EMA, FDA- ANDA Readiness

-OSD Generics SolutionPost Formulation Development

Horch Guo, May . 2016, Changzhou, ChinaHongxing.guo@yahoo.com

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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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