Understanding andAccounting for
Excipient Variability inContinuous Tablet
Manufacturing (CM)Content Overview

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3

CM as the future ofmanufacturing in our industry

4

CM processes must be robust enough to produce ­consistent products
despite variations in raw materials, such as excipients.

Understanding how excipients
behave in CM processes

5

The parameters that dictate control vary from product to product,
grade to grade and even batch to batch.

Accounting for Variability

11

MVA Stretch Batch Approach delivers extensive historical datasets
and expert knowledge that can help developers better ­understandvariation in the design of robust CM ­processes.

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QbD in action

5

The value of expertiseand partnership

13

Insights gleaned from Stretch ­Batches inform risk assessments andfocus the design of ­experiments on the most important parameters
for that product - ultimately shortening the route to ­market.

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Let’s talk!

Continuous Tablet Manufacturing / February 2021

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Introduction

As pharmaceutical production moves from batch-wise to continuous
manufacturing, individual processing steps, such as blending of the active
pharmaceutical ingredient (API) with excipients, have to be re-designed tocontinuous operations.
Whilst the cost and quality benefits of CM are well documented, s­ uccessful
implementation relies on an in-depth understanding of how raw materials
and their mixtures – including excipients – behave in continuous processes.
This whitepaper will outline some of the key learnings from DFE Pharma’s­excipients in CM processes variability experiments, before setting out
DFE Pharma’s Stretch Batch Approach and how it can work in practice.
Ultimately, it will demonstrate why DFE Pharma is fast becoming thepharma industry’s preferred global partner in the robust development ofcontinuous tablet ­manufacturing processes.

Continuous Tablet Manufacturing / February 2021

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CM as The Future
Of Manufacturing“Whilst excipients are a small

Continuous processing or manufacturing is at the forefront of advanceelement of the overall drugfor the pharmaceutical market. Unlike the stop and start mode of batch­development process, they are

manufacturing, in CM, materials are continuously fed into a closed system­crucial. Having studied how thewithin which all process steps take place.

natural parameters of excipient­variation impact continuous

The benefits to pharma include:­processes, DFE Pharma is e
­ merging• Manufacturing lead times are significantly reduced

as the global pharmaceutical• Plant footprint is reduced­excipient expert contributing to• Processing times are decreased

robust drug development. Robust• Unnecessary steps are eliminateddrug development and successful• Contamination risks are minimised

CM starts with, and is dependent• Reduces the likelihood of human error

on dialogue and collaboration• Allows for real-time monitoring

between the pioneers and experts• Requires less physical spacein their respective fields”• Reduces scale-up times• Reduces amount of API usage• Crucially, CM could be 40 to 50% less expensive to run than batchprocessing.
Since 2015, the FDA has approved seven drug products manufactured

Mara van Haandel

by CM, and at least 20 more are in the pipeline.

Innovation Manager,
DFE Pharma

With FDA support for companies transitioning to CM, and the significant
benefits of this streamlined approach resulting in high-quality drug
­products through plant-wide Quality-by-Design approach, CM is verymuch the future for our industry.

Continuous Tablet Manufacturing / February 2021

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Understanding Excipient Variation
Within the CM Process(The Science Behind the Understanding)Any variation in how individual products flows into the manufacturing line
will affect the final product, yet variability in excipients is inevitable. They
can vary by type, or grade, from vendor to vendor, and even from batch tobatch, with each one of these variables able to impact processability andfunctionality.
When building CM processes that result in consistent end-products,­regardless of variability, we need fundamental knowledge of how excipients
behave at each stage.
Mechanistically understanding the behaviour of powders in the feeders/hoppers is a crucial first step, based on the properties of APIs, excipients,
and the total formulation. Yet there is little scientific evidence on theinterplay between equipment performance and input materials.
Electrostatic powder charging, for example, is an important consideration
for the quality of the end-product. Different excipients will have higher orlower charging potentials, and the higher the value, the higher the likelihoodof a non-constant flow. Obviously, this could have implications for thesafety and efficacy of the resulting tablets.

A schematic illustration ofcontinuous tablet manufacturing
using direct compression, wetgranulation, and roller compaction.
Source: Sebastian Escotet,
Fernando Muzzio

Continuous Tablet Manufacturing / February 2021

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2The Experiments
Understanding excipient variability is integral to the CM process but it isextremely complex. The parameters that dictate control vary from productto product, and even from grade to grade. For example, while particle size
distribution (PSD) may be crucial for one product, for another it may bebeta content or surface area.
As experts in this field, DFE Pharma evaluated the behaviour of differing
grades of our own brands of lactose, microcrystalline cellulose and­superdisintegrants when applied to CM processes. We confirmed that thevarying intrinsic properties of the different grades of the well-established,regulatory-approved excipients, had differing effects on equipment­performance.
Using a stainless-steel hopper, we were able to show, for example, thatdiffering particle shapes impacted on the performance of the hopper whenvarying hopper fill.
Despite being free-flowing, SuperTab 21AN, an anhydrous lactose with ashard shape, resulted in more flow around the outside of the equipment
than the inside, as the hopper was being filled. The average trend showed
the mass increasing as the hopper emptied.
Pharmatose 200M, a monohydrate lactose with a tomahawk particle
shape, was found to be a flowing excipient with a medium density andconstant mass flow. This was also the case for Pharmacel 101, a fibrous
microcrystalline cellulose (MCC).

SuperTab® 21AN

Pharmatose® 200M

Pharmacel® 101

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When the hopper was filled constantly, with material being continuously
added to the product, SuperTab 21AN, in contrast to the varying fill ­scenario,
showed a constant mass flow (see figures on the next page).
This was also seen with Pharmatose 200M and Pharmacel 101, but changes
were observed as powder was added. We found that systems needed afive- to 20-second window for stabilisation when using these products.
Such insights are invaluable in the design of CM processes.

Gericke Loss-in-weight feeders

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Result of feeder excipient behaviour – Varying hopper fill
SuperTab 21AN

Pharmatose® 200M

Pharmacel® 101

6

3,5

5

3,0

5
4
3

Mean weight = 5.61 ± 0.44 g/10 sec

1
0

200

400

600

800

1000

3
2

0

1200

Mean weight = 3.93 ± 0.17 g/10 sec

1

0

400

800

SuperTab 21AN

constant

1200

1600

weight/10
sec
Average Average
weight/10
sec

3
1
2
0

600

3
4
2
3
1
2
0

800

1000

0

1200

0

400

800

Average weight/10 sec

Average weight/10 sec

5
4
3

0

Mean weight = 5.24 ± 0.31 g/10 sec

0

200

400
600
Time (secs)

1200

1600

??

2,5

2,5
1,5
2,0
1,0
1,5
0,5
1,0
0
0,5
0

2000

0

20

40

0

40

800

3,5

5
4
3
2

Mean weight = 3.88 ± 0.30 g/10 sec

0

??

??

??

120

140

80

120

160

200

??

??

??

2,5
2,0
1,5
1,0

Mean weight = 2.71 ± 0.16 g/10 sec

0,5
0

0

20

• Flowing excipient• Medium density• Constant mass flow

Varying hopper fill
Mean weight

Constant hopper fill
Mean weight

SuperTab® 21AN

5,61 g/10s

5,24 g/10s

Pharmatose® 200M

3,92 g/10s

3,88 g/10s

Pharmacel® 101

2,75 g/10s

2,71 g/10s

40

60

80

100

120

140

Time (secs)

Time (secs)• Free flowing excipient• Highest density• Constant mass flow in time100

Pharmacel 101

3,0

0

1000

80

®

constant

6

160Time (secs)

Time (secs)

Pharmatose
200M
constant

7

200

3,0
2,0

®

6

160

• Flowing excipient• Low density
3,0• Constant mass flow
3,5Time (secs)

SuperTab
21AN
constant

120

Pharmacel 101

3,5

4
5

Time (secs)

1

80

constant• Medium density
5
6• Constant mass flow

®

2

40

varying

0
400
600
800
1000
??
??
??
??
??
1 0 – Constant
1
Resultof200feeder
excipientbehaviour
hopperfill
Time (secs)
Time (secs)
400

0Time (secs)• varying
Flowing excipient

3200

Mean weight = 2.75 ± 0.20 g/10 sec

0,5
0

2000

6

4
2

0

1,5
1,0

Pharmatose200M

constant•varying
Free flowing excipient• Highest density
6
7 • Core flow observed
5
6 • Powder mass increasing with4
emptying of hopper
5
7

0

2,5
2,0

Time (secs)

Time (secs)

Average Average
weight/10
sec
weight/10
sec

0

4

Average weight/10 sec

2

Average weight/10 sec

7
6
Average weight/10 sec

Average weight/10 sec

varyingvarying

SuperTab® 21AN

Average Average
weight/10
sec
weight/10
sec

Pharmacel 101

Pharmatose200M

varying• Flowing excipient• Low density• Constant mass flow

Continuous Tablet Manufacturing / February 2021

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We know that the more controlled the particle-size distribution (PSD) of theexcipients used, the more reliable the CM process. Understanding this has
been a key factor in DFE Pharma’s proud record on PSD consistency.
The effect of PSD consistency was demonstrated by our twin screw wet
granulation study in which we altered our standard product, Pharmatose
200M, to create excipients that had finer and coarser particle size, andmeasured the effect on continuous unit operation.
After extrusion of the granules, we found differences in mean particle sizes,
and these translated into varying levels of tensile strength in the resulting
tablets. Ultimately, finer lactose produced harder tablets, whereas coarser
excipients led to softer ones.

Granule and Tabletting behavior of lactose monohydrate

4.0

Pharmatose® 200M

3.5
3.0

T.S (Mpa)

2.5
2.0
1.5
Pharmatose® 200M

1.0

Fine

0.5
0

0

5

GranulesN=3 batches
N=5 tests

10
CF (KN)

15

Bulk density(g/ml)

20

CoarseTapped density(g/ml)

Practicle size
(x50: micron)

Extruded material was dried and sieved over an 800 micron sieve

Pharmatose® 200M

0.67

0.82

233

Fines added

0.63

0.80

208

Coarse added

0.70

0.96

244

Summary: When feeding finer lactose monohydrate to a twin screw wet granulationline, harder tablets are produced, whereas coarser lactose monohydrate lead tosofter tablets.

Continuous Tablet Manufacturing / February 2021

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We were also able to show that compactability in anhydrous lactose isdriven by beta-crystals. This experiment involved pressing tablets fromanhydrous and monohydrate products, adapted to feature varying mean
PSD, using increasing compaction force. The result was less variationin tensile strength of the tablets made from anhydrous than frommono­hydrate lactose, clearly demonstrating that the compactability of­anhydrous lactose is driven by the beta crystals in the product, rather
than the particle size of the material.
As these examples show, many factors – from flow to charging potential,
particle size to compactability – influence the behaviour of excipients when
they are applied to the CM process. The Certificate of Analysis (CoA),
which focuses on the monographed parameters rather than functional
characteristics, is not the whole story. Limiting variability without theneed for labour-intensive, drawn out e­ xperimentation that impedes drug
development pathways relies on a solid understanding of all of these factors.

Granule and Tabletting behavior of lactose anhydrous

4.0SuperTab® 21AN

3.5
3.0

T.S (Mpa)

2.5
2.0
1.5
SuperTab® 21AN

1.0

Fine

0.5
0

Coarse0GranulesN=3 batches
N=5 tests

5

10
CF (KN)

15

Bulk density(g/ml)

20

Tapped density(g/ml)

Practicle size
(x50: micron)

Extruded material was dried and sieved over an 800 micron sieve
SuperTab® 21AN

0,64

0,72

510

Fines added

0,62

0,75

360

Coarse added

0,62

0,72

498

Summary: The clear effects shown with Pharmatose® 200M were not visible with
SuperTab® 21AN. This can be explained by the fact that the compctability of anhydrous
lactose is driven by the beta-crystals rather than the particle size of the material.
See page 9 for Phamatose 200M.

Continuous Tablet Manufacturing / February 2021

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3

Accounting for Variability:
DFE Pharma’s‘Stretch Batch Approach’

Many organisations will assess the impact of excipient variability by
testing multiple batches of excipients. However, this is a time-consuming,labour-intensive process that is not always executed diligently.
Instead, DFE Pharma advocate the use of multivariate data analysis (MVA)
statistical techniques, which allow the simultaneous analyses of multiple
variables to investigate patterns or clusters in the excipient dataset.
Our researchers work with our pharma partners to identify the major
relevant sources of variation in the large, complex datasets, as well as noise
variables that have no effect.
Batches near the Hotelling’s T2 95% confidence limit are then selected asa representative of a wide range of possible variation. Termed ‘Stretch
Batches’, these application-specific batches of excipients, based on DFE
Pharma historical data, are truly representative of the possible variation,
while remaining well within the specification limits of the CoAs.
The Stretch Batch Approach uses large data sets to enable MVA to identify
major sources of variation, and facilitate a greater understanding of therelationships between all design inputs, from the desired quality attributes
to process parameters and raw material attributes.

“The stretch batch approach is made possible by the wealth of historicand current data we hold and our understanding of what matters for the
CM process. And it’s important because using well-controlled excipients,
designed for purpose, can reduce life-cycle risk in pharmaceuticaldevelopment and production.”

Insights gleaned from these stretch batches contribute to Quality by Design(QbD) by informing risk assessments and focusing the design of experimentson the most important parameters.
By effectively managing the variations that can impact on product­performance, developers can slash the level of experimentation needed
during product development and have all the information they need toquickly move up to commercial scale production.

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The industry can use the insights gathered from the Stretch Batch
methodology to:• look at how powder properties compare to the CoA• run tests to find out which variations will impact on production
processes or end- product quality• design processes that account for a wide range of variability• reduce the volume of experiments needed to account for variability• demonstrate the safety and consistency of products to regulators• avoid unexpected variation during the transition fromdevelopment- to commercial-scale production

To learn more about what drives variation and how to account for it,
visit the dfepharma.com/cm to read our study, Quality by ­Design:
Using Multivariate Analysis of Batch-to-Batch Excipient Variation
to Reduce Risk by Bastiaan Dickhoff.

Example of MVA scoreplot ofSuperTab® 30GR (M2, PCA-X). Coloured
according to year. No trend is observedin the data over the years. MVA is utilized
to gain insights in variation and to selectStretch Batches, batches near the
Hoteling’s T2 confidence limit.

2011
2012
2013
2014
2015
2016
2017

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QbD in action

DFE Pharma is working with a pioneering pharmaceutical company toactively trial the Stretch Batch Approach, to better understand the design
space and embed QbD into their manufacturing processes.
As part of its continuous manufacturing design process, the company is
exploring the full span of variation they could expect from the product it had
previously purchased from DFE Pharma.

DFE Pharma explains:

In this case, if the company was toAs the company sets about“Our Stretch Batch Approach gives

rely solely on its own testing, then,­designing its first CM process from

customers the data they need tothere would have been a risk thatscratch, it aims to utilise the Stretch

de-risk their CM design process.

greater variation in upcoming

Batch Approach method to design

batches could unexpectedly influencerobust, compliant processes that willprocess or formulation performance.

ensure the quality and consistency“They can use this information to
study how the full span of possibleof its products.

excipient variability might impact on

Deploying the Stretch Batch

the final product, and fully under-­Approach to its historical dataset,

Commenting on the process,stand any potential risks to later

DFE Pharma found that the client

the R&D Team highlight:

phase development. It’s about

had received two “centre point“DFE Pharma can tell us the variati-

providing confidence around thebatches”.

on we can expect from their product,

quality and consistency of the final
product.”

and how to visualise it, as well as
Instead, DFE Pharma supplied productshare some of the origin of thatbatches from all four quadrants

variability. We will then take the“Knowing up front, from entry intoof the MVA plot, representing theinformation and study its impact onlate development, what the potential

maximum range of variability, for

our CM processes.

variables are means the customer

use in their testing programme.

can decide if they need to study“The transfer of information, thatthem in our operational setting, orThrough a deep dive into thedata connection, is very important

if they can consider them to be low

variation, researchers were also able

because it gives us confidence thatrisk.”

to provide full breakdowns of thewe know the design space, andexcipients functional parameters,that we won’t get stuck in a lot ofby flow, PSD and density, to inform‘afterwork’ once we have thetheir studies.

processes up and running on thecommercial plant.”

Want to know more about how DFE Pharma’s collaborations could help you?
Contact: cm@dfepharma.com

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5

The Value of Expertise andPartnership

The pioneering companies making the FDA-recommended move to CM
understand that while traditional processes such as direct compression,roller compaction, or wet granulation are used within the continuous lines,
the role of excipients within them can differ from traditional batch­processing. Pharmaceutical dosage form production requires a thoroughunderstanding of all design inputs, from raw materials such as excipientsand APIs, to formulations, processes or equipment. Without it, the designor quality of the end-drug is compromised.
DFE Pharma’s heritage and understanding of excipient variability, built
over 100 years of research and development, is key to helping the industry
makes this inevitable transition. We have studied how the parameters of
excipient variation within specification may impact processes such ascontinuous feeding, granulation and tableting and can provide valuable
input to improving the consistency and quality of the manufacturing
process. Additionally, we have a wealth of meaningful, historical data
which we have used to devise the Stretch Batch approach.
This novel technique can inform the efficient construction of compliant,Quality by Design (QbD), CM processes by potentially reducing the numberof manufacturing-related experimental studies required during drug
product development.
Robust drug development and successful CM starts with, and is dependenton, dialogue and collaboration between the pioneers and experts in theirrespective fields. Whilst excipients are but a small element of the overall
drug development process, they are central to it.
At DFE Pharma, we are the excipient experts:• we have insight over the variants of consistency• we have the wealth of historical data and proven experience to share• we have a proven knowledge bank through the Stretch Batch approach.
At DFE Pharma, we care. We understand that realising the potential of CM
can help bring life-changing, innovative medicines, that are affordable to all,to market as quickly as possible.
Let’s talk.

Continuous Tablet Manufacturing / February 2021

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DFE Pharma can support you with:• Excipient expertise in selection of excipients for Continuous­Manufacturing• Excipient insights in variation (Score and loading plots using multivariate analysis (MVA))• Excipient stretch batches of the (MVA) historical product space#1 / March 2021

• Multi-functional excipients designed for Continuous Manufacturing

For more information:

dfepharma.com/cm

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