Near Infrared Spectroscopy for

Process Analytical Technology

Yan Wang, Ph.D.

1 21.11.2014
 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Fluid Bed Drying

 Blend Uniformity

 Content Uniformity

 Other Application Cases

2 21.11.2014
Benefits of Improved Control

Conventional methods give product which is fit for intended use,

but advanced control gives:

• better batch to batch consistency

• improved quality
• fewer reworks/rejects
• improved process understanding
• faster response times
• better productivity
• lower cost

3 21.11.2014
Bruker PAT Solutions

• Bruker Optics offers industry’s widest selection of Process Analytical

Technologies based on Vibrational Spectroscopy
• Commitment to Process Analytical Technology
• Global support structure
• Broadest array of PAT technologies
• Proven track record in PAT
• Complete validation support package
• Excellent technical support

4 21.11.2014
Bruker PAT Solutions

Bruker has expertise in implementing

solutions for
• Material ID
• Blending
• Drying
• Compression
• Coating
• Final Product of Tablets and Capsules

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Why use Near Infrared for PAT?

• Fast, non-destructive, no sample extraction or preparation

• Rugged, robust, reliable – process hardened

• Relatively straightforward sampling interface to the process

• Communicate results directly with PLC/SCADA/DCS

• Information rich spectra combined with chemometrics/statistics

enables multi-component analysis

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Process Analytical Technology (PAT)
In-line, On-line, At-line and Off-line

In-line

On-line

Off-line

At-line

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 Process Analytical Technologies
Monitoring of synthesis,
Bulk Material solvent and moisture
contents, material
identification
Blending
Uniformity Mixing

Homogeneity of mix,
moisture content,
Granulation polymorphism

Mixing Excipients Identity test

Potency, content
uniformity,
moisture content, Compression
hardness...
Process & end-point
monitoring, coating
Milling Coating
uniformity

Process & end-

point monitoring, Finished product
coating uniformity,
ID
8 21.11.2014
Process Analytical Technology (PAT)
PAT is not technology specific. It’s not just about vibrational spectroscopy
or NIR. However NIR is applicable to the widest range of applications.

NIR Raman FT-IR FBRM

End Point determination   
Reaction
Monitoring
Kinetics & Mechanism   
Control of Selectivity   
Onset of Nucleation  
Crystallization
Crystal Size 
Crystal Polymorph  
Particle size 
Filtration
Particle Polymorphism  
End Point Determination 
Drying
Particle Size 
Particle Polymorphism  
Particle Size  
Milling
Particle Polymorphism  

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NIR Overview
Advantages and Disadvantages

Advantages Disadvantages
 Fast (5 - 10 sec. Typical)  Not a “primary” method
 Little or no sample preparation  Some chemometrics knowledge
 Simple to operate required
 No waste, no pollution
 Less chemical information compared
 Multi-component analysis
to IR/Raman
 Acceptable accuracy and precision
 Influenced by physical properties of
 Non-destructive and non-invasive
sample
measurement
 Many samples required for
 Measures both chemical and physical
properties calibration model

 Transferable Methods  Long term support required (models,

 Remote monitoring for Process library, instrument etc)

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Advantages of FT-NIR
High Resolution for More Information

2.5
Aspirin @ Various Resolutions
2 cm-1
2

1.5
8 cm-1
Absorbance

25cm-1
.5

0
50 cm-1

6000 5500 5000 4500

Wavenumber (cm-1)

11 21.11.2014
Advantages of FT-NIR
High Resolution for More Information

. 025
Spectrometer Calibration at H20 Vapor Bands
Single beam spectra

. resolution = 25 cm-1
020

. 015 resolution = 2 cm-1

. 010

target: 7.306,74 cm-1

7800 7600 7400 7200 7000 6800 6600
Wavenumber / cm-1

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Advantages of FT-NIR
Why do we need high resolution?

• Not only for solving application questions (mostly 8cm-1

is enough)
• But also for measuring the x-axis accuracy of the
instrument
• Wavelength repeatability: 0.04 cm-1
• Wavelength accuracy: 0.1 cm-1
• X-axis stability is the key for
• Permanently reliable predictions
• Calibration transfer

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Advantages of FT-NIR
Calibration Transfer:
The exceptional performance of the instrument ensures a smooth calibration
transfer not only to other MPA instruments but also to the MATRIX process
spectrometers.

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Maximum Flexibility of Bruker FT-
NIR

Custom-made Instruments:

Each customer buys exactly the instrument that matches his application.
There is no need to purchase anything that is not wanted or needed.

15
Fourier Transform Infrared spectrometer

 Plane Mirrors in a classical

Michelson Interferometer

 Cube-Corner Mirrors in a
ROCKSOLID-Interferometer
Instrument performance: long term
stability in wavelength accuracy

FREQ. DEV. (CM-1) FROM WATER BAND (7306.740 cm-1)

BRUKER 28/N SERIAL #368

Training on source change

Training on source change

0.500

0.400
FREQ. DEV. (cm-1)

0.300

0.200

0.100

0.000

-0.100
1 51 101 151 201 251 301 351 401 451 501 551 601 651

-0.200

INDIVIDUAL 'IT' RUNS (days)

Example of long-term stability in wavelength accuracy/precision:

Frequency deviation is within 0.1 cm-1 for a 2-year period, by monitoring
water vapor band (7306.74 cm-1) on a Bruker FTNIR spectrometer
Maximum Flexibility of MPA

Sample Fiber Optic

Compartment Probes

External Integrating
Transmission Sphere

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 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Granulation

 Blend Uniformity

 Content Uniformity

 Other Emerging Technologies

19 21.11.2014
 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Granulation

 Blend Uniformity

 Content Uniformity

 Other Emerging Technologies

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API Manufacture
Multiple Step Synthesis

Main chemical crystallisation Re-

reaction crystallisation
Fermentation

Reaction end point Mix solvent ratio analysis Mix solvent ratio analysis
analysis

Solvent Heat
recovery Transfer
Fluid

Solvent recovery analysis HTF analysis

21 21.11.2014
API Applications
Case : On-line Reaction Monitoring

Goal: Customer wanted to monitor a simple organic liquid reaction

batch process (8-12 hours) on-line.

Challenges
• Liquid process sample contains catalyst doped carbon 100 m
particles ranging in concentration from 0.05% to 0.5%
• Process samples are highly acidic and at a temperature of 120C.
• Sample is quite viscous at ambient temperatures.
• Customer wants to monitor all three components (A, B & C) with an
accuracy of ~0.5% during the reaction and ~0.1% at end of reaction.
• Sample points are 125m from the instrument location

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API Applications
Case : On-line Reaction Monitoring

At-line Model Development

R2 = 99.96
•Primary method is GC
RMSECV = 0.52%
• Carbon removed by filtering
No. of Factors = 2
sample
Product C • 6mm vial measurements
• Temperature controlled (70C)
Product C
• Developed at-line model using
pulled samples and GC data collected
over several batches

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API Applications
Case : On-line Reaction Monitoring

On-line Probe Installation

Process Specs
• Temperature - 120C
• pH - 0
• Pressure – 100psi
• Flow rate - 370 gpm

24 21.11.2014
API Applications
Case : On-line Reaction Monitoring

On-line Model Development

R2=99.3
RMSECV = 2.6% • Developed model by time-stamping.
No. of Factors = 7
Pulled samples collected over the
course of 10 batches and correlating
these to the on-line NIR spectra
• Used at-line NIR data as calibration
data
Product C

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API Applications
Case : On-line Reaction Monitoring

100

80
Concentration (%)

Component A
60
Component C
40 Component B

20

0
10:33 11:45 12:57 14:09 15:21 16:33

Process control NIR on-line data for 1 batch

• 97% of the reaction monitored on-line
• Final 3 % monitored at-line using filtered process samples collected
by plant operators.
26 21.11.2014
 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Granulation

 Blend Uniformity

 Content Uniformity

 Other Emerging Technologies

27 21.11.2014
Drying

Benefits To improve drying Drawbacks of traditional methods

Process
• Less variation in drug potency.
• Improved tableting
• Less power consumption.
• Reduced cycle time.
• Increasion production capacity.
• Need to sample the material, and
possibly prepare the sample.
• Large possibility of errors during
sampling.
• Cannot be used to adjust the
process immediately.

• Increased profitability • Will permit an extra drying time

that will increase the operating cost

28 Bruker Confidential 21.11.2014

Drying
Traditional Methods
Metro Tech Corp
Karl Fisher Titration
• Based on a chemical reaction
between water and methanol.
• Time consuming.
• Measures total water
• Relatively expensive.
29 Bruker Confidential
Metler Toledo LJ 1
Loss On Drying Moisture Balance
• Based on heat transfer to the medium
• Low heat transfer rate
• Measures free water
• Equipment less expensive than K-F
21.11.2014
Drying
Fluid Bed Dryer Probe Interface

A NIR configuration that is

increasing in popularity are
Fluid Bed Dryer
the non-contact NIR drying
configurations.
Glass View Port

This configuration permits the

light beam to be focused
through a viewing window

Non-Contact NIR

30 Bruker Confidential 21.11.2014

About the emission probe
Q412A emission probe for non-contact measurement

Specifications

Protection: NEMA4, IP66

Illumination: 2 air cooled NIR light sources (12V,

5W)

operation and diagnosis via OPUS

Measurement area: 10mm (right sampling

volume for approval)

Working distance: 100mm

31 Bruker Confidential 21.11.2014

Drying
Multiple measuring points with one instrument

• Fiber optically coupled

• non-contact NIR probes can
be multiplexed so that a
single instrument can have
many heads.
• This reduces the cost per
measurement point.

32 Bruker Confidential 21.11.2014

FBD: Q412A install with the adaptor

Experimental setup of FTNIR Matrix F spectrometer with Q412

emission head for drying monitoring through sight glass window
33 Bruker Confidential 21.11.2014
Drying: issue with a contact probe
Fluid Bed Dryer Probe Interface

Here is an ideal flow of

material.

Potential Problem

. Some drying processes

are susceptible to probe

fouling.

(e.g. high moisture/high

starch)
34 Bruker Confidential 21.11.2014
FBD: Measuring window after drying (probe fouling)

Comparison of contact probe window (left, fouled) and FBD view window
(right, clean), used for non-contact measurement with Q412 emission
35 Bruker Confidential 21.11.2014
FBD: Representative spectra with time acquired
with Matrix FE with emission probe

Raw absorbance spectra of granules with drying time, water bands

decreasing with drying

36 Bruker Confidential 21.11.2014

FBD: Representative spectra with time acquired
with Matrix FE with emission probe

2nd derivative spectra of granules with drying time, water bands

decreasing with drying

37 Bruker Confidential 21.11.2014

FBD: NIR modeling for moisture vs LOD
(calibration and cross validation)

38 Bruker Confidential 21.11.2014

FBD: NIR modeling using water band

39 Bruker Confidential 21.11.2014

FBD: Calibration batch (NIR vs LOD)

FBD Batch 1 (Calibration)

17
16
15
14
13
12
11
Moisture (%wt)

10
9 NIR moisture
8 LOD
7
6
5
4
3
2
1
0
0 5 10 15 20 25 30 35 40 45 50 55

Drying Time (Min)

40 Bruker Confidential 21.11.2014

FBD: Validation batch (NIR vs LOD)

FBD Batch 2 (Calibration)

16
15
14
13
12
11
Moisture (%wt)

10
9
NIR moisture
8
7 LOD
6
5
4
3
2
1
0
0 5 10 15 20 25 30 35 40 45 50 55

Drying Time (Min)

41 Bruker Confidential 21.11.2014

Conclusions

• The emission probe (Q412A) with Matrix FE fits perfectly for fluid-bed
drying
• Non-contact measurement through site view window of FBD
• Right sampling volume: sampling area is 10 mm in diameter
• No probe fouling was found at the end of the drying
• No cleaning required for the emission probe
• Self-referencing for OQ, PQ, and background collection (built-in
spectralon driven by software
• The whole system (Q412A with Matrix FE) complies with USP 1119
protocol
• Validated software functions (OPUS, Quant, and Process packages)
• Low cost of fiber (single fiber) for extended length
• Prediction accuracy and precision matches the reference method used
(LOD)
• Matrix FE with the multiplexer suitable for multi measuring points

42 Bruker Confidential 21.11.2014

 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Blend Uniformity

 Content Uniformity

 Other Emerging Technologies

43 21.11.2014
 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Granulation

 Blend Uniformity

 Content Uniformity

 Other Emerging Technologies

44 21.11.2014
Content Uniformity

Why is Content Uniformity Important?

•The pharmaceutical industry produces over

100,000,000,000 tablets annually
•Tablet “sub-potency” is the #2 reason for
FDA recalls.
•Typical tableting equipment produces 10,000
tablets/min.
•Current USP protocols specifies for content
uniformity, “Assay 10 units individually..” For
dissolution “Take 6 units”.

Are 10 units really representative of

the manufacturing batch?
Content Uniformity
Drawbacks of conventional tests like
HPLC:
- they require slow sample
preparation, slow analysis and are
destructive in nature.
What ifs:
- What if there was a faster method?
- What if the method was non
destructive?
- What if tablets could be measured in
the native solid state?
- What if this technique could be
moved out of QC and be at-line in
the production environment?
Better yet, why not On-line?
This method is NIR!
Benefits of NIR On-line Tablet Analysis
- No operator contact – safety
- No sampling errors
- Sampling – regularly across the
batch ~ 200-300
- Real-time information
- Multi-ingredient uniformity
- Process understanding
- Process finger printing for scale
- Immediate release – reduced cycle
times
Content Uniformity
NIR Methods of Tablet Analysis
Diffuse Reflectance
• High energy
• Assume homogeneity
• Surface measurement
• Analyze small portion of sample
• 1-30 sec measurement time
• Full NIR spectral range 4,000-
12,500 cm-1 (800 to 2500 nm)
• Combination and overtone
bands available
47 Bruker Confidential 21.11.2014
Transmission
• Low energy
• Bulk sample measurement
• Analyze large portion of sample
• 10 sec to 2 min measurement
time
• Limited NIR spectral range
7,000-12,500 cm-1 (800-
1400nm)
• Higher order overtone bands
available
Content Uniformity
MPATM

 For tablet measurements in

transmission.
 Optional built-in integrating
sphere for reflectance work.
 Customized holders available
for tablets/ capsules of different
sizes and shapes.
 Optional 30 position auto-
sampler for both diffuse
reflectance and transmission.
 Liquid transmission and fiber
optic capability in addition.
 Calibration transferability

48 Bruker Confidential 21.11.2014

Steps to get a TANDEM system up and
running

Tablet physical characteristics – is tablet shape acceptable for 10X-T

Near infrared tablet content uniformity (CU)
• not always possible – depends on thickness, compression force,
infrared activity of component of interest - typically the active.
• perform feasibility study (75-125% of nominal values) using lab
prepared samples (with known CU) and production tablets (CU
determined via HPLC after NIR analysis)
130
Content Uniformity (NIR)

120

110 Nominal
100

90

80

70
70 80 90 100 110 120 130
Content Uniformity (HPLC)
TANDEM Design Specification

• Combine tablet physical analysis and content

uniformity in a single fully automated unit at
the press
• Sample tablets regularly across the tablet
batch (~200-300 tablets) – stratified
sampling.
• Retain tablet identity in order to perform post
analysis on measured tablets
• Immediate Benefits!
• No operator contact – safety
• No sampling errors
• Real-time process information
Content Uniformity
Tandem III: Rapid Automated Tablet Analysis

• Tablet physical characteristics

with Dr. Schleuniger Pharmatron
10X Fully automatic tablet testing
system

• Content uniformity with Bruker’s

NIR and measured in transmission.
Content Uniformity
Tandem III: Tablet Flow

Powder
Powder TABLET PRESS
TABLET PRESS Tablets
Tablets

Tablet Separation Unit

Weight
Weight

Thickness

NIR
NIR Diameter
Diameter Hardness
Storage of up
to10 tablets
(optional)
31 station
carousel
WASTE BIN
Content Uniformity

Tablet Press
Tandem III: Design

NIR Transmission
Content Uniformity
analysis

Out-feed
carousel
Pharmatron 10X-T
(weight, thickness,
diameter & hardness)
TANDEM III
Gravity feeds (0) tablets directly
into tablet nest (1)

Tablet positioning in tablet nest

via vibration (2)

Remove of tablet by pressured

NIR air (3)
(0)
(3)

(1)

(2)

54
Performing NIR Measurements
TANDEM III

Bruker NIR Cube Pharmatron 10X

56
TANDEM Features

• Stainless steel enclosures

• IP65 specified - sealed against water
and dust
• Precision of arm movement +/-0.05mm
• 10X-T and Tandem Cube mounted on a
common base plate
• Open architecture for
• easy cleaning
• easy product changeovers
• calibration of balance and other
instruments (e.g. hardness)
 Measurement Results
108.0
Weight corrected NIR Results

106.0

104.0

102.0

100.0

Mean = 103.2
Min. = 99.7
Max. = 106.7
98.0
STDEV = 1.4
%RSD = 1.3

96.0
1 11 21 31 41 51 61 71 81 91 101 111 121 131 141 151 161 171 181 191 201 211
Sample #

58
On-line Graphical Display of NIR Results
On-line Table of NIR Results
On-line Graphical Display of NIR Results

If NIR analysis outliers and out of

specification materials are detected,
this is displayed in the charts.
TANDEM System Implementation

• TANDEM can be interfaced to

almost any tablet press
• Experience with
• Fette
• IMA
• Korsch
• Killian
TANDEM II Conclusions

• On-line analysis of Content Uniformity

• Measure >300 tablets /batch instead of 10 by HPLC

• Stratified Sampling as recommended by PQRI

• Full validation with IQ/OQ/PQ documentation and USP/EP Protocols

• Can be fully integrated with a Tablet Press

• Takes customer in the direction of real time release (RTR)

 Process Analytical Technology
 Overview

 Raw Material ID

 API Applications

 Drying

 Granulation

 Blend Uniformity

 Content Uniformity

 Latest NIR instrument

64 21.11.2014
TANGO. ANALYSIS TO GO.
TANGO. ANALYSIS TO GO.

• Icon based touch screen operation

• Currently 12 languages available
• For Panel-PC with touchscreen and
external PC
• User login with 4 hierarchy levels
• Products can be set up or imported
• Product selection
- by pressing the icon
- via barcode reader
• Includes all necessary evaluation
packages
TANGO. ANALYSIS TO GO.

• Display of 5 or 10 results

• Colored graphs indicate results

within
warning and alarm limits

• Green check/red cross indicates

validity
of result

• Trend display for each product and

component

• Spectrum and details of evaluation

available

• Analysis report as printout or PDF

Integrating Sphere

For all kinds of solid samples, such as

powders powders, ground samples,
unground samples like seeds, pellets,
granulates and liquids with transflection
mirrors

68
Integrating Sphere

Sample

gold-coated Integrating
Sphere

Detector

NIR Beam

ideal for Powders, Granules or

heterogeneous Samples

69
Rotating devices for the Integrating Sphere

70
Analysis of Feed, unground

71
Analysis of Feed, unground

72
Analysis of Feed, unground

73
Measurement: Oils in Sample Compartment

• MPA Multi Purpose

Analyzer with Sample
Compartment
• disposable 8mm Vials
• heatable Vial Holder
o
• Temperature: 50 or 75 C

74
Analysis of Edible Oil

75
New Stainless Steel Transflection Mirrors for
Analysis of Edible Oils & Molasses

Especially for feed industry

• 2nd best option regarding

accuracies compared to
gold coated mirror or even
8mm vial in transmission
(optimum)
• Stainless steel allows
manual cleaning
• Sample and mirror should
be heated together in the
vial
• Heavy mirror with big heat
capacity to maintain
sample temperature
during measurement

76
FT-NIR Analysis of Syrups and Molasses
Transflection Measurement for Oils & Molasses

78
Transflection Measurement for Oils & Molasses

79
External Heating Block

80
 Mid-Infrared Reaction Monitoring

Immersion Probe

ReactionView Multiplexed
Fiber Optics System
(4 or 8 channel)
81 21.11.2014
Mid-Infrared Reaction Monitoring
Process Integration

82 21.11.2014
 www.brukeroptics.com

83 21.11.2014