The Changing Face of Product and Process Development in the QbD Era

James Kraunsoe AstraZeneca Product Development UK/US

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Presentation outline
Designing in R&D a manufacturing process for Operations
What do Manufacturing require? Illustrate approach taken by R&D
Use of appropriate pp p tools How to work smarter

Case studies
Examples for tablet products

Summary and reflections

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Requirements of manufacturing
Operations driven by cost pressures and need to reduce waste
This requires development of Lean/6 Sigma processes and supply chain

Operations have 3 key requirements of R&D

Robust and capable processes
Defined eg, CpK for CQAs and controls >1.67

Operational p flexibility y
Equipment type, scale, operating ranges Flexible or reduced control strategy
Exemplify

Ability to facilitate innovation and to tolerate variation

Use of newer more innovative technology
Eg, Eg via a site transfer

Natural variation eg, raw materials including API

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Development Tools: Paper based

Define Quality Target Pharmaceutical Profile
Define critical quality attributes cf ICHQ8
Target for for a safe, efficacious and quality product

Define process targets that define success wrt manufacturabilty

Process metrics eg, Cpks

Define Quality Risk Managment

Reflect prod product ct and prior kno knowledge ledge (or e experience) perience) Prioritise development activities Identifies sources of variation and develop the understanding to adapt
Impact of equipment scale and type Changes to ra raw material grades grades, s suppliers ppliers
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Development Tools: Practical

7

8 11 6

12

10 9

Design of Experiments studies

Prioritise variables by QRA Perform at small, pilot and large scale
Evaluate formulation/materials and process
Water Amount (%w/w) Time (min)

5 1

2 3 8 5

Impeller tip speed (m/s)

Examples
IR tablets Wet granulation
Example of an evolving design
1.25
Mg stearate A Amount t (%w/w) No of revs

Milling
Reduced factorial design
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100

0.75 45 Low
Milled granule SA (cm2/g)

High

Development Tools: Practical

Product and process characterisation
Imaging I i NMR of ft tablets bl t
Dissolution of modified release tablet
Understanding the impact of raw materials and/or process on the dissolution rate of polymers

Time

Presence of inclusions in immediate release tablets

66 64 High cohesion Low adhesion
Avicel PH102 Avicel PH101
L-HPC LH22

Understanding how material properties affect bulk flow of powders

90 - w ()

Flow characterisation

62 60 58 56 54 52 50

Emocel 50

Prosolv 90HD

Good flow properties

L-HPC LH11

HPC-LF

Poor flow properties

Low cohesion High adhesion

FFc (-)

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Development tools - Practical

Process Analytical Technologies
Particle size during granulation
In-line use FBRM
Monitoring of fine and larger particles with increasing water amount t and d time ti
1-21 um 21-100 um Median 100-1000 um

Time

Granule moiture content during drying

Single g variable monitoring g against g known moisture peak
VAR_337

0.70

In-line NIR

0.60

0.50

0.40

Objective: To confirm process is proceeding as intended

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Manufacturing: Operational flexibility

Roller compaction model: Scale independence
Empirical (from DOE) vs mechanisitic (from theory)
Ribbon Porosity: 20 25% Throughput: > 17 kg/h

Theoretical operating g region g Raw material characterisation Roller compaction model

Experimental operating space: Full scale experiments Intermediate characterisation

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Manufacturing: Managing variability

In-process Granule Size Control for IR tablet intermediate
Combined Feed Forward/Feed Back Loop
STAGE 2: WET GRANULATION STAGE 3: WET MASS DELUMPING STAGE 4: DRYING STAGE 5: DRY MILLING

Change water quantity to x for next batch

Is the granule size distribution too fine? N Y

Granule Size Distribution Measurement

Wet Granulation model

Comil model: C Current t parameters acceptable?

Change Comil Parameters

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Summary and reflections

Manufacturing is a customer
R&D need to know what is important
Output from R&D is choice or flexibility

Operations need to understand why there are constraints

Being smarter about how R&D deliver

Using g Quality y Risk Management g effectively y
Prioritise and rationalise

Maximising opportunities to collect data

Using PATs

Minimising number of experiments

Using DOEs in conjunction with all manufactures Use of models to understand and predict relationships
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