BRINGING
A WHOLENEWDIMENSIONTOLACTOSE
Lactose Learnings
and Evidence Building on
3D Printing in Pharma

Powered by DFE Pharma / December 20191

Introduction

Lactoselearning andevidence
From enabling personalised medicine to accelerating ­building
the drug development pathway, 3D printing offers huge
on 3D
potential in pharmaceutical manufacturing. In order
to embrace this new world of opportunities, we need aprinting
deeper understanding of the materials, processes andin Pharma
techniques involved.
ARE YOU READYFOR THE FUTURE

Information on the most effective use of excipients, forexample, has, until now, been lacking. But a model ofcollaborative working, that has led to this detailed study
on printed lactose, is starting to change that. While thisarea of research is still in its infancy and every use caseis unique, the research set out in this whitepaper showsthat lactose – and collaboration – are yielding results.
We now invite industry, innovators and academia alike toreview the data and to continue working together with
us to develop a deeper understanding of the 3D printingof pharmaceuticals. By pooling knowledge and expertise,
we can quickly and efficiently build the evidence base weneed to contribute to timely, patient-centred medicine
development.

K.A. van den Heuvel-Jansen &C.J. Wiebinga

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20192

Index1
2
3

Challenges andopportunities

4

Tablets are the mainstay of pharmaceutical delivery, but people
can find them difficult to take and manufacturers face production
challenge, particularly in the personalised medicines era.
3D printing could be the solution – but only if we work together
to build the evidence base.

Where we are:techniques & excipients7

As techniques evolve, a significant data gap is opening up.
To help address this, DFE Pharma and the Netherlands Organisation
for Applied Scientific Research (TNO) have investigated the use of­lactose as an excipient in the 3D printing process.

We are commited
to excellence14

As the leading global manufacturer of excipients, we need to makesure you can rely on us. That’s why we are committed to excellence
in innovation, people and quality. Work with us to build the evidencebase and unleash the potential of 3D printing in pharmaceuticals.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20193

1
Tablets need to adapt to thedemands of 21st Century healthcare.
They must be easier to make, easier totake and easier to personalise.

Challenges andopportunities
Despite tablets being the main mode of pharmaceutical delivery
worldwide, there are major challenges both in the way they are
made and the way they are taken.
Traditional facilities, accustomed to operating in the blockbuster
drug era, are not geared towards the small-scale production needed
for clinical trials or orphan drugs, or the creation of designer tablets
for personalised medicine.
Taste, mouthfeel or solubility can make tablets hard to take,­particularly for very young or old people. Matters only get worse
when they need to take multiple tablets, because of co-morbidities
or during complex clinical trials, for example.
Tablets also have a lack of dose flexibility that means breaking
them into segments is the only way to deliver smaller measurements
to children. This is imprecise and unscientific.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20194

3D printing:the next frontier
As well as dose flexibility, 3D printing
can mask taste, enhance solubility andmodify shape, producing tablets thatgeriatric and paediatric populations findeasier to take.
Tablets with multiple APIs are easy tofabricate, and 3D printing even allows forthe delivery of multiple medications, withmultiple time release options, in a single
tablet.
It enables patient-tailored medicine tobe “printed” on demand in pharmacies or
hospitals, making it particularly useful fororphan drugs and personalised medicines,
and holds huge potential in the clinical
trial space, which has a constant demandfor bespoke, small-scale batches.

Embracing these opportunities depends
on a thorough understanding of thetechniques and procedures involved.
The use of excipients in the process, forexample, is currently lacking in bothresearch and application.
Lactose, which is well-established andhas regulatory approval, is a logical place
to start the journey of understanding.
And, as this study shows, it certainly has
an important role to play in embracing
the opportunities of pharmaceutical
3D printing.

What’s more, the 3D printing of­medications can, potentially accelerate
the scaling up of manufacturing whencompared to traditional processes.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20195

Building theevidence
In 2015, Spritam (levetiracetam) was thefirst 3D-printed medication to receive
FDA approval. The epilepsy drug delivers
a high dose via a tablet that dissolves on
the tongue with a small amount of water.
It illustrates the possibilities but has notbeen widely replicated.
While industry and academia have bothtaken their first foray into the technology,
advances have been slow, due, at least inpart, to the siloed nature of the research.

It is unclear how many drug manu­
facturers are investigating the mechanisms
of 3D printing, as generated evidence israrely shared. The information we haveoriginates from academia, yet there is aclear data gap.
This gap could be addressed by­universities, innovators and industry
working together, collaborating on­research and sharing their data.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20196

2

Where we are:techniques & excipients“Breaking out of data silos isimportant – sharing knowledge
and working together accelerates
learning and progresses science forthe good of the whole industry.
That’s why Deakin University
has worked with DFE Pharma to
combine our organisations’

Fused deposition modelling (FDM), long the staple 3D printing
method across sectors, is relatively cheap and accessible. ­It means
universities have created the beginnings of a dataset using thistechnique.

expertise on powder physics.
Together, we have developed thesector’s understanding of thewetting, flow and consolidation
properties of lactose, starch andWhile it is inexpensive and scalable, though, it is not suitable forthermosensitive APIs and it can struggle to provide complete API
release. Crucially, no perfect polymer, or building material, hasbeen identified in drug production.

microcrystalline cellulose (MCC)
in 3D printing.”

Professor Karen Hapgood,
Executive Dean, Deakin University.

Powder bed printing, which was used to develop levetiracetam,is arguably the best method for pharmaceutical manufacturing.
Unlike FDM, it can provide fast and complete API release and issuitable for thermosensitive APIs.
R&D equipment and kit capable of producing large batches
suitable for clinical trial preparation is commercially available, but
it is e­ xpensive, and this has blocked access for many academic­investigators.
The whole sector stands to benefit from the creation of acentralised database that unites industry, innovators and academia
in the common aim of providing patient-centred care.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20197

How does
it work?
A nozzle sprays small droplets of water- or ethanol-based ink
onto a thin bed of powder with a smooth surface. Once solidified,another layer of powder is deposited on the powder bed and thecycle repeats until the desired height is obtained. The API will becontained in the powder or the ink, depending on the use case.

Add powder

Spread powder

Print layer

nozzlepowder bed

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20198

Where we are:excipients

Key to addressing the data gap is developing an understanding of
how to use excipients, as different substances will affect the powder
parameters that are central to the success of the 3D printing process
in different ways.
The flowability, wettability and consolidation of the powder used toprint tablets will determine the resulting tablet’s hardness, friability
and disintegration.
Powder parameters and their importance in the 3D printing of pharmaceuticals
Parameter

Definition

Importance in the 3D printing of pharmaceuticals

Flowability

The ability of apowder to flow

• Powder needs to be able to flow easily through the 3D printer’s
deposition mechanism and be able to create a flat bed• Powder with poor flowability can clog machinery

Wettability

The ability of apowder to absorb
liquid• Poor wettability can lead to balling of the surface• Bleeding is a result of non-optimal wetting. It happens when the liquid
penetrates further in the powder bed then intended• Wettability impacts on tablet disintegration. This affects the dissolution
rate and release characteristics of the resulting tablet• Wettability impacts on the tablet strength

Consolidation

The ability of apowder to bind
together• Powder granules must be able to bind during the 3D printing process inorder to form a tablet• Consolidation impacts on tablet hardness and friability

Tablet parameters and their impact on 3D printed pharmaceuticals
Parameter

Definition

Hardness

The breaking force of a tablet

Friability

The tendency of a tablet to crumble, chip or break

Disintegration

The tendency of a tablet to break down into granules/powder particles once it becomes incontact with an (aqueous) liquid

We need to build the knowledge of how excipients impact on theseparameters in 3D printing before we can begin to understand themost appropriate materials or techniques for each use case.
A repository of excipient usability and applicability, along with theirimpact on powder parameters and those of the resulting tablet, would
provide investigators of all backgrounds with an invaluable tool.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 20199

Test, learn and share: A study in lactose
To date, we know that powder bed printing can result in significant
dust formation during the process, and high friability in the resulting
tablets.
In a bid to overcome this known challenge, DFE Pharma worked with
the Netherlands Organisation for Applied Scientific Research (TNO)
to look at the use of lactose as an excipient in some detail.
Despite lactose being a well-known, well-established and widelyused pharmaceutical excipient, its use in the 3D printing of­pharmaceuticals is rare – possibly because it isn’t easy without
the right expertise and access to materials.
The research team tested 20 lactose grades, all with varying
morphology, and explored their effects on selected criteria, suchas hardness friability and disintegration.
The primary objective was to develop a lactose with sufficient flow,
wetting and binding to be used effectively in the powder bed 3D
printing of pharmaceuticals.

Background
Lactose is a commonly used, regulatory-approved, water-soluble filler for the pharmaceutical industry
and a logical choice as filler material in powder bed printing.
Method• Twenty grades of lactose were used to produce various powder blends for the 3D printing of tablets.
The powders were assessed on wettability, flowability and consolidation. The resulting tablets were tested
for hardness, friability and disintegration• The impact of factors such as line spacing, print direction and rotation were also examined
Key findings• Differing grades of lactose produced differing results in terms of the main investigative parameters• Our study showed that specific grades of lactose monohydrate can be utilised effectively in the 3D printingof pharmaceutical tablets• Twenty grades of lactose were tested for the purposes of this study. For illustrate purposes, the tablebelow details key findings from tests on the two most effective grades

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 201910

Parameter

MethodTop line findings

Wettability oflactose during
3D printing

In order to study the impact The findings concluded that the d10 value should be larger thanof particle size ­distribution 6μm, and preferably in excess of 10μm
(PSD) on ­powder bed
printing, ­wetting tests were
performed by printing asingle layer with different
line spacings

Flow oflactose during
3D printing

Both blends had a flow function (FFC) above 10 and a
Based on the wettability
findings, two lactose grades compressibility index below 15. This is an indication of excellent
flowability and a low compressibility(A+ and B^) with a higher
than 10μm d10 value wereblended with 10% fully
pregelatinized starch* andmeasured on flowability,
density and particle size

Consolidation of
lactose during
3D printing

Circular, 9mm tablets witha height of 2.8mm were
3D printed using lactose
grades A and B

Both grades resulted in tablets with an acceptable variation intablet mass, diameter and height

Left: Grade B
Right: Grade A+ Lactose grade A was milled and classified lactose with a d10 above 20μm
^ Lactose grade B was sieved lactose with a d10 above 20μm
*Lactose alone does not have sufficient binding to result in a robust tablet, so it is advisable to add 10 to 20%
binder to the powder blend to obtain a strong formulation. These results refer to tests using formulations of
10% fully pregelatinized starch as a binder
What else did we learn?
• Milled/sieved lactose monohydrate gave better results compared to anhydrous lactose (less wettability but
smoother layer)• Milled/sieved lactose monohydrate gave better results compared to spray-dried lactose monohydrate(less wettability but improved consolidation)• Tablets formed with fully pregelatinized starch as a binder had less bleeding and friability than those produced
using polyvinylpyrrolidone• Print direction and linespacing impacted on tablet appearance, friability and disintegration• Wettability was improved by replacing the aqueous ink with ethanol, which has a lower surface tension than­water (95% water is 56 σ/mN m−1 compared to 22 σ/mN m−1 for 100% ethanol). However, technical issues suchas powder sticking to the roller and spilling on the powder bed remained. As such, the team concluded that using
an aqueous ink and lactose with the larger d10 value, as described above, was the best solution• The addition of silica resulted in an improved flow, and slightly improved wettability. However, this is not always
the preferred option due to safety and handling considerations
Full details of this study are available on request from the research team.
Email learningaboutlactose@dfepharma.com for more information.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 201911

What this tells us
about the 3D printingof lactose tablets“TNO was excited to combine its
knowledge of printing with DFE
Pharma’s knowledge of powders tocarry out this fundamental pieceof research.
The scientific approach to the studyof lactose as an excipient in the
3D printing of pharmaceuticals

With the initial selection of excipient grades, and the range ofprinter settings tested, we achieved 3D printed tablets with­properties that, while not yet equal to traditional pills, are­approaching the industry standard for hardness and friability(i.e. <1%). Ultimately, lactose works.
It’s worth noting that 3D printed tablets will always look
more irregular and have a rougher surface area than those
produced using traditional methods.

provides us with robust evidence on
which to base our understanding of
how these products work.
The whole sector stands to ­benefit
from this collaborative piece of
research, which provides valuable
insights into the optimal PSD of
lactose in this setting.”

Kjeld van Bommel
PhD, Senior Consultant, TNO

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 201912

Towards data
sharing
While there is still much to learn about
how different grades of lactose canimpart various qualities onto tablets,
this study demonstrates that it is asuitable excipient for the 3D printing ofpharmaceuticals.
What’s more, it contributes to the­common evidence base for 3D printing in
the pharmaceutical industry and highlights the power of collaborative working
in this space.
We are taking the tentative first steps
towards creating the centralised datasetthat we believe is the key to accelerating
progress, and we will continue our­research in this area.
We would invite other organisations towork with us, our knowledge of 30 typesof lactose and our ability to customise
grades to suit each use case, so that we
can all find out more.

By pooling the knowledge and expertiseof industry, innovators and academia,
we can truly move the dial on 3D printing
in pharmaceuticals, and in doing so takehuge strides towards delivering theperson-centred clinical trials and­medicines future.
This is something we take very seriously.
At DFE Pharma we have a dedicatedresearcher who is committed to driving
development in this space and strong
relationships with institutions such as
TNO and respected academic centres
like Deakin University.
To find out more about possible
colla­borations or to request fulldetails on our lactose in 3D printing
study, get in touch on
learningaboutlactose@dfepharma.com

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 201913

3“For just over a year I have been
DFE Pharma’s dedicated researcher
for 3D printing.
Allowing me to gain fundamental
insights in this application, andcollaborate with academia and­commercial organizations.
We are proud to share these first
results and looking forward to­collaborate with you as well.”

Korinde van den Heuvel-Jansen

We are committed
to excellence

As the leading manufacturer of excipients in the world, we need tomake sure you can rely on us. That’s why we only work with highly
skilled people, resulting in excellent and consistent excipients.
We are committed to excellence in innovation
Our innovation team has functions dedicated to the furtherance of
medical science and understanding of continuous manufacturing,
3D printing and biologics.
We are committed to excellent people
We know how a company culture defines its performance.
Therefore, we invest in a culture of excellence. A culture thatputs customers first, is process oriented and cultivates reliability.
A culture that inspires and challenges our team of 360 highly­motivated people. People that come from all over the world andhave a profound knowledge of formulation technology and thepharmaceutical market. People who have experience in a wide
area of fields. People who deeply understand your needs.

MSc, Senior Product Developer,
DFE Pharma

We are committed to excellent quality• We supply from manufacturing sites all over the world.
• Our facilities are dedicated to the manufacture of pharmaceutical
excipients.
• We have implemented a single, uniform quality system based on
ISO 9001:2015 and IPEC* PQG** cGMP and where applicable ICH
Q7***, at all manufacturing sites, including those of the parent
companies.
• A program to monitor the effectiveness of the quality system is inplace and ensures continuous improvement.
• Our customers are welcome to audit our manufacturing facilities inorder to verify our quality status.

*IPEC: International Pharmaceutical Excipients Council; **PQG: Pharmaceutical
Quality Group; ***ICH Q7: applicable for inhalation grade lactose.

Lactose Learnings and Evidence Building on 3D Printing in Pharma
Copyright © 2019 DFE Pharma / December 201914

Learn More About DFE Pharma

Head Office
Klever Strasse 187, P.O. Box 20 21 20, 47568 Goch, Germany
T +49 2823 9288 770, F +49 2923 9288 7799
pharma@dfepharma.com
Worldwide offices
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Photographs courtesy of Netherlands Organisation forApplied Scientific Research (TNO)