Croda Pharma

Empowering
biologics
delivery

Addressing the challengesof vaccine formulation
Excipients | Lipids | Adjuvant Systems

Smart science to improve lives™

Croda Pharma

The building blocks for
vaccine delivery systems
Combining our unique product portfolios and expertise, Croda Pharma and Avanti Polar Lipids are empowering thedevelopment and manufacturing of next generation vaccines. With strong expertise in high quality excipients, a cultureof innovation and specialist scientific knowledge, we support our customers with the development of new and effective
adjuvant systems and ingredients for vaccines.

Adjuvants

Lipids

Surfactants

We are passionately driving our innovation pipeline to expand our unique and comprehensive offer to our customers inboth commercial and academic organisations worldwide.
Our world-class high purity excipients and lipids, together with the diverse portfolio of vaccine adjuvants andimmunomodulators, provide a unique combination of building blocks to develop new adjuvant systems and vaccine
delivery systems. Leveraging over 80 years of expertise, our scientists collaborate with vaccine developers andmanufacturers to create solutions for vaccine formulation challenges.

Smart science to improve lives™

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We put quality at the heartof everything we doThis commitment goes beyond products and consistency of the ingredient systems we bring to market. Our highstandards encompass all levels of customer relationships. We provide customised advice and solutions and welcome
partnerships across industry and research institutions.
This brochure provides insight into our offering for vaccine development across all platforms in Croda Pharma. Discoverhere how we can support you in the development of the next generation vaccines.

Empowering biologics delivery

Small Molecule Delivery

Protein Delivery

Nucleic Acid Delivery

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Adjuvant Systems

Croda Pharma

Our journey to Croda Pharma...............................................5
Offering for vaccines development......................................6
Dedicated production sites................................................... 7
Adjuvants................................................................................. 8
Alhydrogel™......................................................................... 8
Adju-Phos™..........................................................................8
PHAD™................................................................................ 9
3D-PHAD™.......................................................................... 93D-(6-acyl)-PHAD™............................................................ 9
Squalene ............................................................................10
QS 21.................................................................................. 10
Lipids for LNPs...................................................................... 11
Phospholipids......................................................................11
Additional lipids................................................................... 11
Adjuvants development pipeline.......................................12
Cationic Adjuvant Formulation CAF®................................ 12     NanoQuil™- technology.....................................................13
Sourcing sustainable alternatives .....................................13
Additional ingredients for vaccine development.............14
Super Refined™ Polysorbate 80 and 20..........................15
Span™ 85 Pharma............................................................ 16
Plant derived cholesterol....................................................16
Virodex™............................................................................ 16
Contact our experts.............................................................. 17

Smart science to improve lives™

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Our journey
to Croda Pharma
Founded almost 100 years ago, Croda understands thecentral role science plays in our everyday lives. Today,that means using our Smart science to improve lives™.

And now, it manufactures multiple synthetic analoguesof MPL containing a single molecular species. These
are as effective and safe at inducing an immune
response as their natural product predecessor.

Croda Pharma is at the forefront of pharmaceuticalscience, with the ability to deliver high quality
excipients, quickly and at scale. The company has
proven to be crucial for the rapid rollout of many
COVID-19 vaccine programmes. Today we area global, innovative, and application science-led
business that positively impacts the health of millions
of people.

Over the past decade, Avanti has concentrated on
developing high purity lipids for liposomal delivery
systems including Lipid Nanoparticle (LNP). LNP
delivery technology helps solve the stability anddelivery issues associated with mRNA-based vaccines
and therapeutics, as well as gene editing technology.
Driven by sustainability, innovation, and our portfolioof market-leading products, Croda Pharma, much likethe whole Croda organisation, is committed to having a
positive impact on the environment and society.

Leveraging over 80 years of expertise in vaccine
adjuvants development and manufacturing, Croda
Pharma’s industry-leading brands of aluminium-based
adjuvants, Alhydrogel™ and Adju-Phos™, as well as
the saponin-based Quil-A™ are widely recognised
for their unmatched safety and effectiveness in bothhuman and veterinary vaccines. This portfolio of
essential products was acquired into the businessalong with an impressive GMP manufacturing sitefrom Biosector in 2018, including sterile production
and aseptic filling.

Alongside our partners, we continue to develop
adjuvants to target new diseases and pathogens suchas cancer, Alzheimer’s, malaria, tuberculosis, HIV,
Staphylococcus aureus, amongst others.

We are committed to the United Nations
Sustainable Development Goals (SDGs).
By the end of 2030, our technology will bepart of at least 10 clinical phase III trials
across at least 25% of the WHO-listed
pipeline vaccines.

The year 2020 marked another important milestone
in the evolution of the business. Avanti Polar Lipids,(Avanti) joined the Croda group. Founded in 1967,
Avanti is a global leader in the manufacture andsupply of the highest purity lipids for researchand pharmaceutical product development. Avantirevolutionised vaccine development with the introductionof synthetic monophosphoryl lipid A (MPLA)
derivatives.

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Croda Pharma

Offering for vaccines
development
Enabling breakthrough innovation

A focus on scientific endeavour

Our vaccine adjuvant portfolio is founded on strong
research and development. We recognise the need for
new and efficacious adjuvant systems to fight diseases
with prophylactic and therapeutic vaccines. Therefore,
we develop new adjuvant systems and welcome
partners who share our passion, to create the vaccinesof tomorrow.

We are committed to enabling next generation drugdelivery systems. Leveraging innovation, formulation
and application, we are determined to deliver better
excipients, lipids and adjuvants systems for biopharma,
to unlock more treatments.

A unique blend of support andexpertise

With our leading R&D capabilities, we are advancing
our strong pipeline of innovative next generationadjuvants, lipids and high purity excipients.

R&D is our foundation

Our combined experience is based on decades offormulation knowledge with pharmaceutical excipients,
lipid-based formulations, and aluminium- andsaponin-based adjuvants. We make use of our entire
knowledge to ensure quality and consistency to makeyour project successful.

Smart science to improve lives™

We recognise that only an R&D focus will allow us todevelop the new, innovative vaccine adjuvants that are
required to deal with challenging infectious diseases
and pathogens.

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Croda Pharma

Dedicated production sites
Our production site located in Denmark has been dedicated to safe and effective adjuvants for use in humanand veterinary vaccines for more than 80 years. Our expertise in this area is simply unmatched. We support the
major human and veterinary vaccine producers through an experienced team operating the only cGMP certified
manufacturing site including aseptic filling globally, for commercially available aluminium-based adjuvants.
Another major production site is located in Alabama, USA. With decades of combined experience in formulating
lipids, the teams there support vaccine formulation and development activities. Further, formulation services forboth pre-clinical and clinical development using our own cGMP manufactured lipids are offered. Batches can bescaled from a few millilitres to >100 litres to accommodate your stage of clinical development.
Across our other facilities for vaccine components, we work in partnership with our customers to provide aseamless transfer of the formulation for scale-up and manufacturing.

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Croda Pharma

Adjuvants
Alhydrogel™
Alhydrogel is a range of aluminium hydroxide gelsspecifically developed for use as adjuvants in humanand veterinary vaccines.
Alhydrogel has very low conductivity due to theabsence of buffering ions and is positively charged atneutral pH. This allows the product to effectively adsorb
negatively charged antigens.
Alhydrogel products can be combined with otheradjuvant types (such as monophosphoryl lipids) toachieve a well-balanced Th1/Th2 immune response.
Alhydrogel is supplied in two concentrations:
Alhydrogel 1.3% and Alhydrogel 2%. A premium
version (Alhydrogel “85”) with higher protein adsorption
capacity is also available.

Adju-Phos™
Adju-Phos is a range of aluminium phosphate gel
products specifically developed for use as adjuvants invaccines.

The range is manufactured according to EU GMP(Part I: Medicinal Products for Human and VeterinaryUse) certified production of aseptically prepared sterile
products.

Adju-Phos products have a net negative charge atneutral pH and effectively adsorb positively charged
antigens.
Like Alhydrogel, Adju-Phos products can be combinedwith other adjuvant types (such as monophosphoryl
lipids) to achieve a well-balanced Th1/Th2 immune
response.
It is supplied with two variants of pH-values to reduce
injection site discomfort.
Adju-Phos is manufactured according to EU GMP(Part I: Medicinal Products for Human and VeterinaryUse) certified production of aseptically prepared sterile
products.

Smart science to improve lives™

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PHAD™

3D-PHAD™

PHAD, Phosphorylated HexaAcyl Disaccharide,is the first synthetic equivalent to bacterial-derived
monophosphoryl lipid A (MPLA) used as an adjuvant invaccines.

A highly pure PHAD, 3D-PHAD provides ahomogeneous synthetic equivalent for the
3-deacylated MPLA derived from bacterial LPS(lipopolysaccharides).

It boosts the immune system through activation of thetoll-like receptor 4 (TLR4) resulting in production ofproinflammatory cytokines and antigen-specific effector
CD4+ and memory CD8+ T-cells.

Less pyrogenic than its bacterial-derived mimic, it iscomparable to bacterial MPLA and other synthetic
MPLA analogues at eliciting an immune response in aliposomal adjuvant system.

Also referred to as GLA, PHAD, has been administered
to over a thousand human subjects without serious
adverse events.

The product has demonstrated equivalency to PHAD
during extensive preclinical testing, and human trials
are scheduled for launch.

PHAD is available in bulk quantities for vaccine
development and commercial manufacturing.

3D-PHAD is protected under US Pat No. 9,241,988.
Licensing opportunities are available for vaccine or
immunotherapy commercialisation.

3D-(6-acyl)-PHAD™
A synthetic MPLA structural analogue, 3D-(6-acyl)PHAD is most closely related to the reported structureof MPL® Adjuvant used in marketed liposomal adjuvant
systems.
This adjuvant is structurally homogeneous and highly
purified. It mimics the TLR4 agonist activity of bacterial
MPLA.
PHAD, 3D-PHAD, and 3D-(6-acyl)-PHAD havebeen tested extensively in animals using a variety ofantigens. In all cases, these adjuvants exhibit a similar
activity and safety profile to bacterially derived MPL.

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Croda Pharma

Adjuvants
Squalene

QS 21

Squalene is a natural lipid belonging to the terpenoid
family. It is an important component in some vaccine
formulations. Its most common use in licensed vaccines
is in seasonal and pandemic influenza vaccines.

QS 21 is a water-soluble purified triterpenoid saponinmolecule fraction from the bark of the South American
tree Quillaja saponaria Molina.
As an amphiphilic surfactant, it has demonstrated
optimal balance of enhanced immunostimulatory
properties and tolerable reactogenicity and has foundits way into human applications.

Vulnerable people like the elderly are at higher riskof complications and benefit particularly well fromthe availability of efficient vaccines. Squalene-based
adjuvants increase the immunostimulating effect of a
vaccine significantly, hence they are used in seasonal
influenza vaccines for elderly.

Human vaccines containing QS 21 are now commerciallyavailable and used to prevent diseases such as malaria
and shingles. Before this development, it was notpossible to develop effective vaccines against malaria.

Furthermore, there are clinical trials in progress forprophylactic vaccines against tuberculosis, HIV, malaria,
shingles, and other severe diseases using squalene in
combination with a TLR4-agonist.

The adjuvant activity of quillaja saponins was reported
as early as 1925. They have been used in veterinary
vaccines since the 1970s. Croda has manufactured
Quil-A for veterinary vaccines since 1982.

It has been shown that squalene-based emulsions invaccine formulations can help to improve the immune
response. For instance, they increase vaccine antigen
uptake and enhance activation and recruitment ofvarious immune cells at the injection site.

Croda’s QS 21 is derived from Quil-A and is a highly
purified immunostimulant obtained by successive
chromatographic purification cycles.
It is manufactured according to GMP requirements
for Investigational Medicinal Product of the EU and isintended “for investigational use only”. It is supplied as alyophilised product in 5 mg vials and dispatched frozen.

Further benefits relate to an established safety profile,a high tolerance in both adults and children, and a dose
sparing effect.
Squalene has traditionally been sourced from shark liveroil, leading to the search for sustainable alternatives.

Sustainable sourcing

We will be able to provide a sustainably sourced
squalene based on a proprietary bio fermentation
process. Not only is this squalene molecularly identicalto that harvested from sharks, but it is produced
using yeast isoprenoid pathway engineering, which
also ensures higher purity exceeding EP monographrequirements. Comparative studies in adjuvant systems
have demonstrated identical stability.

Smart science to improve lives™

Our ambition to become the most sustainable supplierof innovative ingredients and aligning our approach with
the United Nations Sustainable Development Goals(SDGs) drives us to search for alternatives ensuring
both the high quality requirements for a pharmaceuticalingredient and a secure supply chain.
Find out more for QS 21 in the Adjuvants development
pipelines section.

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Lipids for
LNPs
Lipid Nanoparticles (LNPs) have been shown to beeffective at delivering mRNA vaccines. Traditionally,
LNP systems include four lipid components: Cationiclipid, PEG lipid, structural/neutral lipid, and cholesterol.

Explore some of the lipids from our
GMP portfolio.

The ionizable cationic lipid sequesters the genetic
material through a charge interaction and releases thematerial following a pH change in the endosome. The
PEG lipid component forms the exterior shell to protect
the LNP and decreases particle aggregation.

n

DSPC

n

DMPC

n

DOPC

n

DMPG

Phospholipids:

Additional lipids:

The structural/neutral lipid stabilises the LNP and canprevent premature breakdown. Finally, cholesterol acts
as a stability enhancer and assists in the transfectionof RNA.

n

ALC-0315n

ALC-0159

Further research grade materials are available throughthe Avanti website www.avantilipids.com

11Croda Pharma

Adjuvants
development
pipeline
Cationic Adjuvant Formulation CAF®
A common challenge for adjuvants is that theysignificantly increase the humoral response to vaccine
antigens but induce only very weak cell-mediatedimmunity (CMI) responses. There is therefore aneed for designing vaccine adjuvants that prime
T-cell immunity, for effective vaccines against many
intracellular pathogens.
Croda Pharma continuously increases its offering ininnovative vaccine adjuvant systems. The strategic
collaboration with SSI (Statens Serum Institut, leading
Danish governmental life-science research institute)enables us to offer an even more diverse adjuvant
portfolio.
The CAF technology platform is a range of new,patented, CMI inducing cationic liposomal adjuvants.
Over the past decade, clinical trials have shown these
to be powerful immunostimulators in tuberculosis,
chlamydia, HIV, malaria, pandemic flu and specificcancer studies.
Croda will manufacture and commercialise two CAF
adjuvants:
n CAF01 – a two component liposomal suspension

which induces strong antibody and T-cell (Th1/Th17)
responses in vaccines for infectious diseases. The
potent neonatal adjuvanticity in preclinical studies
suggests that it is fulfilling the requirements for novel
vaccines to be used in early life.
n CAF09b – a second generation, three component

cationic liposomal adjuvant used in cancer
immunotherapy trials, facilitating strong productionof antigen specific CD8 + T-cells after vaccination in
combination with peptide or protein-based antigens.
CAF01 induces systemic immunity, facilitating mucosal
booster responses after mucosal administration of
antigens alone. Preclinical studies indicate CAF09b
could be a potent adjuvant for mucosal applications
directly priming the immune response.

Smart science to improve lives™

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NanoQuil™ technology

Sourcing sustainable alternatives

Saponin-based immunostimulating nanoparticles havepotential for use in vaccinology. We are working on
development and commercialisation of new generation
saponin–based nanoparticles within the NanoQuil range.

Saponins
A recent collaboration agreement* enables our customers
access to the most sustainable source of saponins
in contrast to conventional methods. Our partner
developed a unique and innovative process to grow
Quillaja saponaria Molina biomass in their labs and thenextracting the QS 21 fraction from these young plants.
Our goal is to secure supply independent from harvest
yields and in a scalable way in line with our customers’
demand.
Further efforts are ongoing to expand sustainablesourcing to our saponin-based adjuvants for veterinary
application.
*Partnership agreement with Botanical Solution Inc. (BSI)

Squalene
Traditionally, the natural lipid which is an importantcomponent of adjuvant systems is obtained from sharkliver. An innovative and proprietary bio fermentation
process* delivers high-purity squalene appropriate foruse in vaccine formulations. The method enables asecure and scalable supply chain.

Electron micrograph of NanoQuil

Saponins from the bark of Quillaja saponaria Molina
show a potent activation of dendritic cells and inductionof cytokines/chemokines resulting in a strong stimulationof cell-mediated (Th1) and antibody-mediated (Th2)immune response.

*Partnership agreement with Amyris Inc.

However, saponins are prone to hydrolysis anddegradation at physiological pH at ambient
temperatures. In addition, cell-lytic properties lead to
local reactions at the injection site. This requires abalanced adjuvant dose between the immunostimulatory
effect and the local reaction.
NanoQuil technology has been developed to overcome
the challenges of saponins while securing the benefits.
It consists of a series of immunostimulating nanoparticles
developed for use in both veterinary and human applications.
NanoQuil is based on incorporation of saponin incholesterol resulting in increasing stability of saponins
and reducing negative cell-lytic effect due to its low
reactogenicity.
Micrograph of yeast full of squalene

Discover more on sustainably sourced squalene in the
Adjuvants section.

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Croda Pharma

Additional ingredientsfor vaccine development
Croda offers a comprehensive range of high quality
pharmaceutical components. We continuously expand
the range in response to market needs.

We believe that having the highest quality and purest
grades of components helps our customers formulate
seamlessly and drive products to market quickly andefficiently.

All our components are designed and manufactured
for pharmaceutical use, using Good Manufacturing
Practice (GMP) standards across all our platforms
and manufacturing sites. We were one of the first
excipient suppliers to receive EXCiPACT® certifications
across all our global sites and continue to pioneer new
monograph approvals via our representation on global
monograph industry forums.

Smart science to improve lives™

Croda’s Super Refined™ range of highly purified
excipients is manufactured through proprietaryprocesses that remove impurities without affecting thefundamental structure in any way.

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Super Refined™ Polysorbate 20 and 80
excipients in the pharma industry; from oral, topical,
and injectable applications to blood fractionating,vaccine development and formulation.

It is widely reported in the scientific community thatpolysorbates can prevent proteins from denaturation,
aggregation, surface adsorption and flocculant
formulation during product thawing. They are also usedin downstream and upstream processes as detergents,
washing agents, splitting agents, blocking agents andfor lysing cells.

Super Refined Polysorbates have been developed
to optimise the performance of pharmaceuticalformulations and are recommended when the highest
quality and purity is required. The level of impurities
which are known to have an adverse effect on
formulation stability has been reduced.

Commonly found impurities in standard compendial
grade excipients can negatively influence formulations.
Several types of surfactants oxidise readily when
exposed to the air or UV light, causing them to lose
their properties and potency as solubilising agents.
Purity is an incredibly important factor for successful
vaccine development.

Super Refined Polysorbate 20 and 80 are
manufactured according to GMP standards in
EXCiPACT certified factories and comply with USP/NF,
Ph. Eur., JP and ChP. Chinese DMFs are filed at CDE
including for parenteral use.

Polysorbate 20 and 80 (Tween™ 20 and Tween 80)
are non-ionic surfactants which are widely used as

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Croda Pharma

Span™ 85 Pharma

Virodex™

Span 85 is a non-ionic low HLB surfactant widely usedas dispersant, solubiliser, suspending and wetting
agent. It is used in MF59 adjuvant system, together
with squalene and Polysorbate 80. It is the first o/w
adjuvant approved for human influenza vaccines andunder clinical evaluation for HIV and CMV.

The Virodex range has been developed as a replacement
for Triton™ X-100 with equivalent performance.
The range includes two compendial grade variants
with known parenteral applications. They are REACHcompliant and cGMP EXCiPACT-manufactured tomeet the highest standards in biopharmaceuticalmanufacturing.

Croda’s Span 85 Pharma complies with Ph. Eur. andis manufactured according to GMP standards in the
EXCiPACT certified factories.

Contact our teams for more information on oursustainable bioprocessing solutions, including our
Virodex range for viral inactivation and cell lysis.

Plant derived cholesterol
Cholesterol is an essential ingredient in a wide
range of technologies from adjuvants systems, lipid
nanoparticles for mRNA delivery to cell culture media.
In the last few years, there has been increasing
demand for cholesterol from a plant-based source.
Our plant-based and parental grade cholesterolprovides a high-purity alternative to traditional
egg and animal-based cholesterol and is USP/NF,
JP and parenteral grade Ph. Eur compliant.

Smart science to improve lives™

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Contact our experts
Croda Pharma partners with world leading pharmaceutical organisations to solve the most complex
health and well-being challenges our society faces in this millennium.
We support the entire biologics development lifecycle through local support and worldwide manufacturing
capabilities, helping to bring new vaccines and biologic therapies to market faster and at scale.
We engage with customers through our global network of Croda employees around the world and welcome close
cooperation to develop the products of tomorrow.
To discuss your needs or for any further product information, such as monograph compliance, please contact yoursales representative or email us at:

Europe, Middle East & Africa:
pharma.emea@croda.com
North America:
pharma.usa@croda.com
Latin America:
pharma.latam@croda.com
Asia Pacific:
pharma.asia@croda.com

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Croda Pharma

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Croda Pharma

Avanti Polar Lipids

Non-warranty
The information in this publication is believed to be accurate and is given in good faith, but no representation or warranty as to its completeness or accuracy is made.
Suggestions for uses or applications are only opinions. Users are responsible for determining the suitability of these products for their own particular purpose.
No representation or warranty, expressed or implied, is made with respect to information or products including, without limitation, warranties of merchantability,
fitness for a particular purpose, non-infringement of any third-party patent or other intellectual property rights including, without limit, copyright, trademark and designs.
Unless otherwise stated, any trademarks identified herein are trademarks of the Croda group of companies. Triton™ is a trademark of The Dow Chemical Company or anaffiliated company. CAF® is a registered trademark of Statens Serum Institut.
©2023 Croda International.									Smart science to improve lives™

09/23 HTCMB051v2 EN