managing director a qbd approach to freeman technology ... · ifpac annual meeting continuous...

Event Name © Freeman Technology Ltd, 2014

A QbD Approach to IFPAC Annual Meeting

22nd January 2014 Continuous Tablet Manufacture

Tim Freeman Managing Director

Freeman Technology


Traditional Batch Process Flow for Tablet Manufacture


The traditional approach to tablet manufacture…

….required each process step to be validated and fixed, and quality would be tested for, retrospectively.

But, this requires all potential variables to be consistent, batch to batch, including raw material properties, if quality is to be assured.

However, most raw material specifications for powders are inadequate. They may list particle size distribution, density, water content and some chemical properties, but never particle shape, surface texture, surface energy, elasticity, or many other parameters that are likely to be important.

These variables all influence bulk powder properties like flow, adhesion, compressibility – therefore perhaps it is not surprising that batch to batch problems are often related to variation in raw materials.

RAW MATERIALS PROCESS PRODUCT


Process Flow for continuous tablet manufacture (wet and dry granulation)


QbD applied to Tablet Manufacture

In both batch and continuous, a QbD approach requires a detailed understanding of the material properties and processes employed.

The relationship between material properties and process conditions determines the critical quality attributes of the tablet.

COMPRESSION MILL GRANULATE FEED RAW MATERIAL

COATING MIX (Mg.St) DRY MIX DISPENSE




Specific Variables

Particle Size Particle Shape

Bulk Density Flowability

Particle Surface Properties

Water Content Composition

Malleability

Hopper geometry Material of

construction

Flow mode required (mass or funnel)

Volumetric throughput

Mass / volume

# of screws

Size Material of

Screw design

Construction

Water content Impeller speed

Fill Ratio Time

Screw speed

Temperature

Type Screen size

Media (ball)

Air velocity

Time

(fluid energy)

(Comil)

Speed Feeder type

Dwell time Comp force

Tool geometry

Control mode (force /position)

Type Shear Stress

Strain

Fill level

Material of construction

Residence time Air velocity

Agitation

Type

Air temp.

Residence time

Type Shear Stress

Strain

Fill level

Material of construction

Residence time

Temperature

Spray rate

Pan speed

Air flow




Typical Problems

Particle Size Particle Shape

Bulk Density Flowability

Particle Surface Properties

Water Content Composition

Malleability

Bridging

Sporadic flow

Segregation

Caking

Sporadic flow

Sticking

Agglomeration

Densification

Particle Attrition

Granules too weak / strong

Shape changes

Wrong size

charging Electrostatic

Poor blend

Particle

Wrong water content

Poor uniformity Variable

Sticking

Flaking

Blistering

uniformity

attrition

Electrostatic charging

Granule density too

high / low

Granule size too

large/ small

Particle attrition

Agglomeration

Poor blend

Particle uniformity

attrition

Electrostatic charging

Over blending

Blinding

Tablets too hard / soft

Weight variation too high

Poor content uniformity

Capping / lamination

thickness


What properties are important? Are the same properties important for each process? What attribute (or attributes) dictate(s) good performance in: -

Ø Dispensing from a hopper or IBC? Ø Feeding Ø Blending Ø Wet Granulation Ø Dry Granulation Ø Compression

It is unlikely that one material attribute will be responsible for good performance in every process

So, what knowledge is required?

Material Characteristics


A particle is discrete entity with a set of physical and chemical attributes. As an assembly, particles form powders, which are often defined with certain quality attributes, such as: -

Ø Particle Size (distribution?) Ø Bulk Density Ø Tapped Density Ø Moisture Content

Is that all we need to know to ensure consistent quality and good in-process performance through every process step?

Are we processing particles or powders?


Particle properties


Surface Texture


Particles are complex, and variable

Each particle possesses a set of physical and chemical properties

Ø Elasticity

Ø Plasticity

Ø Porosity

Ø Potential for electrostatic charge

Ø Hygroscopicity

Ø Hardness / Friability

Ø Amorphous content

Ø Size

Ø Shape

Ø Surface Texture

Ø Surface Area

Ø Density

Ø Cohesion

Ø Adhesion

Each will contribute to how the powder behaves as a bulk collection of particles


Powder Behaviour Includes…

Ø How it flows - into a die, out of a hopper, through a feeder or within a mixing process, etc. Flow properties are affected by how aerated or consolidated the powder is, and they may flow differently depending on flow rate.

Ø Compressibility – powders change density when subjected to consolidating stresses.

Ø Adhesion – may stick to containing equipment, or maybe retained within packaging (capsule / blister/ sachet).

Ø Permeability – how easily air can pass between particles. Important during high speed compression, and closed system processing.

Ø Powders are sensitive to electrostatic charge, causing poor flow, poor blend uniformity and sticking.

Ø A powder may change its characteristics if its moisture content increases. Some powders are hydrophobic, others hydrophilic.

Ø Particles may change size, shape and surface properties, if subjected to stress. Some are prone to attrition.

Powders have many behavioural characteristics and it’s these that determine their in-process performance and the quality of the finished product


Friction between particles

Mechanisms of particle interaction and powder flow / behaviour

High Resistance

Low Resistance


Mechanical Interlocking of Particles

Strong interlocking High force required for separation (and often breakage) of particles

Related to particle shape and stiffness


Mechanical Interlocking of particles

Weaker interlocking Lower force required for separation of particles


Liquid bridges between particles

Increased particle – particle adhesion


Cohesive, inter-particulate forces

Increased particle – particle attraction

Ø Van der Waals Ø Electrostatics


Gravitational forces

Gravity is often the only motivating force

F = mg

due to gravity “g” = acceleration


Ø Friction Ø Particle – Particle, Particle - Wall

Ø Mechanical Interlocking

Ø Adhesion / Liquid Bridges Ø Particle – Particle, Particle - Wall

Ø Cohesion Ø Van der Waals, Electrostatics, Covalent, Magnetic

Ø Gravity Ø Often the only motive force

All mechanisms will contribute to powder behaviour to some extent

Mechanisms of Particle Interaction and Powder Flow


Interparticulate forces (fn) are a function of: -

Ø Friction Ø Mechanical interlocking Ø Adhesion Ø Cohesion

The relationship between fn and mg depends on particle physical properties, but also the conditions imposed in the process environment

Ø When powder is in low stress state (dosing, die filling, low shear mixing), cohesive and adhesive forces are dominant in relation to powder behaviour

Ø When powder is consolidated (hopper, feeder, compression), mechanical friction and particle interlocking are most important. Cohesion still contributes to flow, but it’s effect is less significant


Powder required to flow under gravity.

Smooth flow rates and mass flow preferred.

Problems include blockages and channelling, leading to sporadic output (at best). Segregation may also occur.

Require suitable hopper half angle (α) and outlet diameter (B), for a given material of construction, to ensure good performance

Hopper & IBC discharging / dispensing

( )g

HBr

as1=

( ) bddpa -

--= -

sin2sin1cos

21

21


Wall Friction between powder and hopper wall

Properties required to predict flow behaviour in hoppers

Normal Stress (σ) s1

Shear Stress (τ)

sc

FF = sc

s1

Shear Properties of the powder

s t

Normal Stress (σ)

Shear Stress (t)

φ

tW

sW

φ = tan-1 sw

tW


Wall materials

Disk no. Material# Surface Finish Notes Ra value (μm) WFA (°)

1 SS 316 L Brushed 0.19 27.5 ± 0.2

2 SS 316 L Satin finished 0.28 28.8 ± 0.4

3 SS 316 L Electropolished 0.35 31.5 ± 0.0

4 SS 316 L Glass pearl treated 0.45 29.0 ± 0.1

5 SS 316 L Ground, fine 0.61 29.6 ± 0.1

6 SS 316 L Brushed 1.2 31.0 ± 0.3

7 SS316L Rhenolease Conductive, PTFE based 1.85 24.8 ± 0.3

8 SS 316 L Titanium nitride N/A 32.1 ± 0.1

9 SS 316 L CrNi-Coating N/A 34.8 ± 0.1

10 SS 316 L NEDOX SF2 coating Nickel / polymer 0.7 28.1 ± 0.0

11 Aluminium Tufram coating Anodized, Polymer 0.91 27.6 ± 0.3

12 Aluminium Hard slide HSS Anodized, Polymer N/A 27.8 ± 0.0

13 PEEK Milled Polyetheretherketone 2.39 24.3 ± 0.4

14 POM-C Milled Polyoxymethylene copolymer 0.06 13.0 ± 0.1

15 PETP Milled Polyethylene terephthalate 2.1 19.5 ± 0.3

n=3 for all tests WFA values measured for Lactose (Respitose)


Test Data for Lactose (Respitose) W

all F

rictio

n Te

sts

Shea

r Cel

l Co

mpr

essib

ility


Effect of wall friction on hopper half angle

0

5

10

15

20

25

30

35

disk1

4dis

k15

disk7

disk1

3dis

k11dis

k12

disk1

disk1

0dis

k2dis

k4dis

k5dis

k6dis

k3dis

k8dis

k9

Hop

per H

alf A

ngle

(α),

degr

eeHopper Half Angle (α)

low WFA ¾¾® high WFA

`


Wet Granulation

Ø Converts fine powders into larger granules. Benefits include: -

Ø Improved flow

Ø Reduced segregation

Ø Better content uniformity

Ø Improved compression properties

Ø Reduced dusting

Ø Granulation via high shear can be a batch or a continuous process

Ø In both cases, water is introduced whilst the powder is sheared

Ø Process variables: -

Ø Amount of water added

Ø Screw speed (continuous)

Ø Powder feed rate (cont.)

Ø Impeller and chopper speed (batch)

Ø Granulation time (batch)

Ø Water addition rate (batch)


Purpose of this Study

To investigate the change in material properties of both wet

and dry granules as a function of a variation in formulation

and process configuration…..

……and to relate these material properties to tablet

characteristics


GEA ConsiGmaTM 1 Continuous High Shear Wet Granulator and Drying

System

(photo courtesy of GEA Pharma Systems)

Process Variables (granulator)

Ø Water content

Ø Screw Speed

Ø Powder Feed Rate

Ø Barrel Temperature

Process Variables (dryer)

Ø Time

Ø Air Velocity

Ø Air Temperature

(Can also measure online NIR using Lighthouse Probe)


FORMULATION

Two types of formulation were considered in this study: -

1) APAP – 90% API

2) DCP – 90% API

PROCESS VARIABLES

Ø Water content was varied to provide granules with different properties, from under-

granulated to over-granulated (as determined visually). Different ranges were required for

the two different formulations (APAP 8 – 17%, DCP 15 – 25%)

Ø Screw speed was varied to investigate it’s influence on granule properties. The settings

chosen were 450, 600 and 750rpm.

Ø Feed rate of dry powder feeder was also varied for a limited number of samples. Settings

were reduced from 25kg/hr (standard, and equivalent to ConsiGma 25) , to 20 and 15kg/hr.


Granules were characterized using a Powder Rheometer

Blade

Sample in glass Vessel (typ. 10ml to 160ml)


Force

Torque

The Powder Rheometer measures the resistance that the powder, or granules exert on the blade, as the blade forces its way through the sample.

This resistance is expressed as “Flow Energy”, which is calculated from the direct measurements of Torque and Force

(Powder not shown in either image)


Flow Energy is influenced by (as we saw earlier): -

Ø Friction between particles / granules Ø Mechanical interlocking of particles / granules Ø Strength of capillary bonds Ø Strength of cohesive forces

In high shear wet granulation, the addition of water and work (shear) results in larger, denser, more adhesive granules. This means that more water and more work input results in higher flow energy as granules are harder to move (denser, larger, stickier and less compressible).


Ø Blends were mixed and loaded into the feed hopper

Ø Blends were characterised in their dry state using a range of rheometric tests

Ø Wet granules were collected directly at the outlet of the granulator and bagged,

before being measured on the rheometer

Ø Granule stability, with respect to time, was also investigated (although data not

included in this presentation)

Ø Water content, screw speed and feed rate of dry powder blend into granulator was

varied and granule properties measured

Ø Wet granules were dried on the ConsiGma drier, and then tested on the rheometer

Ø For wet granule characterisation, Basic Flowability Energy tests were used (standard

approach), whilst for dry blends (pre-gran) and dried, milled and lubricated

granules, additional Powder Rheometer methods, such as Stability, Variable Flow

Rate, Aeration and Shear Cell, were employed.


Changes in Bulk Material Flow Properties of Wet Granules as a function of Water Content & Screw Speed


Data for wet granules of DCP formulation showing how granules of similar properties can be manufactured using different process settings


Data showing how the flow properties of granules from each “Condition” change as they move through the process (wet, dry, milled, lubricated)


GEA Modul™ S Tablet Press

Tooling 7mm Round

Pre-Compression Upper Position 2.15mm

Pre-Compression Lower Position 4.82mm

Compression Upper Position 2.29mm

Compression Lower Position 4.29mm

(photo courtesy of GEA Pharma Systems)


Relationship between flow properties of wet granules and tablet hardness for each condition


Relationship between flow properties of dry granules and tablet hardness for each condition


Relationship between flow properties of milled granules and tablet hardness for each condition


Relationship between flow properties of lubricated granules and tablet hardness for each condition


Data showing the strong relationship between granule properties and a critical quality attribute of the tablet (hardness) for each type of granule (wet, dry, milled, lubricated)

Condition 1 & 2

Condition 3 & 4


Particle Size & Shape Powder Flow & Powder

Behaviour

Malvern Morphology G3

Freeman FT4


Overlay of the HS Circularity distributions Overlay of volume based Size distributions

Selection of particle images for FlowLac 100, Inhalac 230 and SpheroLac 100 (l to r))

Three grades of lactose


Compressibility – percentage by which the bulk density has changed – as a function of

normal stress

Total Flow Energy as a function of repeated tests & flow rate change

Effect of Size

Effect of Shape

Effect of Size

Effect of Shape


Conclusions 1. Powders (wet or dry) are complex materials.

2. The multiple process steps in a continuous tableting line subject raw materials and intermediates to a range of different environments.

3. Each process operation provides the opportunity to adjust settings in order to improve process efficiency and / or to alter the properties of the material leaving that stage of the process.

4. With sufficient understanding of the relevant material properties and critical process parameters, it is possible to employ a QbD approach to continuous tablet manufacture.

5. Powders have many characteristics, so single number characterization, or even a single technique is not going to thoroughly describe powder behaviour in every process – a multivariate analysis is required.

6. Each stage of the process, from initial feeding to final compression needs to function efficiently in order that product of the desired properties can be can be manufactured. Problems at any stage have the potential to translate downstream, ultimately affecting tablet properties.


Thank you for your attention

For further information, please visit us at

Booth #202

or

www.freemantech.co.uk

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