Midterm report ISTD Essay

This project is designed to make an in-depth study and critical analysis of HR aspects in MedTek.Net India Pvt Ltd. At this point in the project, it reports about the progress we made in analyzing theR training aspects and the progress it made towards its goals; describe obstacles (both internal& external) faced; detail work accomplished and actions to be taken in the future. During the process of project, we got to know and notice lot many interesting facts and points which are really important for the growth and success of the organization. It gave an opportunity for the HR department to  audit the entire HRD aspects of the organization there by adding more value to way we operate. At the end of this project, all parties of the organization; Management, employees, HR department are eager to know more about the findings and improvements that we can make to the organization from the HRD prospect which can bring an edge to the company when compared to our competitors in the market. Below pages of this report offers a brief description about the analysis and work we have done so far in this project. Introduction: Within every organization, there is a need to manage learning in accordance with business requirements. A systematic approach in training and development always adds an edge to the performance of the organization in all means. Objective: Objective of this project is to do complete analysis on the below training aspects, their performance impact and recommendations for betterment of the organization. a) Human Resource Planning, Training Policy, Training Budget. b) Training Needs Assessment System. c) Training & other Development Programmes and their evaluation. d) Strategies for improving HRD activities in the Organization. With our analysis, findings & recommendations, our attempt is to provide viable propositions for betterment in the applicable areas of organization. In this process, we have collected all recorded data like policies, questionnaires, processes followed etc and live data like interviews and one on one discussion with various employees of different departments and external data like market scenario, industry analysis etc. Project Design: We have designed the project in to four phases. 1. Collecting basic data and information related to all training aspects. 2.  Analyzing data, processes and drawing findings for their evaluation procedure. 3. Evaluating the information and processes of various data analyzed. 4. Recommending strategies for the improvement of HRD activities with the help of above in the organization. For any company, training and development is an important aspect which boosts continuous growth and success to the business. We have considered all external and internal components of the existing performance of the organization with respect to the targeted objectives set. Some of the components include absenteeism, work hours of the employee’s w.r.t their performance, performance of the software (IPAS – Integrated Performance Appraisal System) which was initiated recently, employee hiring and job enrichment strategies used for retaining the existing employees, HRD activities practiced for long term growth of the organization etc. Project Implementation We started implementing the project by collating data available from all sources. Simultaneously we started working with people as well by circulating questionnaires and by conducting one on one discussion. Below explanation will give us a brief of what we have studied and analyzed in this process with the help of both data and people. HRD System: Human Resource Planning, Training Policy, Training Budget. Human Resource Planning At MedTek.Net we measure the growth of business by the no of minutes and reports we process per year. Therefore our target of business growth lies in the same and accordingly we plan for resources to recruit per year, it includes both fresher’s and experienced resources. MedTek HR planning for the period of 2012-2013 is focused on the below points to achieve during this time. Below points are analyzed after a detailed discussion with people in the company and after going through the information/data which is all available. 1. Work closely with management to reinforce the need for competitive compensation for individuals MedTek wishes to attract and retain. 2. Invest  in professional development programs to improve leadership capabilities, job skills, and employee productivity. 3. Identifying and attracting right talent at campus level thereby training and employing them in the organization accordingly. 4. Develop comprehensive career management tools, job enrichment strategies, and mentoring programs to help employees prepare for new opportunities. 5. Leverage technology to streamline HR service processes and improve access to employee information. 6. Conduct regular organizational climate assessments and collaborate with senior managers to improve the campus work climate. Review of training policy & budget: As MedTek.Net is a mid sized company they do not really have a fixed annual budget for training. The budget varies as per the requirement and situation of the company although getting approved prior by management. But, with in the limitation HR department tried to encompass the training programs which align the company’s goals and objectives of employee development. Some of the cost effective measures which got imparted in the training budget are: 1. Finding trainers with in the organization wherever it is necessary and possible. 2. Imparting self learning techniques for the employees which not only reduces costs but also helps employees to work on their skills by focusing on their weaknesses and strengths. 3. Encouraging the technique of cross-train employees at work place. This technique really worked at MedTek as employees showed great interest to share their knowledge. It is happening in this way; 2nd level employees train 1st level employees and 2nd level employees will g et trained by their above level i.e. 3rd level employees and vice-versa. Keeping in view of budget constraints and business requirements training policy of Medtek for the year 2012-13 aims to ensure that 1. All new members of staff receive an induction training programme that achieves the common company induction standards. 2. Company invests in training that helps to meet its goals of providing a quality service, which are achieved by increasing the knowledge and skills and competencies of its staff to meet the needs of quality service standards set. 3. All staff has  an annual appraisal which, amongst other matters, reviews all training undertaken and sets goals for the coming year based on the individual training needs assessment. 4. All staff are provided with an annual personal training file, which they will keep. In the file they include details of all training sessions that they attend. The file should also contain a personal development plan filled in at the same time as the appraisal. The personal development plan contains details of any training opportunities that the member of staff seeks to pursue during the year. At MedTek, Training policy and Training budget got framed by keeping in view of companies annual HR planning and business growth. Keeping in view of companies strengths and weaknesses these three components got designed and in the continuous process slight deviation(more or less) is always there to align with industry and market changes and requirements. Analysis on Training needs Identification and Assessment process: Up on detailed analysis and review Training Identification & Assessment process at MedTek usually happens by following the below steps: 1. Data Gathering: One on One discussion with Managers/ Supervisors/ employees, performance Mgmt software, knowledge/ skill test to the employees, questionnaires etc. 2. Post assessing the need, HR department designs a module defining the purpose of the need, target group, resource person and the deliverables. 3. Defining the deliverables and methodology to measure the deliverables are very critical while identifying the need. 4. Training Need Validation: After identifying the list of training needs, the same will be listed and discussed with functional heads of all departments. During this exercise, the relevance of each training need with the forthcoming financial year and the business requirement to be validated. 5. Training Need Prioritization: The training needs identified will be then categorized as high impact and low impact / high cost and low cost. 6. The deliverables of the training needs which may likely to create High Impact on the business with Low Cost will be given fir st priority. The training needs with High Impact and High Cost will be given 2nd Priority and the training needs with Low Impact and Low Cost will be given 3rd Priority. Review and analysis of 2012-2013 annual Training programs planned & conducted: The training programs conducted on continuous basis for the year 2012-2013 at MedTek.Net are mentioned as below: 1. Induction for new joinees- Technical Training, Behavioral Training, HR induction. 2. Technical Training – To all employees designation wise for knowledge and skill improvement. 3. Management Development Sessions – Workshops for the existing managers and potential employees who are identified for promotions. 4. Soft skills and Personality Development Training programs – For the identified team members of different departments. 5. Sponsoring some training workshops for the identified team members which were conducted outside the company premises. T&D activities which left impact towards improvement & development of both the parties i.e. employees & the organization. Employees: Entry Level: Employees at entry level got highly benefited with induction training program as it includes both soft skills, technical and company policies related training. The best part of this training is each employee after training session will be associated with one senior employee as their mentor for 1 month and on-the job assistance/training will be given to them till they get accommodated with the work life at MedTek. It is the responsibility of the mentor to make the new employee comfortable and feedback from the new employee at the end of the mentorship will be taken and will be added to the performance points of the senior employee. This process got succeeded and is yielding some great results so far. Mid Level: Technical Training and personality development programs are popular in this segment of employees at MedTek. Providing mentorship to new employees is also popular as it inculcates self learning process and adds performance points. Proof Readers and Quality Controllers generally comes in to the segment of mid level employees at MedTek. They need high technical knowledge  and skill as they are responsible for the final delivery of report to the clients. Therefore self learning technique and technical training plays a great role for their knowledge and skill improvement. Supervisors and Managers: Management Development sessions which got conducted at both indoor and outdoor left a visible impact in their skill development. In the company where stress and pressure rules, these sessions helped a lot for the managers and supervisors to handle the team members and stress. Organization: As an organization MedTek is able to see advantages in various ways as below: Performance of new recruits got improved and are delivering their full capacity of performance. Quality standard got improved and are getting some good satisfaction mails from the clients about the quality and TAT (Turn Around Time). Management sessions helped the organization to polish and train the employees who are identified to elevate for the next level mgmt positions at different levels. Overall on a note of conclusion, training programs which got implemented are able to deliver clear return on investment for both employees and organization. The success rate is clearly visible and is encouraging for both HR department and management to continue the training programs in a more effective manner for the growth of organization Analysis of T&D evaluation techniques up on which the organization is relying in terms of measuring the outcomes of the T & D programs implemented & planned. At MedTek, training evaluation is done keeping in view of five main elements as mentioned below: Satisfaction and participant reaction, with the help of questionnaires and random one on one discussion. MedTek, also has internal portal where the participants can post their feedback wrt training sessions attended. Knowledge acquisition- This can be evaluated by the scores they get in the technical tests which are conducted very often in the office premises.  Behavioral application – This can be observed eventually and often immediate supervisors or mentors are responsible for recording any change in their behavioral aspects during the course of time. Return on investment (ROI) – Each individual performance in terms of increase in number of minutes they process can be considered to evaluate ROI. Measurable business improvement – Improvement in all four parameters collectively contribute towards business improvement. Keeping in view of the above five elements, below mentioned evaluation techniques are often used at MedTek. 1. Kirkpatrick’s training evaluation model. 2. Robert O Brinkerhoff- The Success Case method 3. The IPO model (Input, Process, Output) 4. Jack Philips Return On Investment HR department pick a combination of one or two from the above models for evaluation process and the evaluation process happen in 3 phases; Pre Training, During the training and Post Training. Results of training evaluation are submitted to senior management and some points of evaluation are accessible to employees as well through portal. Project outputs Management of MedTek.Net is very keen about this project as it gives an opportunity to analyze the entire process of T & D processes we have been conducting every year. It gave an opportunity to observe, compare and study T&D processes and systems other competitors are practicing in the industry. Below are few outputs so far turned up in the project. 1. Because of budget constraints they have challenges in hiring the no’s they require and this could effect the effective HR planning. HR department need to come up with some new strategies to fulfill the requirement of manpower with in the budget. MedTeK HR department was able to succeed so far but, in order to survive for long term they have to plan some strong strategies which can help them for some good no of years. 2. Employees at MedTek are happy with the training programs going on in the company when compared to some of the fellow companies from the same industry. 3. The challenge for both  employees and HR dept is volume fluctuation. The amount of work that they get on any day is often fluctuating and this could really affect the training schedules planned. For HR dept it is a challenging task, as they need to make the employees still connect with the training programs and need to constantly motivate them on this regard. 4. Management wants cost effective hiring or less hiring with out increasing operational costs but operations team demands more head count. 5. So far during the project, we have observed that support departments of the organization like Finance & Accounts, Admin, IT help desk are not getting their fair share of training as the always got mobbed up with work and they are the most stressed out team members in the organization. 6. Post evaluation after evaluating employees performance periodically it is really becoming tough for the HR department to plan for successive training programs for the employees those who are in need of because of the tight work schedules. 7. Time and money are the game pla yers at MedTek when it comes to T&D activities. Both management and employees see the value addition of T&D activities but they want it to be done with in the time frame and budget so that these activities would not affect work and budget stretch. Key Issues addressed 1. As we have observed above both management and employees shows interest towards T&D activities but with in the time frame and budget. On this regard, HR department had a discussion with Management about the long term benefits of T&D activities and tried to enlighten them how and what kind of remarkable changes it can bring to the improvement of business in a more effective manner. 2. HR department also highlighted the importance of hiring few more team members for support teams like Accounts & Finance, admin, IT helpdesk etc and advantages of training them in them which can bring a spearhead change in the way they are operating so far. 3. As it is emergency the temporary or time being strategy for hiring after discussing with managers and senior level mgmt, HR dept gave the options as below. a. Providing more work from home options there by reducing operational costs and paying salary as per the performance i.e. no of minutes processed per month by a resource. b. Recruiting and training fresher’s and making them  ready by the time projects comes in as per the business forecast (In health care industry fresher’s usually get paid only after completing the training). c. Encouraging and motivating existing employees for processing more no of minutes and paying incentives for the extra minutes they process. 4. But, for many concerns at MedTek, hiring more team members is the single answer. But considering the concerns of budget, market conditions and business growth plans, MedTek has to consider the plan of hiring in slow pace (for experienced) and hiring fresher’s at good number and making them job ready with in the short period which really cuts the budget to a greater extent. Impact of the Project 1. The project did really give us enough reason to actually audit entire HRD aspects of the organization which we delayed because of some noted business reasons. 2. It throws light on many aspects which we need to work on for the betterment of both organization and employees success. 3. We are able to clearly figure out the strengths and weaknesses from HR point of view and started working on them in no time. Future Direction of the project We are in the final & crucial phase of completing this project. It will take couple of weeks to draw the final and more detailed analysis of the entire work we have done so far during this project tenure. We are left with Section D analysis which has been carrying out simultaneously and will be finished at the earliest. With the support of my guide we can submit the final version by the 3rd week of October.

Unit 2 M1

Unit 2 m1 Compare the aims and objectives of different types of business. I am going to compare a profit making and non-profit making business. All profit making business or organisation’s main goal is to maximizing profit- try to make the most profit possible. This is most likely to be the aim of business owners and shareholders. Another objective that other businesses have is to survive in the market – survival. It is a short term objective, possibly for small business just starting out, or when a new firm enters the market or at a time of crisis.However, Non-profit organisations are established around a variety of different sectors. These include social services, sports, cultural groups, education, and support groups. Their main objectives include: assisting others to participate in society, providing care and treatment, providing opportunities for people to engage in sporting teams, and promoting cultural or social values. TESCOS Tesco is a large business and it has a lot of aims and objectives. Some of which are: â€Å"To grow the UK core†.Tesco wish to expand on the number of stores in the UK and all over the world, also the number of services they provide. This is as relevant today as it was in 1997. The UK is the largest business in the Group and a key driver of sales and profit. Their objective is to â€Å"improve the shopping trips and driving a strong pace† This year, they are making a ? 1 billion commitment to improve the shopping trip, driving a strong pace of improvement in the things that are important to its customers which will involve the need to use revenue and capital investment.These changes will strengthen the shopping trip for customers, and consequently deliver improved performance for shareholders. â€Å"To be an understanding international retailer in stores & online† and â€Å"to respect their markets outside the UK† In 1997, their international businesses generated 1. 8% of the Group’s profits. In addition, today, they represent 30% and they’re now either number one or number two in eight of their 12 markets outside the UK. So they’re already ‘successful’ and are working  to be an outstanding international retailer in stores and online.OXFAM Oxfam focuses on five areas that are informed by their beliefs as an organization. They are: * All human lives are of equal value. Everyone has fundamental rights which must be recognized and upheld at all times. * Poverty makes people more vulnerable to conflicts and natural disasters. Much of this suffering is unnecessary, and we must relieve it. * Unequal power relations – gender, race, class, caste and disability – make people more vulnerable to poverty and suffering.Women, who make up the majority of the world's poor people, are especially disadvantaged. Unequal power relations must be addressed wherever they occur. * In a world rich in resources, poverty is a morally indefensib le injustice. It can and must be overcome. Too often, poverty is the result of powerful people's decisions. We must challenge and remove unjust policies and practices. * With the right resources, support, and training, people living in poverty can solve their own problems. We're all responsible for working together to overcome poverty and suffering.

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Does Robert Bruce deserve to be remembered as a great Scottish king - Essay Example When Wallace was defeated, Bruce became the custodian of Scotland ruling it with Comyn but they later fell out. Robert Bruce was later excommunicated and banished from Scotland, leading to his exile in modern day Northern Ireland. However, Robert Bruce returned and waged a successful war against the English and their rulers, whereby at the Battle of Bannockburn, he defeated the English army that was under the command of Edward II. After this, the Declaration of Independence was made at Arbroath that made Scotland be recognized as an independent nation with Robert Bruce as the king of Scotland. Robert Bruce is considered one of the greatest kings in the history of Scotland as he led them to many victories against their enemies. This king was born of Norman and Celtic ancestries and led the Scots to most of the wars against the English, especially under King Edward I. Notable amongst his many victories is the victory achieved under his rule at Bannockburn in the year 1314, which culminated in the freedom of the Scots from English rule (Brown 2008, p. 1). Due to the supremacy of the English forces over their northern Scottish neighbours, the Scots were continuously humiliated in wars and battles over resources and territories. However, with the rise in the nationalist fervour amongst the Scots under the leadership of Robert Bruce, the English were defeated at the Battle of Bannockburn, which marked an important defining moment for Scotland and an evaluation of the greatness of Robert Bruce as a leader. The Battle of Bannockburn is considered the highlight of the greatness of Robert Bruce as a great and exceptional leader in the history of Scotland as he led Scottish forces to a major defeat against the English troops (Spiers 2011, p. 7). As at 1313, Robert Bruce had demanded that the remnants of the Balliol regime acknowledge him as the absolute king of the Scotland as well as surrender their

Visual Art Analysis Paper Essay Example for Free

Visual Art Analysis Paper Essay Webster’s Dictionary defines Aesthetics as the branch of philosophy dealing with such notions as the beautiful, the ugly, the sublime, the comic, etc. , as applicable to the fine arts, with a view to establishing the meaning and the validity of critical judgments concerning works of art, and the principles underlying or justifying such judgments or the study of the mind and emotions in relation to the sense of beauty. The Dream of La Malinche is aesthetically pleasing despite the fact that I tend to not be attracted to Surrealism. However this artwork told a story that made me curious to find out who La Malinche really was? My first reaction to this artwork is to notice that the room that she is lying in is dark and shabby with exposed brick and a crack in the wall. Was this woman poor or was she labeled as not deserving better? Is this the aesthetically ugly side of life? Dark walls, broken woman. Yet sprawled on her hip is a beautiful church towering over a village in a fertile valley below. Aesthetically beautiful. Prosperity visible in the village and valley, and poverty in the room that La Malinche lies in. What a contrast! Denis Dutton (Aesthetic Universals), a philosopher identified seven universal traits for human See more: how to write an analysis of a research paper aesthetics. He claimed that technical artistic skills are cultivated and recognized. These skills can be admired. Though people admire art they do not expect it to keep food on their table. But it is expected to follow the rules of composition and to be identified as a certain style. Artwork will always be judged, and with few exceptions art will simulate life. Follow our experiences in life yet with a dramatic flair. Based on these traits La Malinche is beautifully orchestrated and very obviously a combination of a folk story and surrealism. Compared to other works by this artist, this particular painting tells a true story, a meaningful story that has played a part in this artist’s life. Visual Arts 3 Expression At the beginning of the 19th century, artists began to express their feelings through their art rather than through the faces painted on a canvas. The real La Malinche was thought to be a hero by some and a traitor by others. Mother of the Mestizo race and harlot to Cortez the explorer. Mexican artwork of this period tended to combine a woman with fertile land to express fertility to the viewer, so I believe this is some of what the artist was also trying to portray. I also love the symbolism between the mountains painted on her hip versus an actual mountain in Mexico named La Malinche. As I studied about Antonio Ruiz, he was referred to several times as a folk art artist besides being a surrealist. I think this art expresses his love for the history of his people and tells their story more adequately than words can express. I dare to call him a surrealist because I do not see where he is avoiding the unpleasantness of the life by wearing rose colored glasses. I feel that he is expressing the truth of the situation and the beauty that can be found amidst ugliness, accusations and tales. However Woman in World Histories Primary Sources claims the Malinche’s body is the ground supporting an unnamed village and church and her image is to invoke female Aztec deities. The metaphor is the Mexican nation is built on the groundwork of Malinche’s actions. So what expressive qualities does this painting have? The mood language is mysterious. It invokes curiosity. The dynamic state is intense and provoking. The Ideal language would be compassion, courage and fearlessness. Sensation This painting provokes a strong emotion in me. I am not sure that I would label it anger, but I feel a sense of injustice rise up inside me. I understand what the artist was trying to portray in this painting but I also know how I interpret this painting. In my interpretation I want to fight for the dignity of this woman who is treated with obvious disrespect based on the condition of Visual Arts 4 the room in which she lies while a village in a valley appears prosperous. And yet I feel an animosity toward the people who do not recognize the contribution that she made to their society or the number of lives that were probably spared. I feel the history of this story and the artist’s emotions. I feel that the woman in the bed carries a huge load on her shoulders. You can almost feel her despair and have to wonder what heart ache she carries within. Does this prosperous village in the valley sit ignorant of the sacrifices of this fearless woman? This woman instills hope and compassion and a sense of empowerment. It’s like being on an emotional rollercoaster yet the lines of this painting is also like a rollercoaster. The round mountain peaks, the curving roads and the rolling sheets over the woman. The curvy scrolls of the wrought iron bed all encompass this feeling of being on a rollercoaster. Formal Design This painting has been labeled as Surrealism. Surrealism was supposedly born from the Dada Movement. This â€Å"Dada Movement† was a banding together of artists who sought refuge from World War I in Europe. As they banded together they became like our early day protestors. Their art, poetry and music reflected their anti-war cries. After the war people wanted to get away from the intensity of darkness that so many paintings depicted and they wanted something to help them escape the everyday reality. So Surrealism became a way for them to combine dreams and fantasy with some reality. The Principles for all design are Unity, Balance, Dominance, Repetition, Rhythm, Contrast and Theme. There is a unity between the woman living in poverty and the prosperous village. Can there be prosperity without poverty? Or can there be poverty without prosperity? If the prosperous mountain were removed all this art would speak about is poverty. La Malinche would appear as a poor woman on a bed. Would you be curious about her Visual Arts 5 circumstances or would you feel compelled to look away? If La Malinche was removed from the painting you would just have a prosperous village living in a valley. A beautiful fairytale painting. Because the elements of this painting need each other and have unity, this painting has balance. The mountain on La Malinche’s hip gives this painting symmetry. It becomes almost the fulcrum of the painting. Everything balances around the central part of this painting. The mountain, the prosperity takes a dominant position in this painting which could suggest her success in rising above adversity. The rhythm in this painting would be the flow of the village across the sheets, and the flow of the sheets across the woman. There is this continuous theme flowing out from the village. The poverty, the dark room and the woman contrast with the light of the village and it’s prosperity. Each of these principals come together to form the theme of poverty and prosperity. Lightness and Dark. Realism and Surrealism. Technical Properties The Dream of La Malinche is painted on canvas with oils. If skill is truly based on the artists portrayal of his picture, than Ruiz has truly surpassed all other artists in portraying the history and story of this heroic figure. He has an incredible sense of color. And this painting reflects his own personal view on this historical figure. The lightening bolt (or crack in the wall as I call it) has depth to it. This painting does not have the usual bulkiness that you so often see in oil paintings. As an artist Antonio Ruiz is known for his draftsmanship skills. He is considered a great painter of small works and respected for his aesthetic quality. Visual Arts 6 References Dutton, D. , Aesthetic Universals Merriam-Webster Dictionary, Definition of Aesthetics

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