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

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

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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 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
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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 = (Drug substance, excipients, manufacturing, and packaging) 5

Regulatory View for Pharmaceutical Quality

Traditional/Historical 21st Century View ICH Q8/cGMPs FDA Initiative

Design Design Testing

Testing

What Do Really Mean by QbD? What are Regulators 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

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. c. Modified Release Drug Products on the Rise 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

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
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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

CONTROL Materials and Process

TARGET

DESIGN

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
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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
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 Bioequivalence by Testing

Asks Sponsors How They Systemically Arrived at a Bioequivalent Drug Product Bioequivalence by Design

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

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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)
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QTPP for Modified Release Product

Profile Component Active Ingredient Dosage Form Strength Dosage Form Appearance and Characteristics Same Tablet Dose: 10 mg Conforming to Description, Shape and Size Same Scoring as RLD Generally similar in Size and Shape to RLD Assay Impurity CU Friability Stability 95-105% Impurity A < 0.5 % RSD < 3% NMT 1.0% 24 month shelf life Targeted for consistent clinical effectiveness Ensure main degradation product remains below qualification threshold Targeted for consistent clinical effectiveness Needed for patient acceptability Needed for commercial reasons 15 QTPP Target Rationale Pharmaceutical Equivalence Requirement Pharmaceutical Equivalence Requirement Same Dosage Form Pharmaceutical Equivalence Requirement Same Strength Needed for Patient Acceptability Size and Shape Conducive to Patient Safety when Swallowing.

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. Needed to minimize potential food effect of IR component, similar 16 to brand name product

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.

Drug Release Whole versus Half Tablets

Similar drug release of whole and split half tablets. (Precludes ER coating of a compressed tablet core to provide for sustained release of drug).

Generic MR is conveniently scored for administration of the 5 mg dose

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).

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
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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)

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

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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

CONTROL Materials and Process

TARGET

DESIGN

IMPLEMENTATION 19

Formulation Development

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Schematic: MR Drug Product

Active
High Shear Wet Granulation

Active
Wurster Coating

DL (MCC Cores) ER

IR Granules

ER Pellets

Cushioning Excipient

Blending/Lubrication Compression Film Coat

Tablet Core

MR Product

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Formulation (In-Vitro Drug Release)

Past/Present Paradigm If Bioequivalent QbD Paradigm 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)

2. IVIVR 3. PAT Surrogates Measure ER Coating (Terahertz/Raman/NIR)

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Empirically Set Appropriate Tolerances at Select Time Points

100 90 80
Test-F1-Water

70
Test-F1-HCl

60

Test-F1-4.5 Test-F1-6.8 RLD-Water

% Release

50 40 30 20 10 0 0 2 4 6 8 10 12 14

RLD-0.1 N HCl RLD-pH 4.5 RLD-pH 6.8

Development Trial Formulation F-1 (25% ER Coating) Similar Dissolution at three pHs
20 22 24

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Time (Hour)

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

400 350 Concentration (ng/m L) 300 250 200 150 100 50 0 0 4 8 12 Time (Hour) 16 20 24
RLD Test F-1

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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)
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400 350
Concentration (ng/mL)

300 250 200 150 100 50 0 0 5 10 15 Time (hour)

RLD Test F-2 Test-F3

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25

30

T/R ratio AUC0-2 Test F-1 (25% ER Coating) Test F-2 (30% ER Coating) Test F-3 (35% ER Coating) 1.1 0.97 0.81 AUC2-T 1.21 0.98 0.95 AUC2-I 1.10 0.96 0.95 Cmax 1.32 1.03 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

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Formulation (Stability)
Past/Present Paradigm QbD Paradigm

Stable by Testing ( 25 C/60% RH for 24 months)

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

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

Experiment Input Variables Output Characteristics

API: Binder Ratio

%Release in 15 min

HPLC Assay

LOD

Percentage of crystalline API (%)

No binder With PVP K30 With PVP K30 With PVP K30

100:0 90:10 85:15 80:20

85% 85% 90% 80%

99.9% 99.8% 99.6% 99.4%

0.1 0.2 0.3 0.2

80 20 not detected 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 = 5C) for Kollicoat SR 30D with 5% TEC as plasticizer
100 90 80 70 % Released 60 50 40 30 20 10 0 0 5 10 Time (hr) 15 20 25 Uncured 12 h / 60C 24 h / 60C

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 Withstand Compression Pressures during Compression?

Does this Ensure the Sponsor has Developed a Robust Formulation that Can be Reproducibly Manufactured ?

If not, will Cushioning Excipients Rectify this?

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400 376.1 350

300

% Elongation

250

200 142.83 126.31

Dry State Wet State

150

136

100

50 1.340.13 0 0.624.89

38.41 13.02

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

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Process Development/Scale-Up

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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

QbD Paradigm Risk Assessment + Design of Experiments

Classify CPPs versus non-CPPs in the unit Operation

Full Production Batches ( Not Reviewed by OGD) Can Sponsor Reliably Manufacture at Commercial Production Scale (or Even at the Same Scale)?

Define Design Process Space for CPPs At Pilot Scale (Bioequivalence Batch)

Increased Likelihood of a Successful Commercial-Scale Process

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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

Manufacturing Process Steps

Quality Attributes to be Considered

Appearance Dissolution Assay Content Uniformity

Raw Materials: Drug Substance and Excipients

Drug Layering

Assay Coating/Content Uniformity DS Solid State Form LOD

Screen size Screen type

Sieving I

Particle Size Distribution Fines/Agglomerates Usable Yield

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

ER Coating

Dissolution Dose Dumping LOD

Screen size Screen type

Sieving II

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

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Process Variables Wurster insert diameter Partition column diameter Air distribution plate

Table 63. Initial Risk Assessment risk assessment of the ER coating process variables Justification and Initial Strategy Medium Low Medium 7 Wurster HS insert is selected based on its capacity, 2.5 5 kg. By equipment design: 89 mm in diameter. 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 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 size determines a nozzles spray rate capability. Based on potential spray rate, a nozzle with 1.0 mm orifice diameter was selected. Keep nozzle tip and air cap flush for consistency. 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 m was used based on previous experience. Variation of inlet air humidity may have an impact on drug release rate. The impact needs to be evaluated. Typically, a dew point of 10-15 C is used for processing. 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 40-60C is selected based on trial batches in GPCG-1 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 If air volume is too high, spray drying may occur. If air volume is too low, agglomeration may occur. Investigate with DOE 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 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 The coating dispersion may thin due to shear if the coating process is long.

Partition height (gap)

Medium

Nozzle tip diameter Nozzle tip/air cap position Filter Inlet air dew point Shaking interval/duration Inlet air temperature

Medium Low Medium Medium Low Medium

Product temperature

High

Air volume

High

Spray rate/nozzle

High

Atomization air pressure Coating Time

High Medium

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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

Process Variables Initial Risk Assessment Final Risk Assessment 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. 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. 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. 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.

Product temperature

High Low

Air volume

High

Medium

Spray rate

High

Medium

Atomization air pressure

High

Low

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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 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)

Linking Bioequivalence at Commercial Scale Using Empirical Dissolution Test Commercial Scale Drug Product Still Bioequivalent ???

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)

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Linkage of Commercial and Exhibit Batch Process Spaces

CPP 1

CPP 1*

CPP 2

Bioequivalent ANDA Exhibit Batch well within Pilot Scale Design Space
CP P

Scale-up based upon underlying assumptions Similitude, Scale-independence, Empirical or Semi-Empirical Models, Dimensionless Analysis

CP P

Process Validation/Verification (Post-Submission) Map/Confirm Points in Predicted Commercial Scale-Process Space CPP 1*

CPP 1* CPP 2* CPP 2* Bioequivalent Commercial Batch

CP P

P CP

Trial Commercial Batch Not Bioequivalent Detected by IVIVC/IVIVR

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3*

3*

IVIVR/IVIVC and/or PAT tools Adjustments in target coating (30% - 28%) due to the higher coating efficiency at commercial scale

3*

CPP 2*

Conclusions
Therapeutic Equivalence Bioequivalence by Design Bioequivalence: Commercial Scale IVIVR or IVIVC PAT Surrogates

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
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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 Capella Laxma Nagavelli Suhas Patankar Jennifer Maguire Bhagwant Rege Peng Yingxu Youmin Wang Khalid Khan Helen Teng

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