MN Blending 2020 Final

MicroNIR®
Learning Series
MicroNIR for tumble blending

monitoring
Emiliano Genorini and Cristina Malegori
GoToWebinar - April, 30th 2020
viavisolutions.com © 2020 VIAVI Solutions Inc. 1
MicroNIR Learning Series
Schedule of Events
16-Apr-2020 4PM-5PM CET Pharma raw material identification
23-Apr-2020 4PM-5PM CET Granulation and drying monitoring
30-Apr-2020 4PM-5PM CET Tumble blender monitoring
07-May-2020 4PM-5PM CET Tablet compression monitoring
14-May-2020 4PM-5PM CET PAT-Ux and PAT-Wx for hazardous locations

Today’s Agenda
Welcome and company profile Emiliano Genorini and Cristina Malegori

LVF technology Emiliano Genorini
MicroNIR product line Emiliano Genorini
Tumble Blender Monitoring Emiliano Genorini
MBSD (Moving Block Standard
Cristina Malegori
Deviation)
Hands on Cristina Malegori
Q&A Emiliano Genorini and Cristina Malegori

Today’s presenters
Emiliano Genorini Cristina Malegori

MicroNIR account manager MicroNIR field application specialist
EMEA and LATAM cristina.malegori@viavisolutions.com
emiliano.genorini@viavisolutions.com

VIAVI Solutions
Company Profile

VIAVI Solutions
Company Profile

VIAVI Solutions
Company Profile, OSP Business Unit Timeline

VIAVI Solutions
Company Profile, OSP Market Segments
Consumer Electronics Government & Aerospace Anti-Counterfeiting
Automotive Spectral Sensing

VIAVI Solutions
Company Profile, OSP Santa Rosa
Operations and Leadership
Research and Development Teams
Sales and Marketing Teams

MicroNIR Vision

MicroNIR Vision
Evolution

MicroNIR Vision
Smarter World
Miniaturization
Connectivity
Affordability
Enabling
a Smarter
World
Performance

MicroNIR
Technology

MicroNIR Technology
LVF (Linear Variable Filter)
• LVF is one dimensional continuously varying bandpass filter
• Filter is fabricated on glass using hard, dense, and stable

inorganic materials for long life and environmental stability
• Enables a spectrometer that is compact, lightweight, robust,

and has no moving parts or free space optics
• VIAVI LVF was developed for

NASA → OSIRIS-REx mission
to Bennu flies a VIAVI LVF-based
spectrometer

MicroNIR LVF Technology
Advantages
• Small size enables unique applications

• Lamps rated for >40,000 hr lifetime @ < 1 W
• No need of laser
• No moving parts or free-space optics:
- No misalignment
- Long-term stability
- 100% transferability between units
• No fiber optics:
- Nothing to damage or wear out
- Insensitive to temperature variation

MicroNIR
Product Line

MicroNIR Product Line
Overview
Instruments Accessories Software

• Compact & lightweight • Wide variety of accessories to • Full chemometric package
− Miniature but full function support diverse applications − Everything needed to build a
• Robust, reliable, repeatable • Enable NIRS analysis of all complete solution with MicroNIR
types of media instruments and accessories
− Minimal unit-to-unit variation
− Powders, liquids, bulk solids, − Expandable with plug-ins to
simplifies scale-up
live plants, produce, grains, Unscrambler, SIMCA and SOLO
− All instruments share optical polymers, etc. • Fully GMX compliant for
engines for model transfer
• Support rigorous sampling regulated environments
• Models and accessories for methods − 21CFRPart11
diverse applications
− high-performance and − USP 1119 or EP 2.2.40
• OEM versions available repeatable models

Products, 1700ES
• Compact spectrometer engine for

universities, or OEM customers
• USB connection for power and data
• Functionally similar to all other MicroNIR

instruments

Products, IP65 and IP67
OnSite-W PAT-U and PAT-W

• Handheld, wireless model for field, at- • Rugged process monitoring
line, and material identification instruments for factory applications
applications • IP65 and IP67 rated
• Bluetooth or USB connectivity to tablet • PAT-W:
or PC or mobile − Wireless and Ethernet connection
• Internal, rechargeable battery with − Rechargeable Li-ion battery with > 8 hours
continuous run time > than 10 hours of continuous run time
− Multi-axis sensor for positional triggering
• IP65 and IP67 rated for use in wet and in tumble blender
dusty environments − Multiple trigger options

Products, HazLoc
PAT-Ux
PAT-Wx

Process Analytical
Technology

Process Analytical Technology
Introduction
“…a system for designing, analyzing, and controlling manufacturing through

timely measurements (i.e., during processing) of critical quality and
performance attributes of raw and in-process materials and processes, with
the goal of ensuring final product quality…”
Process Analytical Technology (PAT) in Pharmaceutical Development:
http://www.americanpharmaceuticalreview.com/Featured-Articles/115453-Process-Analytical-Technology-
PAT-in-Pharmaceutical-Development
“Quality cannot be tested into products; it should be built-in or should be by

design”
Process Analytical Technology (PAT):
https://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/ucm088828.htm

Introduction

Introduction
Traditional Approach PAT Approach
• The process is developed, frozen and • Real time On-Line and In-Line
validated using 3 commercial batches analysis
• Process safeguarding with SOPs, • Process understanding and
training, etc continuous process verification
• Subsequent quality control via off- • Process control and regulation based on
line investigation in the laboratory statistics
• Multivariate analysis for understanding
complex relationships
Process is understood and

Process is a black box continuously managed

QbT (Quality by Test) vs Quality by Design (QbD), Cost of Quality

Where does NIR fit in pharma process?

Tumble Blender
Monitoring

Tumble Blender
Why is it important?
• The tablet development and manufacturing process

and focus on the critical role that blending plays
in making a quality tablet
• The blending phase it is critical for the distribute

homogenously the APIs and excipients
• A tablet might need to be quick to dissolve in your

body, but it also must not break up in its packaging

Tumble Blender
Status of Art, Sampling
• Blend uniformity testing in the pharmaceutical industry is

traditionally carried out by stopping the blender after a
given time, commonly defined by existing procedures
• The operator then withdraws 10 samples at predefined

locations specified by the current ICH guidelines.
• Samples are then analyzed offline in the QC/QA laboratory

by means of HPLC, UV-Vis, etc

Tumble Blender
• Continuous monitoring is not thereby possible
• Laboratory characterization is labor intensive and

time-consuming
• Operator exposure to API and solvents may require

extra safety measures
• The blend is exposed to the environment

Tumble Blender
• Sampling errors 10-50 times Sample thieves de-mix

powder beds resulting in
greater than analytical errors! heterogeneity increase
• Non-reproducible, therefore cannot

be corrected for statistically
• QbD requires isolation of the greatest

source of variability (sample thief)

Tumble Blender
PAT-W in action

Tumble Blender
Experiment Set Up
• Delay time sets the waiting time after

the accelerometer has reached an
active scanning position
• G1-G3 Parameters are settings of the

gravity switch and are usually kept at
the default settings for most applications
Tumble Blender
Where and why it is important?
Formulation Lab Production

• No sampling required • No sampling required
• Real time feedback • Real time feedback
• Optimize blending time • Continous manufacturing
• Reduce QC laboratory effort • Process validation (only 3 batches
plus 1 at a predefined time) vs.
• QbD vs QbT continous process verification (all
• Define process experimental domain batches)
• See batch to batch reproducibility
• Scale up from R&D to production
• Completely integrated in blending HMI
• Reduce QC laboratory effort

Tumble Blender
Which critical attributes coudl influence the blending?
• Rotation Time
• API concentration
• Excipients
• Particle Size
• Blender Capacity
• Rotation Rate
• Fill level
• Loading Method

Tumble Blender
Effects of Critical Attributes on Blending Profile
0.1 0.1
0.09 0.09
0.08 0.08
0.07 0.07
0.06 0.06
0.05 0.05 60% Filll
0.04 5 Liter Bin 0.04 75% Filll

10 Liter Bin 90% Filll
0.03 0.03
40 Liter Bin
0.02 0.02
0.01 0.01
0 0
0 5 10 15 20 25 30 35 40 0 10 20 30 40 50 60 70 80
0.1
Rotation Number
0.1 0.09
0.09 0.08
0.08 0.07
0.07
0.06
0.06
0.05
0.05 15 rpm
0.04 Active Layered - Centered
0.04 25 rpm
32 rpm 0.03 Active Spot - Off Center
0.03
0.02
0.02
0.01
0.01
0 0
0 5 10 15 20 25 30 35 40 0 5 10 15 20 25 30 35 40
Rotation Number Rotation Number

Tumble Blender
How validate NIR results?
• Taking a sample from the blender is not recommended (Esbensen)

• NIR is a measurement of API and excipient, HPLC a measurement of API
- Therefore, comparing HPLC and NIR is not a good approach
• MBSD (Moving Block Standard Deviation) and PCA (Principal Component Analysis)
are unsupervised methods and require validation method to define threshold:
- Option A → compare multiple blending profiles and observe the coherence
- Option B → measure tablets and check homogeneity
• Option B → QC must take 10 tablets every hour during compression:
- Assess the first three by reference method; these are 100% statistically representative
- If the first three meet potency and variance criteria, the process is validated
- Otherwise, further testing must be done.

Tumble Blender
API+Lactose, Orginal Spectra

Tumble Blender
API+Lactose, Pretreated Spctra (1der+SNV)

Tumble Blender
API+Lactose, MBSD (Moving Block Standard Deviation)
%RSD
Mixing phase End Point
Block (Rotations + 20)

Tumble Blender
API+Lactose, MBSD (Moving Block Standard Deviation)
After 300 rotations all the three

%RSD
All the three blendings are

showing a frist minumum blndeings are showing better
around 200 rotation stable %RSD

Tumble Blender
API+Lactose, PCA Loadings
• In this plot are shown the PC1 and PC2 of the first blending
normalized vs the 1 derivative spectra of Lactose and API
• Lactose has a profile similarto PC1 (indipendently from sign)
• API has profile simialr to PC2 (indipendently from sign)
• Similar consideration can be taken using blending 2 and 3
▪ PC1
▪ PC2
▪ Lactose
▪ API

Tumble Blender
API+Lactose, PCA (Principal Component Analysis)
API effect on blending

Lactose effect on blending
End point

Tumble Blender
API 0.1%, Pretreated Spectra + Spiked PLS
Region where API changes is related to the

linearity of the model

Tumble Blender
API 0.1%, PCA Score Plot
Placebo blending
direction
Active batch blending direction
Active blending direction

specific to absorbance at
1131 nm
Absorbance specific to active

in PC2 direction

Tumble Blender
API 0.1%, PCA Projections

Experiment Set Up

MicroNIR PAT-W
Experiment Set Up
MicroNIR Pro Software 3.1

version

Case Study
Blending monitoring
AIM of the WORK =
API following of the
blending process
Lactose
1. ON-LINE MONITORING
The process can be followed with both the MB approach and the PCA projection
→ Today we will focus on the MB approach
2. END POINT DETERMINATION

The end-point, the moment in which the mixture is as more homogeneous as possible, can
be defined and set as process threshold for further blendings.

MBM - Moving Block Method
The approach
• Moving Block Standard Deviation (MBSD): it is a sensible assessment of uniformity
(less heterogeneity); it is the suitable approach for detect small variations along the
process.
• Moving Block Mean (MBM): it is a robust assessment of uniformity (less
heterogeneity); it is the suitable approach for complex mixtures (number of
ingredients/particle size)
• % Relative Standard Deviation (%RSD): it is the percentage ratio of MBSD/MBM for
a single block. It allows the relative variability of the block to its mean. Can be used to
detect process faults.
→ The progression of the blending leads to MB charts showing a plateau when the
endpoint has been reached.
This endpoint must be validated using external information!

MBM - Moving Block Method
The algorithm
• The number of spectra to be included in the
block must be predefined by the analyst to
provide enough information about both macro
and micro changes within the evolving
process.
• The block is moving, like a boxcar, along the

profile, discharging the first spectrum in the
block after the acquisition of a new one.
• For each acquisition, a new block is defined,

and the statistical parameters are calculated.

MBM – The F test
The help of statistics in defining the threshold
• The end-point detection is based

𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 (𝐵1) on Fischer F-Test
𝐹𝑐𝑎𝑙 =
𝑣𝑎𝑟𝑖𝑎𝑛𝑐𝑒 (𝐵2)
• The calculation is performed on
independent block of spectra
• Also in this case, a validation of

the limit is required; the F test is
intended to be a help and not a
rule.

MBM – Moving Block method
Advanced strategies
• The MB method (MBSD, MBM and RSD%)

can be performed on one or multiple
selected regions of the spectra, with the aim
of focusing on the absorption band of specific
ingredients.
• The MB method (MBSD, MBM and RSD%)

can be performed on PC profiles, after
using PCA as compression method.

Hands On

Q&A

Q&A
MicroNIR Team for you
Visit VIAVI MicroNIR Spectrometer website
Feel free to contact us at MicroNIR@viavisolutions.com
Thank you for attending MicroNIR Webinar

Presentation and recording will be sent tomorrow

viavisolutions.com

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MicroNIR®

MicroNIR for tumble blending

16-Apr-2020 4PM-5PM CET Pharma raw material identification

23-Apr-2020 4PM-5PM CET Granulation and drying monitoring

30-Apr-2020 4PM-5PM CET Tumble blender monitoring

07-May-2020 4PM-5PM CET Tablet compression monitoring

14-May-2020 4PM-5PM CET PAT-Ux and PAT-Wx for hazardous locations

viavisolutions.com © 2020 VIAVI Solutions Inc. 2

Welcome and company profile Emiliano Genorini and Cristina Malegori

viavisolutions.com © 2020 VIAVI Solutions Inc. 3

Emiliano Genorini Cristina Malegori

viavisolutions.com © 2020 VIAVI Solutions Inc. 4

viavisolutions.com © 2020 VIAVI Solutions Inc. 5

viavisolutions.com © 2020 VIAVI Solutions Inc. 6

viavisolutions.com © 2020 VIAVI Solutions Inc. 7

Consumer Electronics Government & Aerospace Anti-Counterfeiting

Automotive Spectral Sensing

viavisolutions.com © 2020 VIAVI Solutions Inc. 8

Operations and Leadership

Research and Development Teams

Sales and Marketing Teams

viavisolutions.com © 2020 VIAVI Solutions Inc. 9

viavisolutions.com © 2020 VIAVI Solutions Inc. 10

viavisolutions.com © 2020 VIAVI Solutions Inc. 11

viavisolutions.com © 2020 VIAVI Solutions Inc. 12

viavisolutions.com © 2020 VIAVI Solutions Inc. 13

• LVF is one dimensional continuously varying bandpass filter

• Filter is fabricated on glass using hard, dense, and stable

• Enables a spectrometer that is compact, lightweight, robust,

• VIAVI LVF was developed for

viavisolutions.com © 2020 VIAVI Solutions Inc. 14

• Small size enables unique applications

viavisolutions.com © 2020 VIAVI Solutions Inc. 15

viavisolutions.com © 2020 VIAVI Solutions Inc. 16

Instruments Accessories Software

viavisolutions.com © 2020 VIAVI Solutions Inc. 17

• Compact spectrometer engine for

• USB connection for power and data

• Functionally similar to all other MicroNIR

viavisolutions.com © 2020 VIAVI Solutions Inc. 18

OnSite-W PAT-U and PAT-W

viavisolutions.com © 2020 VIAVI Solutions Inc. 19

viavisolutions.com © 2020 VIAVI Solutions Inc. 20

viavisolutions.com © 2020 VIAVI Solutions Inc. 21

“…a system for designing, analyzing, and controlling manufacturing through

“Quality cannot be tested into products; it should be built-in or should be by

viavisolutions.com © 2020 VIAVI Solutions Inc. 22

viavisolutions.com © 2020 VIAVI Solutions Inc. 23

Process is understood and

viavisolutions.com © 2020 VIAVI Solutions Inc. 24

viavisolutions.com © 2020 VIAVI Solutions Inc. 25

viavisolutions.com © 2020 VIAVI Solutions Inc. 26

viavisolutions.com © 2020 VIAVI Solutions Inc. 27

• The tablet development and manufacturing process

• The blending phase it is critical for the distribute

• A tablet might need to be quick to dissolve in your

viavisolutions.com © 2020 VIAVI Solutions Inc. 28

• Blend uniformity testing in the pharmaceutical industry is

• The operator then withdraws 10 samples at predefined

• Samples are then analyzed offline in the QC/QA laboratory

viavisolutions.com © 2020 VIAVI Solutions Inc. 29

• Continuous monitoring is not thereby possible

• Laboratory characterization is labor intensive and