Content PART I: ANDA Roadmap PART II: Understanding of CPPs & CQAs PART III: Scale-Up and Technology Transfer PART IV: Process Validation & Sampling 2

Transcription

1 EMA, FDA- ANDA Readiness -OSD Generics Solution Post Formulation Development Horch Guo, May. 2016, Changzhou, China

2 Content PART I: ANDA Roadmap PART II: Understanding of CPPs & CQAs PART III: Scale-Up and Technology Transfer PART IV: Process Validation & Sampling 2

3 PART I: ANDA Roadmap 3

4 ANDA Product Development Roadmap - QbD based 1 Market Survey & Kick-off 2 Pre- Formulation 3 Formulation Development 4 Process Dev. & Scale-UP 5 Exhibit batches(pv) 6 ANDA Filing -Raw Materials -QTPP -Raw Materials Audit -Equip. Qualification -PV Protocol -Mfg. & Ana Equip. -Mfg Rooms -Containments -CQAs -CMAs -Method of Mfg.Dev. -CV Method Develop. -Tooling -CPPs & CQAs -Method of Mfg. (IPC,Sampling) Dev. -Method of Mfg. (IPC,Sampling) -Method of Pkg. -CV -Process Varialbes & Range -Method of Pkg. Dev. -Scale-UP -CV Protocol 4

5 QTPP & & CQA & CPPs 5

6 PART II: CPPs & CQAs 6

7 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 Process Design Process Performance -Desired Clinical Performance -Dosage Form -Excipients -Stability -Unit Operations -Control Strategy -Cpk -Robustness 7

8 Quality Right at First Time - Patient based integrated RA (Q8, Q9, Q10) ICH Q8/9/10- Patient based risk assessment QMS: ISO 9001:2005 8

9 Quality Right at First Time - Design Space & Robustness Quality issue & Cost Design Parameter Design Space Operation Range Design Space Knowledge Space 9

10 Quality Right at First Time - Operation / Design Space & Robustness 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 Process Understanding Critical Quality Attribute (CQA) a process output which is critical to achieving the product quality/safety/efficacy (e.g. impurity profile, stability, dissolution) Robust Process Normal Operating Range (NOR) Non-Robust Process Normal Operating Range (NOR) Proven Acceptable Range (PAR) Proven Acceptable Range (PAR)

11 Quality Right at First Time -Operation Process/ Reliable & Robust Risk Assessments (FMEA) -The Variability on CPPs Critical Process Parameter (CPP) -Intrinsic API properties (solubility, stability) -Formulation Principle -Manufacturing Costs -Volume considerations Technology -Wet Granulation -Dry Granulation -Extrusion Process Design -Define the CPPs and PARs Process Control Strategy -Control Range

12 Quality Right at First Time -Operation/ Variations Control key points People Equipment/Utilities Environment Materials Profile & 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 Unknown variations are the major threat for Quality ( We do not know what we do not know )

13 OSD -Operation & PPs & QAs Operation Process Parameter Quality Attributes Milling Wet granulation -Mill type -Speed -Blade configuration/type -Screen type and size -Feed rate 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) -Particle size distribution -Particle shape -Bulk/tapped density -Flow properties -Polymorphic form -Moisture content -Flow property -Particle size and distribution -Granule size and distribution -Bulk density Wet granulation 13 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

14 OSD-Operation & PPs & QAs 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 Mixing 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 -Type and geometry of mixer -Order of addition -Mixer load level -Time of rotations -Holding time for final blend -Granule size and distribution -Granule strength and uniformity -Particle size -Flow -Bulk/tapped density -Moisture content -Residual solvents -Blend uniformity -Particle size distribution -Bulk/tapped density -Moisture content -Flow properties 14

15 OSD -Operation & PPs & QAs 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 Coating -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 -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 -Target tablet weight -Weight uniformity -Content uniformity -Hardness -Thickness -Tablet porosity -Friability -Visual attributes - -Weight of core tablets -Appearance -Visual attributes -% Weight gain -Film thickness -Color uniformity -Hardness -Thickness -Friability 15

16 PART III: Scale-Up and Technology Transfer 16

17 Scale-Up & Technology Transfer 17

18 Scale-Up Wet Granulation CQAs related -Flow property -Particle size and distribution -Granule size and distribution -Bulk density -API & Excipients ratio -Binding solution properties CPPs related 18

19 Scale-Up Dry Granulation CQAs related -Particle size & Particle size distribution -Particle flowability -Particle shape -API & excipients ratio CPPs related Scale Batch Size(Kg) Roller width (mm) Roller diameter (mm) Roller gap (mm) Roller pressure (bar) Mill Screen orifice size (mm) Lab Pilot Commercial

20 Scale-Up Blending & Lubrication Scale Batch Size(Kg) Blender Capacity (L) CQAs related -Particle size & Particle size distribution -Particle flowability -Particle shape -API & excipients ratio Volume Fill Level (%) Rotation Speed (rpm) Final Blending (min) Lubrication (min) Lab Pilot Commercial CPPs related 20

21 Scale-Up Coating 21

22 PART IV: Process Validation & Sampling 22

23 PV Lifecycle 制 业 药 23

24 CPP & CQA & PV -Quality Risk Management 24

25 PV-Quality Risk Management A successful validation program depends on information and knowledge from product and process development 25

26 PV -Deliverables 26

27 PV Sampling plan e.g. Blending Step Sampling Test Sample a minimum of 10 locations distributed throughout the mixer/blender at three different levels (top, middle and bottom). Assay (potency) In-process controls Holding time 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 27

28 Cleaning -Validation phase- Cleaning Validation Evaluation on the critical points for the equipment selection and design 3 continuous CV for campaign production CV Sampling Identify Product & Process contacted surface area and risk evaluation Develop the equipment based cleaning recipe and CVP QC analysis Cleaning Validation Master Plan Develop and validate the analysis method (API residual and recovery testing) Cleaning Validation Report 28 -Cleaning Validation team with early involvement is most important for cleaning & cross-contamination!

29 More information... Authorities:

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31 Thanks for your attention! 31