Professional Documents
Culture Documents
*Opinions expressed in this presentation are those of the speaker and do not necessarily reflect the views or policies of the FDA
Therapeutic Equivalents - Have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling
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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Quality cannot be tested into products; Quality can only be built into products
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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)
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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Implementation of QbD?
Labeled Use Safety and Efficacy
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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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
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
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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
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.
Similar drug release of whole and split half tablets. (Precludes ER coating of a compressed tablet core to provide for sustained release of drug).
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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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.
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
TARGET
DESIGN
IMPLEMENTATION 19
Formulation Development
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Active
Wurster Coating
DL (MCC Cores) ER
IR Granules
ER Pellets
Cushioning Excipient
Tablet Core
MR Product
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1. IVIVC
Perform Drug Release Testing at Multiple pH Media (Speeds)
100 90 80
Test-F1-Water
70
Test-F1-HCl
60
% Release
50 40 30 20 10 0 0 2 4 6 8 10 12 14
Development Trial Formulation F-1 (25% ER Coating) Similar Dissolution at three pHs
20 22 24
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Time (Hour)
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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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)
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25
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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
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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%Release in 15 min
HPLC Assay
LOD
No binder With PVP K30 With PVP K30 With PVP K30
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
Formulation (Manufacturability)
Past/Present Paradigm 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?
Does this Ensure the Sponsor has Developed a Robust Formulation that Can be Reproducibly Manufactured ?
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300
% Elongation
250
150
136
100
50 1.340.13 0 0.624.89
38.41 13.02
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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
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)
Drug Layering
Sieving I
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
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-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.
Medium
Nozzle tip diameter Nozzle tip/air cap position Filter Inlet air dew point Shaking interval/duration Inlet air temperature
Product temperature
High
Air volume
High
Spray rate/nozzle
High
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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Product temperature
High Low
Air volume
High
Medium
Spray rate
High
Medium
High
Low
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Bioequivalence: Scale-Up
Past/Present Paradigm Bioequivalent Exhibit Batch QbD Paradigm Bioequivalent Exhibit Batch
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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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*
P CP
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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
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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