Wednesday, August 26, 2020

Micro and Macro Management free essay sample

Full scale Management In a straightforward definition the board is the individual or people who control or direct a business or other endeavor. Be that as it may, the executives is a lot bigger than only one individual or little gathering of individuals. The executives is likewise the act of taking care of, oversight, bearing, and control (www. word reference. com). It is a lot bigger than one individual, or even a little gathering of individuals; the executives is all over. We use the board in all parts of our day by day lives, regardless of whether it is sorting out an occasion, or dealing with a buy request. The executives must be masterminded through various levels so as to be effective, starting with small scale the executives, in the long run its way up the stepping stool to full scale the executives. Smaller scale and large scale parts are the center make up of each business, each having various characteristics and qualities that structure the general structure squares to progress. During the preparation of another worker, most organizations utilize the smaller scale the board procedure to give the direction and devices the representative needs to get fruitful with that business. We will compose a custom paper test on Small scale and Macro Management or on the other hand any comparable theme explicitly for you Don't WasteYour Time Recruit WRITER Just 13.90/page Miniaturized scale the board is utilized my chiefs to watch and control crafted by their representatives. It includes giving representative littler undertakings, while they screen and evaluate the work being done (www. word reference. com). Small scale the board is regularly utilized in the start of any business or foundation; essentially, you have to begin some place. In the opening of another business, direction will consistently should be offered from coordinate workplaces to guarantee a spotless progress in the initial procedure. When a business is set up, the executives will thusly smaller scale deal with their workers; directing them through the methodology and duties the organization requires. Since miniaturized scale overseeing includes managers neglecting the errands their workers are embraced, intermittently it is thought of as an apathetic strategy. Through the eyes of a partner, small scale overseeing can be de persuading, thusly making uncertainty and absence of trust in the work environment. Despite the fact that miniaturized scale overseeing is utilized as an early on apparatus, it tends to be drawn out for a more drawn out term of time. Doubt, incredulity, and vulnerability are ordinary emotions a representative may understanding if their manager is mishandling the technique for small scale overseeing. The job of administrator is a significant situation of oversight in any association. The director/supervisor plays a key capacity, in the everyday needs of the association, by finding a parity of work effectiveness and overseeing staff. This equalization turns out to be significantly increasingly pervasive when doling out tasks or interfacing with subordinates. This paper will investigate a few angles or entanglements, directors could wind up associated with; and will distinguish strategies used to conquer these circumstances when managing subordinates. The situation of chief holds numerous obligations in an association; those duties go from managing demands from upper administration and overhauling employee’s needs, and keeping in mind that seeing to postulations duties, the supervisor despite everything needs to oversee the general heading of their area of expertise. The numerous errands a director must work inside, requires the chief to be adaptable and

Saturday, August 22, 2020

Life Without Music Essay

Music is from numerous points of view the texture of our lives and the meaning of society. It is a token of how things used to be, a sign of how things are, and a perspective on where society is going. Music is an immediate impression of the image of society. Music can be an approach to convey messages, a beautiful medium, an artistic work, or simply a wellspring of amusement. Regardless of what it is utilized for, music is the ideal workmanship and our lives would be significantly less complete without it that life as we probably am aware it would not in any way be the equivalent without music. Music is the ideal craftsmanship. It has development, since it advances over a set timeframe. Every melodic work have a start and an end. In any case, music doesn't confine the crowd in the way that motion pictures or realistic craftsmanship does. The audience can make whatever picture she or he needs to when tuning in to music. It is a craftsmanship that interests to the cognizant brain, yet the best music additionally claims to the inner mind. No idea is required to appreciate great music, however it is regularly thought-motivating. Instrumental music doesn't tie the audience into a fixed layout in the manner that writing and verse do: the response to music is not quite the same as individual to individual. In spite of the fact that it is presumably the most hard to deliver the ideal symbolism in instrumental music, it very well may be finished. Beethovens Opus 27, Number 2, Piano Sonata No. 14, First Movement gives the picture of a drained elderly person composing by the light of the moon and his energy without utilizing any words whatsoever. Music with verses is frequently alluded to as â€Å"words set to music.† This isn't generally the situation. In some cases it is progressively precise to allude to music with verses as â€Å"music set to words.† This structure both broadens and confines the writers aesthetic range. Verses make it simpler for arrangers to draw out their primary thoughts without communicating them in notesNnot all writers have the intensity of Beethoven! In any case, they confine the pictures of the melodic work similarly that exposition and verse limit their subject. Regardless of whether instrumental or melodious, music originates from the individuals and can illuminate all of us. It was during the 1960s that the social upset and the battles for social equality propelled such performers a s Bob Dylan, Janis Joplin and Joan Baez to compose tunes of dissent. Thusly, the music of these craftsmen, and numerous others, impacted the more youthful ages and spread the news of the insurgency. Without music, numerous young people of the time would not have been given the impact of the time or its related attitude. Music was, and keeps on being, a sort of social training to the more youthful age. Youngsters go to well known music for their ways of thinking and get a feeling of their place on the planet. Truth be told, clubs of youngsters are frequently characterized by the music they tune in to: â€Å"punks† tune in to underground rock and overwhelming metal; â€Å"nerds† are presumed to tune in to old style music; the â€Å"in† swarm tunes in to the most recent material elective music brings to the table; the â€Å"loners† tune in to darken pop craftsmen or great stone. Youth culture would be significantly less striking than it is if the world had no music. Ages would not be started to activity without music. The war drums of crude people groups were a sort of music. It was they that mixed the Cavemen and the Vikings to take an interest in decad e-long wars. Musics social impact is ever-present. Our general public is formed by it. Not exclusively is music the etch of society; it is a steady string that goes through nature. Music is all over the place: the sound of falling water, the stir of leaves underneath, the call of wild birdsNeven the sound of heavy traffic is a sort of music. The basic meaning of music is â€Å"a arrangement of pitches and rhythms that have a general coherence.† This definition is constrained to man-made music. â€Å"Synthetic† music is extremely only one sort of music. The hints of nature are all piece of the more prominent Music of the universe. Man-made music is altogether impacted by the genuine music of nature. The beat of the heart is the steady bass drum. The sound of strolling feet is the rotating catch drum. The stir of leaves in the breeze is the most noteworthy string area. A waterways streaming sound rounds out the concordance. The Symphony of Nature is the mother of keeps an eye on own music. The nonappearance of the more noteworthy Music can't be thought of. Music is the Universe. The possibility of a nonattendance of man-made music would be nearly as unfathomable. For people to make music is inescapable. It is as normal as suspected. With humanity being encircled by natures Music, he must choose the option to make music of his own. In this manner, the possibility of a world without music is exceptionally speculative. One would sooner think about an existence without encounters or a year without days. A day in a world without music may continue this way: One would stir to the sound of a radio host talking about governmental issues. While in transit to work, the radio show would comprise of meetings with celebrated characters. The work day would be appallingly exhausting, since the workplace would not have any improvements (these would have been made by specialists who had been affected by music). That night, the TV ads would have no jingles, just ladies advancing kitchen cleaners in white kitchens. The challengers of Jeopardy! would record their inquiries for Final Jeopardy in complete quiet, without the renowned tune. The night film would be practically quiet. It would appear to resemble a quiet film, with no coincidental or signature music to increase the in any case flat entertainers. In the café, the date would be exhausting and unenlightening. Neither he nor she would have the option to come out with any remotely keen thoughts without music out of sight to keep the mind working. The evenings dreams would not be scored with an upbeat tune or a moderate nocturne. They would happen peacefully, a dreary, dull universe of nothing. This â€Å"world without music† appears to have confusions and breaks in it. It doesn't bode well and doesn't exactly account for itself. Music is basic for the world to try and bode well. It is as in a general sense innate as gravity is known to man. Any endeavor to limit or control music, for example, is made in socialist governmental issues, is both vain and unreasonable. One can't challenge the broadloom of the universe when making political arrangements! To feel that the regular inclination to make music in the picture of the more prominent Music can be stifled is an activity in na*vet. Music is societys mark. The historical backdrop of human artists is rich, and has many fine individuals covering its positions. Music has changed the masterful and non-imaginative world inconceivably, to such an extent that a world without music is simply an unnerving dream. The very possibility is hard to consider. A world without music would be a tranquil spot undoubtedly.

Friday, August 21, 2020

The Growing Problem Of Digital Piracy On The Internet Thesis

The Growing Problem Of Digital Piracy On The Internet Thesis The Growing Problem Of Digital Piracy On The Internet â€" Thesis Example > Figure 1: ………. ..…………………………………………………………………………… 63AbstractWith the rapid growth of internet usage and the increased bandwidth and speed of connection, the frequency and seriousness of digital piracy has mushroomed (Ellacoya, 2007). It is very common today for users to share copyrighted materials among themselves without proper license or permissions. This peer-to-peer (p2p) sharing is made even easier because of the growth of virtual communities. This project will examine p2p networks that appear to be using the internet illegally (digital piracy) and will examine the range of responses developed by companies to combat this activity (Ellacoya, 2007). This topic is of intense interest to those who produce and provide music, movies, software and games. The central question that will drive this study: “How can the frequency of digital piracy activity be contained or reduced? ” The research approach will be to administ er a confidential questionnaire to specific p2p users between the ages of 15-28, to interview (face-to-face) users of p2p programs and to solicit expert opinion from professionals. The expected outcome of this research will be a better understanding of the motivations that digital pirates exhibit for their behavior. Based on these findings, a set of recommended protections for digital rights will be recommended. 1.1 IntroductionDigital piracy in the earlier definition refers to the illegal copying of any digital software, digital documents, goods, digital audio (including video and music), for any other reason except to backup without any prospected permission from the owner and compensation to the immediate copyright holder. In specific, digital piracy as a term had been declared illegal since the Copyright Act of 1976 in the United States an act that spread globally to other parts of the world. It was an act amended in the No Electronic Theft (NET) Act earlier before its incepti ons. Digital piracy in the earlier definition refers to the illegal copying of any digital software, digital documents, goods, digital audio (including video and music), for any other reason except to backup without any prospected permission from the owner and compensation to the immediate copyright holder. In specific, digital piracy as a term had been declared illegal since the Copyright Act of 1976 in the United States an act that spread globally to other parts of the world. It was an act in the amendment of  the No Theft (NET) Act earlier before its inceptions (Bachman, Paternoster, Ward, 1992; Nagin Paternoster, 1993; Hickman Piquero, 2000; Tibbetts Myers, 1999; Piquero Tibbetts, 1996; Tibbetts, 1997). These acts made the distribution and copying of digital content over the Internet and other places, a felony offense. The laws produced few court cases for pirating music, software, and movies directly from the Internet. The World Intellectual Property Organization (WIPO) d eveloped treaties in assisting in the copyrights protection (Ellacoya, 2007). Specifically, WIPO developed three treaties precluding the unlawful taking of any copyrighted material: The Performers and Producers of Phonograms Treaty, The Copyright Treaty, and The Databases Treaty. Regardless of the establishment of these treaties, Rao (2003) argued that the rates of piracy international increased in the 2000 and 2001 and has been increasing by the day. Therefore, piracy has developed as a worldwide behavior in the recent times. Because of the Internet attributes, piracy took place mostly in almost complete deceit that made the tracking of piracy rates nearly impossible. An industry groups in their research results estimated software piracy as accounting for nearly 11 billion dollars in term of lost revenue and was a substantial contributor to job losses and reducing the government’s revenues (Business Software Alliance, 2003).

Sunday, May 24, 2020

4 Small Items That Will Damage Your Best Thesis Title

Even though it may seem like a small part of the work, in truth, the title of your thesis paper plays a key role in the first impression it makes on a reader. That’s why you have to take some time to come up with the best thesis title you can. Luckily, this doesn’t need to be a difficult task. Many people overthink the process. As a result, they fall into a number of common mistakes. To come up with a strong thesis title, keep these tips in mind. 1. Don’t Use Unnecessary Words The title of your thesis should clearly express what topic you’re exploring. However, it should also be concise. After brainstorming through your ideas and choosing the best one, look at it carefully to make sure there aren’t any unnecessary words cluttering it up. If you find any, remove them until you come up with a version of your thesis title that makes sense, but doesn’t have any unneeded words. 2. Don’t Use Complex Nouns This is a mistake that students of all ages make. Whether they’re working on a high school paper or finishing up a major thesis for a graduate program, they think they’ll impress their readers if they use big, complex nouns. Luckily, the English language is full of synonyms. After you decide on a thesis title, take a look through a thesaurus to find out if there is a way you can further simplify your title with less complex words. 3. Don’t Be Vague Again, your thesis title should clearly communicate what kind of argument or point you’ll be making in your work. Obviously, for a paper as long as a thesis, there’s no room in the title to fully develop the main ideas, but that’s not an excuse to come up with something so vague that a reader has no idea what the paper will be about. Take your time to decide on a title that makes your main point clear without being overlong. This process can be a little challenging, but it is worth the efforts. 4. Don’t Be Boring A thesis title isn’t a headline for a celebrity gossip magazine. You don’t want to exaggerate your topic or try too hard to capture a reader’s attention. On the other hand, you also don’t want to go too far in the other direction, coming up with a thesis title that’s simply too boring to entice a person to read more. The point is, your thesis is supposed to make an interesting, unique argument. Ideally, your thesis should be something that a person interested in. Thus, your title has to make the reader sure that the plot will be truly informative and useful. If you succeed in writing a strong, compelling thesis paper, then you should also focus on coming up with a title that reflects its content. Your title should convince a reader that your work is worth their time. It’s no secret that a thesis paper can be an intimidating assignment. When you’re finished writing it, you may be tempted to just slap on a title that’s simple and to-the-point. However, this is an important part of your work. It’s worth your time to make it perfect.

Thursday, May 14, 2020

Masculinity And The Sociality Of Cooking Essay - 1411 Words

I. Masculinity in modern society is continuously changing all around us. The academic journal â€Å"Masculinity and the sociality of cooking in men’s everyday lives†, written by Nicklas Neuman, Lucas Gottzen, and Christina Fjellstrom highlights both gender roles and how masculinity affect society. The journal was published in â€Å"The Sociological Review† in November of 2017. From we what we know about the social in any common relationship, the woman cooks for the man and the man only cooks in leisure situations. The authors are suggesting that there must be a cultural transition and need for studies of gendered divisions of domestic work. The author doesn’t not state a clear social theory, but his study is centered around masculinity and gendered†¦show more content†¦The original interview approach was inspired by previous work on how men communicate their different sociolinguistic perspectives. (Coates, 2003; Edley and Wetherell, 1999; Cough an d Edwards, 1998). III. The study conducted is interested is analyzing how masculinity and sociality are perceived to men in their everyday domestic cooking experiences. In society it is common for the man to cook within partnerships. The sociologist who conducted the study proposed that maybe this culture in rapidly changing. They took their study to Sweden, due to the fact they realized out of every culture their Scandinavian culture has the largest growth between men and women when it comes to domestic cooking. They want to see how masculinity has been formed in the mind of men by hearing about their stories and experiences. Since masculinity is learned throughout life, rather than being an inherent culture among men. For their sample size, the sociologist selected thirty-one men. All these men were between the ages of twenty-two and eighty-eight. The sociologist coined the term purposeful sampling, where they believed the subjects they chose would provide the best answers; making sure that the stor ies went in-depth. To conduct the study, the sociologist interviewed all the men. Most of the interviews conducted,Show MoreRelatedStephen P. Robbins Timothy A. Judge (2011) Organizational Behaviour 15th Edition New Jersey: Prentice Hall393164 Words   |  1573 Pages T. A. Judge, and J. D. Kammeyer-Mueller, Staffing Organizations, 7th ed. (Madison, WI: Mendota House/Irwin, 2011) Other Interests Although he cannot keep up (literally!) with Dr. Robbin’s accomplishments on the track, Dr. Judge enjoys golf, cooking and baking, literature (he’s a particular fan of Thomas Hardy and is a member of the Thomas Hardy Society), and keeping up with his three children, who range in age from 23 to 9. Preface Welcome to the fifteenth edition of Organizational Behavior

Wednesday, May 6, 2020

Jack the Ripper Essay - 918 Words

Jack the Ripper is one of the most well-known serial killers of the ages. Although everyone knows the name, â€Å"Jack the Ripper,† nobody really knows of his true identity. When the murder victims were found the press and the detectives could never put a name with the crime. Jack the Ripper is a mythic figure comparable with Frankenstein and Dracula. The Rippers first three murdered whores, in 1888, were believed to be by the same person. These murdered victims all seemed to occur around the Parish Church of Saint Mary, also called â€Å"the White Chapel.† (Fido†¦1) â€Å"Jack the Ripper,† was the name given to an unidentified serial killer in the White Chapel district of London in 1888. The name came from a letter left at the crime scene, written by†¦show more content†¦Newspaper coverage and widespread, enduring coverage of the Jack the Ripper case were strongly enforced. Even with all the coverage investigators could not connect anyone with the murders. In 1888, over a time period of 10 weeks, Jack the Ripper walked the streets of East End. This is where he encountered and murdered several prostitutes between the hours of midnight and dawn. The victims’ bodies were thrown around like rag-dolls, laid out, cut throats, and their abdomens had been ripped open. This way of murder was sought to be very repetitive, giving the Ripper an almost instant notification sign. Nobody knows the exact number of women that were killed by Jack the Ripper. Though the investigators believe there were only five victims. Even with the investigators analysis, through the weeding process it is proven that there were only four victims of murder by Jack. (Evans†¦ 21) It was decided that the local police of the White Chapel area were not capable of catching Jack the Ripper alone. For this reason they got the assistance of the Central Office at Scotland Yard, also known as the CID. The CID was a top investigation agency that would help th e patrol officers of the White Chapel district to solve the case. (Evans†¦ 21) Jack’s killing field, â€Å"the heart of the Eastland,† was mainly the White Chapel and Spital fields area, this was an area of only one square mile. White Chapel was mainly womenShow MoreRelatedEssay Jack the Ripper1209 Words   |  5 Pages â€Å"Jack the Ripper† Jack the Ripper was a notorious serial killer, whom some believe never even existed at all. From August to November 1888, Jack the Ripper terrorized the East End of London by being responsible for the death and mutilation of at least seven female prostitutes. The destitute East End is also known as the White Chapel district of London, England. A few of the prostitutes were targeted as they were leaving brothels in and around the White Chapel district. Jack the Ripper seemedRead MoreJack the Ripper Essay2373 Words   |  10 PagesJack the Ripper Source Related In August 1888 a killer who became known as Jack the Ripper committed the first of a sequence of murders. To this day the description of the killer remains a mystery. A mad person who is violent and dangerous who emerge to kill without warning and with no guilt, horribly killed five women in the EastRead MoreThe Mystery Of Jack The Ripper2600 Words   |  11 PagesNobody could ever put a face to the so known, â€Å"Jack the Ripper†. Beginning in 1891 and finally evolving in 1891, ten murders took place in the area of London known as the East End. They weren’t randomly chosen either they all were street prostitutes. As well as a case that they were trying to correlate the same murderer with, so it was included in the file. The â€Å"Pinchin Street torso† , but it had no association with the other murders. In this case they had discovered a female torso which had beenRead MoreSerial Killers : Jack The Ripper1546 Words   |  7 Pagescase that sticks out from the others and because of this many do remember. The case, almost as old as modern policing itself, is simply remembered by name coined for the killer, Jack the Ripper. What makes Jack the Ripper such a mystery is the fact that he was never caught. The five murders carried out by Jack the Ripper were located at Whitechapel. Whitechapel is a small town in London which was stricken with poverty. Families lived in very small single room houses. These houses were cramped withRead MoreJack the Ripper and H.H. Holmes1279 Words   |  5 Pageswondered what happened to Jack the Ripper? Did he actually get away with it and die free, or was he arrested for different misdemeanors? It is possible that he had a connection to another well-known murderer, H.H. Holmes, but not just any connection. By looking at The Devil in the White City, we can see that there are things about murderer H.H. Holmes that are very similar to Jack the Ripper. This could mean that we finally have an answer to the mystery: who was Jack the Ripper? Let us begin with HolmesRead More Jack the Ripper Essay1777 Words   |  8 Pages Jack the Ripper was one of the most famous and renowned killers in history. Even though he was not the first serial killer, he was the first killer to strike on a metropolis setting. Jack the Ripper was in his prime at a time when the media had a strong control over society and society as a whole was becoming much more literate. Jack started his killing campaign at a time of political controversy between the liberals and social reformers along with the Irish Home rule partisans. The reports ofRead MoreThe Legend Of Jack The Ripper1841 Words   |  8 Pagesperiod and mothers of small families had to prostitutes themselves in order to provide meals for their families. Between August and November of 1888, a notorious murderer rose to the surface, slaughtering at least five women escorts. The legend of Jack the Ripper is one of the most famous, yet unsolved mysteries of English crime. I. Suspected Murder Victims August 31, 1888, was the first killing, Mary Ann Nichols was found dead on the side of a street at four o’clock in the morning. She had been deadRead More Jack the Ripper Essay1224 Words   |  5 Pages Jack the Ripper terrorized the streets of London of unknown reasons. With his ability to disappear he was impossible to track, therefore making him one of the most interesting and clever criminals known to man. In 1888, five prostitutes were brutally murdered within a tiny area of the East End of London. The killings rapidly occurred over an 11- week period but they have both haunted and fascinated people for over a hundred years. (Jakubowski 16) There is no reason to believe that the victimsRead More Jack The Ripper Essay923 Words   |  4 Pages Jack The Ripper In August 1888, the first of a series of murders was committed by a killer who became known as Jack the Ripper. To this day the identity of the killer remains a mystery. Five women were brutally killed in the East End of London, by a maniac who appeared to kill without warning and with no remorse. 1)What can you learn from Source A? Source A tells us that the two murders were aimed directly at the poorest people in East End at the time, and usuallyRead MoreInvestigation of Jack the Ripper Essays1436 Words   |  6 PagesInvestigation of Jack the Ripper Jack the ripper was an unknown serial killer, he kept his true identity a secret from the world. Many people today see Jack the Ripper as a mystery which will never be solved. People have tried for many years to find out the mystery of Jack the Ripper but can not and will not succeed. The fact that no one knows the identity of him keeps the mystery of the unknown killer alive. It will stay a mystery forever, all we know is that he was

Tuesday, May 5, 2020

ERP Technology & its Challenges Samples †MyAssignmenthelp.com

Question: Discuss about the ERP Technology its Challenges. Answer: Introduction Technology has improved and has enhanced over the period of years. There have been many automated systems that the business organizations are using in the present scenario so that they may gain benefits out of the same. These business organizations are now looking for implementation of the software packages that provide them with an integrated platform for the execution of the business activities. Enterprise Resource Planning (ERP) packages are an example of such integrated software packages that being extensively used. Enterprise Resource Planning (ERP): Meaning Definition ERP stands for Enterprise Resource Planning and it is a process that includes the integrated business mechanisms and activities. There are many significant business tasks that are covered and are executed by using and ERP package, such as, planning, decision making, inventory, sales, marketing, finance, human resources, procurement etc (Kilic, Zaim Delen, 2014). There are various vendors and service providers that have developed and launched their ERP packages in the market. Some of the popular vendors include SAP, Oracle and Microsoft. On the basis of the business needs and requirements, ERP packages can be classified in different types, such as, industry specific ERP systems, web based ERP, ERP packages for small businesses and likewise (Sodomka Klcova, 2016). Need Advantages of ERP Technology The growth and use of ERP in the business organizations is because of the requirements of these business units and the benefits that are offered by the ERP packages. The business firms and organizations that have been successful in the implementation of the ERP packages have managed to achieve a competitive edge over the others. The manual operations that were previously carried out by the resources in the organizations have now been replaced by their automated versions through ERP packages. This had led to the enhancement and improvement in the productivity levels of the employees (Ovidiu, 2010). Planning is an essential activity in the business organizations. ERP packages have provided the ability to carry out efficient planning and estimations. A strong integration and collaboration is required for the success of the business organizations. ERP packages have provided the organizations with the ability to have a string integrated environment. Management of the changes in the business organization is made easy with the aid of the ERP packages. These changes may comprise of the modifications in the business requirements or specifications along with the number of users or customers. There may also be changes in the technological concepts and aspects (Matende Ogao, 2013). The overall management of the information is made easy through ERP packages and software. The information operations and activities, such as, storage, retrieval and management can be made smoother through these packages (Kocakulah Willett, 2011) (Chauhan, Dwivedi Sherry, 2012). The additional and unnecessary infrastructural and operational costs are avoided through the successful implementation of the ERP packages. This leads to the enhancement of the overall budget and expenses of the organization. ERP systems work on the information sets that are associated with the business organizations along with the real-time data and information as well. This leads to the improvement of the customer-centric operations and activities. The reporting structure of the organizations is improved with the implementation of ERP packages which makes it possible for all the resources to have updated information at all times. The overall communication strategy and architecture also improves. ERP packages also assist the organizations in the adherence and compliance to several legal policies, regulatory frameworks and laws. This reduces the probability of the legal risks and issues (Hasibuan Dantes, 2012). These systems have an inherent quality of scalability which provides the organizations with various different capabilities, such as, flexibility and adaptability. The relationship and the engagement with the customers also improve with the implementation of the ERP packages. This is because of the reason that the business operations are streamlined and the customer preferences and choices are also taken into consideration for the execution of business tasks and activities (Sadrzadehrafiei, 2013). Challenges in ERP Technology There can be many challenges that may come up in association with the ERP technology. These challenges are as listed below. There are various factors that are associated with the selection of the suitable ERP package for an organization. Some of these factors include the size of the software, the automated systems already in use, the requirements and specifications of the organization, scope of the system and many more. The selection of the system, therefore, emerges as one of the major challenges (Babaei, Gholami Altafi, 2015). ERP systems and packages have experienced many changes and transformations in the recent years. In the past, these packages were mostly batch processed and integrated. However, these systems have now shifted towards the real-time based integration. The transition process from batch integration to real-time integration is a major challenge (Momoh, Roy Shehab, 2010). Initially, organizations tend to implement the basic ERP packages that have limited requirements and specifications involved. There are a few operations covered by these systems and once the organization expands, the needs of these organizations also rise. This often leads to the presence of multiple ERP packages to support and maintain which becomes troublesome at times (Singla, 2009). There are several technical issues that may come up in association with the ERP technology and packages: There are a number of existing servers and workstations that are installed in the organization. With the implementation and deployment of the ERP technology, there are many modifications that need to be done to these servers and workstations. The speed and bandwidth of the internet servers and the network connections shall also be considered and shall be enhanced as per the requirements of the ERP system. This may have an impact on the existing systems and operations being carried out in the organization (Nordin Adegoke, 2015). Compatibility and integration of the ERP package with the rest of the software and hardware installed in the organization can come up as a challenge. In the first attempt of the ERP implementation in the business organization, it would be necessary to migrate and move the existing and legacy data sets to the new platform. There may be issues in the data quality and consistency in the process of migration. Security may be one of the major challenges that may come up with the deployment and implementation of the ERP technology and package in the organization. Some of these security issues that may crop up are as listed below. There are a lot many ERP packages and software that may go unpatched. It becomes required to install updates and patches in the ERP packages and the failure to do so may lead to the enhancement of the complexity. Poor configuration of the ERP packages and systems may lead to the increased probability of the backdoor access for the attackers. This may lead to the enhancement of the security vulnerabilities as well (Zafeiropoulos, Metaxiotis Askounis, 2005). Outdates web interfaces used in the ERP technology may lead to the occurrence of the security attacks such as SQL injection and web based security risks and attacks. There are a lot many access points that are present in the ERP package which leads to the issues associated with the violation of the access control and authentication. This may lead to breaching and leakage of information. There may be availability attacks that may come up with the occurrence and execution of flooding attacks such as denial of service and distributed denial of service attacks. The availability of the services, information and operations may be impacted as a result of these attacks on security (Acharya, Jethava Patel, 2013). There can also be issues with the integrity of the information associated with the ERP packages. There are vast data sets that are involved in ERP packages that may be exposed to the risks such as alteration of the contents without adequate permission to do so. Malware attacks are also common in case of the automated systems and applications that may be witnessed in case of ERP packages as well. Resolution of the ERP Challenges The challenges that have been illustrated above can be further understood with the case studies associated with the implementation of the ERP packages in the organizations. There have been many success and failure stories in the past. The success stories have been described below to describe the challenges and the reasons of success or failure of the ERP packages and system. ERP Success Story Cadbury is an organization that is one of the worlds largest manufacturers of chocolates and is based out of Birmingham, United Kingdom. The ERP technology was successfully implemented in the organization with the adherence to the following points. The strongest point involved in the successful implementation of ERP in Cadbury was the correct planning and estimation activities that were involved. The choice of the vendor was done according to the requirements of the ERP package in the organization and the analysis involved was also extensive. Effective communication channel was developed with the ERP vendor with the development of a portal called vendor connect for this purpose (Singh, 2017). Implementation methodology that was used by the organization was also apt. Cross-functional implementation was done so that the series of phases were involved rather than implanting all the functionalities all at once. The management also made sure that the monitoring tasks were adequately carried out so that the team members were aware of all the deviations and errors. ERP Failure Story There was another organization called Hersheys that attempted the implementation of ERP but failed in its attempt to do so. There were many challenges that came up for the organization which gradually led to failure. The schedule that was estimated by the vendor and the team of analysts was 48 months. However, the organizational leadership forced the vendor and the project team to implement and complete the project in a period of 30 months only. The incorrect schedule design was a major challenge that led to the failure of the project. Because of the incorrect schedule design and estimation, there were many critical tasks and activities that were missed out during the implementation. One such activity was testing of the critical features that led to the presence of many bugs in the final delivery of the project (Gross, 2011). The implementation methodology that was selected by the management was also not correct. The selected methodology included Big Bang implementation of the ERP technology which led to the failure of the project. There are two scenarios that have been described above which include the success and the failure of the ERP technology in the organizations. The challenges associated with the ERP technology can be overcome by using and adhering to the points listed under the approach followed by Cadbury. Also, there shall be used and implementation of the security controls and mechanisms to avoid the security risks and attacks. There shall also be advanced use of monitoring and control processes by the management and leadership covering the adequate selection of the vendor, methodology, estimations etc. The processes must be validated and verified at every step so that the end result that is achieved is positive. Conclusion Enterprise Resource Planning a process that includes the integrated business mechanisms and activities. There are many significant business tasks that are covered and are executed by using and ERP package, such as, planning, decision making, inventory, sales, marketing, finance, human resources, procurement etc. ERP offers many benefits to the organizations in which it is implemented. Some of these benefits include streamlining of operations, enhanced productivity and accuracy, integration of the business operations, reduced legal risks and increased customer engagement and satisfaction levels. There can also be certain challenges that may be observed in association with the ERP technology. These challenges may include technical issues such as compatibility, integration and installation issues or data quality and consistency issues. There may also be a number of security issues that may be observed in association with the ERP packages. It shall be ensured that adequate planning and c ontrol is involved in the selection, development and deployment of the ERP technology in the organization. References Acharya, V., Jethava, S., Patel, A. (2013). Case Study of Database Security in Campus ERP System. International Journal Of Computer Applications, 79(15), 1-4. https://dx.doi.org/10.5120/13814-1546 Babaei, M., Gholami, Z., Altafi, S. (2015). Challenges of Enterprise Resource Planning implementation in Iran large organizations. Information Systems, 54, 15-27. https://dx.doi.org/10.1016/j.is.2015.05.003 Chauhan, R., Dwivedi, R., Sherry, A. (2012). Critical success factors for offshoring of enterprise resource planning (ERP) implementations. Business Systems Research, 3(1). https://dx.doi.org/10.2478/v10305-012-0001-5 Gross, J. (2011). A Case Study on Hershey's ERP Implementation Failure Driving successful enterprise software projects. Pemeco.com. Retrieved 5 October 2017, from https://www.pemeco.com/a-case-study-on-hersheys-erp-implementation-failure-the-importance-of-testing-and-scheduling/ Hasibuan, Z., Dantes, G. (2012). Priority of Key Success Factors (KSFS) on Enterprise Resource Planning (ERP) System Implementation Life Cycle. Journal Of Enterprise Resource Planning Studies, 1-15. https://dx.doi.org/10.5171/2011.122627 Kilic, H., Zaim, S., Delen, D. (2014). Development of a hybrid methodology for ERP system selection: The case of Turkish Airlines. Decision Support Systems, 66, 82-92. https://dx.doi.org/10.1016/j.dss.2014.06.011 Kocakulah, M., Willett, D. (2011). Enterprise Resource Planning (ERP) System Implementation: Promise and Problems. Review Of Business Information Systems (RBIS), 7(3), 35. https://dx.doi.org/10.19030/rbis.v7i3.4522 Matende, S., Ogao, P. (2013). Enterprise Resource Planning (ERP) System Implementation: A Case for User Participation. Procedia Technology, 9, 518-526. https://dx.doi.org/10.1016/j.protcy.2013.12.058 Momoh, A., Roy, R., Shehab, E. (2010). Challenges in enterprise resource planning implementation: state of the art. Business Process Management Journal, 16(4), 537-565. https://dx.doi.org/10.1108/14637151011065919 Nordin, N., Adegoke, O. (2015). Learning from ERP Implementation: A Case Study of Issues and Challenges in Technology Management. Jurnal Teknologi, 74(1). https://dx.doi.org/10.11113/jt.v74.3369 Ovidiu, S. (2010). The Advantages and Risks of Using ERP System in the Context Globalization. Retrieved 5 October 2017, from https://modtech.ro/international-journal/vol2no22010/Ovidiu_Sava.pdf Sadrzadehrafiei, S. (2013). The Benefits of Enterprise Resource Planning (ERP) System Implementation in Dry Food Packaging Industry. Retrieved 5 October 2017, from https://ac.els-cdn.com/S2212017313003381/1-s2.0-S2212017313003381-main.pdf?_tid=77abbd6a-a846-11e7-b678-00000aab0f01acdnat=1507040806_f9052d1931fe40f04bef070a3b30da63 Singh, V. (2017). Enterprise Resource Planning Implementation Success and Failure Stories |. Sapyard.com. Retrieved 5 October 2017, from https://www.sapyard.com/enterprise-resource-planning-implementation-success-and-failure-stories/ Singla, A. (2009). Enterprise resource planning systems implementation: a literature analysis. International Journal Of Business And Systems Research, 3(2), 170. https://dx.doi.org/10.1504/ijbsr.2009.024860 Sodomka, P., Klcova, H. (2016). Classification of ERP System Services. Journal Of Systems Integration, 66-78. https://dx.doi.org/10.20470/jsi.v7i3.263 Zafeiropoulos, I., Metaxiotis, K., Askounis, D. (2005). Dynamic risk management system for the modeling, optimal adaptation and implementation of an ERP system. Information Management Computer Security, 13(3), 212-234. https://dx.doi.org/10.1108/09685220510602031

Monday, April 6, 2020

Cultural Conflict between Christian Western Countries and Islamic Countries of the East

Table of Contents Introduction Western colonization and Islam Religious differences Christian democracy vs. Islam authoritarianism The holy war Conclusion Works Cited Introduction There is a widespread thesis by Huntington that defines the conflict in the world today as the clash of civilizations. This conflict goes beyond social classes and economic groups (Huntington p.28). It is a cultural conflict between two civilizations that share different ideologies.Advertising We will write a custom research paper sample on Cultural Conflict between Christian Western Countries and Islamic Countries of the East specifically for you for only $16.05 $11/page Learn More The 21st century has seen a surge of violent ethnic clashes, especially in the Islamic nations of the East. In the eyes of the democratic western world, the violence is directly attributed to the oppressive political systems of the East. The conflict has now shifted to a raging clash between the Christian West and the Islamic East, especially after the September 11 attack on the United States. The assumption of many is that the conflict between the West and the East is political. The Islamic East is fighting off the efforts of the West to convert them into democratic states. On the contrary, you would be surprised to learn that even among the western countries, there are many similar views on democracy similar to the ones that are held by the Islamic East. These countries disagree on the basis of politics. Therefore, there has to be something else that fuels the conflict between the East and West. From my analytical point of view, I agree with experts who trace the cause of this conflict to cultural differences between the two civilizations. Eastern Islamic countries are by far the most conservative people in the world today. On the contrary, the western world claims to share the most liberal ideologies. A cultural gap ensues that ultimatum leads to conflict. Western colon ization and Islam The western colonization of the East in the 18th and 19th centuries left a series of mixed reactions amongst the Islam colonies. The West brought with it ideologies such as modern education, democratic government, and Christian religion. This western experience became an eye opener for the Muslim community. There was a general consensus that the West had come to water down their Islam identity. Therefore, there was the need to redefine the role of the Islam faith in the modern community. While all Muslims denounced western culture, some supported the idea of developing Islam alternatives to western culture. Others supported total Islamization without traces of the western influence. To the West, islamization is the main bone of contention with the East, claiming there is no democracy in Islam. For the East, the issue is not about democracy or lack of it, but about the cultural differences between the two groups (Aslan 12). Religious differences Religion has a deepe r impact on culture than it may seem to be at first glance. This is the main source of conflict between Muslims and Christians. For example, Islam allows polygamy up to a fourth wife. For Muslims, it is an acceptable culture. For the Christians, polygamy is condemned. In fact, the Western people view the Muslim practice as oppression to women (Landscheidt and Wollny 1). The western social values give women more freedom.Advertising Looking for research paper on cultural studies? Let's see if we can help you! Get your first paper with 15% OFF Learn More For instance, they allow gender equality and sexual liberalization. They prove to be more tolerant when it comes to educating women, political representation, divorce, homosexuality and abortion. All these freedoms allowed to women by the West are an abomination in the conservative Islamic East. They are viewed as sacrilege to their religion. Therefore, it is important for the East to shun the western values. The Sharia l aw, which is adopted by Islam states as the rule of law, is based on the teachings of the Koran. For Muslims, all aspects of their lives as pertains to religion and social rules of behavior are provided in the holy book. As a monotheistic religion that believes in only one God, Allah, Islam believes that all rules and laws were set by God. Therefore, it is an accepted culture amongst Muslims that the laws, even those which govern their politics, are based on religion (Landscheidt and Wollny 3). Christianity deviates from this in various ways. The reformation of Christianity in the 16th century led to the formation of many breakaway factions of the church. The church and politics were separated, and the quest for freedom and democracy took root. Therefore, the rules of law that govern the western world are not based on religion in the least. Rather, they are based on a merger of the rights and freedoms of individuals. This is one of the aspects of the western world that Islam cannot agree with. Their law is not based on religion. Christian democracy vs. Islam authoritarianism In terms of politics, the clash between the West and the East seems to be endless. The Christian West runs on democracy. These are set of rules that ensure the freedom of individuals in the society. Each person has the freedom to determine what is right and wrong. Democracy is seen as the height of civilization and goes hand in hand with freedom. The Muslim interpretation of Islamic law reiterates that all human actions are determined by Allah (Landscheidt and Wollny 4).Therefore, whatever one does is done to His glory. The independence of Muslims is curtailed by this very reason and explains why most Islamist states have authoritarian-hierarchical types of leadership in government. The leader, seen as Allah’s instrument, is obeyed to the latter and normally has power the people. This is what the West interprets as oppression or dictatorship. Islamic societies support the kind of le adership where religion has a strong influence on society. This is different in the West, where religion is separated from leadership. Therefore, religious leadership does not play an active role in peoples’ lives. Whilst the Christian West upholds freedom, the Islamist East upholds justice and doing what their religion says is right. Muslims feel justified to fight off the influence of the West. In the economic front, the West is seen as a formidable force that infiltrates weaker economic markets, tapping their potential at low cost of cheap local labor while reaping huge profits.Advertising We will write a custom research paper sample on Cultural Conflict between Christian Western Countries and Islamic Countries of the East specifically for you for only $16.05 $11/page Learn More A majority of Eastern Islamic countries are under-developed in terms of technology and reel from the effects of high unemployment rates (which they blame on the wester n type of education). This kind of exploitation by the West seems to fortify the belief of Islam states that they have to fight the unjust practices by the West, and the culmination of such fights are ‘terrorist’s attacks such as the September, 11 or the perpetual war on Iraq. The holy war These attacks by the Islam East are a result of the holy war, what they call ‘jihad’. According to Muslims, the translation of jihad as the ‘holy war’ is misconstrued. It is not that Muslims attack other cultures in a bit of religious fanaticism as there is no outright depiction of such attacks in the Koran. Rather, the Koran demonstrates that there are two existences of the world; the peaceful part, Islam and the part at war (designated to non-believers). Accordingly, Muslims are expected, as part of their duty, to merge the two parts of the world. That is to mean, they should spread peace (Islam) to the rest of the warring world (non-believers). Therefore, there is a need to defend their country, as well as their religion even to the extent of war and other extremities. After all, by acting according to the Koran, one expects a great reward in Heaven. The Christian western world, with its ideologies of freedom, globalization, liberalism, advanced technology, and economic monopoly is seen by Islam as a perpetration of all that is ‘evil’. Consequently, a Muslim feels that it is a calling to root out the evil so as to defend the loss of its religious societal values. Muslims believe that the ideal kind of world (and government) is of the kind that prophet Muhammad led in Medina (Aslan 69). This means that the society should have one leader, who bids people to do the will of Allah in fulfillment of their religious duties. Modernization, which is a concept introduced and epitomized by the western world, is a representation of the abolishment of any and all religious laws in relation to leadership. This is far removed from the Islamic concept of religion and leadership. Overly, Islamic states find their model of governance to be superior to the western model that is based on democracy, which goes against the requirements of Allah. To achieve the ideal state that relies on the religious rules that uphold the interdependence of state and religion, Muslims feel that the jihad is justified, and it is a means to enforce Islamic principles even if it means using violence. Extremists of Islamic fundamentals take this as a step further. They form a large network of supporters, acquire arms and weapons and fling themselves to the core of jihadist movements. This is what has culminated in terror groups, the kind that plotted the September 11 attacks. Terrorism has now become a widespread threat, especially to the western world. The western world mistakenly thinks that this is a political war. Therefore, it responds in that manner. The United States of America invaded Iraq in response to the September 11 attacks.Adv ertising Looking for research paper on cultural studies? Let's see if we can help you! Get your first paper with 15% OFF Learn More This is what they termed as the war on terror. Consequently, other democracies of the western world joined forces to end the war on terror by subverting the political and economic state of the Islamic nation. In solidarity, other Islamic nations of the East continue to attack the West. Spain became a victim of this violence when on March 11; similar bomb explosions shook Madrid for supporting the United States by sending its troops to Iraq. Consequently, Spain withdrew its troops. The Islamic East saw this as a victory for its cause. In order to protect the state of Islam, violent threats such as terror attacks on the western world seem to give them the desired response for the western governments to withdraw their invasion of Islamic countries. Their reasoning is simple: the West should stop meddling in its Islamic culture by perpetrating their values of modernity, democracy, and freedom. Conclusion It is difficult to predict the end of the conflict between the largely Christian We stern countries and largely Islamic countries of the East. Political strife may be solved at tables, at conventions, but cultural strife is more delicate to handle. Islam, as a religion, is deeply rooted in the Muslim culture and has existed for over 1500 years; Christianity has existed for the past 2000 years. The Islam political system is embedded in its religion; in the Koran. Demanding a shift away from their Islamic ideologies would be tantamount to demanding Islamic reformation without their free will. These ideologies revolve around all aspects of society which include politics, social values and religion itself. Western effort to assert their ideologies on democracy, freedom, and other social values on these societies may be deemed as an affront to Islam (Funk and Abdul Aziz 15). The western Christian states emerge to be at the forefront of civilization, judging by their liberality. This freedom was not achieved overnight. It was a ferocious battle that started in the 16th c entury with reformist movements and stretched on for more than a century. Eventually, religion was separated from politics and society indulged in freedom. The Islamic reformation should not be a battle between Christianity and Islam. In that way, the conflict will never end. Rather, the reformation should be a religious conflict amongst the subsets of Islam; mainstream vs. liberal, traditionalists vs. modernists and so on, that they may find their own middle ground in their own religion. As for Muslims, their interpretation of the laws in the holy Koran should not be so radical as to infringe on the religious cultures of others. After all, the very Koran orders the believers of the Islam faith to dialogue with the non-believers in order to appeal to them. It does not say to bomb them into submission. A further call is made of religious tolerance towards other faiths such as Christians and Jews that have been in existence for as long as Islam was conceived (Landscheidt and Wollny 16 ). The Christian west, having achieved economic and technological advancement way ahead of the conservative Islam states, should strive to foster coherence with their globalization agenda. Barging into the Eastern markets with capitalist ideas will not augur well with the East that views such assault as injustice, therefore the need to retaliate. Rather, globalization can be used effectively to improve the education system of the East and to create employment opportunities to lift their standards in life, with both groups of civilizations viewing each other in mutual respect of their religion, culture and politics. Works Cited Aslan, Reza. No god but God, New York: Random House Publishing Group, 2005. print. Funk, Nathan, and Said Abdul. â€Å"Islam and the West:Narratives of conflict and conflict transformation.† International Journal of Peace Studies, 25.2 (2004): 1-28. Print. Landscheidt, Dennis, and S. Wollny. The conflict between the Western world and  Islam, Californi a: ICM, 2004. Print. This research paper on Cultural Conflict between Christian Western Countries and Islamic Countries of the East was written and submitted by user Titus May to help you with your own studies. You are free to use it for research and reference purposes in order to write your own paper; however, you must cite it accordingly. You can donate your paper here.

Sunday, March 8, 2020

stock markets history essays

stock market's history essays Once there was a time when shares in business corporations were rarely bought and sold because few companies were considered promising financial profits (Blume 21). That is hard to believe considering almost everybody has invested in some stock today. The stock market went through some distinct changes since its inception, and has evolved into a shaping force in the world today. There is one idea that sparked the fire which produced the stock market: capitalism. Everything the stock market is, and was, rooted in the basic idea of capitalism. Without that idea, stocks and bonds would never have come to be. Capitalism is an economic system in which the means of production and distribution are privately or corporately owned and development is proportionate to the accumulation and reinvestment of profits gained in a free market (Peterson). When a person buys a stock, which means they own a part of the company in which they invested. The average person can thereby invest in a public c ompany and receive a piece of that company's success, or failure. This process helps not only the smart investors, but the companies as well. The investors' money must go somewhere, and that place is the treasury of the company they endorsed (Simonson). The company then uses that money for its financial needs, providing the company an income in addition to simple sales profits. Then, the investors make or lose money based on how much that company makes. Basically, people invest in an idea, and make money based on how that idea performs in the real world (Blume 35-39). While the stock market is based upon capitalism, the community shunned this type of enterprise in 1792 because of financial panic (Blume 23). However, these practices were not shunned by all America in 1792. People wanted a way to trade stocks without the public stock auctions (which were banned because of lack of profits), so they tried something different than s...

Friday, February 21, 2020

The wife of President James Madison Essay Example | Topics and Well Written Essays - 1500 words

The wife of President James Madison - Essay Example We the People of the United States, in Order to form a more perfect Union, establish Justice, insure domestic Tranquility, provide for the common defense, promote the general Welfare, and secure the Blessings of Liberty to ourselves and our Posterity, do ordain and establish this Constitution for the United States of America. Unknown to her, she was invoking the Preamble when she honored the soldiers after each battle won since is it an action of common defense. Isn’t it an act of promoting general welfare when she mobilized the society who contributed their own funds to reestablish Washington, the seat of the government, when it was destroyed by the enemies? In effect she was demonstrating domestic tranquility when she tried to unite political parties by throwing parties bringing together two opposing political parties; introducing social etiquette and protocol included. In renovating the White House she wanted every Americans to take pride of it; because to her, the White Ho use is the representation of authority, and a common defense. When she installed dignity to women’s position at a time when gender equality reigns, she is practically framing the constitutional rights of women of equality. Gender equality later on became part of the Constitutional Amendment. I believe Dolley Madison had every right to be called the â€Å"last founders† because she put into practice the idealism prescribed in the Constitution long before it was penned into law. She created symbolic ties that brought the government.

Wednesday, February 5, 2020

Ecological Footprints Assignment Example | Topics and Well Written Essays - 750 words

Ecological Footprints - Assignment Example   An ecological footprint is a vital tool for measuring the consumption of the earth. It gives a simple assessment overview of how our lifestyles affect the environment. In turn, these facts can be useful in the future, to help promote wise management of ecological assets. Apart from that, it challenges individuals and households to take personal and collective initiatives in the protection of nature (Ferng, 2001). For example, a household or an individual can get to use public transport to reduce their ecological footprint, or they can choose to adopt the use of organic substances to help protect the environment. It is, therefore, true to say that, the ecological footprint varies directly proportional to the rate of human consumption, this means that an increase in the rate of human consumption significantly increases the footprint and vice versa. Compared to most of my classmates, my ecological footprints is on the higher side, this means that my consumption is slightly on the ri se. According to the results, rated at 40.8percent, Yuni has the highest percentage of ecological footprint, while Charles took the least percentage with a total footprint of 16.8 percent. Equated to my 34.4 percent, it is evident that I need to reduce my resources consumption and waste disposal. If everybody on the planet could adopt my choice of lifestyle, then we would need 7.7 planets to provide the required resources. Charles will need 4.1 planets to expedite if all the people adopted his lifestyle.  

Tuesday, January 28, 2020

Physico-chemical Processes that Occur During Freezing

Physico-chemical Processes that Occur During Freezing 1. Introduction Lyophilization respectively freeze-drying is an important and well-established process to improve the long-term stability of labile drugs, especially therapeutic proteins.[1] About 50% of the currently marketed biopharmaceuticals are lyophilized, representing the most common formulation strategy.[2] In the freeze-dried solid state chemical or physical degradation reactions are inhibited or sufficiently decelerated, resulting in an improved long-term stability.[3] Besides the advantage of better stability, lyophilized formulations also provide easy handling during shipping and storage. [1] A traditional lyophilization cycle consists of three steps; freezing, primary drying and secondary drying.[1] During the freezing step, the liquid formulation is cooled until ice starts to nucleate, which is followed by ice growth, resulting in a separation of most of the water into ice crystals from a matrix of glassy and/or crystalline solutes.[4-5] During primary drying, the crystalline ice formed during freezing is removed by sublimation. Therefore, the chamber pressure is reduced well below the vapor pressure of ice and the shelf temperature is raised to supply the heat removed by ice sublimation.[6] At the completion of primary drying, the product can still contain approximately 15% to 20% of unfrozen water, which is desorbed during the secondary drying stage, usually at elevated temperature and low pressure, to finally achieve the desired low moisture content.[7] In general, lyophilization is a very time- and energy-intensive drying process.[8]   Typically, freezing is over within a few hours while drying often requires days. Within the drying phase, secondary drying is short (~hours) compared to primary drying (~days).[1, 4] Therefore, lyophilization cycle development has typically focused on optimizing the primary drying step, i.e., shortening the primary drying time by adjusting the shelf temperature and/or chamber pressure without influencing product quality.[5, 9] Although, freezing is one of the most critical stages during lyophilization, the importance of the freezing process has rather been neglected in the past.[10]   The freezing step is of paramount importance. At first, freezing itself is the major desiccation step in lyophilization [6] as solvent water is removed from the liquid formulation in the form of a pure solid ice phase, leading to a dramatic concentration of the solutes.[11-12] Moreover, the kinetics of ice nucleation and crystal growth determine the physical state and morphology of the frozen cake and consequently the final properties of the freeze-dried product.[11-13] Ice morphology is directly correlated with the rate of sublimation in primary and secondary drying.[14] In addition, freezing is a critical step with regard to the biological activity and stability of the active pharmaceutical ingredients (API), especially pharmaceutical proteins.[1] While simple in concept, the freezing process is presumably the most complex but also the most important step in the lyophilization process.[10] To meet this challenge, a thorough understanding of the physico-chemical processes, which occur during freezing, is required. Moreover, in order to optimize the freeze drying process and product quality, it is vital to control the freezing step, which is challenging because of the random nature of ice nucleation. However, several approaches have been developed to trigger ice nucleation during freezing. The purpose of this review is to provide the reader with an awareness of the importance but also complexity of the physico-chemical processes that occur during freezing. In addition, currently available freezing techniques are summarized and an attempt is made to address the consequences of the freezing procedure on process performance and product quality. A special focus is set on the critical factors that influence protein stability. Understanding and controlling the freezing step in lyophilization will lead to optimized, more efficient lyophilization cycles and products with an improved stability. 2. Physico-chemical fundamentals of freezing The freezing process first involves the cooling of the solution until ice nucleation occurs. Then ice crystals begin to grow at a certain rate, resulting in freeze concentration of the solution, a process that can result in both crystalline and amorphous solids, or in mixtures.[11] In general, freezing is defined as the process of ice crystallization from supercooled water.[15] The following section summarizes the physico-chemical fundamentals of freezing. At first, the distinction between cooling rate and freezing rate should be emphasized. The cooling rate is defined as the rate at which a solution is cooled, whereas the freezing rate is referred to as the rate of postnucleation ice crystal growth, which is largely determined by the amount of supercooling prior to nucleation.[16-17] Thus, the freezing rate of a formulation is not necessarily related to its cooling rate.[18] 2.1 Freezing phenomena: supercooling, ice nucleation and ice crystal formation In order to review the physico-chemical processes that occur during freezing of pure water, the relationship between time and temperature during freezing is displayed in figure 1. When pure water is cooled at atmospheric pressure, it does not freeze spontaneously at its equilibrium freezing point (0 °C).[19] This retention of the liquid state below the equilibrium freezing point of the solution is termed as â€Å"supercooling†.[19] Supercooling (represented by line A) always occurs during freezing and is often in the range of 10 to 15 °C or more.[12, 18] The degree of supercooling is defined as the difference between the equilibrium ice formation temperature and the actual temperature at which ice crystals first form and depends on the solution properties and process conditions.[1, 6, 11, 20] As discussed later, it is necessary to distinguish between â€Å"global supercooling†, in which the entire liquid volume exhibits a similar level of supercooling, and â€Å"lo cal supercooling†, in which only a small volume of the liquid is supercooled.[14] Supercooling is a non-equilibrium, meta-stable state, which is similar to an activation energy necessary for the nucleation process.[21] Due to density fluctuations from Brownian motion in the supercooled liquid water, water molecules form clusters with relatively long-living hydrogen bonds [22] almost with the same molecular arrangement as in ice crystals.[11, 15] As this process is energetically unfavorable, these clusters break up rapidly.[15] The probability for these nuclei to grow in both number and size is more pronounced at lowered temperature.[15] Once the critical mass of nuclei is reached, ice crystallization occurs rapidly in the entire system (point B).[15, 21-22]   The limiting nucleation temperature of water appears to be at about -40 °C, referred to as the â€Å"homogeneous nucleation temperature†, at which the pure water sample will contain at least one spontaneously f ormed active water nucleus, capable of initiating ice crystal growth.[11] However, in all pharmaceutical solutions and even in sterile-filtered water for injection, the nucleation observed is â€Å"heterogeneous nucleation†, meaning that ice-like clusters are formed via adsorption of layers of water on â€Å"foreign impurities†.[6, 11] Such â€Å"foreign impurities† may be the surface of the container, particulate contaminants present in the water, or even sites on large molecules such as proteins.[23-24] Primary nucleation is defined as the initial, heterogeneous ice nucleation event and it is rapidly followed by secondary nucleation, which moves with a front velocity on the order of mm/s through the solution. [14, 25] Often secondary nucleation is simply referred to as ice crystallization, and the front velocity is sometime referred to as the crystallization linear velocity.[14] Once stable ice crystals are formed, ice crystal growth proceeds by the addition of molecules to the interface.[22] However, only a fraction of the freezable water freezes immediately, as the supercooled water can absorb only 15cal/g of the 79cal/g of heat given off by the exothermic ice formation.[12, 22] Therefore, once crystallization begins, the product temperature rises rapidly to near the equilibrium freezing point.[12, 26] After the initial ice network has formed (point C), additional heat is removed from the solution by further cooling and the remaining water freezes when the previously formed ice crystals grow.[12] The ice crystal growth is controlled by the latent heat release and the cooling rate, to which the sample is exposed to.[22] The freezing time is defined as the time from the completed ice nucleation to the removal of latent heat (from point C to point D). The temperature drops when the freezing of the sample is completed (point E).[21] The number of ice nuclei formed, the rate of ice growth and thus the ice crystals` size depend on the degree of supercooling.[14, 20] The higher the degree of supercooling, the higher is the nucleation rate and the faster is the effective rate of freezing, resulting in a high number of small ice crystals. In contrast, at a low degree of supercooling, one observes a low number of large ice crystals.[14, 19] The rate of ice crystal growth can be expressed as a function of the degree of supercooling.[23]   For example for water for injection, showing a degree of supercooling of 10 °C +/- 3 °C, an ice crystal growth rate of about   5.2cm/s results.[23] In general, a slower cooling rate leads to a faster freezing rate and vice versa. Thus, in case of cooling rate versus freezing rate it has to be kept in mind â€Å"slow is fast and fast is slow†. Nevertheless, one has to distinguish between the two basic freezing mechanisms. When global supercooling occurs, which is typically the case for shelf-ramped freezing, the entire liquid volume achieves a similar level of supercooling and solidification progresses through the already nucleated volume.[12, 14] In contrast, directional solidification occurs when a small volume is supercooled, which is the case for high cooling rates, e.g. with nitrogen immersion. Here, the nucleation and solidification front are in close proximity in space and time and move further into non-nucleated solution. In this case, a faster cooling rate will lead to a faster freezing rate.[12, 14] Moreover, as ice nucleation is a stochastically event [6, 18], ice nucleation and in consequence ice crystal size distribution will differ from vial to vial resulting in a huge sample heterogeneity within one batch.[6, 14, 27] In addition, during freezing the growth of ice crystals within one vial can also be heterogeneous, influencing intra-vial uniformity.[5] Up to now, 10 polymorphic forms of ice are described. However, at temperatures and pressures typical for lyophilization, the stable crystal structure of ice is limited to the hexagonal type, in which each oxygen atom is tetrahedrally surrounded by four other oxygen atoms.[23] The fact that the ice crystal morphology is a unique function of the nucleation temperature was first reported by Tammann in 1925.[28] He found that frozen samples appeared dendritic at low supercoolings and like â€Å"crystal filaments† at high supercooling. In general, three different types of growth of ice crystals around nuclei can be observed in solution[15]: i) if the water molecules are given sufficient time, they arrange themselves regularly into hexagonal crystals, called dendrites; ii) if the water molecules are incorporated randomly into the crystal at a fast rate, â€Å"irregular dendrites† or axial columns that originate from the center of crystallization are formed; iii) at higher coo ling rates, many ice spears originate from the center of crystallization without side branches, referred to as spherulites. However, the ice morphology depends not only on the degree of supercooling but also on the freezing mechanism. It is reported that â€Å"global solidification† creates spherulitic ice crystals, whereas â€Å"directional solidification† results in directional lamellar morphologies with connected pores.[12, 14] While some solutes will have almost no effect on ice structure, other solutes can affect not only the ice structure but also its physical properties.[19] Especially at high concentrations, the presence of solutes will result in a depression of the freezing point of the solution based on Raoults`s Law and in a faster ice nucleation because of the promotion of heterogeneous nucleation, leading to a enormously lowered degree of supercooling.[21] 2.2 Crystallization and vitrification of solutes The hexagonal structure of ice is of paramount importance in lyophilization of pharmaceutical formulations, because most solutes cannot fit in the dense structure of the hexagonal ice, when ice forms.[23] Consequently, the concentration of the solute constituents of the formulation is increased in the interstitial region between the growing ice crystals, which is referred to as â€Å"cryoconcentration†.[11-12] If this separation would not take place, a solid solution would be formed, with a greatly reduced vapor pressure and the formulation cannot be lyophilized.[23] The total solute concentration increases rapidly and is only a function of the temperature and independent of the initial concentration.[4] For example, for an isotonic saline solution a 20-fold concentration increase is reported when cooled to -10 °C and all other components in a mixture will show similar concentration increases.[4] Upon further cooling the solution will increase to a critical concentration, ab ove which the concentrated solution will either undergo eutectic freezing or vitrification.[7] A simple behavior is crystallization of solutes from cryoconcentrated solution to form an eutectic mixture.[19] For example, mannitol, glycine, sodium chloride and phosphate buffers are known to crystallize upon freezing, if present as the major component.[12] When such a solution is cooled, pure ice crystals will form first. Two phases are present, ice and freeze-concentrated solution. The composition is determined via the equilibrium freezing curve of water in the presence of the solute (figure 2). The system will then follow the specific equilibrium freezing curve, as the solute content increases because more pure water is removed via ice formation. At a certain temperature, the eutectic melting temperature (Teu), and at a certain solute concentration (Ceu), the freezing curve will meet the solubility curve. Here, the freeze concentrate is saturated and eutectic freezing, which means solute crystallization, will occur.[7, 19] Only below Teu, which is defined as the lowest temperat ure at which the solute remains a liquid the system is completely solidified.[19] The Teu and Ceu are independent of the initial concentration of the solution.[7] In general, the lower the solubility of a given solute in water, the higher is the Teu.[19] For multicomponent systems, a general rule is that the crystallization of any component is influenced, i.e. retarded, by other components.[11] In practice, analogous to the supercooling of water, only a few solutes will spontaneously crystallize at Teu.[11] Such delayed crystallization of solutes from a freezing solution is termed supersaturation and can lead to an even more extreme freeze concentration.[11] Moreover, supersaturation can inhibit complete crystallization leading to a meta-stable glass formation, e.g. of mannitol.[12, 23] In addition, it is also possible that crystalline states exist in a mixture of different polymorphs or as hydrates.[11] For example, mannitol can exist in the form of several polymorphs (a, b and d) und under certain processing conditions, it can crystallize as a monohydrate.[11] The phase behavior is totally different for polyhydroxy compounds like sucrose, which do not crystallize at all from a freezing solution in real time.[11] The fact that sucrose does not crystallize during freeze-concentration is an indication of its extremely complex crystal structure.[11] The interactions between sugar -OH groups and those between sugar -OH groups and water molecules are closely similar in energy and configuration, resulting in very low nucleation probabilities.[11] In this case, water continues to freeze beyond the eutectic melting temperature and the solution becomes increasingly supersaturated and viscous.[11] The increasing viscosity slows down ice crystallization, until at some characteristic temperature no further freezing occurs.[11] This is called glassification or vitrification.[18]   The temperature at which the maximal freeze-concentration (Cg`) occurs is referred to as the glass transition temperature Tg`.[11, 29] This point is at the intersection of t he freezing point depression curve and the glass transition or isoviscosity curve, described in the â€Å"supplemented phase diagram† [30] or â€Å"state diagram† (figure 2).[11] Tg ´ is the point on the glass transition curve, representing a reversible change between viscous, rubber-like liquid and rigid, glass system.[19] In the region of the glass transition, the viscosity of the freeze concentrate changes about four orders of magnitude over a temperature range of a few degrees.[19] Tg` depends on the composition of the solution, but is independent of the initial concentration.[4, 11, 27]   For example, for the maximally freeze concentration of sucrose a concentration of 72-73% is reported.[31] In addition to Tg` the collapse temperature (Tc) of a product is used to define more precisely the temperature at which a structural loss of the product will occur. In general Tc is several degrees higher than Tg`, as the high viscosity of the sample close to Tg` will pre vent .[10] The glassy state is a solid solution of concentrated solutes and unfrozen, amorphous water. It is thermodynamically unstable with respect to the crystal form, but the viscosity is high enough, in the order of 1014 Pa*s, that any motion is in the order of mm/year.[4, 11, 29] The important difference between eutectic crystallization and vitrification is that for crystalline material, the interstitial between the ice crystal matrix consists of an intimate mixture of small crystals of ice and solute, whereas for amorphous solutes, the interstitial region consists of solid solution and unfrozen, amorphous water.[19, 23] Thus, for crystalline material nearly all water is frozen and can easily be removed during primary drying without requiring secondary drying.[19] However, for amorphous solutes, about 20% of unfrozen water is associated in the solid solution, which must be removed by a diffusion process during secondary drying.[19] Moreover, the Teu for crystalline material or the Tg` respectively Tc for amorphous material define the maximal allowable product temperature during primary drying.[19] Eutectic melting temperatures are relatively high compared to glass transition temperatures, allowing a higher product temperature during primary drying, which resu lts in more efficient drying processes.[19] If the product temperature exceeds this critical temperature crystalline melting or amorphous collapse will occur, resulting in a loss of structure in the freeze-dried product, which is termed â€Å"cake collapse†.[11, 19] 2.3 Phase separation and other types of freezing behavior A characteristic property of multicomponent aqueous solutions, especially when at least one component is a polymer, is the occurrence of a liquid-liquid phase separation during freezing into two liquid equilibrium phases, which are enriched in one component.[11, 19] This phase separation behavior has been reported for aqueous solutions of polymers such as PEG/dextran or PVP/dextran but is also reported for proteins and excipients.[32-33] When a critical concentration of the solutes is reached, the enthalpically unfavorable interactions between the solutes exceed the favorable entropy of a solution with complete miscibility.[34] Another proposed explanation is that solutes have different effects on the structure of water, leading to phase separation.[35] Besides the separation into two amorphous phases, two other types of phase separation are stated in literature; crystallization of amorphous solids and amorphization from crystalline solids.[18] Crystallization of amorphous solids often occurs when metastable glasses are formed during freezing. In this case, e.g. upon extremely fast cooling, a compound that normally would crystallize during slower freezing is entrapped as an amorphous, metastable glass in the freeze-concentrate.[12, 23] However, with subsequent heating above Tg`, it will undergo crystallization, which is the basis for annealing during freeze-drying (see 3.3).[19] Without annealing, the metastable glass can crystallize spontaneously out of the amorphous phase during drying or storage.[18] Amorphization from crystalline solids, that can be buffer components or stabilizers, predominantly occurs during the drying step and not during the freezing step.[18, 36]   Additionally, lyotropic liquid crystals, which have the degree of order between amorphous and crystalline, are reported to form as a result of freeze-concentration. However, their influence on critical quality attributes of the lyophilized product are not clarified.[19] Moreover, clathrates, also termed gas hydrates, are known to form, especially in the presence of non-aqueous co-solvents, when the solute alters the structure of the water.[23] 3. Modifications of the freezing step As aforementioned, the ice nucleation temperature defines the size, number and morphology of the ice crystals formed during freezing. Therefore, the statistical nature of ice nucleation poses a major challenge for process control during lyophilization. This highlights the importance of a controlled, reproducible and homogeneous freezing process. Several methods have been developed in order to control and optimize the freezing step. Some of them only intend to influence ice nucleation by modifying the cooling rate. Others just statistically increase the mean nucleation temperature, while a few allow a true control of the nucleation at the desired nucleation temperature. 3.1 Shelf-ramped freezing Shelf-ramped freezing is the most often employed, conventional freezing condition in lyophilization.[37] Here, at first, the filled vials are placed on the shelves of the lyophilizer and the shelf temperature is then decreased linearly (0.1 °C/min up to 5 °C/min, depending on the capacity of the lyophilizer) with time.[37-38] As both water and ice have low thermal conductivities and large heat capacities and as the thermal conductivity between vials and shelf is limited, the shelf-ramped cooling rate is by nature slow.[11] In order to ensure the complete solidification of the samples, the samples must be cooled below Tg` for amorphous material respectively below Teu for crystalline material. Traditionally, many lyophilization cycles use a final shelf temperature of -50 °C or lower, as this was the maximal cooling temperature of the freeze-drier.[7] Nowadays, it is suggested to use a final shelf temperature of -40 °C if the Tg` or Teu is higher than -38 °C or to use a temper ature of 2 °C less than Tg` and Teu.[1] Moreover, complete solidification requires significant time.[11] In general, the time for complete solidification depends on the fill volume; the larger the fill volume the more time is required for complete solidification.[11] Tang et al.[1]   suggest that the final shelf temperature should be held for 1 h for samples with a fill depth of less than or equal to 1 cm or 2 h for samples with a fill depth of greater than 1 cm. Moreover, fill depth of greater than 2 cm should be avoided, but if required, the holding time should be increased proportionately. In order to obtain a more homogeneous freezing, often the vials are equilibrated for about 15 to 30 min at a lowered shelf temperature (5 °C 10 °C) before the shelf temperature is linearly decreased.[1] Here, either the vials are directly loaded on the cooled shelves or the vials are loaded at ambient temperature and the shelf temperature is decreased to the hold temperature. [1, 5, 9] Another modification of the shelf-ramped freezing is the two-step freezing, where a â€Å"supercooling holding† is applied.(7) Here, the shelf temperature is decreased from room temperature or from a preset lowered shelf temperature to about -5 to -10 °C for 30 to 60min hold. This leads to a more homogenous supercooling state across the total fill volume.[1, 5] When the shelf temperature is then further decreased, relatively homogeneous ice formation is observed.[5] In general, shelf-ramped frozen samples show a high degree of supercooling but when the nucleation temperature is reached, ice crystal growth proceeds extremely fast, resulting in many small ice crystals.[9, 39] However, the ice nucleation cannot be directly controlled when shelf-ramped freezing is applied and is therefore quite random.[4] Thus, one drawback of shelf-ramped freezing is that different vials may become subject to different degrees of supercooling, typically about +/- 3 °C about the mean.[4] This results in a great variability in product quality and process performance.[4] Moreover, with the shelf-ramped freezing method it is not practical to manipulate the ice nucleation temperature as the cooling rates are limited inside the lyophilizer and the degree of supercooling might not change within such a small range.[1, 14] 3.2 Pre-cooled shelf method When applying the pre-cooled shelf method, the vials are placed on the lyophilizer shelf which is already cooled to the desired final shelf temperature, e.g. -40 °C or -45 °C.[1, 13-14] It is reported that the placement of samples on a pre-cooled shelf results in higher nucleation temperatures (-9,5 °C) compared to the conventional shelf-ramped freezing (-13.4 °C).[14] Moreover, with this lowered degree of supercooling and more limited time for thermal equilibration throughout the fill volume, the freezing rate after ice nucleation is actually slower compared to shelf-ramped freezing.[40]   In addition, a large heterogeneity in supercooling between vials is observed for this method.[14] A distinct influence of the loading shelf temperature on the nucleation temperature is described in literature.[13-14] Searles et al.[14] found that the nucleation temperatures for samples placed on a shelf at -44 °C were several degrees higher than for samples placed on a -40 °C shelf. Thus, when using this method the shelf temperature should be chosen with care. 3.3 Annealing Annealing is defined as a hold step at a temperature above the glass transition temperature.[12] In general, annealing is performed to allow for complete crystallization of crystalline compounds and to improve inter-vial heterogeneity and drying rates.[1, 19] Tang et al.[1] proposed the following annealing protocol: when the final shelf temperature is reached after the freezing step, the product temperature is increased to 10 to 20 °C above Tg` but well below Teu and held for several hours. Afterwards the shelf temperature is decreased to and held at the final shelf temperature. Annealing has a rigorous effect on the ice crystal size distribution [17, 41] and can delete the interdependence between the ice nucleation temperature and ice crystal size and morphology. If the sample temperature exceeds Tg`, the system pursues the equilibrium freezing curve and some of the ice melts.[12, 41] The raised water content and the increased temperature enhance the mobility of the amorphous phas e and all species in that phase.[12] This increased mobility of the amorphous phase enables the relaxation into physical states of lower free energy.[12] According to the Kelvin equation ice crystals with smaller radii of curvature will melt preferentially due to their higher free energy compared to larger ice crystals.[12, 37, 41] Ostwald ripening (recrystallization), which results in the growth of dispersed crystals larger than a critical size at the expense of smaller ones, is a consequence of these chemical potential driving forces.[12, 41] Upon refreezing of the annealed samples small ice crystals do not reform as the large ice crystals present serve as nucleation sites for addition crystallization.[41] The mean ice crystal radius rises with time1/3 during annealing.[37, 41] A consequence of that time dependency is that the inter-vial heterogeneity in ice crystal size distribution is reduced with increasing annealing time, as vials comprising smaller ice crystals â€Å"catch u p† with the vials that started annealing containing larger ice crystals.[12, 17, 37, 41] Searles et al.[41] found that due to annealing multiple sheets of lamellar ice crystals with a high surface area merged to form pseudo-cylindrical shapes with a lower interfacial area. In addition to the increase in ice crystal size, they observed that annealing opened up holes on the surface of the lyophilized cake. The hole formation is explained by the diffusion of water from melted ice crystals through the frozen matrix at the increased annealing temperature. Moreover, in the case of meta-stable glass formation of crystalline compounds, annealing facilitates complete crystallization.[42] Above Tg` the meta-stable glass is re-liquefied and crystallization occurs when enough time is provided. Furthermore, annealing can promote the completion of freeze concentration (devitrification) as it allows amorphous water to crystallize.[41] This is of importance when samples were frozen too fast a nd water capable of crystallization was entrapped as amorphous water in the glassy matrix. In addition, the phenomenon of annealing also becomes relevant when samples are optimal frozen but are then kept at suboptimal conditions in the lyophilizer or in a freezer before lyophilization is performed.[11] 3.4 Quench freezing During quench freezing, also referred to as vial immersion, the vials are immersed into either liquid nitrogen or liquid propane (ca. -200 °C) or a dry ice/ acetone or dry ice/ ethanol bath (ca. -80 °C) long enough for complete solidification and then placed on a pre-cooled shelf.[9, 16] In this case the heat-transfer media is in contact with both the vial bottom and the vial wall [10], leading to a ice crystal formation that starts at the vial wall and bottom. This freezing method results in a lowered degree of supercooling but also a high freezing rate as the sample temperature is decreased very fast, resulting in small ice crystals. Liquid nitrogen immersion has been described to induce less supercooling than slower methods [9, 37, 39] , but more precise this faster cooling method induces supercooling only in a small sample volume before nucleation starts and freezes by directional solidification.[12, 14]   While it is reported that external quench freezing might be advantag eous for some applications [39], this uncontrolled freezing method promotes heterogeneous ice crystal formation and is not applicable in large scale manufacturing.[7] 3.5 Directional freezing In order to generate straight, vertical ice crystallization, directional respectively vertical freezing can be performed. Here, ice nucleation is induced at the bottom of the vial by contact with dry ice and slow freezing on a pre-cooled shelf is followed.[9] In this case, the ice propagation is vertically and lamellar ice crystals are formed.[9] A similar approach, called unidirectional solidification, was described by Schoof et al. [43]. Here each sample was solidified in a gradient freezing stage, based on the Power-Down principle, with a temperature gradient between the upper and the lower cooling stage of 50 K/cm, resulting in homogenous ice-crystal morphology. 3.6 Ice-fog technique In 1990, Rowe [44] described an ice-fog technique for the controlled ice nucleation during freezing. After the vials are cooled on the lyophilizer shelf to the desired nucleation temperature, a flow of cold nitrogen is led into the chamber. The high humidity of the chamber generates an ice fog, a vapor suspension of small ice particles. The ice fog penetrates into the vials, where it initiates ice nucleation at the solutio Physico-chemical Processes that Occur During Freezing Physico-chemical Processes that Occur During Freezing 1. Introduction Lyophilization respectively freeze-drying is an important and well-established process to improve the long-term stability of labile drugs, especially therapeutic proteins.[1] About 50% of the currently marketed biopharmaceuticals are lyophilized, representing the most common formulation strategy.[2] In the freeze-dried solid state chemical or physical degradation reactions are inhibited or sufficiently decelerated, resulting in an improved long-term stability.[3] Besides the advantage of better stability, lyophilized formulations also provide easy handling during shipping and storage. [1] A traditional lyophilization cycle consists of three steps; freezing, primary drying and secondary drying.[1] During the freezing step, the liquid formulation is cooled until ice starts to nucleate, which is followed by ice growth, resulting in a separation of most of the water into ice crystals from a matrix of glassy and/or crystalline solutes.[4-5] During primary drying, the crystalline ice formed during freezing is removed by sublimation. Therefore, the chamber pressure is reduced well below the vapor pressure of ice and the shelf temperature is raised to supply the heat removed by ice sublimation.[6] At the completion of primary drying, the product can still contain approximately 15% to 20% of unfrozen water, which is desorbed during the secondary drying stage, usually at elevated temperature and low pressure, to finally achieve the desired low moisture content.[7] In general, lyophilization is a very time- and energy-intensive drying process.[8]   Typically, freezing is over within a few hours while drying often requires days. Within the drying phase, secondary drying is short (~hours) compared to primary drying (~days).[1, 4] Therefore, lyophilization cycle development has typically focused on optimizing the primary drying step, i.e., shortening the primary drying time by adjusting the shelf temperature and/or chamber pressure without influencing product quality.[5, 9] Although, freezing is one of the most critical stages during lyophilization, the importance of the freezing process has rather been neglected in the past.[10]   The freezing step is of paramount importance. At first, freezing itself is the major desiccation step in lyophilization [6] as solvent water is removed from the liquid formulation in the form of a pure solid ice phase, leading to a dramatic concentration of the solutes.[11-12] Moreover, the kinetics of ice nucleation and crystal growth determine the physical state and morphology of the frozen cake and consequently the final properties of the freeze-dried product.[11-13] Ice morphology is directly correlated with the rate of sublimation in primary and secondary drying.[14] In addition, freezing is a critical step with regard to the biological activity and stability of the active pharmaceutical ingredients (API), especially pharmaceutical proteins.[1] While simple in concept, the freezing process is presumably the most complex but also the most important step in the lyophilization process.[10] To meet this challenge, a thorough understanding of the physico-chemical processes, which occur during freezing, is required. Moreover, in order to optimize the freeze drying process and product quality, it is vital to control the freezing step, which is challenging because of the random nature of ice nucleation. However, several approaches have been developed to trigger ice nucleation during freezing. The purpose of this review is to provide the reader with an awareness of the importance but also complexity of the physico-chemical processes that occur during freezing. In addition, currently available freezing techniques are summarized and an attempt is made to address the consequences of the freezing procedure on process performance and product quality. A special focus is set on the critical factors that influence protein stability. Understanding and controlling the freezing step in lyophilization will lead to optimized, more efficient lyophilization cycles and products with an improved stability. 2. Physico-chemical fundamentals of freezing The freezing process first involves the cooling of the solution until ice nucleation occurs. Then ice crystals begin to grow at a certain rate, resulting in freeze concentration of the solution, a process that can result in both crystalline and amorphous solids, or in mixtures.[11] In general, freezing is defined as the process of ice crystallization from supercooled water.[15] The following section summarizes the physico-chemical fundamentals of freezing. At first, the distinction between cooling rate and freezing rate should be emphasized. The cooling rate is defined as the rate at which a solution is cooled, whereas the freezing rate is referred to as the rate of postnucleation ice crystal growth, which is largely determined by the amount of supercooling prior to nucleation.[16-17] Thus, the freezing rate of a formulation is not necessarily related to its cooling rate.[18] 2.1 Freezing phenomena: supercooling, ice nucleation and ice crystal formation In order to review the physico-chemical processes that occur during freezing of pure water, the relationship between time and temperature during freezing is displayed in figure 1. When pure water is cooled at atmospheric pressure, it does not freeze spontaneously at its equilibrium freezing point (0 °C).[19] This retention of the liquid state below the equilibrium freezing point of the solution is termed as â€Å"supercooling†.[19] Supercooling (represented by line A) always occurs during freezing and is often in the range of 10 to 15 °C or more.[12, 18] The degree of supercooling is defined as the difference between the equilibrium ice formation temperature and the actual temperature at which ice crystals first form and depends on the solution properties and process conditions.[1, 6, 11, 20] As discussed later, it is necessary to distinguish between â€Å"global supercooling†, in which the entire liquid volume exhibits a similar level of supercooling, and â€Å"lo cal supercooling†, in which only a small volume of the liquid is supercooled.[14] Supercooling is a non-equilibrium, meta-stable state, which is similar to an activation energy necessary for the nucleation process.[21] Due to density fluctuations from Brownian motion in the supercooled liquid water, water molecules form clusters with relatively long-living hydrogen bonds [22] almost with the same molecular arrangement as in ice crystals.[11, 15] As this process is energetically unfavorable, these clusters break up rapidly.[15] The probability for these nuclei to grow in both number and size is more pronounced at lowered temperature.[15] Once the critical mass of nuclei is reached, ice crystallization occurs rapidly in the entire system (point B).[15, 21-22]   The limiting nucleation temperature of water appears to be at about -40 °C, referred to as the â€Å"homogeneous nucleation temperature†, at which the pure water sample will contain at least one spontaneously f ormed active water nucleus, capable of initiating ice crystal growth.[11] However, in all pharmaceutical solutions and even in sterile-filtered water for injection, the nucleation observed is â€Å"heterogeneous nucleation†, meaning that ice-like clusters are formed via adsorption of layers of water on â€Å"foreign impurities†.[6, 11] Such â€Å"foreign impurities† may be the surface of the container, particulate contaminants present in the water, or even sites on large molecules such as proteins.[23-24] Primary nucleation is defined as the initial, heterogeneous ice nucleation event and it is rapidly followed by secondary nucleation, which moves with a front velocity on the order of mm/s through the solution. [14, 25] Often secondary nucleation is simply referred to as ice crystallization, and the front velocity is sometime referred to as the crystallization linear velocity.[14] Once stable ice crystals are formed, ice crystal growth proceeds by the addition of molecules to the interface.[22] However, only a fraction of the freezable water freezes immediately, as the supercooled water can absorb only 15cal/g of the 79cal/g of heat given off by the exothermic ice formation.[12, 22] Therefore, once crystallization begins, the product temperature rises rapidly to near the equilibrium freezing point.[12, 26] After the initial ice network has formed (point C), additional heat is removed from the solution by further cooling and the remaining water freezes when the previously formed ice crystals grow.[12] The ice crystal growth is controlled by the latent heat release and the cooling rate, to which the sample is exposed to.[22] The freezing time is defined as the time from the completed ice nucleation to the removal of latent heat (from point C to point D). The temperature drops when the freezing of the sample is completed (point E).[21] The number of ice nuclei formed, the rate of ice growth and thus the ice crystals` size depend on the degree of supercooling.[14, 20] The higher the degree of supercooling, the higher is the nucleation rate and the faster is the effective rate of freezing, resulting in a high number of small ice crystals. In contrast, at a low degree of supercooling, one observes a low number of large ice crystals.[14, 19] The rate of ice crystal growth can be expressed as a function of the degree of supercooling.[23]   For example for water for injection, showing a degree of supercooling of 10 °C +/- 3 °C, an ice crystal growth rate of about   5.2cm/s results.[23] In general, a slower cooling rate leads to a faster freezing rate and vice versa. Thus, in case of cooling rate versus freezing rate it has to be kept in mind â€Å"slow is fast and fast is slow†. Nevertheless, one has to distinguish between the two basic freezing mechanisms. When global supercooling occurs, which is typically the case for shelf-ramped freezing, the entire liquid volume achieves a similar level of supercooling and solidification progresses through the already nucleated volume.[12, 14] In contrast, directional solidification occurs when a small volume is supercooled, which is the case for high cooling rates, e.g. with nitrogen immersion. Here, the nucleation and solidification front are in close proximity in space and time and move further into non-nucleated solution. In this case, a faster cooling rate will lead to a faster freezing rate.[12, 14] Moreover, as ice nucleation is a stochastically event [6, 18], ice nucleation and in consequence ice crystal size distribution will differ from vial to vial resulting in a huge sample heterogeneity within one batch.[6, 14, 27] In addition, during freezing the growth of ice crystals within one vial can also be heterogeneous, influencing intra-vial uniformity.[5] Up to now, 10 polymorphic forms of ice are described. However, at temperatures and pressures typical for lyophilization, the stable crystal structure of ice is limited to the hexagonal type, in which each oxygen atom is tetrahedrally surrounded by four other oxygen atoms.[23] The fact that the ice crystal morphology is a unique function of the nucleation temperature was first reported by Tammann in 1925.[28] He found that frozen samples appeared dendritic at low supercoolings and like â€Å"crystal filaments† at high supercooling. In general, three different types of growth of ice crystals around nuclei can be observed in solution[15]: i) if the water molecules are given sufficient time, they arrange themselves regularly into hexagonal crystals, called dendrites; ii) if the water molecules are incorporated randomly into the crystal at a fast rate, â€Å"irregular dendrites† or axial columns that originate from the center of crystallization are formed; iii) at higher coo ling rates, many ice spears originate from the center of crystallization without side branches, referred to as spherulites. However, the ice morphology depends not only on the degree of supercooling but also on the freezing mechanism. It is reported that â€Å"global solidification† creates spherulitic ice crystals, whereas â€Å"directional solidification† results in directional lamellar morphologies with connected pores.[12, 14] While some solutes will have almost no effect on ice structure, other solutes can affect not only the ice structure but also its physical properties.[19] Especially at high concentrations, the presence of solutes will result in a depression of the freezing point of the solution based on Raoults`s Law and in a faster ice nucleation because of the promotion of heterogeneous nucleation, leading to a enormously lowered degree of supercooling.[21] 2.2 Crystallization and vitrification of solutes The hexagonal structure of ice is of paramount importance in lyophilization of pharmaceutical formulations, because most solutes cannot fit in the dense structure of the hexagonal ice, when ice forms.[23] Consequently, the concentration of the solute constituents of the formulation is increased in the interstitial region between the growing ice crystals, which is referred to as â€Å"cryoconcentration†.[11-12] If this separation would not take place, a solid solution would be formed, with a greatly reduced vapor pressure and the formulation cannot be lyophilized.[23] The total solute concentration increases rapidly and is only a function of the temperature and independent of the initial concentration.[4] For example, for an isotonic saline solution a 20-fold concentration increase is reported when cooled to -10 °C and all other components in a mixture will show similar concentration increases.[4] Upon further cooling the solution will increase to a critical concentration, ab ove which the concentrated solution will either undergo eutectic freezing or vitrification.[7] A simple behavior is crystallization of solutes from cryoconcentrated solution to form an eutectic mixture.[19] For example, mannitol, glycine, sodium chloride and phosphate buffers are known to crystallize upon freezing, if present as the major component.[12] When such a solution is cooled, pure ice crystals will form first. Two phases are present, ice and freeze-concentrated solution. The composition is determined via the equilibrium freezing curve of water in the presence of the solute (figure 2). The system will then follow the specific equilibrium freezing curve, as the solute content increases because more pure water is removed via ice formation. At a certain temperature, the eutectic melting temperature (Teu), and at a certain solute concentration (Ceu), the freezing curve will meet the solubility curve. Here, the freeze concentrate is saturated and eutectic freezing, which means solute crystallization, will occur.[7, 19] Only below Teu, which is defined as the lowest temperat ure at which the solute remains a liquid the system is completely solidified.[19] The Teu and Ceu are independent of the initial concentration of the solution.[7] In general, the lower the solubility of a given solute in water, the higher is the Teu.[19] For multicomponent systems, a general rule is that the crystallization of any component is influenced, i.e. retarded, by other components.[11] In practice, analogous to the supercooling of water, only a few solutes will spontaneously crystallize at Teu.[11] Such delayed crystallization of solutes from a freezing solution is termed supersaturation and can lead to an even more extreme freeze concentration.[11] Moreover, supersaturation can inhibit complete crystallization leading to a meta-stable glass formation, e.g. of mannitol.[12, 23] In addition, it is also possible that crystalline states exist in a mixture of different polymorphs or as hydrates.[11] For example, mannitol can exist in the form of several polymorphs (a, b and d) und under certain processing conditions, it can crystallize as a monohydrate.[11] The phase behavior is totally different for polyhydroxy compounds like sucrose, which do not crystallize at all from a freezing solution in real time.[11] The fact that sucrose does not crystallize during freeze-concentration is an indication of its extremely complex crystal structure.[11] The interactions between sugar -OH groups and those between sugar -OH groups and water molecules are closely similar in energy and configuration, resulting in very low nucleation probabilities.[11] In this case, water continues to freeze beyond the eutectic melting temperature and the solution becomes increasingly supersaturated and viscous.[11] The increasing viscosity slows down ice crystallization, until at some characteristic temperature no further freezing occurs.[11] This is called glassification or vitrification.[18]   The temperature at which the maximal freeze-concentration (Cg`) occurs is referred to as the glass transition temperature Tg`.[11, 29] This point is at the intersection of t he freezing point depression curve and the glass transition or isoviscosity curve, described in the â€Å"supplemented phase diagram† [30] or â€Å"state diagram† (figure 2).[11] Tg ´ is the point on the glass transition curve, representing a reversible change between viscous, rubber-like liquid and rigid, glass system.[19] In the region of the glass transition, the viscosity of the freeze concentrate changes about four orders of magnitude over a temperature range of a few degrees.[19] Tg` depends on the composition of the solution, but is independent of the initial concentration.[4, 11, 27]   For example, for the maximally freeze concentration of sucrose a concentration of 72-73% is reported.[31] In addition to Tg` the collapse temperature (Tc) of a product is used to define more precisely the temperature at which a structural loss of the product will occur. In general Tc is several degrees higher than Tg`, as the high viscosity of the sample close to Tg` will pre vent .[10] The glassy state is a solid solution of concentrated solutes and unfrozen, amorphous water. It is thermodynamically unstable with respect to the crystal form, but the viscosity is high enough, in the order of 1014 Pa*s, that any motion is in the order of mm/year.[4, 11, 29] The important difference between eutectic crystallization and vitrification is that for crystalline material, the interstitial between the ice crystal matrix consists of an intimate mixture of small crystals of ice and solute, whereas for amorphous solutes, the interstitial region consists of solid solution and unfrozen, amorphous water.[19, 23] Thus, for crystalline material nearly all water is frozen and can easily be removed during primary drying without requiring secondary drying.[19] However, for amorphous solutes, about 20% of unfrozen water is associated in the solid solution, which must be removed by a diffusion process during secondary drying.[19] Moreover, the Teu for crystalline material or the Tg` respectively Tc for amorphous material define the maximal allowable product temperature during primary drying.[19] Eutectic melting temperatures are relatively high compared to glass transition temperatures, allowing a higher product temperature during primary drying, which resu lts in more efficient drying processes.[19] If the product temperature exceeds this critical temperature crystalline melting or amorphous collapse will occur, resulting in a loss of structure in the freeze-dried product, which is termed â€Å"cake collapse†.[11, 19] 2.3 Phase separation and other types of freezing behavior A characteristic property of multicomponent aqueous solutions, especially when at least one component is a polymer, is the occurrence of a liquid-liquid phase separation during freezing into two liquid equilibrium phases, which are enriched in one component.[11, 19] This phase separation behavior has been reported for aqueous solutions of polymers such as PEG/dextran or PVP/dextran but is also reported for proteins and excipients.[32-33] When a critical concentration of the solutes is reached, the enthalpically unfavorable interactions between the solutes exceed the favorable entropy of a solution with complete miscibility.[34] Another proposed explanation is that solutes have different effects on the structure of water, leading to phase separation.[35] Besides the separation into two amorphous phases, two other types of phase separation are stated in literature; crystallization of amorphous solids and amorphization from crystalline solids.[18] Crystallization of amorphous solids often occurs when metastable glasses are formed during freezing. In this case, e.g. upon extremely fast cooling, a compound that normally would crystallize during slower freezing is entrapped as an amorphous, metastable glass in the freeze-concentrate.[12, 23] However, with subsequent heating above Tg`, it will undergo crystallization, which is the basis for annealing during freeze-drying (see 3.3).[19] Without annealing, the metastable glass can crystallize spontaneously out of the amorphous phase during drying or storage.[18] Amorphization from crystalline solids, that can be buffer components or stabilizers, predominantly occurs during the drying step and not during the freezing step.[18, 36]   Additionally, lyotropic liquid crystals, which have the degree of order between amorphous and crystalline, are reported to form as a result of freeze-concentration. However, their influence on critical quality attributes of the lyophilized product are not clarified.[19] Moreover, clathrates, also termed gas hydrates, are known to form, especially in the presence of non-aqueous co-solvents, when the solute alters the structure of the water.[23] 3. Modifications of the freezing step As aforementioned, the ice nucleation temperature defines the size, number and morphology of the ice crystals formed during freezing. Therefore, the statistical nature of ice nucleation poses a major challenge for process control during lyophilization. This highlights the importance of a controlled, reproducible and homogeneous freezing process. Several methods have been developed in order to control and optimize the freezing step. Some of them only intend to influence ice nucleation by modifying the cooling rate. Others just statistically increase the mean nucleation temperature, while a few allow a true control of the nucleation at the desired nucleation temperature. 3.1 Shelf-ramped freezing Shelf-ramped freezing is the most often employed, conventional freezing condition in lyophilization.[37] Here, at first, the filled vials are placed on the shelves of the lyophilizer and the shelf temperature is then decreased linearly (0.1 °C/min up to 5 °C/min, depending on the capacity of the lyophilizer) with time.[37-38] As both water and ice have low thermal conductivities and large heat capacities and as the thermal conductivity between vials and shelf is limited, the shelf-ramped cooling rate is by nature slow.[11] In order to ensure the complete solidification of the samples, the samples must be cooled below Tg` for amorphous material respectively below Teu for crystalline material. Traditionally, many lyophilization cycles use a final shelf temperature of -50 °C or lower, as this was the maximal cooling temperature of the freeze-drier.[7] Nowadays, it is suggested to use a final shelf temperature of -40 °C if the Tg` or Teu is higher than -38 °C or to use a temper ature of 2 °C less than Tg` and Teu.[1] Moreover, complete solidification requires significant time.[11] In general, the time for complete solidification depends on the fill volume; the larger the fill volume the more time is required for complete solidification.[11] Tang et al.[1]   suggest that the final shelf temperature should be held for 1 h for samples with a fill depth of less than or equal to 1 cm or 2 h for samples with a fill depth of greater than 1 cm. Moreover, fill depth of greater than 2 cm should be avoided, but if required, the holding time should be increased proportionately. In order to obtain a more homogeneous freezing, often the vials are equilibrated for about 15 to 30 min at a lowered shelf temperature (5 °C 10 °C) before the shelf temperature is linearly decreased.[1] Here, either the vials are directly loaded on the cooled shelves or the vials are loaded at ambient temperature and the shelf temperature is decreased to the hold temperature. [1, 5, 9] Another modification of the shelf-ramped freezing is the two-step freezing, where a â€Å"supercooling holding† is applied.(7) Here, the shelf temperature is decreased from room temperature or from a preset lowered shelf temperature to about -5 to -10 °C for 30 to 60min hold. This leads to a more homogenous supercooling state across the total fill volume.[1, 5] When the shelf temperature is then further decreased, relatively homogeneous ice formation is observed.[5] In general, shelf-ramped frozen samples show a high degree of supercooling but when the nucleation temperature is reached, ice crystal growth proceeds extremely fast, resulting in many small ice crystals.[9, 39] However, the ice nucleation cannot be directly controlled when shelf-ramped freezing is applied and is therefore quite random.[4] Thus, one drawback of shelf-ramped freezing is that different vials may become subject to different degrees of supercooling, typically about +/- 3 °C about the mean.[4] This results in a great variability in product quality and process performance.[4] Moreover, with the shelf-ramped freezing method it is not practical to manipulate the ice nucleation temperature as the cooling rates are limited inside the lyophilizer and the degree of supercooling might not change within such a small range.[1, 14] 3.2 Pre-cooled shelf method When applying the pre-cooled shelf method, the vials are placed on the lyophilizer shelf which is already cooled to the desired final shelf temperature, e.g. -40 °C or -45 °C.[1, 13-14] It is reported that the placement of samples on a pre-cooled shelf results in higher nucleation temperatures (-9,5 °C) compared to the conventional shelf-ramped freezing (-13.4 °C).[14] Moreover, with this lowered degree of supercooling and more limited time for thermal equilibration throughout the fill volume, the freezing rate after ice nucleation is actually slower compared to shelf-ramped freezing.[40]   In addition, a large heterogeneity in supercooling between vials is observed for this method.[14] A distinct influence of the loading shelf temperature on the nucleation temperature is described in literature.[13-14] Searles et al.[14] found that the nucleation temperatures for samples placed on a shelf at -44 °C were several degrees higher than for samples placed on a -40 °C shelf. Thus, when using this method the shelf temperature should be chosen with care. 3.3 Annealing Annealing is defined as a hold step at a temperature above the glass transition temperature.[12] In general, annealing is performed to allow for complete crystallization of crystalline compounds and to improve inter-vial heterogeneity and drying rates.[1, 19] Tang et al.[1] proposed the following annealing protocol: when the final shelf temperature is reached after the freezing step, the product temperature is increased to 10 to 20 °C above Tg` but well below Teu and held for several hours. Afterwards the shelf temperature is decreased to and held at the final shelf temperature. Annealing has a rigorous effect on the ice crystal size distribution [17, 41] and can delete the interdependence between the ice nucleation temperature and ice crystal size and morphology. If the sample temperature exceeds Tg`, the system pursues the equilibrium freezing curve and some of the ice melts.[12, 41] The raised water content and the increased temperature enhance the mobility of the amorphous phas e and all species in that phase.[12] This increased mobility of the amorphous phase enables the relaxation into physical states of lower free energy.[12] According to the Kelvin equation ice crystals with smaller radii of curvature will melt preferentially due to their higher free energy compared to larger ice crystals.[12, 37, 41] Ostwald ripening (recrystallization), which results in the growth of dispersed crystals larger than a critical size at the expense of smaller ones, is a consequence of these chemical potential driving forces.[12, 41] Upon refreezing of the annealed samples small ice crystals do not reform as the large ice crystals present serve as nucleation sites for addition crystallization.[41] The mean ice crystal radius rises with time1/3 during annealing.[37, 41] A consequence of that time dependency is that the inter-vial heterogeneity in ice crystal size distribution is reduced with increasing annealing time, as vials comprising smaller ice crystals â€Å"catch u p† with the vials that started annealing containing larger ice crystals.[12, 17, 37, 41] Searles et al.[41] found that due to annealing multiple sheets of lamellar ice crystals with a high surface area merged to form pseudo-cylindrical shapes with a lower interfacial area. In addition to the increase in ice crystal size, they observed that annealing opened up holes on the surface of the lyophilized cake. The hole formation is explained by the diffusion of water from melted ice crystals through the frozen matrix at the increased annealing temperature. Moreover, in the case of meta-stable glass formation of crystalline compounds, annealing facilitates complete crystallization.[42] Above Tg` the meta-stable glass is re-liquefied and crystallization occurs when enough time is provided. Furthermore, annealing can promote the completion of freeze concentration (devitrification) as it allows amorphous water to crystallize.[41] This is of importance when samples were frozen too fast a nd water capable of crystallization was entrapped as amorphous water in the glassy matrix. In addition, the phenomenon of annealing also becomes relevant when samples are optimal frozen but are then kept at suboptimal conditions in the lyophilizer or in a freezer before lyophilization is performed.[11] 3.4 Quench freezing During quench freezing, also referred to as vial immersion, the vials are immersed into either liquid nitrogen or liquid propane (ca. -200 °C) or a dry ice/ acetone or dry ice/ ethanol bath (ca. -80 °C) long enough for complete solidification and then placed on a pre-cooled shelf.[9, 16] In this case the heat-transfer media is in contact with both the vial bottom and the vial wall [10], leading to a ice crystal formation that starts at the vial wall and bottom. This freezing method results in a lowered degree of supercooling but also a high freezing rate as the sample temperature is decreased very fast, resulting in small ice crystals. Liquid nitrogen immersion has been described to induce less supercooling than slower methods [9, 37, 39] , but more precise this faster cooling method induces supercooling only in a small sample volume before nucleation starts and freezes by directional solidification.[12, 14]   While it is reported that external quench freezing might be advantag eous for some applications [39], this uncontrolled freezing method promotes heterogeneous ice crystal formation and is not applicable in large scale manufacturing.[7] 3.5 Directional freezing In order to generate straight, vertical ice crystallization, directional respectively vertical freezing can be performed. Here, ice nucleation is induced at the bottom of the vial by contact with dry ice and slow freezing on a pre-cooled shelf is followed.[9] In this case, the ice propagation is vertically and lamellar ice crystals are formed.[9] A similar approach, called unidirectional solidification, was described by Schoof et al. [43]. Here each sample was solidified in a gradient freezing stage, based on the Power-Down principle, with a temperature gradient between the upper and the lower cooling stage of 50 K/cm, resulting in homogenous ice-crystal morphology. 3.6 Ice-fog technique In 1990, Rowe [44] described an ice-fog technique for the controlled ice nucleation during freezing. After the vials are cooled on the lyophilizer shelf to the desired nucleation temperature, a flow of cold nitrogen is led into the chamber. The high humidity of the chamber generates an ice fog, a vapor suspension of small ice particles. The ice fog penetrates into the vials, where it initiates ice nucleation at the solutio