Date post: | 10-Apr-2018 |
Category: |
Documents |
Upload: | hemanth0207 |
View: | 233 times |
Download: | 0 times |
of 29
8/8/2019 ventura (1)
1/29
1
AAPS WORKSHOP
SEPTEMBER 11 12, 2006
Quality By Design
Implementation
Dominic Ventura, Ph.D.
8/8/2019 ventura (1)
2/29
2
Quality by DesignThe Desired State
Product quality and performance achieved andassured by design of effective and efficientmanufacturing processes
Product specifications based on mechanisticunderstanding of how formulation and processfactors impact product performance
An ability to affect continuous improvement andcontinuous real time assurance of quality
8/8/2019 ventura (1)
3/29
3
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 reliablyPREDICTED over the DESIGN SPACE established formaterials used, process parameters, manufacturing,environmental and other conditions.
Guidance for Industry: PAT A Framework for Innovative PharmaceuticalDevelopment, Manufacturing and Quality Assurance,page 6
8/8/2019 ventura (1)
4/29
4
Quality by Design?Product Development Knowledge (Public Databases or in Submissions)
Level of Sophistication
HIGH
MEDIUM
LOW
Details Resolve
HIG
MEDIU
LO(HISTORICAL) DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
HEURISTIC RULES
EMPIRICALMODELS
MECHANISTICMODELS
1stPrinciples
Dr. Ajaz Hussein
8/8/2019 ventura (1)
5/29
5
Material
CharacteristicsHamaker constant
Dielectric constant
Youngs modulus
Particle
AttributesPSD
Shape
Composition
Equipment
DesignGeometry
Constituent parts
Material properties
Operating
ConditionsSpeed of moving parts
Temperature
Humidity
Bulk MechanicalPropertiesAngle of repose
Unconfined yield stress
Forces Actingon Particles
Adhesion forces
Impact forces
Performance
of a Unit
Dr. Ajaz HusseinAIChE Journal 47: 107-125 (2001)
Quality by Design
Performance of a Solids Processing Units
8/8/2019 ventura (1)
6/29
6
Quality by DesignThe Way Forward
Identify and control all sources of
variability
Raw materials
Process
Environmental
Manage variability through the
process
Uncertainty the inability to determine or
the ambiguity in the true state of a system
caused by a combination of variability and
incomplete knowledge (ICH Q9)
Reduce UNCERTAINTY Control VARIABILITY
Mitigate risk
Knowledge transfer to manufacturing and regulatorybodies
8/8/2019 ventura (1)
7/29
7
MANUFACTURING
EXCELLENCE
LEVELS
OF
MANUFACTURING
EXCELLENCE
TIME
L
AU
N
C
H
Learning Before Doing
Learning By Doing
QbD
Continuous Improvement
8/8/2019 ventura (1)
8/29
8
Where To Start
Dosage Form Considerations
Extended Release vs. Immediate?
Clinical Considerations
Established IVIVcDrug Product Attributes
Low Dose?
Drug Substance Attributes
Stable Polymorph, hydroscopic?
8/8/2019 ventura (1)
9/29
9
Basic Concept of BCS
Drug
Product
Absorbed
drug
Dissolved
Drugkd
kp
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.
8/8/2019 ventura (1)
10/29
10
DEFINITIONS
Critical Quality AttributesPurity
Potency
BioavailabilityCritical Process Parameters
- Critical To Quality Attributes
(API, DP properties that can affect
CQAs)
- Key Process Variables
8/8/2019 ventura (1)
11/29
11
DrugDrug
ReleaseRelease
RateRate
Disintegration,Disintegration,
Erosion and GranuleErosion and Granule
DissolutionDissolution
APIAPISolubilizationSolubilization
(rate/extent)(rate/extent)
PorosityPorosity
APIAPI Form SelectionForm Selection
(Salt, Polymorph, Particle(Salt, Polymorph, Particle
Size)Size)
HardnessHardness WettingWetting
Swelling/Swelling/
WaterWater
PenetrationPenetration
DP Excipient Selection, DP Process SelectionDP Excipient Selection, DP Process Selection
API Form Selection, API Process SelectionAPI Form Selection, API Process Selection
Quality AttributesQuality Attributes
Of Drug ProductOf Drug Product
Features of Quality by Design: doing things consciously*Features of Quality by Design: doing things consciously*
*A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification*A Quality by Design Approach to Dissolution Based on the Biopharmaceutical Classification
System, R. ReedSystem, R. Reed
8/8/2019 ventura (1)
12/29
12
RISK MANAGEMENT
Risk Benefit
8/8/2019 ventura (1)
13/29
13
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
8/8/2019 ventura (1)
14/29
14
ELEMENTS OF A SUCCESSFUL QbD
PROGRAM
Robust Product
Process
Formulation
& Materials
Equipment
8/8/2019 ventura (1)
15/29
15
Risk Prioritization Matrix
QUALITYATTRIBUT
8/8/2019 ventura (1)
16/29
16
Tablet Hardness
Basic risk facilitation methods
Cause EffectDiagram
for Tablet
Hardness
Compression
Roller Compaction
Raw MaterialBlending
EnvironmentalMaterial
Transfer
Hardness of Tablet
(Friability)
Pre & Post CompressionPress speed
Feeder speedMaterial addition
Feed frame settingFill Weight
Cam selectionTooling
Roll GapRoll force
Porosity (den)PSD
Ribbon strength
APIHPMC
TALCMg. Stea
Temp.Humidity
Blend time
Blend rpm
Order ofddn.Fill Vol.
Discharge rateSurface
DischargeStorage
MoistureTransport
8/8/2019 ventura (1)
17/29
17
Pareto Chart: Relative Importance of
Inputs
0.00%
2.00%
4.00%
6.00%
8.00%
10.00%
12.00%
14.00%
HPM
C
K100CR
POROSITY
PRESSSPEED
CO
MPRESSION
FORCE
FE
EDER
SPEED
LUBETIME
PSD
OFINTRA-
GRANU
LAR
BLEND
APIPARTICLESIZE
BLEND
TIME
PRE-C
OMPFORCE
EXCIPIENT
PA
RTICLESIZE
8/8/2019 ventura (1)
18/29
18
DEFINITIONS
Design Space Clinical Relevance
Control Space Process Capability
Control Strategy Change Control
Continuous Improvement
Regulatory Considerations
8/8/2019 ventura (1)
19/29
19
Robust Manufacturing Processes
Process and Control Parameters
Clinical relevance
Ribbon Attributes
Porosity
Process Parameter Attributes
Blending time/end point
Roll force
Roll gap
Roll speedFeed screw rate
Milling conditions
Blend time/end point
Compression forcePress speed
Feeder speed
Granule Attributes
psd
Tablet Attributes hardness
Bin Blend
Roller Compaction
Bin Blend
Compression
Film Coating
Raw MaterialAttributes
Hypromellose Viscosity, Methoxyl,hydroxypropyl content,
Particle size
Blend Uniformity
Blend Uniformity
Pan Speed
EEF
Appearance,
Tablet weight gain
8/8/2019 ventura (1)
20/29
20
Critical & Non Critical Parameters
Control Space/Design Space (Example)
Table 3.1-6: Roller Compaction
Unit Operation
Critical / Non-
Critical
Parameter
Control Space Design Space Key Attributes
Roller Compaction
-Roll Gap
-Roll Force
CriticalCritical
Table 3.1-7 for
100 mg andTable 3.1-8 for
200 mg
Table 3.1-7 for 100
mg andTable 3.1-8 for 200
mg
Particle Size
Distribution
(in line)
Tablet Hardness
Dissolution
-Feed Screw Speed Non-Critical
Not Applicable Not Applicablea
Roll Speed Non-Critical7-9 6-10
Milling
-Pre-granulator
-Fine Screen
granulator
Non-Critical
Non-Critical
Adjust rpm to
maintain
throughput
Adjust rpm to
maintain throughput
a. Controlled by Roll Gap
8/8/2019 ventura (1)
21/29
21
52.11%
Polymer conc. 40-52.1%
Roll Gap 1.8 2.2 mm
Roll force 45-65 bar
Polymer conc. 40-52.1%
Roll Gap 3.0-3.8 mm
Roll force 55-65 bar
Poly
mer
Roll
force
R
oll
g
ap
40%
55 bar 65 bar
3.0 mm
3.8 mm
40%
52.11%
Scale
up
Poly
mer
Roll
force
R
oll
gap
45 bar 65 bar
1.8 mm
2.2 mm
Pilot-scale (design space) Manufacturing scale (predicted
design space)
Quality by Design -Tablet DevelopmentScale-up Parameters for Roller Compaction
8/8/2019 ventura (1)
22/29
22
Quality by Design - Tablet DevelopmentConfirmation of Design Space at Mfrg Scale
Poly
mer
Roll
force
Roll
gap
52.1%
40.0%
55 bar 65 bar
3.0
mm
3.8
mm
4.0 mm
2.8 mm
3.2 mm
3.4 mm
3.6 mm
3.8 mm
70 bar
Failed batch
Good batch
Batches ManufacturedOutside the of the RollCompaction DesignSpace Fail TabletCompression
8/8/2019 ventura (1)
23/29
23
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 batchesIn certain cases where response of critical quality attribute
studied/investigated was insignificant, extrapolation was used toexpand/establish design space
Control SpaceSubset of design space established on the basis of processcapability, prior knowledge
Intent is to stay within the control space during commercialmanufacturing
8/8/2019 ventura (1)
24/29
24
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
DOEs) 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
8/8/2019 ventura (1)
25/29
25
Design Space and Control Space
Design SpaceMulti-dimensional space that encompasses combinations of productdesign, manufacturing process design, critical manufacturing processparameters and component attributes that provide assurance of suitableproduct quality and performance
Control SpaceMulti-dimensional space that encompasses process operatingparameters and component quality measurements that assure process orproduct quality. It is a subset of the design space
Control Strategy
Strategy/Methodology to mitigate risks associated with the batch whenthe critical and non-critical process parameters fall outside the controlspace butwithin the design space
8/8/2019 ventura (1)
26/29
26
Control strategy - Critical Process Parameters
HPMC
Single point dissolution within control space
Dissolution profile when HPMC outside control space butwithin design space is used
Roll Gap and Roll Force
Single point dissolution within control spaceDissolution 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 ReportForms
If control space is revised based on experience duringmanufacturing, will manage the change through the plant changecontrol system and notify the agency via the annual report
8/8/2019 ventura (1)
27/29
i i f i i i
8/8/2019 ventura (1)
28/29
28
Decision Tree for Batch Disposition Based
on Control/Design Space Non-CPPs
Are all non-CPPs withintheir control
spaces?
Generate anEventReportForm
NO
YES
Batch
disposition
No action,proceed as
usual
Impact of Eventand action
assessed by QA
Track and TrendEvents to monitor
type and number ofoccurrences
React and studywhen number of
occurrences indicateout of trends
8/8/2019 ventura (1)
29/29
29
Closing Statement
Lead or Bleed!
Just Do It!
The future aint what it use to be!