Albachem: Commercialisation of the chemical synthesis of biologically active human proteins
Submitting InstitutionsUniversity of St Andrews,
University of Edinburgh
Unit of AssessmentChemistry
Summary Impact TypeTechnological
Research Subject Area(s)
Chemical Sciences: Organic Chemistry
Biological Sciences: Biochemistry and Cell Biology, Microbiology
Summary of the impact
Impact: EaStCHEM spin out Albachem (1994), subsequently
incorporated into the Almac group,
enabling the latter company to become a world leader in the provision of
Significance: Chemical synthesis is competitive with recombinant
methods for commercial
production of the therapeutic polypeptides that represent ~50% of drugs in
big pharma pipelines
and have a market value in 2008 of over $13B. The value attributable to
Ramage's methods for
polypeptide syntheses over the REF period is estimated at approximately
Beneficiaries: Drug manufacturers, contract research
organisations, patients, clinicians.
Research: Studies (1993-6) led by Ramage (at the University of
Edinburgh) on new methods for
high-yield total syntheses and purification of long polypeptides.
Reach: Almac's protein-manufacturing team remains in the UK with
24 staff members. The Almac
Group, headquartered in N. Ireland, has 3300 employees globally (1300
outside UK) and sells to
600 companies worldwide.
Proteins and polypeptides are attractive research tools and therapeutic
agents. They combine
biological activity, low toxicity and high selectivity. But they are
expensive. While solid-phase
peptide synthesis was already a routine procedure, the cumulative outcome
of sub-100% yields for
each of many steps in the process had limited the length of peptides that
could be produced and
purified in useful quantities to < 50-60 amino acid residues. Most
biologically or clinically interesting
proteins are bigger. Furthermore, many proteins of interest to
biotechnology and pharmaceutical
companies contain disulfide bonds, creating additional challenges for
Professor Robert Ramage, FRS, of EaStCHEM recognised an unmet need for
synthesis using solid-phase chemistry as a versatile alternative to
recombinant gene expression.
From 1993-5 the Ramage group published, [1, 2] and patented  new
solid-phase and protecting
group methodologies for peptide synthesis. The work allowed the total
synthesis of hitherto
inaccessible long polypeptides. He demonstrated the usefulness of these
manufacturing biologically active proteins that provided detailed insights
Ramage recognised that resolution of the product from acetylated
truncated peptides was key. He
researched methods for derivatising the peptide N terminus with a
removable tag for affinity
purification on a solid support. He introduced the base-labile
tetrabenzo[a,c,g,i]fluorenyl-17-methoxycarbonyl (Tbfmoc) for affinity
purification on porous
graphitised carbon.[1,2] In a key paper, he described a convenient
synthesis of Tbfmoc and its
application to the production of proteins containing up to 85 amino acids.
The hydrophobicity of
Tbfmoc was further exploited to simplify peptide purification by
reverse-phase HPLC. The Ramage
group showed that Tbfmoc could be added directly to the N terminus rather
incorporated as a Tbfmoc-Gly(cine)-OH. Thus, crucially, any peptide could
be made with retention
of its native N-terminal residue. This discovery was patented (US Patent
No: 6,566,520, 2003) 
and paved the way for the spin out of Albachem (1994). The University
supported Albachem by
contributing infrastructure, funding, collaborations and technical
assistance to transfer crucial
knowhow from academia into the commercial environment. Albachem remained
University until 2002.
The utility of Tbfmoc was dramatically demonstrated in the production of
a biologically active
cytokine (monocyte chemoattractant protein 1, MCP-1). This contained 76
residues and two
disulfide bonds. Critically, Tbfmoc was removable under mild
conditions, preserving the nascent
protein product in a reduced state (-SH). Subsequent oxidative folding
yielded the correct disulfide
pattern and fully active cytokine. Albachem thus demonstrated to the world
its capability of
producing large quantities of purified cell-signaling proteins. This
established its credentials as a
world-leader. Cumulatively, the 1993, 1995 and 1996 papers underpinned
establishment, subsequent growth and assimilation into CSS that later
became the Almac group.
The Ramage group's work expanded protein therapeutics by facilitating
access to multiple-gram
quantities of material suitable for use in laboratories, animal models and
prospects are exciting. Routine recombinant methods for protein
production, besides being
expensive, provide little flexibility for new developments because the
building blocks are
constrained to genetically encoded amino acids. No such limitations apply
to synthetic proteins of
the kind accessible via strategies based on Tbfmoc and its
successors that can incorporate a vast
range of chemistries.
R. R. Ramage: PI, lead inventor on patents, from 09/84 to retirement in
A. R. Brown, S. I. Irving, G. Raphy, C. Jamieson: PhD students and PDRAs
in Ramage group.
Y. A. Lam, C. M. Pickart: collaborators, School of Public Health, Johns
Hopkins Univ., USA.
A. Alban, M. Landon, R. J. Mayer, R. Layfield: collaborators in
University of Nottingham Medical
References to the research
Underpinning research has been published in international,
high-quality, peer reviewed, academic
journals and receives citations from across the research area:
 * Affinity purification of synthetic peptides and proteins on porous
A. R. Brown, S. I. Irving, R. Ramage
Tet. Letters 1993, 34, 7129-7132. doi:10.1016/S0040-4039(00)61617-9.
26 cits, JIF 2.4.
 * (17-tetrabenzo[a,c,g,i]fluorenyl)methylchloroformate (tbfmocCl) a
reagent for the rapid and
efficient purification of synthetic peptides and proteins
A. R. Brown, S. I. Irving, R. Ramage, G. Raphy
Tetrahedron, 1995, 51, 11815-11830. doi:10.1016/0040-4020(95)00743-R.
17 cits, JIF 2.8.
 * A solid phase approach to quinolones using the DIVERSOMER®
A. A. MacDonald, S. H. DeWitt, E. M. Hogan, R. Ramage
Tet. Letters, 1996, 37, 4815-4818. doi:10.1016/0040-4039(96)00944-6.
45 cits, JIF 2.4.
 The total chemical synthesis of monocyte chemotactic protein-1
A. R. Brown, M. Covington, R. C. Newton, R. Ramage, P. Welch
J. Pept. Sci. 1996, 2, 40-46. doi:10.1002/psc.46.o.
8 cits, JIF 2.1.
 Inhibition of the ubiquitin-proteasome system in Alzheimer's disease
Y. A. Lam, C. M. Pickart, A. Alban, M. Landon, C. Jamieson, R. Ramage, R.
J. Mayer, R. Layfield.
Proc. Natl. Acad. Sci, USA. 2000, 97, 9902-9906. doi:10.1073/pnas.170173897.
198 cits, JIF 9.7.
 US Patent No: 6,566,520, 'Support for synthesis and purification of
compounds' filed 1999,
issued 2003). S. H. DeWitt, A. A. MacDonald, R. R. Ramage.
Details of the impact
Ramage's innovations in synthesis and purification of long polypeptides
Albachem as a world leader in the supply of chemically synthesised
The subsequent synthesis of biologically active peptides that afforded
insights into the structure-
function relationships of antimicrobial peptides , cytokines , and
the ubiquitination process 
demonstrated to the world the usefulness of Albachem's procedures. The
Almac group (at that
time CSS) noticed Albachem's success and recognising the future earnings
Albachem - thus taking a "quantum leap into protein synthesis".[S1] "The
allowed Almac to add very significant synthetic chemistry expertise to
its core competencies and,
critically, to establish a position at the interface between chemistry
and biology. Access to
Ramage's innovations transformed [Almac's] market differentiation by
allowing provision of
specialist services to its clients worldwide with a focus on the
The skills and expertise resident in Albachem and derived from Ramage's
original research, were
key [S3] to the Almac group's subsequent success in worldwide protein and
peptide sales (> £6M
revenue in REF period attributed to the technology described in Professor
Ramage's papers, not
including revenue generated through Almac's GMP capability that was built
on technical expertise
flowing from Albachem[S4]). Elaboration of the methodologies described in
Section 2 for the
chemical synthesis of long polypetides allows Almac to produce proteins in
high yield and purity.
Almac has made over 7000 peptides. Almac can also make polypeptides with
acids that offer new research avenues to their customers. They specialise
synthesised cytokines. There are >60 of these in their catalogue with
biotinylation and site-specific
fluorescent labelling or PEGylation available. "A legacy of a research
focus developed at ...
Edinburgh and in Albachem is our ongoing development of protocols for
synthesis of chemokines...
As well as being long polypeptides, chemokines are challenging to
manufacture because they
contain ... cysteines that form disulfide bridges following oxidation.
Starting from methods that are
founded on Ramage's original technologies, we have robust laboratory
protocols that have been
applied to several GMP campaigns on a range of chemokine products."
[S4] In effect, Albachem
became the specialist R&D arm of the Almac group that offers protein
and peptide services. "it is
easy to trace a clear pathway from research carried out in Professor
Ramage's lab in the early
1990s, through the spinning out of Albachem and its eventual acquisition
by Almac, to significant
past, present and future economic and health benefit impacts".[F1]
Almac is nowadays a global-reach company with 3300 staff (2000 in UK) and
a £300M turnover
with £14.3M profit in 2012 and total profits 2008-12 of £55M based on
sales to 600 companies
including all the market leaders. Peptide-based therapeutics represents
the fastest-growing class
of new drugs, accounting for ~2% of drugs on the market, but comprisinĝ50%
of drugs in the
pipelines of major drug manufacturers. The market for peptide drugs is
growing by 7.5% annually
and will be more than $13 billion this year.
2. Human Capital:
A total of 14 Almac employees (eight PhD level) remain in Gladsmuir, East
Lothian, Scotland, while
large-scale GMP polypeptide manufacture occurs in a dedicated facility
established (2006) by
Almac in Craigavon, employing a further 14 people. In the REF period "we
have trained many
chemists in peptide synthesis, in both full-time appointment and on
significant human capital contribution to the economy".[F1]
If it were not for Ramage's pioneering work with Tbfmoc, Almac — who
employ people around the
world — would have looked overseas when it chose to buy into the protein
synthesis business. They
may have not been able to make such rapid inroads into the market and
certainly would not be
employing any researchers in Scotland.
Impact Development Timeline:
1994 Albachem spun out from Ramage's research. Distinguishes itself by
its unique capacity to
2002 Current Operations Manager (PhD, University of Edinburgh 1995) joins
2004 CSS/Almac acquires and expands Albachem.[S3]
2005 The Almac Group further expands peptide synthesis efforts,
2006 Almac establishes a dedicated facility in Craigavon, employing a
further 14 staff.
2007 Almac announces' `First in Man' approach to peptides, embraces
development of peptide
synthesis, full analytical support, and GMP [batch production, and CMC
manufacturing and controls) documentation].[S1]
2008 The current Almac Operations becomes Senior Group Leader in protein
2013 Almac is fully established as a global-reach company with 3300 staff
(2000 in UK), £275M
turnover and £15M profit.
Sources to corroborate the impact
[S1] A 'First in Man' approach to peptides, article containing 'quantum
[S2] 'Integrating Technologies for Complete Chemical Synthesis'. Article
highlights the importance
of Ramage/Albachem to protein synthesis in Almac http://www.almacgroup.com/wp-content/uploads/Integrating_Technologies.pdf.
[S3] 'Broadening the Custom Synthesis portfolio'. Article explains how
crucial Albachem was seen
to be by CSS (CSS became part of Almac) http://www.almacgroup.com/wp-content/uploads/SP2_S_Barr_profile_July_20051.pdf.
[S4] 'Modern Perspectives on Peptide Synthesis'. Article by current Almac
Operations Manager in
his capacity as leader of protein synthesis for Almac. http://www.almacgroup.com/wp-content/uploads/Modern-Perspectives-on-Peptide-Synthesis.pdf.
[F1] Comments in corroborating letter made by the Operations Manager for