AAPS WORKSHOP

SEPTEMBER 11 – 12, 2006

Quality By Design
Implementation

Dominic Ventura, Ph.D.

1
 Quality by Design
The Desired State
• Product quality and performance achieved and
assured by design of effective and efficient
manufacturing processes

• Product specifications based on mechanistic

understanding of how formulation and process
factors impact product performance

• An ability to affect continuous improvement and

continuous “real time” assurance of quality

2
 Quality by Design
Mitigating Risk in Pharmaceutical Development
A process is well understood when:

• All critical sources of variability are identified and explained

• Variability is managed by the process, and,
• Product quality attributes can be accurately and reliably
PREDICTED over the DESIGN SPACE established for
materials used, process parameters, manufacturing,
environmental and other conditions.

Guidance for Industry: PAT – A Framework for Innovative Pharmaceutical

Development, Manufacturing and Quality Assurance,
page 6

3
 Quality by Design?
Product Development Knowledge (Public Databases or in Submissions)

Level of Sophistication Details Resolved

1st
Principles
HIGH HIGH
MECHANISTIC
MODELS

EMPIRICAL
MODELS MEDIUM
MEDIUM
HEURISTIC RULES

LOW (HISTORICAL) DATA DERIVED FROM LOW

TRIAL-N-ERROR EXPERIMENTATION 4
Dr. Ajaz Hussein
 Quality by Design
Performance of a Solids Processing Units

Performance
of a Unit

Bulk Mechanical Forces Acting

Properties on Particles
Angle of repose Adhesion forces
Unconfined yield stress Impact forces

Material Particle Equipment Operating

Characteristics Attributes Design Conditions
Hamaker constant PSD Geometry Speed of moving parts
Dielectric constant Shape Constituent parts Temperature
Young’s modulus Composition Material properties Humidity
5
AIChE Journal 47: 107-125 (2001) Dr. Ajaz Hussein
 Quality by Design
The Way Forward
Reduce UNCERTAINTY Control VARIABILITY

Uncertainty – the inability to determine or • Identify and control all sources of

the ambiguity in the true state of a system variability
caused by a combination of variability and
incomplete knowledge (ICH Q9) • Raw materials
• Process
• Environmental
• Manage variability through the
process

• Mitigate risk
• Knowledge transfer to manufacturing and regulatory
bodies
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 MANUFACTURING
EXCELLENCE

L
A QbD
U Learning Before Doing
LEVELS
N
OF Learning By Doing
MANUFACTURING C
EXCELLENCE H Continuous Improvement

TIME
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 Where To Start
 Dosage Form Considerations
Extended Release vs. Immediate?
 Clinical Considerations
Established IVIVc
 Drug Product Attributes
Low Dose?
 Drug Substance Attributes
Stable Polymorph, hydroscopic?

8
 Basic Concept of BCS

Drug Dissolved Absorbed

Product Drug drug
k kp
d

kd = dissolution rate
• function of drug solubility and drug
product quality attributes

kp = permeability rate
• major function of API structure
• minor dependence on salt form and
excipients. 9
 DEFINITIONS
 Critical Quality Attributes
Purity
Potency
Bioavailability
 Critical Process Parameters
- Critical To Quality Attributes
(API, DP properties that can affect
CQA’s)
- Key Process Variables
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 Drug
Release
Quality Attributes Rate
Of Drug Product Disintegration,
Erosion and Granule
Dissolution

Swelling/
API
Porosity Hardness Wetting Water Solubilization
Penetration
(rate/extent)

API Form Selection

DP Excipient Selection, DP Process Selection
(Salt, Polymorph, Particle
API Form Selection, API Process Selection Size)

Features of “Quality by Design”: doing things consciously* 11

*A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification
System, R. Reed
RISK MANAGEMENT

Risk Benefit

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 Quality Risk Assessment (QRA)

• FMEA: Risk scores based on

probability, severity, and detectability
• Risk Prioritization Matrix
• Quality Function Deployment
• Fish bone or Ishikawa diagram
• Pareto Chart

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ELEMENTS OF A SUCCESSFUL QbD
PROGRAM

Robust Product

Process
Formulation
& Materials
Equipment 14
Risk Prioritization Matrix

QUALITY
ATTRIBUTE
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 Tablet Hardness
Basic risk facilitation methods
Compression
Blending Raw Material
Tooling Cam selection

Surface Discharge rate Fill Weight Feed frame setting

Mg. Stea TALC

Material addition Feeder speed

Fill Vol. Order of ddn.

HPMC API Press speed Pre & Post Compression

Blend time
Blend rpm
Hardness of Tablet
Storage
(Friability)
Discharge Roll force Roll Gap
Transport
Moisture PSD Porosity (den)
•Cause Effect
Diagram
Humidity Temp.
Ribbon strength for Tablet
Hardness
Material
Transfer Environmental Roller Compaction

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 0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
HPMC K 100 CR

POROSITY

PRESS SPEED

COMPRESSION
FORCE

FEEDER SPEED

LUBE TIME

PSD OF INTRA-
GRANULAR BLEND

API PARTICLE SIZE

Inputs

BLEND TIME

PRE-COMP FORCE

EXCIPIENT
PARTICLE SIZE
Pareto Chart: Relative Importance of

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 DEFINITIONS
Design Space  Clinical Relevance

Control Space  Process Capability

Control Strategy  Change Control

Continuous Improvement
Regulatory Considerations

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 Robust Manufacturing Processes
Process and Control Parameters
Process Parameter Attributes
Raw Material Hypromellose Viscosity, Methoxyl,
Attributes hydroxypropyl content,
Particle size
Bin Blend Blending time/end point Blend Uniformity
Roll force Ribbon Attributes
Roll gap • Porosity
Roller Compaction Roll speed
Granule Attributes
Feed screw rate
• psd
Milling conditions

Bin Blend
Blend time/end point Blend Uniformity
Compression force Tablet Attributes
• hardness
Compression Press speed
Feeder speed
Pan Speed Appearance,
Film Coating EEF Tablet weight gain
Clinical relevance 19
 Critical & Non Critical Parameters
Control Space/Design Space (Example)
Table 3.1-6: Roller Compaction

Critical / Non-
Unit Operation Critical Control Space Design Space Key Attributes
Parameter

Roller Compaction
-Roll Gap Table 3.1-7 for Table 3.1-7 for 100
-Roll Force Critical 100 mg and mg and
Critical Table 3.1-8 for Table 3.1-8 for 200
200 mg mg

-Feed Screw Speed Non-Critical Particle Size

Not Applicable Not Applicable a
Distribution
(in‑line)
Roll Speed Non-Critical 7-9 6-10 Tablet Hardness

Dissolution
Milling
-Pre-granulator Non-Critical Adjust rpm to Adjust rpm to
-Fine Screen Non-Critical maintain maintain throughput
granulator throughput

a. Controlled by Roll Gap

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 Quality by Design - Tablet Development
Scale-up Parameters for Roller Compaction

Pilot-scale (design space) Manufacturing scale (predicted

design space)

2.2 mm 3.8 mm

Scale
up

Roll
gap
Roll
gap

52.11% 52.11%

m oly
m ly

1.8 mm
Po

3.0 mm

P
er
er

40% 40%
Roll Roll
force force
45 bar 65 bar 55 bar 65 bar

Polymer conc. 40-52.1% Polymer conc. 40-52.1%

Roll Gap 1.8 –2.2 mm Roll Gap 3.0-3.8 mm
Roll force 45-65 bar Roll force 55-65 bar

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 Quality by Design - Tablet Development
Confirmation of Design Space at Mfrg Scale
4.0 mm

Failed batch
3.8 mm Good batch
3.8
mm 3.6 mm

3.4 mm 70 bar
Roll
gap

52.1%
3.2 mm
er
m
ly
3.0
Po

mm • Batches Manufactured
40.0%
2.8 mm Outside the of the Roll
Roll Compaction Design
55 bar force 65 bar Space Fail Tablet
Compression
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Control/Design Space – Critical Process
Parameters
• Critical Process Parameters (CPP) identified using a risk analysis
investigated extensively using a DOE.
• Design Space
– Established on the basis of the DOE and experience during
manufacture of clinical/registration batches
– In certain cases where response of critical quality attribute
studied/investigated was insignificant, extrapolation was used to
expand/establish design space
• Control Space
– Subset of design space established on the basis of process
capability, prior knowledge
• Intent is to stay within the control space during commercial
manufacturing
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 Control/Design Space – Non-
Critical Process Parameters
• Non-Critical Process Parameters – those identified as low
risk which lead to low probability of product failure
• Design Space
– Established on the basis of range studies (in some cases
DOE’s) and manufacturing experience at various scales
• Control Space
– Subset of design space established on the basis of process
capability, prior knowledge
• Intent is to stay within the control space during commercial
manufacturing
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 Design Space and Control Space
Design Space
Multi-dimensional space that encompasses combinations of product
design, manufacturing process design, critical manufacturing process
parameters and component attributes that provide assurance of suitable
product quality and performance
Control Space
Multi-dimensional space that encompasses process operating
parameters and component quality measurements that assure process or
product quality. It is a subset of the design space
Control Strategy
Strategy/Methodology to mitigate risks associated with the batch when
the critical and non-critical process parameters fall outside the control
space but within the design space

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Control strategy - Critical Process Parameters
• HPMC
– Single point dissolution within control space
– Dissolution profile when HPMC outside control space but
within design space is used
• Roll Gap and Roll Force
– Single point dissolution within control space
– Dissolution profile when roll gap and roll force are outside
control space but within design space is used
• Impact of product being manufactured outside control space and
within design space will be assessed through the Event Report
Forms
• If control space is revised based on experience during
manufacturing, will manage the change through the plant change
control system and notify the agency via the annual report
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 Decision Tree for Batch Disposition Based on
 
 
 
Control/Design Space – CPP’s
 
 
  Are all CPPs Are all CPPs Full
within their NO within their NO
  Investigation
control design
  according to
  spaces? spaces?
plant systems
 
 
  YES Event Report Forms will be
YES
  generated when CPP’s are outside
  control space
  Log sample for Log sample for but within the design space
  regular (single full (multi-point
  point) dissolution dissolution)
  testing in LIMS testing in LIMS
  Track and Trend
  Events to monitor
  type and number of
  Evaluate
occurrences
  data for
  dispositi
  on
 

React and study

Note: Decision for testing is based when number of
on data entry captured in MBR where occurrences indicate
the control and design space values out of trends
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will be identified
 Decision Tree for Batch Disposition Based
 
on Control/Design Space – Non-CPP’s
 
 
 
  Are all non- Generate an
  CPPs within NO Event
  their control Report
  spaces? Form
 
 
  YES
 
  Track and Trend
Impact of Event Events to monitor
  No action, and action
  type and number of
proceed as assessed by QA
  occurrences
usual
 
 
 
 
  Batch
  disposition
  React and study
  when number of
  occurrences indicate
out of trends

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 Closing Statement
• Lead or Bleed!

• Just Do It!

• The future ain’t what it use to be!

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