural Products (10)Polysaccharides (10)Sterols (10)Phospholipids (10)Surfactants (10)Anionic Surfactants (11)Soaps (11)Detergents (11)Cationic Surfactants (11)Nonionic Surfactants (11)Finely Divided Solids (12)Methods to Prepare Emulsions (13)Classical Gum Methods (13)Dry Gum Method (13)Wet Gum Method (13)“In Situ” Soap Method (13)Lime Water/Vegetable Oil Emulsions (13)Other Soaps (13)With Synthetic Surfactants (13)Required HLB of the Oil Phase (14)HLB of Surfactant Mixtures (14)Emulsion Stability (15)Sedimentation or Creaming (15)Factors - Stoke’s Law (15)Droplet Size (15)Density Difference (15)The Gravitational Constant, g (15)Viscosity (15)Breaking or Cracking (16)Thermodynamics of Emulsions (17)Microemulsions (18)References (19)Selected Readings (19)Introduction and BackgroundDefinitionsEmulsions are pharmaceutical preparations consisting of at least two immiscible liquids.Due to the lack of mutual solubility, one liquid is dispersed as tiny droplets in the other liquid to form an emulsion. Therefore,emulsions belong to the group of prepara-tions known as disperse systems.The USP also defines several dosage forms that are essentially emulsions but historically are referred to by other names. For example;Lotions are fluid emulsions orsuspensions intended for external application.Creams are viscous liquid or semi-solid emulsions of either an oil-in-water (O/W) or the water-in-oil (W/O) type. They are ordinarily used topically. The term cream is applied most frequently to soft, cosmetically acceptable types of preparations.Microemulsions are emulsions withextremely small droplet sizes and usually require a high concentration of surfactant for stability. They can also be regarded as isotropic, swollen micellar systems.Multiple emulsions are emulsions that have been emulsified a second time,consequently containing three phases. They may be water-in-oil-in-water (W/O/W) or oil-in-water-in-oil (O/W/O).Fluid emulsions are generally composed of discrete, observable liquid droplets in a fluid media, while semi-solid emulsions generally have a complex, more disorganized structure.The liquid which is dispersed as droplets iscalled as the dispersed , discontinuous or internal phase, and the liquid in which thedispersion is suspended is the dispersion medium or the continuous or external phase.For example, if olive oil is shaken with water,it breaks up into small globules andbecomes dispersed in water. In this case the oil is the internal phase, and water is the external phase.The dispersed particles or globules can range in size from less than 1 µm up to 100 µm. An emulsion is rarely a monodis-perse system, e.g., all the particles are rarely of the same size. A typical emulsion contains a distribution of many sizes, making it a polydisperse system.Types of EmulsionsBased on the nature of the internal (or exter-nal) phase, emulsions are of two types; oil-in-water (O/W) and water-in-oil (W/O). In an O/W type the oil phase is dispersed in the aqueous phase, while the opposite is true in W/O emulsions. Figure 1 depicts these two types of emulsions.Figure 1: Representation of Two Types of EmulsionsO/W Emulsion W/O Emulsion (water black)(oil white)When two immiscible phases are shaken together, either type of emulsion can result.However, this result is not random, but is dependent primarily on two factors; most importantly the type of emulsifier used and secondly the relative ratio of the aqueous and oil phases (phase volume ratio). The emulsifiers and their role in the type of emulsion are discussed in detail later in this chapter.In terms of the phase volume ratio, the percent of the internal phase is generally less than 50%, although emulsions can have internal phase volume percent as high as 75%. Uniform spheres, when packed in a rhombohedral geometry occupy approxi-mately 75% of the total volume. Phase volumes higher than 75% require that the droplets of dispersed phase be distorted into geometric shapes other than perfect spheres. Although it is rare to find emulsions with higher than 75% internal volume, phase volumes of over 90% have been reportedin literature.Formation of an EmulsionWhen two immiscible liquids are placedin contact with each other, they form two separate layers. The liquid with higher density forms the lower layer and the one with lower density forms the upper layer. When this two-layer system is shaken vigorously, one of the layers disperses in the other liquid forming an unstable emul-sion. If left unstirred, the dispersed phase comes together and coalesces into larger drops until the layers become separate again. If no other ingredient is added, this process of separation is usually completein a matter of a few minutes to a few hours. Therefore, a liquid dispersion is inherently an unstable system.However, when an emulsifier is present in the system, it reduces the interfacial tension between the two liquids and forms a physical barrier between droplets, hence lowers the total energy of the system(see discussion on Thermodynamics of Emulsions), thereby reducing the tendency of the droplets to come together and coalesce. Consequently, the globules ofthe internal phase may remain intact for long periods of time, forming a “stable”emulsion. It should be noted, however,that even with an emulsifier, an emulsionis a thermodynamically unstable system and will eventually revert to bulk phases. The time required for this process is determined by kinetics.Determination of Emulsion TypeSeveral tests can be used to determine whether a given emulsion is an O/W or W/O type. These are as follows:Miscibility or Dilution TestThis method is based on the fact that an emulsion can be diluted freely with a liquid of the same kind as its external phase. Typically, a small amount of the emulsion is added to a relatively large volume of water and the mixture is stirred. If the emulsion disperses in water, it is considered to bean O/W type emulsion. If, however, the emulsion remains undispersed, it is a W/O type emulsion.Staining or Dye TestThis test is based on the fact that if a dye is added to an emulsion and the dye is soluble only in the internal phase, the emulsion contains colored droplets dispersed inthe colorless external phase. This can be confirmed by observing a drop of emulsion under a low power microscope. An example of such a dye is scarlet red, which is an oil soluble dye. When added to an O/W type emulsion, followed by observation under the microscope, bright red colored oil drops in an aqueous phase can be seen clearly. Electrical Conductivity TestThis test is based on the fact that onlythe aqueous phase can conduct electrical current. Thus, when a voltage is applied across a liquid, a significant amount of electrical current will flow only when the path of the current is through a continuous aqueous phase. Since oil is a non-conductor of electricity, when tested for conductivity, a W/O type emulsion will show insignificant current flow.Often times a single test may not be conclu-sive. In such circumstances, more than one test may need to be carried out to confirm the emulsion type.Physical State of EmulsionsMost emulsions are either liquid or semi-solid at room temperature. In general, due to their high viscosity, the semi-solid emulsions are relatively more physically stable. Liquid emulsions are more commonly compounded for internal use, while semisolids are usually for external use or for use in body cavities (rectal or vaginal).Other terms commonly used to describe emulsions are lotion and cream . The term lotion refers to a disperse system that flows freely under the force of gravity. A cream is a product that does not flow freely under the force of gravity. It should be noted, however,that these terms are meaningful only when the product is at room temperature. A cream product may behave like a lotion with a temperature increase of a few degrees. The physical state of the final product is also influenced by its intended use. For example suntan lotions are dispensed as lotions instead of creams because they need to be applied on large body surface. Lotion form makes it easy to pour and spread the product. For application over a small portion of skin, a cream is the preferred form of an emulsion.Pharmaceutical Applications of Emulsions There are several reasons for formulation of a product as an emulsion. These include the following:•To disguise the taste or smell of oils or oil soluble drugs. These emulsions are normally O/W types with the aqueous phase containing sweeteners and flavoring agents to mask the poor taste of oils. An O/W type of emulsionalso makes it easy to rinse off the residual dose from the mouth and does not leave an oily taste. Mineral oil and cod liver oil are emulsified for this reason.•To improve the absorption of poorly soluble drugs. Oil soluble drugs may not be soluble enough to be absorbed efficiently. An example of such a drug is cyclosporin, which is dispensed as a microemulsion. •To deliver nutrients and vitamins by intravenous injection. Intralipid is an emulsion product for administering an oil by the IV route.•To serve as a vehicle for the topical administration of a variety of drugs.Kb is the binding constant of the preservative with the surfactantSweeteners are added to emulsions to produce a more palatable preparation, toand sorbitol.AntioxidantsAntioxidants are often added to prevent oxidation of vegetable oils and/or the active drug.Table 1. Typical AntioxidantsEmulsifiersEmulsifiers are substances that have the ability to concentrate at the surface of a liquid or interface of two liquids, many of them reducing the surface or interfacial tension. Those emulsifiers that reduce surface tension are also called surfactants .Emulsifiers in general are discussed inmore detail in a later section of this chapter.GuidelinesBefore selecting a formula for an emulsion,one needs to consider several factors.These are listed below.Type of Emulsion DesiredSince O/W emulsions are more pleasant to touch and swallow, they are generally preferred. Preparations for internal use are almost always O/W type products.Externally used emulsions may be of either type. Creams and lotions that are used primarily to provide oil to the skin need to be W/O due to high concentration of oils in these preparations.The equation shows that the effective concentration in the aqueous phase will always be a fraction of the total concentration.Solvents such as alcohol, glycerin and propylene glycol are often used as apreservative at concentrations approaching 10%. See Table 5, Typical Preservatives in Section 9 of this manual.BufferMany chemical buffer systems have been used in emulsions to control the pH. The optimal pH is chosen to ensure activity of the emulsifier, control stability of the drug and to ensure compatibility and stability of other ingredients.FlavorFlavoring agents enhance patient accept-ance of the product, which is particularly important for pediatric patients.ColorColorants are intended to provide a more aesthetic appearance to the final product.Emulsions are generally not colored with the exception of some topical products. Sequestering AgentsSequestering agents may be necessary to bind metal ions in order to control oxidative degradation of either the drug or other ingredients. HumectantsHumectants are water soluble polyols that prevent or hinder the loss of water from semi-solid emulsions, i.e., topical creams.They also contribute to the solvent proper-ties of the aqueous phase and contribute to the sweetness of oral preparations. The most common are glycerin, propylene glycolToxicityMost emulsifiers are not suitable for internal use. For orally given emulsions, acacia is commonly used as an emulsifying agent.Taste is another factor in selection ofingredients. In this regard, most polysaccha-rides are tasteless and, hence, suitable from a taste standpoint.Method of PreparationSoaps and acacia are excellent forextemporaneous preparations. While soaps allow the preparation to be made by simply mixing the ingredients and shaking, acacia can be used in a pestle and mortar to prepare emulsions.Typical FormulasCod Liver Oil Emulsion (polysaccharide emulsifier)Preparationing a ratio of 4:2:1 for oil, water and gums(both combined), prepare a primary emulsion by dry gum method. (See Methods to Prepare Emulsions on page 13.)2.Dilute with water to a flowable consistency andpour in a measuring device.3.Add alcohol diluted with equal volume of water,followed by the benzaldehyde and saccharin sodium.4.Dilute to volume (200 mL) with waterPreparation1.Add benzyl benzoate to the wax in a beakerand heat in a water bath until the wax melts and the temperature reaches 60°C.2.In a separate beaker, add an appropriate volumeof water and heat to the same temperature.3.Add the water to the oil phase with continuousstirring.4.Continue to stir until the mixture begins tothicken and cools to room temperature.Preparation1.Mix the two powders in a mortar and trituratewell, taking care that all the lumps and large particles have been reduced.2.Then add oil slowly with constant trituration untilall the oil has been added. Triturate to form a smooth paste.3.Then add the limewater and triturate briskly toform the emulsion.Note: The emulsifier, calcium oleate (from limewater and olive oil), preferentially forms O/W emulsions.Protective Lotion (divalent soap emulsifier)Benzyl Benzoate Emulsion (emulsifying wax emulsifier)Preparation1.Mix the paraffins, cetostearyl alcohol andstearic acid in a beaker and heat in a water bath to about 60°C.2.Heat water and chlorocresol together to thesame temperature.3.Add the aqueous phase to the oil phase andstir until congealed and cooled to room temperature.Note:The emulsifier is triethanolamine stearate formed in situ.Preparation1.Melt the sorbitan monostearate and stearicacid in the liquid paraffin and cool to 60°C. 2.Mix the sorbitol solution, preservatives,polysorbate 60 and water and heat to the temperature of the oil mixture.3.Add the aqueous solution to the oil phase andstir until it has congealed and cooled to room temperature.Note:Propylene glycol serves as a solvent for the preservatives.Preparation1.Mix and melt the wax and paraffin together.2.Dissolve borax in water and heat both containerson a water bath to 70°C.3.Add the aqueous phase to the oil phase andstir until it has congealed and cooled to room temperature.Note:The fatty acid in white beeswax reacts with borax (sodium borate) to make a sodium soap which acts as an W/O type emulsifier.Barrier Cream (soap emulsifier)All Purpose Cream (synthetic surfactant emulsifier)Cold Cream (soap emulsifier)Surfactants or surface active agents are molecules that consist of two distinct parts,a hydrophobic tail and a hydrophilic head group. They are generally classified based on the hydrophilic properties of the head group (ionic charge, polarity, etc.). Since the hydrophobic chains do not vary much in their properties, the nature of surfactants is dependent mainly on the head group structure.A common problem with sterol-containing emulsifiers is that being complex mixtures of natural substances, they are prone to variability in their quality and, hence, performance. Also, these agents usually contain some degree of an odor, which varies with the purity and source. Some semi-synthetic substitutes are available that seek to overcome some of the problems associated with these agents.There are of basically three types of emulsifiers: natural products, surface active agents (surfactants), and finely divided solids. Based on whether a stable emulsion can be produced, emulsifiers are also classified either as primary emulsifying agents which produce stable emulsions by themselves, or secondary emulsifying agents (stabilizers) which help primary emulsifiers to form a more stable emulsion.of cholesterol. Cholesterol itself is a very efficient emulsifier and produces W/O type emulsions. Consequently, its use is limited to topical preparations such as Hydrophilic Petrolatum USP which readily absorbs water forming a W/O cream. Woolfat or lanolin contains a considerable amount of choles-terol esters and can absorb up to 50% of its own weight of water.This group of emulsifiers, which numbers in the hundreds, contain a polyoxyethylene chain as the polar head group. They arenonionic and, thus, are compatible with ionic compounds and are less susceptible to pH changes. There are several such surfactants official in the USP/NF , typified by sorbitan monooleate (a partial ester of lauric acid with sorbitol), polysorbate 80(polyoxyethyl-ene 20 sorbitan monooleate) which contains 20 oxyethylene units copolymerized sorbitanAmine soaps consist of an amine, such as triethanolamine, in the presence of a fatty acid. These surfactants are viscous solutions and produce O/W type emulsions. They offer the advantage that the final pH of the preparations is generally close to neutral,and, therefore, allows their use on skin for extended periods of time.monooleate) and polyoxyl 40 stearate(a mixture of stearic acid esters with mixed poloxyethylene diols equivalent to about40 oxyethylene units).The large number of nonionic emulsifiers results from the large number of possible combinations of various alkyl groups with polyoxyethylene chains of varying lengths. Compounds with saturated and/or large alkyl groups, such as stearyl, tend to be solids or semisolids while oleyl (also large, but unsaturated) compounds tend to be liquids. Also, the longer the polyoxyethylene chain, the higher the melting point.To characterize such a large number of compounds, they are each assigned an HLB number. The HLB number or hydrophile-lipophile balance, is a measure of the relative hydrophilic vs lipophilic character of the molecule as determined by the relative size of the polyoxyethylene chain vs the alkyl group. HLB numbers range from 0 for a pure hydrocarbon to 20 for a pure poly-oxyethylene chain. Some typical valuesare listed in Table 3.Ionic surfactants, such as sodium lauryl sulfate, were not included in the original definition of the HLB system but have been included as the HLB system was developed. The HLB number of 40 for sodium lauryl sulfate is outside of the range of 0 to 20 and simply means that sodium lauryl sulfate is much more soluble or hydrophilic thana pure polyoxyethylene chain.Table 3. Typical HLB Numbersof EmulsifiersFinely Divided SolidsFinely divided solids function as emulsifiers because of their small particle size. Fine particles tend to concentrate at a liquid-liquid interface, depending on their wetability, and form a particulate film around the dispersed droplets. They are seldom used as the primary emulsifier.phase. The emulsion type will depend on the type of soap formed.Basically the formula is divided into anoil phase and an aqueous phase with the ingredients dissolved in their proper phases (oil or water). The surfactant(s) is added to the phase in which it is most soluble. The oil phase is then added to the aqueous phase with mixing, and the coarse mixture passed through an homogenizer.When waxes or waxy solids are included in the formulation, the use of heat is necessary,as described above.Required HLB of the Oil Phase.It has been found that various oils and lipid materials form stable emulsions withsurfactants that have a certain HLB value.This HLB value is called the required HLB of the oil or lipid. Theoretically, any surfac-tant with the required HLB would produce a stable emulsion with the indicated oil or lipid. Some examples are given in Table 4.Table 4. Required HLB Values for Typical Oils and LipidsHLB of Surfactant MixturesIt may be difficult to find a surfactant with the exact HLB number required for a given oil phase in an emulsion. Fortunately, the HLB numbers have been shown to be additive for a mixture of surfactants. Thus, if one required a surfactant with a HLB of 10, one could use a mixture of sorbitan monooleate (HLB = 4.7) and polysorbate 80 (HLB = 15.6). Such a mixture can be calculated on the basis of a simple weighted average as follows.Suppose 5 g of surfactant mixture is required. Let = the g of sorbitanmonooleate, then 5 = the g of polysorbate 80 required.(4.7)+(5- )(15.6) = 10(5)4.7 + 78.0- 15.6= 10(5)10.9= 28= 2.57 and 5- = 2.43Thus a mixture of 2.57 g of sorbitanmonooleate and 2.43 g of polysorbate 80would have a HLB of 10.Griffin 2described an experimental approach for the formulation of emulsions using synthetic emulsifiers.1.Group the ingredients on the basis of theirsolubilities in the aqueous and oil phases.2.Determine the type of emulsion required andcalculate an approximate required HLB value.3.Blend a low HLB emulsifier and a high HLBemulsifier to the required HLB.4.Dissolve the oil soluble ingredients and the lowHLB emulsifier in the oil phase. Heat, if necessary,to approximately 5 to 10°over the melting point of the highest melting ingredient or to a maximum temperature of 70 to 80°C.5.Dissolve the water soluble ingredients (exceptacids and salts) in a sufficient quantity of water.6.Heat the aqueous phase to a temperature whichis 3 to 5°higher than that of the oil phase.7.Add the aqueous phase to the oil phase withsuitable agitation.8.If acids or salts are employed, dissolve them inwater and add the solution to the cold emulsion.9.Examine the emulsion and make adjustments inthe formulation if the product is unstable. It may be necessary to add more emulsifier, change to an emulsifier with a slightly higher or lower HLB value or to use an emulsifier with different chemical characteristics.In addition to chemical degradation of various components of an emulsion, which can happen in any liquid preparation, emulsions are subject to a variety of physical instabilities. Sedimentation or Creaming Factors - Stoke’s LawCreaming usually occurs in a liquid emulsion since the particle size is generally greater than that of a colloidal dispersion. The rate is described by Stoke’s Law for a single particle settling in an infinite container under the force of gravity as follows:d =d 2(2- 1)gdt 18where:d /d t= the sedimentation rate in distance/time d = droplet diameter 2= droplet density1= emulsion medium density g = acceleration due to gravity = viscosity of the emulsion mediumSince for most oil phases, 2< 1, then sedimentation will be negative, i.e., the oil droplets will rise forming a creamy whitelayer. While Stoke’s Law does not describe creaming quantitatively in an emulsion, it does provide a clear collection of factors and their qualitative influence on creaming.Droplet SizeReducing droplet size can have a significant effect on creaming rate. Since the diameter is squared in Stoke’s Law, a reduction in size by ¹⁄₂will reduce the creaming rate by (¹⁄₂)2or a factor of 4.Emulsion StabilityDensity DifferenceIf the difference in density between the emulsion droplet and the external phase can be matched, the creaming rate could be reduced to zero. This is almost impossi-ble with most oils and waxy solids used in emulsions.The Gravitational Constant, gThis parameter is not of much interest since it can not be controlled or changed unless in space flight.ViscosityViscosity turns out to be the most readily controllable parameter in affecting the creaming rate. While the viscosity in Stoke’s Law refers to the viscosity of the fluid through which a droplet rises, in reality the viscosity that controls creaming is the viscosity of the entire emulsion. Thus, doubling the viscosity of an emulsion will decrease the creaming rate by a factor of 2.There are three major ways to increase the viscosity of an emulsion:•Increase the concentration of the internal phase•Increase the viscosity of the internal phase by adding waxes and waxy solids to the oil phase.•Increase the viscosity of the external phase by adding a viscosity building agent. Most of the suspending agents described in the Suspensions Section in this manual have been used for this purpose.Creaming does not usually occur in a semi-solid emulsion.Breaking or CrackingThis problem arises when the dispersed globules come together and coalesce to form larger globules. As this process continues, the size of the globules increases, making it easier for them to coalesce. This eventually leads to separation of the oil and water phases. For cracking to occur, the barrier that normally holds globules apart has to break down. Some of the factorsthat contribute to cracking are as follows:•Insufficient or wrong kind of emulsifier in the system.•Addition of ingredients that inactivate the emulsifier. Incompatible ingredients may show their effect over a period of time.An example of such an incompatibilitywill be to use large anions in thepresence of cationic emulsifier.•Presence of hardness in water. The calcium and magnesium present in hard water can replace a part of the alkalisoap with divalent soap. Since thesesoaps form different kinds of emulsions, phase inversion usually takes place.•Low viscosity of the emulsion •Exposure to high temperatures can also accelerate the process of coalescence.This is due to the fact that at an elevated temperature, the collisions between theglobules can overcome the barrier tocoalescence, thereby increasing thechance that a contact between twoparticles will lead to their fusion.Temperature may have an adverse effect on the activity of emulsifiers, particularly if these are proteinaceous in nature.However, this usually happens at temper-atures higher than 50°C. Conversely, areduction in temperature to the point that the aqueous phase freezes also will break the emulsion.•An excessive amount of the internal phase makes an emulsion inherently less stable because there is a greater chance of globules coming together.Cracking is the most serious kind of physical instability of an emulsion. Cracking of an emulsion usually renders it useless. In creams, the problem of cracking may show up as tearing. This is a process where one phase separates and appears like drops on top of the cream.The basic difference between creamingand cracking is that the globules in creaming do not coalesce to form larger particles. Therefore, creaming is a less serious problem and most preparations that show creaming can be shaken to redisperse the internal phase to its original state. A com-mon example of creaming is the formation of cream on top of whole milk due to collection of emulsified fat of the milk. This problem is solved by homogenizing the milk to reduce the particle size of dispersed fat, thereby reducing the rate at which they travel tothe surface.。
Micro-Injection moulding surface treatment effects on part demoulding
Micro-Injection moulding: surface treatment effects on part demoulding C.A. Griffiths 1, S. S. Dimov 1, E.B. Brousseau 1, C. Chouquet 2, J. Gavillet 2, S. Bigot 11Manufacturing Engineering Centre, Cardiff University, Cardiff CF24 3AA, UK2French Atomic Energy Commission (CEA), Laboratory of Innovation for New Energy Technologies andNanomaterials (LITEN), 38054 Grenoble, FranceAbstractMicro injection moulding as a replication method is one of the key technologies for micro manufacture. The understanding of process constraints for a selected production route is essential at both the design stage and during mass production. In this research a tool surface treatment is used to study the effects of demoulding a part with micro features. In particular a tool coated with diamond like carbon (DLC) will be compared to an identical tool without coating. Through a range of experimental trials the effects of four process parameters, namely melt and mould temperature, and cooling and ejection time will be used to evaluate the demoulding process. Using two polymer materials PP and ABS, a special attention is paid to the forces present in demoulding and conclusions are made about the influence of DLC surface treatments and the factors affecting demoulding.Keywords: Micro Injection Moulding, Surface treatment, Demoulding, Micro-fluidics,1. IntroductionMicrofluidic technologies have found a largevariety of new applications in fields such asbiotechnology, cytometry, medical diagnostics andmicro chemistry. The successful development of suchnew micro devices is highly dependent onmanufacturing systems that can reliably andeconomically produce large quantities of microcomponents. In this context, micro injection moulding(IM) of polymer materials is one of the key technologies for micro manufacturing. In order to achieve an economical and reliable production of microfluidic parts it is important to study systematically the factors that affect the micro IMprocess. An important step in micro injection mouldingwhich can affect the mechanical properties of theproduced components is part demoulding. During the solidification process of the moulding cycle, the polymer melt shrinks onto the mould cavity walls and features. The part-mould forces that develop at thisstage have to be overcome for subsequent part removal. To avoid yielding when breaking the bond between the polymer and the tool cavity, the maximum equivalent stress applied for part removal should notexceed the tensile yield stress of the material [1]. Thus, the factors that influence the demoulding process have to be studied carefully to avoid destroying parts and features and/or introducing further internal stress to a component through plastic deformation. In this paper, the effect of different surface treatment on the demoulding behaviour of parts with micro features is reported. The paper is organised asfollows. The next section discusses the importantfactors affecting ejection behaviour, especially part-mould forces and surface treatment methods. Then, the experimental set-up and test tool used to investigate the effects of cavity coatings on the demoulding forces are described together with the design of the carried out experiments. Finally, the experimental results are presented and the interdependence between tool surface treatment and demoulding forces in micro IM is analysed. 2.0 Demoulding factors 2.1 Part-mould forces In polymer IM, the predicting the adhesion forces between the part and the tool is a complex task due to its dependence on part geometry and on process parameters such as the temperature and the pressure used during the process. Ejection forces (F E ), also called release forces (F R ), have been identified as a total friction between the tool and the polymer interface. Previous research studies on IM forces anddemoulding behaviour found that there are instances in which the friction effects can be difficult to explain. Inparticular, [2] showed that injection pressure did not affect F E noticeably and that during processing the coefficient of friction (µ ) is different to published data. [3] observed that the number of ejector pins affects the part-mould forces. More specifically, an increase in the number of ejector pins resulted in a reduced stressdistribution in the moulded part. In another study, F E was found to increase with the increase of the tool surface roughness [4]. In [5, 6], the holding pressure and surface temperature of the cavity were found tosubstantially influence F E . Together with high surface to volume ratio (SV R ) and high aspect ratio micro features, present challenges in micro IM call for the decrease of part-mould forces and tool wear, and thus to maintain optimum mechanical and structural stability forreplicating quality parts and increasing tool life.2.2 Tool Coatings One method that can be used for improving thewear resistance of tool surfaces is to apply surface treatments. In particular, the wear of a surface can be reduced with traditional methods such as heat treatment and nitriding. In addition, previous research found that techniques like physical vapour deposition (PVD) and chemical vapour deposition (CVD) resulted in moulds with significantly better wear resistance [7-9]. At the same time, the surface quality of the moulded parts was improved due to reduction of the part-mould forces.© 2008 Cardiff University, Cardiff, UK. Published by Whittles Publishing Ltd. All rights reserved.S. Dimov and W. Menz (Eds.)Multi-Material Micro ManufactureThe surface treatment of tools using Pulsed Laser Deposition (PLD) of diamond like carbon (DLC) coatings results in tools with hard surfaces of up to 70Gpa. Optimisation of deposition can lead to DLC surfaces with µ in the range of 0.05-0.2µ, an order of magnitude lower than that of ceramic coatings [10]. Another role that tool coating can fulfill is to protect against undesirable polymer and tool interactions. In particular, metal tools employed to produce micro parts for medical products run the risk of releasing metal ions [11]. For example, nickel is a common contact allergen and at the same time it is a material that is commonly used for the manufacture of micro tools. By coating the cavities, a barrier between the tool and the polymer can be created. Furthermore, due to the amorphous nature of DLC coatings it is possible to introduce tunable antibacterial elements and thus to counteract contamination [12]. Based on the findings of previous studies, it is clear that surface treatments can reduce part-mould forces and tool wear. This research investigates the effects that the tool coating can have on part demoulding in micro IM.3.0 Experimental set-up3.1 Test materialsTwo commonly used materials in injection moulding, Acrylonitrile Butadiene Styrene (ABS), and Polycarbonate (PC) were selected to conduct the planned experiments. The machine used to perform the micro injection moulding tests was a Battenfeld Microsystem 50.3.2 Part design and tool manufactureThe part design used in this study is a 15mm x 20mm x 1mm micro fluidics platform (Figure 1). The design includes features commonly found in micro fluidics components such as reservoirs and channels. The pin dimensions are 500 µm in diameter and 600 µm in height, and the cross section of the main channels is 200 x 200 µm. Two identical tools were manufactured in brass. They were produced using micro milling. The moving and fixed halves of the mould were assembled to a primary mould and then inspected for parallelism and shut off of the mating faces.Figure 1. Micro fluidics platform and Ejector positions 3.3 DLC Surface treatmentThe DLC thin film was elaborated in a Low Frequency Plasma Enhanced Chemical Vapor Deposition reactor. Prior to deposition, the substrate were cleaned first in acetone and ethanol by an ultrasonic washer and then in a Ar + H2 etching plasma. In order to improve adhesion a Si-C:H intermediate layer (0.5µm) was deposited on the substrate using a plasma of tetramethylsilane (TMS) and argon. Then, 2µm DLC film was deposited onto the Si-C:H interlayer. Mechanical characterisations of this DLC coating were also performed and values are summarised in Table 1. Table 1. Mechanical properties of DLC filmProperties Values Hardness [GPa] 22 ±2Young Modulus [GPa]160 ±10Friction coefficient 0.05Wear rate [mm3.N-1.m-1] 510-73.4 Force measurementsIn this study, variations in force during the ejection stage of the IM process were assessed using a Dynisco PCI piezoelectric force transducer with a measuring range from 0 to 10,000 N. The sensor output signals were downloaded onto a PC using a National Instruments cDAQ-9172 USB data acquisition unit and the measured values were accessed through the National Instruments Labview 8 software.Each tool had to be modified to accommodate the force transducer. An ejector sub assembly was manufactured to house the four pins used for part removal. To carry out the force measurements, the transducer was positioned in the middle of the ejector plate sub assembly (Figure 2). When the ejector assembly moves the transducer is subjected to a mechanical load and proportional voltage that is monitored with a National Instruments NIFigure 2. Force transducer and ejector assembly Table 2. L9 fractional orthogonal array for ABST b [ºC] Tm[ºC] t c [s] t e [s]TrialValue Value Value Value1 A1 220 B1 40C1 1 D1 02 A1 220 B2 60C2 5 D2 53 A1 220 B3 80C3 10 D3 104 A2 250 B1 40C2 5 D3 105 A2 250 B2 60C3 10 D1 06 A2 250 B3 80C1 1 D2 57 A3 280 B1 40C3 10 D2 58 A3 280 B2 60C1 1 D3 109 A3 280 B3 80C2 5 D1 0 Table 3. L9 fractional orthogonal array for PCT b [ºC] T m [ºC] t c [s] t e [s]TrialValue Value Value Value1 A1 280 B1 80 C1 1 D1 02 A1 280 B2 100 C2 5 D2 53 A1 280 B3 120 C3 10 D3 104 A2 300 B1 80 C25 D3 105 A2 300 B2 100 C3 10 D1 06 A2 300 B3 120 C1 1 D2 57 A3 320 B1 80 C3 10 D2 58 A3 320 B2 100 C1 1 D3 109 A3 320 B3 120 C2 5 D1 03.5 Design of experimentsDue to the fact that the filling performance of micro moulds relies heavily on the temperature control during injection, the effects of barrel temperature (T b) and mould temperature (T m) were investigated. After filling it is necessary for the part temperature to be sufficiently low to facilitate the demoulding without part deformation. Therefore the cooling time after filling (t c) and the use of a delay for the ejection time (t e) were also taken into account. Thus, given that four factors at three levels each were considered, a Taguchi L9 orthogonal array (OA) was selected. (see Table 2 and 3).The response of each tool surface treatment to each set of control parameters was analysed by measuring F E during the part ejection. Given that two tool surfaces, untreated, and DLC and two materials, PC and ABS, are investigated, four L9 OAs were defined.4. Analysis of the results4.1 Average Force resultsIn this study, L9 OAs were employed to ensure that the experimental results were representative of the considered processing window. For each trial, the effects of the applied surface treatments on F E were investigated and then based on the conducted trials the F E mean values were calculated for each of the OAs as shown in Figure 3. For the untreated tool on average both ABS and PC results were subjected to the highest demoulding forces of all the experiments. ABS had a higher average than PC. For the tool with the DLC coating, both materials experienced a reduced demoulding force compared to the untreated tool. The average ABS results were the lowest of all experiments, and compared to the untreated tool results there were a F E reduction of 41.6% for the DLC treated tool. For PC, the reduction of F E was 10.68%.Figure 3. The average demoulding force for the OAs 4.2 Optimum parameters levelsThe average demoulding force based on trials conducted for each combination of control parameters was calculated in order to determine the optimum parameter levels for the investigated surface treatment and polymers employing the Taguchi method. The value of a given parameter is considered to be optimum, the best of the selected three levels, if its corresponding average F E is the lowest. Figure 4 shows the results of the experiments. By applying this method, it is possible to identify theoretically the best set of parameters within the investigated processing window with respect to F E. The theoretical best set of processing parameters are provided in Table 4.Figure 4. Main effects for each combination ofsurface treatments and polymersTable 4. The theoretical best set of processing parametersT b [ºC] T m [ºC] t c [s] t e [s] Untreated & ABS 250 80 5 5 Untreated & PC 300 120 10 0DLC & ABS 220 40 1 10DLC & PC 320 120 1 04.3 Parameters contribution to optimum performanceBased on the experimental results, an analysis of variance (ANOVA) was performed in order to assess the contribution of each processing parameter to the resulting demoulding behaviour. Table 5 shows the percentage contribution of each parameters. Based on this analysis and the selection of the best parameters levels (Table 4), it is possible to compute the lowest theoretical demoulding force for each combination of surface treatment and polymer as shown in Table 6. Table 5. Percentage contribution of each parameterUntreated tool DLC coatingABS PC ABS PC T b 10.3 27.7 72.9 12.4T m38.8 42.3 23.3 -t c- - - 48.2t e 11.1 - - 35.0Table 6. The lowest theoretical demoulding forceUntreated tool DLC coatingABS PC ABS PCF E [N] 12.62 9.33 7.90 7.995. ConclusionsThe paper reports an experimental study that investigates part demoulding behaviour in micro IM, with a particular focus on the effects of surface treatments on the demoulding forces. In particular, the demoulding performance of a representative microfluidics part was studied as a function of tool surface treatment in combination with four process parameters, T b, T m, t c and t e, employing the design of experiment approach. The following conclusions can be made based on the reported research:•The average demoulding forces measured for both PC and ABS showed clearly that surfacetreatments reduce significantly F E incomparison with untreated tools.•From the conducted experiments, it is immediately apparent that there is not aunique selection of parameter levels as far asthe demoulding behaviour is concerned thatcan be considered optimum for each type ofsurface treatment or polymer investigated inthis research.•By conducting an ANOVA analysis it was possible to assess process parameters’contribution to optimum performance. Thelowest theoretical demoulding forcescomputed for each combination of tooltreatment and polymer showed again thatDLC coatings reduce significantly thedemoulding forces for the polymersconsidered.Finally, it is important to stress that in micro IM the polymer properties become an even more important factor in selecting surface treatments. Experimental studies and simulations of demoulding behaviour should precede the tool manufacture. AcknowledgementThe research reported in this paper is funded by the EPSRC Programme “The Cardiff Innovative Manufacturing Research Centre” and the EC FP6 Project “"Surface Enhanced Micro Optical Fluidic Systems (SEMOFS)". Also, it was carried out within the framework of the EC FP6 Networks of Excellence, “Multi-Material Micro Manufacture (4M): Technologies and Applications”.References[1].Navabpour, P., et al., Evaluation of non-stick properties of magnetron-sputtered coatings for moulds used for the processing of polymers. Surface and Coatings Technology, 2006. 201(6): p. 3802-3809.[2].Sasaki, T., et al., An experimental study on ejection forces of injection molding. Precision Engineering, 2000. 24(3): p. 270-273.[3].Bataineh, O.M. and B.E. Klamecki, Prediction of local part-mold and ejection force in injection molding. Journal of Manufacturing Science and Engineering-Transactions of the Asme, 2005. 127(3): p. 598-604. [4].Pouzada, A.S., E.C. Ferreira, and A.J. Pontes, Friction properties of moulding thermoplastics. Polymer Testing, 2006. 25(8): p. 1017-1023.[5].Pontes, A.J. and A.S. Pouzada, Ejection force in tubular injection moldings. Part I: Effect of processing conditions. Polymer Engineering and Science, 2004. 44(5): p. 891-897.[6].Pontes, A.J., et al., Ejection force of tubular injection moldings. Part II: A prediction model. Polymer Engineering & Science, 2005. 45(3): p. 325-332. [7].Mitterer, C., et al., Industrial applications of PACVD hard coatings. Surface and Coatings Technology, 2003. 163-164: p. 716-722.[8].Heinze, M., Wear resistance of hard coatings in plastics processing. Surface and Coatings Technology, 1998. 105(1-2): p. 38-44.[9].Cunha, L., et al., Performance of chromium nitride and titanium nitride coatings during plastic injection moulding. Surface and Coatings Technology, 2002. 153(2-3): p. 160-165.[10].Voevodin, A.A., M.S. Donley, and J.S. Zabinski, Pulsed laser deposition of diamond-like carbon wear protective coatings: a review. Surface and Coatings Technology, 1997. 92(1-2): p. 42-49.[11].Grill, A., Diamond-like carbon coatings as biocompatible materials-an overview. Diamond and Related Materials, 2003. 12(2): p. 166-170.[12].Hauert, R., A review of modified DLC coatings for biological applications. Diamond and Related Materials, 2003. 12(3-7): p. 583-589.。
适合挤出滚圆的物料性质与微丸成型性预测指标研究探讨
参考内容
挤出滚圆法是一种常用的制备微丸的工艺，具有制备过程简单、生产效率高、 产品质量稳定等优点。本次演示对挤出滚圆法制备微丸的研究进展进行了综述， 介绍了挤出滚圆法的原理、优点、影响因素以及在中药微丸制备中的应用。
1、挤出滚圆法的原理
挤出滚圆法是将药物溶液或悬浮液通过挤出机头挤出成小液滴，然后在高速旋 转的滚圆机上滚成球形，再经过干燥或固化制成微丸的工艺。该工艺利用液滴 在高速旋转的滚圆机上产生表面张力，使液滴形成球形，并在滚圆过程中不断 滚动，最终形成致密的球形颗粒。
二、挤出滚圆的基本原理和影响 因素
挤出滚圆的基本原理是：将物料通过挤出机挤出成条状物，然后通过切刀将其 切割成小的颗粒，这些颗粒在滚动模中滚动并成型。在这个过程中，物料的性 质、挤出条件、滚动时间和温度等都会对微丸的成型性产生影响。
三、物料性质与微丸成型性的关 系
物料的性质如硬度、粘度、弹性、塑性等都会影响微丸的成型性。例如，硬度 高的物料在挤出过程中不易变形，而硬度低的物料则容易变形。物料的粘度则 影响其在挤出过程中的流动性和成型性。弹性物料在挤出过程中容易保持其形 状，而塑性物料则容易变形。
四、预测指标的建议
针对物料性质与微丸成型性的关系，我们可以提出以下预测指标的建议：
1、物料硬度：可以通过硬度计进行测量。硬度过高的物料可能需要降低挤出 压力或提高切刀速度以降低微丸的变形程度。硬度过低的物料可能需要增加挤 出压力或减小切刀速度以增加微丸的形状稳定性。
2、物料粘度：可以通过粘度计进行测量。粘度过高的物料可能需要提高挤出 温度或增加挤出压力以降低其粘度，从而改善微丸的成型性。粘度过低的物料 可能需要降低挤出温度或减小挤出压力以增加其粘度，从而改善微丸的成型性。
关键词：挤出滚圆，物料性质， 微丸成型性，预测指标
宇航员英语试题及答案
宇航员英语试题及答案一、选择题（每题2分，共20分）1. What is the term for a person who travels in space?A) AstronautB) NavigatorC) PilotD) Engineer2. The International Space Station (ISS) orbits the Earth approximately how many times a day?A) 15B) 24C) 30D) 453. Which of the following is NOT a stage of a rocket launch?A) IgnitionB) Lift-offC) AscentD) Descent4. What does NASA stand for?A) National Aeronautics and Space AdministrationB) North American Space AssociationC) National Association for Space AdvancementD) None of the above5. Who was the first person to walk on the moon?A) Neil ArmstrongB) Buzz AldrinC) Yuri GagarinD) Alan Shepard二、填空题（每题1分，共10分）6. The first human-made object to reach the surface of the moon was ________.7. The term "zero gravity" is often used to describe thestate of ________ in space.8. An astronaut's job can be described as ________ and________.9. The sun is a ________ star, and it is the center of our solar system.10. The first woman to walk in space was ________.三、简答题（每题5分，共30分）11. Explain the purpose of a spacesuit.12. What is the significance of the Hubble Space Telescope?13. Describe the process of docking a spacecraft with the ISS.14. What are the challenges faced by astronauts during long-duration spaceflights?四、阅读理解（每题2分，共20分）Read the following passage and answer the questions.The Mars Rover is a robotic vehicle designed to explore the surface of Mars. It is equipped with various scientific instruments to gather data about the planet's geology, climate, and potential for past life. The first successful Mars Rover was Sojourner, which landed on Mars in 1997. Sincethen, several other rovers have been sent, each with more advanced capabilities.15. What is the primary function of the Mars Rover?A) To communicate with EarthB) To explore the surface of MarsC) To study Mars' atmosphereD) To transport astronauts16. When did the first Mars Rover land on Mars?A) 1997B) 2000C) 2005D) 201017. What kind of data does the Mars Rover collect?A) Only geological dataB) Only climatic dataC) Geological, climatic, and potential life dataD) Data on Mars' potential for future human colonization18. How many Mars Rovers have been sent to Mars since the first one?A) OneB) TwoC) ThreeD) Several19. What is the name of the first successful Mars Rover?A) CuriosityB) OpportunityC) SpiritD) Sojourner20. What does the passage imply about the capabilities of later Mars Rovers compared to the first one?A) They are the sameB) They are less advancedC) They are more advancedD) There is no information provided五、写作题（共20分）21. Write an essay about the future of space exploration and how it might benefit humanity. (200-250 words)答案：一、1. A2. A3. D4. A5. A二、6. Luna 27. weightlessness8. scientific research, exploration9. G-type main-sequence10. Svetlana Savitskaya三、11. A spacesuit is designed to protect astronauts from theharsh conditions of space, such as extreme temperatures, vacuum, and radiation. It provides life support, maintains pressure and oxygen levels, and allows for mobility during spacewalks.12. The Hubble Space Telescope has been instrumental in expanding our understanding of the universe. It has provided high-resolution images of distant galaxies, nebulae, and stars, contributing to significant discoveries in astrophysics.13. Docking a spacecraft with the ISS involves a carefully choreographed sequence of maneuvers, including approaching the station, aligning with it, and securing the connection using a docking mechanism.14. Long-duration spaceflight presents challenges such as bone density loss, muscle atrophy, psychological effects, and exposure to radiation.四、15. B16. A17. C18。