INSIDE THIS ISSUE...

18

Contents
5 ......... From the editor – Second coming
6 ......... News
14 ....... US global view: Balancing deregulation with
............ quality and integrity
15 ....... Europe global view: Parting with plastic
66 ....... People

EVENTS
16 ....... Calendar
18 ....... Specialty & Custom Chemicals America:
............ Chemicals in cowboy country
20 ....... Specialty & Custom Chemicals America:
............ Exhibitor insight

PHARMACEUTICALS
22 ....... Managing and redesigning chemical processes with enzymes
26 ....... Continuous processing in pharma
30 ....... Novel approaches to ADC manufacturing 28
AGROCHEMICALS
51
34 ....... Can Russia supply its own needs?

COSMETICS & PERSONAL CARE

38 ....... Clays go with the flow

MATERIALS, OILS & ENERGIES

40 ....... Fuel cell catalyst research continues

FOCUS ON PEPTIDES & PROTEINS

44 ....... ‘Needle to needle’: Manufacturing neoantigen peptides
48 ....... Advanced SPPS
54 ....... CDMOs expand capacity to support recent
............ market trends

SPECIAL FEATURE
56 ....... SOCMA annual dinner: Lead generation and
............ audit efficiency to the fore

REGULATION & COMPLIANCE

58 ....... Readying the ship for ‘no deal’
62 ....... REACH and a no-deal Brexit

58
DCAT member company

www.specchemonline.com FEBRUARY 2019 • Speciality ChemicalS Magazine • 3

 From the Editor

Publishing Director: Jon Fellows

Operations Director: Andrew Stevens
Head of Production: Charles Dragazis
Editor: Dr Andrew Warmington
editor@specchemonline.com
US editor: Gregory Morris
gdlm@enterpriseandindustry.com
Europe editor: Vanessa Zainzinger
vanessa.zainzinger@gmail.com
Project Manager: Steph Cotter
Design: Andrew Pollard
Global Commercial Manager:
Russell Priestley
russell@specchemonline.com
North American Sales: Greg Pigott
greg@specchemonline.com
Japan and South Korea Agent:
(Mizo) Sadao Mizoguchi
mijinc7@ybb.ne.jp
Global Agent:
Ben Jones
bjones@centurygloballlc.com
Second coming
@specchemmags As you can probably tell from the photo, it’s not Charlotte any more!
After two years away, I am very pleased to be back as editor of
Speciality Chemicals Magazine is owned and
published by TRMG Ltd.
Speciality Chemicals Magazine with effect from this issue. Charlotte
has just taken up an appointment as deputy news editor at Chemical
Watch, as the former deputy news editor has been promoted to replace,
er, me as commissioning editor there. It’s a very small world in
TRMG Ltd chemicals journalism…
Winchester Court Going forward, I am looking forward to reconnecting with old friends
1 Forum Place, Hatfield
Herts, AL10 0RN, UK
and contacts at industry events and otherwise. First stop will be DCAT
Tel: +44 (0)1707 273999 Week in New York in March, so if you are going to be there – especially
www.trmg.co.uk if you have news in the pipeline or technology innovations to discuss in
While every effort is made to ensure the
more detail, please get in touch to set up a meeting. Then it will be
accuracy of this publication, TRMG Ltd and In-Cosmetics in Paris in April and, of course, Chemspec Europe in June.
the editor cannot accept liability for any Things are never quite the same when you go back. The magazine
statement or error contained herein.
© Speciality Chemicals Magazine 2019
I have inherited has a different owner in TRMG, which is a dedicated
publisher with a strong belief in print, a different layout and a different
SUBMISSION GUIDELINES editorial calendar to the one I left in September 2016. And the fine
Speciality Chemicals Magazine welcomes
and chemicals industry never stands still. There have been plenty of
contributions from academia and industry.
changes that have passed me by while I was focusing on different parts
• News and commentaries, up to 200 words of the industry.
with one accompanying table or graphic;
So I am interested to hear from you about what direction you think we
• Feature articles, typically up to 800 words
with two tables or graphics. should be taking SCM. Does the schedule, always with the same very
broad feature headings of Pharmaceuticals, Agrochemicals, Cosmetics &
Submissions should be made by email to the editor
(editor@specchemonline.com). We will let you know Personal Care, Materials, Oils & Energies and Regulation & Compliance,
within three weeks if your contribution has been accepted
for publication. All submissions are subject to review
address your needs? Or did you like it better of old, when we had more
by the editor. If accepted, content may be edited and/ different features, each of them appearing less often? It’s a cliché, I
or abridged, to ensure it is in line with the values,
requirements and style of the magazine. know, but this is your magazine, not mine. There are plenty of other
Articles not accept for the magazine might be
considered for online publication only. Online publications publications and plenty of other information sources out there. We are
may also be included in our fortnightly newsletter.
Feature articles must have a technical (rather
here to be the best and serve you.
than marketing or promotional) focus. They may This month we feature a wide array of feature articles from industry
concentrate on a specific industry sector (for example,
pharmaceuticals, agrichemicals, cosmetics and personal and from our team of global reporters. I am now planning towards the
care) but should be understandable to experts in all fields.
To this end, please start your main article with a brief
April and May issues, so your ideas are welcome. This issue also has two
explanation of the topic and define abbreviations that articles on Brexit, the very thorny and immediate issue that is consuming
might not be widely known. Where appropriate, facts cited
in your article should be referenced. Intelligent insights so much of Europe’s energy right now. We run to a monthly schedule
into the state and future of industry are encouraged.
Headings should be no longer than 12 words and
and things are changing so fast almost every day that it is possible that
a short stand-first is required, summarising the content they will be out of date by when you read this. But at the time of going
of the article and giving the name and affiliation of the
author, in under 30 words. Figures and tables should be to press, a ‘no-deal’ Brexit was still very much a possibility, so we have
numbered and each should be provided with a caption.
Text should be submitted in Word format. Bar charts, line included them. Rarely has the traditional Arabic curse of ‘May you live in
graphs and other graphical representations of data should
be provided as separate files in an editable format (for
interesting times’ seemed so true.
example, xls). Chemical formulae should be provided in
PDF format and photographs must have a minimum 300
dpi to enable colour printing. Dr Andrew Warmington
EDITOR

www.specchemonline.com FEBRUARY 2019 • Speciality ChemicalS Magazine • 5

GLOBAL NEWS
Four become one in Seqens
Pharmaceutical synthesis and
speciality ingredients firm Novacap
has announced that it is combining
all of its CDMO subsidiaries – PCI
Synthesis, PCAS, Uetikon and Protéus
– into a new company called Seqens.
This is being rolled out over the 24
manufacturing plants and three R&D
centres in Europe, North America and
Asia during Q1, with signage and
websites being updated accordingly.
The management teams at each
operation will remain in place.
“As Seqens, we can better leverage
our strong expertise to develop and
produce highly complex molecules
with unique skills and the largest
continuum of technologies available
on the market. I am proud of
what we have achieved so far,
working across a range of fields
such as QHSE, industrial methods
Animal NGO criticises
ECHA on testing
NGO Cruelty Free International
has launched a European-wide
petition to stop the European
Chemicals Agency (ECHA) from
“unlawfully flouting European
cosmetics animal testing bans”.
The agency, it says, “is interpreting
the bans so narrowly as to render
them pointless” by asking for tests
on substances used mainly or
exclusively on cosmetics, ostensibly
on the grounds of worker safety.
Recent examples have included
octocrylene and triclosan, which
are respectively used as a UV filter
and a preservative in cosmetics.
“The point has come where
many cruelty-free brands are
no longer able to reformulate
their products because of the
steady creep of regulatory testing
and could be faced with having
6 • Speciality ChemicalS Magazine • February 2019
and processes, quality, sales and
marketing, finance, innovation,
legal and more,” said Pierre Luzeau,
formerly CEO of Novacaps and now
CEO of Seqens.
Novacaps said that the name
“refers naturally to the company’s
core synthesis activities, combined
with the sequencing of molecules,
competencies and technologies to
take science to the next level”.
Seqens will have about 3,200
employees, including more than
300 scientists, engineers and other
experts, working on the development,
scale-up and manufacturing of
drug substances from pre-clinical
through to commercial phase. It
also has a portfolio of APIs and
proprietary products, and is active in
the electronics, cosmetics, food and
home care sectors.
to withdraw large numbers of
products,” said Dr Katy Taylor,
director of science and regulatory
affairs. She called on consumers
and cosmetics companies to
register their disquiet and urged
all to look to the Leaping Bunny
certificate as the best assurance
that products and ingredients are
‘cruelty-free’.
R The Leaping Bunny is the logo certifying
‘cruelty-free’ production
In brief
Innospec opens new lab
Speciality chemicals firm Innospec
has completed construction on
its new innovation centre at The
Woodlands, Texas. This covers
just over 2,000 m2, increasing
laboratory space by 70%, and
will be dedicated to developing
technologies and applications
for the oil and gas industry,
covering all aspects of drilling,
fracturing, stimulation, completion,
production and midstream
activities. It will house all of
the research, development and
technical services functions and be
the consolidated base for the sales
and customer service teams.
Coagulant reorganisation
Tessenderlo Group subsidiary
Produits Chimiques de Loos (PCL)
is to increase capacity for its
Ecoferric iron-based coagulants
by 25% at Loos, France, over the
next three years. This will include
expansions, modernisation and
streamlining the diverse raw
material sources used. Some
of the new capacity will come
onstream in 2019. It follows
on from the modernisation and
expansion of the site’s membrane
electrolysis facility for chlorine,
sodium hydroxide and potassium
hydroxide.
ADC linker deal signed
Johnson Matthey has concluded
a strategic manufacturing
partnership for the large-
scale production of CL2A-
SN-38, the drug-linker used
in Immunomedics’ lead
antibody-drug conjugate (ADC),
sacituzumab govitecan. This drug
is currently under priority review at
the FDA for accelerated approval
and, if approved, would be the
first therapy for metastatic triple-
negative breast cancer. CL2A-
SN-38 is produced at Johnson
Matthey’s facility in Devens,
Massachusetts.
www.specchemonline.com

Nouryon launches third ‘Imagine Chemistry’
Nouryon, the former AkzoNobel
Specialty Chemicals, has launched
the third edition of its ‘Imagine
Chemistry’ collaborative innovation
challenge, under which start-ups,
scale-ups, university spin-outs
and other potential partners are
invited “to tackle chemistry-related
challenges and uncover new ways to
create value for customers”.
Participants can submit their ideas
via the dedicated website
(www.imaginechemistry.com)
until 8 March. In May, 20 finalists
will be invited to an intensive three-
day event at Nouryon’s RD&I centre
at Deventer, Netherlands, to work
with experts and business leaders
to further develop their ideas into a
joint value case. The 2019 edition
features five programmes:
£ Sustainable bio-based surfactants
for everyone (in partnership with
Unilever): novel bio-based, non-
hazardous surfactants and building
blocks for new surfactants
£ Performance-boosting
nanoparticles: small-particle means
to make products more sustainable,
durable, and/or functional
£ Sensing in demanding chemical
environments: innovative sensing
systems to help Nouryon’s own
chemical processes approach
100% resource efficiency
www.specchemonline.com
£ Label-free chemistries: products with
ingredients that require no chemical
warning labelling and which can
safely and simultaneously control
interface and fluid properties
£ Pushing the frontiers of chemical
innovation: an open challenge for
innovative ideas on developing
more sustainable chemistry
The programme partners have
also been expanded to include:
Unilever; seed investor High-Tech
Gründerfonds; the Green Chemistry
& Commerce Council (GC3),
which seeks to drive the commercial
adoption of green chemistry; venture
capital firm Icos Capital; research
and advisory firm Lux Research; UK
innovation agency Knowledge
Transfer Network; Dutch
accelerator StartupDelta; the
European Commission’s Enterprise
Europe Network; and S/park, the
chemical technology-focused open
innovation centre at Deventer.
Separately, Nouryon has opened a
new headquarters office in Mumbai
that brings together research, sales
and business support functions as
it expands in India. The company
is currently upgrading an organic
peroxides facility in Mahad and
a monochloroacetic acid plant in
Gujarat, the latter being a joint
project with local chemicals
manufacturer Atul.
february 2019 • Speciality ChemicalS Magazine •
In brief
Genomatica goes commercial
Genomatica has announced
large-scale commercial production
of its Brontide natural butylene
glycol, which is used in personal
care to replace petroleum-
based glycol in new and existing
formulations. The company said
that it has produced over 600
tonnes in less than five weeks,
packaged in thousands of drums,
at a Novamont fermentation-
based production plant in Italy. It
will be supplied to Daicel, Azelis
and Viachem to meet rising
demand from their customers.
Clariant in Saudi deal
Clariant has signed a
memorandum of understanding
with Saudi Kayan, an affiliate of
its largest shareholder, Sabic, to
evaluate forming a joint venture
to establish a manufacturing
facility for alkoxylates. This would
combine Clariant’s production
technology with Saudi Kayan’s
raw materials and would be
based in the latter’s Petrochemical
Company complex at Jubail
Industrial City. Alkoxylates are
produced from ethylene oxide
and used in many applications in
Clariant’s home care, personal
care and industrial applications
segments.
Nanomilling programme
Lubrizol subsidiary Particle
Sciences has launched its
new ‘Nanomilling Feasibility
Programme’, which is designed
to assess nanomilling as a
dissolution and solubility
enhancement option for poorly
water-soluble APIs. Under this,
it would nanomill a client API
with GRAS-approved excipients,
measure particle size distribution
and obtain short-term stability
data to identify promising
formulations, then send pre-
clinical test samples back for
pharmacokinetic studies, all within
eight weeks in some cases.
7
GLOBAL NEWS

Cambrex completes Avista buy

Cambrex has completed the acquisition of contract
development, manufacturing and testing firm Avista
Pharma Solutions from Ampersand Capital Partners,
as announced on 20 November 2018. Avista’s four
sites at Durham, North Carolina, Longmont, Colorado,
Agawam, Massachusetts, and Edinburgh, UK, plus its
service offer, will be integrated into Cambrex’s global
network, bringing this to 12 facilities employing about
2,000 people.
The company said that this buy would strengthen
its position as “the leading, fully integrated small
molecule CDMO across the entire drug lifecycle”.
Avista brings in further API and drug product
development and cGMP manufacturing capabilities, Carolina, in response to a growing number of new
plus stand-alone analytical, microbiology testing and projects. In total, it will fit out 120m2 of analytical
solid-state sciences. laboratory space and will hire nine chemical R&D and
“Adding Avista today and Halo Pharma in September six analytical R&D scientists, as well as installing ten
significantly increases our customer base and funnel of UPLC instruments.
projects, provides significant cross-selling opportunities The fit-out and expansion is expected to be completed
and allows us to offer an integrated service offering by the end of the year. It follows on from a $3.2 million
for most small molecules from the pre-clinical stage investment in a 1,020m2 analytical laboratory, which
through the commercial stage,” commented Steve was completed in April 2018. This brings to $9 million
Klosk, president and CEO of Cambrex. Halo had the level of investment by Cambrex at High Point. The
brought in extra formulation development and finished site was acquired as part of PharmaCore in 2016. It
dosage manufacturing. produces complex APIs and intermediates requiring
Earlier, Cambrex had also announced that it is multi-step synthetic processes in batches from mg to up
investing $1 million at its site in High Point, North to 100kg for Phase I-II clinical trials

Brenntag shuffles the decks

Brenntag, the world’s largest chemical
distributor, has continued to adapt
its portfolio. It has acquired Pachem
Distribution in Canada, adding
an expected €13 million/year to
revenues, and almost simultaneously
sold its Danish-based vaccine
adjuvant production subsidiary
Brenntag Biosector to Croda
International for €72 million in cash.
Based in Montreal and dating back
to 1993, Pachem mainly distributes
about 2,000 speciality chemicals
and ingredients to customers in the
personal care, pharmaceuticals,
and household, industrial and
institutional cleaning markets. It has
a fully equipped application and
formulation laboratory for personal
care, offering technical and R&D
services for customers and suppliers.
Current president Paul Caghassi will
remain at the helm.
Markus Klaehn, CEO of Brenntag
North America, said that the buy
“is in line with our focus industry
growth strategy as it strengthens
Brenntag’s specialties capabilities in
the life science segments in Canada”.
Synergies are expected from
complementary product portfolios
and leverage from a larger combined
customer base. The deal also gives
Brenntag Canada “access to prime
product lines for personal care
specialties of key suppliers,” he said.
Brenntag Biosector, meanwhile
supplies the Alhydrogel and
Adju-Phos brands of aluminium-
based adjuvants, plus aponin-based
adjuvants for both human and
veterinary vaccines, from its facility in
Frederikssund, Denmark. Brenntag
said that it “holds a unique position
within the Brenntag Group and,
although very successful, it is a
non-core business for us”.
Croda itself already offers
pharmaceutical excipients through
its Health Care business and views
this as an important extension of its
capabilities in the field. As a result,
it said, it will not only have access to
the existing brands and Biosector’s
development pipeline for second
and third generation adjuvant
platforms but will also become
the only supplier in the world
with an aseptic and GMP-certified
manufacturing site for vaccine
adjuvants. Biosector managing
direction Peter Tygesen will remain
in his position.

8 • Speciality ChemicalS Magazine • february 2019 www.specchemonline.com

BASF to expand MSA
BASF has announced plans to expand capacity for its
Lutropur brand of high-purity methane sulfonic acid
(MSA) at the Ludwigshafen verbund site (pictured)
by around 65% to about 50,000 tonnes/year. The
additional volumes are expected to be available
worldwide in late 2021. The company’s Care
Chemicals division is already the world market leader.
MSA is a strong organic acid that is used in
applications from chemical and biofuel synthesis
to industrial cleaning and metal surface treatment
in the electronics industry. It is marketed as an
environmentally friendly alternative to sulfuric,
phosphoric and acetic acids, which is readily
biodegradable as well as non-oxidising, colour- and
odour-free and with highly soluble salts.

Lonza plans China

biologics facility
Lonza Pharma & Biotech has concluded an agreement,
under which GE Healthcare will deliver an off-the-shelf
biologics facility to it in Guangzhou, China, by 2020.
The company said that the new facility would give it “a
strategic base in China to respond to growing demand
for high-quality CDMO services in the country”.
The 17,000m2 site will include 6,500m2 of lab
space for Lonza’s proprietary cell-line construction,
including the GS gene expression system, process
development, cell banking and pilot labs. It will
also house a KUBio unit for small-scale GMP R Lonza facility in China
manufacturing of antibodies, equipped with
GE’s single-use biomanufacturing technologies, of understanding with the GDD to take the project
including 1,000- and 2,000-litre bioreactors, forward.
plus Lonza’s automation platforms for clinical and Lonza Pharma & Biotech now has a global biologics
early commercial supply. This is all part of a wider network offering development and manufacturing at
initiative between GE Healthcare and the Guangzhou every stage. This includes small-, mid- and large-scale
Development District (GDD) to develop further the assets in Switzerland, the US, the UK, Spain
large-scale manufacturing of biopharmaceuticals and Singapore. The Chinese facility will have about
in China. Lonza has also signed a memorandum 160 employees.

www.specchemonline.com febrUARY 2019 • Speciality ChemicalS Magazine • 9

GLOBAL NEWS
Roquette acquires
most of Crest
S Buying Pravesha takes Roquette further into India
France’s Roquette has completed
the acquisition of a majority stake
in Crest Cellulose, from Pravesha
Industries, a major pharmaceutical
packaging company in India, and
formed a joint venture with Pravesha.
Crest has facilities in Hyderabad and
Nellore and makes a wide range
of pharmaceutical excipients. Terms
were not disclosed.
The company said that this
addition will reinforce its position
“as a major supplier to the
pharmaceutical industry and a
global leader in superior natural-
based pharmaceutical excipients”.
It follows the acquisition of Blanver
Pharmaceutical’s excipients division in
2017 and takes Roquette further into
the Indian pharmaceuticals sector,
which has been growing at 10%/year
and reached $33 billion in 2017.
Paul Smaltz, vice president
of the Roquette Pharma global
10 • Speciality ChemicalS Magazine • febrUARY 2019
business unit, commented: “With
its manufacturing plant designed
and built according to the highest
pharma standards and quality
systems, Crest Cellulose will enlarge
our cellulose-based excipients
offering to customers with superior
solutions and will bring us closer
to our customers in India and the
whole of Asia.”
The company has also concluded
an agreement with Thermo Fisher
for the distribution of its portfolio
of pharmaceutical ingredients in
the US and Canada, including the
newly launched Kleptose BioPharma
HPB and HP grades hydroxypropyl
ß-cyclodextrins, some recently
acquired microcrystalline cellulose
products and other excipients.
The latter will bring its Doe & Ingalls
brand of chemical storage and
supply chain services to
the agreement.
In brief
Tosoh takes stake in Semba
Via its Tosoh Bioscience division in
the Americas, Japan’s Tosoh,
a chlor-alkali giant that is also
active in the life sciences, is to take
a 33.3% stake in chromatography
firm Semba Biosciences. Tosoh
said that this will help it to build
synergies with its Toyopearl liquid
chromatography separation
and purification media business
and expand to related fields,
“thereby moving towards its goal
of becoming a total solutions
provider in the biopharmaceutical
purification field”. Terms were
not disclosed.
Firm goes aniline-free
Following testing at its mill to
ensure equal performance in
operation, Absolute Denim,
a Thailand-based denim
manufacturer that makes up to
1.5 million pairs of jeans/month,
has become the first company to
switch all of its indigo dyeing to
Archroma’s aniline-free system.
Instead, it is using Denisol Pure
Indigo 30 liquid dye, which the
Swiss firm launched in May 2018
as “a non-toxic way to produce the
traditional, iconic indigo blue that
consumers associate with denim
and jeans”.
Electrolyte expansion
Mitsubishi Chemical plans to
increase capacity for formulated
electrolyte in lithium-ion batteries
at its Yokkaichi plant in Japan from
11,000 to 16,000 tonnes/year, by
debottlenecking the manufacturing
process, more efficient shipping
and transportation, and digitalising
the product inspection process. This
comes in response to rapid growth
in demand for electric and hybrid
vehicles, particularly in Japan itself,
where they account for about 25%
of all passenger vehicle sales.
www.specchemonline.com

Albemarle takes
stake in Australian
lithium production
Speciality chemicals giant
Albemarle has concluded an
$11.5 billion asset sale and
share subscription agreement
with Australian mining firm Mineral
Resources (MRL). Under this, it
will take a 50% stake in MRL’s
Wodgina hard rock lithium project
in Western Australia and form a
50-50 joint venture with MRL to
produce spodumene concentrate
and battery-grade lithium hydroxide
(LiOH). The deal excludes the
mineral rights, iron ore and
tantalum.
Following on from completion,
which is expected in 2H 2019,
and the construction and ramp-up
of the spodumene concentration
plant, the project is expected to
produce approximately 100,000
tonnes/year of lithium carbonate
equivalent (LCE). This will be
used as feedstock for a future
plant to make battery-grade
lithium hydroxide, using
Albemarle technology.
This follows the signing on
21 November of an exclusivity
agreement between Albemarle and
MRL in relation to the potential
joint venture. CEO Luke Kissam
described this as “consistent with
our corporate strategy of pursuing
M&A opportunities that can
accelerate and de-risk our organic
growth strategy”. Wodgina has an
estimated 30 years+ of mine life
and is said to be a world-class hard
rock lithium deposit.
As part of this development,
the company has since begun
earthworks at the Kemerton
Strategic Industrial Area, where its
LiOH) conversion site is located.
This followed on from the required
environmental approval from the
Australian federal and the Western
Australia state government for the
Kemerton plant. Due onstream in
stages during 2021, the site will
have an initial capacity of 60,000
tonnes/year and will be able to
expand to 100,000 in time.

Italmatch to buy BWA Water Additives

Genoa-based Italmatch Chemicals, a speciality chemicals company
focused on additives for water and process treatment, oil and gas, industrial
lubricants and plastics, has signed an agreement to acquire BWA Water
Additives, which is also active in the oil and gas, industrial water treatment
and desalination industries. The deal, for which terms were not disclosed, is
expected to close in Q1 2019, subject to customary regulatory approvals. It
will be financed by a mixture and debt and equity.
Italmatch, which is owned by private equity firm Bain Capital, commented:
R BWA will add substantially to Italmatch’s “This combination of two highly complementary companies allows the
water treatment capabilities development of strategic, commercial and industrial synergies, consistent with
the aim of expanding and broadening our current production and marketing
capabilities for water management chemicals”.
Italmatch dates back to 1997 and currently has seven sites in Europe, five in the Asia-Pacific region and five in
North America, with sales and distribution subsidiaries in eight other countries. There are about 800 employees and
passed to Bain’s ownership in October 2018, with the management retaining a minority stake. BWA dates back
about 40 years, mainly at a site in Manchester, UK, and emerged from Clariant about a decade ago.

www.specchemonline.com febrUARY 2019 • Speciality ChemicalS Magazine • 11

GLOBAL NEWS
Catalent invests in
biomanufacture
Catalent has begun a three-year,
$200 million capital investment
in its Biologics business
to expand drug substance
manufacturing capacity and
drug product fill-finish capacity
at two sites in the US. This
comes in response to “projected
growth among existing and
future customers” and follows
the announcement in December
of a $14 million investment in
packaging capabilities.
At Madison, Wisconsin, home
to its GPEx mammalian cell
line development technology,
Catalent will build out two new
suites, each with a 2 x 2,000
litre single-use bioreactor
system, providing additional
capacity at the 2,000- or
4,000-litre batch scale and
doubling the firm’s commercial
biomanufacturing capacity.
Work should be completed by
mid-2021, the company said.
In addition, 7,300 m2 of
GMP and non-GMP fill-finish
capacity will be added at the
much larger Bloomington
site in Indiana, which focuses
on biologics development
and manufacturing. This will
include high-speed flexible vial
line, using both ready-to-use
components and bulk filling at
a filling speed of 300 units/
minute and a high-speed flexible
syringe/cartridge line with a
filling speed of over 300 units/
minute and a fully automated
vial inspection machine.
12 • Speciality ChemicalS Magazine • febrUARY 2019
Adama to buy
Chinese firm
Israeli crop protection firm
Adama, itself a subsidiary of
ChemChina, has entered into a
non-binding memorandum of
understanding to buy parts of
the crop protection business of
Jiangsu Huifeng Bio Agriculture,
a chemicals manufacturer based
in Dafeng, Jiangsu province. The
company said that this will give it
“access to backward-integrated
and competitive positions in key
molecules”, as well as a strong
commercial presence and wide
portfolio of product registrations
in China.
Huifeng Bio had sales of $506
million in agriculture last year, of
which $389 million were in active
ingredients and intermediates,
the rest in formulated products. It
had supplied intermediates and
active ingredients to Adama and
others until March 2018, when
Chinese environmental regulators
required it to halt production due to
an investigation.
The company has since invested
heavily in rectifying these problems;
its formulation activities resumed
operation in November and eight
synthesis lines have also now
resumed. Further work is going
to rectify outstanding issues and
completion of the deal is subject to
this being done satisfactorily and full
resumption of production at all in-
scope facilities.
Centrient is the
new name
Singapore-based DSM Sinochem
Pharmaceuticals (DSP) has been
renamed Centrient Pharmaceuticals
following the completion in
October of its sale by DSM and the
Sinochem Group to Bain Capital
Private Equity. The company will
also adopt a corporate brand
identity and website. It makes
pharmaceutical intermediates,
APIs and finished dosage forms.
S Peptide manufacture at Almac
Almac adds second
high-throughout
GMP peptide facility
Global CDMO Almac Group
has brought online a second
high-throughout facility for
the GMP manufacture of
its NeoPeptides brand of
neoantigen-derived peptides at
its site in Edinburgh, UK. This
follows the conversion of the
facility from non-GMP to GMP
manufacture in 2018, by means
of a pharmaceutical quality
system that was developed
specifically for this process.
Following a successful MHRA
inspection, the site has been
producing NeoPeptides since
September and released over 80
in its first week of operation.
NeoPeptides are used in
the production of patient-
specific, individualised cancer
vaccines. Speed in production
is absolutely critical and the
whole supply chain “is focused
on minimising the time between
the initial patient biopsy and the
ultimate vaccine administration”,
the company stated. Further
expansions of the facility and
service offering are anticipated
in the coming months.
Demand is growing rapidly
for these peptides, which are
based on replicating a series of,
usually 10-30, neoepitopes from
within a specific tumour that has
been biopsied and genetically
sequenced to identify the epitope
mutations. Each is unique to
the patient and is manufactured
and administered only once.
They function by enabling the
body’s immune system to fight
the cancer.
www.specchemonline.com
 Global View
GLOBAL VIEW
FROM THE US
Balancing deregulation
with quality and integrity
As Washington rolls back oversight, standards take on new importance
At the SOCMA annual meeting
in New York on 11 December,
Michael Stadelmaier, procurement
manager at BASF, highlighted how
compliance with environmental
and safety standards has benefitted
the entire industry. “When I came
into the business there was concern
about midnight dumping and
potential litigation. Now that seems
to have dissipated. Now everyone
is on board with ChemStewards
and Responsible Care,” he said.
Stadelmaier was speaking as part
of a discussion on the association’s
programmes. BASF, he said,
prioritises its corporate relationships
based on risk. Any that have a
high or medium potential for risk
are subject to a health, safety and
environmental (HSE) audit that can
last between two and five days.
Gene Williams, chairman of the
board of governors for SOCMA
and president of Optima Chemical,
noted the association’s initiative to
identify areas of commonality and
gaps between ChemStewards and
member audits.
Despite the consensus on the
benefits of high standards, there
was an undercurrent at the event
in favour of deregulation in the US.
14 • Speciality ChemicalS Magazine • FEBRUARY 2019
One of the afternoon speakers,
Stephen Moore, distinguished
visiting fellow on the Project for
Economic Growth at the Heritage
Foundation, stated: “I believe
deregulation and the tax cuts,
which I helped write, were the most
important things the administration
has done in the first two years.”
Moore asked for a show of
hands to indicate if those in the
session agreed that deregulation
was the most important issue for
the industry. A firm count was not
possible in the brief poll, but it was
something between a third and a
half of the attendees.
To be sure, Moore had his
differences with current US
economic and trade policy as well.
“The auto and steel tariffs are
a disaster,” he said. “They have
knocked a quarter to half a point
off growth. Those tariffs are just
stupid. I know manufacturers who
tell me they are hurting business.”
Moore got plenty of nods in the
crowd on that note, but less overt
agreement when he advocated a
strong line on China. “We have
a dysfunctional relationship with
China,” he said. “They lie, they
cheat, they steal. It is very tough to
get an agreement.” Considering
how directly the escalating tariff
war with China is affecting
chemical manufacturers, it would
have been interesting to see
another show of hands on support
for the trade sanctions.
During informal discussions after
the session, some questions were
raised about how far deregulation
should go. No one wanted to
return to the days of midnight
dumping. And no company that
has committed time, talent and
treasure to quality operations and
compliance wants to be undercut
by a competitor taking advantage
of relaxed regulation. £
GREGORY DL MORRIS
US Editor
www.specchemonline.com

GLOBAL VIEW
FROM EUROPE
Parting with plastic
Just before we all logged off for our Christmas break, the EU took a
significant step towards making do with single-use plastics
On 19 December, the Council
of the European Union and the
European Parliament provisionally
agreed on a new Directive that
would ban a range of throwaway
products from the market: plastic
cutlery, plates and straws, food
and drink containers made of
expanded polystyrene and products
made from oxo-degradable plastic,
to name a few. For these, Brussels
says, alternatives are “easily
available and affordable”. For
other single-use plastic products,
the Directive would impose
consumption limits or waste
management obligations
for producers.
This is an ambitious proposal
in response to the ever louder
public call to stop plastic pollution.
“Citizens across Europe want to
see an end to our throwaway
culture and politicians have taken
the first step,” said NGO Friends
of the Earth Europe in response
to the agreement. The European
Environmental Bureau similarly
commented: “If we don’t stop
the plastic pollution crisis now,
we’ll regret it forever.” And Frans
Timmermans, the European
Commission’s first vice president
www.specchemonline.com
responsible for sustainable
development, said the agreement
“truly helps protect our people and
our planet”.
But the measures also rely on
the availability of less polluting
alternatives. Enter a challenge for
the speciality chemicals industry,
which is no stranger to exploring
biobased chemicals and materials,
including plastics. The proposed
Directive itself remains vague
on the use of alternatives. This
has encouraged some criticism.
Europe’s biggest plastics industry
association, PlasticsEurope, has
warned that alternatives to plastics
may not be more sustainable and
urged the European Commission
“not to take shortcuts”.
Biobased plastics producers, on
the other hand, say the Directive
fails to acknowledge the potential
of their products. Regulators
should consider “limited, efficient
exemptions for innovative
compostable plastic products that
facilitate organic recycling,” said
François de Bie, chairman of the
European Bioplastics trade body.
He called a general restriction of
single-use cutlery and plates an
“excessive move”.
FEBRUARY 2019 • Speciality ChemicalS Magazine •
GLOBAL VIEW
The provisional agreement
between Parliament and Council
is no guarantee that the Directive
will go through. First, it has to
be submitted for approval to
Parliament and then return to
Council for final adoption. Then,
it would be published in the EU’s
Official Journal, giving the member
states two years to transpose it. But
whether the law will face further
hurdles before it is implemented or
not, it is safe to say that innovative
biochemicals and alternative
materials are – now more than
ever – a space to keep our eyes on
in Europe. £
VANESSA ZAINZINGER
Europe Editor
15
EVENTS
Events Calendar
Specialty & Custom
Chemicals America
12-14 February 2019:
Omni Hotel, Fort Worth, Texas, US
The inaugural event on speciality, custom,
fine and industrial chemicals for multiple
different industries, with a specific US
domestic focus to complement the
‘reshoring’ of manufacturing to the US.
There is a full preview of this event on
pages 18-21
www.texas.chemicalsamerica.com
CPhI South East Asia
12-14 March 2019: Queen Sikrit National
Convention Centre, Bangkok, Thailand
The region’s leading pharma event,
attracting about 5,000 suppliers and
buyers. CPhI South East Asia hosts a
wide range of networking opportunities
for the further development of
business, including dedicated
forums, product showcases, technical
seminars and more
www.cphi.com/sea
European Coatings Show
18-19 March 2019: Nuremberg Exhibition &
Conference Centre, Germany
The major event in the field of coatings,
the European Coatings Show is expected to
attract over 1,000 exhibitors and 30,000
visitors. The conference section covers
trends and technologies in all aspects of
the production of paints, coatings, sealants,
construction chemicals and adhesives
www.european-coatings-show.com
CPhI Japan 2019
18-20 March 2019:
Big Sight Exhibition Centre, Tokyo, Japan
The major pharma exhibition in the rapidly
changing Japanese pharmaceutical
market, with 550+ exhibitors from sectors
including ingredients, contract services
and biopharma through to technology,
packaging and machinery at this and
co-located events
www.cphi.com/japan
16 • Speciality ChemicalS Magazine • FEBRUARY 2019
DCAT Week
18-21 March 2019:
Multiple locations, New York, US
Bringing together thousands of leaders,
innovators and decision-makers in the
global pharmaceuticals industry for a
week of networking, including evening
and side events. Three days of high-
level presentations, including a keynote
address from 2018 Nobel Prize for
Chemistry laureate Dr Frances Arnold,
culminate with the 93rd DCAT Annual
Dinner on 21 March
www.dcatweek.org
In-Cosmetics Global
2-4 April 2019:
Paris Expo Porte de Versailles, France
The world’s largest personal care event,
bringing together 1,800+ exhibitors of
ingredients, fragrances, lab equipment,
testing, regulatory services and more,
with over 34,000 visitors. It also delivers
high-level education, marketing trends
and consumer insights for formulation,
R&D and regulatory professionals
www.in-cosmetics.com
Making Pharmaceuticals
30 April-1 May 2019: Ricoh Arena, Coventry, UK
A small-booth exhibition and
presentations covering the whole gamut of
pharma, including processing, regulatory,
clinical, testing, R&D, ingredients,
exicipients, engineering, packaging and
labelling and more. There is also a full
conference programme alongside it
www.makingpharma.com
CPhI North America 2019
30 April-2 May 2019:
McCormick Place, Chicago, US
Moving out from Philadelphia to the
Mid-West, the North American version of
the world’s largest pharmaceutical series
of events is expected to have nearly 700
exhibitors. It is co-located with multiple
side events, including Informex, the long-
established US custom chemicals event
www.cphinorthamerica.com
www.specchemonline.com
Events
Chemicals in cowboy country
A new US-based speciality chemicals event
launches in Texas in February
THE FIRST SPECIALTY & Custom
Chemicals America event,
organised by the same team
as the annual Speciality & Agro
Chemicals America in Charleston,
will take place in and around the
Omni Hotel at Fort Worth, Texas,
on 12-14 February. The focus is
on the speciality, custom, fine and
industrial chemical markets, with
applications in industries including
crop protection, pharmaceuticals,
cosmetics, paints and coatings,
pulp and paper, soaps and
detergents, oil and gas, fuels,
lubricants and many others.
According to the organisers, the
event’s mission is “to showcase the
distinctive value of the American
chemical industry”. It will also
support the ongoing ‘reshoring’
of manufacturing that has been
seen in recent years. This has
been strengthened by the rise of
new applications in the higher-
technology, higher-value end of
the market, which has always been
mainly domestic.
As with its sister show, Specialty &
Custom Chemicals America will be
based on networking opportunities
at relatively low cost. The exhibition
part is entirely tabletop-based,
allowing all to present their
capabilities in the same way. All
of the 150+ exhibitors
18 • Speciality ChemicalS Magazine • february 2019
have significant manufacturing,
service or sales operations within
North America.
Fort Worth was chosen for
several reasons, notably its
proximity to the heart of the
custom chemicals industry around
Texas, Oklahoma and Northwest
Louisiana, easy connections via
two major airports and its own
attractiveness as a venue. Known
as the ‘City of Cowboys and
Culture’, Fort Worth was recently
named the best downtown in the
US and has a distinctive feel from
its roots in the Old West.
The event format is a three-
day networking forum featuring
an exhibition, exhibitor showcase
presentations and conference
presentations on industry trends,
with breakfast, lunch and evening
cocktail receptions for additional
networking. The exhibits are
open from 13.00 to 17.30 on
Tuesday 12, from 9.30 to 17.30
on Wednesday 13 and from 9.00
to 11.00 on Thursday 14. Key side
events include:
£ Tuesday 12, 9.00-9.30:
Keynote breakfast with speaker
Kelly Hancock, state senator
and owner of Advanced
Chemical Logistics
£ Tuesday 12, 9.30-10.30: Panel
discussion ‘Are we still bullish
about specialties?’ with panellists
from KMCO, Grace Matthews,
Cadence Bank and Edgewater
Capital Partners
£ Tuesday 12, 11.00-15.00:
Exhibitor showcase presentations
£ Wednesday 13, 10.00-
10.45: General session #1
– ‘Sustainability initiatives:
How expectations of a
circular economy strain the
chemical industry’, with Mark
Jones, executive external strategy
and communications fellow,
Dow Chemical
£ Wednesday 13, 14.00-14.45:
General session #2 - Panel
discussion ‘Best practices in
sourcing custom & toll chemical
manufacturing’, with panellists
from Buckman International,
Lubrizol and BASF
£ Thursday 14, 10.00-10.45:
General Session #3 - Panel
discussion ‘Emerging leaders’
outlook on the future of
specialties’, with panellists from
Strem Chemicals, Nation Ford
Chemical, GFS Chemicals and
ChemDesign £
CONTACT
Chemicals America
+1 215 882 9100
support@chemicalsamerica.com
www.texas.chemicalsamerica.com
www.specchemonline.com
Events
Specialty & Custom
Chemicals America:
Exhibitor insight
We asked selected exhibitors at Specialty & Custom Chemicals
America for their latest news and their take on the current state of
the market
What is new with you in
the past year, in terms of
capacities, capabilities and
technologies?
John Harty, business
development director, Kodak
Specialty Chemicals: Our team
continues to bring considerable
capability and capacity to provide
services to a wide array of business
interests, including markets
requiring industrial specialty
polymers, such as pharmaceutical,
personal care, electronics and
agrochemicals, and new emerging
technologies, such as energy.
The diversity of customers is
fuelling Kodak’s growth and
success. Kodak has quite a bit
to offer customers, from tolling
services to custom synthesis,
along with fast scale-up
capabilities, which include process
development, the use of statistical
process control tools and world-
class analytical capabilities. If
one sector is slow, we gain
momentum in another area to
compensate. This diversity and
ability to add value to so many
business sectors have been
instrumental to our success.
Scott Martin, president, Fine
Chemistry Services, Albemarle:
We are adding a new 8,930ft2
(830m2) R&D building at our
Tyrone, Pennsylvania, site. We will
now have kilo lab capability in
addition to our existing pilot plant
and commercial-scale offerings.
At our South Haven, Michigan,
cGMP facility we have added
several ‘isolation’ improvements,
in centrifuging and drying
capacity, to keep up with our
growth there.
S Recent expansion at Nation Ford Chemical
R Kodak’s site at Rochester, New York state
What capabilities are you
showcasing (or launching)
at Specialty & Customs
Chemicals America?
John Harty: We are working to
promote the company’s expertise
in polymers. Kodak has a long
history of producing synthetic
polymers for imaging products
using batch and semi-continuous
processes. Applications in imaging
products include dispersants,
rheology modifiers, matting agents,
dye receptors and durability
enhancers. Our polymerisation
processes include solution,
emulsion and suspension free-
radical addition polymerisations,
solution polyurethanes and anionic
ring-opening polymerisation.
Kodak’s capability of controlling
particle size distribution in oil-in-
water emulsions has proven helpful
for encapsulation technology. We
now have encapsulated products
serving customers in consumer,
agricultural and textile markets.
Jay Dickson, president,
Nation Ford Chemical: We
focus on speed to market for
new technologies. Nation
Ford Chemical has a versatile
equipment list that enables us to
move quickly into new chemistries.
The management team will make
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fast decisions on capital projects
to ensure timely start-ups.
Scott Martin: We will be
informing the industry of our
expanded kilo lab capability,
which complements the
development of regulated starting
materials at Tyrone.
How has the custom chemicals
market in North America
developed in 2018? What
markets/needs are most
driving it?
John Harty: The political climate
with tariffs between the US and
China created both opportunity
and challenges in 2018. This
continues to evolve. The net result
seems to be a return of business
to the US or Western Europe.
However, in our global world,
manufacturers, wherever they may
be, continue to rely on Chinese
raw materials.
Jay Dickson: Nation Ford
Chemical has seen an increase
in the amount of inquiries for
products normally made in China.
This stems from the environment-
related plant shutdowns and US/
China trade uncertainties.
Scott Martin: Pharma is driving
the overall growth of my business
and will continue to do so.
FEBRUARY 2019 • Speciality ChemicalS Magazine •
How do you see the market
developing this year?
John Harty: Kodak envisions
continued growth into diversified
business sectors.
Jay Dickson: 2019 will be a
growth year for highly specialised
chemicals and those companies
experienced in confidential tolling
projects. Opportunities abound
from new product launches to
reviving some chemistries that have
moved to developing countries
over the past 30 years.
Scott Martin: It will be interesting
to see how the tariffs play out. In
the short term, this could have a
large impact on API costs in the US.
Do you have specific investment
plans for this year?
John Harty: Investments will be
driven by Cap-X projects done in
harmony with our customers in order
to enhance our business together.
Jay Dickson: Nation Ford
Chemical is expanding our tolling
capacity by 10% this year, with
possible further increases based on
demand at mid-year.
Scott Martin: Mostly ‘builds’ on
our current capabilities. We have a
cGMP site and a fine chemical site.
So this allows us to fully integrate
the APIs we produce. £
21
Pharmaceuticals

Managing and
redesigning
chemical processes
with enzymes
Professor Tom Moody, VP of technology development &
commercialisation, and Dr Stefan Mix, head of Biocatalysis, at
Almac Sciences, look at the importance of biocatalysis in the
technology mix*
BIOCATALYSIS HAS RISEN to this include the growing availability enzyme catalysis can provide cost-
become a mainstream technology of enzymes, their ability to deliver competitive alternatives to chemical
in pharmaceutical chemistry. A shorter, more expedient synthetic synthesis alone.
Scifinder search of ‘biocatalysis’ routes to sophisticated molecules, Thanks to the development of
gave 666 references to articles with considerably lower toxic large and diverse collections at
published in 2000, growing to solvent and reagent use, and Almac and other companies,
3,571 in 2018. The reasons for the fact that, increasingly often, biocatalysis is becoming a

W Figure 1 – Range of chemistries

performed by biocatalysts

22 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com

widely and generally applied
technology. In part, this is due
to the wide range of chemical
transformations that may now
be achieved biocatalytically. The
synthetic power of enzymes is
their unequalled selectivity for the
chemical reactions they catalyse,
as illustrated in Figure 1, using a
hypothetical molecule.
Several requirements can be
identified for enzymes to achieve
industrial application. Firstly, a
suitable collection of enzymes
needs to be readily available so
that a screening process can be
conducted to identify candidates
for development. These need to be
available at the required scale and
a suitable cost.
In addition, process intensity
for biotransformations needs
to be comparable to chemical
processes, with an achievable
product concentration in the range
of 50-100g/L and a biocatalyst
loading with respect to substrate
input that means the cost of the
enzyme is reasonable. Finally,
processes and enzymes need to be
unencumbered by IP constraints.
When developing an enzyme
process the following points must
be considered:
£ Available development effort and
time in relation to using an off-
the-shelf v. bespoke biocatalyst
W Figure 2 – Options available to access a fit-for-purpose process
www.specchemonline.com
£ Catalyst cost contribution to the
process due to choice of enzyme
formulation and weight charge
£ Space-time-yield from process
design and subsequent
manufacturing cost
£ Assessment of the correct enzyme
class and subsequent route, and
of competing technologies
£ Productivity limitations from:
mass transfer in heterogeneous
systems; enzyme stability
and deactivation; substrate
or product inhibition; and,
thermodynamics
£ Availability and choice of starting
material, route and enzyme class
£ (Very importantly) product
purification, reduction of
bioburden and isolation
Technical knowledge &
experience
First-time scale-up of a chemical
intermediate or delivering a
large-scale manufacturing process
can be complex challenges, relying
on a multi-disciplinary team to
drive success, especially now
with the increasing complexity of
chemical moieties being used in
API synthesis.
When correctly applied,
biocatalysis delivers exquisite
stereocontrol, yield and scalability,
with excellent green credentials.
Unlike chemocatalysis, biocatalytic
FEBRUARY 2019 • Speciality ChemicalS Magazine •
processes do not generate
heavy metal waste, often require
no protection or deprotection
steps and can often be run in
environmentally friendly solvents.
The key to development of a
process is to ensure it is fit for
purpose and ready for scale-up.
Figure 2 highlights the options
available to access a process for
scale-up when using enzymes.
The starting point is identifying an
enzyme hit, via screening off-the-
shelf catalysts, in silico design or
engineering a catalyst for a specific
transformation. These are all now
done in acceptable timelines at
controlled cost.
Next, process development can
be undertaken. Time, cost,
enzyme stability and volume
efficiency should be considered,
as should alternative processing
options, including: substrate
engineering (protecting group
change, ethyl v. methyl ester,
etc.); process intensification
using ultrasound to aid in mass
transfer of insolubles; using
resins and solid supports to
catch and release substrates and
products (if inhibition is an issue);
and, enzyme immobilization.
Enzyme engineering can also be
conducted and is advisable as and
when product costs and volume
productivity grows. P
23
Pharmaceuticals
W Figure 3 – Level 1, 2 & 3 enzyme engineering results, showing fold increase in activity over parental wild-type enzyme
P Integrated technologies
The integration of biology,
chemistry, computation and
analytical science is a great
example of how the combination
of these technologies can result in
the identification of new enzymes
with enhanced properties. The
full benefits of this model come
when the services are all part
of one organisation. Close
proximity of the scientific teams
results in more face-to-face
communication, internally and with
the client, reduces the time spent
coordinating activities and allows
faster escalation and resolution of
critical project issues.
Enzyme engineering has been
streamlined over the last decade,
via the increased use of in silico
methods to predict key functional
hotspots in the enzyme to increase
activity, stability and overall catalyst
performance. Computational
chemistry methods allow for atomic
resolution insight on enzyme
structure and dynamics, ultimately
establishing a link to enzyme
function. Molecular docking and
classical molecular dynamics
simulations are typically employed
to determine the Michaelis-Menten
complex formed between the
enzyme and the substrate.
The elucidation of this complex
facilitates the building of a focused
panel of mutant enzymes for
rapid wet testing. (This typically
24 • Speciality ChemicalS Magazine • FEBRUARY 2019
takes eight to 12 weeks and
involves testing about 100 mutant
enzymes). Subsequently, key
residue positions will be identified
and rationally mutated to change
or improve substrate specificity and
catalytic efficiency. The mutations
predicted to have a beneficial
effect on enzyme activity can be
further grouped into a library of
tailored mutant enzymes, which will
be synthetised and expressed in a
host of choice.
Superfamily co-alignments and
the wet lab results of beneficial
and deleterious mutations permit
the identification of key ‘hot spot’
residues, which can be further
mutated to all possible residues.
Docking the substrate in the
active site results in the
identification of the residues
involved in the first sphere of
interaction and therefore those
most likely to play a role in
catalysis. A combinatorial active
site-testing methodology, with
combinations of double mutations
of residues in the active site or first
sphere of interaction, can also be
used to disclose improved mutants.
Where enzyme stability is an
issue, this approach can be
expanded to include hot spots
involved in stabilising interactions,
such as salt bridges, hydrophobic
stacking and dimer-dimer
interfaces. (This typically takes
12-16 weeks and involves building
and testing a panel of some
10,000 mutant enzymes). Figure 3
highlights a typical in silico round
of activity benefits from the output
of this enzyme engineering and
screening of a focused library of
enzyme design. From this, cost-
effective enzymes can be obtained.
Experienced project teams
Biocatalysis is a multi-disciplinary-
driven business, where the
integration of technology and
services must be firmly set in
the context of working across
different discipline teams. Two of
the challenges this presents are
the need for clear communication
between all parties throughout the
project and focused ownership
of the individual programme
components by the relevant
scientists, and setting agreed KPIs
and what is required of the enzyme.
Effective teamwork is perhaps the
most fundamental benefit of an
integrated outsourcing company.
There are three components to
this for complex chemicals and
enzymatic development projects:
1. Clearly defined roles for all
team members (including
customer values). This is
needed to ensure that all of the
project roles are undertaken,
without having roles duplicated
or missed. All project team
members must understand their
roles at the outset.
www.specchemonline.com
2. An experienced programme that its procedures and policies are *Also contributing to this article
manager. Many interconnected fully fit for purpose for each project. was Dr Derek Quinn, biology senior
tasks need to be completed Enzyme processes are subject to all team leader at Almac Sciences
during the project. To identify of the same quality attributes to that
critical path activities and make of chemical processes.
good decisions about how best
to mitigate the impact of any Conclusion
delays requires an individual Biocatalysis is truly a 21st century
with a good working knowledge technology readily available to all CONTACT
of the component tasks, well- chemists. It brings many benefits, Professor Tom Moody
developed project management including new route options, VP of technology development
abilities and the respect of process simplification, increased & commercialisation
the team members. The speed of delivery, no heavy metals Almac Group
relationship between the client to control and the potential to
and the outsourcing company generate some new IP to protect tom.moody@almacgroup.com
programme manager is a critical your invention. It’s time to give it www.almacgroup.com
success factor. a go. £
3. Clear communication practices
internally and with the client.
This is crucial to any client–
outsourced relationship and
should be characterised by
accuracy and high integrity.
Too much communication is
sometimes as problematic as
too little. Equally problematic
is asymmetric communication
where only one party
communicates well.

Security of supply & IP

Security of supply and protection
of IP and/or maintaining trade
secrets is at the forefront of many
customers’ wish lists, as it should
be. Many want to work with
companies with rigorous systems
to protect IP and their specific
technology when accessing
their product. This is now
considered baseline.
As regulatory standards
tighten, certainty that outsourced
manufacture will be run to the
correct standards, encompassing
operational excellence, use of
ethical suppliers, environmental
considerations and uncompromised
health and safety systems, is
essential. If the CRO’s quality
system is insufficiently robust,
there is a risk that either too much
attention is given to the quality of
the manufacture, leading to the
cost being unnecessarily high, or
too little, leading to a risk of the
process lacking critical detail.
Within top CROs the quality
systems are under regular scrutiny
by several parties, including the
customer. The quality unit ensures

www.specchemonline.com FEBRUARY 2019 • Speciality ChemicalS Magazine • 25

 Pharmaceuticals

Continuous
processing in
pharma
Dr Rui Loureiro, director of R&D – process chemistry development
at Hovione, updates us on the advantages and challenges of
implementing continuous processes in drug substance as well as
drug product manufacture*
THE PHARMACEUTICAL INDUSTRY
is increasingly using continuous
processes in drug product
manufacturing. The advantages
it brings of safety, selectivity and
scalability are compelling, despite
the availability of existing multi-
purpose batch assets. Many
different units need to be developed
in parallel for a fully integrated
process. Continuous tableting is the
most advanced technology platform
in drug development
and manufacturing,
where continuous
processes are
becoming
W Figure 1 – Standard operating windows of batch & flow reactors.
established processes. Hovione
embraced this change with the
installation of a continuous tableting
unit in its New Jersey facility.
However, there are other
technology platforms that are
continuous and increasingly
relevant in the pharma industry.
An example of this is spray drying,
a continuous isolation and drying
process which allows a high
degree of control over the particles
formed. This is a technology of
choice for the production of solid
dispersions and composite particles
for inhalation.
The full development of
continuous processes, scale-up and
control strategy studies still requires
large quantities of valuable
API to be used. To mitigate
that, Hovione has invested in
knowledge and science to
establish development
approaches,
leveraged by
Quality
by
Design (QbD) principles and
modelling, that allow the
scale up to tonnes with limited
experimentations and reduced
API consumption.
Flow chemistry in drug
substance
The introduction of flow chemistry
in drug substance manufacturing
is a more complex proposition,
often requiring a case-by-case
assessment. Flow chemistry
requires custom equipment
and plant design to fit process
requirements, which requires a
different mindset to that for batch
multi-purpose facilities. The level
of customisation is such that 3D
printing of flow reactors is now
a reality. It is quite common to
find a locksmith’s box in the flow
chemistry lab, a lathe fixed to the
bench, and pliers and tube cutting
tools side-by-side with the spatula.
Flow chemistry has limitations
and is not replacing all batch
manufacturing. Where slurries
and solids need to be handled or
the intensification of the process
favours undesired chemical
pathways, batch manufacturing is
still often preferable. Nevertheless,
in recent years, several large
pharma companies have been
heavily investing in continuous
processing in drug discovery

26 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com

U Figure 2 – Times needed to produce product with required quality in flow & batch
and manufacturing as it brings
the benefits of safety and overall
process control and gives access to
batch-prohibited chemistries and
new chemical routes. In this way,
it can manufacture the desired
API via the most efficient chemical
route, using fewer materials,
forming less waste, and saving
time and production costs.
The CDMO and generic pharma
worlds are also adjusting to
this reality and developing the
capacity to take flow chemistry
projects from lab to commercial
manufacturing. For this purpose,
Hovione has invested considerably
U New R&D lab at Hovione’s site in Portugal
www.specchemonline.com
in both knowledge and technology,
including multiple partnerships with
academia that led to several PhD
and MSc programmes, to leverage
the use of continuous processes
by a larger pool of scientists,
technicians and operators. The
company has also invested in
assets from lab-scale development
(plate and coil reactors) up to
cGMP pilot (processing capability
to 10kg/hours) and commercial
tonne-capacity reactors.
Difficult chemistries
Challenging chemistries, like
gaseous HCl, HF and high-pressure
FEBRUARY 2019 • Speciality ChemicalS Magazine •
hydrogenation, are now being
safely implemented in flow. These
continuous processes are scaled
up by increasing the channel
diameter to a level that retains heat
and mass transfer performance,
numbering up the reactor channels
and finally extending the reactor
path to allow higher flow rates
and maintain the residence time at
different scales. The batch size is
then much more flexible and can be
increased by running the process for
longer after reaching steady state.
With the introduction of these
technologies in manufacturing, other
challenges are being raised, such
as the downstream part of chemical
processes, where continuous
work-up is essential in order to
have a fully continuous process in
the manufacture of an API. This
requires membranes, centrifuges
or columns for continuous
extraction and phase separation,
filters and resins for purification,
reverse osmosis for continuous
concentration and crystallisers for
continuous crystallisation. Some
of these are already embedded in
batch trains. P
27
Pharmaceuticals
W Inside the laboratory at Hovione
P Continuous manufacturing
affords steady-state batch
uniformity and batch-to-batch
consistency, leveraging the use of
process analytical technology (PAT)
in-process control to meet real-time
release testing (RTRT), where the
quality of what is being produced
is supported by continuous process
data. With its modular concept and
reduced footprint, manufacturing
units can be built on portable
structures and moved within a site
or from site to site, facilitating tech
transfer and reducing response
time to drug shortages. With all
this in mind, health authorities are
actively engaging in developing
these technologies and sharing
their expectations, focusing on
aspects like the control strategy,
equipment cleaning procedures
and batch definition.
Other aspects
Process understanding is another
angle where the benefits of flow
chemistry are demonstrated. With
instantaneous mass and heat
transfer performance, theory
comes closer to practice and side
reactions are better understood.
Mixing performance, together with
heating and cooling ramps, often
obscures side reactions taking
place in batch. The differences
between equilibration and steady-
state gives valuable process
28 • Speciality ChemicalS Magazine • FEBRUARY 2019
information that would be very
difficult to obtain in batch.
Process development and
optimisation productivity is yet
another important point. Using a
continuous microreactor, a chemist
can test multiple points of the
design space in a single experiment
by adjusting parameters, such as
temperature and ratios, collecting a
sample at steady-state and quickly
adjusting the system settings to the
next data point.
Developing a continuous
process is not a bed of roses. It
often starts with a set of batch
experiments to assess solubility and
screen key process parameters.
Microreactor clogging can be
a nightmare and often requires
diluted concentrations to be
used. Leaks between connections
are another major source of
headaches in the lab, especially
when broad temperature ranges
are used. A week of lab work can
easily be spent fixing these issues.
Fortunately, when all these issues
are solved, a flow of results often
reward the resilient scientist.
The material of construction
for tubing, connectors, valves
and O-rings is also an important
consideration. The flow chemist
always carries a box of HPLC
tubing, fittings, mixers, valves,
back pressure regulators and Luer
lock needles and syringes, made
from stainless steel, Hastelloy,
PEEK, FEP, PTFE, Kalrez, Vitton or
other fluoropolymer elastomers.
The interconnectivity of reactor
parts and PAT can be challenging
and most laboratory analytical
equipment is not designed to
handle the small scale of flow
hardware. That is where creativity
of chemists and analytical chemists
needs to be combined.
Conclusion
Continuous processes in the
pharmaceutical industry presents
tremendous opportunities,
requiring a different mindset from
scientists and engineers. They
also offer safety, quality, capacity
and access to new chemistries,
becoming an enabling technology
for innovative medicines. £
* Also contributing to this article were
Dr Rudi Oliveira, R&D chemist, and
Rafael Antunes, senior director of R&D
CONTACT
Isabel Pina
Director – Corporate
Communications
Hovione
ipina@hovione.com
www.hovione.com
www.specchemonline.com
SpeChem_Feb19_04_Callery.indd 1 17/01/2019 15:54
pharmaceuticals

S ADC Biotechnology‘s site in Deeside, UK

Novel approaches to
ADC manufacturing
Charlie Johnson, CEO of ADC Bio, explains a new manufacturing
concept which combines the bioconjugation and purification stages
Biopharmaceutical companies
are seeking suppliers who
can transform the efficiency
of the highly complex set of
manufacturing processes for
antibody-drug conjugate (ADCs)
within a multi-faceted supply chain.
The need for greatly enhanced
efficiency is directly driving
the demand to bring process
innovation to the market. There is
constant pressure to bring down
development time and the cost
of goods, while still meeting
demands for increasing amounts
of drug required for extended pre-
clinical and clinical programmes,
thereby enabling clinicians to
develop the safest and most
effective therapeutic regimes prior
to drug approval.
Typically, up to five contract
development and manufacturing
organisations (CDMOs) are
involved in the ADC supply chain.
This includes the development and
cGMP manufacture of the cytotoxic
payload, its linker (sometimes
combined as a payload-linker) and
the monoclonal antibody (mAb),
the conjugation of the payload
and mAb and finally, the fill-finish
manufacturing process. Each
element is treated as a discrete
activity, requiring a fully tested and
released product, and typically
involves material shipments across
continental borders.
This approach involves a high
degree of redundancy, risk and
both cost and time penalty for the
ADC product concerned. Recent
analysis by CDMOs suggests that
delivering multiple elements of
the supply chain from a single-
source location, coupled with
abbreviated release testing
could save: up to six months
in development time for a total
clinical supply chain; up to three
for two elements combined (for
example, bioconjugation and mAb
manufacturing); and up to
six for three elements combined
(such as mAb production, and
the bioconjugation and
fill-finish phases).

30 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com

 This equates to saving six months
in achieving the crucial first-in-man S Charlie Johnson – New process telescopes development and conjugation
studies and ultimately multiples
of that in terms of patent life once
an ADC is commercialised and
available on the market. Such a
paradigm shift in approach could
revolutionise the ADC manufacturing
industry, shifting it from one where
the entire supply chain is considered
as a continuum and only the final
ADC considered as a product.
Early-phase specialist CDMOs are
most likely to pioneer the adoption
of such forward-thinking concepts,
which require specialist knowledge
and engagement at the R&D
stage. CDMOs specialising in
commercial product manufacture
arrive too late to drive and develop
such innovation.
There is great potential for
CDMOs to use generic process
optimisation systems, for example,
single-use systems, continuous
processing or process analytical
technologies. Alternatively,
they could use tools developed
specifically for ADC development
and manufacturing, such as
Lock-Release.
This technique streamlines
bioconjugation into four simple
steps: locking the mAb to a resin,
performing the conjugation,
washing the locked ADC free of
residuals and releasing the purified
ADC. Originally developed to limit
ADC aggregation and improve
residual clearance when starting
with purified mAbs – common
problems with the emerging
toxin linker classes – Lock-Release
is also well suited to integrated hugely disruptive to the ADC at present, often uses three CMOs
bioconjugation in which a manufacturing industry, is the for different functions.
combined process achieves both savings it generates: up to three The starting point for conjugation
mAb purification and conjugation. months of manufacturing time will no longer be constrained to the
and up to 25% of the overall costs, use of purified antibodies. With this
Integrated bioconjugation due to simplified R&D, shorter new process, it can instead begin
The concept of integrated integrated manufacturing runs anywhere between the first capture
bioconjugation represents a new and material savings, notably the of the mAb from the cell culture
paradigm in ADC development. replacement of Protein A. supernatant onto a mimetic Lock-
It provides for bioconjugation As ever with process innovation, Release resin and the final stage
concurrent with the mAb there will be challenges to mAb process operations typically
purification process and makes it overcome to bring the full benefits employed. Because this involves
possible to dispense with the need to the market. Implementing it will handling highly potent cytotoxins,
for mAb testing, release, storage require the industry to re-evaluate it will require the conjugation and
and shipping before a conjugate many of its current ingrained purification processes to be carried
can be produced. manufacturing methods and out by integrated bioconjugation
The major benefit, and the to establish precisely how it CDMOs with the necessary high
reason this approach will prove structures the supply chain which, containment infrastructure. P

www.specchemonline.com FEBRUARY 2019 • Speciality ChemicalS Magazine • 31

PHARMACEUTICALS
P The Protein A capture step
is the ‘work-horse’ in the mAb
downstream process. This is a
highly specific binder of antibodies
and results in a significantly
purified mAb bulk and reduced
total process volume in a single
step. Though the conjugation
of the mAb while bound to the
resin is conceivable, a number
of limitations make it unviable.
Protein A – like the mAb itself –
is a protein and, as such, can
be conjugated when employing
certain conjugation chemistries.
This would make it single-use and
consume extra toxin linker – both
cost-prohibitive scenarios.
As a consequence, it became
imperative to develop an answer
and one was found – the
replacement of Protein A with
Lock-Release’s specially developed
mimetic resins. Such small molecule
mimetics retain Protein A’s beneficial
specificity, capacity and scalability,
while having the added and unique
benefit of being compatible with
conjugation chemistries. The resin
costs less than Protein A and this
also offers significant savings in
time, complexity and materials.
Lock-Release starts with antibody
supernatants and facilitates both
the antibody capture step and
subsequent conjugation of the
toxin-linker to generate the ADC.
The regulatory requirements for
viral inactivation, viral clearance
and final polishing steps can then
be met post-conjugation.
32 • Speciality ChemicalS Magazine • FEBRUARY 2019
However, if an ADC proved
not to be stable during certain
processes, the innovators would
look into carrying out some
of these processes prior to
conjugation. Conceptually, they
would capture the antibodies
on the mimetic resins, perform
the required mAb downstream
processing, capture the purified
antibody again on the mimetic
ligand, then perform the
conjugation as the penultimate
downstream process. The final
process would be a simple
formulation of the ADC into the
correct solution.
This approach is not possible
with Protein A, even when it is
compatible with the conjugation
chemistry, as it leaches from the
column during mAb release.
Protein A is known to cause
immunogenic responses in
humans, so its removal is
mandatory and generally
requires multiple purification
steps to remove it to safe levels.
This precludes the use of
protein A at the end of the
purification chain, unlike with the
use of mimetic resins.
Outlook
The novel development process
telescopes antibody downstream
processing and conjugation,
improving efficiency by using
just one set of manufacturing,
analytical development and release
processes. At the same time, it
brings in the use of more cost-
effective and safer resins. Once it is
successfully validated, it will not be
long before its benefits are brought
to the ADC production market,
taking manufacturers away from
existing conventional methods.
ADC Bio has established a
specialist process innovation group
to assess the viability of its new
conjugation process in comparison
with conventional approaches
used in the industry. A side-by-
side case study has been carried
out comparing the traditional
approach carried out at a different
service provider and the new
production process, with the latter
demonstrating significant productivity
and economic advantages.
The group’s first task will be
to establish proof-of-concept
over a 12-18 month project,
demonstrating that the original
antibody production process can
be taken and grafted into the
new conjugation process, how
it works technically and how a
sensible amount of product can be
recovered from the process. £
CONTACT
ADC Biotechnology Ltd.
+44 (0)1244 980850
www.adcbio.com
Agrochemicals

W The Bashkiria Republic houses a fine and speciality chemicals cluster

Can Russia supply

its own needs?
The lack of a domestic fine chemical supply base is particularly
acute in the agrochemical sector. Eugene Gerden reports
The Russian fine chemicals chemical enterprises making defining a list of priorities for
industry is at a crossroads. large-tonnage products. Some speciality chemicals in the years
Despite the ongoing development of these continue to operate, but to come. According to Prime
of its legislative base and switching to fine chemicals would Minister Dmitry Medvedev, who
increased state support, interest be challenging for them, requiring approved the roadmap, there
from large local businesses a complete rebuilding of their are some serious obstacles to the
remains low. This is mainly production processes and sales rapid development of the industry,
due to long payback periods structures. In the meantime, state including the small share private
and generally low demand for efforts to speed the development investments have in it and the long
speciality chemicals in Russia, of the industry have been payback periods of most projects.
according to recent statements insufficient. According to the latest MIT data,
by senior officials at the Ministry An example of these efforts is fine and speciality chemicals
of Industry & Trade (MIT) and a roadmap for the development account for only 10-15% of
local experts. of the industry to 2030. This set chemical production in Russia,
The USSR’s chemical industry some basic principles for the which is significantly lower than in
was mainly focused on giant development of the industry, the EU. In addition, Russia remains

34 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com

‘The rise in prices for fine chemicals in
China contributes to their growth in other
parts of the world’ – Mikhail Danilov
heavily dependent on imports in
most segments; in some, 100%
of materials are imported. China,
South Korea, the EU and, to a
lesser extent, the US are major
importers of fine chemicals into
Russia.
According to Ilya Mazov, director
of development at the Engineering
Chemical-Technological Centre
(IHTC) in Tomsk, one of Russia’s
leading production and research
institutes in speciality chemicals,
domestic production currently
does not match market needs
and there are only about 20-
30 producers. Russia, he adds,
is short of SMEs in speciality
chemicals, while large enterprises
have little interest in this market.
The most complex situation is
currently to be seen in the fine
chemicals for agrochemicals
segment. According to Mikhail
Danilov, marketing director of
Avgust, one of the leaders in
the Russian pesticides market,
the company imports 95% of
its fine chemicals needs. In the
meantime, due to the weak ruble
and the ever rising global prices
for fine chemicals, most Russian
producers are unable to purchase
them in the same volumes as in
the past.
This problem is also particularly
acute in crop protection. It in part
reflects China’s recent closure
of many chemical plants for
environmental reasons. “The rise
in prices for fine chemicals in
China contributes to their growth
in other parts of the world. This
is mainly due to China’s status
of one of the world’s leading
suppliers of fine chemicals
for global agrichemicals’
production,” Danilov says. Similar
trends are also being seen in
other areas of the fine and
speciality chemicals sectors.
The Russian government
believes that the new roadmap
www.specchemonline.com
R Manturov – Long payback
times a challenge
may provide a stimulus for
a further development of the
industry, particularly with regard
to domestic production. According
to Medvedev, it identifies several
directions of travel. Notably in
increasing domestic production
by $1.5 billion, in value terms,
during the next five years and the
reduction of imports by 12-14%.
The new roadmap also involves
the need for the development
of a raw materials base for the
industry. Despite Russia’s rich
energy reserves, it has a shortage
of raw materials for speciality
chemical production, including
organochlorine monomers and
organic compounds. After the
collapse of the Soviet Union,
chemical clusters in Dzerzhinsk
and Usolye-Sibirskiy, which were
key to the functioning of the
Soviet fine chemicals industry,
were completely destroyed
and abandoned.
However, according to
Medvedev, some work in this field
has been done. For example,
over the past two years at least
FEBRUARY 2019 • Speciality ChemicalS Magazine •
eight large-scale projects have
been successfully completed, with
another ten being currently built.
The Bashkiria Republic remains a
centre of production of fine and
speciality chemical production in
Russia, with a special cluster in
which more than 60 companies
operate. Last year about 4,000
different chemicals were produced
in the region and plans are to
increase this to 20,000-30,000 in
the medium term.
Another inhibitor of domestic
production is weak local demand
and a small domestic market,
which is estimated at $7.7 billion,
with growth rates of 4-5%/year.
Although Russia has a strong
chemical science tradition, most of
its discoveries in this field have not
been introduced into commercial
production. In addition, due to
a lack of funding and the lack
of R&D centres within major
enterprises, the level of R&D
activity has been relatively limited.
Until now, such centres have been
located only at research institutes
in Moscow, Novosibirsk, Nizhny
Novgorod and St Petersburg.
Still, there is a possibility
that commercial production
of fine chemicals in Russia will
significantly increase via some
private initiatives in this field.
One of these is the Khimprom
Startup Challenge 2018, a
joint project of a major Russian
chemical producer Khimprom and
the Department of Chemistry at
Moscow State University. As part of
the project, the partners will select
certain types of fine chemicals
with the aim of providing funding
for their further introduction into
commercial production.
The Russian government puts
big hopes on the new project,
acknowledging that domestic
production has been largely
underdeveloped in recent years,
that was mainly due to long P
35
Agrochemicals
‘The new roadmap also involves the need
for the development of a raw materials
base for the industry’
P payback periods of these
projects. Denis Manturov, minister
for industry and trade, says: “In
fine chemistry, the design of the
product in laboratory conditions
requires two to three years, with
another two years to start its
tests, and then launching into
commercial production. That
means the payback periods of
the majority of such products
start from eight to ten years.” He
hopes that domestic products
could be competitive with imports
due to shorter terms of their
production and better flexibility in
delivery dates.
Some Russian producers have
announced their plans to provide
36 • Speciality ChemicalS Magazine • FEBRUARY 2019
stronger competition to imports.
That will be also achieved through
the production of completely new,
unique products. One example
is Zerebra Agro, a plant growth
stimulator made by Nanobiotech.
This, according to company head
Yuri Krutyakov, is the first of its
kind not to use stabilised colloidal
silver to protect plants. He adds
that no other companies have
previously been able to create
a stable formulation of such
a pesticide.
“This is our difference from
manufacturers of crop protection
chemicals,” says Krutyakov. “They
have only formulations, which are
mixtures of active substances of
V Inside Nanobiotech’s laboratory
pesticides. However, our company
conducts such a synthesis by itself.
Silver itself, has been known for a
long time – however, the company
for the first time learned how to
modify it with a special polymer in
order to achieve its stable action.”
Demand for Zerebra Agro
remains steady in the domestic
market. This is not only due to its
properties as a growth stimulator. It
can also stimulate plant immunity
non-specifically, helping them
to fight diseases. The company
gradually entered the market,
overcoming the scepticism of
conservative agrarians, who were
used to trusting only the brands
supplied by Syngenta or Bayer. £
www.specchemonline.com
Cosmetics & Personal Care

Clays go with the flow

Lincy Gurusamy and Melissa Fleckenstein of Elementis’s
Personal Care business segment discuss the use of rheology
and natural clay additives to address consumer trends in
cosmetics and skin care*
INNOVATIVE SENSORY sun care products they buy to deliver such key attributes as: ease
EXPERIENCES continue to provide environmental protection, of application; perfect pigment
rank high among desired moisturising capabilities, improved distribution and stability for
product attributes across all appearance and convenience, as more consistent colour quality;
cosmetic categories. Consumers well as a silky-smooth feel and drying without transfer; instant
expect naturally-derived, high sensory experience when applied. brightening and illuminating
performance products that can In addition to this, makers of effects; soft, silky, weightless
deliver environmental protection, these products face pressure to textures; improved emulsion
moisturisation and improved maintain brand integrity while stability; anti-ageing; hydration;
appearance. Equipped with a seeking approaches and processes and sun-protection properties.
keen understanding of rheology, that enable them to remain cost-
cosmetic formulators can create competitive and compliant with Importance of rheology
cutting-edge formulations that international health, environmental Cosmetic formulators can address
achieve both texture and product and safety standards. trends in consumer attitudes and
performance goals tied directly to The challenge to personal care purchasing behaviours by using
the flow properties of a cosmetic. chemists and formulation experts the science of rheology for the
Consumers increasingly expect is thus to use naturally derived, development of personal care
the cosmetics and skin and high performance additives to products. Achieving texture and

S Lincy Gurusamy S Melissa Fleckenstein

38 • Speciality ChemicalS Magazine • February 2019 www.specchemonline.com


R Effect of Bentone clay loadings on formulation
product performance goals are
tied directly to the rheology of a
product. Effective rheology control
using multi-functional, natural clay-
based rheology modifiers offers
positive impacts on both formulas
and consumer perceptions.
Rheology is the science of flow.
Every time a lotion is poured,
a cream squeezed from a tube
or a lipstick applied, rheology
is involved. Even when products
are at rest, it plays an important
part in controlling stability and
suspension. Understanding a
formulation’s rheological needs
enables cosmetic formulators to
create the best possible products.
The rheology of a system is
described in terms of viscosity
measurements, characteristics
of flow behaviour and the
determination of material structure. type clays, are highly effective
Basic knowledge of these subjects
is essential to product design
and quality evaluation. The user
experience will change by simply
adjusting the rheology of a system. resistance to flow under stress.
Perceptions of key performance
attributes, such as moisturisation,
skin protection and anti-ageing
benefits, are tied to the rheology
properties of a system.
Hydrophilic clays
Rheological additives can
be broadly divided between
aqueous- and non-aqueous-
phase thickeners. Among the
former are natural hydrophilic
clays. These provide thixotropy
– a characteristic flow behaviour
where viscosity reduces as shear
is applied and recovers once it is
removed, allowing the product
to display a desired application
property, as well as suspension
and product stability – to personal
care and cosmetic products.
Controlling the degree of
thixotropy through these natural
clays creates a system that thins
www.specchemonline.com
0.5%
0.5%
Competitive Bentone
clay
No clay magnesium magnesium
aluminium
aluminium
silicate
silicate
R 0.5% Bentone clay v. 0.5% competitive clay
upon the force of application
and allows it to recover its lost
viscosity once the application force
is removed. This flow behaviour
enhances the aesthetics of a
cream on the skin, allows flawless
application of nail polish and
prevents antiperspirants
from dripping.
Hydrophilic clays, specifically
natural hectorite and magnesium
aluminium silicate smectite-
in building viscosity and
providing suspension, due to
their superior yield value. Yield
can be considered as an internal
Viscosity can improve this
internal resistance by reducing
the rate of particle movement
but increased viscosity alone is
not enough to maintain emulsion
stability when it comes to the
coalescence of droplets from
the internal phase. This is what
differentiates these clays from
other rheology modifiers: they
provide viscosity, stability and
suspension, while creating elegant
aesthetics in emulsion systems.
As shown in the top picture,
when the loading of natural
Bentone clay from Elementis
is varied from 0.5% to 5%, the
texture of the formula transforms
from a sprayable milk lotion to
a dewy lotion and finally into a
rich butter cream, while providing
similar moisturisation and skin
protection. The addition of clay
in the emulsion system increases
viscosity, without affecting its
shear-thinning flow behaviour.
This results in a light and elegant
sensory feel for the consumer,
while providing the formulator with
effective rheological control.
The other pictures show the
difference between formulations
0.5%
0.5%
Bentone
clay Competitive
magnesium
magnesium
aluminium
aluminium silicate
silicate
with 0.5% Bentone magnesium
aluminium silicate clay and the
same level of a competitor clay
of the same type when it comes
to two different aspects: long-
term stability and the suspension
of walnut scrubbing beads in an
exfoliating facial scrub formula
after centrifugation.
Conclusion
Hectorite and magnesium
aluminium silicate clays provide
rheology transformation for the
creation of elegant cosmetic
products, offering important
functional benefits to meet
demanding consumer expectations
for superior aesthetics and
formulation stability in a wide
variety of cosmetic formulations.
They are also approved by Ecocert
Greenlife as compliant to the
Cosmos standard for natural and
organic cosmetics. £
* Kimberly Burch, Kate Watermann,
and Christina Schenatzky of
the Elementis Personal Care
Business Segment also contributed
to this article. BENTONE is a
registered trade mark of Elementis
CONTACT
Elementis Personal Care
elementis.communication@
elementis.com
www.elementis.com
MATERIALS, OILS & ENERGIES

U Iron and cobalt are the leading non-precious

metals in replacing platinum

Fuel cell catalyst

research continues
More cost-effective and efficient alternatives to platinum
catalysts are needed for hydrogen fuel cells to be commercially
viable. Dr Cynthia Challener from That’s Nice reports
DESPITE THE SURGE in oil process involves generating energy efficiency by using alloys in which
production, the development and water via the oxygen reduction unused platinum is replaced with
of alternative energy sources is reaction (ORR). The process first non-precious metals (NPMs) like
generally seen as essential for the involves the separation of hydrogen iron and cobalt.
future of humanity. Hydrogen fuel molecules into positively charged However, while these catalysts
cells – notably proton-exchange hydrogen ions and negatively perform well initially, their NPM
membrane fuel cells (PEMFCs) – charged electrons. The electrons portion undergoes oxidation over
are an attractive option, as they are harnessed through an external time, reducing performance. Thus,
are potentially highly efficient circuit to power an electric motor, very large quantities are used, which
and produce only water as a then recombined with the hydrogen leads to reduced energy efficiency.
by-product. They can also be an and oxygen ions generated by the Iron is also associated with Fenton
alternative to batteries, providing ORR to form water. reactions that can degrade fuel
similar environmental advantages The best catalysts developed to cell membranes. Scientists are
with longer running yet shorter date for mediating the ORR are continuing to research new forms of
refuelling times. However, they based on platinum, which is a NPM catalysts that will help to widen
have not yet progressed as far to very expensive rare metal, costing the commercialisation of hydrogen
commercialisation as solar and approximately $30,000/kg. In most fuel cells.
wind energy technologies, largely current fuel cell catalysts, platinum
because of costs. particles are sprayed onto carbon Tungsten carbide catalyst
powder. Only the outer layers of the Researchers at the University of
Need for alternatives atoms play a role in catalysing the Delaware have developed
While there are several different ORR, resulting in poor efficiency. a tungsten carbide nanoparticle
types of PEMFCs, in all cases the key Researchers have tried to boost that catalyst that costs about

40 • Speciality ChemicalS Magazine • february 2019 www.specchemonline.com

$150/kg and can be produced
using a scalable process.1 Their
innovation is a low-temperature
process involving hydrothermal
treatment, separation, reduction
and carburisation to form very
small nanoparticles with a
uniform particle size distribution.
Conventional processes operate at
around 1,500°C and create large
nanoparticles with minimal surface
area for chemical reactions.
When incorporated into the
membrane of a laboratory hydrogen
PEMFC, these nanoparticles
reduced degradation, optimised
performance and improved the
power density, allowing for the fuel
cell stack to be reduced in size. The
research team has applied for a
patent and hopes to commercialise
the technology.
Cobalt embedded in porous
carbon nanofibres
At the University of California,
Riverside (UCR), researchers have
developed a catalyst comprising
cobalt oxide nanoparticles
dispersed in a porous network
of graphite.2 It is prepared by
first creating paper-thin sheets
of carbon nanofibres containing
U The cost of platinum has been a significant
brake on the development of hydrogen fuel cells
www.specchemonline.com
cobalt ions via electrospinning.
Upon heating, these ions are
converted to ultrafine nanoparticles
that catalyse the transformation
of the nanofibres into high-
performance graphitic carbon.
Oxidation then yields the catalyst.
Working in conjunction with
researchers at Stanford University,
the UCR team demonstrated that
the new materials perform similarly
to conventional platinum-carbon
catalysts in laboratory PEMFCs. They
believe that this performance can
be attributed to synergistic effects
obtained from the engineering of
the cobalt oxide with exposed active
sites and the 3D hierarchical porous
graphitic structure. In addition, the
catalyst has greater strength and
durability, due to the fibrous nature
of graphitic carbon.
Co-facial cobalt porphyrin
catalyst
Scientists from the University at
Buffalo have tackled the platinum
challenge by developing a self-
assembling catalyst, consisting
of two cobalt porphyrins linked
by ruthenium ‘clips’.3 An artificial
porphyrin structure was selected
because, in the human body, iron-
february 2019 • Speciality ChemicalS Magazine •
based porphyrins help to convert
oxygen molecules in air into water.
Conventional methods for
porphyrin synthesis are complex,
expensive and produce yields as low
as 1%. As a result, they have not
been usable in commercialisable
catalysts. Molecular self-assembly
means that reactions proceed in
about 48 hours and there is no
need for difficult time-consuming
purification steps. The new process
generates 79g of co-facial cobalt
porphyrins for every 100g of
starting material. The method also
allows for easy fine-tuning of the
structure by changing the lengths
of the ‘clips’.
Single-atom catalysts
Researchers at Washington
University are developing single-
atom NPM catalysts with the
potential to mediate the ORR
in hydrogen fuel cells, because
forming the catalysts at the
nanoscale increases their reactivity
and stability.4 The catalysts are
generated from iron or cobalt
salts and glucosamine in a unique
(though fairly simple) high-
temperature process that is relatively
cost-effective and scalable. P
41
MATERIALS, OILS & ENERGIES

P The iron catalyst was shown to

be more stable than commercial
platinum catalysts in laboratory
tests. They maintained their activity
and did not become contaminated,
unlike most NPM catalysts
developed for fuel cells. This
increased robustness is attributed
to the production process, which
results in a greater number of
active sites on the catalyst.

Cobalt reactor approach

To solve the problem of inefficiency
when larger quantities of NPMs
are used as catalysts in hydrogen
fuel cells, University of Wisconsin–
Madison researchers created a
separate nearby ‘reactor’ and used
a quinone to move two electrons
and protons at a time between
the reactor and the fuel cell.5 The
quinone picks up the electrons and
protons at the fuel cell electrode
and transports them to the reactor,
where the ORR takes place.
The choice of quinone was key,
because many were found to
degrade to a tar-like substance
after a short period. To overcome
this problem, the researchers
designed a highly stable quinone
derivative that lasts to up to 5,000
hours: a 100-fold improvement.
This requires more stability and
the energy output – 20% of that
of current fuel cells – must be
increased. However, scientists are
encouraged by these initial results.
Atomically dispersed
manganese catalysts
A second group of researchers
at the University at Buffalo have
developed a catalyst for use in
hydrogen fuel cells based on the
widely available and inexpensive
metal, manganese.6 This is
prepared using a straightforward
two-step process of adding carbon
and tetranitrogen to the metal.
The nitrogen changes the structure
of the manganese, resulting in a
more stable configuration that can
mediate the ORR, with performance
comparable to platinum catalysts
in laboratory tests. The researchers
are working to improve the carbon
microstructure of the catalyst and
the nitrogen addition process to
further enhance performance.
…or better use of platinum
Meanwhile, some researchers are
investigating ways to reduce the
amount of platinum required by
boosting the efficiency of platinum-
based catalysts. Volkswagen,
for instance, has worked with
Stanford University to develop a
new production to replace spraying
platinum on carbon.7
They have established a means
for distributing an even layer
of platinum atoms on a carbon
substrate, increasing catalyst activity
while dramatically reducing the
quantity of platinum required,
potentially reducing costs and
thus boosting both performance
and service life. The technique
could also be used to enhance the
performance of other technologies,
such as lithium-ion batteries.
Meanwhile, researchers at Brown
University have developed a new
ORR cobalt–platinum alloy catalyst
with reduced platinum content and
higher durability.8 It consists of alloy
nanoparticles with a structure in
which an outer shell of alternating
layers of platinum and cobalt
atoms surrounds a pure platinum
core. The layered structure smooths
and tightens the platinum lattice,
increasing reactivity while protecting
the cobalt atoms from leaching
and oxidation.
V Flow diagram of a fuel cell
In a laboratory test using a
PEMFC, the catalyst outperformed
a traditional platinum alloy catalyst,
maintaining its activity after 30,000
voltage cycles. To confirm its
performance in an actual fuel cell,
the researchers had it tested at the
Los Alamos National Laboratory.
Promisingly, it exceeded US
Department of Energy (DoE) targets
for the year 2020 in both reactivity
and durability, with an initial activity
of 0.56 amps/mg (DoE target
0.44) and 0.45 amps/mg (DoE
target 0.26) after 30,000 cycles. An
application for a provisional patent
has been submitted. £
References can be found on
www.specchemonline.com
CONTACT
That’s Nice
89 Fifth Avenue
Floor 5, Suite 500
New York
NY 10003-3020
US
+1 212 366 4455
www.thatsnice.com

42 • Speciality ChemicalS Magazine • february 2019

Peptides & Proteins
‘Needle-
to-needle’:
Manufacturing
neoantigen
peptides
Trishul Shah of PolyPeptide
Laboratories looks at the
prospects for individualised
peptide therapeutics*
TRADITIONAL TREATMENTS FOR cancer have mainly
used surgery, chemotherapy and/or radiation to
remove and destroy cancer cells. This means they
rely on processes and systems external and foreign
to the human biome. Chemotherapy and radiation
treatments destroy normal cells as well as cancer cells
and they have unpleasant side effects. In the late 1990s
and early 2000s, some progress was made through
better monitoring and more focused chemotherapy
agents. The advent of significantly improved genetic
analysis has opened the door to better options. With
more understanding of genetic mutations, more
individualised treatment can be offered.
Neoantigen peptides
One key area of focus is the use of patient-specific
neoantigens to generate or enhance an immune
response from the patient’s own disease-fighting
systems. Peptides called antigens adorn the surface
of all cells. Cancer cells are prone to developing
mutations that may result in a change in the amino
acid sequence to the surface peptides. These
‘neoantigens’ stimulate the patient’s own immune
system to produce T-cells that attack cancer cells.
Individualised neoantigen peptide cocktails,
synthetically manufactured, are now being explored
to treat cancer. During this ‘needle-to-needle’
process, the tumour cells undergo a biopsy, the cells
are subsequently sequenced and, with the use of
bioinformatics, patient-specific neoantigen peptides are
predicted. The unique cocktail is then manufactured
and administered to treat the specific cancer.
44 • Speciality ChemicalS Magazine • February 2019
R Microwave synthesiser
During the sequencing of the tumour cell, over 100
different neoantigen peptide sequences are identified
but, with the use of proprietary bioinformatics
algorithms, the number can be reduced to ten to 80,
helping to speed their manufacture. Depending on the
type of cancer and the algorithm used, the peptides
range in length from ten to 40 amino acids.
Typically, patients would require these peptides to be
administered within two months of the biopsy. Thus,
up to 80 peptides containing up to 40 amino acids
need to be manufactured and formulated in six to
eight weeks, whereas in traditional peptide therapeutic
manufacturing the typical timeline is five months for
the drug substance and two more months to formulate
the drug product. There is also very little leeway in the
timelines. Manufacturing neoantigen peptides requires
a completely different and pragmatic approach,
where high throughput, low cost and GMP production
are significant.
Co-ordination for success
A high level of coordination is required between the
various departments of the manufacturing site. Strong
project management is critical to success. To avoid
any conflict or disruption to the normal manufacturing
environment, it is essential to set up resources and
personnel dedicated to and trained for neoantigen
peptide manufacturing. The use of GMP-released raw
materials is imperative to ensure control and quality
of the manufacturing process. Such materials are
readily available at organisations that focus on GMP
manufacturing, like the PolyPeptide Group.
www.specchemonline.com
 Quality assurance (QA) plays a key role in the
oversight of the manufacturing process, so a
close partnership between QA and manufacturing
is paramount for high throughput and quality.
Standard batch records used in traditional peptide
manufacturing do not allow the flexibility and speed
needed for neoantigen peptide manufacturing,
therefore a simple GMP batch record format needs
to be developed and used. In the long term, to avoid
transcription errors, the sponsor and the manufacturer
can integrate a laboratory information management
system (LIMS) to transfer the peptide sequences and
the critical quality attributes of the peptides.
Alternative routes
In traditional peptide therapeutics, quantities range
from tens of grams to 100kg, depending on the
indication. Neoantigen peptides are needed in
mg quantities, so automation, which is critical
for high throughput and low cost, is more easily
implemented. To ensure high throughput, different
types of automated synthesisers can be implemented
depending on the need – microwave or parallel. The
former uses microwave heating to increase the rate
of peptide-resin production but each is synthesised
individually. The latter can produce up to 24 peptide
resins in one go.
With microwave synthesisers, each peptide-resin
is processed further while new ones are being
synthesised, providing an efficient flow. Those produced
from parallel synthesisers are only processed once all
of those in a group have been synthesised and the
time taken to produce them is significantly longer. This
does not offer an efficient flow because not all the
Figure 1 – ‘Needle-to-needle’ concept
www.specchemonline.com
peptide-resins in that group can be further processed
at once. Any failure in the parallel synthesiser would
impact them all, while any failure in the microwave
synthesiser would only impact the one under synthesis.
Parallel synthesisers allow in-line cleavage
capabilities, whereas separate operations to cleave
the peptide-resin are required in microwave
synthesisers. Both types have their advantages and
disadvantages, and both may work better for different
types of sequences. Therefore, both are viable options
for neoantigen peptides. It is nevertheless more
important for contract manufacturers and peptide
synthesiser manufacturers to collaborate closely and
thus quickly alleviate any challenges that arise.
Following the cleavage of the peptide-resins, the
crude peptides are purified using the semi-preparatory
automated purification systems that contract
manufacturers use for design of experiment studies. A
platform approach is followed, where the purification
resin is dedicated to each patient rather than each
peptide. Cleaning verification is performed between
each patient sub-set. Each purified peptide is isolated
on a manifold lyophiliser, with each lyophiliser
dedicated to a patient sub-set. This approach permits
high throughput and lower costs.
A similar approach should be employed to test
the peptides’ critical quality attributes. A UPLC-MS
method should be developed and qualified to test
them all for purity and to confirm identity. Additional
testing parameters, such as residual solvents, counter-
ion, peptide content, moisture, bioburden and
endotoxin, can be tested on a platform basis on a
statistical number of batches. The sponsor and the
contract manufacturer should agree on a strategy P
February 2019 • Speciality ChemicalS Magazine • 45
Peptides & Proteins
T Parallel synthesiser
P for these additional tests and understand their
impact on throughput and costs.
Additional challenges
As stated above, the number of peptides required
per patient can vary from ten to 80. The probability
of successful manufacture decreases with increased
number, greater length and greater complexity. To
ensure the success of the programme, it is important
for the manufacturer and the sponsor to align on an
acceptable attrition rate, so as to ensure that not too
much time is spent on challenging peptide sequences.
To further complicate the matter, these challenging
sequences tend to be immunogenic and preferred for
stimulating T-cell production. Quite a lot of work is
being performed to improve the predictive nature of
the bioinformatics algorithms in order to reduce the
number of sequences, thus improving the number of
shots on target.
Peptide manufacturers can take a similar approach
to predict the ease of manufacture and thereby
46 • Speciality ChemicalS Magazine • February 2019
further improve the success rate. For
instance, PolyPeptide has proprietary
internal algorithms based on data
collected over the years that help to
predict challenges in manufacturing
specific peptide sequences. This allows
the organisation to make educated
decisions on manufacturing strategies for
each individual peptide, increasing the
likelihood of success.
The long-term success of individualised
peptide therapeutics raises questions
about the validation strategy for their
manufacture. Late-stage traditional
peptide therapeutics manufacturing
undergoes ‘product’ validation, where
a full quality by design approach is
applied to each individual peptide. This
approach would be very time-consuming
and costly if applied in individualised
peptide therapeutics.
Additionally, using the resources
required to validate each individual
peptide would not be practical. Rather
a platform approach where the overall
process is validated would be more
appropriate. Once process validation
is completed, continuous process
verification can be performed to ensure
the process is operating within control.
Outlook
Currently, neoantigen peptide treatments
are offered in conjunction with standard,
first-in-line, traditional treatments for
late-stage cancers. If these new individual
treatments prove successful, they could
be used as a primary standard of care
option for a wide variety of cancers.
These therapeutics provide a highly
fascinating approach to cancer treatment requiring a
pragmatic process for ‘needle-to-needle’. The success
of this process depends on close partnerships between
stakeholders, including investigators, sponsors,
manufacturers and regulatory authorities, to establish
an effective and safe pathway. £
*The author would like to thank Timothy F. Culbreth,
president of the US sites at the PolyPeptide Group, for
his comments and review.
CONTACT
Trishul Shah
Director – Business Development
PolyPeptide Group
trishul.shah@polypeptide.com
www.polypeptide.com
Peptides & Proteins
Advanced SPPS
Olivier Ludemann-Hombourger of PolyPeptide Laboratories and
N. Petitjean of Ypso-Facto look at the challenge of large-scale
peptide synthesis on solid supports*
SOLID-PHASE PEPTIDE synthesis (SPPS) is well
established and routinely applied on efficient automatic
synthesisers, which are available at laboratory scale.
However, manufacturing peptides at industrial scale
remains a major challenge, considering the complexity
of these multi-step syntheses, the long lead times and
the large volume of reagents and solvents required to
produce the final API. In 2013, we published an article
looking at the way to overcome these challenges from
a holistic point of view.1 This article presents the latest
practices contributing to making the ideal peptide
plant become a reality.
Interest in the large-scale manufacturing of
peptide APIs has boomed since 2003, when the FDA
approved Enfuvirtide (Fuzeon), a 36-amino acid
peptide inhibitor of HIV1 membrane fusion. This offers
a promising future to Fmoc-SPPS, based on the Fmoc
strategy first outlined by L.A. Carpino in the 1970s.2
Indeed, since the emergence of SPPS, many resins,
linkers, protected Fmoc-amino acids and activating
chemistries have been developed. Fewer than ten
peptides were commercially available in 1990,
against about 70 in 2018, while some 170 are now
48 • Speciality ChemicalS Magazine • February 2019
in various clinical phases and over 500 in the pre-
clinical phase. The peptide drug product market was
worth $5 billion in 2003 and $25 billion in 2018; it is
expected to reach $47 billion by 2025.
The main challenge of the coming decade will
be to cope with the growing demand for peptide
manufacturing in an acceptable way. The design
of manufacturing processes also needs to take into
account the evolution of the ecological factor (waste
reduction, green solvent use and technology) of and
the economic pressure on drug products. Typically,
procedures for industrial SPPS are scaled up directly
from the laboratory process: the reactor size is
increased and it is operated mostly manually.
To address these challenges, Polypeptide
Laboratories is running a programme called
Advanced SPPS. This is based on a process
engineering approach along several axes: improving
the process development methodology to obtain a
fundamental understanding of SPPS and develop
predictive tools; and improving the manufacturing
technology by developing advanced control solutions
and fully automating operations.
www.specchemonline.com
S Figure 1 – Extract of the predictive toolbox used for peptide synthesis
Improving development methodology
Valuable knowledge and data have been gained over
years of R&D on several thousand SPPSs. This has
been used to build a predictive toolbox to assess any
new peptide synthesis and identify critical steps (such
as aspartimide, ß-Asp, N-to-O shift, diketopiperazine
formation, oxidation and hydrolysis) and elaborate
a controlled strategy with a smart selection of raw
materials and appropriate operations to minimise
impurity formation. It also facilitates the downstream
process. Figure 1 illustrates the stability, solubility and
charge state of the peptide with regard to pH.
The tool also estimates the potential for aggregation
and the foreseeable impurities, to assist developers
in selecting the most suitable synthetic route. This can
greatly reduce the time required compared to a trial-
and-error approach. Moreover, a new methodology
has been developed to improve process performances
based on a combination of experiments and predictive
simulation. This enables us to understand further
the mechanisms associated with SPPS and adjust the
processes based on this knowledge.
A simulation tool was developed in collaboration with
Ypso-Facto, a company with experience in chemical
process simulation. This was developed based on
information gathered from experiments; the model was
validated by comparing existing experimental results
with their simulated counterparts. The tool combines
a reaction model (about 40 reactions and 50 species/
step), a mass transfer model and adsorption models
that describe the distribution of species between the
liquid and the solid phases, and its influence on the
different reaction rates.
This makes it possible to simulate the successive
steps of deprotection, washing, amino acid activation,
coupling on the resin and acetylation. The evolution of
the concentration of species versus time in the liquid
phase and solid phase are calculated and can be
compared with experimental data. It is thus possible
to determine the best conditions to minimise critical
impurities, such as deletion, insertion or racemisation,
guanidylation products and others, while maintaining
maximum resin conversion.
www.specchemonline.com
The evolution of species versus time and
process performances can also be calculated
for batch and continuous stirred tank reactors
and plug flow reactors. This tool also facilitates
the exploration of new ideas in silico and
running only a minimum of experiments for
validation (Figure 2),
which considerably reduces experimental
efforts to propose solutions toward an
optimised process.
The tool is constantly improved by making
the most of the strong experimental knowledge
of the chemist, the data accumulated over
the years and the approach of the process
engineer. For example, it can identify working
conditions for which the solvent consumption
during the washing steps is reduced by a
factor of two to three compared to common practices.
Coupling times have been reduced by a factor of two
to ten by adjusting reaction-operating conditions, while
keeping the same reagents and chemistry.
Advanced process control & automation
Increasingly stringent standards, increasingly
challenging customer demands and intensifying
competition have forced industries to develop more
reasoned and controlled syntheses. To help with this,
online monitoring methods have been developed.
Thanks to the large quantity of data collected and the
reduction of the analysis time, they can be used at
every stage of product development, offering a better
understanding of the chemical and physico-chemical
phenomena affecting the reaction to establish links
between process and product during manufacturing
and ensuring control and smooth running during
manufacture. P
Q Figure 2 - Evolution of
DIC (red), OBt (blue) and
Fmoc-AA (black) moieties
during coupling
Note: Reactants concentration
about 0.04 mol/L. Crosses
indicate experimental data,
plain lines represent the
simulated evolution of species
in the liquid phase over
time and dashed line
represents the evolution of
main target product on the
resin over time.
February 2019 • Speciality ChemicalS Magazine • 49

S Figure 3 – Online monitoring of the coupling reaction of a lysine on a
Ramage-MBHA resin
P For each step, a suitable instrumentation must
be chosen to match the goals and constraints.4
In any case, it should be compatible with the reaction
medium and provide accurate and robust data
R Advanced SPPS prototype
www.specchemonline.com
Peptides & Proteins
at a frequency adapted to the kinetics of
the reaction.5
With these challenges in mind, Polypeptide
studied the feasibility of online monitoring
of SPPS. By selecting relevant sensors – for
instance, for pH, conductivity and absorbance
– we have demonstrated that the key
parameters of each step can be monitored
qualitatively and quantitatively, looking at
both the solid and the liquid phases. This is
illustrated in Figure 3, displaying the progress
of the coupling reaction of a lysine on a Ramage-
MBHA resin.
Online monitoring helps to improve the SPPS
technology: it facilitates better control of the reaction
(resulting in an improved impurity profile) and
optimised productivity (optimal duration of each
process step). It also helps to reduce the environmental
February 2019 • Speciality ChemicalS Magazine • 51
Peptides & Proteins
P impact of the process by minimising the solvent
volume used. In addition, the use of this data with
the prediction models and advanced control models
previously described will significantly increase the
gains already achieved.
Peptide synthesis involves many repetitive steps,
which brings a high risk of human error when
performed manually. Impurities can be created at
each step, which increases the need for purification
and hence the cost of the final product. Process
automation aims to reduce the operator’s influence.
His mission is then to plan, monitor and control
the process, and handle any situation that has not
been anticipated by the control system. This leaves
the operator more time to focus on more important
tasks. It can also collect more information and make
corrections more precisely, faster and more frequently
than the operator.6
To obtain a fully automated process, it is necessary
to implement an advanced control system at each
stage of the process, based on data obtained in real
time, such as resin or liquid height, temperatures,
pressures, flows, concentrations and others. A fully
automated SPPS prototype has been designed to
implement the automation of the process, integrating
the new online monitoring tools.
For example, an advanced control system in
the reactor was implemented. The performances
obtained during washing steps with such a system
agree with the predictive models, that is, reduced
solvent consumption and washing time compared
to common practices. In the near future, process
52 • Speciality ChemicalS Magazine • February 2019
automation at industrial (GMP) scale will be essential
and will lead the race to competitiveness in the
peptide segment.7
Perspectives
Based on the better process understanding and process
automation, Advanced SPPS has been developed
to get closer to the ‘ideal peptide plant’, featuring
fully automated and greener processes with a drastic
reduction of the manufacturing time as imagined in
2013.1 The overall process cost was reduced, while its
robustness and reproducibility were improved. Seizing
innovation opportunities remains important to further
boost the performances, through a joined research
effort of peptide chemists with process engineers. £
References can be found on www.specchemonline.com
*Also contributing to this article were E. Dropsit and
R. Ravetti of PolyPeptide Laboratories
CONTACT
Olivier Ludemann-Hombourger
General Director
PolyPeptide Laboratories France
oliver.ludemann@polypeptide.com
www.polypeptide.com
 Peptides & Proteins
CDMOs expand
capacity to support
recent market trends
Dr Matthieu Giraud, global director of the Peptides, Lipids &
Carbohydrates platform at CordenPharma, elaborates on the
expansion of peptide offerings to support recent trends in the global
peptide market
R Figure 1 – Top selling peptide drug products by sales (a) & volume (b)
Source: Thomson Reuters, June/September 2018
THE EARLY PEPTIDES were
hormones, but peptides are now
being developed for almost every
therapeutic category ranging
from anti-inflammatory to cancer.
This and the growing number of
54 • Speciality ChemicalS Magazine • february 2019
therapeutic peptides in clinical
trials are the key drivers for
capacity expansion by leading
contract development and
manufacturing organisations
(CDMOs) in the global peptide
API market. CDMOs are focusing
on internal and external capacity
expansion and integration into
the pharma supply chain, which
ultimately boosts manufacturing
activities for peptide APIs across
the globe.
The global peptide API market
was estimated to be valued at
$1.7 billion in 2018 and is
forecast to expand at a compound
annual growth rate (CAGR) of
7.7% to reach $2.9 billion by
2025. North America clearly
dominated the global market, with
a 48.2% value share. This region
represents the highest growth
incremental opportunity by 2025,
of $576.9 million.
In terms of value, the European
market, which accounted for
28.6% of the market in 2018, is
expected to expand at the highest
CAGR, 8.1%.
However, in terms of volume,
the Asia-Pacific market is expected
to witness the highest CAGR of
10.2%. This region accounted
for 16.5% of the world market in
2018, with Latin America (4.2%)
and the rest of the world (2.5%)
taking up the rest.
The US and Europe had over
57% of the global clinical trials
for therapeutic peptides being
carried out in them in 2017. This
represents a market with huge
growth potential. Multiple clinical
studies in over 57 companies are
under way across the two regions.
www.specchemonline.com

R Figure 2 – Peptide length evolution by year. Source: J.L. Lau & M.K. Dunn, Bioorg. Med. Chem., 2017
Peptides early & modern
In the 1980s, nearly all peptides
entering clinical development –
such as Oxytocin, Leuprolin and
Octreotide – were fewer than ten
amino acids long. Average peptide
length has increased (Figure 2) with
each subsequent decade, largely
due to improvements in peptide
synthesis and manufacturing
technology. The availability of
a broader range of popular
molecular targets, including B class
G-protein coupled receptors that
are activated by larger peptide
ligands, has also played a role.
Development candidates are
now more equally distributed in
the various length ranges up to 40
amino acids, meaning that they are
mostly being produced by solid-
phase peptide synthesis (SPPS).
To understand the increase in
complexity, it is worth noting that a
R Figure 3 – Type of peptide conjugation
www.specchemonline.com
40-mer amino acid peptide needs
more than 80 chemical steps.
Drug substance design in the
peptide field has evolved towards
longer and more complex
peptides than ever. Conjugation
has emerged as a mechanism of
choice to alter the physical and
pharmacological characteristics of
peptides. Of particular note is a
higher proportion of conjugated
peptides entering clinical trials over
the last two decades. For example,
pegylation, protein-conjugation
and lipid-conjugation are being
investigated to increase half-life
and formulate extended release
formulations (Figure 3).
More generally, the average
timeline for a drug to be developed
from discovery phase to market
launch is about 15 years, and the
average cost of developing a new
drug has risen to over $2.5 billion,
while the rate of clinical trial failure
for new drugs is about 90%. The
pharmaceutical industry is reaching
a critical stage and companies are
struggling to achieve a return on
their investments.
New, efficient solutions are
necessary to significantly cut
the costs of production. This is
important for patients as well as
pharma companies, as drug prices
are skyrocketing, particularly in the
US. Big Data in R&D can generate
huge success rates by optimising
innovation and improving the
efficiency of research. Predictive
modelling can help to identify
shorter routes to peptide process
development and optimisation.
Role of CDMOs
To address these trends, the
pharmaceutical industry is more
and more turning towards CDMOs,
who are in turn investing heavily to
diversify their capabilities, accelerate
production timing and improve their
cost structure by implementing lean
development and manufacturing.
CordenPharma, for instance, has
developed expertise in both SPPS
and liquid phase peptide synthesis
(LPPS) across its two sites in Boulder,
Colorado, and Brussels in Belgium.
The former focuses on the
development and manufacturing
of APIs from laboratory scale to
commercialisation at multi-tonne
scale. It has both the largest SPPS
equipment available, allowing
an output up to about 1,000kg
of protected peptide/batch and
the largest high-pressure reverse-
phase column, at 100cm, as well
as expertise in peptide precipitation
as an alternative to lyophilisation in
the final isolation step.
The Brussels site, meanwhile,
specialises in the development and
manufacturing of peptides using
both LPPS and SPPS. It has recently
invested to expand its SPPS capacity
with automated equipment. £
CONTACT
CordenPharma
www.cordenpharma.com/contact-us
SPECIAL FEATURE

Lead generation and audit

efficiency to the fore
Discussions at SOCMA’s 97th and last annual meeting in New York
focused on growth and productivity. Gregory DL Morris reports
Playbill magazine lists Phantom of
the Opera as the longest running
show on Broadway, with more than
12,000 shows over more than
30 years. It will still have to triple
that performance to match
SOCMA, which, on 10 December
2018, ran down the curtain on its
annual dinner and meeting in
New York after 97 years.
After the brief formal business
meeting, at which the nominated
slate of candidates for the
board of governors was elected
unanimously, Gene Williams,
chairman of the board and
president of Optima Chemical,
moderated an informal discussion
with board members and a
plenary session of the meeting.
The panellists were active SOCMA
members that had enjoyed
benefits from, and expressed
support for, several of the
association’s initiatives.
“There is a lot of demand for
custom manufacturing in this
industry that is being unmet or
inefficiently met,” said Pat Killian,
vice president and general
manager of Monument Chemical.
“The main problem is that this
sector is so quiet [and confidential]
that people only know the three or
four other companies with which
they already do business. The
whole industry could benefit from
broader exposure to each other,
from the wider capabilities around
the industry.”
Killian was forthright that his
advocacy was enlightened self-
interest. “We still say ‘no’ to about
70% of the requests we get. We
wish we could say yes to more
of them, or at least refer them to
someone else who could say yes.
We don’t have those resources, but
SOCMA does.”
Williams noted that the
association has started a ‘lead

W Jennifer Abril, CEO of SOCMA

56 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com


sheet’ programme that will be
a conduit for contacts across
the organisation. Jennifer Abril,
president and CEO, said that
some form of lead generation has
long been a desire of SOCMA
and most members, but any
such initiative has to be held to
the highest standards of fairness
and compliance with regulations
against anti-competitive practices.
“We have intake specialists who
complete a simple, standard, two-
page form,” Abril explained. “They
ask questions of the company
placing the inquiry. That helps
ensure the information is thorough
and clear. We have already
updated the form to include
logistics and scheduling. The form
goes out to all members at the
same time to ensure fairness. After
that, it is up to them to respond
directly to the lead.”
The lead sheets also “create
more drive for membership,”
said Keith Arnold, president and
CEO of MFG Chemical, and
SOCMA board member. While
any company in the industry can
contact any other on its own,
association membership and the
lead-sheet programme “create
new and efficient access among
members,” he said. “And that
is not as kits of assets, but their
skill sets and expertise for taking
www.specchemonline.com
chemistry from lab to pilot to
commercial scale.”
There can also be unforeseen
opportunities. As manufacturing
processes are implemented, raw
materials, by-products and waste
streams change. “We are always
looking for ways to offer side
streams to someone who can use
them,” said Arnold. For example,
MFG has a dilute stream from one
of its processes that it has been
able to send to another company
as feedstock, rather than have to
pay to have it treated or disposed.
Abril noted that the lead-sheet
programme is one of several
significant changes within the
organisation. Not the least
of these will be shifting the
Specialty & Custom Chemicals
America conference and trade
show to Fort Worth, Texas, in
February. She also stressed
that performance chemicals,
as well as pharmaceuticals
and agrochemicals, were co-
equal segments in the speciality
chemicals universe.
Williams noted a ‘modernisation’
of the landmark ChemStewards
environmental, health, safety and
security (EHS&S) management
programme. “The initiatives will
be to lay ChemStewards over
the EHS&S audits of member
companies to identify areas of
FEBRUARY 2019 • Speciality ChemicalS Magazine •
T A hotel on Times
Square was the location
for SOCMA’s 97th and last
annual dinner
commonality and potential gaps.
We can then provide feedback to
members,” he said.
As with the lead sheets, this is
not a top-down directive to
members, but rather a consensus
method of providing insight.
There is broad agreement across
member companies and the
industry that EHS&S audits are
essential but also laborious and
time-consuming. Compliance
with ChemStewards provides an
efficient basis for making further
auditing more selective.
“We are a Tier 3 company
in ChemStewards,” Arnold of
MFG said in an interview. “That
represents a very rigorous
level of audits. That makes
us a better company to have
those processes in place, but
it also has to be said that we
have the resources to do that. It
makes sense to align audits with
ChemStewards, especially for
smaller companies that do not
have the same resources.”
Williams further noted that
as part of the modernisation of
ChemStewards, SOCMA will
add ‘career ladder’ training for
operators that will stretch from
high-school level mathematics and
chemistry to unit operations
and up to higher-level economics
and optimisation. £
57
REGULATION & COMPLIANCE
Readying
the
ship
for
‘no deal’
Naheed Rehman,
business lead consultant
for chemicals at Envigo,
assesses the ongoing
Brexit challenge
BREXIT HAS MULTIPLE implications for the crop
and chemical substances research market. As an
established CRO in this field, our key priority, and
that of our chemicals and agrochemicals customers,
is continuity with minimised change and disruption.
Consequently, we established a dedicated Brexit
task force as part of our commitment to monitor,
prepare and update our guidance to customers as we
approach the key date of 29 March 2019.
We are preparing for a number of possible
Brexit outcomes, including a worst-case ‘no deal’
scenario between the EU-27 and the UK, in which no
transitional arrangement is in place after 29 March
2019, the UK exits the single market and customs
union and hard borders are introduced.
Movement of animals
For both commercial and animal welfare reasons,
the movement of animals between the UK and
EU is already kept to a minimum. However, we
anticipate that Brexit will include an increase in
58 • Speciality ChemicalS Magazine • February 2019
the administrative burden in completing necessary
documentation for the movement of live animals
at the port of entry. Contingency plans include
consideration of whether to bring in additional animal
stock to maintain availability through the March and
April 2019 period.
Movement of goods to and from EU countries
currently does not require such bureaucratic burdens
as Convention on International Trade in Endangered
Species (CITES) permits, export health certificates,
commercial invoices or shipping statements. However,
all movement of primate samples outside the EU
currently requires a CITES permit and it is possible
that, post-Brexit, these will be additional requirements
for movements to and from the EU.
In preparation for a potential ‘no-deal’, Envigo is
working with suppliers to stock adequate levels of
key goods in order to limit any impact on customs
clearance of supplies into the UK post-Brexit. There
is the possibility of tariffs, adding costs to trade
between the UK and EU (such as product standards or
regulations), but WTO rules dictate that the EU will not
be allowed to penalise the UK unfairly.
The UK would face the same non-trade tariffs as any
other nation without a free trade agreement. Since a
‘no deal’ with a move to WTO protocols is possible,
analysis is underway to understand the impact of tariff
changes, should they occur post-Brexit. One forward-
looking initiative open to companies is to review
www.specchemonline.com
clearing agents to act on their behalf to deliver the
most favourable tariffs possible.
GLP
The performance of GLP studies in the UK falls under
the remit of the OECD council concerning the mutual
acceptance of data (MAD). Any study performed by
a member country should be accepted by any of the
others. Since the UK is an adherent to the OECD MAD
programme in its own right, Brexit has no impact on
the acceptance of Good Laboratory Practice (GLP)-
regulated, non-clinical safety assessment studies
performed there. Furthermore, since OECD regulations
underpin these trials, no divergence between the EU-27
and UK enforcement of GLP is anticipated.
From 29 March 2019, in a ‘no deal’ scenario,
chemical substance companies are likely to be subject
to the laws applying in the UK. The provisions of the
Classification, Labelling & Packaging (CLP) Regulation
may remain valid within the UK on the basis of the
repeal bill, which will – at least temporarily – convert
existing EU law directly into the UK legal system. UK-
based companies exporting products to the EU-27 will
need to classify and label their products according to
CLP regulatory provisions.
Without a deal, the UK chemicals industry will no
longer be bound to the REACH Regulation and there
will be no legal provision for the European Chemicals
Agency (ECHA) to cooperate with UK authorities.
www.specchemonline.com
ECHA has stated that UK authorities will lose access
to the world’s largest database on chemical substance
properties. These agencies will only have access to
public information on its website. This will in turn
impact the UK’s role as an evaluating member state
and in ECHA’s Risk Assessment and Socio-Economic
Analysis Committees.
What next?
The EU Withdrawal Act of June 2018 allows the UK
to transfer EU chemicals regulation into domestic
law. Consequently, the Health and Safety Executive
(HSE) has been preparing statutory instruments and
the legislative process. The HSE would perform the
majority of roles for the UK, such as REACH and
CLP. Moreover, the Department for the Environment,
Food & Rural Affairs (DEFRA) says that it has nearly
completed building the UK’s IT capability for the
registration and regulation of chemical substances for
market entry.
Existing registrations held by UK-based companies
will be transferred directly to the replacement for
REACH, legally ‘grandfathering’ the registrations
into the British regime. Businesses with existing
EU registrations being handled this way would be
required to validate their existing registration with the
HSE by opening an account on the new UK IT system
and providing the required basic information within
60 days of the UK leaving the EU. P
T The pesticides sector is relatively unlikely to be affected
February 2019 • Speciality ChemicalS Magazine • 59
REGULATION & COMPLIANCE
U Customs procedures will be much more complex
under a ‘no deal’ scenario
P A transitional ‘light-touch’ notification process will
be set up for UK companies importing chemicals from
the European Economic Area (EEA) before 29 March
that do not hold a REACH registration. This reduces
the risk of supply chain disruption for companies that
currently rely on a registration held by an EEA-based
commercial entity.
In terms of plant protection, existing regulatory
regimes will remain in place in the short term and
companies will not stop trading. The same applies to
biopesticides, with the UK and EU regulatory regimes
remaining unchanged in the short term, apart from
administrative adjustments.
In the medium to longer term, the UK would not
be legally committed to EU regulatory alignment in
plant protection and would be free to diverge from
developing EU legislation. All current active substance
approvals, PPP authorisations and maximum residue
levels will remain valid in the UK and EU, however.
Furthermore, the UK is not likely to be bound by the
EU Biocidal Products Regulation and a stand-alone
biocidal products regime may be established, with all
decision-making repatriated to the HSE. All current
active substance approvals and UK-approved biocidal
products in place on 29 March 2019 would remain
valid in the UK until their normal expiry date.
60 • Speciality ChemicalS Magazine • February 2019
The HSE will, where possible, continue to process
biocidal products post-exit day, granting national
authorisations and potentially requesting
re-submission of the information supporting original
applications to enable substances to complete
evaluations. The UK will not be legally committed to
medium- or long-term regulatory alignment with the
EU and divergence from EU legislation is likely.
Conclusion
Even in the case of ‘no deal’, industry influencers,
the UK government and regulatory authorities are
preparing and working to deliver as much continuity
and the minimum of change possible for UK-based
chemicals and agrochemicals businesses. £
CONTACT
Chemical Team – Europe
Envigo
+44 1480 892 000
www.envigo.com
www.specchemonline.com
Regulatory&&Compliance
RegulatION Compliance
REACH
and a
no-deal
Brexit
As REACH is currently ‘directly
applicable’ in the UK, there is
no UK implementing legislation,
except in relation to enforcement.
Under the EU Withdrawal Act, EU
Regulations are direct legislation,
which will become part of UK
law on exit day. Under an agreed
Brexit, REACH would continue
to apply in the UK, and it would
continue to use the European
Chemicals Agency (ECHA) system
for the transitional period at least
– and potentially thereafter as an
associate member.
However, in the event of a
no-deal Brexit, the UK would
have no pre-existing registration
system on which to manage and
regulate its own ‘UK REACH’. The
UK government and the Health
& Safety Executive (HSE), its
competent authority for REACH,
have issued guidance on how
UK REACH would operate in the
event of a no-deal Brexit, with
62 • Speciality ChemicalS Magazine • FEBRUARY 2019
Dave Gordon and Anita Lloyd,
partner and director at Squire
Patton Boggs, look at the
legal issues relating to a
proposed ‘UK REACH’ system
in the event of the UK leaving
the EU without a deal
effect either from 30 March or the potentially relied upon by
end of the transitional period. The many others elsewhere – will
government has built an IT system, become invalid.
UK REACH-IT, that will perform UK companies wanting to
the equivalent function to ECHA’s continue supplying into the EU will
REACH-IT platform. need to transfer their registrations
There are complex consequences to EU-based companies, or rely on
for chemical companies and supply their customers making ‘importer’
chains, both for UK companies registrations. This sort of transfer
wishing to retain EU-27 market is not foreseen in the REACH text,
access and for any companies and there are timing issues, due
wishing to do business in the UK. to the need to maintain existing
This article focusses on selected registrations up to the time of exit.
aspects of UK REACH ahead of an Without careful management,
expected UK statutory instrument there could be serious ramifications
on chemical regulation. down the supply chain and serious
interruptions to trade.
REACH & supply chains To keep supply chains open,
REACH works on a ‘whole supply UK manufacturers and importers
chain’ basis. Companies at the will also need to make equivalent
top often have registrations registrations under UK REACH
and authorisations that benefit to those they held under REACH.
those lower down the chain EU- Non-UK companies active in the
wide. With a no-deal Brexit, all UK will also need to consider
registrations and authorisations their status under UK REACH and
held by UK companies – and whether they wish to appoint an
www.specchemonline.com

R Dave Gordon – No system exists to manage ‘UK REACH’ in a no-deal scenario
only representative (OR) to register
instead of their UK importer. If this
whole process does not operate
smoothly, without substantial
duplication of effort and cost, EU-
27 companies that have purchased
from UK companies may look
elsewhere for their supplies.
UK REACH: legal issues
UK-based manufacturers,
importers and ORs who have held
REACH registrations up two years
prior to exit date will be entitled to
have these ‘grandfathered’ into UK
REACH. They need to enter some
basic substance information into
UK REACH-IT by 29 May 2019 and
submit a full registration dossier by
29 March 2021. No registration
fee will apply.
The main legal issue for these
companies is whether they already
own or have full access to the data
they will later need to submit a
full UK REACH registration. They
may also have concerns about
maintaining EU market access and
need to take action under REACH
as well. UK-based companies
importing chemicals from within
the EU-27 did not previously need
a REACH registration, as they were
downstream users. However, they
will be classed as ‘importers’ under
UK REACH and will need to make
sure the substances they import
are registered.
There are several options for
importers. One is registering
www.specchemonline.com
under UK REACH as an importer
and notifying UK REACH-IT by
26 September 2019, followed by
a full registration by 29 March
2021. By making the notification,
the importer benefits from a two-
year exemption before it needs to
submit a full registration. Access
to data, could, however, be a
major issue if the company has not
previously been involved in
REACH registration.
A second is asking their EU
supplier to register under UK
REACH as an OR. However,
this would be considered a new
registration for the OR. To remove
all obligations on the UK importer,
the full OR registration would
R Anita Lloyd – Several options exist for importers
FEBRUARY 2019 • Speciality ChemicalS Magazine •
need to be completed, and a
registration fee equivalent to those
currently levied by ECHA paid,
by 26 September 2019. This is a
substantial undertaking for the EU
supplier, and will incur duplicated
registration costs. The supplier may
also not have full access to the
necessary data.
The final option is notifying
under UK REACH, but working on
the basis that an OR registration
will be completed by the EU
supplier before 29 March 2021.
HSE guidance indicates that this
is possible and that, where an OR
registration is completed within
the two-year period, the importer
will not need to complete its own
registration. The OR’s registration
would still be considered ‘new’, so
fees would be payable.
This could be a sensible
compromise position and remove
the need for the importer to secure
access to data. However, it relies
on good faith or a strong contract
between the parties, and on the
EU supplier being willing to submit
and pay for a new registration.
If the OR does not complete its
registration as planned, the UK
importer could lose market access.
The importer may also be limited
to buying from the EU company
the OR represents if it does not
proceed with its own registration.
Non-UK companies wishing to
supply chemicals into the UK will
need to liaise with their UK P
63
RegulatION & Compliance
P importers regarding registration
options as noted above. If based
outside the EU, these companies
will have already had to consider
REACH and may already have an
OR registration in the UK, giving
them the option of grandfathering
it – and moving their existing
REACH OR registration to another
OR in an EU-27 country.
Suppliers based in the EU-27
seem to be disadvantaged here.
They do not have an existing
REACH OR registration that they
can grandfather into UK REACH.
Like other suppliers, they may
want to retain control of the UK
REACH registration dossier and
data, but may have to pay for
and complete a full UK REACH
registration within 180 days, or
two years if the importer makes
the initial notification.
UK REACH: data issues
To complete UK REACH
registrations, a full dossier of
information and data will need
to be submitted within two years
of the exit date. The companies
obliged to make these registrations
may not currently have access to
the necessary data.
ECHA has developed a database
with the details of all chemicals
registered under REACH. This
64 • Speciality ChemicalS Magazine • FEBRUARY 2019
includes data on chemical names
and properties, and registrant
companies, plus data extracted from
and copies of the dossiers submitted
by companies under REACH.
Some elements of it are publicly
searchable, others are only available
on a more limited basis. Amongst
other things, it will be protected
by database rights and copyright,
which ECHA is likely to own.
The UK government initially
suggested that it could ‘cut and
paste’ data from the REACH
database. However, current
guidance indicates that companies
must provide all of the data.
To have copied data, the UK
would have needed a licence from
the owner. Copying any significant
part of the database without one,
even just the publicly searchable
elements, would infringe copyright
and database rights. ECHA is
under no obligation to grant such
a licence.
There could also be similar issues
with the templates used to submit
dossier data to ECHA. If companies
want to submit data to UK
REACH using one, that may also
require a licence from ECHA, as
reproduction of the dossiers could
also indirectly involve reproduction
of the templates. Dossiers
submitted to ECHA will also be
subject to copyright and parts may
be protected as trade secrets or
confidential information. The UK
government is asking companies to
submit copies of these dossiers to
UK REACH-IT, but the companies
may not own or have sufficient
rights to use this data.
The copyright in each document
in the dossier will usually be
owned by the entity or entities that
created it or possibly by
third parties, such as testing
houses or consultants engaged to
produce reports.
In those circumstances,
companies’ ability to provide
copies to the UK government and
permit them to be subsequently
copied and published would
depend on the scope of their
original licence. Copyright owner
consent would be needed even if
they were only used for submission
to ECHA or REACH compliance.
To further complicate matters,
there are some data sharing
arrangements that are specific to
REACH, because joint registrations
were encouraged to avoid
unnecessary new studies and
tests. Many REACH registration
dossiers have been developed
and submitted by consortia of
companies under a joint
submission or substance
www.specchemonline.com
information exchange forum
(SIEF) agreement.
Under these, companies grant
each other rights to use and
refer to the various parts of the
dossier, but generally only for
REACH purposes. Further use,
such as for UK REACH, is often
not permitted without the consent
of all consortium members. Even
if consent is given, we would
anticipate additional costs for UK
companies that do not own their
REACH registration data, either to
purchase additional rights to use
data in UK REACH or to generate
their own studies if necessary.
Conversely, if a UK company
owned data but had granted
rights to a REACH consortium,
it might automatically leave the
consortium when the UK leaves
the EU. In such cases, the
consortium agreement is likely
www.specchemonline.com
to govern what happens to such
existing rights.
For example, the data may be
irrevocably licensed to the REACH
consortium, but the UK company
may no longer benefit from future
cost sharing or payments for access
to it. This would depend upon the
terms of individual agreements and
could present issues for both sides.
Summary
The two main legal issues we
have identified in relation to the
proposal for UK REACH are:
£ The status of EU-27 suppliers to
UK companies, who may wish
to make an OR registration. This
could be in the interests of both
sides, but does not benefit from
the ‘grandfathering’ provisions
£ Access to data required for UK
REACH registrations
The requirement to submit a
FEBRUARY 2019 • Speciality ChemicalS Magazine •
full dossier to UK REACH within
two years of exit date could lead
to significant additional costs
for companies who do not own
the data associated with existing
REACH registrations. If they cannot
negotiate access to the existing
data, then new and duplicate
animal testing would be required,
something the REACH regime was
designed to avoid. £
CONTACT
David Gordon
Partner
Squire Patton Boggs
+44 121 222 3204
dave.gordon@squirepb.com
www.squirepattonboggs.com
65
People

Optima president to Airedale

chair SOCMA board
SOCMA elected Gene Williams, president of Optima
Chemical, as chairman of its board of governors
during its 97th annual business meeting in December
in New York. During the same meeting it added five
new members to the Class of 2021, who will all serve
three-year terms: Paul Ameis of VanDeMark Chemical;
Mara Gliozzi of McGean; Joe Beatty of FAR Chemical;
Pat Killian of Monument Chemical; and Ronald Lehman
of Solvay Novecare. In addition, Chuck Hinton of Ethox
Chemicals and Ephraim Honig of Strem Chemicals were
named to fill two vacant seats on the board.
Shaun Clancy was named the recipient of the
association’s 2018 Distinguished Service Award “for
his exceptional contributions to the speciality and fine
chemical industry”. Clancy, who retired in June 2018,
was director of product and regulatory services at
Evonik and a SOCMA board member, who, among
things, played a key role in shaping the Chemical Risk
Management Committee for more than 15 years.
Biesterfeld Russia
names
Marr to
board
UK-based speciality chemicals company Airedale
Chemical has announced that Daniel Marr has been
appointed to its board as commercial director, a
new role within the company as it expands into more
markets and industries this year. Marr, who joined
Airedale as marketing manager in 2011, moving
on to become head of marketing in 2015. In his
new role, he will oversee the technical, compliance
and marketing departments while continuing to
support the company’s growing sales team. Airedale
Chemical, a third generation, family-run company
based in Cross Hills, has supplied speciality chemicals
to the agricultural, food and drink, manufacturing and
healthcare industries for more than 45 years.

appoints Dikina
general manager
Svetlana Dikina has become general manager at Biesterfeld Rus in
Wienand
Moscow, with responsibility for all Russian business activities of the
Biesterfeld Plastic, Spezialchemie and Performance Rubber divisions.
takes helm at
Dikina is a chemist who began her career in R&D in cosmetics,
household and oral care and later worked as a business manager
Siegfried
in these markets in Russia. Dr Wolfgang
Wienand has
succeeded Dr Rudolf
O’Day moves from Roche to Gilead Hanko, who has
retired, as CEO of
Gilead Sciences has appointed Daniel O’Day, currently CEO of Swiss-based API
Roche Pharmaceuticals, as both chairman of the board of directors manufacturer and
and CEO from 1 March. He is replacing John C. Martin and John CDMO, Siegfried.
F. Milligan, who have stepped down from these roles. Until the end Wienand, a German
of February, O’Day will remain in his role at Roche to ensure a national and former
smooth transition, with chief patient officer Gregg Alton acting as champion foil fencer, who came fourth in
interim CEO since 1 January. the Atlanta Olympic Games in 1996 and
O’Day had been with Roche in various capacities in the US, won the World Cup series the next year,
Switzerland, Denmark and Japan since 1987. Most recently he was had held senior management positions at
president of Roche Molecular Diagnostics in California in 2006 and Evonik Industries before joining Siegfried
subsequently returned to Roche headquarters to lead the Diagnostics as chief scientific officer in 2010. In 2011,
division before assuming his current position in 2012. The company he was named chief strategy officer,
has already appointed William Anderson, currently CEO of its with responsibility for strategy and M&A,
Genentech subsidiary, as O’Day’s replacement, with effect from 1 among other things. He had also manged
January. Anderson had been with Roche since 2006 and was head the group’s global R&D activities since
of global product strategy before assuming his current role in 2017. May 2017.

66 • Speciality ChemicalS Magazine • FEBRUARY 2019 www.specchemonline.com