Lecturer: Miquel Galan
These subjects aim to cover areas of freeze drying which are relevant to the professionals in the Pharmaceutical Industry. Theory and practice will be fully interrelated. New developments continuously challenge to professionals in terms of regulations, technology and trends, and participants will gain a better knowledge of the process as well as validation.
1. Fundamentals of lyophilization process
This session provides background information on the rules of freeze drying to better understand the requirements of a freeze drying plant. The problems encountered in the different steps are analyzed with the parameters influencing them.
Reviews of different engineering approaches in freeze dryer design. Which are the best suited for my process?
Plant main subsystems
Ancillary processes
Qualification and Validation
Conventional mechanical systems available today offer refrigeration capacity sufficient to reach a low temperature limit down to -55ºC on the product shelves and to -75ºC on the ice condenser coils. It is presented a new cryogenic cooling system capable of attaining with full controllability -90ºC on the shelves and temperatures down to 120ºC on the coils. This method starts with evaporation of LN2 producing gaseous nitrogen (GN2) at the needed temperature. This GN2 is the cooling element used for the required heat transfer in the process.
Most of the freeze-drying processes are developped on lab-scale and pilot-scale freeze dryers. The workshop intends to explain what are the essential components of a lab-scale freeze dryer (0.5 sqm shelf surface, 20 kg ice capacity) and how it is used to develop a recipe. It will high-light the features of the control system that allow understand and analyse the process in detail and adjust the recipe parameters. A cycle will be started to show a real-life example and discuss specifically how the freeze-dryer is operated. The following points will be addressed:
Presentation
of equipment and control system
Presentation
of cycles: freeze drying cycle, performance cycle, de-icing
Setting-up
recipe parameters and integrating machine constraints
Specific
sequences: loading on pre-cooled shelves, pressure rise test, stoppering,
cycle acknowledgement
Operator
control during cycle: modification of recipe parameters, inhibition of
out-of-range product
temperature
sensor
Running
and monitor a cycle
Reading
and analysing cycle reports
2. Compliance of control systems to 21 CFR Part 11
Compliance of equipment control systems to 21 CFR Part 11 has become a must for all pharmaceutical and biotech companies. It is applicable to new equipment but also requires existing equipment to be upgraded and validated.
The lecture intends to explain the basic requirements of 21 CFR Part 11 and how they are applied on the control system of a freeze dryer. It will also provide pratical details on how to evaluate compliance through gap analysis and how to validate such control systems. Finally, it will provide a case-study on retrofit of the control system of an existing freeze dryer. The following points will be addressed:
Historical
and legal back-ground, relation to GAMP and other guidelines
Data
integrity Access control Electronic signatures 21 CFR Part 11 gap analysis
Validation
of control system
Case
study: retrofit of existing control systems
On many occurences, operator-handling of a product to be freeze-dried is not the suitable solution, either because the product needs to be isolated or because it is toxic to the operator, but also when the rate of loading and unloading needs to be increased. This lectures proposes to review the various alternatives that are available and explain the pros and cons of each. The following points will be addressed:
Manual
and semi-automated systems
Integration
of laminar air flow, temperature control, moisture control
Fully
automated systems
Integration
of isolator
Impact
of each system on freeze-dryer design
Lecturer: Peter HASELEY
Part 1: VHP - Alternative way to steam strerilization of FD
VHP (Vaporized Hydrogen Peroxide) - an alternative to steam sterilization in freeze-dryers. Other areas of application such as the disinfection of isolators, rooms, etc.
Freeze-drying and here again ER measurements and their importance for cycle development Etch effects during freezing and during drying Technical solutions to prevent this damaging effec TLC (Thermodynamic Lyophilization Control) A reliable control method for modern freeze-drying systems. This control system was developed in view of the increasing number of systems that are loaded and unloaded automatically.
Lecturer: Lawrence A. ULFIK
The following topics will be reviewed:
What are the practical methods of diagnosing vacuum leaks in freeze drying systems? What use are alert and action limits in the normal operation of freeze drying systems, as concerns vacuum integrity? What effect does leak rate have on product quality?
What are some symptoms of refrigeration failure in freeze drying systems?
What should one do for recharging a refrigeration system in a production and research freeze drying system?
What is the method of choice in changing refrigerant gas from environmentally unfriendly to environmentally friendly gas in a freeze drying system?
What are the appropriate maintenance schedules for freeze drying system on a daily, monthly and yearly and 3-5 year basis? Please describe what needs to be checked and how it is done?
What are procedures for isolating and finding a leak in a refrigeration system?
What are procedures for isolating a vacuum leak in a freeze dryer with external and internal condenser, one or two vacuum pumps?
Assuming one has just installed a brand new freeze dryer, or one that is new to your facility. What needs to be checked to ensure that the system runs well initially for the first 6 months of use?
How does refrigeration cooling effect the operation of the system? What are symptoms of heat rejection in condenser receivers? What does one look for as concerns the temperature at the top, middle and bottom of the receiver under conditions such as overcharge, undercharge, suction leak, and high head pressure?
What is the importance of installation qualification of a freeze dryer? List and discuss the pros and cons of areas such as low voltage, power outages, communications failure, high humidity, and lack of HVAC and any others that may be important in your situation.
Professor Louis REY
Professor Yasuyuki SAGARA
Department of Global Agricultural Sciences, Graduate
School of Agricultural and Life Sciences,
The University of Tokyo, Yayoi 1-1-1 Bunkyo-ku Tokyo 113-8657, JAPAN
A mathematical model has been developed to determine the thermal conductivity and permeability for the dried layer of food samples undergoing sublimation dehydration. An automatic measurement system has developed for the data acquisition as well as determination of these transport properties by applying the drying data to the model. The values of transport property were presented for several food materials indicating the critical processing factors for the drying rate of each material.
Some structural models were developed for predicting the permeability of water vapor flowing through the dried layer. In a cellular food model, the resistance of a cell membrane to the molecular transfer of water vapor was determined from both value of permeability and microscopic observation of the dried layer. The model was considered to play an important role in predicting optimum heating program for the surface temperature of materials.
A micro-slicer image processing system (MSIPS) has been developed for measuring the three-dimensional (3-D) structure and distribution of ice crystals formed in frozen food materials. The system has functions to reconstruct the 3-D image based on the image data of exposed cross sections obtained by multi-slicing of a frozen sample with the minimum thickness of 1ìm and display the internal structure as well as an arbitrary cross section of the sample choosing observation angles The effects of freezing conditions on the morphology and distribution of ice crystals were demonstrated quantitatively from the observations of raw beef and model solution systems stained by fluorescent indicator.
A technical cooperation project has been carried out between university and industries for optimizing the design and operation of industrial freeze-dryer to produce egg soups. In the project a new heating program was developed to shorten the drying time for the batch-type freeze dryers in industrial scale.
Marc HENRIST, Alain CARAPELLE, Frederic RABECKI
The Centre Spatial de Liege (CSL) was involved in the lyophilization process since 1991, when a large incident occurred to precious books from the National Archives. After a successful restoration, several further occasions took place up to now for freeze-drying flooded documents in vacuum chambers, normally devoted to space equipment testing. Customers range from ministries to particulars.
Due to several drawbacks associated to the use of vacuum chambers in clean rooms, it has been decided to create a spin-off company (SVA - Special Vacuum Applications, Ltd) in charge of the operations, with its own equipment including a large vacuum chamber. A grant from the regional authorities has enabled to master various aspects of the document salvation process, including sterilization for the prevention of fungus and mould.
The presentation describes the present and future equipment and processes associated with large scale lyophilization of damaged documents.
Perlina D. SAYABOC, Leodegario PADUA and Mia V. de la CRUZ
Insecticidal activity of freeze dried bacterial cells and bacterial suspension were tested against the lesser grain borer, Rhizopertha dominica (F). Six strains each freeze dried bacterial cells and bacterial suspension were bioassayed using adults of R. dominica. Freeze dried bacterial cells were used at the rate of 0.05g, 0.10g and 0.15g per gram of diet while bacterial suspension were mixed with the insect diet at the rate of 250ul per 20g diet. Results showed that the freeze dried materials gave higher mortality at 52.3% as compared to the suspensions which gave 21.5% mortality.
P. HASELEY , and G. W. OETJEN
With increasing costs and the limited availability of new pharmaceutical products, the pilot plant shown can be operated with a minimum of product which permits determining reproducible process data and the corresponding tolerances. Approximately 10 to 40 g of solids in the solution (depending on the maximum permissible residual moisture content) are recommended. Smaller amounts are possible if the consequences for the data are studied.
With these small amounts of product, a high and measurable uniformity of temperature and pressure for all the vials is required. The plant is designed to achieve this goal. All the data measured and calculated are the same as the data that will be used in the production freeze-dryer. The process can be run without the need of temperature sensors in the product. This is necessary to permit loading an unloading the production unit automatically.
The pilot plant and its operation are automated in the same way as the production unit. The thermodynamic data measured during the process are used for the control of freezing, main drying, change-over to secondary drying and for the in-process determination of the residual moisture content.
Irina BAKALTCHEVA and Thomas REID
Development of a freeze-drying protocol for complex cellular systems such as red blood cells or platelets involves the optimization of four individual steps: 1. Pretreatment, 2. Freezing, 3. Primary drying and 4. Secondary drying. Pretreatment includes any method of treating the cells prior to freezing. Its goal is to increase product stability against the stresses of freezing and drying. Different approaches have been applied to reduce the damaging effects during the freeze-drying of red blood cells or platelets. The main emphasis is usually on designing a lyoprotective medium that contains high molecular weight cryoprotectants such as hydroxyethyl starch (HES), polyvinyl pyrrolidone (PVP), dextran or albumin and low molecular weight carbohydrates such as glucose, sucrose or trehalose. Recently, we have introduced reversible cross-linking and CO-treatment as a pretreatment approach in red cell lyophilization (Bakaltcheva et al. 2000).
Unfortunately both approaches suffer limitations that still prohibit the successful establishment of a freeze-dried red blood cell or platelet product. The first approach requires a low molecular weight cryoprotectant, usually a carbohydrate to be permeable to the cell membrane. In 1986, Womersley et al. reported that, in order for membrane preservation to be accomplished, the carbohydrate had to be present on both sides of the membrane. Failure to achieve this would greatly diminish the capacity of the carbohydrate to protect the membrane against desiccation-induced damage. This is easily achieved with phospholipid vesicles, which can be made de novo in the presence of a carbohydrate, but presents a challenge when dealing with intact cells. It has been shown that the monosaccharide glucose, which can penetrate the red cell via the glucose transporter, is also a more effective lyoprotectant compared to the non-permeable disaccharides sucrose and trehalose (Goodrich et al. 1993). However, the low permeability of the red cell or platelet membrane to glucose and its insufficient load inside the cell is a major limitation to successful lyoprotection. Unfortunately, cryprotectants such as glycerol and DMSO, which easily permeate the red cell and the platelet membrane are not dryable and therefore can not be utilized in freeze-drying or drying procedures.
Recently we have identified a compound which is highly permeable and dryable at the same time. A lyophilized platelet product is currently under development in our laboratory utilizing the newly identified lyo-protectant. Results will be presented and discussed.
Arnaud SERFASS and Christophe de Saint LEGER
On many occurences, operator-handling of a product to be freeze-dried is not the suitable solution, either because the product needs to be isolated or because it is toxic to the operator, but also when the rate of loading and unloading needs to be increased. This lectures proposes to review the various alternatives that are available and explain the pros and cons of each. The following points will be addressed:
Arnaud SERFASS and Christophe de Saint LEGER
Compliance of equipment control systems to 21 CFR Part 11 has become a must for all pharmaceutical and biotech companies. It is applicable to new equipment but also requires existing equipment to be upgraded and validated.
The lecture intends to explain the basic requirements of 21 CFR Part 11 and how they are applied on the control system of a freeze dryer. It will also provide pratical details on how to evaluate compliance through gap analysis and how to validate such control systems. Finally, it will provide a case-study on retrofit of the control system of an existing freeze dryer. The following points will be addressed:
Joan C. MAY, Ph.D.
Center for Biologics Evaluation and Research, U.S. Food
and Drug Administration,
Rockville, MD 20852
The U.S. Food and Drug Administration regulation [21CFR610.13a] states that each lot of dried product be tested for residual moisture and meet and not exceed established limits as specified by an approved method on file in the product license application. Methodology in use for the determination of residual moisture in freeze-dried products includes the gravimetric or loss on drying method, many modifications of the Karl Fischer method, gas chromatography, the Moisture Evolution Analyzer, thermogravimetry (TG) and thermogravimetry/mass spectrometry (TG/MS). The residual moisture content in the freeze-dried biological product influences product potency and product stability. Research into new moisture methodology involves factors such as small single dose sample size, controlling ambient humidity during analysis, and water retention properties of the product and formulation constituents. TG and TG/MS methodology has been effective in determining moisture content in very small sample sizes in single dose vials. Water vapor pressure methodology has been used to determine the moisture content of the headspace in several freeze-dried biological products using an electro-optical dew point measurement instrument. This information complements results from gravimetric, Karl Fischer, thermogravimetric or TG/MS residual moisture testing of the freeze-dried cake. These studies impact upon formulation and stability for freeze-dried products through better understanding of moisture migration and equilibrium between the components of the container, container closure and the freeze-dried cake.
P MATEJTSCHUK, M. ANDERSEN and P. PHILIPS
Standards Division, National Institute for Biological Standards Control
(NIBSC),
South Mimms, Potters Bar, EN6 3QG. UK
International biological standards are routinely prepared in flame-sealed glass DIN ampoules, which are unsurpassed in providing an inert environment ideally suited to long term storage. The majority of these standards are freeze-dried. During routine processing of biologicals in ampoules we have observed ring-like deposits (annuli) at the neck (constriction) of the ampoule at a frequency of 1-2% of the containers being freeze dried. A number of experimental runs were performed in order to investigate the nature of this phenomenon.
Formulation the occurrence of the annuli was assessed for a range of different formulations, with both protein and carbohydrate standards.
Location The location of the abnormal ampoules was mapped in terms of their location within a tray and also within the shelves of the dryer and also between freeze driers.
Characterisation The annulus was removed from ampoules from several freeze drying runs of different biologicals and analysed in terms of its biological composition
Freeze Drying Cycle The freezing and primary drying parameters were modified to study their impact on the frequency of the annuli.
The results of these studies and the impact of the ampoule assembly and dimensions will be discussed.
Hanna WILLEMER
Electrical resistance measurements (ER) can be done with commercially available instruments.
The interpretation of the plots and their first derivation can become difficult or misleading. This paper presents typical ER-measurements of various products and tries to establish some guidance for their interpretation. The evaluation of the plots is supported on complimented by cryomicroscope studies.
Miquel GALAN
RD and Innovation Manager, TELSTAR INDUSTRIAL, S.L.
Josep Tapiolas, 120, E-08226 TERRASSA (Barcelona), Spain
These subjects aim to cover areas of freeze drying which are relevant to the professionals in the Pharmaceutical Industry. Theory and practice will be fully interrelated. New developments continuously challenge to professionals in terms of regulations, technology and trends, and participants will gain a better knowledge of the process as well as validation.
Reviews of different engineering approaches in freeze dryer design. Which are the best suited for my process?
Plant main subsystems
Ancillary processes
Qualification and Validation
Marjorie Janssen
This paper will be a general discussion of the methods, problems and results of freeze-drying flowers. The main objectives of this paper are to show that the drying of flowers is a very complex and often frustrating task. It is very much an art rather than a science, and may not be in the case of other applications of not as sophisticated as used by others but none the less unique in its own right. Floral preservation may not play an important part in saving lives but it provides us with a means of enhancing the quality of our lives. Flowers are a beautiful tribute to nature and by preserving that beauty we are also extending our appreciation of nature.
Jos CORVER
Technology Manager BOC Edwards Pharmaceutical Systems
When a cold chamber is opened to a warm environment air gets exchanged: thermo-syphoning. Cold air is escaping from the chamber at the bottom part of the opening whereas warm air is pouring in. In order to understand this process better in relationship with cold shelf loading of freeze-dryers, numerical simulations have been done with CFD techniques.
After relatively short times after opening of the slot door the airflow- exchange stabilizes, leading to uncontrolled circulation flow of the warm air getting in. Also a net influx of water vapor is conveyed with this air. This in turn leads to considerable build-up of ice on the cold shelves.
Some potential improvements will be discussed in the presentation.
Ofero A. CAPARIÑO
Department of Agriculture - Bureau of Post-harvest Research and Extension
(BPRE)
CLSU Compound, Science City of Muñoz 3120, Nueva Ecija, Philippines
Aseptically processed mango puree was frozen at 40·C and 65·C using ultra-low temperature freezer and 192·C by direct immersion to liquid nitrogen. All samples were freeze-dried at 0.001-0.05 Torr. Drying of samples was continued until the moisture content of 2-3% was attained. Results of the study revealed that the freezing time required to lower the temperature of the product down to the freezing temperature of -40·C, -65·C and -192·C was approximately 278 minutes (4.6 hr), 370 minutes (6.0 hr) and 15 minutes (0.25 hr), respectively. The freezing point of mango puree was found at -2.42·C which was lower than freezing point of water ( 0·C). Direct immersion to liquid nitrogen (-192·C) during freezing yielded the shortest drying time of 16 hr compared with freezing at -40·C and -65·C which required 18 and 22.5 hr of drying, respectively. Such effect was attributed to increase in surface area due to cracks which developed during freezing as a consequence of thermal shock. In terms of the percent powder recovery, the study did not show any significant difference among all treatments. The physico-chemical properties of the control sample and the reconstituted mango puree produced at 40, -65·C and -192·C, showed that the total soluble solids originally present in the original mango puree (control) were not affected by the freezing methods prior to freeze drying Sensory evaluation of the puree indicated no significant differences in aroma, characteristic flavor, sweetness and general acceptability between those of the control and the reconstituted purees. There were no significant differences in color, aroma and general acceptability among the products pre-frozen at 40, -65·C and -192·C.
Armansyah H. Tambunan
Department of Agricultural Engineering, Bogor Agricultural University, Bogor,
INDONESIA
Jamu is Indonesian traditional herb medicine, which traditionally prepared from tropical herbs and used as medicine or as healthy food. The application of freeze-drying to process the jamu ingredients is advantageous in order to preserve its active component, but still considered to be costly and inefficient. One of the reasons for the high operation cost is its high consumption of energy, which one another used to provide the sublimation heat. This study is aimed to evaluate heat flow characteristics from the heating plate to the product in the vacuum chamber during the first and secondary drying stage.
In the study, heat was supplied by a heating plate, radiated through vacuum to the surface of the product and conducted through the dried layer. It was assumed that heat arrived at the product used to sublimate the ice crystal and to elevate the temperature of the dried layer. The effect of other operating parameters, such as chamber pressure and freezing rate, to the heat flow characteristic was also discussed in this study.
Thorsten Fischer
The presentation is dealing with system specific testing defined by an in house standard called SQP to authorize the use of lyophilizers for routine production under GMP-guidelines.
The document was developed with the intention to harmonise the testing firstly on our site (Germany) and then upgrade it in a second step of harmonisation (still to do) to a global policy / procedure.
The presentation will introduce you into the idea of the SQP-document. It will show how Aventis Behring prepare a qualification document (IQ/OQ/PQ) from an existing DQ and documents defining testings and requirements to fullfill called qualification procedures.
With respect on the complexity for the amount of qualification activities the presentation will focus on the system specific testing for the equipment and the automation system.
Starting with a short introduction to the technical construction of a lyophilizer the presentation will show the required testing and give some acceptance criteria.
The features of system specific testing will deal with the qualification performed for the automation system, vacuum system, ventilation system, temperature system (shelf temperature distribution study), Sterilization in place (OQ + PQ) [use of biological indicators], Stoppering, CIP
In total the presentation should give you an experience report and an idea of the amount of work and the requirements to pass, before start using a new lyophilizer for routine production.
Pardo J. M.1, Padar S.2, Suess
F.2, Niranjan K.3
1 Facultad de Ingeniera, Universidad de la Sabana, Campus Puente del Comn, Cha,
Colombia.
2 Visiting Students, School of Food Bioscience, The University of Reading. UK.
3 School of Food Bioscience. The University of Reading. UK
Freezing kinetics of coffee brews has been related successfully to sublimation kinetics assuming that the mean size of the ice crystal formed during freezing is equivalent to the mean pore size left by the subliming ice. The well-known Neumanns model for freezing kinetics has been coupled with a theory for solidification, and the resultant equation which is largely valid for dilute solutions has been modified empirically to include the effect of high coffee solute concentrations. Ice crystal size distributions formed at different freezing rates and solute concentrations, were determined experimentally, and the validity of the model has been confirmed.
The model developed for the primary drying stage (i.e. ice sublimation) is based on a uniform ice front retreating downwards through a rectangular slab. This model is an extension of the well known URIF model, which includes transient variations in physical properties and permeability of the freeze drying sample; the relevant equations have been solved using finite difference method. The movement of vapour through the porous solid has been treated analogous to the flow through a set of capillary tubes having mean radius equal to the mean hydraulic radius of the ice crystals formed during freezing. This model successfully predicts the sublimation rates and transient temperature profiles observed in experiments undertaken using a Stokes (Model 800-001-5) pilot plant freeze drier. It is concluded that the mean hydraulic radius of ice crystals formed during freezing can be used to link freezing kinetics with sublimation kinetics. Freezing kinetics of coffee brews has been related successfully to sublimation kinetics assuming that the mean size of the ice crystal formed during freezing is equivalent to the mean pore size left by the subliming ice
Fei Liu, Xiaozhou Lu and Zhifu Luo
Department of Isotope, Chain Institute of Atomic Energy, Beijing 102413,
China
Radiopharmaceuticals provide vital information that aids in the diagnosis and therapy of various medical maladies. Radiopharmaceuticals labeled with Technetium-99m has been combined with the technology of single photon emission computed tomography (SPECT) and applied to nuclear medicine clinical diagnosis. Molybdenum-99/Technetium-99m (Mo-99/Tc-99m) generator and its kits have been applied to hospitals for diagnosis many diseases in every section of human organs such as brain, myocardium, renals, bone, lungs, lymph, thyroid and so on. SPECT imaging with Technetium-99m Radiopharmaceuticals have become available for clinical use, including perfusion agents for the heart (Tc-99m-MIBI (Cardiolite®)) and the brain (Tc-99m-ECD (Neurolite®)) and Tc-99m-HMPAO (Ceretech®), as well as an agents that images renal function (Tc-99m-MAG3, Tc-99m-DTPA) provided the ability to diagnosis and visualize in a noninvasive manner.
All the Technetium-99m imaging kits must been lyophilized and frozen drying in order to protect the stability and convenient use of the kits. Because lyophilization can be used for the Technetium-99m diagnostic products containing reductant ingredients (SnCl2·H2O) that are unstable in the presence of water. Lyophilization of the Technetium-99m kits generate a highly stable material with a long shelf life, which can easily be reconstituted into a liquid form just prior to injection, and products in lyophilized form can be delivered in convenient.
Isotope department, China Institute of Atomic Energy is the first unit in our country that engaged in the research and production of radiopharmaceuticals for many years. Mo-99/Tc-99m generator and its kits have been applied to hospitals that contain nuclear medicine facilities throughout the country and the rate of occupation to the national market is over 90%. We have one GMP production line of the Mo-99/Tc-99m generator and a Technetium-99m kits lyophilization production line and facilities (Consol-12, Virtis and Laboconcal).
Lyophilization of the Technetium-99m kits:
The pH of the kit formulation was adjusted to appropriate values. Lyophilization of the kits was carried out using freeze dryer (Consol-12, Virtis). One milliliter of the formulation aliquet was added to each of a 10mL glass vial. The vials were shelf frozen to -40 C to -50 C temperature (some kinds of the products were frozen with nitrogen). Shelves temperature was subjected in the different period and sublimation followed by final sealing.
Ana Maria I. B. Ayrosa1, Bluma L.
Faintuch2, Ronaldo N. M. Pitombo1
1 Biochemical and Pharmaceutical Technology Department,
Pharmaceutical Sciences School of Sao Paulo University Sao Paulo Brazil.
2 Energetic and Nuclear Research Institute IPEN Sao Paulo Brazil.
The safe practice of nuclear medicine requires the continuous supply of high quality radiopharmaceuticals prepared under strict GMP guidelines. These efforts result in reducing costs and increasing the efficiency of resource utilization. An important consideration when providing labile products to nuclear medicine centers is ensuring the preservation of their physicochemical properties for several months before labeling. This was performed by stabilizing the stannous ligand complex by freeze-drying against air oxidation and hydrolysis. Standardization of the variables involved in the freeze-drying procedure is important for stability and efficiency of radioisotopic kits, but few studies are available in this area. This investigation aimed to define the best freeze-drying model for several kits routinely prepared for labeling with Tc-99m. Representative samples (2 ml) of DTPA, MDP, ECD and Pyrophosphate, produced by the Radiopharmacy Center (IPEN/CNEN - Brazil) were aseptically collected for determination of freezing and freeze-drying curves, moisture sorption isotherms and nuclear magnetic resonance (NMR) variables. The temperature profile was assessed between 0·C and -40·C, and NMR parameters were given by a Pulse NMR Spectrometer. The glass transition temperature (Tg) was derived from the spin-spin relaxation time (T2) on the pulse spectrometer, and data from sorption isotherms were analysed by the BET equation to find out water monolayer. The completion of nucleation point and the onset the solidification corresponded to -3·C till -7·C, depending on the product. The drying time during freeze-drying varied between 17 and 20 hours. Tg calculated by NMR stayed about -30·C, and residual moisture after freeze-drying was in the range of 0.6% - 2.1% w/w. The water sorption isotherms at 25·C were classified as type I, according to BET classification, and fitted well to the chosen model.