PMID- 38508870
OWN - NLM
STAT- MEDLINE
DCOM- 20240408
LR  - 20240411
IS  - 1520-6904 (Electronic)
IS  - 0022-3263 (Print)
IS  - 0022-3263 (Linking)
VI  - 89
IP  - 7
DP  - 2024 Apr 5
TI  - Process Mass Intensity (PMI): A Holistic Analysis of Current Peptide 
      Manufacturing Processes Informs Sustainability in Peptide Synthesis.
PG  - 4261-4282
LID - 10.1021/acs.joc.3c01494 [doi]
AB  - Small molecule therapeutics represent the majority of the FDA-approved drugs. 
      Yet, many attractive targets are poorly tractable by small molecules, generating 
      a need for new therapeutic modalities. Due to their biocompatibility profile and 
      structural versatility, peptide-based therapeutics are a possible solution. 
      Additionally, in the past two decades, advances in peptide design, delivery, 
      formulation, and devices have occurred, making therapeutic peptides an attractive 
      modality. However, peptide manufacturing is often limited to solid-phase peptide 
      synthesis (SPPS), liquid phase peptide synthesis (LPPS), and to a lesser extent 
      hybrid SPPS/LPPS, with SPPS emerging as a predominant platform technology for 
      peptide synthesis. SPPS involves the use of excess solvents and reagents which 
      negatively impact the environment, thus highlighting the need for newer 
      technologies to reduce the environmental footprint. Herein, fourteen American 
      Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) 
      member companies with peptide-based therapeutics in their portfolio have compiled 
      Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in 
      peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes 
      at various development stages in pharma, classified according to the development 
      phase. This is the most comprehensive assessment of synthetic peptide 
      environmental metrics to date. The synthetic peptide manufacturing process was 
      divided into stages (synthesis, purification, isolation) to determine their 
      respective PMI. On average, solid-phase peptide synthesis (SPPS) (PMI  approximately  13,000) 
      does not compare favorably with other modalities such as small molecules (PMI 
      median 168-308) and biopharmaceuticals (PMI  approximately  8300). Thus, the high PMI for 
      peptide synthesis warrants more environmentally friendly processes in peptide 
      manufacturing.
FAU - Kekessie, Ivy
AU  - Kekessie I
AUID- ORCID: 0009-0000-2844-9051
AD  - Early Discovery Biochemistry - Peptide Therapeutics, Genentech, Inc., A Member of 
      the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States.
FAU - Wegner, Katarzyna
AU  - Wegner K
AD  - Active Pharmaceutical Ingredient Development, Ipsen Manufacturing Ireland Ltd., 
      Blanchardstown Industrial Park, Dublin 15, Ireland.
FAU - Martinez, Isamir
AU  - Martinez I
AD  - Green Chemistry Institute, American Chemical Society, 1155 16th St North West, 
      Washington, District of Columbia, 20036, United States.
FAU - Kopach, Michael E
AU  - Kopach ME
AUID- ORCID: 0000-0002-3590-702X
AD  - Synthetic Molecule Design and Development, Eli Lilly and Company, Indianapolis, 
      Indiana 46285, United States.
FAU - White, Timothy D
AU  - White TD
AD  - Synthetic Molecule Design and Development, Eli Lilly and Company, Indianapolis, 
      Indiana 46285, United States.
FAU - Tom, Janine K
AU  - Tom JK
AUID- ORCID: 0000-0002-3531-8751
AD  - Drug Substance Technologies, Amgen, Inc., 1 Amgen Center Drive, Thousand Oaks, 
      California 91320, United States.
FAU - Kenworthy, Martin N
AU  - Kenworthy MN
AD  - Chemical Development, Pharmaceutical Technology & Development, Operations, 
      AstraZeneca, Macclesfield, SK10 2NA, United Kingdom.
FAU - Gallou, Fabrice
AU  - Gallou F
AUID- ORCID: 0000-0001-8996-6079
AD  - Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland.
FAU - Lopez, John
AU  - Lopez J
AUID- ORCID: 0000-0002-0551-6511
AD  - Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland.
FAU - Koenig, Stefan G
AU  - Koenig SG
AUID- ORCID: 0000-0002-1878-614X
AD  - Small Molecule Pharmaceutical Sciences, Genentech, Inc., A Member of the Roche 
      Group, 1 DNA Way, South San Francisco, California 94080, United States.
FAU - Payne, Philippa R
AU  - Payne PR
AD  - Outsourced Manufacturing, Pharmaceutical Development & Manufacturing, Gilead 
      Alberta ULC, 1021 Hayter Rd NW, Edmonton, T6S 1A1, Canada.
FAU - Eissler, Stefan
AU  - Eissler S
AD  - Bachem AG, Hauptstrasse 144, 4416 Bubendorf, Switzerland.
FAU - Arumugam, Balasubramanian
AU  - Arumugam B
AD  - Chemical Macromolecule Division, Asymchem Life Science (Tianjin) Co., Ltd., 71 
      Seventh Avenue, TEDA Tianjin 300457, China.
FAU - Li, Changfeng
AU  - Li C
AD  - Chemical Macromolecule Division, Asymchem Life Science (Tianjin) Co., Ltd., 71 
      Seventh Avenue, TEDA Tianjin 300457, China.
FAU - Mukherjee, Subha
AU  - Mukherjee S
AUID- ORCID: 0000-0002-9359-990X
AD  - Chemical Process Development, Bristol Myers Squibb, New Brunswick, New Jersey 
      08903, United States.
FAU - Isidro-Llobet, Albert
AU  - Isidro-Llobet A
AUID- ORCID: 0000-0001-9108-5916
AD  - GSK, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, U.K.
FAU - Ludemann-Hombourger, Olivier
AU  - Ludemann-Hombourger O
AD  - PolyPeptide Laboratories France SAS, 7 Rue de Boulogne, 67100 Strasbourg, France.
FAU - Richardson, Paul
AU  - Richardson P
AUID- ORCID: 0000-0002-3700-8749
AD  - Chemistry, Pfizer, 10578 Science Center Drive (CB6), San Diego, California 09121, 
      United States.
FAU - Kittelmann, Jorg
AU  - Kittelmann J
AD  - CMC API Development, Novo Alle, 2880 Bagsvaerd, Denmark.
FAU - Sejer Pedersen, Daniel
AU  - Sejer Pedersen D
AUID- ORCID: 0000-0003-3926-7047
AD  - Chemical Development, Novo Alle, CMC API Development, 2880 Bagsvaerd, Denmark.
FAU - van den Bos, Leendert J
AU  - van den Bos LJ
AD  - EnzyTag B.V, Daelderweg 9, 6361HK, Nuth, Netherlands.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Review
DEP - 20240320
PL  - United States
TA  - J Org Chem
JT  - The Journal of organic chemistry
JID - 2985193R
RN  - 0 (Peptides)
RN  - 0 (Solvents)
SB  - IM
MH  - *Peptides/chemistry
MH  - Chemistry Techniques, Synthetic
MH  - *Solid-Phase Synthesis Techniques
MH  - Solvents
PMC - PMC11002941
COIS- The authors declare the following competing financial interest(s): K.W. is an 
      employee of IPSEN and owns stock or stock options. M.N.K. is an employee of 
      AstraZeneca and owns stock or stock options. S.M. is an employee of Bristol Myers 
      Squibb and owns stock or stock options. J.L. and F.G. are employees of Novartis 
      and own stock or stock options. L.J.vdB. owns stock or stock options in EnzyTag. 
      O.L.H. is an employee of PolyPeptide Laboratories. B.A. and C.F. Li are an 
      employee of Asymchem Life Science own stock or stock options. A.I-L. is an 
      employee of GSK and owns stock or stock options. I.A.K. and S.G.K. are employees 
      of Genentech, a Member of the Roche Group, and own stock or stock options. M.E.K. 
      is an employee of Eli Lilly and Company. S.E. is an employee of Bachem and owns 
      stock or stock options. P.R. is an employee of Pfizer Inc. and owns stock or 
      stock options. D.S.P. is an employee of Novo Nordisk and owns stock. J.K. is an 
      employee of Novo Nordisk and owns stock. All other authors declare no competing 
      financial interest.
EDAT- 2024/03/21 00:44
MHDA- 2024/04/08 06:42
PMCR- 2024/04/09
CRDT- 2024/03/20 22:32
PHST- 2024/04/08 06:42 [medline]
PHST- 2024/03/21 00:44 [pubmed]
PHST- 2024/03/20 22:32 [entrez]
PHST- 2024/04/09 00:00 [pmc-release]
AID - 10.1021/acs.joc.3c01494 [doi]
PST - ppublish
SO  - J Org Chem. 2024 Apr 5;89(7):4261-4282. doi: 10.1021/acs.joc.3c01494. Epub 2024 
      Mar 20.