Impact of controlled ice nucleation on process performance and quality attributes of a lyophilized monoclonal antibody
Impact of controlled ice nucleation on process performance and quality attributes of a lyophilized monoclonal antibody
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DOI：
10.1016/j.ijpharm.2013.04.041
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发表时间：
2013-06-25
影响因子：
5.8
通讯作者：
Shah, Rakhi B.
中科院分区：
文献类型：
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作者：
Awotwe-Otoo, David;Agarabi, Cyrus;Shah, Rakhi B.
评价了一种有效且潜在可扩展的技术来控制模型单抗制剂的冷冻过程中的冰核步骤，并比较了该技术对最终冻干产品的工艺性能和质量属性的影响，并与传统的货架斜坡式冷冻方法进行了比较。受控成核在-2.3~-3.2℃范围内形成均匀成核，而不受控成核在-10~-16.4℃下形成随机成核。受控成核周期(0.13g/h/瓶)的一次干燥升华速率(dm/dt)高于非控制成核周期(0.11g/h/瓶)。这是由于形成了较大的冰晶，导致了较低的产品阻力(R-p)，并在受控成核周期的一次干燥过程中减少了19%。与未控制成核相比，受控成核可使冻干蛋糕外观更加美观，无明显塌陷或收缩，且重建时间缩短。在两次成核循环中，冻干蛋糕的颗粒大小、浓度(A(280)(Nm))和聚集体(A(410)(Nm)的存在没有观察到差异。SEC和Protein A-Hplc分析证实了这一点，它们在两个循环之间显示出相似的峰形和保留时间。然而，失控成核导致蛋糕的比表面积(0.90m(2)/g)大于受控成核(0.46m(2)/g)。未控制成核制得的冻干饼呈海绵状，孔洞较小，而控制成核制得的蛋糕呈板状结构，孔洞较大。当控制成核导致最终产品的残余水分含量(2.1+/-0.08%)高于未控制成核(1.62+/-0.11%)时，通过提高二次干燥温度来解决这一问题。爱思唯尔出版公司(Elsevier B.V.)
An efficient and potentially scalable technology was evaluated to control the ice nucleation step of the freezing process for a model monoclonal antibody formulation and the effect on process performance and quality attributes of the final lyophilized product was compared with the conventional shelf ramping method of freezing. Controlled ice nucleation resulted in uniform nucleation at temperatures between -2.3 and -3.2 degrees C while uncontrolled nucleation resulted in random nucleation at temperatures between -10 and -16.4 degrees C. The sublimation rate (dm/dt) during primary drying was higher in the controlled nucleation cycle (0.13 g/h/vial) than in the uncontrolled nucleation cycle (0.11 g/h/vial). This was due to the formation of larger ice crystals, leading to lower product resistance (R-p) and 19% reduction in the primary drying for the controlled nucleation cycle. Controlled ice nucleation resulted in lyophilized cakes with more acceptable appearance, no visible collapse or shrinkage and decreased reconstitution times compared with uncontrolled nucleation. There were no observed differences in the particle size, concentration (A(280) (nm)) and presence of aggregates (A(410) (nm)) between the two nucleation cycles when the lyophilized cakes were reconstituted. These were confirmed by SEC and protein A-HPLC analyses which showed similar peak shapes and retention times between the two cycles. However, uncontrolled nucleation resulted in cakes with larger specific surface area (0.90 m(2)/g) than controlled nucleation (0.46 m(2)/g). SEM images of the lyophilized cakes from uncontrolled nucleation revealed a sponge-like morphology with smaller pores while cakes from controlled nucleation cycle revealed plate-like structures with more open and larger pores. While controlled nucleation resulted in a final product with a higher residual moisture content (2.1 +/- 0.08%) than uncontrolled nucleation (1.62 +/- 0.11%), this was resolved by increasing the secondary drying temperature. Published by Elsevier B.V.