EMA, FDA- ANDA Readiness
-OSD Generics SolutionPost Formulation Development
Horch Guo, May . 2016, Changzhou, [email protected]
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Content
PART I: ANDA Roadmap
PART II: Understanding of CPPs & CQAs
PART III: Scale-Up and Technology Transfer
PART IV: Process Validation & Sampling
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PART I: ANDA Roadmap
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ANDA Product Development Roadmap- QbD based
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1Market Survey
& Kick-off
3Formulation
Development
4Process Dev. & Scale-UP
2Pre-
Formulation
5Exhibit
batches(PV)
6ANDA Filing
-Raw Materials
-Mfg. & Ana Equip.
-Mfg Rooms
-Containments
-Raw Materials Audit
-CMAs
-Method of Mfg.Dev.
-CV Method Develop.
-Equip. Qualification
-Tooling
-CPPs & CQAs
-Method of Mfg. (IPC,Sampling) Dev.
-Process Varialbes & Range
-Method of Pkg. Dev.
-Scale-UP
-CV Protocol
-PV Protocol
-Method of Mfg. (IPC,Sampling)
-Method of Pkg.
-CV
-QTPP
-CQAs
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QTPP & & CQA & CPPs
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PART II: CPPs & CQAs
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Quality Right at First Time -QbD- QbD Concept
Product Knowledge
Process Understanding
Product Specification
Product Quality Attributes
Process Parameters
Process Controls
Product Performance
Product Design
ProcessDesign
ProcessPerformance
-Desired Clinical Performance
-Dosage Form-Excipients-Stability
-Unit Operations-Control Strategy
-Cpk-Robustness
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Quality Right at First Time - Patient based integrated RA (Q8, Q9, Q10)
ICH Q8/9/10- Patient based risk assessment QMS: ISO 9001:2005
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Quality Right at First Time- Design Space & Robustness
Quality issue & Cost
Design Parameter Design Space
Knowledge SpaceDesign
Space
Operation Range
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Robust Process Non-Robust Process
Critical Process Parameter (CPP)
A process input that must be kept within a proven acceptable range (PAR) in order to ensure that the final product will be within its CQA limits
Critical Quality Attribute (CQA)
a process output which is critical to achieving the product quality/safety/efficacy (e.g. impurity profile, stability, dissolution)
Process Understanding
Normal Operating Range (NOR)
Proven Acceptable Range (PAR)
Normal Operating Range (NOR)
Proven Acceptable Range (PAR)
Quality Right at First Time- Operation / Design Space & Robustness
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Critical Process Parameter (CPP)
-Intrinsic API properties (solubility, stability)-Formulation Principle-Manufacturing Costs-Volume considerations
Technology
-Wet Granulation-Dry Granulation-Extrusion
Risk Assessments (FMEA)
-The Variability on CPPs
Process Design
-Define the CPPs and PARs
Process ControlStrategy
-Control Range
Quality Right at First Time-Operation Process/ Reliable & Robust
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Unknown variations are the major threat for Quality
(“We do not know what we do not know”)
Quality Right at First Time-Operation/ Variations Control key points
People Equipment/Utilities Environment MaterialsProfile & education Adequate design Zone concept Specifications
Job description Measurement systems containment Supplier management
Regular training Specifications Layout Packaging
Supervision Qualification Hygiene Storage/transport
Communication Calibration Microbiology monitoring Testing
Procedures Maintenance Pest control
Rewarding Cleaning
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OSD -Operation & PPs & QAs
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Operation Process Parameter Quality Attributes
Milling -Mill type-Speed-Blade configuration/type-Screen type and size-Feed rate
-Particle size distribution-Particle shape-Bulk/tapped density-Flow properties-Polymorphic form
Wet granulation High Shear Granulation-Pre-binder mixing time-Impeller speed/configuration/location-Chopper speed/configuration-Spray nozzle type/location-Method of binder addition-Binder fluid temperature-Binder addition rate/time-Post-granulation mix/kneading time-Bowl/product temperature-Power consumption (kW)
-Moisture content-Flow property-Particle size and distribution-Granule size and distribution-Bulk density
Wet granulation Fluid Bed Granulation-Mixing time-Spray nozzle type/number/pattern/configuration-Method of binder addition-Binder fluid temperature-Binder fluid addition rate/time-Inlet airflow, temperature, volume and dew point-Exhaust air temperature and flow rate-Filter property and size-Filter shaking intervals-Product temperature
-Moisture content-Flow property-Particle size and distribution-Granule size and distribution-Bulk density
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OSD-Operation & PPs & QAs
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Operation Process Parameter Quality Attributes
Drying Fluid Bed Dryer-Inlet air volume, temperature, and dew point-Exhaust air temperature and flow-Filter properties-Filter shaking intervals-Product temperature-Total drying time
-Granule size and distribution-Granule strength and uniformity-Particle size-Flow-Bulk/tapped density-Moisture content-Residual solvents
Drying Tray Dryer-Number of carts and trays per chamber-Amount of product per tray-Drying time and temperature-Airflow-Inlet air dew point-Vacuum/microwave dryer-Jacket temperature-Condenser temperature-Impeller speed-Vacuum strength-Microwave frequency-Electric field-Energy supplied-Product temperature
-Granule size and distribution-Granule strength and uniformity-Particle size-Flow-Bulk/tapped density-Moisture content-Residual solvents
Mixing -Type and geometry of mixer-Order of addition-Mixer load level-Time of rotations-Holding time for final blend
-Blend uniformity-Particle size distribution-Bulk/tapped density-Moisture content-Flow properties
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OSD -Operation & PPs & QAs
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Operation Process Parameter Quality Attributes
Dry Granulation -Roller type-Roll speed-Gap setting-Roll pressure force-Temperature-Roller gap-Auger screw rate
-Appearance-Ribbon/particle size and shape-Ribbon density, strength, and thickness-Moisture content
Compression -Compression speed and force-Precompression force-Feed frame type and speed-Hopper design, height, and vibration-Tablet weight and thickness-Depth of fill-Punch penetration depth
-Target tablet weight-Weight uniformity-Content uniformity-Hardness-Thickness-Tablet porosity-Friability-Visual attributes-
Coating -Total pre-heating time-Spray nozzle type/number/pattern/configuration-Individual gun spray rate-Total spray rate-Pan rotation speed-Atomization air pressure-Pattern air pressure-Inlet airflow, temperature, and dew point-Exhaust air temperature and airflow-Product temperature-Total coating time
-Weight of core tablets-Appearance-Visual attributes-% Weight gain-Film thickness-Color uniformity-Hardness-Thickness-Friability
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PART III: Scale-Up and Technology Transfer
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Scale-Up & Technology Transfer
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Scale-Up –Wet Granulation
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CQAs related-Flow property-Particle size and distribution-Granule size and distribution-Bulk density-API & Excipients ratio-Binding solution properties
CPPs related
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Scale-Up –Dry Granulation
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Scale Batch Size(Kg)
Roller width(mm)
Roller diameter(mm)
Roller gap(mm)
Roller pressure(bar)
Mill Screen orifice size(mm)
Lab 5.0 25 120 1.2-2.4 20-77 1.0
Pilot 50.0 40 120 1.8 50 1.0
Commercial 150.0 75 200 2.0-4.0 31-121 1.0
CQAs related-Particle size & Particle size distribution-Particle flowability-Particle shape-API & excipients ratio
CPPs related
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Scale-Up –Blending & Lubrication
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Scale Batch Size(Kg)
Blender Capacity(L)
Volume Fill Level (%)
Rotation Speed (rpm)
Final Blending (min)
Lubrication(min)
Lab 5.0 17.6 49 20 5 3-5
Pilot 50.0 150 56 12 8 4
Commercial 150.0 500 50 8 12 3-4
CQAs related-Particle size & Particle size distribution-Particle flowability-Particle shape-API & excipients ratio
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Scale-Up –Coating
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PART IV: Process Validation & Sampling
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PV Lifecycle
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CPP & CQA & PV
-Quality Risk Management
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PV-Quality Risk Management
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“A successful validation program depends on information andknowledge from product and process development”
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PV -Deliverables
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PV –Sampling plan – e.g.
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Step Sampling TestBlending •Sample a minimum of 10 locations
distributed throughout the mixer/blender at three different levels (top, middle and bottom).
•Sample size should not be greater than three times (3X) the weight of the dosage unit.
•Sample quantities larger than 3X can be used if they can be scientifically justified.
•Composite sample
Assay (potency)In-process controlsHolding time
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Cleaning-Validation phase- Cleaning Validation
-Cleaning Validation team with early involvement is most important for cleaning & cross-contamination!
Evaluation on the critical points for the equipment selection and design
Identify Product & Process contacted surface area and risk evaluation
Cleaning Validation Master Plan
Develop and validate the analysis method (API residual and recovery testing)
Develop the equipment based cleaning recipe and CVP
3 continuous CV for campaign production CV Sampling
QC analysis
Cleaning Validation Report
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Authorities:
• www.sda.gov.cn
• www.who.int
• www.ich.org
• www.fda.gov
• www.ema.europa.eu
• www.pda.org
• www.pics.org
More information....
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Thanks for your attention!
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