Impact of excipient and blend properties on feeding
consistency for continuous manufacturing
Authors: Pauline Janssen1, Maarten Jaspers1
1DFE Pharma, Klever Str. 187, 47574 Goch, Germany, Pauline.janssen@dfepharma.com

PurposeConclusions
The feeding behavior of excipients is shown to be dependent on the physical-chemical
properties like size, shape, density, flow, internal friction and wall friction. Selection of theright excipient grade for consistent feeding is necessary. Caution should also be taken
when pre-blends are used in a continuous manufacturing line, as binary powder mixtures
do show strongly non-linear feeding behavior. In DFE Pharma’s view it is key that users
communicate openly with their suppliers to understand the full set of physical chemical
properties of excipients to minimize feeder variation in continuous manufacturing systems.

100%MCC

1.5

1.5

1.5

1.5

1.5

1.0
0.5

01020
Time (min)

1.0
0.5
030

01020
Time (min)

1.0
0.5
0030

1020
Time (min)

1.0
0.5
0030

Mass/s (g)2.0Mass/s (g)2.0Mass/s (g)2.0Mass/s (g)1020Time (min)1.00.50030

2.5

2.5

2.0

2.0

2.0

2.0

2.0

1.5
1.0
0.5
00

1020
Time (min)1.5
1.00.50030

1020
Time (min)

1.5
1.0
0.5
0030

1020
Time (min)

1.5
1.0
0.5
0030

Mass/s (g)2.5
Mass/s (g)2.5
Mass/s (g)2.5

Mass/s (g)Mass/s (g)75%MCC

2.00

Mass/s (g)SuperTab® 11SD

Pharmacel® 102 (B)Pharmacel® 102 (A)Pharmacel® 101 (B)Pharmacel® 101 (A)Primellose®

Primojel®

SuperTab® 40LL

SuperTab® 30GR

SuperTab® 24AN

SuperTab® 21ANSuperTab® 50ODTSuperTab® 11SD (NZ)

SuperTab® 11SD (EU)

Pharmatose® 80M

Pharmatose® 125M

Pharmatose® 150M

Pharmatose® 200M (NZ)

Pharmatose® 200M (EU)

50% MCC

1020Time (min)301020Time (min)301020Time (min)301020Time (min)

30

1.5
1.0
0.5
0030

1020Time (min)

5030

0.6

0.6

0.6

0.6

0.6

Sieved lactose

Superdisintegrant

Granulated lactose

Microcrystalline cellulose

0.2001020
Time (min)

0.4
0.2
030

01020Time (min)

0.4
0.2
030

01020Time (min)

0.4
0.2
0030

1020Time (min)

0.4
0.2
030

00.8

0.8

0.8

0.6

0.6

0.6

0.6

0.6

0.4
0.2
001020Time (min)

30

0.4
0.2

01020
Time (min)

30

0.4
0.2
001020Time (min)30

Mass/s (g)0.8Mass/s (g)0.8Mass/s (g)Pharmacel® 102 (B)Pharmacel® 102 (A)Pharmacel® 101 (B)Pharmacel® 101 (A)Primellose®

Primojel®

SuperTab® 40LL

Pharmatose® 200M

Anhydrous lactose

SuperTab® 30GR

SuperTab® 24AN

SuperTab® 21AN

SuperTab® 50ODTSuperTab® 11SD (NZ)

SuperTab® 11SD (EU)

Pharmatose® 80M

Pharmatose® 125M

Pharmatose® 150M

Pharmatose® 200M (NZ)

Pharmatose® 350M

Pharmatose® 200M (EU)00.4

Mass/s (g)10Mass/s (g)20Mass/s (g)0.8Mass/s (g)0.8Mass/s (g)0.8Mass/s (g)0.8Mass/s (g)0.8SuperTab® 21AN

40

Milled lactose

0.4
0.2
00

1020
Time (min)

30

0.4
0.2
00

Spray dried lactose

Figure 2: Non-linear feeding behavior is observed for lactose-MCC blends with varying ratios.

Feeding variability per second (%)

Figure 1: Feed rates and feeding variability of pure excipients.

2.0

Feed rate (g/s)

Powder feeding behavior becomes even more complicated when blends of different
materials are evaluated. None of the four different excipient compositions evaluatedhere show a fully linear relationship for the feeding behavior as a function of mixture
composition. For blends of modified lactose monohydrate grades (SuperTab® 30GR andSuperTab® 11SD) with MCC, the feed rate of the blend is dominated by the feed rate of MCC.
Furthermore, blends of milled lactose (Pharmatose® 200M) with MCC show non-linear
behavior for feeding variability with maximum variability in a 50:50 blend. This may be theresult of chunk formation or segregation during feeding, due to differences in physicalchemical powder properties between the products.

Pharmatose® 350M

Pharmatose® 450M
6025% MCC

2.00.0Result(s)The feedrate and feeding variability of excipients is shown to be highly dependent on thetype and shape of the particles. Granular and spherical lactose particles have feed rates
between 1.3 and 2.3 g/s, while smaller tomahawks have feed rates below 0.5 g/s. Feeding
variability of pure excipients is higher than observed in literature, which is explained by thelower timescale for calculation of the RSD (3,4). In general, materials with low feed rateshow a high variability in feed rate. Anhydrous lactose is the exception on this, as for thismaterial both a low feed rate and a low variability is observed. The difference in feed rates
and feeding variability is shown to be dependent on a full set of excipient physical-chemical
properties; size and flow alone are not enough to fully understand performancein a feeder system.

1.0

Pharmatose® 450MFeeding consistency of excipients is evaluated by a volumetric force feeder. The feeder usedin this study is a stainless-steel Force Feeder FF1 from Thermo Haake and contains a single
feeding screw with a diameter of 15mm and a pitch of 15mm. The rotational speed of thefeeder and agitator was set at 40%, corresponding to 24 rpm. The feedrate was monitored
every second with BalanceLink Software of Mettler Toledo. Subsequently the output per
second is calculated, and the feeding variability is calculated as the relative standard
deviation over the output per second. Blends of lactose and MCC are prepared by blending
lactose with 25%, 50% and 75% Pharmacel® 101 (%w/w) for 10 minutes in a Turbula blenderat 96rpm. Lactose grades tested are Pharmatose® 200M, SuperTab® 11SD, SuperTab®30GR,
and SuperTab® 21AN.

1.5

0.5

Feeding variability per second (%)

Methods

SuperTab® 30GR

2.0

The ability to feed powder consistently and continuously is regarded as one of the criticalrequirements for finished product quality and therefore stringent control on feedingis required (2). The accuracy of powder feeding can be impacted by intrinsic material
attributes, such as particle size, electrostatic charging, flow, bulk density, or wall friction.
These properties are usually known for pure materials, but properties of powder mixtures
are often unknown and hard to predict due to strongly non-linear interactions.
The goal of this study is to understand the feeding variability of different types of excipientsand binary excipient mixtures in a volumetric feeding system. 20 pure excipients are tested,varying from milled to sieved, granulated to spray dried and round to fibrous. Furthermore,
a spray dried, granulated, anhydrous and milled lactose grade are mixed with MCC toevaluate the changes in feeding accuracy upon mixing.

0% MCC

2.5

Feed rate (g/s)

Continuous manufacturing (CM) gains more and more interest in the pharmaceuticalindustry, which is guided by the FDA in Pharma 4.0. With CM gaining ever so importance,
understanding of physical properties of powders to predict behavior in different processunits is crucial. Raw material feeding is usually one of the first units of operation in acontinuous manufacturing line. Handling a high number of feeders, however can bechallenging and costly. Especially clustering more than six feeders around a single transition
is difficult and expensive (1). Pre-blending of excipients may be a logical process choice
when the number of feeders in a continuous manufacturing system is limited.

1.5

1.0

0.5

References
1. Oka, S., Escotet-Espinoza, M. S., Singh, R., Scicolone, J. V., Hausner, D. B., Ierapetritou,
M., & Muzzio, F. J. (2017). Design of an integrated continuous manufacturing system.
Jukka Rantanen, 4.
2. Blackshields, C. A., & Crean, A. M. (2018). Continuous powder feeding forpharmaceutical solid dosage form manufacture: a short review.
Pharmaceutical development and technology, 23(6), 554-560.
3. Wang, Y., Li, T., Muzzio, F. J., & Glasser, B. J. (2017). Predicting feeder performancebased on material flow properties. Powder Technology, 308, 135-148.
4. Hanson, J. (2018). Control of a system of loss-in-weight feeders for drug productcontinuous maufacturing. Powder Technology, 331, 236-243.

6050403020100.00255075100

MCC content (%)

SuperTab® 30GRSuperTab® 11SD002550MCC content (%)

SuperTab® 21AN 			

Figure 3: Feed rates and feeding variability of lactose-MCC blends with varying ratios.

Pharmatose® 200M

75100