Scribd Logo
Upload

Welcome to Scribd!

  • 34 views

    Development of An Efficient Single-Step Freeze-Drying Cycle For Protein Formulations - Chang1995 PDF

    Uploaded by

    Javier Rigau

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content

    You might also like

    Development of An Efficient Single-Step Freeze-Drying Cycle For Protein Formulations - Chang1995 PDF

    Uploaded by

    Javier Rigau
    34 views7 pages

    Original Title

    Development of an Efficient Single-Step Freeze-Drying Cycle for Protein Formulations_Chang1995.pdf

    Copyright

    © © All Rights Reserved

    Available Formats

    PDF or read online from Scribd

    Did you find this document useful?

    Is this content inappropriate?

    Report this Document

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    Download as pdf
    34 views7 pages

    Development of An Efficient Single-Step Freeze-Drying Cycle For Protein Formulations - Chang1995 PDF

    Uploaded by

    Javier Rigau

    Copyright:

    © All Rights Reserved
    Download as PDF or read online from Scribd
    Flag for inappropriate content
    Download as pdf
    of 7
    Pharmaceutical Research, Vol. 12, No. 6, 198 Development of an Efficient Single-Step Freeze-Drying Cycle for Protein Formulations Byeong S. Chang" and Norman L. Fischer! Received August 24, 1994: accepted January 20, 1998 Purpose. An eicient freeze-drying cycle for recombinant human inteleukin-1 receptor antagonist (rhIL-Ira) formulations, which contained glycine and sucrose as excipients, was developed. Meth- ‘ds. Development was based on characterizing the frozen formule tions by thermal analysis and by examining the effect of various lyophilization process parameters on the sublimation rate of ice. Results, Thermal analysis showed thatthe metastable glass of aly cine in frozen formulation could be devitrfied by slowly warming the frozen product to ~ 15°C. During drying, the sublimation rate of ice was inereased as a linear function ofthe difference between the ‘vapor pressure of ce atthe product temperature (Po) and the cham ber pressure (Pc). Therefore, the product temperature (T,) was maintained as high as possible at temperatures below Tp of the {ormulaton, in order to maximize the Pg without allowing the co: lapse of cake. Although various combinations of shelf temperatures ‘and chamber pressures could be used to obtain the same T,, the ‘combination of higher shelf temperature and lower chamber’ pres Sure was used to maximize sublimation rate. Conclusions. single: step drying cycle was developed to take advantage of these obser- vations. The shelf temperature was set forthe secondary drying and the product temperature during primary drying was maintained be- low Ts’ by adjusting the chamber pressure. As the sublimation com- pleted, the product temperature increased naturally to the she tem perature forthe secondary drying. This process resulted in success ful drying of 1 ml of rhlL-Ira formulation to 0.4% moisture content within 6 hours. KEY WORDS: rhiL-Ira; lyophilization; eyele development, bl mation rat; shelf temperature; chamber pressure INTRODUCTION ‘The development of protein-based pharmaceuticals has been major interest since recombinant DNA technology allowed mass-production of valuable proteins, which have been discovered as mediators of critical human physiological functions. Unfortunately, many purified proteins have a mar~ ‘inal stability in solution. Understanding the nature of der {uration and investigating methods for stabilization have be- ‘come an important responsibility for formulation scientists, because protein denaturation during storage and delivery renders a protein product unusable. Freeze-drying is consid. fered one of the best ways to preserve proteins, with the potential to yield products that are stable as well as conve- nent to ship and handle. Water is important for the degra- "Department of Formulation and Pharmaceutical Development, ‘Synergen, In., 1885 3rd Street, Boulder, Colorado 80303 +o whom correspondence should be addressed at Amgen, Inc. ‘Amgen Center, 1830 De Havilland Drive, Thousand Oaks, Califor nia 91320. 1 Report dation of proteins because ofits role as & medium for the movement of molecules, as an environment fostering con- formational changes, and as a reactant for adverse reactions such as hydrolysis. Therefore, many degradation reactions of proteins can be either suppressed or completely elimi nated by simply removing water with freeze-drying. Im- proved stability provides many benefits, such as storage at room temperature, convenient handling, extended shelf, and the capacity to distribute the product widely. However, freeze-drying is known to be a time consum- ing and expensive process. In fact, in many industries freeze- drying is rate-limiting process, because ofthe cost ofthe instrumentation and long drying cycles. fn order to develop an economical drying process, formulations should be opt- mized to get the maximum allowable temperature during pri- rary drying, which can be ether the collapse temperature oF the eutectic melting temperature. This wil allow the formu lations to be freeze-dried at higher temperatures without compromising the appearance of cake (1). A. sufficient knowledge of the structural state of the maximally freeze- concentrated matrix surrounding the ice crystals is neces- sary to optimize the formulation and the drying eyele so that the collapse of cake during the primary drying process is, avoided @, 7, 11). Thermal analysis techniques such as dif- ferential scanning calorimetry (DSC) have been successfully used to determine the collapse temperature and to monitor crystallization of constituents (1). Various process variables affect the efficiency of the freeze-drying. The product temperature is important be- cause the sublimation is generally faster at higher tempera- tures, but drying at temperatures above the collapse temper- ature may compromise the appearance of the cake. In addi- tion to visual problems, product in a collapsed cake often does not reconstitute easily. Although several mathematical models have been presented to describe sublimation rate uring the primary drying process, very litle practical infor- tation is available about how to optimize the process pa- rameters. Pikl (11) and Livesley et al. (6) have presented a ‘model in which the difference of chamber pressure and va- por pressure of ice at product temperature isthe major driv- ing force. Understanding the relative contribution of these parameters tothe sublimation rate isan important step inthe ‘optimization of «freeze-drying cycle and is also important to ain theoretical insight into what is important. ‘The purpose ofthis study was to find an efficient way to freeze

    You might also like