Q&A: Formulations and Improving Patient Adherence

The Future of Drug
Manufacturing Innovation
Korinde van den Heuvel, Senior Product Developer at DFE Pharma, discusses how excipient
innovation and 3D powder bed printed tablets research can help pharma companies
achieve worldwide security of supply

PMPS: What are the main challenges
facing tablet production today?
Korinde van den Heuvel: Despite
tablets being the main mode ofpharmaceutical delivery worldwide,
there are major challenges in theway they are made and the way
they are taken. Traditional facilities
are not geared towards the smallscale production needed for clinicaltrials, orphan drugs, or the creationof designer tablets for personalisedmedicine. Taste, mouthfeel, orsolubility can make tablets hard totake. Tablets also have a lack of dose
flexibility. Smaller measurements areoften delivered by breaking tablets intosegments, which results in imprecisedosing.

new era of personalised medicines.
What’s more, the 3D printing ofmedications can potentially accelerate
the scaling up of manufacturing.
Why is 3D tablet printing a growth area?
Aside from the reasons above, theongoing COVID-19 pandemic has led

both pharma companies and global
political leaders to recognise potential
supply challenges, and reinforced theneed for worldwide stocks. Becauseof this, we have seen renewed interest
in 3D printing. This technology has
the potential to offer global security ofsupply. Instead of one large facility, local
3D printers can be given recipes for

Why should pharma companies consider
3D printed tablets?

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Images: DFE Pharma

From enabling personalised medicine
to accelerating the drug development
pathway, 3D printing offers huge
potential to meet the above challenges.
It offers opportunities in shapemodifications, dose flexibility, solubility
enhancement, and multiple pills
with multiple active pharmaceuticalingredients (APIs). There is huge
potential to deliver bespoke, small
batches in the clinical trials market.
When it comes to patient-centred
medicine, 3D printed tablets, which
can be created on demand in local
healthcare settings could open up a

Pharmaceutical Manufacturing and Packing Sourcer | October 2021

Images: DFE Pharma

production of specific medicines relevantto their location’s healthcare needs.
Are there any other changes you see asa result of the pandemic?

powder bed printing technology. Thisdiffers from conventional tablets wherecompaction and flow behaviour arecrucial.
Why use powder bed printing?

We have already seen huge changes in
the use of medicines and demand for
new vaccines as a result of COVID-19.
There has also been a shift in demandfor existing therapies, and changes inboth patient and research participant
behaviour with greater use of remoteconsultations and decentralised clinical
trials. Disruptions in the supply chain
due to manufacturing shutdown
and international restrictions havehighlighted the urgent need for areliable and consistent supply.
What do you need to consider when
producing 3D printed tablets?

Fused deposition modelling has long
been the staple 3D printing method
across sectors because it is relatively
cheap and accessible. However, it is
not suitable for thermosensitive APIs
and can struggle to provide complete
API release. Crucially, no perfectpolymer or building material has been
identified in drug production. Powder
bed printing is arguably the best
method for pharma manufacturing
because it can provide fast andcomplete API release and is suitable
for thermosensitive APIs.
Are there regulatory considerations?

Critical material attributes are vital whenselecting excipients for a 3D-printed
formulation. Flowability, wettability,
and consolidation are the main
characteristics for 3D printing using

The overall approach to acceptance,
validation, and registration of 3D
printed tablets is similar to that of any
other product. There must be a risk

Pharmaceutical Manufacturing and Packing Sourcer | October 2021

assessment, followed by evaluationand validation of critical parameters.
However, limited data on 3D printing
and the relatively low number ofproducts on the market could makethis more challenging. A key advantage
of powder bed 3D printing is that it
has already been commercialised
and approved by the FDA. In 2015,
Spritam (levetiracetam), produced
using ZipDose Technology from
Aprecia Pharmaceuticals, was the first
3D-printed medication to receive FDAapproval.
Are there any excipient-specificconsiderations?
We know powder bed printing canresult in significant dust formation
during the process, and high friability
in resulting tablets. Lactose is a goodoption to overcome the challenges foundin the 3D printed tablet production
process. However, greater understandingof the impact of different lactose grades
is needed. This is why we recently
carried out a research project on the69use of lactose as an excipient for 3D
tablet printing in collaboration withindependent research organisation, The
Netherlands Organisation for Applied
Scientific Research (TNO).

Results show how hydrophilic andhydrophobic APIs can be successfully
formulated into 3D powder bed printed
pharmaceutical tablets.

What more is needed?
The whole sector would benefit fromthe creation of a centralised databaseon 3D-printed tablet research. This
database should bring together industry,innovators, and academia. We need todevelop an understanding of how to use
excipients. Bridging the data gap on how
different excipients impact the powder
parameters central to the success of the
3D printing process is vital. This will help
us learn which materials or techniques
are appropriate for each case. Once
that is achieved, we need to study
the interaction between the different
excipients themselves, and their effecton both hydrophobic and hydrophilic
APIs. We envisage a repository
including data on excipient usability
and applicability and their impact on
powder and tablet parameters. This
would provide investigators with aninvaluable tool, and help unite us all in
the common aim of providing patientcentred care.

How did the results compare to traditional
tablets?

How did your recent research help
address this data gap?

Blends of two lactose grades with ahigher than 10μm d10 value wereblended with 10% fully pre-gelatinised
starch and measured on flowability,density, and particle size. Both blends
had a flow function above 10 and acompressibility index below 15. Thisis an indication of excellent flowability
and a low compressibility. Circular 9mm
tablets with a height of 2.8mm were
3D printed using these lactose grades.
Both grades resulted in tablets withan acceptable variation in tablet mass,diameter, and height.

The primary objective of our research
was to develop a lactose-based blend
with sufficient flowability, wettability,and binding to be used effectively
in powder bed 3D tablet printing.
20 lactose grades, all with varying
morphology, were screened in alactose binder blend and tested for3D powder bed tablet printing. We
explored the effects of the lactose
grades on criteria including hardness,friability, and disintegration. We
also examined the impact of factors
such as line spacing, print direction,and rotation. Formulations withacetaminophen and diclofenac sodium
were printed. The results show howhydrophilic and hydrophobic APIs canbe successfully formulated into 3D
powder bed printed pharmaceutical
tablets.

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Our research resulted in 3D-printed
products with properties that, while
not yet equal to traditional tablets, areapproaching the industry standard for
hardness and friability. However, it isworth noting 3D printed tablets will
always look more irregular and have arougher surface area than traditionaltablets.
What were the findings on wettability?
Wetting tests were performed by printing
a single layer with different line spacings.
The findings concluded that the PSD
was of importance, and in particular,
the d10 value. It was found that the d10value should be larger than 6μm, andpreferably in excess of 10μm.
How are flow and consolidation impacted?

How do your findings impact the future of3D printed tablets?
This study shows lactose is an ideal
excipient for a 3D powder bed tablet
printing platform. However, it also has
a wider impact. It contributes to thecommon evidence base for 3D printing
in the pharma industry and highlights

the power of collaborative working.
This research is the first step towards
creating a centralised dataset, which
could accelerate progress throughout theindustry.
What would you like to see happen now?
Pooling the knowledge and expertiseof established pharma companies,
innovators, and academia will allow us
to make huge strides towards a personcentred clinical trials and medicines
future offering a truly global supply.
In what other areas can we expect to see
new developments?
The stabilisation of biological drugs ischallenging, as they are sensitive totemperature and light, susceptible toshearing and degradation, and not as
durable and robust as small molecules.
Sucrose has a stabilisation effect on
biologics during the formulation, and new
kinds of stabilisers are now being used
to support COVID-19 vaccine supply
challenges.

Having joined DFE Pharma in April 2014,
Korinde van den Heuvel is a Senior ProductDeveloper who has worked on multiple oral
solid dose (OSD) projects, as well as focusing
on 3D printing of pharmaceutical tablets. Priorto working at DFE Pharma, Korinde worked
in formulation development at Synthon for
10 years developing various generic and OSD
forms, such as orally disintegrating, immediate
release, and modified release tablets andcapsules. Korinde holds a Master’s degree in
Organic Chemistry from the Radboud University
in Nijmegen, The Netherlands.

Pharmaceutical Manufacturing and Packing Sourcer | October 2021