Quality by Design Example for
Generic Modified Release Drug Products
Andre Raw*, PhD
andre.raw@fda.hhs.gov
*Opinions expressed in this presentation are those of the speaker
and do not necessarily reflect the views or policies of the FDA
1
A Generic Drug is Therapeutically
Equivalent To the Brand-Name Product
• Generic Drugs Account for 70-75% of Prescriptions in US
• Therapeutic Equivalents
- Have the same clinical effect and safety profile when
administered to patients under the conditions specified in
the labeling
• FDA Practice
Pharmaceutical Equivalence + Bioequivalence
= Therapeutic Equivalence
2
Pharmaceutical Equivalence
Same active ingredient(s)
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, excipients, packaging...
3
What is Pharmaceutical Quality?
Janet Woodcock (Center Director for Drugs)
- Free of contamination and reproducibly
delivering the therapeutic benefit promised in the
label
ICH Q8 R(2): The suitability of either a drug
substance or a drug product for its intended use
Quality cannot be tested into products;
Quality can only be built into products
4
Quality by Design (QbD)
Quality by Design “means that product and
process performance characteristics are
scientifically designed to meet specific
objectives... To achieve QbD objectives,
product and process characteristics important
to desired performance must be derived from a
combination of prior knowledge and
experimental assessment during product
development.”
Pharmaceutical Quality = ƒ (Drug substance, excipients,
manufacturing, and packaging)
5
Regulatory View for Pharmaceutical Quality
Traditional/Historical
21st Century View
ICH Q8/cGMP’s FDA Initiative
Design
Design
Testing
Testing
6
What Do Really Mean by QbD?
What are Regulator’s Expectations for QbD?
Industrial Consortium Developed Examples
to Attempt to Illustrate QbD Concepts
• Conformia “ACE Tablets” (US)
• “Examplain” HCl Tablets (EU)
• “Sakura Tablet” (Japan)
All Immediate
Release Products
7
But there is a Dichotomy
1. Traditional Review Paradigm for ANDAs: For the most part highly
successful for immediate release/solution products
2. However modified-release and other complex dosage forms are seen as
potentially problematic in ANDAs for generics
a. Modified Release Drug Products Introduce increasingly Complex
i. Bioequivalence Issues
ii. Chemistry, Manufacturing and Controls Issues
b.
Modified Release Drug Products on the Rise
c.
Complexities often ignored by ANDA sponsors rush to be the first to
file to obtain 180-day exclusivity
3. Consumer Complaints/Generic Skepticism on some Modified Release
Products
8
Modified-Release QbD Example
1. Developed by the Office of Generic Drugs (2009-2011)
http://www.gphaonline.org/sites/default/files/DraftExampleQbDforMRTablet%20Ap
ril%2026.pdf
2. Vetted Extensively within the Agency. Three Workshops with the US
Generic Pharmaceutical Association (2011)
3. Intended to illustrate the types of development studies ANDA
applicants may use as they implement QbD for these complex products.
Provide a concrete illustration of the QbD principles from ICH Q8(R2)
4. Development of a real product may differ from the example
a. Different Products will have Different Issues
b. There are Scientifically Valid Alternative Approaches
9
5. Full-Implementation of QbD in the review assessment by 2013
Implementation of QbD?
Labeled Use
Safety and Efficacy
DEFINE Quality
Target Product Profile
DESIGN Formulation
and Process
IDENTIFY Critical Material Attributes
and Critical Process Parameters
TARGET
DESIGN
CONTROL Materials
and Process
IMPLEMENTATION
10
QbD Now Asks Sponsors to Define their
Quality Target Product Profile (QTPP)
Asks whether Generic Firms are Focusing
Product Design at the Right Target
11
Quality Target Product Profile
ICH Q8(R2) Definition
QTPP : A prospective summary of the quality
characteristics of a drug product that ideally will
be achieved to ensure the desired quality, taking
into account safety and efficacy of the drug
product.
12
QbD MR Example
Past/Present Paradigm
QTPP: Guiding Quality
Surrogates Used in the
Development of the
ANDA Formulation and Process
Equivalent to the RLD
ANDA Formulation/Process
Submitted Without Context
Claimed to be Acceptable Based Upon
a Passing BE study to the RLD
Asks Sponsors How They Systemically
Arrived at a Bioequivalent Drug Product
“Bioequivalence by Testing”
Raw, Lionberger, and Yu, Pharmaceutical Research 28 (7) 2011.
“Bioequivalence by Design”
13
Generic MR (10 mg) Tablet
Label
Active ingredient Z (BCS Class I)
Indication: Immediate onset of effect similar to the IR product, as
well as for maintenance of the effect, for once a day dosing.
PK: MR provides for plasma concentrations of Z comparable to
immediate release product through the first two hours for immediate
onset of effect, and a sustained release phase to maintain plasma
concentrations of the drug through 24 hours
Dose:
10 mg Tablet
Conveniently Scored for 5 mg Dose
Taken without Regard to Food (No Food Effect)
14
QTPP for Modified Release Product
Profile Component
QTPP Target
Rationale
Active Ingredient
Same
Pharmaceutical Equivalence Requirement
Dosage Form
Tablet
Pharmaceutical Equivalence Requirement
Same Dosage Form
Strength
Dose: 10 mg
Pharmaceutical Equivalence Requirement
Same Strength
Dosage Form
Appearance and
Characteristics
Conforming to Description,
Shape and Size Same
Scoring as RLD
Needed for Patient Acceptability
Size and Shape Conducive to Patient
Safety when Swallowing.
“Generally” similar in Size
and Shape to RLD
Assay
95-105%
Targeted for consistent clinical effectiveness
Impurity
Impurity A < 0.5 %
Ensure main degradation product remains
below qualification threshold
CU
RSD < 3%
Targeted for consistent clinical effectiveness
Friability
NMT 1.0%
Needed for patient acceptability
Stability
24 month shelf life
Needed for commercial reasons
15
PK
Fasting Study and Fed Study
90 % confidence interval of the PK parameters,
AUC0-2, AUC2-24, AUC0-∞ and Cmax should
fall within BE limits.
Additional Bioequivalence
Parameters Needed
Based Upon Labeling
Generic MR provides for:
1. Initial plasma concentrations
through the first two hours that
provide for a clinically
significant effect
2. Sustained release phase
designed to maintain plasma
concentrations for
maintenance of effect
Biphasic Drug
Release
(IR and ER)
Must provide for biphasic release of drug,
with initial rapid release followed by sustained
release ER of dose.
Maximize the feasibility of
achieving the target goals of
AUC0-2, AUC2-24, AUC0-∞ and
Cmax under fasting and fed
conditions.
Disintegration
Rapidly disintegrating tablet matrix design
that releases IR and ER component in particulates
(<1 mm in diameter). Precludes the use of a non
disintegrating tablet ER matrix.
Needed to minimize potential food
effect of IR component, similar
16
to brand name product
Drug Release
Whole versus
Half Tablets
Similar drug release of whole and split half
tablets.
Generic MR is conveniently
scored for administration of the
5 mg dose
(Precludes ER coating of a compressed tablet
core to provide for sustained release of drug).
Drug Release
Initial Target
Rapid release (NMT 15 min) using USP
apparatus II (paddle) at 50 rpm in 0.1 HCl
(4 mg equivalent)
and
Similar drug release using USP apparatus II
(paddle) in pH 6.8 (buffer).
Drug Release
(Revised Target)
Target: Similar Drug Release Profile
(Based upon Convolution of IVIVR)
Apparatus III: 10 dpm in phosphate
buffer pH 6.8 (250 mL)
Initial target goals used to
maximize the feasibility of
achieving the bioequivalence
target goals of AUC0-2, AUC2-24,
AUC0-∞ and Cmax under fasting
and fed conditions
Revised Drug Release Target
Convolution of IVIVR Target:
Similarity (not F2) of the in-vitro
release maximizes feasibility of
achieving the bioequivalence
target goals of AUC0-2, AUC2-24,
AUC0-∞ and Cmax
17
“Bioequivalence by Design”
Formulation Designed Based Upon an Understanding
Of Critical Quality Attributes to Provide a Equivalent
Exposure Profile Needed to Achieve Equivalent Clinical
Characteristics in Target Patient Population.
Is Formulation Designed using a QTPP that
Targets Equivalence to the RLD?
If QTPP Surrogate Does not Target Equivalence
To the RLD, May Be Acceptable
Sponsors Should Provide Justification Based On
Drug Pharmacokinetic and Clinical Profile
18
Implementation of QbD?
Labeled Use
Safety and Efficacy
DEFINE Quality
Target Product Profile
DESIGN Formulation
and Process
IDENTIFY Critical Material Attributes
and Critical Process Parameters
TARGET
DESIGN
CONTROL Materials
and Process
IMPLEMENTATION
19
Formulation Development
20
Schematic: MR Drug Product
Active
Active
Wurster
Coating
High Shear
Wet Granulation
ER
IR Granules
Cushioning
Excipient
DL (MCC Cores)
ER Pellets
Blending/Lubrication
Compression
Tablet Core
Film Coat
MR Product
21
Formulation (In-Vitro Drug Release)
QbD Paradigm
Past/Present Paradigm
If Bioequivalent
Meaningful Dissolution Methods:
Derived from Data in Pilot BE on Experimental
Formulations and Used to Guide Development
1. IVIVC
Perform Drug Release Testing
at Multiple pH Media (Speeds)
“Empirically” Set Appropriate
Tolerances at Select Time Points
2. IVIVR
3. PAT Surrogates
Measure ER Coating (Terahertz/Raman/NIR)
22
100
90
80
Test-F1-Water
70
Development Trial Formulation F-1
(25% ER Coating)
Similar Dissolution at three pHs
% Release
Test-F1-HCl
60
Test-F1-4.5
50
Test-F1-6.8
RLD-Water
40
RLD-0.1 N HCl
RLD-pH 4.5
30
RLD-pH 6.8
20
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time (Hour)
USP Recommended Method (USP Apparatus II – pH 6.8 at 50 rpm)
400
Concentration (ng/mL)
350
300
RLD
Test F-1
250
200
150
100
50
0
0
4
8
12
Time (Hour)
16
20
24
23
USP Recommended Method
(USP Apparatus II, pH 6.8, 50 rpm)
USP 3 apparatus
(250 mL, pH 6.8, 10 dpm)
Comparative in-vitro release characteristics of the RLD and the prototype
test formulations using the discriminating method (right) and nondiscriminating method (left)
F-1 (25% ER Coating)
F-2 (30% ER Coating)
F-3 (35% ER Coating)
24
400
Concentration (ng/mL)
350
300
RLD
Test F-2
250
Test-F3
200
150
100
50
0
0
5
10
15
20
25
30
Time (hour)
T/R ratio
AUC0-2
AUC2-T
AUC2-I
Cmax
Test F-1 (25% ER Coating)
1.1
1.21
1.10
1.32
Test F-2 (30% ER Coating)
0.97
0.98
0.96
1.03
Test F-3 (35% ER Coating)
0.81
0.95
0.95
0.75
Final IVIVR using PK dat for test product
obtained from F1, F2, F3
In USP 3 apparatus (250 mL, pH 6.8, 10 dpm)
y = -4.344E-3 + 0.954 × x
x = Fraction in-vitro release
y = Fraction in-vivo release
SEP=0.037
MAE=0.027 AIC= -51.54
25
Formulation (Stability)
Past/Present Paradigm
Stable by Testing
( 25 C/60% RH for 24 months)
QbD Paradigm
Has the Applicant Optimized the Formulation
To Achieve “Stability by Design”
API/Excipient Compatability?
Amorphous Dispersion (API/Binder) on
MCC Core Physically Stable?
Limited Testing Sufficient to Ensure
Stability on Future Production Batches?
Plasticizer Optimal to Minimize Curing
“Not all Batches Placed on Stability”
26
Amorphous Dispersion (API/Binder) on
MCC Core Physically Stable?
Experiment
Input Variables
API: Binder
Ratio
Output Characteristics
%Release in
15 min
HPLC
Assay
LOD
Percentage of crystalline
API (%)
No binder
100:0
85%
99.9%
0.1
80
With PVP K30
90:10
85%
99.8%
0.2
20
With PVP K30
85:15
90%
99.6%
0.3
not detected
With PVP K30
80:20
80%
99.4%
0.2
not detected
*Amorphous-crystallinity ratio as determined by XRPD after 1 month storage at 40 C/75% RH.
XRPD Analysis: API crystals (a), Binder (b) and Amorphous API with 15% Binder (d). 27
Plasticizer Optimal to Ensure Adequate Curing
to Minimize Changes in Drug Release on Storage)?
Coating formulation optimized to enure low minimum film formation temperature
(MFT = 5°C) for Kollicoat SR 30D with 5% TEC as plasticizer
100
90
80
Uncured
12 h / 60°C
24 h / 60°C
% Released
70
60
50
40
30
20
10
0
0
5
10
15
20
25
Time (hr)
Confirmed in pilot scale process development studies
28
Formulation (Manufacturability)
Past/Present Paradigm
Manufacturable at Exhibit
(Biobatch) Scale?
Does this Ensure the Sponsor has
Developed a Robust Formulation that
Can be Reproducibly Manufactured ?
QbD Paradigm
Excipients Selected to Ensure a Robust Process?
What is the Elongation Percentage for the ER
Coating Polymers? Can ER Coating Withstand
Compression Pressures during Compression?
If not, will Cushioning Excipients Rectify this?
29
400
376.1
350
% Elongation
300
250
Dry State
200
Wet State
142.83
150
126.31
136
100
38.41
50
1.340.13
0
0.624.89
13.02
Polymer 4ER Polymer 5ER Polymer 1ER Polymer 2 ER Polymer 3 ER
30
Process Development/Scale-Up
31
Manufacturing Process
Past/Present Paradigm
Exhibit (Biobatch) Production Record
No Data to Classify
10 x Scale-Up
CPPs versus
Same Equipment/
non-CPPs
Operating Principle
Full Production Batches
( Not Reviewed by OGD)
Can Sponsor Reliably Manufacture at
Commercial Production Scale
(or Even at the Same Scale)?
QbD Paradigm
Risk Assessment
+
Design of Experiments
Classify CPPs versus
non-CPPs in the unit Operation
Define Design Process Space for CPPs
At Pilot Scale (Bioequivalence Batch)
Increased Likelihood of a Successful
Commercial-Scale Process
32
Material Attributes and
Process Parameters
Particle size
Density
Moisture content
Excipient type/grade/level
Lot-to-lot variation
Viscosity
Inlet air volume
Inlet air temperature
Product temperature
Spray rate per nozzle
Nozzle diameter and number of nozzle
Atomization air pressure
Partition diameter and height
Capacity utilized
Inlet air dew point
Filter
Screen size
Screen type
Inlet air volume
Inlet air temperature
Product temperature
Spray rate per nozzle
Nozzle diameter and number of nozzle
Atomization air pressure
Partition diameter and height
Capacity utilized
Inlet air dew point
Filter
Coating dispersion: Solid content,
Viscosity and sedimentation
Screen size
Screen type
Manufacturing
Process Steps
Raw Materials:
Drug Substance and
Excipients
Drug Layering
Sieving I
ER Coating
Sieving II
Quality Attributes
to be Considered
Appearance
Dissolution
Assay
Content Uniformity
Assay
Coating/Content Uniformity
DS Solid State Form
LOD
Particle Size Distribution
Fines/Agglomerates
Usable Yield
Dissolution
Dose Dumping
LOD
Particle Size Distribution
Sieve Cut vs. Dissolution
Fines/Agglomerates
Usable Yield
IR Granules from ANDA# aaaaaa
Extragranular Excipients
Holding time
Material transfer method
Order of addition
Charging to Blender
Blend Uniformity
Blender Type/Geometry
No. of revolutions (time and speed)
Capacity utilized
Intensifier bar (on/off)
Holding time
Pre-Lubrication and
Lubrication Blending
Blend Uniformity
Particle Size Distribution
Density
Flowability/Compressibility
Pre-compression force
Main compression force
Press speed
Feeder speed/Type
Ejection force
Hopper design: Height and Vibration
Hopper fill
Compression
Assay
Content Uniformity (whole and split)
Weight Variation
Hardness
Friability
Disintegration
Usable Yield
33
Process Variables
Wurster insert diameter
Partition column diameter
Table
63. Initial risk assessment of the ER coating process
variablesand Initial Strategy
Risk
Assessment
Justification
Medium
Low
7″ Wurster HS insert is selected based on its capacity, 2.5 – 5 kg.
By equipment design: 89 mm in diameter.
Medium
The air distribution plate can impact the fluidization pattern of beads passing through the partition column.
C plate is selected based on the size of beads and previous experience.
Partition height (gap)
Medium
Partition gap can impact the circulation rate of beads passing through the coating zone. When the gap is too
big, insufficient differential pressure to draw beads up the partition column can be generated. When the gap
is too small, the circulation rate of beads goes up, but the mass flow of beads will be limited. The partition
height was set at 25 mm based on bed fill level and prior knowledge.
Nozzle tip diameter
Medium
Nozzle tip size determines a nozzle’s spray rate capability. Based on potential spray rate, a nozzle with 1.0
mm orifice diameter was selected.
Air distribution plate
Nozzle tip/air cap position
Low
Keep nozzle tip and air cap flush for consistency.
Filter
Medium
A filter bag is used to prevent loss of material and to allow air to pass through. A filter bonnet with a size
of 200 μm was used based on previous experience.
Inlet air dew point
Medium
Variation of inlet air humidity may have an impact on drug release rate. The impact needs to be evaluated.
Typically, a dew point of 10-15º C is used for processing.
Shaking interval/duration
Inlet air temperature
Low
Medium
To prevent beads from being trapped in the filter bag.
60 sec/5sec: based on prior knowledge.
Inlet temperature will be adjusted to reach the desired product temperature.
The range of 40-60ºC is selected based on trial batches in GPCG-1
Product temperature
High
Product temperature is a function of inlet air temperature, air volume, and spray rate.
If product temperature is too high, spray drying may occur and results in large amount of fines.
If product temperature is too low, agglomeration may occur.
Investigate with DOE
Air volume
High
If air volume is too high, spray drying may occur.
If air volume is too low, agglomeration may occur.
Investigate with DOE
Spray rate/nozzle
High
If spray rate is too high, agglomeration may occur.
If spray rate is too low, spraying time may be too long and spray drying may occur.
Investigate with DOE
Atomization air pressure
High
If atomization air pressure is too high, attrition to the beads may occur.
If atomization air pressure is too low, agglomeration may occur.
Investigate with DOE
Coating Time
Medium
The coating dispersion may thin due to shear if the coating process is long.
34
DOE Screening Design to Investigate which
‘High Risk’ Parameters are Critical in ER Coating
35
Critical Process Parameters Investigated (23-1 factorial DOE) to Define a ER
Layering Design Space at Pilot Scale Studies using 18 Wurster HS Insert
Design Space for 40 Kg ER Layering Using
GPC-120 equipped with a 18” Wurster Insert
36
Updated risk assessment of the ER coating process variables
Process Variables
Product temperature
Air volume
Spray rate
Atomization air pressure
Initial
Risk Assessment
High
High
High
High
Final
Risk Assessment
Low
Justification for the Mitigated Risks
Product temperature range is identified. In the studied range,
ER coated beads with consistent quality were produced at 40
kg scale. Product temperature is a scale independent
parameter, and can be applied to other scales.
Medium
Air volume range is identified. In the studied range, ER
coated beads with consistent quality were produced at 40 kg
scale. Air volume is a scale dependent parameter. For
commercial scale production, we plan to increase the air
volume 3 folds, because coating change from 18″ to 32″
Wurster is a scale-out process instead of a scale-up process.
However, further adjustment may be necessary.
Medium
Spray rate range is identified. In the studied range, ER
coated beads with consistent quality were produced at 40 kg
scale. Spray rate is a scale dependent parameter. For
commercial scale production, we plan to increase the spray
rate 3 folds, because coating change from 18″ to 32″
Wurster is a scale-out process instead of a scale-up process.
However, further adjustment may be necessary.
Low
Atomization air pressure is identified. In the studied range,
ER coated beads with consistent quality were produced at 40
kg scale. Atomization air pressure is a scale dependent
parameter. However, ER coating change from 18″ to 32″
Wurster is a scale-out process instead of a scale-up process.
The three nozzles used in the 32″ Wurster are identical to
the one used in the 18″ Wurster. The atomization air
pressure for each nozzle is kept the same.
37
Bioequivalence: Scale-Up
Past/Present Paradigm
Bioequivalent Exhibit Batch
QbD Paradigm
Bioequivalent Exhibit Batch
Linking Bioequivalence at Commercial Scale:
Scale-Up
1. IVIVC
2 IVIVR
Linking Bioequivalence at Commercial
Scale Using “Empirical” Dissolution Test
Commercial Scale Drug
Product Still Bioequivalent ???
3. Unit operation incorporating ER mechanism
scale-independent process parameters.
4. Linking drug product critical quality material
attributes of ER coating between scales
38
(PAT tools)
Bioequivalence: Scale-Up
Based upon IVIVR (T50%) increased from 5.6 h to 6.6 h on commercial scale
compared to pilot scale failing a predefined critical quality attributed in development
Despite Similitude of Design 18” Wurster with 32” Wurster failure of scale-up
Attributable to higher coating efficiency at commercial scale (72-98% of equipment
capacity compared to pilot scale (50-70% of equipment capacity)
39
40
Linkage of Commercial and Exhibit Batch Process Spaces
CPP 1*
CPP 2*
Bioequivalent ANDA
Exhibit Batch well within
Pilot Scale Design Space
CP
P
CP
P
3*
3
CPP 2
CPP 1
Scale-up based upon underlying assumptions
Similitude, Scale-independence,
Empirical or Semi-Empirical Models,
Dimensionless Analysis
Process Validation/Verification
(Post-Submission)
Map/Confirm Points in Predicted
Commercial Scale-Process Space
CPP 1*
Trial Commercial Batch
Not Bioequivalent
Detected by IVIVC/IVIVR
3*
3*
CP
P
P
CP
IVIVR/IVIVC and/or PAT tools
Adjustments in target coating (30% -Æ 28%)
due to the higher coating efficiency
at commercial scale
CPP 2*
CPP 2*
CPP 1*
Bioequivalent
Commercial Batch
41
Conclusions
Bioequivalence: Commercial Scale
IVIVR or IVIVC
PAT Surrogates
Therapeutic Equivalence
“Bioequivalence by Design”
QbD
Enhance Quality of MR Products
Drug Product Stability
Formulation “Stability by Design”
Commercial Manufacturing
Excipient Selected
CPPs versus non-CPPs
Understanding CPP Process Space
42
Acknowledgements
•
•
•
•
•
•
•
•
•
Lawrence Yu
Robert Lionberger
Lane Christensen
Nilufer Tampal
Om Anand
Ubrani V Venkataram
Quamrul Majumder
Dipak Chowdhury
Roslyn Powers
Peter Capella
Laxma Nagavelli
Suhas Patankar
Jennifer Maguire
Bhagwant Rege
Peng Yingxu
Youmin Wang
Khalid Khan
Helen Teng
43