« LYOPHILIZATION
Table 1. Considerations for Freeze-Drying Process Design, Development, and Scale-Up
Criteria
Pre-lyophilization formulation characterization
Cycle development technology
Process characterization and robustness
Parameter(s) Tc, Tg’
MTM [4] Spectroscopic Techniques [5,6] PAT [7]
Mathematical modeling [4,8-12] QbD approach
Post-lyophilization product characterization
Appearance residual water reconstitution time crystallinity cake morphology α and β relaxation specifi c surface area density XRPD, SEM, BET
Impact
• Increase knowledge of formulation properties that defi ne the lyophilization cycle
• Reduce batch cost and cycle time
• Gain process understanding and ability to assess the impact of cycle excursions
• Identify Critical Process Parameters
• Improve understanding of formulation and process impact on drug product stability
• Identify Critical Quality Attributes
BET = Brauner-Emmett-Teller (for specifi c surface area measurement); QbD = Quality by Design; SEM = scanning electron microscopy; Tc = collapse temperature; TDLAS = tuneable diode laser absorption spectroscopy; Tg’ = glass transition temperature; XRPD = X-ray powder diff raction
drying above this temperature results in loss of cake structure. For an amorphous formulation matrix, the maximum allowable product
LYOPHILIZATION T E C H N O L O G Y ,
I N C . Integrating Science and Technology Development Sciences Clinical Manufacturing Technical Services
Product Design Formulation Development Design Space Studies Process Engineering Thermal Analysis Clinical Material Preparation
Technical Services Quality and Regulatory Support
On-site Training Consulting
30 INDIAN DRIVE • IVYLAND, PA 18974 USA PHONE +1 (215) 396-8373 • FA X +1 (215) 396-8375 w w w. l y o t e c h n o l o g y. c o m • i n q u i r y @ l y o - t . c o m
temperature is Tg’ (the glass transition temperature of the maximally freeze-concentrated solution) or Tc (the collapse temperature). For a low protein concentration, the Tc is 1 to 2°C higher than the Tg’ and, hence, the maximum allowable product temperature during primary drying is usually set to Tg’. Typically drying above Tg’ results in cake collapse, which could impact product stability. However, for a high concentration protein formulation, visible collapse may not be observed for drying significantly above Tg’ [13-15], which could result in a shorter cycle time and high throughput. Further, having data to support that drying above Tg’ does not compromise product quality is useful, for processes where product temperature is maintained below Tg’, to support temperature and pressure excursions that are occasionally encountered on production-scale dryers. Figure 1 clearly shows that Tc is within 1 to 2°C of Tg’ up to a protein concentration of about 50 mg/mL. However, at a protein concentration greater than 50 mg/mL, the difference between Tg’ and Tc increases significantly, and at 100 mg/mL the difference is approximately 8°C. This difference is critical for defining the maximum allowable product temperature during primary drying because, for every 1°C increase in product temperature, drying time decreases by approximately 13%. Thus, a systematic thermal characterization of the formulation matrix is essential to design, develop, and optimize the freeze-drying cycle.
www.americanpharmaceuticalreview.com |
| 79
»
Page 1 |
Page 2 |
Page 3 |
Page 4 |
Page 5 |
Page 6 |
Page 7 |
Page 8 |
Page 9 |
Page 10 |
Page 11 |
Page 12 |
Page 13 |
Page 14 |
Page 15 |
Page 16 |
Page 17 |
Page 18 |
Page 19 |
Page 20 |
Page 21 |
Page 22 |
Page 23 |
Page 24 |
Page 25 |
Page 26 |
Page 27 |
Page 28 |
Page 29 |
Page 30 |
Page 31 |
Page 32 |
Page 33 |
Page 34 |
Page 35 |
Page 36 |
Page 37 |
Page 38 |
Page 39 |
Page 40 |
Page 41 |
Page 42 |
Page 43 |
Page 44 |
Page 45 |
Page 46 |
Page 47 |
Page 48 |
Page 49 |
Page 50 |
Page 51 |
Page 52 |
Page 53 |
Page 54 |
Page 55 |
Page 56 |
Page 57 |
Page 58 |
Page 59 |
Page 60 |
Page 61 |
Page 62 |
Page 63 |
Page 64 |
Page 65 |
Page 66 |
Page 67 |
Page 68 |
Page 69 |
Page 70 |
Page 71 |
Page 72 |
Page 73 |
Page 74 |
Page 75 |
Page 76 |
Page 77 |
Page 78 |
Page 79 |
Page 80 |
Page 81 |
Page 82 |
Page 83 |
Page 84 |
Page 85 |
Page 86 |
Page 87 |
Page 88 |
Page 89 |
Page 90 |
Page 91 |
Page 92 |
Page 93 |
Page 94 |
Page 95 |
Page 96 |
Page 97 |
Page 98 |
Page 99 |
Page 100 |
Page 101 |
Page 102 |
Page 103 |
Page 104 |
Page 105 |
Page 106 |
Page 107 |
Page 108 |
Page 109 |
Page 110 |
Page 111 |
Page 112 |
Page 113 |
Page 114 |
Page 115 |
Page 116 |
Page 117 |
Page 118 |
Page 119 |
Page 120 |
Page 121 |
Page 122 |
Page 123 |
Page 124 |
Page 125 |
Page 126 |
Page 127 |
Page 128 |
Page 129 |
Page 130 |
Page 131 |
Page 132 |
Page 133 |
Page 134 |
Page 135 |
Page 136 |
Page 137 |
Page 138 |
Page 139 |
Page 140 |
Page 141 |
Page 142 |
Page 143 |
Page 144 |
Page 145 |
Page 146 |
Page 147 |
Page 148 |
Page 149 |
Page 150 |
Page 151 |
Page 152 |
Page 153 |
Page 154 |
Page 155 |
Page 156