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, PR2 Integrated Project Team, MSD Intl GmbH (PR Branch), Las Piedras, PR3 ACDS-PAT, Merck, West Point

Helping the World Be Well through Innovative Manufacturing

Drug Product Manufacture

Pre-Blending Compression CoatingBlending & LubricationMilling

Hot Melt ExtrusionPre-Blending Compression Coating

Blending & LubricationMilling

Hot Melt Extrusion

Blend Uniformity

by PAT

API Assayby PAT Blend

Uniformityby PAT

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

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Disadvantages of Traditional Blend Sampling

• 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

Conventional procedure:

Blend Uniformity samples are collected using a powder thief and analyzed using HPLC, UV-Vis, LIBS or other off-line laboratory technique

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

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• Reduces sample analysis burden on laboratory

• Improved safety profile as product exposure eliminated

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NIR BU Method Considerations-Instrumentation

• Instrumentation- Performance

attributes- Functional attributes- Data collection

parameters• Spectroscopy

- API, placebo excipient- Got specificity?

• # of Sample/Reference scans– 4/128

• Effective sample size– 200-800mg*

• Analyzer/bin interface– Sapphire window lid with clamp

• Spectral resolution– 8cm-1

• Spectral coverage range– 5550-7400cm-1

• Data acquisition trigger– Internal at 150-160°

• Spectral collection time– 1.5s

API

Placebo

Raw Absorbance spectra• Sampling interface

– Non-contact– Sapphire window– Tri-clamp

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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

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%)

Scale Up Challenge

• Scale up: 1400L IBC- Different Pivot Point

- Axis of Rotation Shifted up

- Bi-directional rotation

Axis of rotation

Pre-blending Blending

API blend batches as part of Process ValidationAll batches pass BU specificationsBatch #6 stands out as atypical

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

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

Acknowledgements

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West PointMike GentzlerSteve Conway

Andre HermansJessica MillerColleen Neu

Brandon Ricart

Las PiedrasGlenda Rodriguez

Luz RodriguezAna Diaz

…and others

Las Piedras SLTPatrick Breen

Humberto DiazLuis O. GarciaAndrew Wirths