Freeze-drying parameters, processing

While examination of the final product is essential to ensure that the lyophilization process performs consistently and as intended, the monitoring of freeze-drying parameters also ensures that they are maintained within an acceptable range and provides an additional degree of assurance that the process is under control. 

Compared to many other pharmaceutical processes, freeze-drying is intrinsically more complex. This is because process parameters and product characteristics are inherently interdependent. The freeze-drying parameters affect the product being freeze-dried, but the converse is also true. A marked impact on the course of freeze-drying may be caused by the chemical composition of the solution and sub-... 

The thermodynamic and structural properties of the frozen product The effects of the programmable freeze-drying parameters on dependent process variables... 

Examination of the reproducibility of the freeze-drying parameters, to show that the process and the equipment can be maintained within a state of control... 

Maelkki Nikkilae, Aalto and Heinonen [31, 32] stress the importance of the raw material quality of onions. Stieger [33] has investigated the suitablity of various strawberry varieties. Processes for flavour preservation have been thoroughly examined with cultivated mushrooms, leading to an illumination of the most important freeze drying parameters [34[. 

As the pressure increases from low values, the pressure-dependent term in the denominator of Eq. (101) becomes significant, and the heat transfer is reduced from what is predicted from the free molecular flow heat transfer equation. Physically, this reduction in heat flow is a result of gas-gas collisions interfering with direct energy transfer between the gas molecules and the surfaces. If we use the heat conductivity parameters for water vapor and assume that the energy accommodation coefficient is unity, (aA0/X)dP — 150 I d cm- Thus, at a typical pressure for freeze drying of 0.1 torr, this term is unity at d 0.7 mm. Thus, gas-gas collisions reduce free molecular flow heat transfer by at least a factor of 2 for surfaces separated by less than 1 mm. Most heat transfer processes in freeze drying involve separation distances of at least a few tenths of a millimeter, so transition flow heat transfer is the most important mode of heat transfer through the gas. 

AMSCO International Inc. [2.14] offers complete installations for VHP sterilization of freeze drying plants, which are programmable and automatic 4 to 400 g H202 per injection can be preset, as well as the parameter of the drying-, sterilization- and venting phases. The process is documented. Figure 2.47 shows an AMSCO-VHP generator. 

I have tried to show the interconnection between the property of the product, the goal to make it stable and the necessary processes to achieve this. The problems of the different process steps are discussed with examples and the parameters are described which influence each step. I have avoided following the many theoretical attempts describing one or more of the freeze-drying steps, but have restricted myself to a few equations which permit the calculation of process and product data with sufficient accuracy, or at least, allow an estimate, if some data is mentioned. 

Particle size is one of the most important characterization parameters for sohd hpid nanoparticle dispersions, and parameters relahng to particle size are consequently reported in all stndies on these systems. Particle size determinations are predominantly performed to conhrm that the desired colloidal size range has been obtained dnring preparation and that it is retained upon storage or further processing (e.g., during freeze drying or sterilization). 

In modern freeze-drying systems, the filter integrity test is carried out automatically. All the relevant process parameters are documented by the control system of the unit. The important thing is to make sure that after every integrity test, the filter and the entire piping system are perfectly dry. This is effected by means of the installed liquid ring pump. 

At the PC level, the freeze-drying process and all secondary processes are visualized, controlled and documented. Such secondary processes include condenser defrosting, CIP/SIP, plant tests, failure statistics, calibration values, counter of operating hours, plant schematic, table of valves, actual temperature and pressure values, recipes, start parameters and machine parameters. 

Heinzelmann, K., Franke, K., Velasco, J., and Marquez-Ruiz, G. (2000). Micro-encapsulation of fish oil by freeze-drying techniques and influence of process parameters on oxidative stability during storage. Fur. Food Res. Technol. 211,234 239. 

Before concentrating on process parameters (Section III), we will briefly outline the behavior of the product during the three separate but interdependent stages of freeze-drying freezing, sublimation (primary drying), and desorption (secondary drying). 

The selection of the process parameters that need to be quantified and validated requires a knowledge of the many variables that may have an effect on the product. There is no universal validation framework, and the critical parameters should be identified based on the profile of the freeze-drying cycle, as well as on the characteristics, requirements, and release specifications of the product. The present section will be restricted to give examples of process parameters that are frequently assessed in validation reports. 

The freeze-drying data are also suitable for trend analysis. The reproducibility of the freeze-drying process can be followed over years and the database may be used to trace back the drift of a specific parameter from its initial values. 

If lyophilizers of different types are used to lyophilize a drug product according to a same freeze-drying cycle, useful information about process robustness can sometimes be gained by comparing the values of the dependent parameters. The analytical properties, in particular the activity and the moisture of product batches manufactured in different lyophilizers, also deserve comparison. 

The validation of lyophilization cycles is a complicated issue because the process parameters and the characteristics of the product are closely interrelated. The process affects the final product, but the characteristics of the product undergoing lyophilization impact the dependent operating parameters, the freeze-drying pattern, and dictate the basic requirements for a successful process. This interdependence limits the opportunities of using placebo formulations and most of the validation runs must be performed with active product. The high cost and limited availability of some materials, as well as the need to validate the process under conditions that are representative of routine production, justify that part of the validation is performed in a concurrent fashion. The concurrent validation should then be completed by a retrospective review of the data accumulated for commercial batches, so as to track the reproducibility, the reliability, and the trends of the process over a longer period of time. 

In most commercial freeze drying processes, chamber pressure, shelf temperature, and time are the only controllable process parameters. Product temperature is not directly controlled. It is the balance between heat and mass transfer that determines the product temperature. Obviously, shelf temperature is important in determining the heat transfer and product temperature. However, because much of the heat is transferred through the gas phase (i.e., collisions of gas molecules with the hot shelf surface and the cold vial bottom), heat transfer as well as mass transfer Eq. (1) is determined, in part, by the chamber pressure. Therefore, product temperature is determined by shelf temperature, chamber pressure, the heat transfer characteristics of the vials, and the mass transfer characteristics of the product and semistoppered vials. 

The technology for freeze drying/dry heat treatment is complex and there are many process parameters to control (e.g., temperatures of the shelf, product and condenser freezing and drying rates pressures of the chamber and condenser and temperature and distribution of heat in the oven). 

During the studies, temperature and pressure must be controlled during all stages of the freeze drying cycle and uniform temperatures must be distributed throughout the oven used for the dry heat step. Process parameters such as the amount of moisture retained by... 

This paper presents the application of a model based predictive control strategy for the primary stage of the freeze drying process, which has not been tackled until now. A model predictive control framework is provided to minimize the sublimation time. The problem is directly addressed for the non linear distributed parameters system that describes the dynamic of the process. The mathematical model takes in account the main phenomena, including the heat and mass transfer in both the dried and frozen layers, and the moving sublimation front. The obtained results show the efficiency of the control software developed (MPC CB) under Matlab. The MPC( CB based on a modified levenberg-marquardt algorithm allows to control a continuous process in the open or closed loop and to find the optimal constrained control. 

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