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Quality by Design Example forGeneric Modified Release Drug Products

Andre Raw*, PhDandre.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

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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 PracticePharmaceutical Equivalence + Bioequivalence = Therapeutic Equivalence

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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...

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What is Pharmaceutical Quality?Janet Woodcock (Center Director for Drugs)

- Free of contamination and reproduciblydelivering 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

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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)

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Regulatory View for Pharmaceutical Quality

21st Century ViewICH Q8/cGMP’s FDA Initiative

Testing

Design

Traditional/Historical

TestingDesign

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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

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But there is a Dichotomy1. 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 Complexi. Bioequivalence Issuesii. 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

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Modified-Release QbD Example1. Developed by the Office of Generic Drugs (2009-2011)http://www.gphaonline.org/sites/default/files/DraftExampleQbDforMRTablet%20April%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 examplea. Different Products will have Different Issuesb. There are Scientifically Valid Alternative Approaches

5. Full-Implementation of QbD in the review assessment by 2013

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Implementation of QbD?

Labeled UseSafety and Efficacy

DEFINE QualityTarget Product Profile

IDENTIFY Critical Material Attributesand Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN IMPLEMENTATION

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QbD Now Asks Sponsors to Define their Quality Target Product Profile (QTPP)

Asks whether Generic Firms are Focusing Product Design at the Right Target

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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.

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Past/Present Paradigm QbD MR Example

Asks Sponsors How They Systemically Arrived at a Bioequivalent Drug Product

“Bioequivalence by Design”

Claimed to be Acceptable Based Upon a Passing BE study to the RLD

“Bioequivalence by Testing”

ANDA Formulation/Process Submitted Without Context

QTPP: Guiding Quality Surrogates Used in the Development of the ANDA Formulation and ProcessEquivalent to the RLD

Raw, Lionberger, and Yu, Pharmaceutical Research 28 (7) 2011.

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Generic MR (10 mg) Tablet

LabelActive ingredient Z (BCS Class I)

Indication: Immediate onset of effect similar to the IR product, aswell as for maintenance of the effect, for once a day dosing.

PK: MR provides for plasma concentrations of Z comparable toimmediate release product through the first two hours for immediateonset of effect, and a sustained release phase to maintain plasma concentrations of the drug through 24 hours

Dose: 10 mg TabletConveniently Scored for 5 mg DoseTaken without Regard to Food (No Food Effect)

15Needed for commercial reasons24 month shelf lifeStability

Needed for patient acceptabilityNMT 1.0% Friability

Targeted for consistent clinical effectivenessRSD < 3%CU

Ensure main degradation product remainsbelow qualification threshold

Impurity A < 0.5 %Impurity

Targeted for consistent clinical effectiveness95-105%Assay

Needed for Patient AcceptabilitySize and Shape Conducive to PatientSafety when Swallowing.

Conforming to Description,Shape and Size SameScoring as RLD

“Generally” similar in Sizeand Shape to RLD

Dosage FormAppearance and Characteristics

Pharmaceutical Equivalence Requirement Same Strength

Dose: 10 mgStrength

Pharmaceutical Equivalence RequirementSame Dosage Form

TabletDosage Form

Pharmaceutical Equivalence Requirement Same Active Ingredient

RationaleQTPP TargetProfile Component

QTPP for Modified Release Product

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Needed to minimize potential foodeffect of IR component, similarto brand name product

Rapidly disintegrating tablet matrix designthat releases IR and ER component in particulates(<1 mm in diameter). Precludes the use of a nondisintegrating tablet ER matrix.

Disintegration

Maximize the feasibility ofachieving the target goals ofAUC0-2, AUC2-24, AUC0-∞ andCmax under fasting and fedconditions.

Must provide for biphasic release of drug,with initial rapid release followed by sustainedrelease ER of dose.

Biphasic DrugRelease(IR and ER)

Additional BioequivalenceParameters NeededBased Upon Labeling

Generic MR provides for: 1. Initial plasma concentrationsthrough the first two hours thatprovide for a clinicallysignificant effect

2. Sustained release phasedesigned to maintain plasmaconcentrations formaintenance of effect

Fasting Study and Fed Study 90 % confidence interval of the PK parameters, AUC0-2, AUC2-24, AUC0-∞ and Cmax should fall within BE limits.

PK

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Initial target goals used tomaximize the feasibility ofachieving the bioequivalencetarget goals of AUC0-2, AUC2-24,AUC0-∞ and Cmax under fastingand fed conditions

Rapid release (NMT 15 min) using USPapparatus 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 ReleaseInitial Target

Generic MR is convenientlyscored for administration of the 5 mg dose

Similar drug release of whole and split halftablets.

(Precludes ER coating of a compressed tabletcore to provide for sustained release of drug).

Drug ReleaseWhole versusHalf Tablets

Revised Drug Release Target

Convolution of IVIVR Target:Similarity (not F2) of the in-vitrorelease maximizes feasibility ofachieving the bioequivalencetarget goals of AUC0-2, AUC2-24,AUC0-∞ and Cmax

Target: Similar Drug Release Profile (Based upon Convolution of IVIVR)

Apparatus III: 10 dpm in phosphate buffer pH 6.8 (250 mL)

Drug Release (Revised Target)

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Is Formulation Designed using a QTPP that Targets Equivalence to the RLD?

“Bioequivalence by Design”

Formulation Designed Based Upon an UnderstandingOf Critical Quality Attributes to Provide a Equivalent

Exposure Profile Needed to Achieve Equivalent Clinical Characteristics in Target Patient Population.

If QTPP Surrogate Does not Target Equivalence To the RLD, May Be Acceptable

Sponsors Should Provide Justification Based On Drug Pharmacokinetic and Clinical Profile

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Implementation of QbD?Labeled Use

Safety and Efficacy

DEFINE QualityTarget Product Profile

IDENTIFY Critical Material Attributesand Critical Process Parameters

DESIGN Formulation and Process

CONTROL Materials and Process

TARGET DESIGN IMPLEMENTATION

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Formulation Development

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Schematic: MR Drug ProductActive

High ShearWet Granulation

IR Granules

Active

DL (MCC Cores)

ER

Wurster Coating

ER Pellets

Blending/LubricationCushioningExcipient

Compression

Tablet CoreFilm Coat

MR Product

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Formulation (In-Vitro Drug Release)

Past/Present Paradigm

If Bioequivalent

Perform Drug Release Testingat Multiple pH Media (Speeds)

“Empirically” Set AppropriateTolerances at Select Time Points

QbD Paradigm

2. IVIVR

Meaningful Dissolution Methods:Derived from Data in Pilot BE on ExperimentalFormulations and Used to Guide Development

3. PAT SurrogatesMeasure ER Coating (Terahertz/Raman/NIR)

1. IVIVC

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0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16 18 20 22 24

Time (Hour)

% R

elea

se

Test-F1-Water

Test-F1-HCl

Test-F1-4.5

Test-F1-6.8

RLD-Water

RLD-0.1 N HCl

RLD-pH 4.5

RLD-pH 6.8

0

50

100

150

200

250

300

350

400

0 4 8 12 16 20 24

Time (Hour)

Con

cent

ratio

n (n

g/m

L)

RLDTest F-1

USP Recommended Method (USP Apparatus II – pH 6.8 at 50 rpm)

Development Trial Formulation F-1(25% ER Coating)

Similar Dissolution at three pHs

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Comparative in-vitro release characteristics of the RLD and the prototype test formulations using the discriminating method (right) and non-discriminating method (left)

F-1 (25% ER Coating)F-2 (30% ER Coating) F-3 (35% ER Coating)

USP 3 apparatus(250 mL, pH 6.8, 10 dpm)

USP Recommended Method (USP Apparatus II, pH 6.8, 50 rpm)

25

0

50

100

150

200

250

300

350

400

0 5 10 15 20 25 30

Time (hour)C

once

ntra

tion

(ng/

mL)

RLDTest F-2Test-F3

0.750.950.950.81Test F-3 (35% ER Coating)

1.030.960.980.97Test F-2 (30% ER Coating)

1.321.101.211.1Test F-1 (25% ER Coating)

CmaxAUC2-IAUC2-TAUC0-2

T/R ratio

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 × xx = Fraction in-vitro release y = Fraction in-vivo release

SEP=0.037 MAE=0.027 AIC= -51.54

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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”

Limited Testing Sufficient to Ensure Stability on Future Production Batches?

“Not all Batches Placed on Stability”

API/Excipient Compatability?

Amorphous Dispersion (API/Binder) on MCC Core Physically Stable?

Plasticizer Optimal to Minimize Curing

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*Amorphous-crystallinity ratio as determined by XRPD after 1 month storage at 40 C/75% RH.

Amorphous Dispersion (API/Binder) on MCC Core Physically Stable?

not detected0.299.4%80%80:20With PVP K30

not detected0.399.6%90%85:15With PVP K30

200.299.8%85%90:10With PVP K30

800.199.9%85%100:0No binder

Percentage of crystalline API (%)

LODHPLCAssay

%Release in 15 min

API: BinderRatio

Output CharacteristicsInput VariablesExperiment

XRPD Analysis: API crystals (a), Binder (b) and Amorphous API with 15% Binder (d).

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Plasticizer Optimal to Ensure Adequate Curingto 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

0

10

20

30

40

50

60

70

80

90

100

0 5 10 15 20 25Time (hr)

% R

elea

sed

Uncured12 h / 60°C24 h / 60°C

Confirmed in pilot scale process development studies

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Formulation (Manufacturability)

Past/Present Paradigm QbD Paradigm

Manufacturable at Exhibit (Biobatch) Scale?

Excipients Selected to Ensure a Robust Process?What is the Elongation Percentage for the ER Coating Polymers? Can ER Coating WithstandCompression Pressures during Compression?

If not, will Cushioning Excipients Rectify this?Does this Ensure the Sponsor has

Developed a Robust Formulation that Can be Reproducibly Manufactured ?

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1.340.13 0.624.89

142.83

38.41

126.31

13.02

136

376.1

0

50

100

150

200

250

300

350

400

% E

long

atio

n

Polymer 4ER Polymer 5ER Polymer 1ER Polymer 2 ER Polymer 3 ER

Dry StateWet State

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Process Development/Scale-Up

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Manufacturing Process Past/Present Paradigm

Exhibit (Biobatch) Production Record

10 x Scale-UpSame Equipment/

Operating Principle

Full Production Batches( Not Reviewed by OGD)

No Data to Classify CPPs versus

non-CPPs

QbD Paradigm

Risk Assessment +

Design of Experiments

Classify CPPs versus non-CPPs in the unit Operation

Increased Likelihood of a Successful Commercial-Scale Process

Can Sponsor Reliably Manufacture atCommercial Production Scale(or Even at the Same Scale)?

Define Design Process Space for CPPsAt Pilot Scale (Bioequivalence Batch)

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Raw Materials:Drug Substance and

Excipients

ER Coating

Sieving II

Pre-Lubrication andLubrication Blending

Charging to Blender

Compression

Drug Layering

Sieving I

Raw Materials:Drug Substance and

Excipients

ER Coating

Sieving II

Pre-Lubrication andLubrication Blending

Charging to Blender

Compression

Drug Layering

Sieving I

Quality Attributesto be Considered

ManufacturingProcess Steps

Material Attributes andProcess Parameters

Particle sizeDensity

Moisture contentExcipient type/grade/level

Lot-to-lot variationViscosity

Inlet air volumeInlet air temperatureProduct temperatureSpray rate per nozzle

Nozzle diameter and number of nozzleAtomization air pressure

Partition diameter and heightCapacity utilized

Inlet air dew pointFilter

Screen sizeScreen type

Inlet air volumeInlet air temperatureProduct temperatureSpray rate per nozzle

Nozzle diameter and number of nozzleAtomization air pressure

Partition diameter and heightCapacity utilized

Inlet air dew pointFilter

Coating dispersion: Solid content,Viscosity and sedimentation

IR Granules from ANDA# aaaaaaExtragranular Excipients

Holding timeMaterial transfer method

Order of addition

Screen sizeScreen type

Blender Type/GeometryNo. of revolutions (time and speed)

Capacity utilizedIntensifier bar (on/off)

Holding time

Pre-compression forceMain compression force

Press speedFeeder speed/Type

Ejection forceHopper design: Height and Vibration

Hopper fill

AppearanceDissolutionAssayContent Uniformity

AssayCoating/Content UniformityDS Solid State FormLOD

DissolutionDose DumpingLOD

Particle Size DistributionSieve Cut vs. DissolutionFines/AgglomeratesUsable Yield

Blend UniformityParticle Size DistributionDensityFlowability/Compressibility

Blend Uniformity

AssayContent Uniformity (whole and split)Weight VariationHardnessFriabilityDisintegrationUsable Yield

Particle Size DistributionFines/AgglomeratesUsable Yield

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Table 63. Initial risk assessment of the ER coating process variables

A filter bag is used to prevent loss of material and to allow air to pass through. A filter bonnet with a sizeof 200 μm was used based on previous experience.MediumFilter

Keep nozzle tip and air cap flush for consistency.LowNozzle tip/air cap position

Nozzle tip size determines a nozzle’s spray rate capability. Based on potential spray rate, a nozzle with 1.0mm orifice diameter was selected.MediumNozzle tip diameter

Partition gap can impact the circulation rate of beads passing through the coating zone. When the gap is toobig, insufficient differential pressure to draw beads up the partition column can be generated. When the gapis too small, the circulation rate of beads goes up, but the mass flow of beads will be limited. The partitionheight was set at 25 mm based on bed fill level and prior knowledge.

MediumPartition height (gap)

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.MediumAir distribution plate

By equipment design: 89 mm in diameter.LowPartition column diameter

7″ Wurster HS insert is selected based on its capacity, 2.5 – 5 kg.MediumWurster insert diameter

Justification and Initial StrategyRisk AssessmentProcess Variables

The coating dispersion may thin due to shear if the coating process is long.MediumCoating Time

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

HighAtomization air pressure

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

HighSpray rate/nozzle

If air volume is too high, spray drying may occur.If air volume is too low, agglomeration may occur.Investigate with DOE

HighAir volume

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

HighProduct temperature

Inlet temperature will be adjusted to reach the desired product temperature. The range of 40-60ºC is selected based on trial batches in GPCG-1MediumInlet air temperature

To prevent beads from being trapped in the filter bag. 60 sec/5sec: based on prior knowledge.LowShaking interval/duration

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.MediumInlet air dew point

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DOE Screening Design to Investigate which‘High Risk’ Parameters are Critical in ER Coating

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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

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Updated risk assessment of the ER coating process variables

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.

LowHighAtomization air pressure

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.

MediumHigh

Spray rate

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.

MediumHighAir volume

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.

LowHigh

Product temperature

Justification for the Mitigated RisksFinal Risk Assessment

Initial Risk AssessmentProcess Variables

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Bioequivalence: Scale-Up Past/Present Paradigm

Bioequivalent Exhibit Batch

Linking Bioequivalence at Commercial Scale Using “Empirical” Dissolution Test

Scale-Up

Bioequivalent Exhibit Batch

QbD Paradigm

Linking Bioequivalence at Commercial Scale:

1. IVIVC

2 IVIVR

3. Unit operation incorporating ER mechanismscale-independent process parameters.

4. Linking drug product critical quality material attributes of ER coating between scales (PAT tools)

Commercial Scale DrugProduct Still Bioequivalent ???

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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

Bioequivalence: Scale-Up

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)

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Linkage of Commercial and Exhibit Batch Process Spaces

Bioequivalent ANDA Bioequivalent ANDA Exhibit Batch well withinExhibit Batch well withinPilot Scale Design Space Pilot Scale Design Space

CPP 1*CPP 1*

CPP

2*

CPP

2*

CPP 3*

CPP 3*

Trial Commercial Batch Trial Commercial Batch Not BioequivalentNot Bioequivalent

Detected by IVIVC/IVIVRDetected by IVIVC/IVIVR

CPP 1*CPP 1*

CPP

2*

CPP

2*

CPP 3*

CPP 3*

Bioequivalent Bioequivalent Commercial BatchCommercial Batch

CPP 1*CPP 1*

CPP

2*

CPP

2*

CPP 3*

CPP 3*

Process Validation/Verification(Post-Submission)

Map/Confirm Points in Predicted Commercial Scale-Process Space

IVIVR/IVIVC and/or PAT tools Adjustments in target coating (30% - 28%)

due to the higher coating efficiency at commercial scale

Scale-up based upon underlying assumptions Similitude, Scale-independence,

Empirical or Semi-Empirical Models,Dimensionless Analysis

CPP 1CPP 1

CPPCPP

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CPP 3CPP 3

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Conclusions

QbD

Drug Product StabilityFormulation “Stability by Design”

Commercial Manufacturing Excipient Selected

CPPs versus non-CPPsUnderstanding CPP Process Space

Therapeutic Equivalence “Bioequivalence by Design”

Bioequivalence: Commercial ScaleIVIVR or IVIVC

PAT Surrogates

Enhance Quality of MR Products

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Acknowledgements

• Lawrence Yu• Robert Lionberger • Lane Christensen • Nilufer Tampal• Om Anand• Ubrani V Venkataram• Quamrul Majumder• Dipak Chowdhury• Roslyn Powers

Peter CapellaLaxma NagavelliSuhas PatankarJennifer MaguireBhagwant RegePeng YingxuYoumin WangKhalid KhanHelen Teng