LEISTRITZ EXTRUSIONSTECHNIK GMBH

refreshing
E X T R U S I O N

e x t r u s i o n
technology
P H A R M A
Pioneer in Pharma Extrusion

In the last two decades, extrusion technology has become an interesting alternative to customary manufacturing pro-
cesses for pellets, tablets or transdermal systems. In this established technology for continuous processing of pharma-
ceutical masses twin screw extruders are used. An important fact: The FDA encourages continuous processing that
supports multi-unit operations (PAT initiative).
Leistritz Extrusion Technology is the technology leader in this area. The company has delivered extruders into the phar-
maceutical industry for many years and therefore has extensive know-how.

Basic Principle
The extruder’s main task is mixing, homogenising and sometimes also degassing of the material. This is done in a con-
tinuous process (extrusion terminology typically refers to a throughput in kg/h). That means: By means of gravimetric
feeders each ingredient of a formulation (solid, liquid or gaseous state of aggregation) can be fed into the machine. That
way, carrier and auxiliary substances as well as active components can be added into various parts of the processing
unit in an exact proportion. Depending on the final product (pellets, tablets, transdermal systems) various extrusion lines
can be used.

The extrusion process is suited for:

incorporating an API into a matrix (i.e. wax, cellulose, starch
and further polymers)
granulation of a tablet premix
compounding of an antibacterial TPU premix
stripping off the volatile content from a formulation
coatings for transdermal applications
implementation of various dosage forms
reactive extrusion

Tablets
or Strand cutting
pellets
Strand cutting by strand pelletizer
or sizing machine (e.g. cutting or
cone mill)

Pellets
for Strand forming
capsules
Pellets are cooled and conveyed
by an air stream in the same
equipment, e.g. LMP

Transdermal
systems Final form
e.g. patches
Packaging

2
 P H A R M A E X T R U S I O N

Main Applications
In pharma extrusion, there are two kinds of processes that need to be distinguished: wet extrusion and hot melt extru-
sion. In wet extrusion, liquid is fed into a powdery substance. The liquid is used for granulation of the extrudate (mate-
rial in the extruder) and normally is removed in a later drying phase. In hot melt extrusion, the fluid state is reached by
melting the excipient during the process above its glass transition point. After being discharged from the extruder, the
extrudate is cooled and thus solidified.

Typical
Pharmaceutical
Feeding a premix or
split feeding the active Forms
ingredients and
Strand cooling by air-cooling on e.g. carrier materials
belt, vibration or spiral conveyors

Strand cooling Strand shaping

Mixing,
Extruder Wet
homogenizing
extrusion
Shaping of the extrudate by
discharging via a die head
Feeding a premix or
split feeding the active
Strand cutting directly after
discharge of the extrudate „hot ingredients and
face” by a “hot face pelletizer” carrier materials

Melting,
mixing,
Strand cutting Strand shaping homogenizing, Extruder
dispersing

Shaping of the extrudate in

cylindrical shape by discharging
Feeding a premix or
via a die head
split feeding the active Melt
Direct forming and cooling in a
ingredients and extrusion
carrier materials
calender system

Melting,
mixing,
Forming and cooling Shaping homogenizing, Extruder
dispersing

Shaping of the extrudate into a film

or strip via a flat film die

3
Pioneer in Pharma Extrusion

The main advantages of hot melt extrusion are:

EUDRAGIT® NE as precipitation inhibitor

enhancement of solubility % Felodipine dissolved

time t [min]

Verapamil·HCl Tablets

taste masking

sustained release

stability of the formulation

(in relation to the processing
technique)
little use of additives
efficiency of production
process free of solvents
source: Evonik

4
 P H A R M A E X T R U S I O N

The main focus in wet extrusion is on

production of granule particles for functional coatings
spherical particles
small particle size distribution
controlled drug release
uniformity of drug content
easy processing by means of continuous
granulation and online monitoring
batch size adaptation by changed
processing times

source: Heinrich-Heine-University, Düsseldorf

Process Technology when Manufacturing Solid Pharmaceuticals

Advantages of the continuous extrusion process compared to established batch processes:

homogenous mixing efficiency
self-cleaning/self-emptying of the extruder screws
easy automation and control
easy scale-up ➞ reduction „time to market“
short product change cycle
reliable reproduction of formulation quality
single stage processing (incl. shaping of the pharmaceutical form)
low operating and investment costs

Benefits for the product:

short residence time and small range of residence
time distribution
high throughput
small particle size distribution
high dosing of active agent possible
low material content in extruder at a high throughput
dosing of several components (solids, fluids and suspensions)
possible, i.e. the extrusion line also ensures correct
implementation of formulation valves
possibility of adding fluid into the running process

5
Pioneer in Pharma Extrusion

Extruder Engineering
Two types of extruders can be used in the pharmaceutical industry: the single screw and the twin screw extruder. Single
screw extruders are the simplest extrusion system worldwide. The principle: One screw, which by means of various
screw geometries facilitates various processes, rotates inside the barrel. As the name implies, two screws are used for
operation in the twin screw extruder. The screws either rotate in the same direction (co-rotating) or in the opposite direc-
tion (counter-rotating).

Advantages of twin screw extruders (co- and counter-rotating)

compared to conventional manufacturing techniques:
melting properties
very good mixing effect - homogenizing of the product
self-emptying due to second screw (defined residence time possible)
high shear rate in order to crush agglomerates
sealed off processing section to prevent cross-contamination
short processing time
integration of several process steps in one machine
little space required (yet with the same production capacity)
trouble-free scale-up to production scale (transfer of lab results to
production size)
flexible screw geometry and segmented barrels
exact temperature control
higher throughput

Distinction between counter-rotating and co-rotating twin screw extruders

GG = counter-rotating; low shear GL = co-rotating; high shear

OD ID OD ID

GG GL
v=p.n.D

The tightly intermeshing screw profile of co-rotating twin screws provides an immensely significant effect: self-emptying.
By means of a high shear rate created in the gap between the screws, they clean each other out. The extruder
discharges the material automatically.

6
 P H A R M A E X T R U S I O N

Extrusion Lines in GMP Design

For the special demands in the pharmaceutical industry, Leistritz presents an extruder series including according
auxiliary equipment in GMP design.

Extruders for pharmaceutical applications are characterized not just by visible features like the usage of stainless steel.
This machine generation provides everything that meets the GMP requirements of the industry: special fittings, material
combinations, surface textures and an increased documentation for qualification. The extrusion lines have an outstand-
ingly detailed design for all components with respect to cleaning, excellent process stability to ensure continuous pro-
duct quality, an optimal process control, and complete documentation.

example: ZSE 50 HP-PH

7
Processing Unit

Processing Unit - the Heart of the Extruder

The processing unit consists of screws and barrels, which are manufactured from highly alloyed steels as they are in
direct contact with the product.

Barrel
The barrels of Leistritz extruders are designed as modular systems, which comprise several barrel modules that are
either flanged together or - depending on the size of the line - connected by internal tie rods. There are no sealing ele-
ments between the barrels. The sealing is ensured solely by pretensioning force. The cross section of the barrels of the
twin screw extruder is characterized by a barrel opening in shape of a horizontal 8. The inner surface of the barrel can
have an especially hardened and honed layer in order to minimize corrosion and mechanic wear.

8
 P H A R M A E X T R U S I O N

Screw
The screw is the most important part of the extruder. Its design distinguishes the processes that the extruder can fulfill
and therefore the quality and quantity of the extruded material. The spiral flights of the screws are whirled into a cylindri-
cal steel rod. There are two ways to manufacture a screw: You can either prepare a so called compact screw or produce
a segmented screw, which has proven to be very practical, especially for twin screw extruders. The screw elements are
internally splined and can be slid and fixed on the according counterpart - the splined screw shaft. The advantages of
the segmented screws are obvious: The screw profile can be altered at any time.

9
Overview

Already in the mid 1980s Leistritz delivered extruders for the pharmaceutical industry. The extrusion lines for wet and hot
melt extrusion are renown all over the world and stand for cutting edge technology.

Phases in Drug Research and Development

Evaluation Development Pilot-scale Production

Clinical samples
Research Preclinical tests Phase 1 Phase 2 Phase 3 Application Admitted
for
admission

approx 5,000 250 4.7 3.3 1.5 1.2 1.0
to 10,000
substances

Years 0 1 2 3 4 5 6 7 8 9 10 11 12 13
Extruder NANO 16 ZSE 18 HP-PH ZSE 27 HP-PH ZSE 40 HP-PH ZSE 50 HP-PH

Leistritz offers the appropriate extrusion line for each phase.

Leistritz pharma extruders at a glance:

GL = co-rotating twin screw extruder

Type Diam. Torque Version Screw Drive

Screws Screws Speed Power
(mm) (Nm) (rpm) (kW)
NANO 16 16 42 GL 500 2.24
ZSE 18 HP-PH 18 71 GL 500 & 1,200 3.9
ZSE 27 HP-PH 27 268 GL 500 & 1,200 15
ZSE 40 HP-PH 40 830 GL 400 37
ZSE 50 HP-PH 50 1,570 GL 400 70

10
NANO 16 P H A R M A E X T R U S I O N

The NANO 16 twin screw extruder, integrated with a new micro-plunger feeder, is used in the evaluation stage, so the
extrudability of the formulation is tested (this is no basis for scale-up calculations). By means of its 3-lobed screw el-
ements, it facilitates facilitates the continuous extrusion process for batch samples from 20 to 100 grams. The NANO
16 utilizes a segmented design for barrels and screws, a stainless steel process section, and as an option a state-of-
the-art control/data acquisition.
The NANO 16 is mainly characterized by the micro-plunger feeder. Until now, there was no possibility to run very small
batches on a twin screw extruder in a starved fed mode. The micro-plunger feeder consists of a piston which slides
within a stainless steel tube. The tube is filled with a 20 to 100 cc batch. After being positioned to the bottom of the
feed barrel, the piston is pushed upwards by a variable speed drive to facilitate precision feeding at extremely low
rates.
The NANO 16 has a torque of 42 Nm, which facilitates processing of highly viscous ingredients.

micro-plunger feeder

The NANO 16 is also available as a version with a 12 L/D processing

unit and an even smaller micro-plunder feeder. This way small batch-
es of up to 10 cc can be processed.

11
ZSE 18 HP-PH

The twin screw extruder ZSE 18 HP-PH is developed for use in labs and small production. It is suited for throughputs
from 200 g/h to 5 kg/h.

approx. 2,290

approx. 1,700
approx. 1,270

approx. 700

example: ZSE 18 HP-PH

12
ZSE 27 HP-PH P H A R M A E X T R U S I O N

The ZSE 27 HP-PH has all the specific parameters of a large scale production machine in order to be able to project lab
scale compounding for production settings as accurately as possible (1 to 25 kg/h).

The processing unit and the drive unit are built as compartments with a subdiving wall - an important feature with regard
to the cleaning aspect. The processing unit can be separated from the extruder by means of a trolley. The barrel seg-
ments can then be disassembled for cleaning (also see on page 14-15).

approx. 3,650 approx. 1,150

approx. 1,800

example: subdividing wall

ZSE 27 HP-PH
clamping flange

quick-release
coupling

13
ZSE 40 HP-PH

The ZSE 40 HP-PH is designed as a production scale machine.

The frames of processing unit and drive unit are made of

stainless steel. The surfaces are polished in order to as-
sure easy cleaning. The cover can be removed manually
at any time. This way, necessary reconfiguration of the
barrel segments can be done.

14
ZSE 50 HP-PH P H A R M A E X T R U S I O N

The ZSE 50 HP-PH is a production scale machine that is able to gain higher throughputs. Since it is designed with a
modular layout, it is adaptable to various processing tasks. The processing unit can be disassembled, cleaned and
reassembled with small technical effort.

approx.. 4,630

approx.. 2,120
ca. 1.050

approx. 1,050
approx. 2,190 approx. 2,100
approx. 800
approx. 170

approx. 280

approx. 490
approx. 90

Frames of processing and drive

unit are separated. Thus, the two
parts can easily be set up even in
narrow spaces.

Cleaning of barrel segments:

• detach the pluggable electricity and cooling
water supplies
• open the clamping flange and pulling out the
barrel
• dock the trolley to the processing unit
• slightly lift of the processing unit and move
the trolley aside

15
Engineering Solutions

Containment:
The significance of processing high potent drugs has
grown in Hot Melt Extrusion. This development leads
to higher requirements for work safety. The most ef-
fective method when working with products of OEL
classes 4 and 5 is the isolator technology. The en-
gineering of such a line is a highly demanding task,
since three line components have to be isolated:
dosing unit, extruder and downstream equipment.
The Leistritz engineers have developed customized
solutions which meet the requirements in terms of
handling in the isolator, cleanliness and hermeticity. A
mock-up study ensures the safe and ergonomic work
of the operators.

Washing-in-Place:
The washing-in-place-kit simplifies the cleaning. The cleaning tube is plugged to the adapter (notch). The screws and
the barrel (made of stainless steel) are rinsed with water. They are disassembled and cleaned in a washing machine.

16
Leistritz Micro Pelletizer (LMP) P H A R M A E X T R U S I O N

LMP 2.0
One of the most frequently used pharmaceutical forms for sustained release applications are capsules filled with micro
pellets in spherical, semi-spherical and lenticular shapes (approx. 1.5 - 3 mm). The pellet size depends on the formula-
tion and the process parameters.
In combination with Leistritz pharmaceutical extruders, the redesigned LMP 2.0 produces micro pellets in a continu-
ous process. The pellets are cooled off and transported in a circulated air stream. The handling of this device is very
convenient. For an effective pressure build up as well as a better melt distribution at the die, a melt pump can be easily
integrated. More homogeneous pellets are the result. The LMP 2.0 can be run with or without melt pump. The LMP 2.0
is available in two versions: for the extruder sizes ZSE 18 HP-PH and ZSE 27 HP-PH.

configuration of vacuum conveyor

according to process requirements

Technical Data:
LMP principle:
Drive water-cooled AC drive One or two cutting blades cut the dis-
Drive power 1.1 KW charged melt and catapult it into the cut-
ting chamber.
Cutting blades 1 - 2, flexible, stainless steel
Blade speed 0 - 3,000 rpm
Diameter of hole circle 50 mm/70 mm
Dimensions (L, W, H) 500 mm x 700 mm x 1,700 mm
700 mm x 1,250 mm x 1,400 mm
Extrusion height 1,050 mm

Data for LMP 18 2.0

17
Documentation, Validation
and Automation
Documentation and Validation
The validation of pharma extrusion lines within the scope of GMP requirements is inevitable in order to produce con-
stantly high-class products. With its qualification package, Leistritz offers design, installation and operational specifica-
tions for the GMP compliant extrusion lines including equipment and computer system (PLC SCADA and visualisation).
The package also contains conclusive quality control plans for FATs (Factory Acceptance Tests) and SATs (Site Accept-
ance Tests).

The great advantage: This qualification package simplifies and reduces the validation effort (for the customer) by refer-
ring to test results made by Leistritz during IQ (Installation Qualification) and OQ (Operation Qualification).

Automation
The main objective of Leistritz’ automation and control engineering is to integrate all common up- and downstream
aggregates necessary in pharma extrusion, in one visualization and operating unit (control of e.g. gravimetric feeder, the
start up of pelletizers or liquid feeders). All quality relevant parameters are displayed and recorded.

Consequently, the control unit plays a major role, because it reflects the process. Therefore, it is important to specify the
design and verify it in a very early project stage.

With a control unit, which meets the high standards of GAMP and 21 CFR Part 11, Leistritz offers a specifically developed
solution for the operation of extruder lines.

Macromatex S7 Pharma:
The main page shows an overview of the
whole extrusion line as well as the most im-
portant parameters.

18
Automation P H A R M A E X T R U S I O N

Macromatex S7 Pharma
S7 control unit as Human-Machine-Interface (HMI)

based on Microsoft Windows 7, iFix with iHistorian (GE Fanuc or Intellution) and
Microsoft SQL data base (MSDE)

Scope of function:
••• Operating and monitoring
••• Trend graphs with free configuration of groups
••• Recipe management
••• Start-up assistance (sequence)
••• Audit trail
••• Batch report function
••• Windows security und password administration
••• 21CFR11 and 4-eyes-principle as an option possible

Software documentation:
••• Hardware design specification
••• Software design specification
••• Alarm list
••• Interlock matrix
••• SPS assignment
••• MSR list with measuring range and entry limits
••• Disaster recovery manual
••• Operating manual

Basic Control
Standard control unit

••• IP 52 system of protection

••• Mounted on the machine frame (left in direction
of extrusion)
••• Operation and display devices:
• PPID temperature controllers (amount according to
processing length)
• On- / off-drive
• Screw speed - potentiometer with default setting
• Display of screw speed - digital
• Power consumption (torque) in % - digital
• Emergency switch off

Further operation and display devices can be integrated in the
control unit and/or control cabinet.
19
LEISTRITZ GROUP

LEISTRITZ
TURBOMASCHINEN TECHNIK GMBH
Turbine and Compressor Blades

LEISTRITZ
PUMPEN GMBH
Screw Pumps and Systems

LEISTRITZ
EXTRUSIONSTECHNIK GMBH
Extruders and Extrusion Lines

LEISTRITZ
PRODUKTIONSTECHNIK GMBH
Tubing Technology/Sheet Metal Forming,
Machine Tools, Tools

Partner for
Modern Technology

www.leistritz.com
LEISTRITZ EXTRUSIONSTECHNIK GMBH LEISTRITZ Machinery (Taicang) Co., Ltd. Leistritz Advanced
Markgrafenstr. 29-39 . D-90459 Nürnberg Shanghai Branch Technologies Corp. . BU Extrusion
Phone +49 (0) 911 / 43 06 - 240 Phone +86 21 6352 3268 Phone +1 908 685 2333
Fax +49 (0) 911 / 43 06 - 400 Fax +86 21 6352 3138 Fax +1 908 685 0247
eMail extruder@leistritz.de eMail sales@leistritz-china.cn eMail sales@alec-usa.com

LEISTRITZ France Extrusion LEISTRITZ Italia Estrusione LEISTRITZ SEA Pte Ltd.
Singapore office
Phone +33 (474) 250 893 Phone +39 0331 500 956
PH_V_10_GB / 23.12.14

Fax +33 (474) 250 864 Fax +39 0331 482 586 Phone +65 6569 3395
eMail extruderfr@leistritz.com eMail info@leistritz-italia.com Fax +65 6569 3396
eMail extruderasia@leistritz.com

refreshing extrusion technology