Kilogram-Scale GMP Manufacture of Tirzepatide Using a Hybrid SPPS/LPPS Approach with Continuous Manufacturing

被引：41

作者：

Frederick, Michael O. ^{[2
]}

Boyse, Raymond A. ^{[1
]}

Braden, Timothy M. ^{[2
]}

Calvin, Joel R. ^{[2
]}

Campbell, Bradley M. ^{[2
]}

Changi, Shujauddin M. ^{[2
,3
]}

Coffin, Stephanie R. ^{[4
]}

Condon, Carmel ^{[1
]}

Gowran, Olivia ^{[5
]}

Groh, Jennifer McClary ^{[2
]}

Groskreutz, Stephen R. ^{[2
]}

Harms, Zachary D. ^{[2
]}

Humenik, Ashley A. ^{[1
]}

Kallman, Neil J. ^{[2
]}

Klitzing, Nicholas D. ^{[2
]}

Kopach, Michael E. ^{[2
]}

Kretsinger, Juliana K. ^{[6
]}

Lambertus, Gordon R. ^{[2
]}

Lampert, Jeffrey T. ^{[1
]}

Maguire, Laura M. ^{[1
]}

Moynihan, Humphrey A. ^{[1
]}

Mullane, Nessa S. ^{[1
]}

Murphy, John D. ^{[5
]}

O'Mahony, Marie E. ^{[1
]}

Richey, Rachel N. ^{[2
]}

Seibert, Kevin D. ^{[2
]}

Spencer, Richard D. ^{[1
]}

Strege, Mark A. ^{[2
]}

Tandogan, Nil ^{[2
]}

Torres, Frank L. Torres ^{[7
]}

Tsukanov, Sergey, V ^{[2
]}

Xia, Han ^{[2
]}

机构：

[1] Eli Lilly Kinsale Ltd, Tech Serv, Mfg Serv, Kinsale P17 NY71, Cork, Ireland

[2] Eli Lilly & Co, Lilly Res Labs, Synthet Mol Design & Dev, Indianapolis, IN 46285 USA

[3] Vertex Pharmaceut Inc, Engn & Mat Sci, 50 N Ave, Boston, MA 02210 USA

[4] Eli Lilly & Co, Commercializat Tech Ctr, Indianapolis, IN 46285 USA

[5] Eli Lilly Kinsale Ltd, Qual Control Labs, Kinsale P17 NY71, Cork, Ireland

[6] Eli Lilly & Co, Lilly Res Labs, Bioprod Res & Dev, Indianapolis, IN 46285 USA

[7] Eli Lilly & Co, Engn Tech Ctr, Indianapolis, IN 46285 USA

来源：

ORGANIC PROCESS RESEARCH & DEVELOPMENT | 2021年 / 25卷 / 07期

关键词：

tirzepatide; hybrid SPPS/LPPS synthesis; synthetic peptide; nanofiltration; PHASE PEPTIDE-SYNTHESIS; TECHNOLOGY; RECOVERY;

D O I：

10.1021/acs.oprd.1c00108

中图分类号：

O69 [应用化学];

学科分类号：

081704 ;

摘要：

The large-scale manufacture of complex synthetic peptides is challenging due to many factors such as manufacturing risk (including failed product specifications) as well as processes that are often low in both yield and overall purity. To overcome these liabilities, a hybrid solid-phase peptide synthesis/liquid-phase peptide synthesis (SPPS/LPPS) approach was developed for the synthesis of tirzepatide. Continuous manufacturing and real-time analytical monitoring ensured the production of high-quality material, while nanofiltration provided intermediate purification without difficult precipitations. Implementation of the strategy worked very well, resulting in a robust process with high yields and purity.

引用

页码：1628 / 1636

页数：9

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