BUCHI NIRWare User Manual

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NIRWa re 1.5

Operation Manual

11593587 en

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Product Identiﬁcation: Operation Manual, NIRWare 1.5 115 93587 e n

Publication date:

04.2013, Version A

BÜCHI Labortechnik AG Meierseggstrasse 40 Postfach CH-9230 Flawil 1

E-Mail: quality@buchi.com

BUCHI reserves the right to make changes to the manual as deemed necessary in the interest of experience; especially in respect to structure, illustrations and technical depth.

This manual is copyright. Information from it may not be reproduced, distributed, or used for competitive purposes, nor made available to third parties. The manufacture of any component with the aid of this manual without prior written agreement is also prohibited.

Contents

1. Welcome 1

2. Introduction 3

2.1. NIRWare Management Console ................................................................ 4

2.2. NIRWare Operator ..................................................................................... 6

2.3. NIRCal 5 ..................................................................................................... 7

3. General work flow 9

4. Software Installation 11

4.1. Important Notes ....................................................................................... 11

4.2. System requirements ............................................................................... 11

4.3. Installation procedure ............................................................................... 11

4.4. What has been installed ........................................................................... 13

4.5. Software removal ..................................................................................... 15

4.6. Software Licenses .................................................................................... 18

4.7. Software Registration ............................................................................... 19

4.8. Activating the licenses ............................................................................. 20

2.1.1. Application Designer ..................................................................... 4

2.1.2. Sample Management .................................................................... 4

2.1.3. Administrative Tools ...................................................................... 4

2.1.4. Security Designer .......................................................................... 5

2.1.5. Library Designer ............................................................................ 6

4.5.1. BUCHI NIRSolutions ................................................................... 15

4.5.2. BUCHI Database Manager ......................................................... 16

4.5.3. Microsoft SQL Server 2008 R2 ................................................... 16

4.5.4. Remove further software ............................................................. 18

5. Tutorial 21

5.1. Logon ....................................................................................................... 21

5.2. Defining a new password ......................................................................... 21

5.3. Creating a qualitative application ............................................................. 22

5.3.1. Introduction ................................................................................. 22

5.3.2. Creating an application for reference measurement .................. 24

5.3.3. Measuring reference spectra ...................................................... 27

5.3.4. Defining a property and a property value .................................... 36

5.3.5. Creating a basic calibration by using the NIRCal wizard ............ 40

5.3.6. Integrating a qualitative calibration into an application ............... 50

5.3.7. Routine use for ID check............................................................. 55

5.4. Creating a quantitative application ........................................................... 58

5.4.1. Introduction ................................................................................. 58

5.4.2. Creating an application for acquisition of calibration spectra ..... 59

5.4.3. Measuring reference spectra ...................................................... 62

5.4.4. Defining a property and a property value .................................... 70

5.4.5. Creating a basic calibration by using the NIRCal wizard ............ 76

5.4.6. Integrating a quantitative calibration into an application ............. 84

5.5. Content Uniformity Test (CUT) ................................................................ 90

NIRWare 1.5 Software Manual Contents  iii

5.5.1. Development of an application for Content Uniformity Testing

(CUT) of Solid Dosage Forms .................................................................. 90

5.6. Using applications and calibrations in Life Cycle state "Created" ......... 102

5.6.1. Application for development (Life Cycle state "Created") ......... 102

5.6.2. Application in routine use (Life Cycle state 'Approved') ............ 104

5.7. Importing license protected applications (e.g. BUCHI or Ingot Pre-

Calibrated Applications) ...................................................................................... 105

5.8. Measuring an SST ................................................................................. 106

5.8.1. Manual SST measurement ....................................................... 107

5.8.2. Automatic SST measurement ................................................... 107

5.9. Measuring a NADIA ............................................................................... 107

5.10. Measuring a reference ........................................................................... 109

5.10.1. Internal / External Reference .................................................. 109

5.11. Carrying out a measurement with the Operator..................................... 110

5.12. Extended Wavelength Range ................................................................ 125

5.12.1. How to Setup NIRWare for the Extended Range ................... 125

5.12.2. Limitations, Risks and Warnings ............................................. 128

6. NIRWare Suite 131

6.1. NIRWare Management Console ............................................................ 131

6.1.1. Management Console ............................................................... 131

6.1.2. Filter .......................................................................................... 134

6.2. Application Designer .............................................................................. 137

6.2.1. Introduction Application Designer ............................................. 137

6.2.2. Comparing external reference spectra and defining the tolerance limit 142

6.2.3. Parameter list ............................................................................ 143

6.2.4. Assigning a property ................................................................. 143

6.2.5. Calculated property ................................................................... 147

6.2.6. Property settings ....................................................................... 153

6.2.7. Definition of calibration range, warning and action limits .......... 157

6.2.8. Bias and Slope calculation ........................................................ 158

6.2.9. Instrument parameters .............................................................. 162

6.2.10. Measurement cell specific settings ......................................... 168

6.2.11. Report parameters .................................................................. 169

6.2.12. Operator configuration parameters ......................................... 171

6.2.13. Bar code configuration ............................................................ 175

6.2.14. Settings for LIMS .................................................................... 177

6.2.15. Cyclic Measurement configuration .......................................... 178

6.3. Sample Management ............................................................................. 184

6.3.1. Introduction Sample Manager ................................................... 184

6.3.2. Batches ..................................................................................... 186

6.3.3. Properties .................................................................................. 189

6.3.4. Samples .................................................................................... 193

6.3.5. Measurements .......................................................................... 201

6.3.6. Reports overview ...................................................................... 212

6.4. Administrative Tools ............................................................................... 216

6.4.1. Introduction Administrative Tools .............................................. 216

6.4.2. System Logger .......................................................................... 217

6.4.3. Lifecycle Templates .................................................................. 219

6.4.4. NIRWare Configuration ............................................................. 222

6.4.5. Database Maintenance ............................................................. 223

6.4.6. Customer Information Configuration ......................................... 233

6.4.7. Import / Export .......................................................................... 234

6.5. Security Designer ................................................................................... 251

6.5.1. Introduction Security Designer .................................................. 251

6.5.2. Users and Groups ..................................................................... 252

6.5.3. Security Policies ........................................................................ 262

6.6. LIMS Interface ........................................................................................ 266

iv  Contents NIRWare 1.5 Software Manual

6.6.1. Introduction LIMS Interface ....................................................... 266

6.6.2. General Options ........................................................................ 267

6.6.3. Digital Signature Options .......................................................... 268

6.6.4. Import Options .......................................................................... 269

6.6.5. Export Options .......................................................................... 272

6.7. Library Designer ..................................................................................... 278

6.7.1. Introduction Library Designer .................................................... 278

6.7.2. Creating a new library ............................................................... 279

6.7.3. Spectra ...................................................................................... 284

6.7.4. Library Spectra Viewer .............................................................. 286

6.7.5. Validate Library ......................................................................... 287

6.7.6. Library Test ............................................................................... 289

6.8. Lifecycle ................................................................................................. 292

6.8.1. Lifecycle introduction ................................................................ 292

6.8.2. Lifecycle states ......................................................................... 293

6.8.3. Lifecycle actions ........................................................................ 294

6.8.4. Lifecycle transitions ................................................................... 295

6.8.5. Lifecycle templates ................................................................... 298

6.9. Administration ........................................................................................ 301

6.9.1. Installshield Update Service...................................................... 301

6.9.2. BUCHI Control System Service ................................................ 301

6.10. System test ............................................................................................ 303

6.10.1. SST ......................................................................................... 303

6.10.2. NADIA ..................................................................................... 304

7. NIRWare Operator 305

7.1. Introduction Operator ............................................................................. 305

7.2. Tab Overview ......................................................................................... 307

7.3. Operator Wizard ..................................................................................... 309

7.4. Select Application .................................................................................. 312

7.5. Deviating reference spectrum ................................................................ 313

7.5.1. Introduction ............................................................................... 313

7.5.2. Description ................................................................................ 313

7.5.3. Tips and Tricks .......................................................................... 315

7.6. Using the LIMS Interface ....................................................................... 316

7.6.1. Using LIMS Export only ............................................................ 316

7.7. Using bar codes ..................................................................................... 317

7.8. Service module ...................................................................................... 319

7.8.1. Introduction to the Service module ........................................... 319

7.8.2. Changing the instruments TCP/IP address .............................. 322

7.8.3. Activating the primary lamp after lamp change......................... 324

7.8.4. Resetting the lifetime counter of lamp or laser ......................... 325

7.8.5. Running an instrument setup .................................................... 326

8. Server installation of a database 329

8.1. Typical installation scenarios ................................................................. 329

8.1.1. Standalone ................................................................................ 329

8.1.2. Network installation ................................................................... 329

8.2. Worldwide connected N-500 network .................................................... 332

9. NIRWare Database Manager 333

9.1. NIRWare Database Manager................................................................. 333

9.1.1. Introduction ............................................................................... 333

9.1.2. Main window of NIRWare Database Manager.......................... 333

9.1.3. Restore database ...................................................................... 334

9.1.4. PC renamed .............................................................................. 335

NIRWare 1.5 Software Manual Contents  v

ATTENTION

With the general “Read this” symbol, ATTENTIONs indicate the possibility of equipment

damage, malfunctions or incorrect process results, if instructions are not followed.

1. Welcome

Dear customer,

Thank you for choosing the BUCHI NIRFlex N-500 FT-NIR spectrometer with the NIRWare Software Suite. We are sure that it will be a valuable tool for solving your analytical requirements.

NIRWare has been developed to design your complete NIR applications, to manage your samples (spectra and reference values) and to customize the user interface for routine work. In addition it includes all necessary tools for administration including import and export of calibrations and applications, security and lifecycle settings.

The NIRWare Library Designer is an optional software module for identity control using direct spectral comparison methods.

NIRWare does not include a module for calibration development. This is done using the new version of the well-known and proven NIRCal 5 Chemometric Software. NIRCal and NIRWare are closely linked and both use the identical database. The interaction between both is described in detail throughout this manual.

BUCHI has made every effort to ensure the accuracy of the information given in this manual. We would appreciate very much to be informed as soon as you may detect any mistake or omission.

BUCHI is going to improve its products and documentations continuously. Therefore the information in this document will be subject to change without notice. It does not represent a commitment on the part of BUCHI.

The software and/or files may be used or copied only in accordance with the terms of the license agreement. Without the written permission, no part of this manual may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or information storage or retrieval systems, for any purpose.

Should you come across any feature (important or minor), which needs improvement or extension, please do not hesitate to contact us. Your feedback helps us to continuously improve our software and is highly appreciated.

We are convinced that your new NIR system will be very helpful and beneficial for your daily work.

Flawil, March 2013

Warning notices used in this Online Help

NOTE

Useful tips for an easy operation of the software.

NIRWare 1.5 Software Manual Welcome  1

2  Welcome NIRWare 1.5 Software Manual

2. Introduction

NIR spectroscopy covers a wide variety of applications, which in turn place diverse demands on operation and calibration. Especially the software of the NIR system must take this point into account and should therefore be of modular and flexible design.

For years, the BUCHI NIRCal Chemometric Software has proven its worth as a powerful and flexible software package for creating calibrations. It has been substantially expanded and improved for the new generation now available. The wide variations in calibration creation requirements and routine use of NIR spectroscopy have been given special consideration.

The NIRWare Software Suite allows creating routine applications which fulfill a wide variety of needs in terms of data management and the necessary security settings. NIRCal and NIRWare are closely interlinked in one single database.

BUCHI NIRWare Suite bundles several applications:

 NIRWare Management Console including:

 Application Designer  Sample Manager  Administrative Tools  Security Designer  Library Designer

 NIRWare Operator

 NIRCal 5, the advanced chemometric software used for calibration development

All data like applications, calibrations, spectra are stored in a database and are controlled by the lifecycle management.

NIRWare 1.5 Software Manual Introduction  3

2.1. NIRWare Management Console

NIRWare Management Console is related to Microsoft Management Console (MMC). It hosts all Snap-In Modules of the NIRWare Suite except NIRWare Operator. The Management Console can be configured for different Users or User Groups. Closely linked to the NIRWare Software Suite is the NIRCal Chemometric Software.

2.1.1. Application Designer

The design of an application predominantly defines how the operator has to perform a specific analysis. It includes the definition of instrument configuration and instrument parameters and the definition of the required inputs (Batch number, sample name,...), the properties to estimate, the calibrations to be used, the Standard Operating Procedure (SOP) displayed in order to guide the operator and finally to select the report to be displayed.

The Application Designer is very flexible to customize a specific application. For easy use the basic mode is available in which only a few entries are necessary to develop an application. For the advanced user many options and features are available. Different report templates are available for qualitative and quantitative applications.

2.1.2. Sample Management

NIRWare Sample Manager is designed to check previous measurement results and to enter reference values.

The main concept of NIRWare Sample Manager is a software interface allowing to:

 Manage Samples (assign reference values and properties to the sample)  Manage and Print-out results of previous measured samples and system tests  sign results electronically  Manage Properties (create and design properties)

For further details see section: Introduction Sample Manager

2.1.3. Administrative Tools

The entire software is database-oriented. In NIR spectroscopy, vast data volumes are processed. It must be possible to manage these data easily. The NIRWare Administrative Tools allow backups and updates to be made.

Audit Trail / System Logger All relevant operations within all software modules, applications and calibrations are stored in the

Audit Trail. With this tool all changes are traceable. Other log functions for the system and errors are also part of this tool. The Audit Trail is a required part of FDA’s 21 CFR Part 11 regulations. Different filter functions are also available to select the requested entry.

4  Introduction NIRWare 1.5 Software Manual

Life Cycle Templates Different Life Cycle Templates can be selected for configuration. In order to simplify the use of the

lifecycle model there are three pre-defined lifecycle model templates: Unregulated, ER (Electronic Records), and ERES (Electronic Records/Electronic Signatures), which cover different requirements. The lifecycle involves all software modules, applications and calibrations.

NIRWare Configuration In NIRWare Configuration, the IP address of the connected device and the database server to

which NIRWare connects are specified. In addition, installed language packages can be activated and a reset of the grid configuration can be performed here.

Database Maintenance Backup of the database and restore of previous backup files can be performed externally in the

BUCHI Database Manager (BDM). An Archive function is available.

Customer Information Company name and address can be entered. This information will be shown in the header of result

reports.

Import / Export The possibility of efficient and easy data exchange is highly significant. The import and export

functions of the Administrative Tools offer the required and direct options.

Applications, calibrations and samples can be exported from the database to an XML-File. Applications, calibrations and samples previously exported as an XML-File can be imported to the

database. For the selection different filter functions are available.

2.1.4. Security Designer

Especially in regulated environments, authorizations for access to the software or to individual software modules must be precisely defined. A basic precondition for this task is an integrated user management system.

Users and user groups Access authorizations may be assigned exclusively to users and user groups registered in the integrated user management system. For this purpose, you can create and manage users and user groups with individual rights.

Security policies All software components, including applications, can be fully protected against unauthorized

access.

Account Policy With the aid of the Account Policy, the rules are defined for user names and passwords. For

example, it is possible to define the minimum length of the user name as well as the complexity

NIRWare 1.5 Software Manual Introduction  5

and period of validity of the passwords. A password history check and an automatic logout function are implemented as well.

2.1.5. Library Designer

For identity checking at goods receipt, it is not always necessary to apply chemometric procedures such as cluster analysis or SIMCA. Often, a direct comparison of spectra will also produce unambiguous results directly and require fewer reference samples than in chemometric models. With the aid of the Library Designer, it is possible to create and manage the necessary spectral libraries. On the basis of existing spectra, any number of libraries can be created which can be interlinked to allow spectra to be compared. The Library Designer enables you to select from ten different algorithms for spectral comparison and to define the acceptance criteria to ensure optimal matching to your specific task. At the push of a button, you can perform internal and external validations of the libraries.

2.2. NIRWare Operator

All measurements are performed using the NIRWare Operator. Its user interface can be tailored to user specific needs. The integrated standard operating procedures guides users through the application. In the routine mode, only a few sample-specific entries are required, which may also be entered using a barcode reader. The results are displayed directly in the report format on the monitor. Even users with little PC experience will be able to use this software after just a short introduction

Additionally there are tools for instrument tests implemented.

6  Introduction NIRWare 1.5 Software Manual

2.3. NIRCal 5

NIRCal 5 is the proven chemometric software. It is database oriented and includes an integrated user management feature. Calibrations of NIRCal 5 are incorporated directly in the application with the NIRWare Application Designer.

NIRCal is a chemometric software to analyze measured spectra and to develop calibrations. General features of NIRCal:

 Fully database oriented  Internal User Management (via NIRWare Security Designer)  Performance increase (up to 10 times faster than NIRCal 4.21)  Integrated lifecycle model

Please confer to the dedicated NIRCal manual for detailed information.

NIRWare 1.5 Software Manual Introduction  7

3. General work flow

In the development of a routine application, different software modules are used. The application development cycle is summarized below:

1. Develop an application with NIRWare Application Designer

2. Measure the calibration samples with NIRWare Operator

3. Assign reference values to each sample with NIRWare Sample Manager

4. Analyze spectral data and develop a calibration with NIRCal 5

5. Assign the calibration to the application with NIRWare Application Designer

6. Measure and predict measured samples in routine use with NIRWare Operator

NIRWare 1.5 Software Manual General work flow  9

The shown roadmap illustrates the workflow under the Life Cycle Template "Unregulated". The Life Cycle Template "ER" (Electronic Records) and "ERES" (Electronic Records/Electronic

Signatures)", usually used in pharmaceutical industry, contains an additional step. An application or calibration is set in the life cycle state "checked" for test runs before it can be set to the

"approved" state, which is used for released applications and calibrations.

10  General work flow NIRWare 1.5 Software Manual

4. Software Installation

This chapter explains how to install or update the NIRWare Software Suite and introduces the license philosophy.

4.1. Important Notes

A new version of NIRWare cannot be installed at the same time as a previous version. In case of an existing installation of NIRware it will be removed by the setup of the new version. An existing NIRWare database from a prior installation will be upgraded. Therefore it is recommended to backup all needed data prior to installation.

NIRWare 1.5 can run on 32-bit and 64-bit versions of Windows. NIRCal 5.5 runs only on the 64-bit versions of Windows. If you choose to install NIRWare 1.5 on a 32-bit operating system, NIRCal 5.5 will not be installed.

A user with administrator rights for the operating system is required to install the software.

4.2. System requirements

The PC must fulfill the following requirements:

 Windows 7 Professional / Enterprise / Ultimate (32-bit or 64-bit) SP1, 3 GB RAM or higher  Windows 8 Pro (64-bit), .NET 3.5 recommended, 3 GB RAM or higher  Intel Core i3 or higher and 1.4 GHz or faster  3GB RAM or higher  15GB free hard disk space  DVD-ROM drive  1 x 100 Mbit/s LAN (2x 100 Mbit/s LAN recommend)  1280x1024 display resolution

The firewall needs to be stopped during the installation procedure

ATTENTION

For security reasons, we highly recommend to disconnect from the internet before shutting down a firewall.

4.3. Installation procedure

To install the NIRWare software, proceed as follows:

 Insert the Installation DVD. If the installation window does not start automatically, then manually

run the executable ‘Start.exe’. In the opening window, click on ‘Install NIRWare 1.5 and NIRCal

5.5’.

NIRWare 1.5 Software Manual Software Installation  11

 The InstallShield Wizard with the list of software parts to be installed opens. Click ‘Install’ to start

the installation.

 Wait during installation of .NET 4.0 and MS SQL Server 2008 R2…  After automatic installation of .NET 4.0 and MS SQL Server 2008 R2, click OK to confirm the

warning that any older NIRWare version will be automatically uninstalled when installing NIRWare

1.5.

 Follow the installation wizard and use the default options.  Click OK to confirm the complete installation of NIRSolutions.

12  Software Installation NIRWare 1.5 Software Manual

 Click on green check mark to confirm or let the timer run its course. Ensure the setup finishes

successfully and no error message is shown.

 Click Yes to confirm to restart your system

4.4. What has been installed

The following three shortcuts have been added to the desktop for all users (Windows 7 and Windows

Windows 7: These entries have been added to the start menu for all users

Windows 8: These tiles have been added to the Start screen of the user who has done the installation

NIRWare 1.5 Software Manual Software Installation  13

The above tiles are only added to the Start screen of the user who installed NIRWare 1.5. Other users do not see automatically any NIRWare 1.5 tiles on their start screens. Users who want to add NIRWare 1.5 tiles to their start screen have to select the desired apps (right click on the start screen and click on ‘All

apps’, or press the keys Windows-Q to open the search app view) and pin them to the start screen: Right click on the app and then click on ‘Pin to Start’

Example: Pin NIRCal to Start.

Management Console, Operator and NIRCal

 Windows 7: These applications can also be started using the Start menu:

Start / All Programs / Buchi / NIRSolutions / …

 Windows 8: These applications can also be started using the Start screen, if they have been

pinned to the Start screen. Alternatively, just start typing the name of the application on the Start screen until you see the desired application selected.

14  Software Installation NIRWare 1.5 Software Manual

 These three aplications are stored by default here:

C:\Program Files\Buchi\NIRSolutions

BUCHI Database Manager

 Windows 7: This application can be started using the Start menu:

Start > All Programs > Buchi > Database Manager > Buchi Database Manager

 Windows 8: This application can also be started using the Start screen, if it has been pinned to

the Start screen. Alternatively, just start typing the name of the application on the Start screen until you see the desired application selected.

 This application is stored by default here:

C:\Program Files\Buchi\Buchi Database Manager

4.5. Software removal

4.5.1. BUCHI NIRSolutions

Please uninstall the existing software version manually. For this purpose:

 Windows 7: Start > Control Panel > Uninstall a program  Windows 8: On the Start screen start typing control panel until you see the app Control Panel

selected, then hit the enter key, then click on Uninstall a program

 Select BUCHI NIRSolutions from the list and click Uninstall

 Confirm the next few dialog boxes to uninstall BUCHI NIRSolutions, including the one that asks

for a reboot of your system.

 The default shortcuts are removed after the reboot. Manually added shortcuts remain and have to

be deleted manually.

NIRWare 1.5 Software Manual Software Installation  15

4.5.2. BUCHI Database Manager

Please uninstall the existing software version manually. For this purpose:

 Windows 7: Start > Control Panel > Uninstall a program  Windows 8: On the Start screen start typing control panel until you see the app Control Panel

selected, then hit the enter key, then click on Uninstall a program

 Select BUCHI Database Manager from the list and click Uninstall

 Confirm the next few dialog boxes to uninstall BUCHI Database Manager

4.5.3. Microsoft SQL Server 2008 R2

Please uninstall the existing software version manually. For this purpose:

 Windows 7: Start > Control Panel > Uninstall a program  Windows 8: On the Start screen start typing control panel until you see the app Control Panel

selected, then hit the enter key, then click on Uninstall a program

 Select Microsoft SQL Server 2008 R2 (64-bit) from the list and click Uninstall/Change

 Select Remove

16  Software Installation NIRWare 1.5 Software Manual

 Windows 8: If .NET 3.5 is not enabled then Windows asks to enable it.

To download and install this feature, an internet connection is needed.

 Click OK to confirm the Setup Support Rules  Select the instance BUCHISQLSERVER and click Next to remove it

NIRWare 1.5 Software Manual Software Installation  17

 Click Select All to select all features and click Next to remove them

 Click Next to confirm Removal Rules  Click Remove to confirm beeing Ready to Remove  Click Close to finish the uninstallation of SQL Server 2008 R2

4.5.4. Remove further software

The following software versions can be uninstalled easily by going to

 Windows 7: Start > Control Panel > Uninstall a program  Windows 8: On the Start screen start typing control panel until you see the app Control Panel

selected, then hit the enter key, then click on Uninstall a program

 Select the program and click Uninstall

 Microsoft SQL Server 2008 R2 Management Objects (x64)  Microsoft SQL Server 2008 R2 Native Client  Microsoft SQL Server System CLR Types (x64)

The following software versions can also be uninstalled easily in the same way when they are not needed by other installed software

 SAP Crystal Reports runtime engine for .NET Framework 4 (32-bit)  SAP Crystal Reports runtime engine for .NET Framework 4 (64-bit)

4.6. Software Licenses

After Installation of NIRWare or NIRCal the software can be used in DEMO mode for 60 days. Within these 60 days it is recommended to register the software and apply for a license.

18  Software Installation NIRWare 1.5 Software Manual

4.7. Software Registration

The registration form can be saved as an *.xml file and needs to be sent to your BUCHI contact person, for example as an email attachment.

The form can be opened using the "NIRWare Management Console"  Menu: Help > Software Registration... or clicking the button "Register..." on the startup of a trial version.

The registration form:

Please fill out the bold mandatory fields. The AN and SN numbers are necessary for new registrations; they can be found on a sticker on the installation DVD.

Click OK and save the file in a convenient place. Email this saved file to your BUCHI sales representative.

NIRWare 1.5 Software Manual Software Installation  19

4.8. Activating the licenses

- To activate the demo mode start the Management Console and select Demo mode.

- When the software is in demo mode it is valid for 60 days.

- To activate the software and make it a fully valid version, licenses are required.

- Licenses are provided by BUCHI.

- The form can be opened using the “NIRWare Management Console” --> Menu: Help > Software

Registration... or clicking the button “Register...” on the startup of a trial version.

20  Software Installation NIRWare 1.5 Software Manual

5. Tutorial

5.1. Logon

The NIRWare Management Console, the NIRWare Operator and NIRCal 5 are protected by Logon.

After NIRWare is installed, four default users are provided, which do not require password entry at the beginning.

Just type in the corresponding user name and click the green checkmark to log on. The four default users are:

 Administrator  QManager  Designer  Operator

NOTE

We highly recommend to define passwords for the four default users or deactivate the accounts after creating new user accounts with password to control the software access.

5.2. Defining a new password

After a certain time, your password will expire. The number of password expiration days is defined in the submenu Account Policy. You might get a warning before your password expires when a number of days is defined for the property "Show Warning Before Expiration" in the submenu Account Policy.

When you are prompted to change your password, you can do so in the logon window:

NIRWare 1.5 Software Manual Tutorial  21

Click on the icon behind the Password line. The logon window is extended:

Enter your new password in the corresponding line and confirm it below. Then click the check mark button to save your changes.

5.3. Creating a qualitative application

5.3.1. Introduction

This tutorial describes how to create an application for identity check. As an example, the NIRFlex N-500 is used with the measuring cell Solids and the Vial Add-on.

22  Tutorial NIRWare 1.5 Software Manual

The application should be able to check the identity of four different types / forms of sugar: Fructose (= fruit sugar), lactose (= milk sugar), sucrose (= crystal sugar) and fine sucrose (= sugar powder).

Note that sucrose and fine sucrose are of the same chemical composition and only differ in particle size.

The process of creating a ready-to-use NIR application requires reference samples. These are samples of doubtless identity and quality. In combination with their NIR spectra (‘reference spectra’) they provide the necessary data sets for calculating a chemometric calibration. The calibration can then be used for prediction, which means deriving the identity information from the spectra of substances to be tested.

A typical use of an NIR application with such a calibration is the identity check of incoming substances in a pharmaceutical plant.

It is recommended to use dedicated applications for reference measurement and routine use (= prediction).

NOTE

The terms 'reference measurement', 'reference samples' or 'reference spectra' used in the tutorial describes the data collected for calibration development.

To ensure that reference and unknown samples are measured under identical spectrometric conditions, we suggest to start the development of the routine application with a copy of the application for reference measurement, which is then adjusted.

Please keep in mind that only applications in the ‘Approved’ Lifecycle state are visible to (and usable by) a

user from the user group ‘Operators’. These considerations are visualized in the following scheme:

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The upper part of the scheme includes all steps regarding the reference samples. The middle part shows the processes for designing an application for routine use. The last part indicates the routine use, which is the goal of the development process.

In the following, we will use the term ‘Operator user’ for a user account from the user group ‘Operators’,

and ‘Administrator’ for one belonging to the user group ‘Administrators’.

For Logon as such a user, the correct user name and password are required for the corresponding dialog.

5.3.2. Creating an application for reference measurement

This first part of the tutorial covers the development process for a method that allows an operator to collect spectra of reference samples. These are necessary for calculating a qualitative chemometric calibration.

The application development starts in the NIRWare Management Console (MC).

Start the program by clicking the icon shown above and log on as a ‘Designer’ (access to 'Application

Designer' and 'Sample Management') or as an 'Administrator' (full access).

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Left-click on ‘Application Designer’ in the tree menu on the left, then on the subtitle ‘New’. A dialog appears for creating a new application

Fill in the application name and all other requested information into the white fields on the right side. The

‘SOP Text’ will later on tell the Operator how to perform the actual measurement, so it is important to give

a complete description which is easily understandable.

Click the Save icon to save the new application to the database.

Your newly created application is now shown in the tree menu.

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Open it by double-clicking on its field in the tree menu, or by clicking once on the plus-symbol in front of it.

Then select its subtitle ‘Operator Configuration’. You will now see only one field for the SOP text.

To see all of the information fields on the right, click on the ‘Show Advanced Settings’ icon in the menu

bar .

The fields on the right are greyed out, indicating that they cannot be changed right now.

To change the settings, first click on the ‘Edit Data Set’ icon .

Notice the change in the icon bar for Lifecycle state from ‘Created Idle’ to ‘Created Editing’ (see above).

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You can now make changes to all white fields. For our example, we just change the ‘Number of measurement sequences’ from 1 to 3.

This will cause a triplicate measurement of every reference sample, which creates more variation in the spectra set later used for calibration. Thus, we will get more robust calibrations.

Save all changes you made to the database by clicking the respective icon . The fields are greyed out again afterwards, indicating successful saving.

The method for triplicate calibration sample measurement is now still in the ‘Created’ state, where only a

‘Designer’ or ‘Administrator’ can see and use it in the operator software.

To provide this method for the operator user, ‘Put the data set into the next state’ by clicking on the

corresponding icon .

Now the application is in the ‘Approved’ state.

NOTE

Approved applications cannot be changed anymore. To adjust something, you first have to create a copy

of the application, which again starts in the ‘created’ state. Then you can apply changes to this new

application.

The application is now ready for measurement of reference spectra with the Operator software.

5.3.3. Measuring reference spectra

To measure spectra of reference samples, the Operator software is used. Measurement of reference spectra is the second step in the development process.

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Start the operator software by clicking the corresponding icon and log on as an operator user.

Click the ‘Select application’ icon: .

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Select the application you created for spectra measurement of the calibration samples.

Notice the access restrictions for the Operator: He can only see and use ‘Approved’ applications.

Click on the ‘New’ icon of the ‘Measurement description - Batch’ field to create a new batch.

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Type in the name of your batch, then click on the green check mark button.

Then type in the information for AnalysisID and Sample names.

Note: For ‘real’ applications, use ‘speaking’ names that precisely identify each sample just from the name.

Also think of using the autoname functions described in the NIRWare documentation.

If you have filled in and checked all information, prepare the samples for measurement (i.e. place all vials in the Autosampler) and press the green arrow button.

During the measurement sequence, the SOP text field is greyed out. If an ‘Instrument Suitability Test’ (SST) starts, just wait until it is finished. Then the instrument will start

with the measurement sequence. This includes periodic measurement of internal and external references. In our example with the vial Autosampler option, these measurements are automatized. With other options, the software will give a description of what to do.

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First, the external reference is measured.

Then the samples are measured. All spectra are displayed in one window.

Since the intensity of the external reference is so much higher than that of the sample spectrum, the latter are just a flat line on the x-axis.

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To have a closer look on the sample spectrum, deactivate the check box for ‘External Reference’ below

the graphic.

The vial autosampler will automatically continue with the next samples after confirmation of the following message:

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Turn the sample vials and click on the green check mark icon to start the next measurement sequence.

The spectra shown below are all from identical fructose samples.

The strong variations along the y-axis (shift) are typical for reflectance measurements of solids and result from variations in particle size and –orientation, and other sources of variation, e.g. thickness of the glass vials.

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To zoom into the spectrum, click and hold the left mouse icon while dragging the cursor.

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The selected frame will be magnified:

To change back to full view, click on the symbol with the magnification lens above the globus.

NOTE

In the Operator it is possible to delete spectra, but only right after they have been measured and if they are not used for prediction with a calibration. This might be desirable if e.g. a vial was not correctly positioned in the Autosampler. To delete a measurement, click the red cross button (red cross in the upper left corner, not the one next to the magnification lens icon).

You can now select samples from the last measurement sequence for deletion.

To select (or deselect) a line in the list, press and hold the Ctrl-icon on your keyboard while left-clicking on that line. Click on the red cross button to delete the selected measurements.

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After completion of the measurement of your reference samples, switch to the NIRWare Management Console to continue with the next step in application development: the assignment of properties and property values. In this case, it means to add the substance identity behind each spectrum.

5.3.4. Defining a property and a property value

After the spectra of the reference samples have been measured, the properties (here: identities) have to be connected to the reference samples. This is done in the NIRWare Management Console (MC). The so created data sets are later on the basis for building a calibration in NIRCal.

Switch to the MC, and select ‘Sample Management’ from the tree menu.

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Select ‘Properties’ to open a list with all properties that have been defined so far.

NOTE

If the property you need is not in the list, create it by clicking on ‘Properties’ in the tree menu, and then selecting ‘new property’.

Define the type (here: identification) and name of the property.

Note: Additionally, it is possible to define several Substance IDs, for example a company specific number code that is used as substance label. This code can be used later on in the Operator software to define the expected substance in the ID application, instead of the substance name. Also type in your name to document who created this property.

Click on the Save icon to write this property definition to the database.

Create all new properties accordingly.

Now we want to tell the computer which sample belongs to which property.

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Switch to ‘Sample Management – Samples’ to open a list with all samples that have been measured.

Notice that in the list the ‘Time Stamp’ filter is set to a specific date.

Right click the time stamp icon to ignore, or left click on it to edit the filter settings

To shorten the list of samples, you can also use additional filters, e.g. on the ‘Application’ column. This can be helpful if you used dedicated applications for reference spectra measurement of each sample type.

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Select your reference samples by clicking on the topmost reference sample in the list. Then press and hold the Shift-button on your keyboard while scrolling down the list (using the mouse or the arrow keys on your keyboard). Alternative: By pressing ‘Ctrl-Shift-End’ on your keyboard you can highlight everything from the first selection down to the end of the list.

Then click on the `Open existing data set`-icon in the upper left corner to create a new Sample Set .

A window with three lists opens: ‘available properties’, ‘assigned properties’, and ‘samples’.

This allows you to select properties for the samples by shifting them from the ‘available’ to the ‘assigned’ list.

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Select a property that you want to assign to your samples. Then click on the right-arrow key to shift it to

the ‘assigned’ list. Repeat this process for all your properties.

Notice that this assignment created a matrix with check icons in the ‘Samples’ window. By activating the

check icons you can now easily create a matrix that connects sample (=row) and property (=column).

Save these data by clicking on the corresponding icon .

You can now switch to NIRCal to build a calibration based on this data set.

5.3.5. Creating a basic calibration by using the NIRCal wizard

This chapter describes how to create a calibration with NIRCal, using the data set of reference spectra with previously assigned properties. The description here is limited to the use of the NIRCal wizard, since

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detailed optimization procedures and description of NIRCal features are described in the NIRCal documentation.

Start NIRCal and log on as an administrator.

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From the menu, select View/Toolbars and select the Toolbars as shown in the picture To load spectra from the database into your empty project, click on the binocular icon .

Select the spectra from the list, and click on the green check mark icon.

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To simplify the selection, use appropriate filter settings, especially for ‘Time’ and ‘Application’. (Time: right click to ignore time filter, left click to set time filter settings.)

Since we performed triplicate spectra measurement of each sample, we now find three spectra for each individual sample.

Select the NIR-Explorer window, select ‘spectra’ from the tree menu and check if all spectra have been correctly loaded.

Before calculating a first calibration, make sure that ‘CLU’ (for ‘cluster calibration’) is selected in the menu bar

Click on the Overview icon to start a first calculation.

A message appears regarding Calibration- and Validation set selection (C-Set and V-Set):

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Click on YES to let the C/V-selection wizard create a selection.

Note: It is highly recommended to perform the selection sample wise, so that ALL spectra of one individual sample are EITHER in the C- OR V-Set. This is described in detail in the NIRCal documentation. For our example, we will leave the result from the selection wizard untouched.

A full calculation is performed, and the result is visualized in nine windows.

In case that your spectra are all shown in the same color, they are all marked as selected. Press the ‘C’

icon to unselect, so that you can differentiate between the different property colors.

From the menu, select ‘Wizard - Calibration Wizard’ (see above). A dialog appears for defining general parameters.

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Select ‘identification’ as calibration type, and click on ‘OK’.

The wizard now starts with the optimization process, which will take a few minutes. The progress is visualized in the ‘Calibration Q-Value overview’.

In the course of the optimization process, you see the Q-Value rise from zero (no working calibration) up close to 1 (=perfect calibration).

After the wizard is finished, the results are shown in a list where the best calibrations (with the highest Qvalues) are found on top of the list.

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The ten best results are stored in the NIRCal Explorer, and the one with the highest Q-value is set to

‘active’.

From the plot ‘Scores vs. Scores’ of PC1 vs. PC2 you can see an excellent separation for two of the four

properties.

Only one overlap is displayed.

But since we look at a 2-dimensional projection of a multidimensional space, we have to keep in mind that an overlap might only result from the projection, and not from a spatial interpenetration of the clusters in

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the multidimensional space. In other words: we have to check if the overlap is only a question of perspective.

For this purpose, we select a projection to PC1 vs. PC3.

Notice that we see an overlap again, but of different clusters. The overlap from the first projection is now resolved. This proves that the four clusters are in fact separated from each other.

This can be clearly demonstrated by using a 3D- instead of a 2D-projection:

Select from the menu ‘Graphics – Scores – 3D-Scatter’, and have a look at a 3D-projection on PC 1, 2 and 3

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Click on the ‘R’ icon on your keyboard to start (and stop) the autorotation function.

The plot confirms that the calibration from the wizard is well capable to differentiate between all four sugar types.

(Comment: For more complex examples, the same rule for overlap checking applies to 3D- as for 2Dprojections: Look at every overlap from different perspectives.)

Now switch again to the NIRCal Explorer window and have a look at the ‘Calibrations’

Note that the ten best calibrations are stored here. The one with the highest Q-value is set to active (indicated by a red dot).

Since we only need one calibration, we select everything except for the one we want to keep. This is done by holding down the Ctrl-Key while clicking in the list on the calibration to be selected. Then right-click on the selection and choose ‘delete’. A confirmation message appears, which you will answer with YES.

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To save the calibration to the database, click on the ‘save’ icon in the menu bar .

Type in a name for your NIRCal project and click on the ‘Save As’ icon.

So far the calibration is still in the ‘created’ state. If you would try to use it in an application, this would prevent you from changing your application (!) into the next state, because an approved application requires an approved calibration.

It is suggested to recalculate the first calibration. This is a master calibration, which organises the spectra in the project and can never be put the approved LC state. Copy this calibration, open the copy (LC: Edit), rename this: give a short name preferable with date at the end. Make a new calculation after renaming. Put this calibration to "approved" state.

To put your application into the next state, right-click on the name of the calibration in the NC Explorer, select ‘Lifecycle’ and ‘Next’.

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Now your calibration is finished and in the approved state, so it can be used for integration into an application. This is done in the NIRWare Management Console. (Please remember that only applications with an approved calibration can be approved.)

5.3.6. Integrating a qualitative calibration into an application

The final step in creating an application for identity control with NIR is to integrate the calibration into the application.

Remember that we started with an application for triplicate measurement of reference substances. This serves now as a template for the routine application. In effect, we create a copy of the reference method, make adjustments to this, and integrate the calibration. Adjustments involve mainly the number of measurements per sample, the SOP text, and Reports. All instrument parameters remain untouched, ensuring identical spectral conditions for both reference samples and those to be tested.

Both the creation of the routine use application and the integration of the calibration into this is performed in the NIRWare Management Console (MC).

Load the existing application for data acquisition by choosing ‘Open’ from the ‘Application Designer’ in the

tree list. Then select the application from the list on the right:

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The application is now available as a new point in the tree menu.

Click on the ‘Copy’ icon to create a copy of this application.

This copy starts in the ‘created’ state, while the original application remains ‘approved’.

To change the name, you first have to click on the ‘Edit’ icon .

This causes a change from ‘idle’ to ‘edit’ mode.

Now you can change application name and description

Save this change to the database by clicking on the ‘Save’ icon .

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Next we change the ‘number of measurement sequences’ from 3 to 1. From the tree menu, select the ‘Operator configuration’ menu of your application

Remember that the complete view as shown above is only visible if the icon ‘show advanced settings’

was activated.

Again, first change to ‘edit’ mode. Then change the number of measurement sequences to ‘1’. Also type

in an appropriate Standard Operation Procedure (SOP) description:

Save this dataset by clicking on the save icon again.

The application for routine use has been prepared, and the calibration can now be assigned to it.

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On the Properties level click the button to make the property editable.

Select ‘Properties - New’ menu from the tree menu of your application and select the drop down-menu for ‘Assigned Calibration’.

In the ‘Assigned’ column, set a check-mark in front of the calibration you want to use. Click on the green

check-mark button to assign the chosen calibration to the application. A message appears, which you just confirm:

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The properties defined in the selected calibration are now automatically assigned to the application.

A 'Name' can be entered as a label to e.g. translate a foreign property name.

The ‘Unit’ field should be left blank, since we do not create a quantitative application.

Save all changes made to this data set .

Then select your application from the tree and save it also to the database .

Now this newly created application is ready for use in the operator software, but only for administrators.

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NOTE:

To make this application also available for operators, select the application and put it in the approved state .

You can now start with routine ID checking of sugar samples with the Operator software.

5.3.7. Routine use for ID check

The previously developed application was designed for routinely testing of the identity of sugar samples. Similar applications are performed in the pharmaceutical industry, especially for ID testing of incoming raw materials.

To use the previously created application for sugar ID check, switch to the Operator software and log on as an ‘Operator’.

Select your application for routine measurement by clicking on the binocular icon .

Select your application from the list:

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Create a new batch and define name and expected identity of the substance(s) you want to test:

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We want to use the application to check if our sugar samples really consist of lactose (‘milk sugar’). For

demonstration purposes, we choose a sample of fructose (‘fruit sugar’) and one of lactose

As expected substance we choose lactose. If our calibration is working properly, the first sample will be rejected, and the second one accepted.

Press the green arrow button to start the measurement sequence.

Since the identity of the first substance is (deliberately) not the expected one, the following message appears:

Confirm by clicking on the green check mark button. The sample will then be measured a second time. This is the default setting in case of a failed ID test, and can be adjusted in the Management console.

The second sample is accepted, since name, spectral deviations (residual) and distance to cluster are all within the allowed limits of the calibration.

In the report of the rejected sample, we find also more information than just the fact that this sample was rejected:

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The spectrum residual is judged to be OK, which indicates that the spectrum is very similar to those that the calibration was built on.

‘Distance OK’ tells us that the spectral representation falls within the boundaries of a cluster, but because ‘found’ and ‘expected’ substance differ, the sample is falling into the wrong cluster and is thus rejected.

So from the report you can be sure that the sample is not lactose, but -with high probability- fructose. With this information a further investigation is now possible to check if just the label was wrong, or an independent analytical method can be used to confirm the ID suggestion of the NIR application.

This example clearly shows that ID testing with NIR integrates a label check!

5.4. Creating a quantitative application

5.4.1. Introduction

This tutorial describes how to create an application for quantification. As an example, the NIRFlex N-500 is used with the solids cell and the vials (autosampler) option.

The application shall be capable of quantifying

a) the concentration of Lactose (‘milk sugar’) and b) the concentration of Fine Sucrose (‘powder sugar’)

in a mixture of both substances. Concentrations are expressed in % wt. (g / 100 g). In NIRWare 1.5 if there is a 2 component system like this, one property can be calibrated and the other calculated, e.g. Fine Sucrose concentration = 100-Lactose concentration.

The process of creating a ready-to-use NIR application requires calibration samples. These are samples

of doubtless quality and composition. In combination with their NIR spectra (‘calibration spectra’) they

provide the necessary data sets for calculation of a chemometric calibration. The calibration can then be used for prediction, which means deriving the identity information from the spectra of substances to be tested.

It is recommended to use two dedicated applications for acquisition of calibration data and routine use (=prediction).

NOTE

The terms 'reference measurement', 'reference samples' or 'reference spectra' used in the tutorial describes the data collected for calibration development.

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To ensure that all samples are measured under identical spectrometric conditions, we suggest to start the development of the routine application with a copy of the application for acquisition of calibration data, which is then adjusted.

Please keep in mind that only applications in the ‘approved’ Lifecycle state are visible to (and usable by) a user of the ‘Operators’ user group.

These considerations are visualized in the following scheme:

The upper part of the scheme includes all steps regarding the calibration samples. The middle part shows the processes for designing an application for routine use. The last part indicates the routine use, which is the goal of the development process.

In the following, we will use the term ‘Operator user’ for a user account from the user group ‘Operators’,

and ‘Administrator’ for one belonging to the user group ‘Administrators’.

To log on as such a user, the correct user name and password are required for the corresponding dialog.

5.4.2. Creating an application for acquisition of calibration spectra

This first part of the tutorial guides you through the development process for a method that allows an operator to collect spectra of calibration samples. These are required for calculation of a quantitative chemometric calibration.

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The application development starts in the NIRWare Management Console (MC).

Start the program and log on as an ‘Administrator’. Left-click on ‘Application Designer’ in the tree menu on the left, then on the subtitle ‘New’. A dialog appears for creating a new application

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Fill in the application name and all other requested information into the white fields on the right side. The ‘SOP Text’ will later on tell the Operator how to perform the actual measurement, so it is important to give a complete description which is easily understandable.

Click the Save icon to save the new application to the database .

Your newly created application is now shown in the tree menu.

Open it by double-clicking on its field in the tree menu, or by clicking once on the plus-symbol in front of it.

Then select its subtitle ‘Operator Configuration’. You will now see only one field for the SOP text.

To see all of the information fields on the right, click on the ‘Show Advanced Settings’ icon in the menu

bar .

The fields on the right are grayed out, indicating that they cannot be changed right now.

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To change the settings, first click on the ‘Edit Data Set’ icon .

Notice the change in the icon bar for Lifecycle state from ‘Created Idle’ to ‘Created Editing’ (see above).

You can now make changes to all white fields. For our example, we just change the ‘Number of

measurement sequences’ from 1 to 3.

This will cause a triplicate measurement of every reference sample, which creates more variation in the spectra set later used for calibration. Thus, we will get more robust calibrations.

Save all changes you made to the database by clicking the respective icon . The fields are greyed out again afterwards, indicating successful saving.

The method for triplicate reference sample measurement is now still in the ‘Created’ state, where only an

‘Administrator’ can see and use it in the operator software.

To provide this method for the operator user, ‘Put the data set into the next state’ by clicking on the

corresponding icon .

Now the application is in the ‘Approved’ state.

NOTE

Approved applications cannot be changed anymore. To modify any settings or parameters, create a copy of the application. The copy will be generated in LC state "created" and can be edited.

The application is now ready for measurement of reference spectra with the Operator software.

5.4.3. Measuring reference spectra

To measure spectra of reference samples, the Operator software is used.

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Measurement of reference spectra is the second step in the development process.

Start the operator software and log on as an ‘Operator’.

Then press the ‘Select application’ button and select the application you created for the measurement of reference spectra:

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The application is now loaded to the Operator. At the left side, you see fields to fill in information about

batch, analysis sequence and samples. Click on the ‘New’ button of the ‘Batch’ field to create a new

batch:

Type in the name of your batch, then click on the green check mark button:

Then type in the information for AnalysisID and Sample names:

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NOTE

For ‘real’ applications, use ‘speaking’ names that precisely identify each sample just from the name! Also think of using the autoname functions described in the NIRWare documentation.

If you have filled in and checked all information, prepare the samples for measurement (i.e. place all vials in the autosampler) and press the green check mark button.

During the measurement sequence, the SOP text field is greyed out. If an ‘Instrument Suitability Test’ (SST) starts, just wait until that is finished. Then the instrument will start

with the measurement sequence. This includes periodic measurement of internal and external references. In our example with the vial autosampler option, these measurements are automatized. (With other options, the software will give a description of what to do.)

First, the external reference is being measured:

Then the samples are being measured. All spectra are displayed in one window:

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Since the intensity of the external reference is so much higher than that of the sample spectrum, the latter are just a flat line on the x-axis.

To have a closer look on the sample spectrum, deselect the check box for ‘External Reference’ below the

graphic:

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The vial autosampler will automatically continue with the next samples after confirmation of the following dialog:

Click on the green check mark button to start the next measurement sequence. The spectra shown below are all from identical sugar samples:

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Variations in the spectra result from differences in size and orientation of the particles, and from variations between the glass vials.

To zoom into the spectrum, click and hold the left mouse button while dragging the cursor.

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The so defined frame will be magnified:

To change back to full view, click on the symbol with the magnification lens above the globus:

NOTE

It is possible to delete spectra, but only right after they were measured. This might be desirable if for example a vial was not correctly positioned in the autosampler. To delete a measurement, click on the red cross button (red cross in the upper left corner, not the one next to the magnification lens icon).

You can now select samples from the last measurement for deletion:

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To select (or deselect) a line in the list, press and hold the Ctrl-button on your keyboard while left-clicking on that line. Click on the ‘Delete’ button to delete the selected measurements.

5.4.4. Defining a property and a property value

After the spectra of the reference samples have been measured, the properties (here: concentration values) have to be connected to the calibration samples. This is done in the NIRWare Management Console (MC). The so created data sets are later on the basis for building a calibration in NIRCal.

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Switch to the NIRWare Management console, and select ‘Sample Management’ from the tree menu.

Switch to the MC, and select ‘Sample Management’ from the tree menu. Select ‘Properties’ to open a list with all properties that have been defined so far:

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If the property you need is not in the list, create it by clicking on ‘Properties’ in the tree menu, and then

selecting ‘new property’.

Define the type (here: qualification) and edit the name and unit of the property. Also type in your name to document who created this property. Click on the Save icon to write this property definition to the database. Create all new properties accordingly.

Now we want to tell the computer which sample belongs to which property. Switch to MC – Sample Management – Samples to open a list with all samples that have been measured.

Notice that in the list the ‘Time Stamp’ filter is set to a specific date. Right click the time stamp button to ignore, or left click on it to edit the filter settings:

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To shorten the list of samples, you can also use additional filters, e.g. on the ‘Application’ column. This

can be helpful if you used dedicated applications for reference spectra measurement of each sample type. Select your reference samples by clicking on the topmost reference sample in the list. Then press and

hold the Shift-button on your keyboard while scrolling down the list (using the mouse or the arrow keys on your keyboard). Alternative: By pressing ‘Ctrl-Shift-End’ on your keyboard you can highlight everything from the first selection down to the end of the list.

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Then click on the ‘Open existing data set’-button in the upper left corner to create a new Sample Set

This opens a window with three lists: ‘available properties’, ‘assigned properties’, and ‘samples’. This allows you to select properties for the samples by shifting them from the ‘available’ to the ‘assigned’ list.

Select a property that you want to assign to your samples:

followed by a click on the arrow key to the right.

The property ‘Lactose’ has now been shifted to the ‘assigned’ list.

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Repeat this process for all of your properties:

The highlighted matrix cells allow you to define the lactose- and fine sucrose concentrations of each sample:

Complete the matrix list, and save these data to the database by clicking on the save button .

You can now switch to NIRCal to build a calibration on this reference data set.

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5.4.5. Creating a basic calibration by using the NIRCal wizard

This chapter describes how to create a calibration with NIRCal, using the reference spectra with previously assigned properties.

The description here is limited to the use of the NIRCal wizard, since detailed optimization procedures and description of NIRCal features are described in the NIRCal documentation.

Start NIRCal

and log on as an ‘Administrator’. From the menu, select ‘View’ - ‘Toolbars’ and select the toolbars: Calibration, Database, File & Edit, Life

Cycle, Pretreatments, Wizard Workspace, Status Bar.

To load spectra from the database into your empty project, click on the binocular icon .

Select the spectra from the list, and click on the green check mark button:

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To simplify the selection, use appropriate filter settings, especially for ‘Time’ and ‘Application’. (Time: right click to ignore time filter, left click to set time filter settings.)

Since we performed triplicate spectra measurement of each sample, we now find three spectra for each individual sample.

Select the NIR-Explorer window, select ‘spectra’ from the tree menu and check if all spectra have been correctly loaded:

Now make sure that a quantitative method is selected (‘MLR’, ‘PCR’ or ‘PLS’) is selected in the menu bar:

Before we start with the calculations, let’s reconsider that we have reference samples with two property

values. And to this point, both are selected for calibration, as you can see in the NIRCal explorer:

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It is not possible to develop only one calibration for determination of both properties. So we need

to create two calibrations, one for each property. First we start with a calibration for Lactose quantification,

so we deselect the unwanted property ‘Fine Sucrose’. This is done by selecting ‘Properties’ in the NIRCal

tree menu, followed by a right-click on the respective property name in the right part of the explorer

window. From the menu, select ‘Remove from Set’ – ‘Calibration Properties’:

Notice the change in the symbol in front of the property name ‘Fine Sucrose’:

Now we are ready for a first calculation with default settings by clicking on the ‘Overview’ button.

A message appears regarding Calibration- and Validation set selection (C-Set and V-Set):

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Click on YES to let the C/V-selection wizard create a selection. Note: It is highly recommended to perform the selection sample wise, so that ALL spectra of one

individual sample are EITHER in the C- OR V-Set. This is described in detail in the NIRCal documentation.

A full calculation is performed, and the result visualized in seven windows.

Notice that in the ‘Predicted property vs. original property’ window a diagonal calibration curve is shown

for the Property Lactose.

This is a good check for successful deselection of the unwanted property, because it confirms that the actual calibration has only been calculated with regard to Lactose.

Optimization of the calibration is not a topic here, so we leave this job to the patented NIRCal Calibration Wizard: from the menu, select Wizard/Calibration Wizard. A dialog appears for definition of general parameters:

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Select ‘quantification’ as calibration type, and click on ‘OK’. The wizard now starts with the optimization

process, which will take a few minutes. The progress is visualized in the ‘Calibration Q-Value overview’:

In the course of the optimization process, you see the Q-Value rise from zero (no working calibration) up close to 1 (=perfect calibration).

After the wizard is finished, the results are shown in a list where the best calibrations (with the highest Qvalues) are found on top of the list:

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Now switch again to the NIRCal Explorer window, and have a look on the ‘Calibrations’:

Note that the ten best calibrations are stored here. The one with the highest Q-value is set to active (indicated by a red dot). Since we only need one calibration, we select everything, except for the one we want to keep.

This is done by holding down the Ctrl-Key while left-clicking in the right window pane on the calibration to be selected:

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Right-click on the selection and choose ‘delete’. A confirmation message appears, which you will answer with ‘YES’:

To change the name of the calibration, right-click on the calibration name in the left window pane and select ‘Rename’ from the context menu:

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In this case, we rename it to ‘Lactose Quan’.

(Hint: With more complex projects it is also a good idea to start with an identical project name for the

calibration name and then just add a suffix for the respective property. Example: ‘Sugar mixture – lactose’ and ‘Sugar mixture – fine sucrose’.)

To save the calibration to the database, click on the ‘Save’ button in the menu bar .

Type in a name for your NIRCal project and click on the ‘Save As’ button:

So far the calibration is still in the ‘created’ state. If you would try to use it in an application, this would

prevent you from changing your application (!) into the next state, because an approved application requires an approved calibration.

It is suggested to recalculate the first calibration. This is a master calibration, which organise the spectra in the project and can never be put the approved LC state. Copy this calibration, open the copy (LC: Edit), rename this: give a short name preferable with date at the end. Make a new calculation after renaming. Put this calibration to "approved" state.

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and ‘Next’ .

Now your calibration is finished and in the approved state, so it can be used for integration into an application.

Remember that the just created calibration works only for lactose. So we need to start over again to create a second calibration project for fine sucrose. Create a new project by clicking on the respective

button and start over again with spectra loading etc. In the end, you have two calibrations in individual projects, one specialised in Lactose quantification, the

other for Fine Sucrose. For 2 component system a second calibration is not necessary, the second property can be calculated like: Property2= 100-Property1.

After creation of your calibrations in NIRCal, these have now to be integrated to your application. This is done in the NIRWare Management Console.

5.4.6. Integrating a quantitative calibration into an application

The final step in creating an application for quantitative determination with NIR is to integrate the calibration into the application.

Remember that we started with an application for triplicate measurement of reference substances. This serves now as a template for the routine application. In effect, we create a copy of the reference method, make adjustments to this, and integrate the calibration. Adjustments involve mainly the number of measurements per sample, the SOP text, and Reports. All instrument parameters remain untouched, granting identical spectral conditions for both reference samples and those to be tested.

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Both the creation of the routine use application and the integration of the calibration into this is performed

in the NIRWare Management Console (MC) .

Load the application for reference measurement by choosing ‘Open’ from the ‘Application Designer’ in the tree list. Then select the reference application from the list on the right:

The application is now available as a new point in the tree menu:

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Click on the ‘Copy’ icon to create a copy of this application:

This copy starts in the ‘created’ state, while the original application remains ‘approved’:

To change the name, you first have to click on the ‘Edit’ icon . This causes a change from ‘Idle’- to ‘Edit’ mode, allowing you now to make changes to the ‘Value’-fields.

Change the application name, then save .

The application for routine use has been prepared, and the calibration can now be assigned to it.

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On the Properties level click the button to make the property editable.

Select ‘Properties - New’ menu from the tree menu of your application and select the drop down-menu for ‘Assigned calibration’ by clicking on the down arrow symbol at the end of the corresponding value field:

In the ‘Assigned’ column, set a check-mark in front of the calibration you want to use. Click on the green

check-mark button to assign the chosen calibration to the application. A message appears, which you just confirm:

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The property defined in the selected calibration is now automatically assigned to the application (‘Assigned Property’).

A 'Name' can be entered as a label to e.g. translate a foreign property name.

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The ‘Unit’ field has to be filled out as well.

Save all changes to the database by clicking on the icon .

These steps have to be repeated for every other calibration to be used in the application. In this example the Fine Sucrose is calculated = 100-Lactose content. Edit also the lower, upper, warning and action limits beside the property name, unit.

Now you can already use this newly created application as an administrator user in the operator software. To make this application visible to the operator user, you have to put it in the approved state .

Congratulations! You just finished the application development process! You can now start with routine measurement of the contents of Lactose and Fine Sucrose in a mixture of both by using the Operator software.

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5.5. Content Uniformity Test (CUT)

5.5.1. Development of an application for Content Uniformity Testing (CUT) of Solid Dosage Forms

The US Pharmacopeia, the European Pharmacopoeia and the Japanese Pharmacopoeia describe detailed procedures to test the content uniformity of single dosage units. The test indicates the uniformity of the active pharmaceutical ingredient (API) in the dosage unit, such as tablets or capsules, based on the assay of a defined number of samples. This test is requested for batch release.

 Develop a quantitative application as described in the chapter “Creating a quantitative application” for the API.

 After the quantitative application is successfully developed and tested, create a copy of the application.

 To activate the CUT procedure, click on to show the advanced settings of the application.

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From the dropdown list under “Content Uniformity Test according to”, select the procedure you with to use for testing (e.g. General Procedure (Japanese Pharmacopeia, edition 14)

General Procedure (Japanese Pharmacopeia edition 15, European and United States Pharmacopeia)). For details, please refer to the parameter list of the Application Designer.

Please note. Content Uniformity Test is only available for quantitative applications and for the modules NIRFlex Solids

Transmittance and NIRFlex Solids with Tablet Add-on.

 For each calibrated property (e.g. API), enter the Label Claim for the CUT under

“Properties”. NOTE:

A value different to 0 has to be entered.

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The parameters L1, L2 and T are given by the respective Pharmacopeia. Choosing "Individual Monograph", the values for L1, L2 and T can be edited.

 It is recommended to use the Autoname function of the Operator Configuration to create sample names automatically from basic entries as shown in the below example (autoname part 1 = Batch information; autoname part 2 = none; autoname part 3 = Counter).

If CUT is activated in the application, the settings for "Number of repetition of measurements in case of an Out Of Specification" case will be always 0 and "Number of measurement sequences" will be always 1 (even if specified otherwise in the application).

 After all changes on settings are made, set the application in the approved state.  Start the operator and select the developed application for CUT.

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 Create a new batch. Each CUT is handled as an individual batch. When the CUT is finished, the batch will be closed.

 With the autoname function, the sample names are generated automatically.

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 Press on the Start Button to start the CUT. In case a SST is necessary, the following message appears:

 Follow the instructions and click OK. After the SST is finished successfully, the following message appears:

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