Publications
Chimica Oggi-Chemistry Today
Agro FOOD Industry Hi Tech
H&PCToday
     
 
     
p. 24-25 / OVERVIEW ON PEPTIDES
Significant recent eventsin peptide pharmaceuticals: enfuvirtide
GARY W. ERICKSON
Chief Executive Officer, CBL Biopharma, LLC

KEYWORDS: Pharmaceutical peptides, enfuvirtide, hybrid process, large scale solid phase synthesizers.

IT CAN’T BE DONE
In the mid 1990’s, HIV drugs were few and patients quickly developed resistance to these pharmaceutical agents. The peptide enfuvirtide (T-20 or Fuzeon) showed good efficacy as one of the first-in-class viral entry inhibitors.  The challenge was the peptide contained 36 amino acids and the demand would require manufacturing at the multi ton scale. Prior to enfuvirtide, the vast majority of chemically synthesized peptides contained less than 30 amino acids, were highly potent and required less than 50 kgs per year.   Many peptide experts expressed that enfuvirtide “It can’t be done”.  It was too complex, the tonnage too large and the cost would be prohibitive with the production methods at that time.   

”OPENING DOORS” ON PEPTIDE MANUFACTURING AND PEPTIDE DISCOVERY  
Despite the challenges, Trimeris and Roche were able to successfully commercialize enfuvirtide.  As a result, the drug has “opened doors” for several of today’s and future complex peptide pharmaceuticals.  In particular, enfuvirtide impacted and advanced the following synthetic methods and manufacturing areas.

HYBRID PROCESS
Enfuvirtide demonstrated the advantages of the “hybrid process” of chemically synthesizing complex peptides.  In this method, smaller side group protected peptide fragments are synthesized in high yield and purity by solid phase peptide synthesis (SPPS).  The fragments are cleaved from the super acid sensitive resin (2-chlorotrityl chloride resin) and precipitated.  The protected fragments are then coupled in solution, followed by removal of the side group protecting groups, purified by high pressure liquid chromatography and dried.

LARGE SCALE SOLID PHASE SYNTHESIZERS

Solid phase synthesizers were designed and built to produce fragments with a commercial batch size in the many hundreds of kgs.   The basic design of these reactors is now employed by several manufacturers in both small and large scale SPPS.

LOWER MANUFACTURING COSTS FOR ALL PRODUCERS
Enfuvirtide required many tons of raw materials, some of which had never been manufactured at more than tens of kilograms.  The success of raw material suppliers to meet the demand resulted in a precipitous drop in their per kg price.  The leverage of large scale batches and equipment for enfuvirtide has had a lasting effect on current complex peptides.

PRECIPITATION OF PEPTIDES 
Peptides were traditionally isolated and dried by the costly technique of lyophilization.  The commercial volumes of enfuvirtide demanded the more cost effective approach of precipitation and use of a conventional dryer.  Initially seven precipitations were developed to isolate the peptide fragments, intermediates and final peptide.

EXPANDING THE BOUNDARIES OF HIGH PRESSURE LIQUID CHROMATOGRAPHY
In order to avoid multiple chromatography systems and the operational costs associated with these, enfuvirtide...In order to continue reading this article please register to our website – registration is for free and no fees will be applied afterwards to download contents.

OurLatestIssues
Chemistry
Food
hpc
KeepInTouch
Teknoscienza Mobile
Teknoscienze - Viale Brianza 22, Milano - ITALY - P.IVA 06817720151
Teknoscienze S.r.l. © 2012 - tutti i diritti riservati - web terms & conditions - privacy - Credits