Académique Documents
Professionnel Documents
Culture Documents
Objectives
1
8/12/2011
Objectives
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3
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4
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5
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Objectives
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Marketing Regulatory
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Multiple Definitions
8
8/12/2011
Container Closure HDPE bottle with Child Resistant (CR)
System Caps Needed for commercial reasons
Example MR tablet provides initial
Biphasic release of the drug, initial plasma concentrations through the
rapid release followed by sustained first two hours that provide for a
release of dose. Fasting study and fed clinically significant therapeutic
study 90% confidence interval of the effect. Sustained release phase
Dissolution/ PK parameters AUC0‐2, AUC2‐24, designed to maintain plasma
Pharmacokinetic Profile AUC0‐∞, and Cmax should fall within concentrations for maintenance of
Requirements BE limits
BE limits. therapeutic effect
therapeutic effect.
Drug Product Quality
Attributes* See CQAs
At least 24‐month shelf life at room
Stability temperature Needed for commercial reasons
A scored tablet can be divided into
two 5mg tablets. Taken without Pharmaceutical equivalence
Administration regard to food (no food effect). requirement
*Appearance, ID, Assay, CU, Degradation products/residual solvents, Dissolution, Microbial Limits
Yu, Understanding Pharmaceutical QbD presentation
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8/12/2011
Similar in size and shape to
Appearance RLD, scored as RLD Yes
Identification Positive for drug substance Z
Positive for drug substance Z No
Assay 95.0 to 105.0% of label claim Yes
Complies with harmonized
requirements for uniformity of
Content dosage units (both whole and
Uniformity half tablet) Yes
NMT qualification threshold for
specified impurities, NMT ID
Degradation threshold per ICH QB3 (R2) for
Product/Residual un‐ID'd impurities, conform to
Solvent USP 467 No
Must provide rapid initial
Must provide rapid initial
release followed by sustained
release (specified apparatus
and pH buffers), similar release
for whole and half tablets,
alcohol induced dumping
Drug Release comparable to RLD Yes
*Critical Quality Attributes (CQAs) are those that can be potentially impacted by formulation and
manufacturing processes.
10
8/12/2011
Time
Time Hardness
Excipients Batch Size
API Pressure
Tablet Speed
Yrs. Experience
Sampling
Training
Method
Personnel Analytical
11
8/12/2011
Process
Process: Manufacturing process such as blending, compression,
wet granulation, etc.
Intermediate
Intermediate: In-process material such as a powder blend,
uncoated
d tablet,
bl extrudate,
d etc.
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8/12/2011
Process Variables
•Raw material grades
butes
Process Attributes: p
Critical Outputs:
Process Attrib
•In-process material •Critical process attributes
attributes created by that act as inputs to the
process next unit operation
•Process equipment
measurements (dependent
variables)
Weight Gain
of Rotations
Fill Volume
Compresssion Force
nal Speed
Order off Addition
g Design
Press Speed
Atomization
Sprayy Rate
Product Te
Coating W
Blender F
Tooling
Rotation
Number o
ntegration
Uniformity
Content
Tablet Thickness
niformity
ardness
API Unifformity
Weight
ution
ution
Moisture C
Tablet W
Dissolu
Dissolu
Tablet Disin
Tablet Ha
Excipient U
Visual Un
13
8/12/2011
Class Exercise
` Divide room into groups of 3 to 5
` Select one process mapping tool
` 20 minutes to complete
` Discuss what information was gathered with each
tool
14
8/12/2011
4
4 8 12 16 20 Very High 4 Critical quality attributes cannot be met
High 3 Critical quality attributes may not be met
2 2 4 6 8 10
1 1 2 3 4 5
1 2 3 4 5
Probability
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8/12/2011
Objectives
18
8/12/2011
Source: www.ispe.org/pqli
Definition
of Product
Attribute Target Intended
Use and
Dosage Form and Size Product X, XX mg dose
pre-
Strength XX mg API per X mg dosage unit definition
(XX.XX% w/w anhydrous drug load) of Quality
Targets
Appearance/Description Similar to Innovator
(clinical
Identity List API (include compendial references) relevance,
A
Assay C
Commonly l 90 – 110% efficacy,
safety)
Moisture List target
Uniformity Meets USP
Impurities List impurities and known limits
Stability XX Months
PK/PD (Bioequivalence) Passes BE testing
Manufacturing Process Scalable, Reproducible, and Robust
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20
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23
60 4.0
50 5.0 # Failures
40 6.0
7.0
70
8.0
Parameter 1 (units)
30
Parameter 3 (units)
60
50 9.0
40 10.0
0.0
70
1.0
37
60
2.0
50
40 3.0
4.0
70 5.0 # Failures
44
60
6.0
50
7.0
40
8.0
240260 280 300 320 340 240260 280 300 320 340 240260 280 300 320 340
Parameter 4 (units) 9.0
10.0
23
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Objectives
24
8/12/2011
Source: www.ispe.org/pqli
25
8/12/2011
Prior
Process
Know-
Outline
ledge
List of Unit Summary
Operations of Prior
that lead Scientific
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
product etc.), Initial
(
(could
ld b
be Ri k
Risk
analytical) Assessment
to identify
Critical
Quality
Attributes
26
8/12/2011
Unit Operations
Formulation Container
Composition 1 2 3 4 5 6 7 8 Closure System
Dosage Form Low Low Low Low Low Low Low Low Low Low
Strength Low Low Low Low Low Low Low Low Low Low
Appearance Low Low Low Low Low Low Low Low Low Low
Identity Low Low Low Low Low Low Low Low Low Low
Assay Low Low Low Low Low Low Low Low High Low
Uniformity Low High Low Low Low Low Low Low Low Low
Degradation Products Low Low Low Low High Low Low Low Low High
Dissolution High Low Low Low Low High High High High Low
Stability High Low Low Low High Low High Low Low High
PK/PD High Low Low Low Low High High High Low Low
Manufacturing Process High High High High Low High High High Low Low
¾Process Steps
System
p 1-3 have the highest
g risk to the p
product p
progressing
g g
e.g. DoE,
PAT Risk
PAT,
(based on prior knowledge, experience, etc.) Assessment
and Risk
¾ More thorough understanding needed earlier rather than later Control
¾Formulation fixed based on in vivo performance requirements
¾Other Process steps are relatively straightforward
¾ Can be looked at in more detail at a later date (lower priority)
¾Container closure system has been explored
¾ Data in-process (stability)
27
8/12/2011
What is DoE?
` DoE is “a structured, organized method for
determining the relationship between factors (X’s)
affecting a process and the output of that process
(y).” (ICH Q8)
` Process = {unit operation, formulation, assay}
` X’s = controllable (e.g., time, temp, amount of a
component) and uncontrollable (e.g., instrument,
operator, media lot) factors
` y=response
response variable
ariable
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8/12/2011
Goals of DoE
` Efficient experimentation - versus “one factor at a
time”(OFAT)
` Reduced number of runs
` Covers wider space
` Hidden replication
` Effective experimentation - versus “one
factor at a time” (OFAT)
` Mitigates impact of artifacts such as run order and
experimental clustering
` Acknowledges main effects and interactions
Types of Designs
` Screening designs
` Used to identify significant factors
` Used to verify ruggedness
` Response surface designs
` Used to optimize a process
` Used to model a process
` Special designs
` Simplex – iterative optimization
` Mixture – constrained factors
` R b t – stability
Robust t bilit tto noise
i ffactors
t
` Split-plot – experimental units split into two dimensions
` Optimal – model is specified
29
8/12/2011
- +
Factor 1 200 300
Factor 2 1500 2500 • 9 factors each at 2
levels giving 12
Factor 3 300 500 runs
Factor 4 0 60 • Study of main
effects only
Factor 5 43 53 • No interactions
Factor 6 50 80 • No curvature
Data Collection
` Responses:
` Measured material attributes from in-process material
from Unit Operations 1,
1 2,
2 and 3
` Recorded dependent process information
` Calculated process yield
30
8/12/2011
90
• Factor 6 had a significant
80
negative effect on the
70
usable yield
Usable (%)
60
• The higher the value of
Factor 6, the lower the
50
usable yield
40
700 900 1100 1300 1500 1700
Factor 6
Linear Fit
Factors with significant effects (blue) were identified for each unit operation.
One factor (red) could not be evaluated in this design due to equipment
constraints.
31
8/12/2011
Translation to RSM
- +
Factor 1 200 250
Factor 2 2000
Factor 3 500
Factor 4 0 20
Factor 5 48 52
Factor 6 70
Factor 7 800 1600
Factor 8 500
Factor 9 6
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8/12/2011
33
8/12/2011
Objectives
Comparison Summary
` Major QbD Focus ANDA NDA
API √
Excipients √
Formulation √ √
Manufacturing √ √
Packaging √ √
34
8/12/2011
Conclusions
` Independent of the type of submission, QbD
principles can and are being applied in
bio/pharmaceutical development.
development
` Risk management tools provide a means for
determining the focus and how QbD is applied
throughout the development program.
` Higher risk, more complex technology = more
evaluation of p
process steps
p and factors ((CPP)) and
the determination of CQAs.
` The use of multiple tools allows the information to be
analyzed in different ways, providing new insights.
` Extra Slides
35
8/12/2011
ICH Q8 - Highlights
` The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
` Quality should not be tested into products, it
should be built in by design.
` Greater understanding of the product and its
manufacturing process,
process through the
implementation of quality by design, can create
a basis for more flexible regulatory
approaches.
36
8/12/2011
ICH Q9 - Highlights
` QRM is a systematic process for the
assessment, control, communication, and
control off risks to quality off a drug product
across the product lifecycle.
` Two primary principles of QRM:
` The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient
patient.
` The level of effort… of the QRM process should be
commensurate with the level of risk.
37
9/23/2011
Outline
1
9/23/2011
Integrate
g into p
pharmaceutical QbD p process
Increase analytical method operational
flexibility – More robust and efficient.
Greater understanding of method capability
and sources of variability
Regulatory flexibility
Optimum method success over the product
lifecycle
2
9/23/2011
Regulatory Perspective
- Moheb Nasr IFPAC 2009 Baltimore January 2009
Current status of applying QbD principles to analytical methods
3
9/23/2011
4
9/23/2011
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
5
9/23/2011
Technique Selection
Quality Attribute 1 Quality Attribute 2 Quality Attribute 3 Quality Attribute 4 Quality Attribute 5 Quality Attribute 6 Quality Attribute 7 Quality Attribute 8 Quality Attribute 9
Quality
Q lit Att
Attribute*
ib t * to
t be
b
measured: Identification I (per Identificaiton II NIR for API form
Assay Content Uniformity Purity Disintegration Loss on Drying Dissolution
retetion time) (per UV spectrum) confirmation
accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
70% - 130% LC N/A N/A 70% - 130% LC 0.02% - 5% 0 - 30 minutes 0 - 10 % 0 -125% 15%-100%
Type of sample (e.g.,
IPC, intermediate, Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods
finished goods, etc.):
Testing environment
(e.g., on-line, at-line, Release and Release and Release and Release and Release and
release/stability testing Release Release Release Stability
Stability Stability Stability Stability Stability
labs, etc.):
Resolution of PRI,
degradants,
No signal (i.e.
analytical artifacts,
Resolution of PRI, Resolution of PRI, absorbance) was
expcipients and
degradants, Method must be Method must be degradants, observed from a Must be capable of
Needed selectivity/ability filter extractables ≥
analytical artifacts, able to provide a able to provide a analytical artifacts, sample of differentiatign Form
of method to 1.5 from main N/A N/A
expcipients and filter positive ID for positive ID for expcipients and filter formulation D from Form A and
discriminate: band and ≥ 1.0 for
extractables ≥ 1.5 Dimebon Dimebon extractables ≥ 1.5 excipients amorphous form.
separation of
from main band from main band prepared in
specified
dissolution media.
impurities from
each other.
6
9/23/2011
Color Key
RP
column Red: experimental
screening studies
Green:in silico
Plot of log D modeling
Column & pH Alternative
versus pH
selection mechanisms Black: Decision
points
7
9/23/2011
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH
8
9/23/2011
Identifyy method p
parameters that could
influence method performance.
Invite method users from different labs.
Generate process map
Create cause & effect matrix
Scoring of method parameters is based on
knowledge of product and method, and ATP
requirements.
9
9/23/2011
10
9/23/2011
Accuracy
11
9/23/2011
Case Study
Develop a QbD impurity analytical method for a drug product
12
9/23/2011
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Sensitivity (LOQ):
S/N ≥ 10 for API at of 0.05% of nominal
HPLC is chosen for the impurity method
considering all the ATP requirements.
Reserved-phase gradient elution
13
9/23/2011
CHROMATOGRAPHIC CONDITIONS
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011
Gradient Profile
•% Organic Ramp 1 Experimental DOE 1
•% Organic Ramp 2
Detector Wavelength
g Experimental DOE 1
Detector Type (PDA or Single Experimental DOE 1
Wavelength)
Column Age - # of injections Noise OFAT
Column Diameter Controllable Fixed
Column Length Controllable Fixed
Column Storage Solvent Experimental DOE 2
Column Vendor Controllable Fixed
15
9/23/2011
1 Resolution (≥1
1. (≥1.2)2) between these two primary degradation
products (a critical pair for resolution)
2. Accurate quantitation of the primary degradant (± 15% at
0.15 % level)
3. LOQ (S/N ≥ 10 for API at 0.05% of nominal)
The sample set used to evaluate critical method attributes
in the DOE and OFAT studies includes,
A blank (diluent) sample
A stability sample that contain the two primary degradation products.
An LOQ standard
Column temperature
Column
C l b
batch
t h number
b
Mobile phase flow rate
Injection volume
Aqueous mobile phase TFA concentration
Starting organic mobile phase percentage of gradient ramp 1
Starting organic mobile phase percentage of gradient ramp 2
Detector wavelength
Detector type
Note: This is a large number of parameters. In the DOE study, the number might be
reduced.
16
9/23/2011
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33
17
9/23/2011
TFA Ramp
Flow Conc 1 Ramp Primary
Rate in Begin 2 Wave Column Critical Impurity
Temp (mL/ MP Org. Begin Inject. Length Detector Batch LOQ Pair Area Main Band
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Vol (nm) Type # S/N Res
Res. % RT (min)
18
9/23/2011
Region of
Region of unacceptable
acceptable resolution
resolution
95%
confidence
limit
Method operable
99%
design region confidence
limit
(MODR)
Contour Plot of Critical Pair Resolution vs. Ramp 1 Beginning Organic and Ramp 2 Beginning
Organic (Flow rate: 0.8 mL/min, TFA Conc: 0.1%; all other factors set to their centers).
19
9/23/2011
The operable ranges identified by the DOE for the method parameters are independent from each other.
The operable ranges proposed for column temperature, injection volume, wavelength, and detector type
were fully accepted per the DOE outcome.
The operable ranges of flow rate, TFA concentration, ramp 1 organic (%), and ramp 2 organic (%) were
narrowed from the proposed ranges based on the DOE results.
20
9/23/2011
Original column:
Range St
Studied
died
Hig Target Acceptable
Parameter Low Mid h Setting Ranges
Column Temperature (°C) 27 30 33 30 27 ~ 33
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
TFA Concentration in Phase (%) 5
Ramp 1 Beginning Organic (%) 7 10 13 10 7 ~ 11
Ramp 2 Beginning Organic (%) 14 18 22 18 14 ~ 18
Injection Volume (µL) 3 6.5 10 6.5 3 ~ 10
Wave Length (nm) 262 270 278 270 270 ~ 278
Detector Type PDA, UV Any PDA or UV
Column Batch # 1, 2 Any Any
21
9/23/2011
22
9/23/2011
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
Column Temperature (°C)
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
TFA Concentration in Phase (%)
7 10 13 10 7 - 11
Ramp 1 Beginning Organic (%)
14 18 22 18 14 - 18
Ramp 2 Beginning Organic (%)
PDA, UV Either PDA or UV
Detector Type
3 6.5 10 6.5 6.5 - 10
Injection Volume (µL)
262 270 278 270 270 - 278
Wave Length (nm)
23
9/23/2011
Wave
Flow TFA Ramp 1 Ramp 2 Length Col Injection Resolution Primary Main
Rate Conc. Organic Organic (µm) Temp Volume of Critical S/N of Impurity Dimebon
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
C) (µL) Pair LOQ Area % RT
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Run 0 are the conditions set in TM10000613
Q lit attributes
Quality tt ib t used
d ffor th
the assessment:
t
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Limit of quantification: S/N ≥ 10 for 0.05% of the API content
Resolution of critical pairs of degradants: ≥ 1.2
24
9/23/2011
Numbers of
Injection of
Preconditioning
Run Storage Solvent Preconding
(hours)
Sample
1 50/50 ACN/Water 6 3
2 Initial Mobile Phase 9 6
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
6 Initial Mobile Phase 3 6
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
9 Initial Mobile Phase 12 3
10 Initial Mobile Phase 0 3
11 Initial Mobile Phase 6 0
12 Initial Mobile Phase 6 3
13 Initial Mobile Phase 6 3
14 50/50 ACN/Water 6 3
25
9/23/2011
26
Slide 52
TWG6 would need to be more concise...given that you have a summary slide next, I would recommend
skipping
Timothy W. Graul, 9/13/2011
9/23/2011
27
9/23/2011
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x
28
9/23/2011
Within the 3500 injections, the resolution data showed a slightly increasing
linear trend (increased 0.18 - 0.7 unit per 10000 injections).
Within the 3500 injections, the retention time showed a slightly decreasing
linear trend ((decreases between 1.4 to 2.8 minutes per
p 10000 injections).
j )
Conclusions
29
9/23/2011
Conclusions (continued)
DOE experimentation can be used to study multiple
method pparameters and their interactions for
establishment of MODR.
Critical method quality attributes should be selected in
the DOE study (i.e., resolution, accuracy, and LOQ for
an impurity method).
Common MODR can be determined for two similar
HPLC columns where the two columns can used
interchangeably.
QbD method control strategy involves operation of the
method within MODR and implementing system
suitability check.
Acknowledgement
30
9/23/2011
Backup slides
Column Temp: The column temperature range is 30 ± 3 0C which could cover any
potential variations of the column temperature. We learned that the column temp has
a minimum impact p to the method pperformance,, so temp
p range
g selected is suitable for
our future testing needs.
Injection Volume: The injection volume set point is 5 ųL and the range is 3-10
ųL. The 3 ųL is close to the limit of injection volume used in a typical HPLC impurity
method and 10 ųL has doubled the injection volume at the set-point, which is
sufficient for the future testing need.
Flow Rate: The flow rate range is 1.0 ± 0.2 mL/min which will cover potential flow rate
variations of the HPLC system or meet the needs to adjust the flow rate to achieve
desired peak retention time.
UV Wavelength: The UV wavelength range is 270 ± 8 nm that is broad enough for
the purpose of operable region study.
TFA Concentration: TFA target concentration is 0.05% and the range is proposed as
0.05%-0.010%. The TFA concentration lower than 0.05% is not recommended due to
its poor pH buffering capacity.
Ramp 1 and Ramp 2: The selectivity of this impurity method is very sensitive to
organic percentage in the mobile phase. The most impurity peaks are eluted and
separated in the first 20 minutes where the organic percentage in the gradient elution
is changed by only 8%. As a result, a small organic percentage ranges of 10 ± 3%
and 18 ± 4% are commended for gradient ramp 1 and ramp 2, respectively.
Detector type: UV WVD and PDA cover the detectors used for this method.
31
QbD and Knowledge Management
Eda Ross Montgomery | September 15, 2011
Develop specifications Develop post-approval Agree on process for Identify opportunities for
change strategy including NORs and PARs improvement; implement
in batch record as appropriate
Perform risk Assessment Develop “product and Agree on overall control Publish trends and metrics
process description” strategy
strategy for marketing
application
Define design space Develop comparability Agree on trending protocol Set goals for continuous
protocol strategy and process improvement
Tablet CQAs
Stage 6
Conduct Process
DPI CQAs Verification and
Continuous
Process
Improvement
DS CQAs
Comprehensive Quality
Systems
Appearance Specification
Identification Specification
Design
Space
(PAR)
Operating/Control
Space
(NOR)
Predicted Output
Parameter 2
Parameter 1
Edge of Design
Operating/Control Space Space
Minor Change
Equipment malfunctioned
Temperature lowered
PAR
Time
DP
110
100
Response
90 ± d50 PAR
80 ± d50 NOR
60 d50 OFFLINE
Measured(μm)
50
40
• Predictive model built from development runs
• Good agreement between actual and predicted value
Observations
Minor Deviations
Major Deviations
• Use Statistics to
– Establish process capability
– Evaluate inter and intra-batch variability
– Justify sampling procedures and sampling frequency
• Verify suitability of sampling procedures and sampling frequency
– Confirm assumptions around sampling procedures during process
qualification
• Modify as needed during commercial production and/or when changes are made
– Vary sampling frequency
• Development through process qualification
• During continuous process verification
• Perform continuous process verification as described in FDA’s January
2011 Process Validation Guidance
– Ongoing program is needed
– Quality and Technical units review data, evaluate trends, and coordinate
actions
• Tom Gandek
• Kelly Tolton
• Geny Doss
• John Bric
• Simone Ferdinand
• Chris Hooper
• Carole Varanelli
• Antoinette Paone
• Trish Hurter
Th QbD Collaboration
The C ll b ti Imperative:
I ti
How to Get the Most Value
From Your Data and Your Colleagues
Why Collaborate?
The Business Perspective
– The people who develop the new processes are the same ones
who later provide support when there are problems
1
9/23/2011
Why Collaborate?
The Regulatory Perspective
Why Collaborate?
The Regulatory Perspective
2
9/23/2011
Traditional Approach #1
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM Historian
JMP Script
DATA Single Point
7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
6.8
6.7
Excel
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
Layout File
Multi-Point / Continuous
Trend Overlays
Batch 7.0
200 variables
3.0
Records
6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Collect ion Start
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
3.0
Elut ion Begin
0.0
0 200 400 600 800 l
Chromatogram
Overlays
UNICORN UNICORN
(Continuous I/O) “Evaluate”
3
9/23/2011
Traditional Approach #1
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM
U S Historian
JMP Script
DATA Single Point
7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
6.8
6.7
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
Multi-Point / Continuous
Excel
Trend Overlays
Layout File
Batch 7.0
Records 6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
3.0
Chromatogram
Overlays
UNICORN UNICORN
(Continuous I/O) “Evaluate”
Traditional Approach #1
COLLECTION
Weekly Data Report
Continuous
(per Product)
UPSTREAM Historian
JMP Script
DATA Single Point
7.3
/ Continuous
(Release,..)
7.2
7.1
pH
7.0
6.8
6.7
0 20 40 60 80 100 120 140 160
S-3 Time (hours)
Multi-Point / Continuous
Excel
Trend Overlays
Layout File
Batch 7.0
Records
6.0
PURIFICATION 2.0
1.0
5.0
4.0
DATA
Col lection Start
3.0
Wash 1 Begin
Wash 1 Begin
Wash 2 Begin
Wash 2 Begin
ElutionBegin
ElutionBegin
Load Begin
Start Equil
0.0
0 200 400 600 800 l
Chromatogram
Overlays
UNICORN UNICORN
(Continuous I/O) “Evaluate”
4
9/23/2011
Traditional Approach #2
Traditional Approach #2
5
9/23/2011
Quality
Safe and Efficacious Product
• Fast CMC Preparation & Approval
• Fast Time to Market
• High Yield and Quality
• Low Cost MFG
Process
With all the Supporting Data Development
and Institutionalized Knowledge
6
9/23/2011
7
9/23/2011
Discrete data
– Measured once per batch
– MES,
MES EBR,
EBR LIMS,
LIMS ERP
ERP, Paper,
P Others
Oth
Continuous data
– Strip charts – time series profiles
– SCADA, Historians, DCS, PLC, Instruments
Replicate data
– Several measurements, same sample/time
– MES, EBR, LIMS, Paper, Others
Spectral data
– Continuous
C ti d
data,
t discrete
di t extracts
t t and
d deconvolutions
d l ti
Event data
– Batch, equipment records, SCADA, etc.
Keyword and free text data
– Enables records to be retrieved and understood
Context is King
8
9/23/2011
Genealogy Context:
Lot Traceability
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
Genealogy Context:
Lot Traceability
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
9
9/23/2011
Proportionating Genealogy:
Correlating Upstream / Downstream
S2 B1 ID
S1 B1 ID
S2 B2 ID S3 B1 ID
S2 B3 ID
S1 B2 ID S3 B2 ID
S2 B4 ID
S2 B5 ID S3 B3 ID
S1 B3 ID
S2 B6 ID
Proportionating Genealogy:
Correlating Upstream / Downstream
S1 B1 ID S3 B1 ID
S2 B1 ID
S1 B2 ID S3 B2 ID S4 B1 ID
S1 B3 ID S3 B3 ID
S2 B2 ID S4 B2 ID
S1 B2 ID S3 B4 ID
S1 B4 ID S3 B5 ID S4 B3 ID
S2 B3 ID
S1 B2 ID S3 B6 ID
10
9/23/2011
Data Sources
Paper Records
Sponsor Mfg.
CMO
Process Dev.
Pilot Plant
Data Sources
Paper Records
Sponsor Mfg.
CMO
Process Dev.
Pilot Plant
11
9/23/2011
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
HIST
Dynamic
Mapping Engine
Process Dev.
AG
Analysis
Group
Pilot Plant
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
12
9/23/2011
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
Data Sources
RIF
LIMS
Sponsor Mfg.
HIST
CMO
ERP
HIST
Dynamic
Mapping Engine
Process Dev.
CAPA
AG
Analysis
Group
Pilot Plant
MES
SAP
EG
13
9/23/2011
Trending,
g,
Alerting,
Trouble-shooting,
Plotting,
Univariate &
Multivariate
Statistics,
Fermentation,
Chromatography
Chromatography,
Stability, etc.
AG
Analysis
Group Dynamic
Mapping Engine
AG
Analysis
Group Dynamic
Mapping Engine
14
9/23/2011
Data Sources
HIST
HIST
Sponsor Mfg.
CMO LIMS
AG
Analysis
Group
ERP
Dynamic
Mapping Engine
Process Dev.
Data
Warehouse
Pilot Plant RIF
Paper
Records
Industry Myth - #1
NOT TRUE
– Multiple data sources are not the problem
– Multiple data organizations are not the problem
– Need a flexible platform for on-
on-demand contextualization
– Leave the source data where it is, organized “as is”
– Make discrete and continuous data available together
15
9/23/2011
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
HIST
16
9/23/2011
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
HIST
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
HIST
17
9/23/2011
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
HIST
PD Data Access:
The Evolutionary Approach
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
LIMS HIST
18
9/23/2011
19
9/23/2011
Pre-Blending
Milling
Blending
Roller Compaction/Mill
Final
Blend Comp
Coat
Quality Attributes:
■ 10 – known or expected direct impact on safety and/or efficacy of
product
■ 7 – unsure or expected impact on product safety or efficacy, or on
process efficiency
■ 5 – unlikely impact on product quality or process efficiency
■ 1 – no impact on product quality or process efficiency
Process Parameters:
■ 10 – known or expected direct strong impact based on data in hand
or experience
■ 9 – unsure but expect a strong relationship
■ 5 – medium relationship or not sure
■ 1 – known that there is not a relationship
20
9/23/2011
Example Cause-
Cause-and-
and-effect Matrix
Key Attribute Y Y Y
Rank 7 7 7 Exp't
Stratified Tablet Score
Blend Impurity Strategy
Quality Parameter Content
y
Uniformity Profile
Uniformity
Dispense and Pre-Blend
(Focus Area #1)
API Particle Size 10 5 1 112 OFAAT**
Agglomeration of API 10 5 1 112 OFAAT
Container Loading (% fill) 10 5 1 112 DoE
Order of API Addition 10 5 1 112 DoE
Impurity Levels in Excipients 1 1 10 84 DoE/FMEA*
API Impurity Profile 1 1 10 84 OFAAT
API Milling Procedure 5 1 5 77 OFAAT
Blend Time 5 1 1 49 DoE
Sampling Procedure 1 1 1 21 FMEA
RC/Mill and Blend
(Focus Area #5)
Roll Force 10 10 1 147 DoE
Screen Size 10 5 1 112 DoE
Gap Width 10 5 1 112 DoE
Roll Speed 5 1 1 49 DoE
Granulator Speed 5 1 1 49 DoE
**OFAAT - One Factor At A Time
*Failure Mode Effects Analysis
21
9/23/2011
Threshold = 110
Threshold = 110
22
9/23/2011
Self-service, On
Self- On--demand
Access to Designated Parameters
23
9/23/2011
24
9/23/2011
25
9/23/2011
The Results
Raw
Sponsor Mfg. Materials
Process
Step 1
CMO Process
Step 2
Process
Step 3
Process
P
Process Dev. Steps…
Final
Product
Pilot Plant
LIMS HIST
26
9/23/2011
27
9/23/2011
28
9/23/2011
Data Sources
Paper Records
Sponsor
CMO
Self-service, On
Self- On--demand
Access to Designated Parameters
29
9/23/2011
30
9/23/2011
31
9/23/2011
32
9/23/2011
66
33
9/23/2011
LIMS
PRIMR
HIST
34
9/23/2011
Summary
35
9/23/2011
Example Implementations
36
9/23/2011
Thank you
Justin O. Neway, Ph.D.
Vice President and Chief Science Officer
Aegis Analytical Corporation
jneway@aegiscorp.com
http://www.aegiscorp.com
37
A Quality by Design Based Approach to
Process Design, Control and Improvement
Ronald D. Snee
Snee Associates, LLC
IVT’s 3rd Annual Bio/Pharmaceutical Conference on
Quality by Design
San Francisco, CA
September 14-16, 2011
1 Snee Associates, LLC
Agenda
≡ Today’s Realities – Need to Improve
= FDA’s Quality by Design and Process Validation
Guidance
= ISPE Product Quality Lifecycle Implementation Plan
≡ Building Blocks of QbD
≡ Process Performance and Product Quality
= Process Stability and Capability
= A Systems Approach
≡ Tips and Traps – What to Watch Out For
≡ Summary
Raw
Materials
(Xs)
Failure Modes and Effects Analysis
Analyze
Process Variation
Process Variable
Average
Time or Sequence
≡ Consistently produces
tablets that are within
specifications for all tablet
parameters.
≡ Process capability
analysis compares the
process variation to the
lower and upper
specification limits
≡ Broadly used measure of
process capability is the
Ppk index
Common Causes:
−Present all the time
−Influences all process outputs
−Require process changes to reduce
−Minimum variation process is likely
to exhibit
Special Causes:
−Due to outside influences
−Affect some of the process outputs
−Can cause data to form non-normal
patterns
Average
Time or Sequence
0.228
0.226
AVGThickness
0.224
0.222
0.220 4 Tablet
0.218
Presses Used
1 6 12 18 24 30 36 42 48 54 60
Index
50
Press No_
90
120
0.2184 0.2198 0.2212 0.2226 0.2240 0.2254 0.2268 0.2282
AVGThickness
UCL=1.07360
1.07
Individual Value
1.06
_
X=1.05489
1.05
1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181
Sample of 10 Tablets
101
100
Individual Value
99 _
X=98.682
98
97
96
LCL=95.546
95
1 14 27 40 53 66 79 92 105 118
Batch
Within-Batch
Short-Term
Variation
Between-Batch
Long-Term
Variation
Batch
Mean
Group 1
Group 3
Group 2
1.06
_
X=1.05489
1.05
1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181
Sample of 10 Tablets
101
100
Individual Value
99 _
X=98.682
98
LT Variation LT Variation
97 =6% =23%
(p=.41) (p=.14)
96
LV Variation LCL=95.546
95 = 64%
1 14 27 40 53 66 79 92 (p=.001)
105 118
Batch
Tolerance
USL – LSL
Cp =
6 (Short-term Standard Deviation)
Average – LSL
Cpk = = 0.33 Poor
3 (Short-term Standard Deviation)
USL – LSL
Pp =
6 (Long-term Standard Deviation)
Where:
LSL = Lower Specification Limit
USL = Upper Specification Limit
Marginally Capable
LSL USL
LSL
Cp = 1.0 USL
Poor
Capability
Cp < 1.0
40 45 50 55 60 65 44 46 48 50 52 54 56 58
Robust Process
LSL
Cp = 2.0 USL
44 46 48 50 52 54 56
Rating Cp Cpk
Excellent > 1.67 > 1.53
Good 1.33 – 1.67 1.33 – 1.53
Fair 1.00 – 1.33 1.09 – 1.33
Poor < 1.0 < 1.09
Cp Typical % Defective*
2.0 0.00034
1.67 0.023
1.33 0.6
1.0 6.7
* Assumes the Process has Shifted 1.5 Std Dev
Process Capable?
Process
Stable? Yes No
Use SPC to • Shift Average to Target,
Yes Maintain • Reduce Variation Around Average
Performance • Both
• Reduce Variation, • Increase Process Understanding
No • Improve Control • Identify Appropriate Action
1.5
Mean
1.4
1.3
1.2
1.1
1.0
30 60 120
SAMPLE SIZE
Customers Process
Design/Redesign
Process Process
The Process
Performance Improvements
Data
Company
Pdtn Line # 2
Pdtn Line # 1 Pdtn Line # 3
Mfg. Engineer / Operator Team Mfg. Engineer / Operator Team Mfg. Engineer / Operator Team
Process Process
Data Process
Models
Adjustment
Y=f(X)
Monitoring Tools
Periodic •Control Charts
Data Analysis •Capability Analysis
and •Variance
Review Components
•Histograms
•Pareto Charts
Current (X, Y)
Performance
Deviation
Target from Target
Required
Change in X
Current
Performance
=38
Target
Deviation
=34
from Target
38-34=4
Required
Change in X
= -16
Periodic
Monitoring Tools Data Analysis Process
•Control Charts and Improvement
•Capability Review
Analysis
•Variance
DMAIC
Components
•Histograms
•Pareto Charts 46 Snee Associates, LLC
DMAIC Process Improvement Framework
Data Control
Improve
Analyze
Leadership
Measure Teamwork
Stakeholder Building
Define Project Management
PRODUCT DESIGN
Overall
Prospective Risk Analysis PAR,
PST Target Product Profile (TPP) Project Plan Design Space Definition
(e.g. FMEA) NOR
RISK ASSESSMENT Goal
AND
CHARACTERIZATION
Quality Target Product Profile Operations Knowledge acquisition Selection of Final Composition
Execution CPP
RISK MITIGATION (QTPP) Goal (theory, models, DOEs, etc) and Process Parameters
GOT/CMC
AND CONTROL
Flexibility
Critical Quality Attributes Understanding and Control
Goal DP/DS Specifications and and
(CQA) (e.g. Process Analysis
Drivers Regulatory Submission Potential
(safety and efficacy) Characterization)
benefits
Increase Product Understanding Throughout Development x An actionable QTPP becomes available during P2 development (~ P2a-P2b transition). May be
updated as additional information becomes available.
x Process characterization incorporates the elements of prospective risk analysis
x Process analytical technology (PAT) should be encouraged as a control option, where appropriate
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
3 4
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Early Phase Development – Relevant Information can be Extracted from TPP
Product Design to Create Product Design Drivers and QTPP
TPP example:
Base / Preferred Actions for Product Design
1. No Cmax induced AEs 1. Consider appropriate drug delivery technology
Formulation Safety / tolerability to reduce Cmax without impact exposure
2. No significant interactions with commonly
Development prescribed medication (per indication). 2. Case-by-case
Drug
1. Oral dosage form: 1. Consider controlled released formulation to
TPP QTPP Product
a. Base: twice daily achieve once daily dosing
QA
b. Preferred: once daily
Process 2. Develop a formulation provide appropriate
2. Food effect:
Selection release characteristic to mitigate food effect
a. Base: moderate – recommend taking on
empty stomach
Administration
b. Preferred: minimum – no diet restriction
3. Pediatrics and older adults formulation 3. Develop appropriate taste masking formulation
to support PK/registration studies
a. Base: powder for reconstitution
b. Preferred: ready-made suspension or
chewtab
Goal:
Focus on safety and efficacy within the dose range Price / COGs
Estimated $2 per day Develop appropriate commercial composition
COGs: Less than 10% of the selling price and process to achieve target COGs
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
7
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Components of Oral Absorption Early Development on API QAs
• Low solubility + predicted medium-high human dose Evaluate API size reduction
Æ high dose number 1. Explore milling approaches, jet / pin/ slurry mills
Æ exposure concern 2. Understand risk and ensure suitable for scale-up
3. Close collaboration between Chemistry Process, Analytical, and
Pharmaceutical R&D
• What can be done during early formulation development to
understand the risk?
Animal PK: appropriate design of a animal study is essential
1. Cross-over design
2. Need one arm to reference results w/ previous studies
3. Target no less than 5x PSD difference
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
13 14
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Non-Human Primate PK Study Showed Dissolution Results Tablets Prepared for Non-
Bioavailability Is API Particle Size Dependent Human Primate PK 20 mg Tablet
Dose AUClast AUC0-inf AUCExt. F
Formulation Subject
(mg) (hr*ng/ml) (hr*ng/ml) (%) (%) Early method: USP II, pH 6.8, 75rpm
Solution 20 0001M 5550 5660 2.01
20 0002M 4550 4710 3.49
20 0003M 4630 4670 0.910
20 0004M 8870 8910 0.395
N 4 4 4
Mean 5900 5990 1.70
SD 2030 2000 1.37
CV% 34.5 33.4 80.5
Tablet 1 20 0001M 5570 5610 0.729 99.1
20 0002M 3420 3450 0.958 73.2
20 0003M 3910 4010 2.58 85.9
20 0004M 4860 4990 2.69 56.0
N 4 4 4 4
Mean 4440 4520 1.74 78.6
• Tab-1 (small DS, pin milled, d50= 3.1Pm, d90= 8.5 Pm) provided comparable exposure to sol’n API particle size of Compound X impacts both dissolution profiles and in-
• Tab-2 (large DS, slurry milled, d50= 33.9Pm, d90= 131.2 Pm) offered significant lower exposure vivo performance
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 15 16
Sept 14- 16, 2011, San Francisco
Summary
Outcomes
Case Study #2:
• Set the API PSD internal target for early phase (not specification)
o D90 < 10 Pm
o Pin milling achieved required particle size reduction
Next Steps
Addressing Negative Food Effect
• Continue to monitor the lot-to-lot PSD variation in API
• Select appropriate formulation to deliver clinical trial material
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
17
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Typical Factors to Consider in Early
Components of Oral Absorption Formulation/Process Development
Formulation:
(e.g. Solubility Enhancement,
• Formulation Design
Particle Size Distribution, • What is the BCS classification for the compound?
Processing) • Preferred dosage form
• Risk assessment and rationale for choice of excipients
• Rationale for level of excipients in formulation
• Process Design
• Necessary process to achieve specific drug delivery system
• Risk assessment and rationale for choice of process
• Were the risks of scale-up considered in choice of the manufacturing
process?
GI Physiology: • Existing commercial capability, or CM
Physicochemical Properties:
(e.g. Gastric Emptying,
(e.g. Solubility, LogP, pKa,
pH Along GI tract,
Stability)
Bile Salts)
Time (hr)
Collaborated with S. Singh
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 21 22
Sept 14- 16, 2011, San Francisco
Physicochemical Properties and Physiology Food Components Have Positive or no Impact
That Could Induce Negative Food Effect to the Solubility of API or Tablets
• Both skim and whole milk increases the solubility
• Interact physically or chemically with API • Fat, sugars, and amino acid have no effect on the solubility/dissolution of API X
• API X chelates Ca2+ in the food to reduce the solubility • Protein: e.g. albumin, casein, can bind API X and increase the solubility
• API X binds food components to reduce its diffusivity for membrane permeation
Dosing
pH = 5.0
30 min
Drug Transition to SI
Lower solubility in Fed SSIF Slower Dissolution in Fed SSIF
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
27 28
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Tablet Formulations Containing ASD by Hot
Liquid Filled Capsules Melt Extrusion and Spray Drying
• Work flow of LFC development: Lead formulations:
• Solubility screening based on Amgen internal LFC prior experience Direct compression tablet formulations containing 40% ASD (20% DL)
• Evaluate performance using pH gradient method
• Assess physical stability and processibility
• Monitor chemical stability and performance after storage ASD by SD ASD by HME:
API + HPMC-E5 (or PVP k29/32) API + PVP-VA64 (+ PVP k29/32)
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
29 30
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
While Alternative Formulations Dosed in Animal, Non-Human Primate PK Study: Cross-over, 10
Additional Human Data Becomes Available mg
No significant food effect was observed at 100mg dose !! • All tested alternative formulation showed higher exposure than crystalline
- Human Study: cross-over, N = 12 free acid tablets in non-human primate under fasting condition
What are the possible reasons for the negative food effect observed at Compound X AUC (ng.hr/mL)
25mg tablets?
• Smaller N, not a cross-over study, high subject-to-subject variability
• Could food effect be dose level related?
– Hypothesis: Compound X may interact with food components to form
complexation resulting in lower AUC
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
31 32
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Summary
• Appropriate PK study design, both animal and human, is essential Case Study #3:
o Cross-over design is a must
o Set successful criteria while designing the study
o If resource available, power up the study (higher N)
Identifying suitable modified release drug
• Demonstrated alternative formulations can effective enhance delivery technology
bioavailability of a BCS II compound
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
33
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Components of Oral Absorption Challenges
Formulation:
(e.g. Solubility Enhancement,
1. All three components of oral absorption act in concert with each
Particle Size Distribution, other
Processing)
2. How do we separate formulation effects from:
• the other two components of absorption?
• compound distribution, metabolism and excretion?
3. Ultimately, how should we deliver the active ingredient to better
achieve the desired absorption profile and therapeutic outcome in
patients?
GI Physiology:
Physicochemical Properties:
(e.g. Gastric Emptying,
(e.g. Solubility, LogP, pKa,
pH Along GI tract,
Stability)
Bile Salts)
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
35 36
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Product Design Risk Assessment Design and Execute a GI Site Absorption Study
A: oral solution
Key points to cover: as reference
However,
DSB
• Current available IR formulation, only when dosed BID, can provide Last meter of Treatment Solution
ileum
100mg Compound Y to be delivered
sufficient AUC and Ctrough without high Cmax C: dose to Distal Small A
in 80mL of 1.25mg/mL solution)
Bowel via EnterionTM
Capsule B
100mg Compound Y to be delivered
C
in 1mL of 100mg/mL solution)
D
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
37 Sept 14- 16, 2011, San Francisco 38
Sept 14- 16, 2011, San Francisco
Absorption for Compound Y mainly in upper
GI (proximal and distal small intestine) Summary – Implication and Path Forward
Treatment Tmax Cmax AUClast AUCratio Cmax ratio
hr ng/mL ng*hr/mL % %
• Formulation would need to allow absorption in upper GI (proximal and distal
A N 15 15 15 small intestine, within 3 – 6 hrs) and avoid extensive release (i.e. colon)
Mean 1.9 472.7 1660.9 100 100
SD 1.3 234.6 1070.9
CV% 68.8 49.6 64.5
Proximal small intestine (B) vs Oral solution (A) Geo Mean 1.4 418.2 1452.6 100 100
• Conventional sustain release (SR) technology can not reduce Cmax without
negative impact to AUC and Ctrough for Compound Y
• ~11% higher in AUC, ~90% higher in Cmax B N 13 13 13 o Most common technology, such as matrix tablets & multi-particulates capsules, will require
Mean 0.5 851.9 1778.5 107.1 180.2 significant absorption in colon
SD 0.3 226.4 956.5
Distal small intestine (C) vs Oral solution (A) CV% 53.1 26.6 53.8
Geo Mean 0.5 819.6 1624.3 111.8 196.0
• ~41% lower in AUC, ~36% lower in Cmax • “2 to X hrs control release” technology
C N 13 13 13 o Require PKDM input on desired PK parameters, then convert to in-vitro requirements
Mean 1.2 360.3 1036.3 62.4 76.2 o Options: slower dissolving tablets, Osmotic (SCT or Micropump) dosage form
Colon (D) vs Oral solution (A) SD 0.3 269.4 626.7
• ~91% lower in AUC, ~95% lower in Cmax CV% 21.2 74.8 60.5
Geo Mean 1.2 269.0 848.8 58.4 64.3
• Gastric Retention Technology
D N 13 13 13
Mean 1.8 33.5 261.6 15.8 7.1
SD 1.8 36.5 335.3
CV% 100.7 108.9 128.2
Geo Mean 1.0 20.1 133.7 9.2 4.8
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
39 Sept 14- 16, 2011, San Francisco 40
Sept 14- 16, 2011, San Francisco
Selecting the Right Technology for a Controlled
Release Dosage Form
IR
Utilizing Physiologically Based Absorption
therapeutic
Model (GastroPlus) in Product Development window
CR
Plasma drug level
Non-effective region
40
MR matrix tablet
Osmotic tablet
20 MP capsules
% Bioaccessible
0
0 10 20 30
Multiparticulate Time (hr)
Animal PK
technology
400 MR Matrix Tablet
350
Osmotic Tablet
300
250
Multiparticulate (MP)
Capsules
200
150
100
50
0
Plasma concentration (ng/ml)
0 4 8 12 16 20 24
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference Time (hr)
43 44
Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
FDA Publication: Utility of Physiologically GastroPlus is a Repository of Pertinent Data
Based Absorption Modeling in QbD for PK Modeling and Simulation
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
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Sept 14- 16, 2011, San Francisco Sept 14- 16, 2011, San Francisco
Iterative Process Combining Simulations and Built GP Model w/ Existing Cp-Time Profiles
Experimental Testing to Predict in-vivo PK from IV & IR
Validate Deconvolute in-
Build GastroPlus
GastroPlus vivo release from
model
model Cp-time profile
Input the
predicted in- Predict in-
vivo release vivo release
into validated via in-vitro
GP model
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 47 Sept 14- 16, 2011, San Francisco 48
A GP Model was Built Based on IV and IR Cp-
Time Profiles with Estimated PK Parameters Step 2: Validate the GP model
V2 (L/kg) 3.24
k12 (1/h) 7.1
k21 (1/h) 0.35 Optimize Create bio-
formulations relevant in-vitro
Vmax (mg/s) 2.1 x 10-2 with desired method
release
Km (mg/L) 1.12
Oral absorption
(ACAT model) k12
V1 V2 Input the
k21 predicted in- Predict in-
vivo release vivo release
Vmax/Km into validated via in-vitro
GP model
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 49 Sept 14- 16, 2011, San Francisco 50
Validated the GP Model with Additional PK
Profiles from IR Formulations Step 3: Deconvolution
Validate Deconvolute in-
Build GastroPlus
GastroPlus vivo release from
model
model Cp-time profile
Input the
predicted in- Predict in-
vivo release vivo release
into validated via in-vitro
GP model
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
51 Sept 14- 16, 2011, San Francisco 52
Sept 14- 16, 2011, San Francisco
Deconvoluting in-vivo Release Rate from the MR Step 4: (a) Create Bio-Relevant in-vitro
Formulation PK Profiles (12.5mg, fasted) Method, (b) Design Formulation
Validate Deconvolute in-
Build GastroPlus
GastroPlus vivo release from
model
model Cp-time profile
Adjusted in-vivo
dissolution and
absorption
Input the
predicted in- Predict in-
vivo release vivo release
GastroPlus model suggests incomplete in-vivo release into validated via in-vitro
GP model
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 53 Sept 14- 16, 2011, San Francisco 54
Original In-vitro method over predicting the in- Bio-Relevant Dissolution Method Risk
vivo release Assessment
Samples Duodenum Small intestine Ascending Colon Phosphate buffer Phosphate buffer
(Fasted) 1 (Fasted) 2 (Fasted) 3 (50mM) 4 (100mM) 5
Buffer Capacity 5.6 10.0 21.4 18 34
In-vivo release rate at lower GI tract is slower than predicted from original QC (mmol/L/'pH)
dissolution method Dissolution -- -- 20-30 ml 900 ml 900 ml
Volume (liquid/solid: 70%/30%) (100% liquid) (100% liquid)
Only approximately 50% Compound Y is released in human GI tract. Potential
1 Lida et al, Pharm. Res. 23 (1) 2006, 165 – 176 2 Ekarat Et al, Pharm. Res. 25 (7) 2008, 1663-1676
impact: 3 Amalia Et al, Pharm. Res. 26 (9)2009, 2141-2151 4, 5 Determined at Amgen
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
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Sept 14- 16, 2011, San Francisco
Effect of Ionic Strength and Buffer
Concentration on MR Tablet Dissolution Profile Formulation Design Risk Assessment
Consideration while developing a predictive method • Understand the release mechanism of the MR dosage
1. The medium selected needs to be bio-relevant • Matrix vs. Osmostic vs. Multi-particulate
2. DoE to screen buffers, concentration, paddle speed, etc • What factors can impact the release rate
3. Aim to match the in-vivo release profile • Physiological
• Physicochemical
• Formulation composition
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
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Sept 14- 16, 2011, San Francisco
Step 5: Screen Formulations and Predict the Simulated In-Vivo Cp-Time Profiles Using the In-Vitro
Performance Dissolution Profiles as the In-Vivo Release Profiles
% Release
formulations 40 Form 4
method 15
with desired Form 5
20 10
release Form 6
5
0
0
0 4 8 12 16 20 24
-1 4 9 14 19 24
Input the
predicted in- Predict in-
vivo release vivo release Slower release: lower bioavailability, greater food effect, increased variability
into validated via in-vitro Faster release: higher bioavailability, and lower inter subject variability
GP model
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
Sept 14- 16, 2011, San Francisco 59 Sept 14- 16, 2011, San Francisco 60
A MR Formulation with Faster Release Rate was
Selected for Human PK Study
(tid) (bid) (bid)
Summary
IR F1 F2
Peak to Trough 2.09 1.37 1.51
IVT’s 3rd Annual QbD Conference IVT’s 3rd Annual QbD Conference
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9/23/2011
Objectives
1
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Objectives
2
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3
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4
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5
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Objectives
6
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Marketing Regulatory
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Multiple Definitions
8
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Container Closure HDPE bottle with Child Resistant (CR)
System Caps Needed for commercial reasons
Example MR tablet provides initial
Biphasic release of the drug, initial plasma concentrations through the
rapid release followed by sustained first two hours that provide for a
release of dose. Fasting study and fed clinically significant therapeutic
study 90% confidence interval of the effect. Sustained release phase
Dissolution/ PK parameters AUC0‐2, AUC2‐24, designed to maintain plasma
Pharmacokinetic Profile AUC0‐∞, and Cmax should fall within concentrations for maintenance of
Requirements BE limits
BE limits. therapeutic effect
therapeutic effect.
Drug Product Quality
Attributes* See CQAs
At least 24‐month shelf life at room
Stability temperature Needed for commercial reasons
A scored tablet can be divided into
two 5mg tablets. Taken without Pharmaceutical equivalence
Administration regard to food (no food effect). requirement
*Appearance, ID, Assay, CU, Degradation products/residual solvents, Dissolution, Microbial Limits
Yu, Understanding Pharmaceutical QbD presentation
9
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Similar in size and shape to
Appearance RLD, scored as RLD Yes
Identification Positive for drug substance Z
Positive for drug substance Z No
Assay 95.0 to 105.0% of label claim Yes
Complies with harmonized
requirements for uniformity of
Content dosage units (both whole and
Uniformity half tablet) Yes
NMT qualification threshold for
specified impurities, NMT ID
Degradation threshold per ICH QB3 (R2) for
Product/Residual un‐ID'd impurities, conform to
Solvent USP 467 No
Must provide rapid initial
Must provide rapid initial
release followed by sustained
release (specified apparatus
and pH buffers), similar release
for whole and half tablets,
alcohol induced dumping
Drug Release comparable to RLD Yes
*Critical Quality Attributes (CQAs) are those that can be potentially impacted by formulation and
manufacturing processes.
10
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Time
Time Hardness
Excipients Batch Size
API Pressure
Tablet Speed
Yrs. Experience
Sampling
Training
Method
Personnel Analytical
11
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Process
Process: Manufacturing process such as blending, compression,
wet granulation, etc.
Intermediate
Intermediate: In-process material such as a powder blend,
uncoated
d tablet,
bl extrudate,
d etc.
12
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Process Variables
•Raw material grades
butes
Process Attributes: Critical Outputs:
p
Process Attrib
•In-process material •Critical process attributes
attributes created by that act as inputs to the
process next unit operation
•Process equipment
measurements (dependent
variables)
Weight Gain
of Rotations
Fill Volume
Compresssion Force
nal Speed
Order off Addition
g Design
Press Speed
Atomization
Sprayy Rate
Product Te
Coating W
Blender F
Tooling
Rotation
Number o
ntegration
Uniformity
Content
Tablet Thickness
niformity
ardness
API Unifformity
Weight
ution
ution
Moisture C
Tablet W
Dissolu
Dissolu
Tablet Disin
Tablet Ha
Excipient U
Visual Un
13
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Class Exercise
` Divide room into groups of 3 to 5
` Select one process mapping tool
` 20 minutes to complete
` Discuss what information was gathered with each
tool
14
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4
4 8 12 16 20 Very High 4 Critical quality attributes cannot be met
High 3 Critical quality attributes may not be met
2 2 4 6 8 10
1 1 2 3 4 5
1 2 3 4 5
Probability
15
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Drug Layer Formulation Variables
Drug Drug Viscosity of
Product
Product Core Selection substance
Core Selection substance Binder
Binder Binder lot to
Binder lot to API/Binder
API/Binder drug
drug layering
layering
CQA (type/size) particle size type/grade lot variation ratio solution
Assay Low Low Medium Low Medium Medium
Content
Uniformity High Low Medium Low Medium Medium
Drug
Release Low Low High Medium High Medium
16
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17
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Objectives
18
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Source: www.ispe.org/pqli
Definition
of Product
Attribute Target Intended
Use and
Dosage Form and Size Product X, XX mg dose
pre-
Strength XX mg API per X mg dosage unit definition
(XX.XX% w/w anhydrous drug load) of Quality
Targets
Appearance/Description Similar to Innovator
(clinical
Identity List API (include compendial references) relevance,
A
Assay C
Commonly l 90 – 110% efficacy,
safety)
Moisture List target
Uniformity Meets USP
Impurities List impurities and known limits
Stability XX Months
PK/PD (Bioequivalence) Passes BE testing
Manufacturing Process Scalable, Reproducible, and Robust
19
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Prior
Process
Know-
Outline
ledge
List of Unit Summary
Operations of Prior
that lead Scientific
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
product etc.), Initial
(could be Risk
analytical) Assessment
to identify
Critical
Quality
Attributes
20
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21
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22
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23
60 4.0
50 5.0 # Failures
40 6.0
7.0
70
8.0
Parameter 1 (units)
30
Parameter 3 (units)
60
50 9.0
40 10.0
0.0
70
1.0
37
60
2.0
50
40 3.0
4.0
70 5.0 # Failures
44
60
6.0
50
7.0
40
8.0
240260 280 300 320 340 240260 280 300 320 340 240260 280 300 320 340
Parameter 4 (units) 9.0
10.0
23
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Objectives
24
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Source: www.ispe.org/pqli
25
9/23/2011
Prior
Process
Know-
Outline
ledge
List of Unit Summary
Operations of Prior
that lead Scientific
to Knowledge
intended (drug
drug substance,
substance process,
or drug unit ops,
product etc.), Initial
(
(could
ld b
be Ri k
Risk
analytical) Assessment
to identify
Critical
Quality
Attributes
26
9/23/2011
Unit Operations
Formulation Container
Composition 1 2 3 4 5 6 7 8 Closure System
Dosage Form Low Low Low Low Low Low Low Low Low Low
Strength Low Low Low Low Low Low Low Low Low Low
Appearance Low Low Low Low Low Low Low Low Low Low
Identity Low Low Low Low Low Low Low Low Low Low
Assay Low Low Low Low Low Low Low Low High Low
Uniformity Low High Low Low Low Low Low Low Low Low
Degradation Products Low Low Low Low High Low Low Low Low High
Dissolution High Low Low Low Low High High High High Low
Stability High Low Low Low High Low High Low Low High
PK/PD High Low Low Low Low High High High Low Low
Manufacturing Process High High High High Low High High High Low Low
¾Process Steps
System
p 1-3 have the highest
g risk to the p
product p
progressing
g g
e.g. DoE,
PAT Risk
PAT,
(based on prior knowledge, experience, etc.) Assessment
and Risk
¾ More thorough understanding needed earlier rather than later Control
¾Formulation fixed based on in vivo performance requirements
¾Other Process steps are relatively straightforward
¾ Can be looked at in more detail at a later date (lower priority)
¾Container closure system has been explored
¾ Data in-process (stability)
27
9/23/2011
What is DoE?
` DoE is “a structured, organized method for
determining the relationship between factors (X’s)
affecting a process and the output of that process
(y).” (ICH Q8)
` Process = {unit operation, formulation, assay}
` X’s = controllable (e.g., time, temp, amount of a
component) and uncontrollable (e.g., instrument,
operator, media lot) factors
` y=response
response variable
ariable
28
9/23/2011
Goals of DoE
` Efficient experimentation - versus “one factor at a
time”(OFAT)
` Reduced number of runs
` Covers wider space
` Hidden replication
` Effective experimentation - versus “one
factor at a time” (OFAT)
` Mitigates impact of artifacts such as run order and
experimental clustering
` Acknowledges main effects and interactions
Types of Designs
` Screening designs
` Used to identify significant factors
` Used to verify ruggedness
` Response surface designs
` Used to optimize a process
` Used to model a process
` Special designs
` Simplex – iterative optimization
` Mixture – constrained factors
` R b t – stability
Robust t bilit tto noise
i ffactors
t
` Split-plot – experimental units split into two dimensions
` Optimal – model is specified
29
9/23/2011
- +
Factor 1 200 300
Factor 2 1500 2500 • 9 factors each at 2
levels giving 12
Factor 3 300 500 runs
Factor 4 0 60 • Study of main
effects only
Factor 5 43 53 • No interactions
Factor 6 50 80 • No curvature
Data Collection
` Responses:
` Measured material attributes from in-process material
from Unit Operations 1,
1 2,
2 and 3
` Recorded dependent process information
` Calculated process yield
30
9/23/2011
90
• Factor 6 had a significant
80
negative effect on the
70
usable yield
Usable (%)
60
• The higher the value of
Factor 6, the lower the
50
usable yield
40
700 900 1100 1300 1500 1700
Factor 6
Linear Fit
Factors with significant effects (blue) were identified for each unit operation.
One factor (red) could not be evaluated in this design due to equipment
constraints.
31
9/23/2011
Translation to RSM
- +
Factor 1 200 250
Factor 2 2000
Factor 3 500
Factor 4 0 20
Factor 5 48 52
Factor 6 70
Factor 7 800 1600
Factor 8 500
Factor 9 6
32
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33
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Objectives
Comparison Summary
` Major QbD Focus ANDA NDA
API √
Excipients √
Formulation √ √
Manufacturing √ √
Packaging √ √
34
9/23/2011
Conclusions
` Independent of the type of submission, QbD
principles can and are being applied in
bio/pharmaceutical development.
development
` Risk management tools provide a means for
determining the focus and how QbD is applied
throughout the development program.
` Higher risk, more complex technology = more
evaluation of p
process steps
p and materials ((CPP,
CMA) and the determination of CQAs.
` The use of multiple tools allows the information to be
analyzed in different ways, providing new insights.
` Extra Slides
35
9/23/2011
ICH Q8 - Highlights
` The aim of pharmaceutical development is to
design a quality product and its manufacturing
process to consistently deliver the intended
performance of the product.
` Quality should not be tested into products, it
should be built in by design.
` Greater understanding of the product and its
manufacturing process,
process through the
implementation of quality by design, can create
a basis for more flexible regulatory
approaches.
36
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ICH Q9 - Highlights
` QRM is a systematic process for the
assessment, control, communication, and
control off risks to quality off a drug product
across the product lifecycle.
` Two primary principles of QRM:
` The evaluation of the risk to quality should be based
on scientific knowledge and ultimately link to the
protection of the patient
patient.
` The level of effort… of the QRM process should be
commensurate with the level of risk.
37
Abstract
Pharmaceutical companies are increasing their use of outsourcing
of manufacturing processes as a strategy for remaining competitive
in the global marketplace. This has placed greater emphasis on
process management at Contract Manufacturing organizations. Two
parties are now involved and it is critical that process knowledge
and understanding is developed and communicated back and forth
between the two parties. Quality by Design (QbD) is a disciplined
A Quality by Design Based Approach to and systematic approach for effectively developing and
Process Design, Control and Improvement communicating the needed process understanding. QbD provides
the common language needed to enhance the outsourcing process.
Ronald D. Snee This presentation will introduce the building blocks of QbD with a
Snee Associates, LLC
focus on how the needed process understanding is developed to
IVT’s 3rd Annual Bio/Pharmaceutical Conference on enable effective process development, transfer, improvement and
Quality by Design control. The concepts, methods and benefits involved will be
San Francisco, CA introduced and illustrated with pharmaceutical case studies and
September 14-16, 2011 examples.
1 Snee Associates, LLC 2 Snee Associates, LLC
Agenda Today’s Environment
{ Outsourcing to CMOs is on the increase
{ Today’s Environment { Some companies want to develop partnerships to reduce
{ QbD – What, Why and the Building Blocks the number of CMOs utilized
Design Space, Process Control and Risk Management { Partnerships are more easily praised than practiced
{ Developing Process Understanding Viewed as a continuing, never ending process
{ Experimental Strategies for Process Design Common language
Common method of working together
Identifying the Critical Control Parameters (CCP)
Development of trust
Experimentation – Right Data in the Right Amount at the
{ Process understanding is critical to success
Right Time
Process design, improvement and control
{ QbD Monitoring System for
Communication and collaboration
Process Performance and Product Quality
{ FDA updated Process Validation Guidance (Jan 2011)
{ QbD Enables Successful Tech Transfer Elaborates on QbD techniques for process development,
{ Summary risk analysis and process control
Design Space
Product Is
Predicted
to Be
Within Specs
Control Point
(105, 11.5)
Design Space
Process Understanding Reduced Process Variation
is Required to Create the
Control Control Design Space Enhanced Prediction of
Space Q Space Z Process Performance
Analyzing Process Variation Leads to
{ Increased Process Understanding
{ Reduced Process Variation
11 Snee Associates, LLC
{ Reduced Risk 12 Snee Associates, LLC
Predicting Process Performance
Check List for Process Understanding Controlled Variables (Xs)
• Press speed
{ Critical variables (Xs) that drive the process are known • Compression forces
{ Critical uncontrolled (Environmental) variables that • Pre-compression forces
Y = f (X)
affect the process output (Ys) are known and: • Punch separation
Process has been designed to be insensitive to these Process Inputs (Xs) Process Outputs (Ys)
uncontrolled variations (robustness) • Raw Materials • Thickness
• Energy Compression
{ Measurement systems are in place and the amount of Process • Hardness
• Tooling • Friability
measurement variation is known
• Weight
{ Process capability is known • Yield
Uncontrolled Variables (Xs) • Waste
{ Process failure modes are known
• Ambient Temp and Humidity • Dissolution
{ Process control procedures and plans are in place • Shift
{ You can accurately predict process performance • Operators
• Machine
QbD Provides Methods and Tools for • Raw Material Lot
Developing Process Understanding • Powder Flow Characteristics
13 Snee Associates, LLC 14 Snee Associates, LLC
Using Quality by Design to
Improve Dissolution Performance
Case Study – Product in Late Stage Development Strategy of
New formulation in development for 8 years – validation
not complete
Using QbD product successfully launched in 1 year Experimentation
Design of Experiments (DOE) identified
Variable with largest effect was previously unknown
Critical interactions between 4 raw material variables
• Strategy:
and 5 process variables The science of planning and directing an activity
New measurement method identified need to tighten raw • What strategy do you adopt when using
material specs
experimentation to improve a process?
Quality by Design • What critical issues do you consider and
• Increases Process Understanding Enabling Timely
Process Optimization and Control pay attention to?
• Enables You to Obtain the
Right Data at the Right Time in the Right Amount
Historical
Process Map C&E Matrix FMEA
Data
Reducing
Experimentation Risk List of
Candidate
Ensuring that We Don’t Miss Any Tribal Knowledge Xs
{ Need a strategy for experimenting in this environment Qualitative (reactor type, catalyst, team)
that minimizes the amount of experimentation { Type of output variables (Y) – continuous or discrete?
{ An effective Strategy: { Can the factors be studied over their full ranges?
Diagnose the experimental environment { Resource constraints – time, funds($$), people
Decide the quality of information needed { Quality of prediction required:
Select the appropriate experimental design Identify “key drivers”, find “sweet spot”, define
Conduct the experiment design space or make predictions?
{ Is the available scientific theory useful:
Has a theory been developed for all responses?
Average
Process Variable
Lower Control Limit (LCL)
Time or Sequence
{ Consistently produces
product that is within
specifications for all
product parameters.
{ Process capability Reducing Process Risk
analysis compares the Improving Process Stability and Capability
process variation to the
lower and upper
specification limits Statistical Process Control
{ Broadly used measure of Process Capability Indices
process capability is the
Ppk index
UCL=1.07360
1.07
Average
1.06
_
X=1.05489
Process Variable
1.05
Lower Control Limit (LCL) Individual Value
1.04
Time or Sequence LCL=1.03619
1.03
Control Limits Are Not Specification Limits! 1 19 37 55 73 91 109 127 145 163 181
Sample of 10 Tablets
Individual Value
97 standard deviations
96
LCL=95.546 Process Stability Long-Term Variation
95 Not a Problem < 20%
1 14 27 40 53 66 79 92 105 118
Batch May be A Problem 20 – 30%
Corrective Action Needed > 30%
Between-Batch 1.06
_
Long-Term X=1.05489
Variation
Individual Value 1.05
Batch
Mean 1.04
LCL=1.03619
1.03
1 19 37 55 73 91 109 127 145 163 181
Sample of 10 Tablets
101
Process Risk Using
100
99 _
Process Capability Indices
X=98.682
98 • Short-Term (Cp and Cpk)
LT Variation LT Variation
Individual Value
97 =6% =23%
(p=.41) (p=.14) • Long-Term (Pp and Ppk)
96
LV Variation LCL=95.546
95 = 64%
1 14 27 40 53 66 79 105
92 (p=.001)118
Batch
Average – LSL
USL – Average Cpk = = 0.33 Poor
Cpk = = 1.33 Good!! 3 (Short-term Standard Deviation)
3 (Short-term Standard Deviation)
Marginally Capable
Two traditional measures of process performance: LSL USL
LSL
Cp = 1.0 USL
Poor
USL – LSL
Pp = Capability
6 (Long-term Standard Deviation) Cp < 1.0
Where: 40 45 50 55 60 65 44 46 48 50 52 54 56 58
Periodic Process
Capability Indices are Highly Variable when Reports &
Information to Analysis and Improvement
Estimated from Small Samples System
Management Reviews
Current
Current (X, Y) Performance
Performance =38
Deviation Target
Deviation
Target from Target =34
from Target
38-34=4
Required Required
Change in X Change in X
= -16
Batch
Production Sense of Lean Six Sigma
Over Time Tools
Urgency Results ($$)
Grams
Raw Material Lot
500 LCL=516.5
4.9
Variation 400
Lot 3
300 4.8
Better Raw Material
% ACTIVE INGREDIENT
200
Subgroup 0 10 20 30 40 50 60 4.7
Specs Required
A:Batch 62 72 84 94 104
4.6
1 12 24 36 48 60 72 84 96 108
Used DMAIC to Identify Key Drivers of Process Yield Batch
Raw Material Lot Variation Had the Largest Effect
5.2
A
B
A B
5.1 CC
B B B
A B B A
A BA B BB B B BBB BBB BB BB B B B
AB B B BBB B
5.0 B A A BB B B B BB B B B B B B
AA BB B B B B D
B B C A B B C
A B BB B D B
A B A BB B A A DD B
4.9 D
B C D ANALYST
A B B BB B B B
4.8 A C
A B CC
% ACTIVE INGREDIENT
A A D D
A
A A 4.68 4.77 4.86 4.95 5.04 5.13 5.22
4.7
A A A % ACTIVE INGREDIENT
A
4.6
1 12 24 36 48 60 72 84 96 108
Batch
2100
Yield
2000
1 2 3 4
Team
# Deviations
{ Monitor the prediction residuals to detect deterioration in
the prediction accuracy of the model
Type of Process
Residual = Observed Y – Predicted Y
Improvement DMAIC { Monitor the predictor variables (Xs) to detect a shift of the
process outside the design space region of the data used to
Implemented and Improvement build the original model
Confirmed Process
0.18 UCL=0.1800
0.25 { Model prediction residuals were all within the control
0.16
0.20
0.14 _
limits indicating that the regression model predicted
_ 0.15 X=0.15
X=0.125
0.12 well
0.10
Individual Value
Individual Value
0.10
0.05 Two of the prediction points (5,6) were slightly outside
0.08
LCL=0.0700
0.00 LCL=-0.0000
0.06 the region of the data
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Observation Observation
{ The model is predicting well. There is no need to
Component B Component C update the model at this time
I Chart of B I Chart of C
0.75 1 0.16
UCL=0.15
0.70 UCL=0.7 0.14
0.65 0.12
0.10
0.60
0.08 _
0.55 _ X=0.075
X=0.535
0.06
0.50
Individual Value
Individual Value
0.04
0.45
0.02
0.40
LCL=0.37 0.00 LCL=-0.0000
0.35
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
Observation Observation
{ Regular management reviews are essential You Can’t Successfully Control, Improve or Transfer a
Process that You Don’t Understand
{ Rapid and smooth start-up { Rapid and smooth start-up { QbD produces process understanding that is
{ Predictable outcome – No { Predictable Outcomes – No fundamental to creation of
surprises surprises Design Space and sustaining performance
{ High product quality { High quality product and reduced Process control and improvement system
operating costs { QbD concepts, methods and tools provide a common
{ Sustainable product and { Sustainable product and process language and methodology for working together
process quality over time quality over time resulting in
Fewer investigations Fewer investigations Regulatory flexibility,
{ Satisfied customers { Satisfied client Improved process performance and compliance
{ Competitive Advantage { Competitive Advantage Enhanced bottom-line results for all parties involved
Gary W. Denney
Director, Product R&D
Eli Lilly and Company
Agenda
• Establishing
g a ICH Q10 Integrated
g Quality
y System
y
• Integrating QbD and Quality Systems
• QbD Implementation
• QRM and Knowledge Management
• QbD Benefits
B fit
• Discussion / Q&A
1
Pharmaceutical Quality System
Q10
Pharmaceutical Development
•Life Cycle
y Approach
pp
Q8
10 •Quality System Elements
•Life Cycle Approach 8
•Enablers
•Product knowledge 9 •QS for Control Strategy Execution
•Design space
•Verification
•Product & Process development
•Continuous Improvement
•Control Strategy Development
10
9
9
3
Management Responsibilities
Knowledge Management
Enablers
Quality Risk Management
2
ICH Q10 Pharmaceutical Quality Systems
3
Integrated Quality Systems
Complaints
Manufacturing/
Development Distribution
4
Integrated Quality Systems
MANUAFACTURNG
QUALITY SYSTEM
Product R&D QS
Lilly Quality
Standards
10
5
Lilly’s Quality System Approach
Integrated Business
Standards Processes
Robust
Governance/ g
Organization
Management
Controls
11
•Clear
Clear requirements to
meet both compliance
and patient expectations Integrated
Standards
•Owned by Quality and the
business
Quality Standards covering
• Quality Systems
• Commercialization Contract Manufacturing
Commercialization, Manufacturing, Clinical Supply Manufacturing
• Facilities, Utilities, Maintenance, Equipment, and Computer Systems
• Materials
• Production
• Packaging and Labeling
• Laboratories
12
6
Lilly’s Quality System Approach
13
•Management Involvement
Robust
•Escalation Governance/
•Decision Making Management
•Auditing Controls
14
7
Lilly’s Quality System Approach
•Right People
•Right Role
Organization
•Clear Accountability
•Right Span of Control
Examples of Organization includes:
• Defined personnel qualifications
• Formal and documented training
• Defined responsibilities for roles
• Monitoring and maintenance of personnel qualifications
• Appropriate and effective organizational structure
• Education & training
• Leadership
15
• Clear requirements
to meet both • Simple
compliance and • Effective
Effecti e
patient
• Efficient
expectations Integrated Business
• Owned by quality Standards Processes • Agile
and the business
Robust
• Management
g Governance/ • Right People
Organization
Involvement Management • Right Role
• Escalation Controls • Clear Accountability
• Decision Making • Right Span of
Control
• Auditing
16
16
8
Lilly’s Quality System Approach
External Environment External Internal
•Q8, Q9, Q10 implementation Environment Trends
•Batch Release/QP responsibilities
•Regulatory Enforcement
•Emerging Markets
Internal trends
•Deviations Integrated Business
•Recalls Standards Processes
•Agency observations
•Audit observations
Robust
17
Integrating QbD
and Quality Systems
18
9
Quality Systems and QbD
19
20
10
QbD Business Processes
21
22
11
Quality by Design Leadership
Lilly’s
Lilly s Approach to QbD
• Establish an enterprise wide QbD vision
• Provide leadership and stewardship for QbD Implementation
• Provide a forum for cross-functional consulting on QbD
• Ensure Lilly representation for external QbD initiatives
• Ensure organizational QbD education
• Incorporate learning
23
QbD Education
24
12
QbD Education
25
QbD implementation
26
13
Level of QbD Adoption
27
Implementation Challenges
• External Challenges
• Internal Challenges
• Benefits
28
14
Internal Challenges
Small
Molecule
Large
DP
Molecule
API
Complexity of Small Qb
Molecule
the Business API D Large
Molecule
DP
Devices
29
Cross-Network Differences
30
15
Cross-Network Complexities
31
Within-Network Complexities
32
16
Internal QbD Perspectives
Costs
• Is the upfront investment worth the potential gains
• Increased workload on project teams
• Determination of ROI
Adoption
• “We’ve done this all along”
• Limited or skeptical support at best
33
34
17
Quality Risk Management
and
Knowledge Management
35
36
18
Quality Risk Management
Weak Sustainability Strong
High High
Majority time & resources
8 10 spent on improving control
9 strategies, closing knowledge
gaps, which lends focus to
Majority of time Proactive
manufacturing excellence
Knowledge
and resources
Cost
Including; reduced cycle
spent times, improved yields ,
understanding Reactive
efficient qualification,
cause and effect validation, training
relationship
p in Elimination of
order to provide Level 3 Deviations and
Low assurance Factory Loss Low
Weak Strong
Robustness
37
6
Knowledge
4 Product 1
3 Product 2
Product 3
2
0
1 year 2 years 3 years 4 years 5 years 6years
38
19
Quality Risk Management
39
Benefits of QbD
Implementation
40
20
The Path to QbD Implementation
Increased Investment to Start
(e.g., development costs,
pment & Manufacturing Costs
organizational planning,
new tool implementation) Meet Patient Needs
(e g reliable performance and supply)
(e.g., reliable performance and supply)
Current State
Transition
Decreased Expenses
• Empirical development approach (e.g., lower manufacturing
• Quality by testing & inspection and compliance costs,
• Frozen process with reactive changes familiarity with tools)
Desired State
Develop
• Quality by design development
• Flexible process & continuous improvement
Initial QbD Efforts QbD Fully Realized
QbD Implementation Progress
41
42
21
Benefits to QbD Implementation
Regulatory Benefits
• Flexibility for process changes within design space
• Reduction in number of post approval supplements
Company Benefits
• Higher likelihood of best process first
• More thorough process understanding earlier
• Fewer failures and recalls, improved safety record
43
44
22
ICH Q10 and QbD
Ensures Compliance
45
Acknowledgements
46
23
47
24
Implementing QbD in the
Development of Generic Drug
Products
Disclaimer: Opinion expressed in this presentation represents solely the views of the author
Presentation Outline
n Requirements for QbD in Generics
n Quality Target Product Profile
n Criticality and Critical Quality Attributes
n Therapeutical Equivalents
n Status of Question-based Review (QbR)
n Use of prior knowledge in generics
n Risk Assessments-identify the CPP’s and CMA’s
n Implementation of QbD
n Control Strategy
n Summary
Application of
Design space • Develop a design space PAT Tools
Experiments
Control Strategy Trospium XR 60mg Commulative Dissolution Profile - Apparatus IV
100
90 INNOVATOR L/N 0702997
80
NB574A-11
70
% R elease
60
50
40
30
20
10
0
0 2 4 6 8 10 12
Time (hours)
*Adapted from GPhA FDA QbD Workshop, May 2010, “Quality by Design for ANDAs: An Example for Immediate Release Dosage 3rd Annual IVT
Forms” – Draft Example QbD Immediate Release Dosage Forms Conference
What are the general Expectations
(generics)?
*for generics – adapted from GPhA FDA QbD Workshop, May 2011, “Define Quality by 3rd Annual IVT
Design for Generic Drugs”, Lawrence Yu, Ph.D. presentation Conference
Quality Target Product Profile (QTPP) –
Beginning with the end in mind
n Natural extension of the Target Product profile for product quality
n Prospective summary of the quality characteristics of the drug product taking into
account the safety, efficacy (and manufacturability) of the drug product
n Factors to be considered
Identify Critical Quality Attributes of the Drug Product
Route of Administration (Oral versus Intravenous drug product)
Type of dosage form (Immediate versus modified release)
High dose versus low dose
Target population
Type of therapy (life saving versus quality of life)
For e.g. Administration of dosage form via a specific type of feeding tube for
pediatric and dysphagic patients
Administration of split or crushed tablet (draft guidance just issued by FDA)
Sprinkle formulation requires to meet a bead size criteria (new guidance)
Adapted from “ Quality Target Product Profile with Examples”, Robert LionbergerI, 3rd Annual IVT
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 Conference
Summary: QTPP in Generic Drug Development
n QTPP is the starting point and is used as a starting point to identify what is
the drug product CQA
Brainstorm list of
Prior QTPP
Quality Attributes
Knowledge
(potential CQAs)
List of CQAs
Identity; Assay;
Critical Quality Attributes Drug Substance CQA’s
Description; Purity;
Physical Properties
n Continuum of Criticality
Several levels of criticality may be used to describe multiple levels of risk
- As attribute or parameter boundaries approach edges of failure, the level
of criticality increases with the level of risk
Inputs: Outputs:
M1 CQA1
Critical
M2 CQA2 Quality
Attributes
Material Attributes
CQA3
P1
P2 Relationships:
CQA1 = function (M1)
P3 CQA2 = function (P1, P3)
Process CQA3 = function (M1, M2, P1)
Parameters
P2 might not be needed in the
establishment of design space
3rd Annual IVT
Conference
Therapeutic Equivalence and Pharmaceutical
Equivalence as applicable to Brand Drug
n Therapeutic Equivalents
- “… have the same clinical effect and safety profile when administered top
patients under the conditions specified in the labeling.”
n Pharmaceutical Equivalence
Same active ingredients
Same dosage form
Same route of administration
Identical in strength or concentration
Meet compendial or other applicable standards of strength, quality, purity, and
identity
May differ in shape, release mechanisms, excipients, packaging, expiration
date, etc.,
n Currently the QbR questions will be revised in 2011 and a new system is planned to
be implemented from January 2013.
This will include enhanced understanding through the use of QbD
concepts that will help reduce the post market related issues
OPS MAPP 5016.1: that applies the principles of ICH Q8(R2), Q9, and Q10
to the CMC review process.
n It is relevant to submission–
Clearly delineates similarities and differences
Properly links CQA’s with CMA’s and CPP’s
n It is justifiable/qualifiable
Through scientific rationale
Supported by relevant data
“Use of Prior Knowledge in QbD – IR and MR Examples”, Khalid M. Khan, M. S., R. Ph., CMC, Division of Chemistry III,
3rd Annual IVT
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 Conference
Use of prior knowledge
n Prior knowledge can reduce the number of experiments that need to be
studied for a given product and process.
n Due to the nature of the generic business, a number of standard
technology platforms are extensively used. Thus, there is extensive prior
knowledge and experience with these processes. These include
Direct compression/Roller compaction/ Wet granulation
Blending, milling, compression and film coating
Drug Layering/ DR or ER coating / Encapsulation
“Use of Prior Knowledge in QbD – IR and MR Examples”, Khalid M. Khan, M. S., R. Ph., CMC, Division of Chemistry III,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 3rd Annual IVT
Conference
Take Home : Prior Knowledge
“Use of Prior Knowledge in QbD – IR and MR Examples”, Khalid M. Khan, M. S., R. Ph., CMC, Division of Chemistry III,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011
Inputs: TPP and prior Inputs: DOE results Inputs: DOE results and Inputs: manufacturing
knowledge (commonly bench/pilot scale process process knowledge
Risk obtained from similar knowledge
Assessment products and/or scientific
literature)
Outputs: DOE strategy Outputs: Additional or Outputs: Preliminary Outputs: various (could be
refined DOE strategies (if manufacturing control change control plans,
Risk Control necessary) and a strategy and refined refined control strategies,
(Plans & preliminary manufacturing design space revalidation, etc.)
design space
Outputs)
DOE results trigger next DOE results and Scale-up and Manufacturing experience
risk assessment bench/pilot scale demonstration batch triggers potential process
manufacturing experience results trigger potential and control strategy
trigger next risk process and control refinement
Risk Review assessment strategy refinement
Set Thresholds
H IG H HIGH
RISK
P Urgent attention
R MED
O MEDIUM
B RISK
Regular review
LOW
LOW
RISK
Monitor
LO W MED H IG H
IM P A C T
Feeder Speed
Coater Type
Mixing time
Spray Rate
Dew Point
Inputs Outputs
Tablet Yield (Compression) Coating Yield
Hardness (Compression) Moisture
Appearance(Compression) 1. Material transfer Dissolution profile
Friability (Compression) 2. Color suspension Tablet Weight
Tablet Shape 3. MaterialPreparation
transfer Appearance
Tablet Embossing 4. Coating Stability
Moisture (Drying and Hold Time, 5. Discharge Degradation
Tablet size
Raw Material (coating) Characteristics -
Wettability of Tablet Surface
Hygroscopicity of tablet (formulation)
Tablet dissolution
Tablet Defects
Key
Moisture
HIGH RISK
MEDIUM RISK
n Agency is does not recommend using any specific risk assessment tool
n The justification for each identified risk is most important and a clear
strategy should be summarized in the assessment process.
&
Quality
Process Risk Assessment
Perform
Experiments Understanding
Identify and Prioritize
Process Parameters
Experimental
Prioritization Planning
Level of Sophistication
1st
Principles
HIGH
MECHANISTIC
MODELS
EMPIRICAL
MODELS
MEDIUM
HEURISTIC RULES
Use of DoE e in QbD – IR and MR Examples”, Y. Peng., CMC, Office of Generic Drugs, GPhA/FDA QbD Workshop for 3rd Annual IVT
ANDAs, May 2011 Conference
Steps Involved in DoE Study
Use of DoE e in QbD – IR and MR Examples”, Y. Peng., CMC, Office of Generic Drugs, GPhA/FDA QbD Workshop for 3rd Annual IVT
ANDAs, May 2011 Conference
39
QbD Implementation Aspects - People
Quality by Design
Formulation
Operations Development
Regulatory Analytical
Affairs Development/PAT
Technology
Chemometrics
Quality
Statistics
Operations
UCL
LCL
Stable Process
LSL
Process understanding
Determination of
Cause – Effect relationships
(Risk Identification with subsequent Risk Analysis)
Risk-based classification
(Risk Evaluation)
September 15, 2011 F. Erni – EFPIA Working Group 3rd Annual IVT
43 Shailesh K. Singh, Ph.D. Conference
State of Control Strategies
Adapted from “ Control Strategy in Generci Drug Development”, Youmin Wang, Ph.D.,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011
Control Strategy
Adapted from “ Control Strategy in Generci Drug Development”, Youmin Wang, Ph.D.,
Office of Generic Drugs, GPhA/FDA QbD Workshop for ANDAs, May 2011 3rd Annual IVT
45 September 15, 2011 Shailesh K. Singh, Ph.D. Conference
Control Strategy
It is not just Manufacturing Controls
QbD APPLICATION
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
COMPLIANCE BY DESIGN (CbD)
COMPLIANCE BY DESIGN (CbD)
and
COMPLIANCE MASTER PLAN (CMP)
A LIFECYCLE Approach
Paul L. Pluta, PhD
OUTLINE / OBJECTIVES
1. Why?
2. Quality by Design (QbD)
– Compliance by Design (CbD) comparison
3. Validation Master Plan (VMP)
– Compliance Master Plan (CMP) comparison
4. Lifecycle Approach
– Process Validation Lifecycle comparison
5. Implementation
6. Benefits and Problems
7. Discussion
1
9/6/2011
WHY CbD / CMP / LIFECYCLE APPROACH?
Development has been revolutionized by QbD ‐‐ an organized
approach with defined objectives and steps. Industry and
regulatory have strongly embraced and supported QbD.
Validation Master Plans (VMP) are successful and widely
V lid i M Pl (VMP) f l d id l
accepted documents useful to industry and regulatory.
The FDA Process Validation Guidance has introduced the lifecycle
approach to process validation.
Coincident with growth and success of QbD have been serious
GMP
GMP compliance incidents (heparin, glycerin, Viracept, J&J,
li i id t (h i l i Vi t J&J
Genzyme).
Can QbD, VMP, and lifecycle approaches be applied to
improve compliance?
3
CbD / CMP / LIFECYCLE OVERVIEW
QUALITY SYSTEMS
Development of system
– Objective and attributes of quality systems
j q y y
– Parameters to achieve objectives and attributes
– Variation affecting parameters
– Control of variation
Performance of system
Maintaining system
– Maintain and monitor system
– Improvement projects
Documentation
2
9/6/2011
QUALITY BY DESIGN
• Target product profile (TPP) and critical quality
attributes (CQA)
• Drug substance and excipient properties
• Formulation design and development
• Manufacturing process design and development
• Identification of critical process parameters (CPP)
and critical material attributes (CMA)
• Risk assessment and design space
Risk assessment and design space
• Scale up, identification of variables, and control
strategy
Red = Original QbD
5
COMPLIANCE by DESIGN
CbD is an organized approach to compliance with
quality systems. CbD has a defined structure with
objectives and associated content CbD continues
objectives and associated content. CbD continues
throughout the lifecycle of the quality systems.
CbD approaches quality systems as a development
project in the manner of QbD.
Can compliance be improved by using QbD concepts?
3
9/6/2011
COMPARISON –
COMPLIANCE BY DESIGN and QUALITY BY DESIGN
Objectives and critical compliance attributes (CCA)
– What are the goals of each quality system?
– What makes a quality system successful?
Critical compliance parameters (CCP)
– What factors may significantly influence the success of the quality system?
Input variation and control
– What variation in quality system operation is expected and how is it
controlled?
Ongoing maintenance and management
– How is performance monitored and maintained?
How is performance monitored and maintained?
Continuous improvement projects
– How can the quality system be improved?
CbD approach equivalent to QbD
Ongoing maintenance and management = Stage 3 process validation
Continuous improvements expected from ongoing monitoring.
7
VALDIATION MASTER PLAN
Sections discuss site validation categories
– Validation policy
– Equipment
– Facilities (HVAC)
Facilities (HVAC)
– Utilities
– Process
– Cleaning
Tables with document references (IQ, OQ, PQ)
Validation commitments and timelines
Regular updates (quarterly?) related to needs frequency
Regular updates (quarterly?) related to needs frequency
Note “chapters” of VMP
VMP is routinely requested by regulatory auditors.
4
9/6/2011
COMPLIANCE MASTER PLAN
CMP is an organized approach to documenting the CbD
methodology. CMP has a defined approach, structure, and
content CMP is a working document that is continually
content. CMP is a working document that is continually
maintained throughout the quality systems lifecycle.
Can compliance documentation be improved by use of VMP
concepts?
COMPLIANCE MASTER PLAN
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
• Packaging and Labeling System
• Laboratory Control System
• Training System
• Validation System
• Product Review System
• Stability System
• Product Complaint System
• Others
Red = FDA Quality Systems
Note “chapters” of CMP
10
5
9/6/2011
COMPLIANCE MASTER PLAN
SYSTEM TITLE
• System and subsystem descriptions
S t d b t d i ti
– Objective and critical attributes
– Critical parameters affecting objective
– Input variables and control strategy
– Ongoing maintenance and management
• Continuous improvement project status
• References (includes project reports)
11
LIFECYCLE APPROACH
FDA Process Validation Guidance (January 2011)
Lifecycle Approach to Process Validation
• Stage 1. Process Design
– Includes QbD, PAT, risk management
• Stage 2. Process Qualification
• Stage 3. Continued Process Verification
Process validation always ongoing
P lid ti l i
Continuous improvements expected
12
6
9/6/2011
LIFECYCLE APPROACH
1. Understanding and planning
2 Performance
2.
3. Maintenance and monitoring
• System performance
4 Continuous improvement
4. Continuous improvement
Application to equipment, computer systems, etc.
13
LIFECYCLE APPROACH
Validation Evolution
1978 ‐‐ CGMP includes Validation
1978 CGMP includes Validation
14
7
9/6/2011
LIFECYCLE APPROACH
Recent speakers on various aspects of validation and
qualification have adopted the lifecycle approach to their
fields.
– Equipment
– Facilities
– Utilities
– Cleaning
– Computer systems
Can compliance be improved by use of lifecycle concepts of
Can compliance be improved by use of lifecycle concepts of
process validation?
Are quality systems designed, maintained, and monitored to
yield continuous system improvements?
15
LIFECYCLE APPROACH
ICH Q10. Pharmaceutical Quality Systems
• Pharmaceutical Development
• Technology Transfer
Technology Transfer
• Manufacturing
• Product Discontinuation
ICH Q10 focus ‐‐ product performance
throughout product lifecycle.
g p y
CbD focus ‐‐ quality systems performance throughout
quality system lifecycle.
16
8
9/6/2011
IMPLEMENTATION AND EXAMPLES
Overview and approach
Material System
• Multiple subsystems
Training System
• One system serves all site areas
One system serves all site areas
17
CbD / CMP / LIFECYCLE IMPLEMENTATION
1. Identify systems in the organization
– FDA systems (6) are major systems
– Addition “subsystems” are identified in FDA Quality System
– Other systems support multiple major systems
Other systems support multiple major systems
2. For an individual system:
– Identify complete business process
– Identify subsections
– Identify objectives , CCA, CCP, variation, controls for all subsections
– Gap analysis of subsections
– Risk analysis of subsections
3. Continuous improvement projects based on gap analysis,
3 Continuous improvement projects based on gap analysis
risk analysis, and ongoing monitoring
4. Documentation in CMP
5. Repeat for all systems based on risk.
18
9
9/6/2011
CbD / CMP LIFECYCLE IMPLEMENTATION
– Identify complete business process
– Identify system subsections
– Identify objectives and CCA, CCP, variation, and controls for all
subsections
– Gap analysis of subsections
– Risk analysis of subsections
– Initiate improvement projects
– Documentation
Above analysis and evaluation conducted by management,
each section staff, and QA ‐‐ with cross functional input
– Staff participation critical
– Cross‐functional input critical
Ex: Process experience, incoming test data, vendor audits
Ex: Process experience, deviations, CAPA, training
19
EXAMPLE: MATERIAL SYSTEM BUSINESS PROCESS
1. Identify approved vendors to source incoming materials
– Vendors approved by Vendor QA
2. Receive incoming materials
3. Store incoming materials – quarantine status
4. Submit samples for testing
5. Receive and evaluate test results
6. Transfer tested materials to materials to status areas
– Approved or Rejected. Materials on test remain in quarantine
7. Dispense approved materials to manufacturing and packaging locations
8. WFI, gas, and compressed air distribution
9. Received and store manufactured / finished products – quarantine
status
t t
10. Transfer tested materials to status areas
– Approved or Rejected. Materials on test remain in quarantine
11. Transfer approved materials to distribution center
12. Ship approved materials from distribution center to customer
20
10
9/6/2011
COMPLIANCE BY DESIGN
MATERIAL SYSTEM SUBSECTIONS
Incoming Materials ‐‐ Sourcing
Incoming Materials – Storage/testing/disposition
Incoming Materials
Drug dispensing
Water/gas/air testing/distribution
Finished Products – Storage/testing/disposition
Finished Products – Distribution
Finished products – Offsite distribution
Above customized to site organization
21
COMPLIANCE BY DESIGN ‐‐ MATERIAL SYSTEM
INCOMING MATERIALS ‐‐ SOURCING
System objective and critical attributes
• Obtain high quality materials (API, excipients, commodities) from QA‐approved vendors for eventual
dispensing to product manufacturing
Critical parameters affecting objective
• QA audit, investigate, and approve material suppliers
• Vendor procedure, process, and management changes
p ,p , g g
Input variables and control strategy
• Material variation
• Vendor outsource commodity items
Ongoing maintenance and management
• Approved supplier list
• Material specifications
• Material test data monitoring
• Non‐conforming materials received
Continuous improvement project status
1. Risk analysis of incoming materials. See Appendix for project description.
2. Supplier risk evaluation. See Appendix for project description.
Reference documentation
• Risk analysis of incoming materials. J. Doe, 1‐1‐10.
• Supplier risk evaluation. J. Smith 1‐4‐10
Appendix
1. Project Description: Risk analysis of Incoming Materials.
2. Project Description: Supplier Risk Evaluation.
22
11
9/6/2011
COMPLIANCE BY DESIGN ‐‐ MATERIAL SYSTEM
INCOMING MATERIALS – STORAGE / TESTING / DISPOSITION
System objective and critical attributes
• Storage of high quality materials (API, excipients, commodities) prior to dispensing to
product manufacturing. Materials stored according to recommended temperature.
Materials stored according to QA disposition (Approved, Quarantine, Rejected)
Critical parameters affecting objective
p g j
• Vendor storage recommendations
• Vendor expiration date recommendations
• Power supply to storage areas
Input variables and control strategy
• Storage recommendations per vendor checklist.
• Expiration date recommendations per vendor checklist.
• Alarm system for temperature limits
Ongoing maintenance and management
Ongoing maintenance and management
• Material inventory list ongoing
• Facility monitoring system
Continuous improvement project status
• Refrigeration backup generator
Reference documentation
• Material requirements
23
TRAINING SYSTEM BUSINESS PROCESS
Functions, work centers, procedures (training modules), and personnel
Training system uses validated tracking software
Training system defines training categories
Function defines work centers
Function assigns procedures to work centers
‐ Procedures include training category and retraining frequency (risk based)
g
‐ Training modules written
‐ Training modules approved
Function assigns personnel to work centers
Functions, work centers, procedures, and personnel entered into tracking software
QA approval
1. Personnel trained according to category and frequency
2. Personnel training completion in tracking system
3. Training status reported by software
4 T i i
4. Training modules evaluated by trainees
d l l db i
24
12
9/6/2011
TRAINING CATEGORIES
Company information (general news, holidays)
Awareness of common procedures (ethics, analytical
methods, tablet machine parameters) –
th d t bl t hi t ) read and
d d
sign
Policies and procedures – (GMP) ‐‐ classroom
Performance (OtJ) training (HPLC, tablet machine
operation) qualification
SME qualification (expert designation)
External continuing education (scientific meetings)
25
COMPLIANCE BY DESIGN – TRAINING SYSTEM
System objective and critical attributes
• Provide effective training to site personnel
Critical parameters affecting objective
• Development of high quality training modules
• Selection of appropriate training category and retraining frequency
Selection of appropriate training category and retraining frequency
• Competency of training instructors
Input variables and control strategy
• Employee experience and learning motivation
• Work center recommendations on training category and retraining frequency
Ongoing maintenance and management
• Training module completion records
• Trainee evaluations
• Correlation of training modules and exception events
C ti
Continuous improvement project status
i t j t t t
1. Risk analysis of site positions. See Appendix
2. Training Module X development
Reference documentation
• Risk analysis of site positions. J. Jones, 1‐1‐10.
Appendix
Project Description: Risk Analysis of Site Positions
26
13
9/6/2011
COMPLIANCE MASTER PLAN
• Introduction and policy
• Quality System
• Facilities and Equipment System
• Materials System
• Production System
Production System
• Packaging and Labeling System
• Laboratory Control System
• Training System
• Validation System
• Product Review System
• Stability System
• Product Complaint System
Product Complaint System
• Others
Each system with subsections has description, objectives, CQA, CCP, variation,
control of variation, projects completed (improvements), commitments, etc.
CMP available to auditors
27
CbD / CMP / LIFECYCLE POSITIVES
• Organized and comprehensive focus on compliance based on risk to
the patient and the organization – Based on successful concepts
• System design ‐‐ Gap analysis
• Risk analysis
• Cross‐functional systems thinking
Cross‐functional systems thinking
• Consistent prioritized mitigation activities across functions – based
on risk
• Variation identification and control strategy
• Centralized tracking of commitments
• Continuous improvements based on systems monitoring
• Standardized audit expectations and documentation
• Organization commitment, transparency, and credibility
Organization commitment transparency and credibility
• Track organization accomplishments completed
• Strong message to employees
• Strong message to auditors
• Potential “credit” in audits for projects completed and new
commitments identified
28
14
9/6/2011
CPD / CMP / LIFECYCLE NEGATIVES
Difficult
• Getting organized is extremely difficult!
• Risk analysis is difficult
• Gap analysis is difficult
• Changes are difficult
Transparency
• Being open about gaps and deficiencies may have
regulatory and political risks
O ga at o a co
Organizational commitments
t e ts
• Headcount needed to correct deficiencies
Do the benefits outweigh the negatives?
29
OTHER THOUGHTS
ASTM E2500
• Addresses validation criticism by risk prioritization
• Pfizer using
FDA Comments
• Prosecution of responsible executives / management
• Transparency
p y
• Generally positive comments on QbD ‐‐ Concerns about implementation
• Site organization according to systems
ICH Q10 Pharmaceutical Quality System Elements
• Process performance and product quality monitoring system
• CAPA system
• Change management system
• Management review of process performance and product quality
Medical Devices
• Management controls
• Design controls
• CAPA
• Production and process controls
• Sterilization process controls
• Sampling plans instructions
30
15
9/6/2011
GETTING STARTED
1. Identify high risk areas
– Example: Sourcing of incoming materials
– Example: Aseptic core area training
2. Senior management discussion –
d risks to operation
k
3. Function management discussion – risks to operation
4. Identify receptive individuals in high risk area
5. Training of appropriate individuals
6. Start slowly
7
7. Communication Modify strategy as needed to insure
Communication. Modify strategy as needed to insure
success
8. Expand effort based on success
31
COMPLIANCE BY DESIGN AND COMPLIANCE MASTER PLAN
LIFECYCLE APPROACH ‐‐ SUMMARY
• CbD based on QbD, CMP based on VMP
• Lifecycle approach based on lifecycle approach to process validation
– Design, Perform, Monitor
• Identify quality systems: FDA, Quality Systems, support systems
• Identify business process of systems Æ system subsections
• Identify objectives and CCA, CCP, variation, controls, gaps, and risks
• Continuous improvement projects based on gap, risks, monitoring
• Documentation in CMP
• Positives: Organized and comprehensive focus based on risk to the patient and the
organization, strong message to employees and to auditors, “credit” in audits
• Negatives: Difficult, transparent, deficiencies identified
• Consistent with FDA direction (Process Validation, risk), ASTM E2500, and ICH Q8,
Q9, Q10
• Cost effective ‐‐ High risk activities emphasized and prioritized
• Implementation approach
32
16
9/6/2011
INTERACTIVE DISCUSSION
Comments on CbD
Comments on CMP
Comments on Lifecycle
33
REFERENCES
Pluta, Paul L. and Richard Poska. “Compliance by Deisgn (CbD)
and Compliance Master Plan (CMP). An Organized Approach
to Compliance.” J. GXP Compliance, V 14, #2, Spring 2010.
Pluta, Paul L., Richard Poska, and Timothy J. Fields. “Compliance
Pluta, Paul L., Richard Poska, and Timothy J. Fields. Compliance
by Design and Compliance Master Plan” Pharmaceutical
Technology, V35, #3, March 2011.
Nash, Robert A. “The Concept of Establishing a Compliance
Master Plan (CMP).” J. Validation Technology, V 12, #2,
February 2006.
Borkar M M A A Shirwaikar and P G Shilotri “Step
Borkar, M.M., A.A. Shirwaikar, and P.G. Shilotri. Step by Step
by Step
Approach to Quality System Implementation and Regulatory
Compliance.” J. GXP Compliance, V 9, #2, January 2005.
Yu, Lawrence X., et. al., “Quality by Design for Generic Drugs.”
PharmTech.com, October 2, 2009.
34
17
9/6/2011
COMMERCIAL
Book chapter authors
Pilot program
Pilot program
• System or subsection using CbD approach
Writers for JVT and JGXP
• Sample journals
• Brochure with example papers
• New features and ongoing features
35
PAUL L. PLUTA, PhD
Editor‐in‐Chief
• Journal of Validation Technology
• Journal of GXP Compliance
Adj
Adjunct Associate Professor
A i P f
• University of Illinois at Chicago (UIC) College of Pharmacy, Chicago, IL, USA
Editor and Chapter Author
• Cleaning and Cleaning Validation, Volume 1. Basics, Expectations, and
Principles. PDA and Davis Healthcare International (DHI) Publishing, 2009
• Cleaning and Cleaning Validation, Volume 2 . Applications of Basics and
Principles PDA and Davis Healthcare International (DHI) Publishing 2011
Principles. PDA and Davis Healthcare International (DHI) Publishing, 2011
(expected)
Contact: paul.pluta@comcast.net
36
18
9/23/2011
Outline
1
9/23/2011
Integrate
g into p
pharmaceutical QbD p process
Increase analytical method operational
flexibility – More robust and efficient.
Greater understanding of method capability
and sources of variability
Regulatory flexibility
Optimum method success over the product
lifecycle
2
9/23/2011
Regulatory Perspective
- Moheb Nasr IFPAC 2009 Baltimore January 2009
Current status of applying QbD principles to analytical methods
3
9/23/2011
4
9/23/2011
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
5
9/23/2011
Technique Selection
Quality Attribute 1 Quality Attribute 2 Quality Attribute 3 Quality Attribute 4 Quality Attribute 5 Quality Attribute 6 Quality Attribute 7 Quality Attribute 8 Quality Attribute 9
Quality
Q lit Att
Attribute*
ib t * to
t be
b
measured: Identification I (per Identificaiton II NIR for API form
Assay Content Uniformity Purity Disintegration Loss on Drying Dissolution
retetion time) (per UV spectrum) confirmation
accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
70% - 130% LC N/A N/A 70% - 130% LC 0.02% - 5% 0 - 30 minutes 0 - 10 % 0 -125% 15%-100%
Type of sample (e.g.,
IPC, intermediate, Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods
finished goods, etc.):
Testing environment
(e.g., on-line, at-line, Release and Release and Release and Release and Release and
release/stability testing Release Release Release Stability
Stability Stability Stability Stability Stability
labs, etc.):
Resolution of PRI,
degradants,
No signal (i.e.
analytical artifacts,
Resolution of PRI, Resolution of PRI, absorbance) was
expcipients and
degradants, Method must be Method must be degradants, observed from a Must be capable of
Needed selectivity/ability filter extractables ≥
analytical artifacts, able to provide a able to provide a analytical artifacts, sample of differentiatign Form
of method to 1.5 from main N/A N/A
expcipients and filter positive ID for positive ID for expcipients and filter formulation D from Form A and
discriminate: band and ≥ 1.0 for
extractables ≥ 1.5 Dimebon Dimebon extractables ≥ 1.5 excipients amorphous form.
separation of
from main band from main band prepared in
specified
dissolution media.
impurities from
each other.
6
9/23/2011
Color Key
RP
column Red: experimental
screening studies
Green:in silico
Plot of log D modeling
Column & pH Alternative
versus pH
selection mechanisms Black: Decision
points
7
9/23/2011
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH
8
9/23/2011
Identifyy method p
parameters that could
influence method performance.
Invite method users from different labs.
Generate process map
Create cause & effect matrix
Scoring of method parameters is based on
knowledge of product and method, and ATP
requirements.
9
9/23/2011
10
9/23/2011
Accuracy
11
9/23/2011
Case Study
Develop a QbD impurity analytical method for a drug product
12
9/23/2011
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Sensitivity (LOQ):
S/N ≥ 10 for API at of 0.05% of nominal
HPLC is chosen for the impurity method
considering all the ATP requirements.
Reserved-phase gradient elution
13
9/23/2011
CHROMATOGRAPHIC CONDITIONS
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011
Gradient Profile
•% Organic Ramp 1 Experimental DOE 1
•% Organic Ramp 2
Detector Wavelength
g Experimental DOE 1
Detector Type (PDA or Single Experimental DOE 1
Wavelength)
Column Age - # of injections Noise OFAT
Column Diameter Controllable Fixed
Column Length Controllable Fixed
Column Storage Solvent Experimental DOE 2
Column Vendor Controllable Fixed
15
9/23/2011
1 Resolution (≥1
1. (≥1.2)2) between these two primary degradation
products (a critical pair for resolution)
2. Accurate quantitation of the primary degradant (± 15% at
0.15 % level)
3. LOQ (S/N ≥ 10 for API at 0.05% of nominal)
The sample set used to evaluate critical method attributes
in the DOE and OFAT studies includes,
A blank (diluent) sample
A stability sample that contain the two primary degradation products.
An LOQ standard
Column temperature
Column
C l b
batch
t h number
b
Mobile phase flow rate
Injection volume
Aqueous mobile phase TFA concentration
Starting organic mobile phase percentage of gradient ramp 1
Starting organic mobile phase percentage of gradient ramp 2
Detector wavelength
Detector type
Note: This is a large number of parameters. In the DOE study, the number might be
reduced.
16
9/23/2011
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33
17
9/23/2011
TFA Ramp
Flow Conc 1 Ramp Primary
Rate in Begin 2 Wave Column Critical Impurity
Temp (mL/ MP Org. Begin Inject. Length Detector Batch LOQ Pair Area Main Band
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Vol (nm) Type # S/N Res
Res. % RT (min)
18
9/23/2011
Region of
Region of unacceptable
acceptable resolution
resolution
95%
confidence
limit
Method operable
99%
design region confidence
limit
(MODR)
Contour Plot of Critical Pair Resolution vs. Ramp 1 Beginning Organic and Ramp 2 Beginning
Organic (Flow rate: 0.8 mL/min, TFA Conc: 0.1%; all other factors set to their centers).
19
9/23/2011
The operable ranges identified by the DOE for the method parameters are independent from each other.
The operable ranges proposed for column temperature, injection volume, wavelength, and detector type
were fully accepted per the DOE outcome.
The operable ranges of flow rate, TFA concentration, ramp 1 organic (%), and ramp 2 organic (%) were
narrowed from the proposed ranges based on the DOE results.
20
9/23/2011
Original column:
Range St
Studied
died
Hig Target Acceptable
Parameter Low Mid h Setting Ranges
Column Temperature (°C) 27 30 33 30 27 ~ 33
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
TFA Concentration in Phase (%) 5
Ramp 1 Beginning Organic (%) 7 10 13 10 7 ~ 11
Ramp 2 Beginning Organic (%) 14 18 22 18 14 ~ 18
Injection Volume (µL) 3 6.5 10 6.5 3 ~ 10
Wave Length (nm) 262 270 278 270 270 ~ 278
Detector Type PDA, UV Any PDA or UV
Column Batch # 1, 2 Any Any
21
9/23/2011
22
9/23/2011
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
Column Temperature (°C)
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
TFA Concentration in Phase (%)
7 10 13 10 7 - 11
Ramp 1 Beginning Organic (%)
14 18 22 18 14 - 18
Ramp 2 Beginning Organic (%)
PDA, UV Either PDA or UV
Detector Type
3 6.5 10 6.5 6.5 - 10
Injection Volume (µL)
262 270 278 270 270 - 278
Wave Length (nm)
23
9/23/2011
Wave
Flow TFA Ramp 1 Ramp 2 Length Col Injection Resolution Primary Main
Rate Conc. Organic Organic (µm) Temp Volume of Critical S/N of Impurity Dimebon
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
C) (µL) Pair LOQ Area % RT
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Run 0 are the conditions set in TM10000613
Q lit attributes
Quality tt ib t used
d ffor th
the assessment:
t
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Limit of quantification: S/N ≥ 10 for 0.05% of the API content
Resolution of critical pairs of degradants: ≥ 1.2
24
9/23/2011
Numbers of
Injection of
Preconditioning
Run Storage Solvent Preconding
(hours)
Sample
1 50/50 ACN/Water 6 3
2 Initial Mobile Phase 9 6
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
6 Initial Mobile Phase 3 6
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
9 Initial Mobile Phase 12 3
10 Initial Mobile Phase 0 3
11 Initial Mobile Phase 6 0
12 Initial Mobile Phase 6 3
13 Initial Mobile Phase 6 3
14 50/50 ACN/Water 6 3
25
9/23/2011
26
Slide 52
TWG6 would need to be more concise...given that you have a summary slide next, I would recommend
skipping
Timothy W. Graul, 9/13/2011
9/23/2011
27
9/23/2011
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x
28
9/23/2011
Within the 3500 injections, the resolution data showed a slightly increasing
linear trend (increased 0.18 - 0.7 unit per 10000 injections).
Within the 3500 injections, the retention time showed a slightly decreasing
linear trend ((decreases between 1.4 to 2.8 minutes per
p 10000 injections).
j )
Conclusions
29
9/23/2011
Conclusions (continued)
DOE experimentation can be used to study multiple
method pparameters and their interactions for
establishment of MODR.
Critical method quality attributes should be selected in
the DOE study (i.e., resolution, accuracy, and LOQ for
an impurity method).
Common MODR can be determined for two similar
HPLC columns where the two columns can used
interchangeably.
QbD method control strategy involves operation of the
method within MODR and implementing system
suitability check.
Acknowledgement
30
9/23/2011
Backup slides
Column Temp: The column temperature range is 30 ± 3 0C which could cover any
potential variations of the column temperature. We learned that the column temp has
a minimum impact p to the method pperformance,, so temp
p range
g selected is suitable for
our future testing needs.
Injection Volume: The injection volume set point is 5 ųL and the range is 3-10
ųL. The 3 ųL is close to the limit of injection volume used in a typical HPLC impurity
method and 10 ųL has doubled the injection volume at the set-point, which is
sufficient for the future testing need.
Flow Rate: The flow rate range is 1.0 ± 0.2 mL/min which will cover potential flow rate
variations of the HPLC system or meet the needs to adjust the flow rate to achieve
desired peak retention time.
UV Wavelength: The UV wavelength range is 270 ± 8 nm that is broad enough for
the purpose of operable region study.
TFA Concentration: TFA target concentration is 0.05% and the range is proposed as
0.05%-0.010%. The TFA concentration lower than 0.05% is not recommended due to
its poor pH buffering capacity.
Ramp 1 and Ramp 2: The selectivity of this impurity method is very sensitive to
organic percentage in the mobile phase. The most impurity peaks are eluted and
separated in the first 20 minutes where the organic percentage in the gradient elution
is changed by only 8%. As a result, a small organic percentage ranges of 10 ± 3%
and 18 ± 4% are commended for gradient ramp 1 and ramp 2, respectively.
Detector type: UV WVD and PDA cover the detectors used for this method.
31
9/23/2011
Outline
1
9/23/2011
Integrate
g into p
pharmaceutical QbD p process
Increase analytical method operational
flexibility – More robust and efficient.
Greater understanding of method capability
and sources of variability
Regulatory flexibility
Optimum method success over the product
lifecycle
2
9/23/2011
Regulatory Perspective
- Moheb Nasr IFPAC 2009 Baltimore January 2009
Current status of applying QbD principles to analytical methods
3
9/23/2011
4
9/23/2011
Knowledge Space
Method Operable
Design Region
Target
Method
Conditions
O ti off the
Operation th method
th d within
ithi the
th MODR
5
9/23/2011
Technique Selection
Quality Attribute 1 Quality Attribute 2 Quality Attribute 3 Quality Attribute 4 Quality Attribute 5 Quality Attribute 6 Quality Attribute 7 Quality Attribute 8 Quality Attribute 9
Quality
Q lit Att
Attribute*
ib t * to
t be
b
measured: Identification I (per Identificaiton II NIR for API form
Assay Content Uniformity Purity Disintegration Loss on Drying Dissolution
retetion time) (per UV spectrum) confirmation
accuracy required:
±1.5% N/A N/A ±1.5% ±10% ±10% ±10% ±2% N/A
Range required:
70% - 130% LC N/A N/A 70% - 130% LC 0.02% - 5% 0 - 30 minutes 0 - 10 % 0 -125% 15%-100%
Type of sample (e.g.,
IPC, intermediate, Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods Finished goods
finished goods, etc.):
Testing environment
(e.g., on-line, at-line, Release and Release and Release and Release and Release and
release/stability testing Release Release Release Stability
Stability Stability Stability Stability Stability
labs, etc.):
Resolution of PRI,
degradants,
No signal (i.e.
analytical artifacts,
Resolution of PRI, Resolution of PRI, absorbance) was
expcipients and
degradants, Method must be Method must be degradants, observed from a Must be capable of
Needed selectivity/ability filter extractables ≥
analytical artifacts, able to provide a able to provide a analytical artifacts, sample of differentiatign Form
of method to 1.5 from main N/A N/A
expcipients and filter positive ID for positive ID for expcipients and filter formulation D from Form A and
discriminate: band and ≥ 1.0 for
extractables ≥ 1.5 Dimebon Dimebon extractables ≥ 1.5 excipients amorphous form.
separation of
from main band from main band prepared in
specified
dissolution media.
impurities from
each other.
6
9/23/2011
Color Key
RP
column Red: experimental
screening studies
Green:in silico
Plot of log D modeling
Column & pH Alternative
versus pH
selection mechanisms Black: Decision
points
7
9/23/2011
0
0 2 4 6 8 10 12 14
Log D
-1
-2
-3
-4 pH=2.7
pH
8
9/23/2011
Identifyy method p
parameters that could
influence method performance.
Invite method users from different labs.
Generate process map
Create cause & effect matrix
Scoring of method parameters is based on
knowledge of product and method, and ATP
requirements.
9
9/23/2011
10
9/23/2011
Accuracy
11
9/23/2011
Case Study
Develop a QbD impurity analytical method for a drug product
12
9/23/2011
Resolution:
Resolution
R l ti off critical
iti l pairs
i off d
degradants
d t ≥ 1.2
12
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Sensitivity (LOQ):
S/N ≥ 10 for API at of 0.05% of nominal
HPLC is chosen for the impurity method
considering all the ATP requirements.
Reserved-phase gradient elution
13
9/23/2011
CHROMATOGRAPHIC CONDITIONS
0 90 10
2 90 10
20 82 18
30 45 55
30.1 90 10
35 90 10
14
9/23/2011
Gradient Profile
•% Organic Ramp 1 Experimental DOE 1
•% Organic Ramp 2
Detector Wavelength
g Experimental DOE 1
Detector Type (PDA or Single Experimental DOE 1
Wavelength)
Column Age - # of injections Noise OFAT
Column Diameter Controllable Fixed
Column Length Controllable Fixed
Column Storage Solvent Experimental DOE 2
Column Vendor Controllable Fixed
15
9/23/2011
1 Resolution (≥1
1. (≥1.2)2) between these two primary degradation
products (a critical pair for resolution)
2. Accurate quantitation of the primary degradant (± 15% at
0.15 % level)
3. LOQ (S/N ≥ 10 for API at 0.05% of nominal)
The sample set used to evaluate critical method attributes
in the DOE and OFAT studies includes,
A blank (diluent) sample
A stability sample that contain the two primary degradation products.
An LOQ standard
Column temperature
Column
C l b
batch
t h number
b
Mobile phase flow rate
Injection volume
Aqueous mobile phase TFA concentration
Starting organic mobile phase percentage of gradient ramp 1
Starting organic mobile phase percentage of gradient ramp 2
Detector wavelength
Detector type
Note: This is a large number of parameters. In the DOE study, the number might be
reduced.
16
9/23/2011
7 Ramp 1
13 7 Ramp 1 13
Beginning Beginning
Organic (%) O
Organic
i (%)
0.1
TFA Conc in
MP (%)
22
at o 2
0.05
R Fl 1.
Graphical
e w
/
in L
m (m
Organic (%)
8
Beginning
0.
27 33 27 33 27 33 27 33
)
Ramp 2
View of the
278
TFA Conc in
0.1
Design of
MP (%)
Wave Length (nm)
DOE
e w2
0.05
at o 1.
/
in L
14
m (m
R Fl8
0.
27 33 27 33 27 33 27 33
)
onc in
MP (%)
0.1
TFA Co
22
at o 2
0.05
R Fl 1.
e w
/
in L
m (m
8
Organic (%)
0.
27 33 27 33 27 33 27 33
Beginning
)
Ramp 2
262
TFA Conc in
0.1
MP (%)
at o 2
14
e w
/
R Fl 1.
in L
0.05
m (m
8
27
0.
27 33 27 33 33 27 33
17
9/23/2011
TFA Ramp
Flow Conc 1 Ramp Primary
Rate in Begin 2 Wave Column Critical Impurity
Temp (mL/ MP Org. Begin Inject. Length Detector Batch LOQ Pair Area Main Band
Run Block ((°C)
C) min) (%) (%) Org. (%)
Org Vol. (µL)
Vol (nm) Type # S/N Res
Res. % RT (min)
18
9/23/2011
Region of
Region of unacceptable
acceptable resolution
resolution
95%
confidence
limit
Method operable
99%
design region confidence
limit
(MODR)
Contour Plot of Critical Pair Resolution vs. Ramp 1 Beginning Organic and Ramp 2 Beginning
Organic (Flow rate: 0.8 mL/min, TFA Conc: 0.1%; all other factors set to their centers).
19
9/23/2011
The operable ranges identified by the DOE for the method parameters are independent from each other.
The operable ranges proposed for column temperature, injection volume, wavelength, and detector type
were fully accepted per the DOE outcome.
The operable ranges of flow rate, TFA concentration, ramp 1 organic (%), and ramp 2 organic (%) were
narrowed from the proposed ranges based on the DOE results.
20
9/23/2011
Original column:
Range St
Studied
died
Hig Target Acceptable
Parameter Low Mid h Setting Ranges
Column Temperature (°C) 27 30 33 30 27 ~ 33
Flow Rate (mL/min) 0.8 1.0 1.2 1.0 1.0 ~1.2
0.07
0.05 0.1 0.05 0.05 ~ 0.075
TFA Concentration in Phase (%) 5
Ramp 1 Beginning Organic (%) 7 10 13 10 7 ~ 11
Ramp 2 Beginning Organic (%) 14 18 22 18 14 ~ 18
Injection Volume (µL) 3 6.5 10 6.5 3 ~ 10
Wave Length (nm) 262 270 278 270 270 ~ 278
Detector Type PDA, UV Any PDA or UV
Column Batch # 1, 2 Any Any
21
9/23/2011
22
9/23/2011
Range Studied
Target Acceptable
Parameter
Setting Ranges
Low Mid High
27 30 33 30 27 - 33
Column Temperature (°C)
0.8 1.0 1.2 1.0 1.0 - 1.2
Flow Rate (mL/min)
0.05 0.075 0.1 0.05 0.05 - 0.075
TFA Concentration in Phase (%)
7 10 13 10 7 - 11
Ramp 1 Beginning Organic (%)
14 18 22 18 14 - 18
Ramp 2 Beginning Organic (%)
PDA, UV Either PDA or UV
Detector Type
3 6.5 10 6.5 6.5 - 10
Injection Volume (µL)
262 270 278 270 270 - 278
Wave Length (nm)
23
9/23/2011
Wave
Flow TFA Ramp 1 Ramp 2 Length Col Injection Resolution Primary Main
Rate Conc. Organic Organic (µm) Temp Volume of Critical S/N of Impurity Dimebon
Iminium Band
Run (mL/min) (%) (%) (%) DAD ((°C)
C) (µL) Pair LOQ Area % RT
01 1.0 0.05 10 18 270 30 5 2.1 24 0.11 15.4
1 1.2 0.05 11 14 278 30 5 2.1 17 0.11 14.2
2 1 0.075 11 14 270 30 5 2.2 10 0.11 20.3
3 1 0.05 11 18 270 30 5 1.9 18 0.11 13.8
4 1 0.075 7 14 278 30 5 2.9 33 0.10 24.6
5 1 0.05 7 18 278 30 5 2.3 17 0.10 18.6
6 1.2 0.075 7 18 270 30 5 2.2 22 0.11 19.3
7 1.2 0.05 7 14 270 30 5 3.1 10 0.12 21.2
8 1.2 0.075 11 18 278 30 5 1.9 10 0.11 14.8
1
Run 0 are the conditions set in TM10000613
Q lit attributes
Quality tt ib t used
d ffor th
the assessment:
t
Accuracy:
100% ± 15% for impurity levels ≤ 0.15%
100% ± 10% for impurity levels > 0.15%
Limit of quantification: S/N ≥ 10 for 0.05% of the API content
Resolution of critical pairs of degradants: ≥ 1.2
24
9/23/2011
Numbers of
Injection of
Preconditioning
Run Storage Solvent Preconding
(hours)
Sample
1 50/50 ACN/Water 6 3
2 Initial Mobile Phase 9 6
3 50/50 ACN/Water 9 6
4 50/50 ACN/Water 0 3
5 50/50 ACN/Water 6 0
6 Initial Mobile Phase 3 6
7 50/50 ACN/Water 3 6
8 50/50 ACN/Water 12 3
9 Initial Mobile Phase 12 3
10 Initial Mobile Phase 0 3
11 Initial Mobile Phase 6 0
12 Initial Mobile Phase 6 3
13 Initial Mobile Phase 6 3
14 50/50 ACN/Water 6 3
25
9/23/2011
26
Slide 52
TWG6 would need to be more concise...given that you have a summary slide next, I would recommend
skipping
Timothy W. Graul, 9/13/2011
9/23/2011
27
9/23/2011
1 x x x x x x x
1200 injections
1800 injections
3000 injections
120 injections
360 injections
600 Injections
2 x x x x x x x
3 x x x x x x x
28
9/23/2011
Within the 3500 injections, the resolution data showed a slightly increasing
linear trend (increased 0.18 - 0.7 unit per 10000 injections).
Within the 3500 injections, the retention time showed a slightly decreasing
linear trend ((decreases between 1.4 to 2.8 minutes per
p 10000 injections).
j )
Conclusions
29
9/23/2011
Conclusions (continued)
DOE experimentation can be used to study multiple
method pparameters and their interactions for
establishment of MODR.
Critical method quality attributes should be selected in
the DOE study (i.e., resolution, accuracy, and LOQ for
an impurity method).
Common MODR can be determined for two similar
HPLC columns where the two columns can used
interchangeably.
QbD method control strategy involves operation of the
method within MODR and implementing system
suitability check.
Acknowledgement
30
9/23/2011
Backup slides
Column Temp: The column temperature range is 30 ± 3 0C which could cover any
potential variations of the column temperature. We learned that the column temp has
a minimum impact p to the method pperformance,, so temp
p range
g selected is suitable for
our future testing needs.
Injection Volume: The injection volume set point is 5 ųL and the range is 3-10
ųL. The 3 ųL is close to the limit of injection volume used in a typical HPLC impurity
method and 10 ųL has doubled the injection volume at the set-point, which is
sufficient for the future testing need.
Flow Rate: The flow rate range is 1.0 ± 0.2 mL/min which will cover potential flow rate
variations of the HPLC system or meet the needs to adjust the flow rate to achieve
desired peak retention time.
UV Wavelength: The UV wavelength range is 270 ± 8 nm that is broad enough for
the purpose of operable region study.
TFA Concentration: TFA target concentration is 0.05% and the range is proposed as
0.05%-0.010%. The TFA concentration lower than 0.05% is not recommended due to
its poor pH buffering capacity.
Ramp 1 and Ramp 2: The selectivity of this impurity method is very sensitive to
organic percentage in the mobile phase. The most impurity peaks are eluted and
separated in the first 20 minutes where the organic percentage in the gradient elution
is changed by only 8%. As a result, a small organic percentage ranges of 10 ± 3%
and 18 ± 4% are commended for gradient ramp 1 and ramp 2, respectively.
Detector type: UV WVD and PDA cover the detectors used for this method.
31
Profiting From Quality by Design
Analyzing QbD Impact on Product Lifecycle Costs
Stephen M. Tyler
Director, Global Quality Systems
Global Pharmaceutical Operations
Overview
$ Billions
#
* Source: http://www.in-pharmatechnologist.com/Processing-QC/Pfizer-aggressively-pursuing-cost-saving-real-time-release
# Source: http://www.firstwordpharma.com/forward/emailref?path=node/830916
90
80
Total Quality
Related Costs
70
Failure
60
40
30 Appraisal
20
10 Prevention
decrease in labor 30
nonconformances. Implemented
Average HPD spent on NCRs
20 2010 AVG HPD = 4.5
Assuming 2011 AVG HPD = 2.5 YTD
work days/year 10
equates to annual
5
hidden cost
savings of 0
01/02/07
03/02/07
05/02/07
07/02/07
09/02/07
11/02/07
01/02/08
03/02/08
05/02/08
07/02/08
09/02/08
11/02/08
01/02/09
03/02/09
05/02/09
07/02/09
09/02/09
11/02/09
01/02/10
03/02/10
05/02/10
07/02/10
09/02/10
11/02/10
01/02/11
03/02/11
05/02/11
~$170,000
Total
Savings
$1.09MM
KEY
A Already studied
B Planned pre-RSL
C Planned post-RSL
D Studies not planned
X identified after risk assessment
19
Profiting From Quality by Design.pptx Company Confidential
© 2011 Abbott
QbD Profitability
Regulatory Flexibility
Process Product
Focuses on the extrusion part of the BCS Class IV Drug - tablet dosage
process form required
This is the most critical process for Poorly soluble pharmacokinetic
this product enhancer in formulation
Provides a molecular dispersion of Degradation products form with heat
poorly soluble API
• Drug and enhancer dispersed in a
hydrophilic polymer via extrusion
• Milled extrudate compressed into
tablets
Twin Screws
Heated Barrel
Die
Drive
Extrudate
Assembly
Conveying
Process
Controlled
GMP
Controlled
Critical
Product /
Target Product /
Prior Process Control Regulatory
Product Process
Knowledge Design Strategy Flexibility
Profile Dev.
Space
Janet Andre
Nancy Christensen
Liam Feely, PhD.
Steven Laurenz
Yanhui Hu
Stephen M. Tyler
Director, Global Quality Systems
Global Pharmaceutical Operations
Stephen.Tyler@abbott.com
Robert A. Forbes, Ph.D., Sr. Research Scientist, Analytical Sciences Research and Development
Bryan C Castle,
Castle Ph
Ph.D.,
D Director
Director, Analytical Sciences Research and Development
Arzoxifene Hydrochloride--decision not to
submit for marketing authorization
Indications: Osteoporosis & Breast Cancer Risk Reduction
Route of Administration: Oral 20 mg Tablet HCl
O
N
O
OCH3
HO S
Arzoxifene HCl
Step 2 1) H2O2 Br
H2SO4 , sulfolane O
2491420
2) aq. NaHSO3, AcOH
Et2 N
O S
O
OMe Manufacturing Site 1
3) EtOAc ReX
2492986
O N
Step 3 O O N
N
O
1) 315699starting material O O
1) H2
2492986 O Pd/C, O
DMF, KOt-Bu O S OMe H3PO4 O S OMe
Et2 N O 2) aq. KOH Et2 N
2) 1-butanol
3) aq. NaCl / NaOH washes 2492987
2492988
O N
1)KOH
Step 4
2) con HCl O
O N 3) iPrOH washes
O O S OMe
HCl *HCl
353381 Arzoxifene Free base
water, MeOH S
HO OMe 353381
Arzoxifene HCl
Manufacturing Site 2
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on 3
B. Castle & R. Forbes Quality by Design (QbD)
Guides for QbD of the Drug Substance Process and Controls
ICH Q111 on Approaches to Development
Traditional approach
•ID potential CQAs associated with drug substance so that those characteristics having
p
and impact on p
product q
quality
y can be studied and controlled
•Defining an appropriate manufacturing process
•Defining a control strategy to ensure process performance and drug substance quality
E h
Enhanced
d approach,
h also
l iincludes
l d
•A systematic evaluation, understanding and refining of the manufacturing process,
including:
• Identifying
y g through
g e.g.,
g p prior knowledge,
g experimentation
p and risk assessment, the material
attributes and process parameters that can have an effect on drug substance CQAs
• Determining the functional relationships that link material attributes and process parameters to
drug substance CQAs
•Using the enhanced approach in combination with quality risk management to establish
an appropriate
i t control
t l strategy
t t which
hi h can, for
f example,
l include
i l d a proposall ffor a d
design
i
space and/or real-time release testing
1 ICH Q11, Development and Manufacture of Drug Substances, 19-May-2011, Step 2 version
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Step_2/Q11_Step_2.pdf
1 FDA Guidance for Industry, Process Validation: General Principles and Practices, Jan 2011, Rev 1
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070336.pdf
processing conditions,
isolation/purification points,
What goes on
critical process parameters,
ranges, assay control points
Wh t comes outt
What verification of success with final
drug substances assays
O
O S OMe
Et N
HO S OMe 2491419
NB Et
S
379361
B
Br
HO S OMe
430206
0.024
0.022
0.020
0.018
0.016
0 014
0.014
Lot 4
A219133
0.012 Lot 3
AU
A217078
0.010
Lot 2
A217072
0 008
0.008
0.006
Lot 1
A213606
0.004
0.1% std
0 002
0.002
0.000
Blank
-0.002
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00
Minutes
Analytical
Test Procedure Acceptance Criteria
Identification / Assay / Purity Tests
Identity HPLC The relative retention time ratio between the sample and
(B11315) the standards must compare qualitatively for a positive
result
l for
f identity.
id i
Assay Not less than 97.5 %
Total Impurities Not more than 1.0 %
LSN 2491419 Not more than 0.50 %
Largest Unspecified Not more than 0.15 %
Impurity
Other Tests
Physical Appearance1 Visual It is a practically white to yellow to light brown solid.
1
“Physical Appearance” is equivalent to the ICH term “Description.”
24
91
O S OMe
4
Br
20
OMe
Et N O
O Et 2521689
O S OMe
Et N
Et 2491420
Br
Br
O
O S OMe
Et N O
Et
2521691
Lot 3
Peak Results
2492986
0.010 Nam e RT Are a %
1 LSN2521689 4.40 0.05
LSN 2
2 LSN2526306 7.72 0.11
LSN 2491420
0
0.008 3 LSN2521691 9.69 0.13
4 LSN2495649 9.92 0.06
521691
26306
5 LSN2491420 12.59 0.34
95649
21689
0.006
LSN 252
LSN 25
L
LSN 249
LSN 252
AU
0.004
Lot 5
0.002 Lot 4
Lot 3
Lot 2
Lot 1
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00 18.00
Minutes
Br
O
O S OMe
Et N
Et 2491420
Identification Tests
Identity HPLC Retention time compares to standard
(B11342)
Br
OH
Assay Test O
O S OMe
Assay HPLC Not less than 96.5% Et N O
Et 2521689
Purity Tests
Br
Br
Specified Impurities HPLC
O
LSN 2521689 (B11342) Not more than 0.40% O S OMe
Et N O
E
Et
LSN 2521691 Not more than 0.50% 2521691
Br
LSN 2495649 Not more than 1.3%
O
LSN 2491420 Not more than 1.0% O S OMe
O O
Et N
Anyy unspecified
p Impurity,
p y, Et
N t more th
Not than 00.15%
15% 2495649
excluding LSN 2526306 Br
Other Tests O
O S OMe
Physical Appearance Visual Practically white to yellow solid Et N
Et 2491420
Cl
O OMe
O S
N
O (Converts to desired product)
2526306
O N
O N
O N O N
N O
O O
N
O OCH3
HO O
315699 O OCH3 HO S
Br O HO S
H2 KOH
O OCH 3 HO S
O O OCH3 S OCH3
OMe OCH3 S HO
S N O
O S N O
N O O
O 353381
2492988 (unreacted)
2492987 467739
2492986 (unreacted)
O N
KOH O N
Br
O OMe O
S H2 O
N O Br OH
O OCH3 O2
N O S
O OCH 3
O S
N 2492988 O
2491420
KOH
O
OH S
Br
OCH 3 472701
HO S
430206
O-
O N+
OCH 3
HO S
615901
OCH3
O OCH3 HO S
O S 430206
N
2491420
O
OCH3 H2 KOH
315699
N O S
2491419 OCH3
HO S
379361
O
OCH3
N O S
O
2828615
O N
H2 KOH
315699
Br OH
O OH
O OMe
O S
N OCH3
O S
2521689 HO
2537460
O N
H2 KOH
315699
Br Br
O O Br
OCH3
O S
N O OCH3
HO S
2521691
2528468
615901
2528468
379361
472701
430206
467739
0.045
Lot 11
0.040
Lot 10
0.035
Lot 9
0.030 Lot 8
Lot 7
AU
0.025
Lot 6
0.020 Lot 5
Lot 4
0.015
Lot 3
0 010
0.010
Lot 2
0.005 Lot 1
0.10% Standard
0 000
0.000
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
Only 615901 and 2528468 above limit of disregard. Note that 379361 over-responds ~2X
LSN2537460
OH HPLC Not more than 0.50% High rejection capability of Form V
(B11474) process (90%)
O
O
OH S
LSN472701
HPLC Not more than 0.50% Specification of NMT 0.25% at API and
OCH3
(B11474) good rejection capability of Form V
HO S process (80%)
LSN379361
Any Unspecified HPLC Not more than 0.10% Control for API specification of NMT
Impurity (B11474) 0.10% for unknowns/unspecified
impurities.
Other Tests
Physical Appearance1 Visual
It is a practically white to yellow to brown Required test. Set based upon historical
solid batches.
1
“Physical Appearance” is equivalent to the ICH term “Description.”
Note: Several potential impurities were controlled via the “Any unspecified impurity” limit.
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on 17
B. Castle & R. Forbes Quality by Design (QbD)
Specifications Were Established for Arzoxifene
HCl Process Using Traditional Approach
In order to support
pp timing g for p
process validation campaign
p g
activities analytical methods were transferred to the
manufacturing sites
• Methods fully validated vs.
vs ICH standards (including robustness)
• Methods transferred to QCLs using collaborative study protocol
In parallel,
parallel our organic chemistry and engineering
partners were engaged in quality by design activities
for the final synthetic route
• Efforts were delayed due to need to change API crystal form
based upon pivotal BE study
• S th ti route
Synthetic t (protecting
( t ti group)) alsol changed
h d llate
t iin
development due to manufacturability issues
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on 18
B. Castle & R. Forbes Quality by Design (QbD)
Benefits of a QbD submission
Higher level of assurance of product quality for patient
• Design quality in versus testing for compliance to specifications
• Increased understanding leads to better and more robust processes
• Process for better identifying and managing risks
On-going
g g assurance that equipment
q p capability
p y does not change?
g
• The quality of the intermediates will not affect : API physical properties, identity, or water content.
• API Potency and purity can be impacted by levels of byproducts in the intermediates
• Thus impurity level was the response to assess impact on drug substance CQAs for DS mapping
for intermediate steps.
15-Sep-2011 IVT’s 3rd annual Bio/Pharmaceutical Conference on
B. Castle & R. Forbes Quality by Design (QbD)
QbD Approach for Arzoxifene HCl
Restrict the size of the design space to
ensure all outcomes of the combined
variables result in acceptable quality product
(meets FPC or CQA for API)
Conduct a design of
Identify critical process experiments
i t (DOE) using
i
parameters (CPPs) and all high (CPPs) and
other parameters with the medium-risk parameters
potential to have interaction
effects (medium-risk
parameters))
p
-6σ +6σ
Upper Spec Limit
CQA
Target Parameter
Lower Lower Upper set-points
Upper
Failure PAR Lower Upper Failure
PAR
limit limit DS DS limit
limit
limit limit
Lower limit Upper limit
for risk for risk
assessment assessment
For more info see: K. Seibert , et. al, J. Pharm. Innov. (2008) 3:105-112.
1 OMe
The chemical structure of Compound 457815 is: S .
2 OH
The chemical structure of Compound 153546 is: HO S .
Table 3.2.S.2.3.2
3.2.S.2.3.2-4
4 Specifications for Compound 315699,
Analytical
Test Method Acceptance Criteria
Assay HPLC NLT 96.0%
Total Impurities HPLC NMT 1.0%
Any Unspecified Impurity HPLC NMT 00.10%
10% Tight control of
Specified Impurities HPLC unspecified impurities
1
027195 NMT 0.50%
433294 2
NMT 0.15%
Limits based upon
NLT = Not less than NMT = Not more than
rejection data
1 HO OH
The
h chemical
h i l structure off Compoundd 027195 is:
i .
N O
2 N
The chemical structure of Compound 433294 is: O
Table 1-2. Arzoxifene Hydrochloride Step 1 Design Space Limits for MRPs
Tightened
Operation Parameter Target 6σ Lower Limit Upper Limit vs. PAR? Risk
DMAP (eq) 0.1 0.006 0.08 0.12 No Med
Protection Reaction TEA (eq) 1.05 0.063 1.0 1.1 Yes Med
Dec-Cl (eq) 1.05 0.063 1.0 1.1 Yes Med
2491419 Wash Water volume (vol) 3 0.18 2 4 No Med
Bromination NBS (eq)
( ) 1.07 0.0642 1.02 1.12 Yes Med
The worst case combination of the MRPs was: DMAP (eq) at the high set-point,
and Dec-Cl (eq), TEA (eq), Water (vol), NBS (eq) all at the low set-points; in
conjunction with all other low risk process parameters (LRPs) at set-points
expected to increase impurity levels.
O
O S OMe
Et N
Et 2491419
3.87%
Does not meet
specification limt of
NMT 0.5%
The isolated intermediates made from the bracketing studies typically contained
maximal amounts of pprocess byproducts,
yp , and thereby
y served as worst-case
examples of intermediate purity.
Table 2-1. Arzoxifene Hydrochloride Step 2 Design Space Limits for MRPs
Tightened
Operation Parameter Target 6σ Lower Limit Upper Limit vs. PAR? Risk
Sulfolane ((vol)) 6.0 0.36 5.5 7 No Med
1st Crystallization Water Add Rate (vol/hr) 2.16 1.06 2.0 5.0 Yes Med
LSN2492986
OM e
Br O Br OM e
S
0.020 OM e
O Br O
S
O Br S
LSN2526307
N O
OMe Br S O
0.015 O
O O
N O O
LSN2491 420
OM e O N
AU
Br O OH N
A
S
0.010
LSN2495649
LSN2521691
Br O
S
LSN2521689
OH
LSN2526306
0.005 O
O
N
0.000
O O O O
OH O O O O
N N N N
Arzoxifene HCl Step 3 Design Space
Table 3-1 Arzoxifene Hydrochloride Step 3 Design Space Limits for MRPs
Target 6σ Lower Upper Tightened Risk
Operation
O ti P
Parameter
t Li it
Limit Li it
Limit vs. PAR?
Coupling Reaction
PEP (eq) 1.09 0.065 1.03 1.15 Yes Med
KOtBu (eq) 1.05 0.06 1.0 1.1 Yes Med
9361
0.014 6 11.01 0.05
379
7 2799691 13.07 0.13 Å NMT 0.10% New impurity
AU
0.012
0.010
Observed
0.008
39
91
2528468
8
46773
430206
6
279969
0.006
0.004 472701
0.002
0.000
-0.002
0.00 2.00 4.00 6.00 8.00 10.00 12.00 14.00 16.00
Minutes
S S 18 03 0 091 S S
Impurities exceeding specification limits were also observed in other PAR and DS study samples
N O N
O Br N
O
Br 315699 O OMe
(Base)
O N O S
OMe O O O
S O
N O H2
O OCH3 OCH3 KOH
- S O S OCH3
O O S
2492986 O O
452661 O
OCH3
S OCH3
N O
O S
Long addition HO
2799691
Results of QbD experiments for all three steps did not meet the
specifications established using the traditional approach
• Impurities that were not specified needed to meet the NMT 0.10% any
unspecified impurity limit
OMe
OMe
Br O
S
Br S
O OMe OMe
O Br
N
O
OMe O
O
Br O Br S N
OMe S O
828615
OH
O
S
O
O
28
O
Br O O
S N
N
O
O
N
O
O
N
New Impurity
Observed
Step 2 Lot 2828615 2521689 2521691 2495649 2491420
MM7-H70350-053 0.22% 0.13% 0.07% 0.09% 0.41%
Limit NMT 0.15% NMT 0.40% NMT 0.50% NMT 1.3% NMT 1.0%
% Rejection
S
Step 1L
Lot 2491419 S
Step 2L
Lot 2828615
Step 1 to Step 2
RJ2-H70246-093 3.77% MM7-H70350-053 0.22% 94%
H2 O KOH
315699 OCH 3
O
OCH 3 N O S OCH3
N O S HO S
O
2491419
379361
2828615
Already a
specified
ifi d iimpurity
it
0.5 wt% of 2828615 was spiked into a step 3 reaction and the
isolated free-base contained 0.21% of compund 379361 (Spec.
limit = NMT 0.5%)
Analytical
Test Procedure Acceptance Criteria
Identification / Assay / Purity Tests
Identity HPLC The relative retention time ratio between the sample and
(B11315) the standards must compare qualitatively for a positive
result for identity.
Assay Not less than 97.5 94.0 %
Total Impurities Not more than 1.0% (No Limit)
LSN 2491419 Not more than 0.5 4.0 %
Largest Unspecified
ifi d Not more than
h 0.15
01 %
Impurity
Other Tests
Physical Appearance1 Visual It is a practically white to yellow to light brown solid.
1
“Physical Appearance” is equivalent to the ICH term “Description.”
N2492986
OMe
Br O Br OM e
S
LSN
0.020 OMe
O Br O
S
O Br S
LSN2526307
N O
OMe Br S
O
0.015 O
O O
N O O
91420
OMe O N
AU
Br O OH N
S
0 010
0.010
LSN249
LSN2495649
LSN2521691
Br O
S
LSN2521689
OH
LSN2526306
0.005 O
O
N
0.000
0.012
3
0 010
0.010
0.008
0.006
2799691
615901
0.004
0.002
0 000
0.000
LY353381
0.024 Pe ak Res ults
Corre cte d
0.022 Nam e RT
Area%
OCH 3
0 020
0.020
HO S 1 379361 7.16
7 16 0 21
0.21 Å NMT 0.50%
0 50%
379361
3 467739 8.59 0.09
0.016
4 430206 9.70 0.15 ÅNMT 0.25%
0.014
(new spec)
Br
AU
0.012
OCH3
0.010 HO S
430206
30206
0.008
0 006
0.006
43
472701
1
467739
0.004
0.002
0.000
2799691
0.50%
0.015
467739
0.25%
AU
0 010
0.010 0.25%
615901
430206
0.005
0.000
Arzoxifene HCl
0.020
0.015
0 010
0.010 0.11%
0.06%
467739
615901
0.005
0 000
0.000
Completion
p of the mapping
pp g resulted in a final design
g space
p
in which all possible combinations of all process parameters
(high, medium and low risk) result in drug substance that
meets the critical quality attributes
As a result, the risk that byproducts will be present in an intermediate at levels that
will cause the final drug substance to fail to meet the critical quality attributes is
extremely low.
Therefore the quality of the intermediates has been ensured by robust process
design, and routine testing against specifications in not needed.
The final design space includes one CPP and one CIPC for the arzoxifene HCl
manufacturing process:
Table 3.2.S.2.4
3.2.S.2.4-1
1 Arzoxifene Hydrochloride Critical In-Process
In Process Controls
Step Critical Process Parameter Critical Specification
Step 3 Deprotection Reaction Temperature % LSN2492988 remaining in-situ by
HPLC
Step 4 Milling Feed Rate Particle size by Laser-Light Scattering
Bernard
B dMMcGarvey,
G Ph.D.
Ph D
Eli Lilly and Company
Siegfried Schmitt
PAREXEL Consulting
IVT Conference
Sept , 2011
San Francisco, California.
1
Introduction………
Bernard McGarvey, Ph.D.
Engineering Advisor
Eli Lilly and Company
1
Let’s get warmed up…….
2
Slide Intentionally left blank
3
Notable Quotes on Risk Management
“Progress always involves risks. You can't steal second base and
keep your foot on first." Frederick B. Wilcox
“Risk is like fire: If controlled it will help you; if uncontrolled it will rise
up and destroy you.” Theodore Roosevelt
4
Principles of QRM
QRM is NOT!!!!!!!!!!!!!!!!!!!!!!!
10
5
So – what is Risk anyway!
1. Assessing risks
11
3. It involves trade-offs.
12
6
Consider the following scenario………
The Slick Oil Transportation Company owns a fleet of oil tankers that it uses
for transporting crude oil products around the world. You have just been
informed that one of the company’s tankers that was carrying Naphtha was
involved in a collision
collision. It was towed into a nearby port and most of Naphtha
was transferred to another ship. The damage was severe enough that the
tanker must be moved to a shipyard where it can be cleaned and the damage
surveyed and repaired. The port fire authorities and local fire departments
have said that the ship’s tanks must be inerted before it can be moved to the
shipyard. The current procedure says that the ship should be inerted with
Nitrogen. However, just to prove that Murphy’s Law is valid, unforeseen
circumstances have led to a scarcity of Nitrogen and so it will not be available
for at least a week. The procurement department has located a sufficient
supply of Carbon Dioxide cylinders nearby and if this could be used, the
tanker could be moved immediately. Since the use of carbon dioxide is not
indicated in the current procedure, using it will mean that a temporary change
will need to be approved.
13
14
7
The case for not proceeding……….
15
16
8
Slide Intentionally left blank………
17
18
9
Slide Intentionally left blank………
19
This is based
on the
hazard/harm
model from
ISO 14971
20
10
Risk Model Examples
Bacteria
Bacteria in a
Vial
Bacteria enters
patient.
This is based
on the
hazard/harm
model from
ISO 14971
22
11
The “Swiss Cheese” Model
23
Prior to placing a new product on the market, a risk analysis has shown
th t the
that th risk
i k that
th t a patient
ti t will
ill b
be h
harmed
db i l usage iis 10-88.
by a single
In its first year on the market the product is used 1,000,000 times by
patients (100,000 patients, each patient uses it 10 times).
After 5 more years on the market, the sales have grown and now the
product is used by 1,000,000 patients (each patient still uses the
product 10 times p
p per yyear).
) The p
product/process
p has not been modified
in any way over the 5 years.
Question: Based on your notion of risk to the patient, has the risk to the
patient increased between year 1 and year 6?
24
12
This slide intentionally left blank……
25
One view………………………
26
13
Second view………….
27
Initial Perform
Control Strategy
gy Risk Assessment
28
14
QRM along the product life cycle:
Manufacturing
Execute Control Strategy
CAPA / Improvements
Change Management
Note: Use an existing risk assessment if available. If a risk assessment does not
already exist, then it may be created as the quality system elements are implemented.
29
Microsoft Word
Microsoft Office
Excel 97-2003 Worksheet
Microsoft Office
Excel
Flowchart
30
15
Knowledge Management for QRM
•Therefore
Th f it represents
t a significant
i ifi t quantity
tit off product/process
d t/
knowledge.
31
Role-Based Multi-User
Collaboration via the Web
Collaboration
32
16
A Process for Quality Risk Management
Bernard
B dMMcGarvey,
G Ph.D.
Ph D
Eli Lilly and Company
Siegfried Schmitt
PAREXEL Consulting
IVT Conference
Sept , 2011
San Francisco, California.
1
1
A Potential QRM Process
2
3. Applied QRM Process Example
1. Decide to Use Formal QRM
2. Develop the Risk Question
3
3. F
Form a QRM Team
T
4. Identify the requirements (CQAs)
5. Determine Potential Harms and Severity
6. Develop a Process Flow Chart
7. Identify Unit Operations With Greatest Risk
8. Determine Process Steps With Greatest Risk
9. Determine Level of Risk Associated With Existing Controls
Recommend Actions and New Controls
10. Determine Level of Residual Risk and Risk Acceptance
3
3. Prioritization can be Built into the QRM Process
The QRM Funnel
Formal QRM?
CQAs
**But we still document our rationale so that it is evident that we did do a risk assessment. 8
4
3. The Risk Question
10
5
3. QRM Tools
• Brainstorming -- an informal analysis tool that is used to identify hazards and harms. It can be
used at any point in the QRM process.
• Fishbone (Ishikawa) Diagram -- a diagram used to associate multiple possible causes with a
g effect. Major
single j branches represent
p major
j causes, and minor branches represent
p detailed causal
factors.
• PHA -- useful when limited information is available. The PHA, or Preliminary Hazard Analysis
relies heavily on prior knowledge from subject matter experts and similar products.
• FMEA -- used to evaluate potential failure modes for systems, products, or processes and
their effects. It is also useful to identify additional controls required to mitigate risks.
• FTA -- a diagram used to identify root causes of a potential failure. You need full knowledge of a
complete system in order for this tool to be effective.
• HACCP -- best used to identify and manage risks associated with physical, chemical and
bi l i l hazards,
biological h d including
i l di microbiological
i bi l i l contamination.
i i It is
i only
l effective
ff i when h allll the
h
critical control points of a system are identified and understood.
• Risk Assessment Matrix -- used to qualitatively determine the level of risk associated with an
activity before applying any risk management strategies.
11
12
6
Form a QRM Team…………..
13
Patient
Patient
Requirement Product Design CQAs/QAs
Requirements
Categories
No microbial
Safety Closure System Integrity Microbial Purity (Sterility, Endotoxin)
contaminants
Minimal foreign
Safety particulate Foreign Particulate Control Particulate Matter
contamination
14
7
Determine Potential Harms & Severity
15
16
8
Process Flow Chart
17
18
9
Identify Process Steps with Greatest Risk
19
Potency Out of
Specification
Reaction
Temperature
Too High
20
10
Determine Level of Risk
Associated with Existing Controls
21
• Process Step: A descriptive name for the process step that is being assessed (drying, milling, heating,
crystallizing,….)
• Function: The purpose of the step being assessed (the more precise the definition of the function, the easier it is to
identify the failure modes).
• Dry product until LOD reaches 1%
• Stir contents for 1 hour between 78 and 82 Deg C
• Add reactants at 10 kg/min +- 0.5 kg/min
• Requirement/CQA: already defined
• Failure Mode: Any failure to meet the purpose of the process step
• LOD never reaches 1%
• Temperature goes above 82 Deg C
• Temperature goes below 78 Deg C
• Reactant addition rate is above 10.5 kg/min
• Impact: What impact will this failure mode have on the CQA. This drives the severity of the failure mode
• LODs above 1% may impact the purity of the product
• Temperatures above 82 deg C may create an impurity
• A slow reactant rate may allow an impurity to form.
22
11
Typical Columns in an FMEA
• Failure Cause: What are the basic causes that will lead to the failure mode.
– A failure of the air heater may slow down the drying rate.
– A failed coolant flow control valve may cause the temperature to rise.
– A iincorrect entry off a set point
An i might
i h cause the
h addition
ddi i rate to be
b below
b l 9.5
9 5 kg/min.
k / i
• Control: This is a control system (or part of a control system) that prevents the failure mode from occurring or
prevents the failure cause leading to the failure mode.
– Maintenance is used to reduce the risk of a valve failing.
– Second person verification may be used to detect the entry of an incorrect set point.
• Severity: A measure of the possible consequences of a hazard (based on impact to a CQA).
• Occurrence: A measure of how likely a failure cause can occur.
• Detection: The ability to discover or determine the existence, presence or fact of a hazard during routine
manufacturingg and the ability
y to correct or impact
p the consequences
q of a hazard,, prior
p to leadingg to harm.
• RPN: The product of Severity, Occurrence and Detection (S x O x D)
• Recommended Action(s): An action that should be taken if the risk is deemed unacceptable.
• Action(s) Taken: Description of actions taken.
23
24
12
Relationship Between FMEA and RCA
25
FMEA RCA
Incorrect label
Failure Cause Causal Factor
Attached to drum
26
13
A word regarding detection
27
28
14
Example for an automobile…..
29
2 Is it managed?
2.
3. Is it practical?
4. Is it being used?
30
15
4. Prevention Control vs Detection
Control?
1. Imagine a PAT device that measures the weight of
product in every vial after it has been filled.
4. Is it Managed?
16
4. Is it Practical?
17
4. Is it being used?
35
36
18
Length Available
for Crimping Frequency LSL Freq USL Freq
0 0 0.01 0 0.033 0
0.00040404 0 0.01 3335 0.033 3335
0.000808081 0
0.001212121 0 4000
0.001616162 0
0.002020202 0 3500
0.002424242 0
0.002828283 0 3000
0.003232323 1
0.003636364 1 2500
0.004040404 1
0.004444444 1 Frequency
2000
0.004848485 2 LSL
0.005252525 0 1500 USL
0.005656566 4
0.006060606 4 1000
0.006464646 4
0.006868687 8
500
0.007272727 15
0.007676768 14
0
0.008080808 17
0 0.005 0.01 0.015 0.02 0.025 0.03 0.035 0.04 0.045
0.008484848 26
0.008888889 28
0.009292929 29
0.00969697 54
0.01010101 58
0.010505051 101
0.010909091 83
0.011313131 141
0.011717172 149
0.012121212 194
0.012525253 223
0.012929293 257
0.013333333 361
0.013737374 398
0.014141414 430
0.014545455 556
0.014949495 611
0.015353535 728
0.015757576 881
0.016161616 951
0.016565657 1070
0.016969697 1207
0.017373737 1320
0.017777778 1633
0.018181818 1637
0.018585859 1862
0.018989899 1959
0.019393939 2151
0.01979798 2388
0.02020202 2493
0.020606061 2642
0.021010101 2751
0.021414141 2962
0.021818182 3083
0.022222222 3085
0.022626263 3271
0.023030303 3220
0.023434343 3324
0.023838384 3335
0.024242424 3327
0.024646465 3191
0.025050505 3255
0.025454545 3174
0.025858586 3063
0.026262626 2895
0.026666667 2928
0.027070707 2653
0.027474747 2464
0.027878788 2347
0.028282828 2143
0.028686869 2071
0.029090909 1861
0.029494949 1690
0.02989899 1502
0.03030303 1406
0.030707071 1200
0.031111111 1034
0.031515152 936
0.031919192 796
0.032323232 732
0.032727273 575
0.033131313 555
0.033535354 447
0.033939394 394
0.034343434 302
0.034747475 253
0.035151515 205
0.035555556 187
0.035959596 129
0.036363636 133
0.036767677 91
0.037171717 81
0.037575758 62
0.037979798 37
0.038383838 35
0.038787879 29
0.039191919 26
0.03959596 16
0.04 51
9/1/2011
Siegfried Schmitt
Principal Consultant
Agenda
Ch ll
Challenges tto iimplementing
l ti QRM
1
9/1/2011
Detecting risks
Detecting risks
2
9/1/2011
Resource allocation
3
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9/1/2011
Reference
http://www.parexel.com/services-and-capabilities/consulting/strategic-compliance/
10
8/31/2011
Siegfried Schmitt
Principal Consultant
Agenda
• Defining
D fi i Q Quality
lit LLevels
l and
dQQuality
lit MMetrics
ti
1
8/31/2011
Introduction
Siegfried.Schmitt@parexel.com
+44 7824 592401
•First applied
pp risk management
g in the late 80s in p
production
•Established quality systems for global operations for both,
medical devices and pharmaceuticals
•Technical editor of the PDA Technical Report on
“Implementation of QRM for Commercial Pharmaceutical and
Biotech Manufacturing Operations"
2
8/31/2011
Oops... [www.who.int]
Not explicitly:
The standard operating procedure (SOP) on Quality Risk
Management should define how the management system
operates and its general approach to both planned and
unplanned risk management.
management It should include scope
scope,
responsibilities, controls, approvals, management systems,
applicability, and exclusions. [www.mhra.gov.uk]
3
8/31/2011
A Real Example
4
8/31/2011
Infrastructure includes:
•Quality standard
•A dedicated quality risk management organisation
•Business processes
•A libraryy of risk assessments
5
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8/31/2011
Compliance Risk
Production Production
Laboratory Control
Out of Specification Stability Testing Testing
System
10
8/31/2011
Compliance dashboard
Deliver
Staffing Q lit
Quality
y in full
Delivery Cost
Goals
on time
11
8/31/2011
Compliance
Reference - https://store.pda.org/bookstore
12
8/31/2011
Reference - https://store.pda.org/bookstore
13