Quality by Design in Pharmaceutical Development

Nowadays, Quality by Design (QbD) is a systematic approach and fundamental requirements for pharmaceutical formulationsdevelopment. Where includes defining quality target product profile (QTPP), identifying critical material attributes (CMAs), critical process parameters (CPPs) and critical quality attributes (CQAs).

While QbD does increase the workload during the product development stage, it protects against variability later on, reducing risk and saving time.

You can read also: A Brief Discussion on QbD Tools

The purpose of QbD is to assure the quality of a pharmaceutical product through scientific development and risk management tools. Where several guidelines on pharmaceutical development, quality risk management, and pharmaceutical quality systems are applicable throughout the product lifecycle. Design space and control strategies for risk management are also QbD elements.

Objectives of QbD

• To achieve meaningful product quality specifications that are based on clinical performance.
• To increase process capability and reduce product variability and defects by enhancing product and process design, understanding, and control.
• To increase product development and manufacturing efficiencies.
• To enhance root cause analysis and post approval change management.

Elements of QbD

• Quality target product profile (QTPP) and Critical quality attributes (CQAs)
• Product design and Critical material attributes (CMAs)
• Process design and Critical process parameters (CPPs)
• Linking CMAs and CPPs to CQAs
• A control strategy (that includes specifications for the drug substance(s), excipient(s), and drug product as well as controls for each step of the manufacturing process.)
• Process capability and continual improvement

QbD tools and studies also include prior knowledge, risk assessment, mechanistic models, design of experiments (DoE) and data analysis, and process analytical technology (PAT).

The basic objectives of DoE are screening, optimization, and robustness. It involves the execution of experimental design on the basis of suitable variables along with statistical evaluation of obtained responses and exploration of the design space using mathematical or graphical approach.

Read also: Design of Experiments (DoE) | Minitab

The effects of variations in process parameters and material attributes are investigated in process robustness studies. The analysis of these experiments identifies CPPs and CMAs that could affect drug product quality and establishes limits for these CPPs and CMAs within which the quality of drug product is assured.

Excipients Selection

The selection of excipients or additives for generic drug development should be RLD based and to be compatible with API. A guideline is also available for 'Incorporation of Pharmaceutical Excipients into Product Development Using Quality by Design', which is published by IPEC. Where includes some recommendations related to the impact of excipient variability on drug product quality during development and how excipient variability can be managed in the control strategy.

Related:

• A Guide to Select Pharmaceutical Excipients in Formulation Development
  
• Regulatory Guidelines for Pharmaceutical Excipients

A list of Input material attributes, Process parameters and Quality attributes

Input material attributes		Process parameters		Quality attributes
Blending/mixing
• Particle size  • Particle size distribution  • Fines/oversize  • Particle shape  • Bulk/tapped/true density  • Cohesive/adhesive properties  • Electrostatic properties  • Moisture content		• Type and geometry of mixer  • Mixer load level  • Order of addition  • Number of revolutions   • Agitating bar (on/off pattern)  • Discharge method  • Holding time  • Environment temperature and RH		• Blend uniformity • Potency • Particle size • Particle size distribution • Bulk/tapped/true density • Moisture content • Flow properties • Cohesive/adhesive properties • Powder segregation • Electrostatic properties
Size reduction/comminution
• Particle/granule size  • Particle/granule size distribution  • Fines  • Particle/granule shape  • Bulk/tapped/true density  • Adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph  • Moisture content  • Granule porosity/density	Ribbon milling  • Ribbon dimensions  • Ribbon density  • Ribbon porosity/solid fraction		• Particle/granule size • Particle/granule size distribution • Particle/granule shape • Particle/granule shape factor (ratio) • Particle/granule density/Porosity • Bulk/tapped/true density • Flow properties • API polymorphic form • API crystalline morphology • Cohesive/adhesive properties • Electrostatic properties • Hardness/Plasticity • Viscoelasticity • Brittleness • Elasticity
	Impact/cutting/screening mills  • Mill type  • Speed  • Blade configuration, type, orientation  • Screen size and type  • Feeding rate Fluid energy mill  • Number of grinding nozzles  • Feed rate  • Nozzle pressure  • Classifier Granule/ribbon milling  • Mill type  • Speed  • Blade configuration, type, orientation  • Screen size and type  • Feeding rate
Wet granulation
• Particle size distribution  • Fines/Oversize  • Particle shape  • Bulk/tapped/true density  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph  • Moisture content		High/low shear granulation  • Type of granulator (High/low shear, top/bottom drive)  • Fill level  • Pregranulation mix time  • Granulating liquid or solvent quantity  • Impeller speed, tip speed, configuration, location, power consumption/torque  • Chopper speed, configuration, location, power consumption  • Spray nozzle type and location  • Method of binder excipient addition (dry/wet)  • Method of granulating liquid addition (spray or pump)  • granulating liquid temperature  • granulating liquid addition rate and time  • Wet massing time (post-granulation mix time)  • Bowl temperature(jacket temperature)  • Product temperature  • Post mixing time  • Pump Type: Peristaltic, Gear type  • Granulating liquid vessel (e.g., pressurized, heated) Fluid bed granulation  • Type of fluid bed  • Inlet air distribution plate  • Spray nozzle (tip size, type/quantity/ pattern/configuration/position)  • Filter type and orifice size  • Fill level  • Bottom screen size and type  • Preheating temperature/time  • Method of binder excipient addition (dry/wet)  • Granulating liquid temperature  • Granulating liquid quantity  • Granulating liquid concentration/viscosity  • Granulating liquid holding time  • Granulating liquid delivery method  • Granulating liquid spray rate  • Inlet air, volume, temperature, dew point  • Atomization air pressure  • Product and filter pressure differentials  • Product temperature  • Exhaust air temperature, flow  • Filter shaking interval and duration		• Endpoint measurement • Blend uniformity • Potency • Flow • Moisture content • Particle size and distribution • Granule size and distribution • Granule strength and uniformity • Bulk/tapped/true density • API polymorphic form • Cohesive/adhesive properties • Electrostatic properties • Granule brittleness • Granule elasticity • Solid form/polymorph
Drying
• Particle size, distribution  • Fines/oversize  • Particle shape  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph  • Moisture content		Fluidized bed  • Inlet air volume, temperature, dew point  • Product temperature  • Exhaust air temperature, flow  • Filter type and orifice size  • Shaking interval and duration  • Total drying time Tray  • Type of tray dryer  • Bed thickness/tray depth (depth of product per tray)  • Type of drying tray liner (e.g., paper, plastic, synthetic fiber, etc.)  • Quantity carts and trays per chamber  • Quantity of product per tray  • Drying time and temperature  • Air flow  • Inlet dew point Vacuum/microwave  • Jacket temperature  • Condenser temperature  • Impeller speed  • Bleed air volume  • Vacuum pressure  • Microwave power  • Electric field  • Energy supplied  • Product temperature  • Bowl and lid temperature  • Total drying time		• Granule size and distribution • Granule strength, uniformity • Flow • Bulk/tapped/true density • Moisture content • Residual solvents • API polymorphic form or transition • Purity profile • Moisture profile (e.g. product temperature vs. LOD) • Potency • Cohesive/adhesive properties • Electrostatic properties
Roller compaction/chilsonation
• Particle size, distribution  • Fines/oversize  • Particle shape  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Bulk/tapped/true density  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph		• Type of roller compactor  • Auger (feed screw) type/design (horizontal, vertical or angular)  • Deaeration (e.g., vacuum)  • Auger (feed screw) speed  • Roll shape (cylindrical or interlocking).  • Roll surface design (smooth, knurled, serrated, or pocketed)  • Roll gap width (e.g., flexible or fixed)  • Roll speed  • Roll pressure  • Roller temperature  • Fines recycled (yes or no, # of cycles)		• Ribbon appearance (edge attrition, splitting, lamination, color, etc.) • Ribbon thickness • Ribbon density (e.g., envelop density) • Ribbon porosity/solid fraction • Ribbon tensile strength/breaking force • Throughput rate • API polymorphic form and transition
Extrusion–Spheronization
• Particle size, distribution  • Fines/oversize  • Particle shape  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Bulk/tapped/true density  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph		• Type of extruder (screw or basket) • Screw length, pitch, and diameter • Screw channel depth • Screw blade configuration • Number of screws (single/dual) • Die or screen configuration (e.g., radial or axial) • Die length/diameter ratio • Roll diameter (mm) • Screen opening diameter (mm) • Screw speed (rpm) • Feeding rate (g/min) • Type and scale of spheronizer • Spheronizer load level • Plate geometry and speed • Plate groove design (spacing and pattern) • Air flow • Residence time		• Extrudate • Density • Length/thickness/diameter • Moisture content • API polymorphic form and transition • Content uniformity • Throughput • Pellets after spheronization • Pellets size and distribution • Pellets shape factor (e.g. aspect ratio) • Bulk/Tapped density • Flow properties • Brittleness • Elasticity • Mechanical strength • Friability
Hot melt extrusion
• Particle size, distribution  • Fines/oversize  • Particle shape  • Melting point  • Density  • Solid form/polymorph  • Moisture content		• Screw design (twin/single) • Screw speed • Screw opening diameter (mm) • Solid and liquid feed rates • Feeder type/design • Feed rate • No. of zones • Zone temperatures • Chilling rate		• Extrudate density • Length/thickness/diameter • Polymorphic form and transition • Content uniformity • Throughput
Tabletting
• Particle/granule size and distribution  • Fines/oversize  • Particle/granule shape  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Bulk/tapped/true density  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph  • Moisture		• Type of press (model, geometry, number of stations) • Hopper design, height, angle, vibration • Feeder mechanism (gravity/forced feed, shape of wheels, direction of rotation, number of bars) • Feed frame type and speed • Feeder fill depth • Tooling design (e.g., dimension, score configuration, quality of the metal) • Maximum punch load • Press speed/dwell time • Precompression force • Main compression force • Punch penetration depth • Ejection force • Dwell Time		• Tablet appearance • Tablet weight • Weight uniformity • Content uniformity • Hardness/tablet breaking force/tensile strength • Thickness/dimensions • Tablet porosity/density/solid fraction • Friability • Tablet defects • Moisture content • Disintegration • Dissolution
Encapsulation
• Particle/granule size and distribution  • Fines/oversize  • Particle/granule shape  • Cohesive/adhesive properties  • Electrostatic properties  • Hardness/plasticity  • Bulk/tapped/true density  • Viscoelasticity  • Brittleness  • Elasticity  • Solid form/polymorph  • Moisture		• Machine type • Machine fill speed • Tamping Force • No. of tamps • Auger screw design/speed • Powder bed height		• Capsule appearance • Weight • Weight uniformity • Content uniformity • Moisture content • Slug tensile strength • Disintegration • Dissolution
Pan coating
• Tablet dimensions  • Tablet defects  • Hardness/plasticity  • Density  • Porosity  • Moisture content		• Type of pan coater (conventional or side-vented) • Pan (fully perforated or partial perforated) • Baffle (design, number, location) • Pan load level • Pan rotation speed • Spray nozzle (type, quantity, pattern, configuration, spray pattern) • Nozzle to bed distance • Distance between nozzles • Nozzle orientation • Total preheating time • Inlet air flow rate, volume, temperature, dew point • Product temperature • Individual nozzle spray rate • Total spray rate • Atomization air pressure • Pattern air pressure • Exhaust air temperature, air flow • Total coating, curing time and drying time		• Coating efficiency • Core tablet weight before and after preheating • Moisture (gain/loss) during preheating • Environmental equivalency factor • Coated drug product (e.g., tablet or capsule) appearance • % weight gain • Film thickness • Coating (polymer and /or color) uniformity • Hardness/breaking force/Tensile strength • Friability • Moisture (gain/loss) during overall process • Residual solvent(s) • Disintegration • Dissolution • Tablet defects • Visual attributes
Fluid bed coating
• Tablet dimensions  • Tablet defects  • Hardness/plasticity  • Density/porosity moisture content		• Type of fluid bed coater • Fluid bed load level • Partition column diameter • Partition column height • Number of partition columns • Air distribution plate type and size • Filter type and orifice size • Filter differential pressure • Filter shaking interval and duration • Spray nozzle (type, quantity, pattern, configuration) • Nozzle port size • Total preheating time • Spray rate per nozzle • Total spray rate • Atomization air pressure • Inlet air flow rate, volume, temperature, dew point • Product temperature • Exhaust air temperature, air flow • Total coating, curing and drying time		• Coating efficiency • Core tablet weight before and after preheating • Moisture (gain/loss) during preheating • Environmental equivalency factor • Coated drug product (e.g., tablet or capsule) appearance • % weight gain • Film thickness • Coating (polymer and /or color) uniformity • Hardness/breaking force/tensile strength • Friability • Moisture (gain/loss) during overall process • Residual solvent(s) • Disintegration • Dissolution • Tablet defects • Visual attributes
Laser drilling
• Size/dimensions  • Polymer type membrane thickness		• Conveyor type • Conveyor speed • Laser power • Number of pulses • Type(s) of lens(es) • One or two sided • Number of holes		• Opening diameter (internal and external) • Depth • Shape of the opening