1. Helping the World Be Well through Innovative Manufacturing
Process Analytical Technology (PAT) for Blend Uniformity Challenges and Lessons Learned
Jim Donato1, K. Ganeshwar Prasad1, Fernando Rodriguez-Ares2, Shaira Davila1,
Brandye Smith-Goettler3, Manoharan Ramasamy3, Peter Brush3
1 Pharmaceutical Commercialization Technology, MSD Intl GmbH (PR Branch), Las Piedras, PR
2 Integrated Project Team, MSD Intl GmbH (PR Branch), Las Piedras, PR
3 ACDS-PAT, Merck, West Point
Helping the World Be Well through Innovative Manufacturing

2. Drug Product Manufacture
API Assay
by PAT
Blend
Uniformity
by PAT
Blend
Uniformity
by PAT

3. Why Blend
The uniformity of the blend is critical in the establishment of the uniformity of the dosage units
Powder blending of active/excipient is an important and common unit operation for solid oral dosage systems
Direct compression, roller compaction, wet granulation, hot melt extrusion
For most formulations, it is important to ensure the uniformity of the excipients as well as the API
Inhomogeneity may lead to:
Poor flow, sticking/picking/capping/delamination, improper disintegration and/or dissolution, sub- and/or super- potent tablets

4. Disadvantages of Traditional Blend Sampling
Conventional procedure:
Blend Uniformity samples are collected using a powder thief and analyzed using HPLC, UV-Vis, LIBS or other off-line laboratory technique
Labor intensive for both the operator and lab personnel (IBC’s moved to different areas to sample/PPE, typically 4 hrs)
Difficult to reproduce sampling technique (and thus blend result)
Blender must be stopped to sample blend
Long turn-around times for sample analysis
Typically not performed once validated in production
Potential for exposure of operators to high potency API’s
Act of sampling, in itself, may produce sample non-uniformity
If anyone in the room has ever had to thief sample an 1800 L bin – they know this is hard work
The results - It is formulation – product – blend dependent

5. NIR as Alternative BU Method
Real-time monitoring
Monitor API, excipients and lubricant
Non-invasive
Minimizes inter-operator variability and sample thief failures
Collects blend sample at each rotation thus providing process understanding
Used for IBC (bin) blenders from 5L (dev) to 1800L+ commercial scale
Reduces sample analysis burden on laboratory
Improved safety profile as product exposure eliminated

6. NIR BU Method Considerations-Instrumentation
# of Sample/Reference scans
4/128
Effective sample size
mg*
Analyzer/bin interface
Sapphire window lid with clamp
Spectral resolution
8cm-1
Spectral coverage range
cm-1
Data acquisition trigger
Internal at °
Spectral collection time
1.5s
Instrumentation
Performance attributes
Functional attributes
Data collection parameters
Spectroscopy
API, placebo excipient
Got specificity?
Sampling interface
Non-contact
Sapphire window
Tri-clamp
API
Placebo
Raw Absorbance spectra

7. NIR BU Method Considerations – Blend Metrics
Qualitative Algorithm
Mathematical transformation to connect spectral variability to blend endpoint – moving block average of spectral variation – either in terms of SD or %RSD
With specificity
Peak Maxima/Minima
Max or Min in range
Peak area, peak average, root mean square
Without specificity
Average spectrum
Standard deviation spectrum
PCA
other
Connect Spectral Variability to Blend Endpoint

8. Blend Control Strategy - PAT end-point control via spectral %RSD
Risk Mitigated
Variations in the lubrication process
impact tablet hardness/tensile strength and in turn disintegration and dissolution due to over-lubrication of the blend
The blend NIRS dataset compiled with data from:
Two manufacturing sites
Four scales (150L, 300L, 600L and 800L)
Two different spectrometers
Fill volumes (27 – 85%)

9. Scale Up Challenge Scale up: 1400L IBC Different Pivot Point
Axis of
rotation
Pre-blending
Blending
Scale up: 1400L IBC
Different Pivot Point
Axis of Rotation Shifted up
Bi-directional rotation
API blend batches as part of Process Validation
All batches pass BU specifications
Batch #6 stands out as atypical

10. NIR Model and Batch Variation
As per thief sampling and NIR protocol, all batches complied with BU specifications
Without NIR, and using only standard BU protocol, no further action needed
With NIR, blend endpoint for Batch #6 was ~2x revolutions compared to others
Without the NIR blend profile, process variability is not visible
Initiated investigation into why blend is different:
Possible causes include: raw material/API variability (particle size, density, fill volume), equipment failures (speed, directional change, blend lid), NIR instrument/sampling/algorithm concerns

11. Conclusions
NIR for online monitoring of BU provides several advantages over powder thief sampling
Multiple components can be monitored simultaneously
API, lubricant, critical excipient
Full blend profiles are obtained rather than single point of data
Slug thief sampling is preferred method of sampling for validation of NIR method
NIR was used to identify several possible processing issues
Sample thief problems and BU failures
Powder blend/lubricant sticking during large scale blending
Overall endpoint variability in commercial scale blending operations
Identified an Out-of-Trend blend profile during process validation

12. Acknowledgements West Point Las Piedras Las Piedras SLT Mike Gentzler
Steve Conway
Andre Hermans
Jessica Miller
Colleen Neu
Brandon Ricart
Las Piedras
Glenda Rodriguez
Luz Rodriguez
Ana Diaz
…and others
Las Piedras SLT
Patrick Breen
Humberto Diaz
Luis O. Garcia
Andrew Wirths