Verification of the EDA Concept Through an Assessment of Theoretical Failure Modes, Failure Mode Analysis, and Case Studies with Real Data - Good Cascade Impactor Practices, AIM and EDA for Orally Inhaled Products - page 257

Environmental conditions
Temperature/Moisture cycling
Start conditions
Equipment control
Change management
Procedures
Time/Duration/Aging
Mechanical stress
Transport stress (e.g. vibration, shaking, etc)
Light

Storage

Charge sources
Magnetic effects
Absorptive components
Holding time
Packaging
Scale
Headspace
Handling
Intermediate container
Order of addition API and
excipients
Equipment type
Material of construction
Adhesion to vessel
Adhesive/Cohesive mixture
Mixing of batches of excipients
Mixing parameters
Demixing
Surface properties of components
Environmental conditions during mixing process
Duration, holding times of powder mixture
Impeller geometry
Vessel geometry
Batch size
Charge/Discharge
Air seal
Pulvodynamics
Type of equpiment
Materials of construction
Shear
Compaction
Segregation

Sealing parameters
Tightness packaging (material, sealing)
Environmental conditions during packaging
Holding times during packaging
Residual solvents packaging material
Contact between packaging material and
bulk product (compatibility)
Mechanical stress - demixing
Forming process and forming design
Electrostatic effects

Packaging (secondary)

Manufacturing process API (e.g PSD)
Changes to manufacturing process API
Manufacturing process dosage unit (e.g
resulting in different levels of excipients)
Manufacturing process excipients (PSD, homogeneity)
Age of components
Stickiness/Humidity of components
Surface excipients (physical-chemical
parameters, pH, H 2 0 Content on surface,
topography)

Mixing (blend formulation)

Storage of components

Components

Process parameters during manufacturing
of packaging material (residual solvent,
humidity)

Manufacturing process for dosage units
(e.g. resulting in different levels of
excipients) - type, consistency, variability
Manufacturing process for device - type,
consistency, variability
Precision/Dimensional tolerances of
device components
Storage of device components

Finished product

Environmental conditions
Overages
Run time
Process parameters
De-mixing in powder bed
Feeding of powder mixture
Electrostatics
Airflow over powder
Powder adhesion
Vacuum pressures
Multiple lane
Process parameters
De-mixing in powder bed
Feeding of powder mixture
Environmental conditions
Electrostatics
Seal temperature
Seal time
Seal pressure
Fill cycle time
Process pauses
Feed hopper size
Feed hopper geometry
Compressed air quality
Consumable quality
Shear
Compaction
Segregation
Overages
Run time
Air flow over powder
Powder adhesion
Influence of employee
Mechanical stress

APSD Change
Manufacturing Reservoir

Screen size

Automated process
Separate or combined materials
Vibration frequency
Scale of batch
Segregation

Sieving

Pressure
Gas flow
Moisture content of gas
Number and angles of jets
Mill size
Feed rate and feed consistency
Mill type
Scale of batch
Material of construction
Operating conditions
Classifier/collection vessel

Filling

Micronization

Pre-Metered

Nozzle gas
Temperature (inlet/outlet)
Nozzle geometry
Inlet gas (drying gas)
Solvent selection
Feed rate
Solution concentration
Scale of batch
Excipients
Collection cyclone

Spray drying

Sampling

In-process controls

Fig. 9.7 Potential causes for APSD changes related to the DPI manufacturing process
( From [ 9 ] —used with permission )

In the second part of the assessment, they repeated the same exercise for a
hypothetical MDI, considering manufacturing process, formulation, device,
device-formulation interactions, storage and accessories, or add-on devices such as
VHCs (Fig. 9.9 ).
Glaab et al. [ 9 ] then went on to examine the various control strategies that could
be put in place not only to detect changes in the quality of the product, excipient, or