The Problem
A formulation performs perfectly during R&D trials. Blend uniformity passes. Content uniformity meets specification. Everything looks robust.
Then the process is transferred into production — and suddenly:
– Blend uniformity results drift
– Out-of-spec results appear intermittently
– Batches are quarantined or rejected
– Investigations, deviations, and CAPAs begin
This is one of the most common and costly challenges pharmaceutical manufacturers face during scale-up.
The frustrating part?
Nothing appears to have changed.
So why does a blend pass in R&D but fail in production?
The Fundamental Difference Between R&D and Production
R&D and pilot-scale blending environments are controlled, forgiving, and simplified.
Production environments are complex, variable, and far less tolerant of small process weaknesses.
In most cases, the formulation is not the problem — the process is.
Key differences include:
– Scale
– Equipment geometry
– Fill volume
– Powder handling method
– Environmental conditions
– Operator interaction
– Transfer steps before and after blending
Each of these can fundamentally alter powder behaviour.
Common Reasons Blends Fail During Scale-Up
Scale Changes Powder Behaviour
Powders do not scale linearly.
At small scale:
– Short blend paths
– Low bed depth
– Minimal segregation opportunity
At production scale:
– Increased powder mass
– Longer flow paths
– Greater shear forces
– Higher risk of stratification and dead zones
Minor formulation differences become amplified at scale.
Blender Geometry Is Not Equivalent
R&D often uses:
– Simplified tumble mixers
– Small V-blenders
– Lab bin blenders
Production introduces:
– Larger IBC blenders
– Different aspect ratios
– Internal geometry changes
– Different intensifier bar effects (or absence)
Two blenders can look similar but behave very differently internally.
If geometry isn’t matched, blend performance won’t be either
Incorrect Fill Volume in Production
One of the most overlooked issues.
Ideal working volume for most tumble blenders is 33–66%.
In production, fill volumes are often adjusted to:
– Increase throughput
– Reduce batch count
– Match downstream process requirements
Outside the optimal fill range:
– Particle movement reduces
– Convective mixing weakens
– Segregation risk increases
The blend may “look” mixed — but analytically, it is not.
Powder Handling Before and After Blending
In R&D:
– Powders are often hand-charged
– Minimal transfers
– Short hold times
In production:
– Vacuum transfer
– Gravity discharge
– Intermediate containers
– Long hold periods
Every transfer step introduces:
– De-mixing
– Particle size stratification
– Electrostatic effects
Many “blending failures” actually occur after the blend is complete.
Environmental Conditions Change at Scale
Production areas experience:
– Higher humidity variation
– Temperature fluctuations
– Airflow from HVAC systems
– Longer exposure times
These factors affect:
– Moisture uptake
– Flowability
– Electrostatic charge
– Adhesion to vessel walls
R&D environments rarely replicate these conditions accurately.
Sampling Error Masks the Real Problem
R&D sampling is often:
– Limited
– Centralised
– Optimistically positioned
Production sampling must:
– Represent the full batch
– Meet regulatory scrutiny
– Withstand audit review
Poor sampling strategies can falsely indicate blend failure — or mask segregation that occurs later in the process.
Diagnostic Questions to Ask
If your blend passes in R&D but fails in production, ask:
– Is the production blender geometrically equivalent to the R&D unit?
– Are fill volumes consistent with validated working ranges?
– Has powder flow been assessed at production scale?
– Are transfer methods introducing segregation?
– Is the sampling strategy truly representative?
– Has the full process (not just blending) been validated?
How a More Robust Scale-Up Strategy Helps
Successful scale-up requires more than copying parameters from R&D.
A robust approach includes:
– Early equipment selection aligned with production geometry
– Understanding powder characteristics at scale
– Designing transfer and containment systems alongside the blender
– Validating blend performance after discharge and transfer
How Terriva Supports Pharmaceutical Manufacturers
At Terriva, we support pharmaceutical manufacturers globally by helping bridge the gap between R&D success and production reliability.
Our approach is:
– Highly consultative
– Powder-behaviour focused
– Grounded in real production environments
We support customers with:
– GMP-compliant powder blenders
– Scalable blender geometry from pilot to production
– Dust-free, segregation-aware powder transfer solutions
– Process reviews focused on blend uniformity and robustness
– Support for URS development and scale-up justification
With installations in 50+ countries, our equipment is designed to deliver repeatable, audit-ready performance — not just lab-scale success.
Final Thought
If your blend passes in R&D but fails in production, the issue is rarely the formulation alone.
It is almost always a combination of scale, equipment, handling, and process design.
Understanding how powders behave beyond the lab is the key to eliminating costly failures — and building a process that performs reliably, batch after batch.
