iqoqpq-3_1-manual-revd-v3.101

PHAZIR RxTM and

microPHAZIR RxTM

IQ/OQ/PQ Manual

Version 3.1

PCX13Rx91-0002 RevD of 143

Polychromix Document Title

PHAZIRTM Rx & microPHAZIRTM Rx Version 3.1 IQ/OQ/PQ Manual Document Number Revision Page PCX13Rx91-0002 D P a g e | 2

Polychromix, 30 Upton Drive, Wilmington, MA 01887 - - - PROPIETARY INFORMATION - - - FSCM: None

PHAZIRTM Rx & microPHAZIRTM Rx Qualification Manual

TABLE OF CONTENTS

Section 1 – Test Procedures ................................................................................................ 5 Chapter 1 Introduction.......................................................................................................... 5

1.0 Introduction .................................................................................................................. 5 1.1 Purpose ......................................................................................................................... 5 1.2 Scope ............................................................................................................................ 6

1.2.1 In-Scope ................................................................................................................ 6 1.2.2 Out-of-Scope ......................................................................................................... 6

1.3 Document History ........................................................................................................ 7 1.4 Overview and organization IQ/OQ/PQ process ........................................................... 8 1.5 Overview of the Polychromix PHAZIR Tools software .............................................. 9 1.6 Method Generation .................................................................................................... 11 1.7 Responsibilities .......................................................................................................... 12 1.8 Polychromix Vendor Qualifications and Quality Systems ........................................ 15 1.9 Frequently Asked Questions and Recommendations ............................................... 16

Chapter 2 Design Qualification .......................................................................................... 21 2.0 Introduction ................................................................................................................ 21 2.1 Overview ................................................................................................................... 21

Referenced Documents ................................................................................................ 23 2.3.1 Product Functional Requirements Specifications for PHAZIR RxTM and microPHAZIR RxTM Near-Infrared Spectrometer ........................................................... 23 2.3.2 Product Functional Requirements Specifications for microPHAZIR RxTM Near-Infrared Spectrometer. ..................................................................................................... 42

Chapter 3 Installation Qualification ................................................................................... 61 3.0 Purpose ....................................................................................................................... 61 3.1 Overview .................................................................................................................... 61 3.2 Installation Qualification Test Procedures ................................................................ 62

Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx & microPHAZIR Rx V3.1 IQ/OQ/PQ Manual Table Of Content of 143



Polychromix, 30 Upton Drive, Wilmington, MA 01887 - - - PROPIETARY INFORMATION - - - FSCM: NoneDoc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx & microPHAZIR Rx V3.1 IQ/OQ/PQ Manual Table Of Content of 143

Chapter 4 Performance Qualification ................................................................................. 71 4.0 Purpose ....................................................................................................................... 71 4.1 Overview .................................................................................................................... 71 4.2 Test Procedures .......................................................................................................... 72

Chapter 5 Operational Qualifications ................................................................................. 74 5.0 Purpose ....................................................................................................................... 74 5.1 Overview .................................................................................................................... 74 5.2 USP 1119 Test Protocol and Using Traceable Standards ......................................... 75 5.3 Working with and Handling Traceable Standards .................................................... 75 5.4 Test Procedures .......................................................................................................... 77

Chapter 6 Glossary ............................................................................................................. 82 6.0 Purpose ....................................................................................................................... 82 6.1 General Terminology and References ....................................................................... 82 6.2 Polychromix Specific Terminology ........................................................................... 92

Chapter 7 USP 1119 ........................................................................................................... 94 7.0 Purpose ....................................................................................................................... 94 7.1 Overview of USP 1119 .............................................................................................. 94 7.2 USP Specification and Acceptance Criteria .............................................................. 94 7.3 USP 1119 Wavelength Accuracy ............................................................................... 96 7.4 USP 1119 Photometric Linearity ............................................................................... 97 7.5 USP 1119 Photometric Noise .................................................................................... 98 7.6 USP 1119 Photometric Noise High Flux .................................................................. 98 7.8 USP 1119 Photometric Noise Low Flux .................................................................... 99 7.9 Working with Traceable Standards ............................................................................ 99 7.10 Examples of Traceable Standards .......................................................................... 100 7.10 Suppliers of Near-infrared Traceable Standards .................................................... 108

IQ-Appendix-A ................................................................................................................. 109 1.0 Purpose ..................................................................................................................... 109 2.0 Overview .................................................................................................................. 109 3.0 Required Software Packages ................................................................................... 109 3.1 Optional Software Packages ................................................................................... 109

Section 2 – Test Logs........................................................................................................ 110 Installation Qualification – IQ Test Log ............................................................................ 111 Operational Qualification – OQ Test Log ......................................................................... 114 Performance Qualification – PQ Test Log ......................................................................... 116 Section 3 – Product Certifications .................................................................................. 117

1.0 Purpose ................................................................................................................ 117 Section 4 - Information .................................................................................................... 122 This section contains the following as applicable: ............................................................ 122 Section 5 - Personnel Training ........................................................................................ 125

Polychromix

Document TitlePHAZIRTM Rx & microPHAZIRTM Rx Version 3.1 IQ/OQ/PQ Manual

Document Number Revision Page PCX13Rx91-0002 D P a g e | 4

Polychromix, 30 Upton Drive, Wilmington, MA 01887 - - - PROPIETARY INFORMATION - - - FSCM: NoneDoc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx & microPHAZIR Rx V3.1 IQ/OQ/PQ Manual Table Of Content of 143

1.0 Purpose ..................................................................................................................... 125 2.0 Background .............................................................................................................. 125 3.0 Training Process....................................................................................................... 126

Section 6 - System Recertification .................................................................................. 131 1.0 Purpose ..................................................................................................................... 131 2.0 Background .............................................................................................................. 131 3.0 Preparatory Actions ................................................................................................. 131 4.0 Requalification Process ............................................................................................ 132 5.0 Record Keeping ....................................................................................................... 133

Section 7 – Traceability Matrix for Functional Requirement Specifications ............. 137 1.0 Purpose ..................................................................................................................... 137 2.0 Background .............................................................................................................. 137

Traceability Matrix for Functional Requirement Specifications ....................................... 138




Section 1 – Test Procedures

Chapter 1 Introduction

1.0 Introduction

Modern pharmaceutical manufacturers require analytical systems to produce accurate and secure data that comply with GMP/cGMP standards. Polychromix has developed a regulatory compliance package to assist customers in regulated industries to execute a comprehensive system qualification and to properly document the qualification process. This manual provides a step-by-step procedure to guide system owners through the IQ/OQ/PQ equipment qualification procedures for Polychromix PHAZIR RxTM and microPHAZIR RxTM Near-Infrared Spectrometer Systems.

1.1 Purpose This manual guides the operator through step-by-step procedures to insure the products being qualified comply with regulatory requirements, industry best practices, and the manufacturers’ specifications and recommendations. This chapter provides an overview of the Polychromix qualification plan including: Design Qualification – DQ Installation Qualification – IQ Operational Qualification – OQ Performance Qualification – PQ

Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx & microPHAZIR Rx V3.1 IQ/OQ/PQ Manual Chapter 1 of 143



Polychromix, 30 Upton Drive, Wilmington, MA 01887 - - - PROPIETARY INFORMATION - - - FSCM: None Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx & microPHAZIR Rx V3.1 IQ/OQ/PQ Manual Chapter 1 of 143

1.2 Scope

1.2.1 In-Scope The plan includes support for: - Polychromix PHAZIR RxTM and microPHAZIR RxTM systems - PHAZIR Tools Software including PHAZIR Setup Utility, PHAZIR Data Management System, and PHAZIR Rx System Software (device firmware).

1.2.2 Out-of-Scope The plan does not support - Non-Polychromix manufactured systems - Models which were released and delivered prior to the release of this

manual. - Non-PHAZIR Rx models - Application methods or calibration, or the method development and/or

method validation processes. - PHAZIR Method Generator software package - Other chemometric and method generation software packages




1.3 Document History This IQ/OQ/PQ manual set is a control document with the following revision, approval, and release dates.

Rev Release Date Approved By Comment 1-0 June-1-2007 DRK Initial release 1.1 June-7-2007 DRK Additional chap 1, recommendations, Reorganization of chap 2.

specifications 1.2 Sept-15-2007 DRK Modifications to accommodate the automated OQ testing with

PHAZIR-OQ and OQ-Test functions 1.5 Nov -17-2007 DRK Modification to accommodate PHAZIR Rx Software Suite

including PHAZIR Data Management Software, PHAZIR Setup Utilities and PHAZIR System Software Management

1.5.1 Dec-20-2007 DRK Updates to enhance support for PHAZIR Rx Software Suite and additional manufacture’s recommendations.

2.0 Jan-25-2008 DRK Updated OQ test procedure to reflect OQ routine for the PHAZIR Systems Software 2.26 release.

“-“ FEB-29-2008 BJM Issued and Controlled Document A Oct-29-2008 BJM Updated for release 2.29 B Jan-16-2009 BJM Updated for release 2.32 C Aug-3-2009 BJM Added Training Section 5, Added Recertification Section 6 D Dec 11, 2009 BJM -Reorganization of manual

-Addition of FRS traceability matrix -Modification to accommodate microPHAZIR Rx -Changes to accommodate change in product naming from PHAZIR Method Generator to Polychromix Method Generator. - Expansion of training and recertification processes -Expansion of Traceability Matrix -Incorporation with system test plans and system test reports (digital only) w/ IQOQPQ manual CD.




1.4 Overview and organization IQ/OQ/PQ process The following figure illustrates the GAMP V-model for IQ-OQ-PQ instrument qualification and the relationship between User Requirement Specifications and Performance Qualification; Functional Requirement Specification and Operational Qualification, as well as the relationship between Design Qualifications Specifications (or Design Specifications) and Installation Qualification.

User Requirements

Functional Specifications

Design Specifications

Performance Qualification

Operational Qualification

Installation Qualification

Installation

Section 1: Test Procedures

- Chapter 1 Introduction - Chapter 2 Design Qualification - Chapter 3 Installation Qualification - Chapter 4 Performance Qualification - Chapter 5 Operational Qualification - Chapter 6 Glossary - Chapter 7 USP 1119

Section 2 contains: Test Logs

- Test Report Log forms





Section 3 contains: Product Certification - Product Certificates

Section 4 – Information - Appendix documents

- Customer order information (quotation, order, and packing lists) - Polychromix certifications (ISO 9001 certificate) - Reference documentation for traceable standards if supplied by Polychromix - Product Certification - PHAZIR Rx and microPHAZIR Rx Regulatory and 21 CFR Part 11

Compliance statement - Product brochures (optional)

Section 5 – Training - Training documents Section 6 – Recertification - Recertification documents Section 7 – FRS Traceability Matrix - FRS Traceability Matrix Note: Sections 3 and 4 and supplemental documents which are independently added to the IQ/OQ/PQ manual.

1.5 Overview of the Polychromix PHAZIR Tools software

The PHAZIR Tools software provides a comprehensive and cost effective solution for meeting demanding regulatory compliance and convenient data management for portable handheld analyzers. The PHAZIR Tools software provides compliance with:

- 21 CFR Part 11 Electronics Records and Signature compliance - USP 1119 NIR Qualification Procedures - Support for Traceable Reference Standards

The PHAZIR Tools software includes three interconnected software packages including

- PHAZIR Rx System Software




- PHAZIR Data Management System - PHAZIR Setup Utility • NOTE: PHAZIR Tools software is compatible with both the

PHAZIR RxTM and microPHAZIR RxTM systems.

The PHAZIR Tools software is installed on the PHAZIR analyzer and offers the following features: - Secure User Logins for controlled access - OQ/PQ time monitor - USP 1119 OQ wizard - Polychromix PQ test The PHAZIR Setup Utility is installed on a MS Windows PC and provides the following functions:

- Setup and maintenance of user accounts - Configuration of OQ/PQ test intervals - Security settings - Sample Information and group identifications - Manage system applications - Configure and synchronize PHAZIR

The PHAZIR Data Management Software is installed on a MS Windows PC and provides the following functions:

- Managing PHAZIR data in an SQL database. - Importing and synchronization of PHAZIR data - Electronic record archiving - Electronic signature management - Report Generation - Export database records to other programs

The three packages in the PHAZIR Tools Software work together to provide a complete regulatory and data management solution and provide connectivity with the optional Polychromix Method Generation Software. The following figure shows the connectivity flowchart and interconnection between the PHAZIR Tools Software packages and the Polychromix Method Generation Software. NOTE: The term “System” denotes both the PHAZIR RxTM and microPHAZIR RxTM products.




NOTE: Polychromix Method Generation software was formerly called PHAZIR Method Generation software NOTE: PHAZIR Tools Software was formerly called PHAZIR Rx Software Suite

PHAZIR System Software

PHAZIR Data Management

System

PHAZIR Setup Utility

PHAZIR Tools Software

Polychromix Method Generation Software

1.6 Method Generation

Methods can be generated for the System using the Polychromix Method Generation Software and potentially with other 3rd party software packages such as Camo Unscrambler software or Umetrics software packages. Method development software and method validation are beyond the scope of this document.





1.7 Responsibilities It is intended that this qualification plan be executed with a trained and certified representative of Polychromix and a representative of the customer. The Polychromix representative serves as the “tester” and the customer representative serves as the “witness”. It is possible for the customer to execute this qualification plan without the assistance of a Polychromix representative. In this case it is recommended that different customer representatives act as “Tester” and “Witness”. The “Testers” responsibilities are as follows: - to review and comprehend the qualification plan - to execute the qualification plan - to document test results and sign the test reports The “Witness’s” responsibilities include: - to observe the execution of the test plan - to co-sign the test reports The “Review and Approval’s” responsibility is to approve the test results. In the event that your company or industry does not require or make a provision for such an approval mechanism, complete the field with “N/A” or a similar disclaimer. Do not leave the field blank.

At the end of each IQ/OQ/PQ chapter there are a series of step-by-step test instructions. A test report log is available for each chapter to assist in documenting the results of each test. In the case of the Operational Qualification and Performance Qualification chapters some test report logs may be automatically generated by the PHAZIR Data Management Software. In these cases the printed test reports are filed along with the chapter test report log. Each test has an acceptance criteria which is to be met in order for a test to be considered “passed” Tests that fail are reported in the non-conforming product section. The “tester” and the “witness” sign and date each report summary log. A chapter is successfully completed only when all tests for the chapter are marked “pass”.




In order for the PHAZIR RxTM or microPHAZIR RxTM system to be qualified and considered ready for use, all tests must have successfully passed the stated criteria. Tests that fail are documented in the test log and are reported in the non-conforming product section. After review and correction of the failure cause, the failed section is retested. Should it not pass the required tests, report the incident to Polychromix for technical assistance.

Polychromix



IQOQPQ Workflow


Document In Test Log






1. System IQ 2. System OQ 3. System PQ

Test Fail Test Fail Test Fail

Test Pass Test Pass Test Pass

Corrective Action

Corrective Action

Corrective Action

RET

EST

RET

EST

RET

EST

Begin Qualification

QualificationComplete




1.8 Polychromix Vendor Qualifications and Quality Systems Polychromix is a qualified vendor with an ISO 9001:2008 registered Quality Management System.

Polychromix products released for use in GMP/cGMP environments are controlled by procedure PCXQrx0009 which controls the following processes associated with the development and release of GMP/cGMP compliant products: Design Life Cycle Design Verification Design Validation Design Change Control Design Release to Manufacturing Product Specifications

Contact Polychromix for additional information regarding the Polychromix ISO 9001:2008 Quality Management System and PCXQrx0009 Qualification Design and Development for Use in Pharmaceutical and Regulated Industries.




1.9 Frequently Asked Questions and Recommendations Before beginning the IQ/OQ/PQ process the authors of the manual recommend the review the following section in order that proper consideration be given in preparation of the start of the IQ/OQ/PQ process. Topic Consideration Recommendation

Do you intend for a Polychromix training representative to assist during the execution of the IQ/OQ/PQ plan?

Make sure that proper arrangements have been made with the representative.

The PHAZIR IQ/OQ/PQ procedure can be executed with, or without, the support of a Polychromix representative. Polychromix recommends having a representative involved if you are not experience in the use of System, PHAZIR Tools Software packages or USP1119 qualifications procedures. Contact Polychromix regarding special training and certification options.

How much time should be allocated to the execution of the System IQ/OQ/PQ process?

Make sure the material in this manual have been reviewed, and approved for use, prior to the beginning the qualification test plan.

The required time will vary but assume approximately 4-6 hours to complete and document the test plan.

Will USP 1119 instrumental qualification test protocols be used for OQ qualification?

USP 1119 is a Near Infrared Qualification Protocol published by USP which tests common near Infrared instrumentation performance parameters including photometric linearity, photometric noise, and wavelength repeatability USP 1119 protocol requires specific traceable reference materials (also called reference standards, certified

Polychromix recommends the use of USP 1119 for pharmaceutical manufactures that are regulated by the US FDA. While USP 1119 is not required by FDA it is a widely accepted protocol and reflects the industry’s best practice. USP 1119 is used in the standard Operational Qualification procedures.




standards, or traceable standard). These standards must be available at the time of the execution this plan. Standards can be purchased, rented, or provided by the customer. Note: Be aware that these standards must be handled properly to avoid damage. Note: These traceable standards are small and easy to misplace. Make sure to store them in a safe location. Note: If the standards are to be supplied by the customer make sure that they are within the certification expiration period.

Consider the following factors for OQ/PQ testing.a. Define how frequently should OQ test procedure be executed?

OQ procedures based on USP 1119 Near-infrared spectroscopy qualification protocol specify the use of traceable wavelength and photometric standards. These standards will need to be available in order to execute OQ test based on USP 1119.

The recommended times for OQ testing to be performed are: • at initial execution of the

IQ/OQ/PQ plan, • followed by annual OQ

testing periods, and • following major instrument

repairs.

b. Define how frequently should PQ test procedures be executed?

The maximum recommended interval durations for PQ testing is weekly. Since the PQ test takes only a few moments and the test standards are provided with the system, it recommended that PQ test be performed each time




the system is turned on. This procedure will ensure complete traceability in records

c. Define a maintenance schedule?

The manufacturer recommends a few basic preventative maintenance practices.

Annual: - Replacement of NIR

source should be annual.- Execution of OQ tests

Preventative service should be scheduled 12 months after installation and not more that 14 months.

Can test or check samples be incorporated into a qualification procedure?

External or check samples should be adequately stable over the period of intended use.

Yes it is a good practice to include check samples as part of an on-going instrument qualification plan. The Polychromix qualification plan does not specifically support test samples in the qualification system but these can be incorporated in customer developed standard operating procedures (SOP).

Time & Date How is the Time/Date set? The time and date settings are

determined by the PC clock. When PHAZIR Setup Utility configures (or synchronizes) with the System, the time and date settings from the PC are transferred to the System.

Since the time & date settings are transferred from the PC to the PHAZIR, ensure that the PCs time & date are set correctly.

Does PHAZIR Rx support daylight savings time?

No, The PHAZIR Rx and microPHAZIR Rx systems do not have special support for daylight savings time changes.

Address daylight saving time, if required, in a separate SOP

Does PHAZIR Rx support GMT time?

Yes, The PHAZIR Setup Utility supports either local time or GMT time. The default setting is local time.

Configure the PHAZIR Setup Utility/ Basic Setup/ GMT Timestamp parameter as required.




Recommendations OQ/PQ Monitor The System supports an OQ/PQ Monitor which continuously keeps track of the period of time since the last successful OQ & PQ tests and compares this to the established expiration period. A color coded icon is continuously displayed on the LCD display. Red=Expired OQ/PQ test, system is not ready for use. White w/ red X = failed OQ/PQ test, system not ready for use. Green=OQ/PQ test passed within expiration period and system is ready for use. Yellow= OQ & PQ test passed but expiration period will expire soon, system can continue to be used.

It is recommended that the PHAZIR Setup Utility OQ/PQ Monitor be enabled for routine GMP use. The status of the OQ and PQ tests is recorded in the System data basing system and can be incorporated in reports to ensure complete system integrity and traceability of results. When enabled the status options are Passed, Failed, and Expired.

Encrypted PHAZIR Data Files Each time the System performs a measurement or analysis the results are stored in an on board database. To transfer records to the PC a PHAZIR Data File is generated. This file can be either an ASCII (or Text) file or a special encrypted file format.

It is recommended that for routine GMP use that the PHAZIR Setup Utility encodes data files option be enabled. This prevents any possibility of unauthorized modification of results.

Secure User Login The PHAZIR Setup Utility Enable Security (Login Required) defines if a user login is required.

This option should allows be turned on for GMP operation.

The PHAZIR Setup Utility Enable Logout on Standby function automatically logs out users when the PHAZIR is left inactive for a specified period of time. This value is configured within the PHAZIR Application and is defined by within PHAZIR Applications created by Polychromix Method Generation Software. The default period is 10 minutes.

It is recommended that the Logout on Standby function be enabled for all users.

The PHAZIR Setup Utility “Idle minutes before Windows software logoff” function will automatically log out users when the PHAZIR Data Management System or PHAZIR Setup Utility is left inactive for a specified period of time. The default period is 10 minutes.

It is recommended that the PHAZIR Setup Utility Idle minutes before Windows software logoff function be enabled for all users.

Electronic Signatures The PHAZIR Tools supports 21 CFR Part 11 electronic signatures. The package supports 4 different signing levels (Level 1 – Level 4) which can be used

Consider your requirements and how to best implement electronic signature with a single or multiple signing levels.

Polychromix




The following are the typically recommended settings for PHAZIRTM Setup Utility Basic Configuration screen and User Settings screen.





Chapter 2 Design Qualification

2.0 Introduction Modern pharmaceutical manufacturers require analytical systems to produce accurate and secure data that comply with GMP/cGMP standard. Polychromix has developed a regulatory compliance package to assist customers in regulated industries to execute and document a comprehensive system qualification. This manual provides a step-by-step procedure to guide system owners through the IQ/OQ/PQ system qualification procedures for Polychromix spectroscopy products.

2.1 Overview This section reviews the critical design qualification criteria for the PHAZIR RxTM and microPHAZIR RxTM Near-Infrared Spectrometer System for design, performance, and reliability parameters. These specifications are listed in terms of the design specification requirements, a brief summary justification for the need for the requirement, and a summary explanation of how the design specification was implemented in the product.

Polychromix Design Qualification Plan Polychromix Inc. is ISO9001:2008 registered with design and manufacture. A copy of the Polychromix registration certification is located in section 4. The design and development of product for regulated markets is controlled by QMS document PCXQrx0009. A copy of the Polychromix PCXQrx0009 procedure is available upon request. Audit results of the Polychromix registered Quality Management System (QMS) are available upon request. This document covers the following design processes that culminate in the information and checklists needed by regulated industries, such as pharmaceutical, to implement the Polychromix verified and validated instrument products for use in their facilities along with needed customer support processes:





Design and Validation plan with requirements for both Hardware, and Software (including Firmware) Design Life Cycle – Design Reviews, Release, Changes, Discontinuance, and Resulting Actions Design Verification Design Validation Design Change Control Design Release to Manufacturing Product Specification Product Manual Design Qualification Summary – (DQ) (Customer Support) EMF (Early Maintenance Feedback) mechanisms – (Customer Support) The Polychromix design validation plan provides a formal record of the undertaken design and development efforts and is controlled throughout the design’s life cycle. Upon design completion, along with successful design verification, and validation, it subsequently becomes a complete and controlled Design Qualification (DQ) document set.




Record Name Maintained By Record Location Retention PeriodDesign plan Engineering Director Engineering

On-LineProduct Life +7Yrs

Preliminary Design Review Optional as Required

Engineering Director EngineeringOn-Line

Product Life +7Yrs

Interim Design Review Engineering Director EngineeringOn-Line

Product Life +7Yrs

Design Verification Document Control EngineeringOn-Line

Product Life +7Yrs

Design Validation Document Control EngineeringOn-Line

Product Life +7Yrs

Final / Release Design Review Document Control EngineeringOn-Line

Product Life +7Yrs

Product Specification Document Control Product Folder On-Line

Product Life +7Yrs

Product Manual Document Control Product Folder On-Line

Product Life +7Yrs

Design Qualification Package - DQ Document Control Product Folder On-Line

Product Life +7Yrs

Early Maintenance Feedback Marketing Web Site Product LifeDesign Personnel Qualifications HR HR Files On-Line Indefinite

Referenced Documents The following documents, at their current revision, form a part of this specification. Conflicts between these documents are governed by this specification. • PCXQ1000 Quality Manual Sections 7.1, and 7.3.1 through 7.3.7 • ISO9000-3 Guidelines for the application of ISO9001 to the development,

supply, and maintenance of software. • Agilent E-seminar Validation of Equipment and Computer Systems in Laboratories • Agilent Primer Good Laboratory Practice (GLP) and Current Good Manufacturing

Practice (cGMP)

2.3.1 Product Functional Requirements Specifications for PHAZIR RxTM and microPHAZIR RxTM Near-Infrared Spectrometer

Note: The microPHAZIR RxTM Functional Requirements Specification is located in paragraph 2.3.2 below.




The system Functional Requirements Specifications (FRS) is organized according to the various categories, the justifications, and implementation.

PHAZIR RxTM Functional Requirement Specifications No. Requirement Justification Implementation 1.0 Operational Performance - Basic Design 1.1 Size The design and form factor of the

PHAZIR Rx system should allow operators to comfortably use the system with one hand.

Complies: The PHAZIR Rx was engineered with ergonomics and operator comfort in mind. The system’s size, weight, and balance permit comfortable operation with one hand.

1.2 Weight Since this is intended to be used by operators who will hold the unit with one hand, the system must fit comfortably in the hand and must not exceed 4.5 lbs

Complies: The PHAZIR Rx weighs less than 4.5 lbs in a typical configuration.

1.3.1 Robustness The system will be used for portable applications. It must be robust, reliable, and capable of being relocated and operated without the need for any optical and mechanical alignment or adjustment.

Complies: The PHAZIR Rx can be operated in a completely portable manner without optical realignment.

1.3.2 Robustness-Orientation

The system must be able to operate in any orientation. This is important as the system may be operated in a horizontal or vertical orientation.

Complies: The PHAZIR can be operated in any orientation without affecting the system performance.

1.3.3 Robustness-environment

The system must be able to tolerate vibration, temperature, and shock conditions that could be expected in routine portable operation.

Complies: The system is rated from operation from 40 to 115 degrees F which is adequate for typical pharmaceutical manufacturing work environments.




1.4 Permanently aligned optical system

The system light modulator must be permanently aligned and robust so that no optical adjustments (either manual or automatic) are required.

Complies: The PHAZIR Rx incorporates a factory permanently aligned optical module which requires no user adjustment.

1.5 Wear-free scanner The systems light modulator must free of any wearing properties that might determinate the optical performance over time or under extreme operation.

Complies: The PHAZIR MEMS chip is a frictionless modulator with no wearing characteristics or performance degeneration with use.

1.6 Source – Life The system light source must be long lasting and operate for a least one year of typically operation.

Complies: The PHAZIR Rx’s light source and operating conditions permit the standard light source to operate for over 2 years of operation. To prevent unscheduled source replacement Polychromix recommends exchanging the light source annually.

1.7 Source Exchange NIR sources must be user changeable without special user supplied tools.

Complies: The PHAZIR Rx source access panel only requires a standard Phillips screwdriver. The Allen wrench used for removing and reinstalling the source module is build into and is stored in the source housing assembly.

1.8 Source – Cost of Ownership

The system must have a low long term cost of ownership.

Complies: The only standard consumable is the NIR light source. The source costs less that $30 and is user replaceable.

1.9 Power – Battery Capacity

The unit must be able to be operated from a battery for a period of time not less than 4 hours (i.e. 50% of a typical work shift).

Complies: The PHAZIR Rx battery operating life is not less than 8 - 10 hours of continuous use.




1.10 Battery Exchange

The battery must be easily replaced by the user within 30 seconds.

Complies: The PHAZIR Rx battery has a quick change mount which can be user interchanged in seconds.

1.11 Battery-Charging ports

Batteries should have independent charging ports so that one or more batteries can be charged when they are disconnected from the PHAZIR Rx.

Complies: Batteries have a separate charging port which allows them to be charged while the PHAZIR Rx is being operated. Optional batteries and chargers are available.

1.12 Main Power In the event that the battery is discharged the system shall be able to operate from main power 110 – 220 VAC.

Complies: The PHAZIR Rx system can operate from main power in the event that a charged battery is not available. Note: A battery must be connected to the PHAZIR Rx for AC power operation.

1.13 Reference & wavelength standard mount

The system must incorporate a suitable reference material for diffuse reflectance background measurements and wavelength verification. The device should attach to the PHAZIR Rx so that is may be accessed without the need for tools to install, use, or remove.

Complies: The PHAZIR Rx incorporates a Reference Cap which contains a background reference material and a polystyrene wavelength verification standard. The Reference Cap attaches under the sampling head with a magnetic attachment mechanism and can be installed and removed without tools.

1.14 Lanyard The system must incorporate a safety lanyard to prevent accidental dropping the system.

Complies: A safety wrist lanyard is attached to the rear mount of the PHAZIR Rx.

1.15 Measurement trigger

The system must incorporate a trigger to start a measurement/evaluation sequence.

Complies: A start measurement trigger is located conveniently under the PHAZIR Rx which permits comfortable one hand operation.




1.16 LED measurement indicators

The system shall incorporate a LED to indicate when a measurement scan is in progress and when the system is ready to use. The color code shall have the following meaning: RED=Measurement in progress GREEN=Ready for Use

Complies: A measurement status LED is located on the rear of the PHAZIR Rx. This indicates if a scan is in progress and if the system is ready for use.

1.17 Color LCD Display The system shall incorporate a color LCD to present the user operating instructions and to present measurements results which could include spectral plots or text results.

Complies: All results and operating instruction required for using the PHAZIR Rx system are presented on the color LCD screen.

1.18 USB Port The system shall provide a standard USB connection in order to upload methods, apply administrative settings, and to retrieve data from the on-board database.

Complies: A standard mini-USB port is available to provide secure communications with a PC.

2.0 Functional Requirements 2.0 Solids Analysis The system must be capable of

performing diffuse reflectance analysis of solids with an adequate analysis area.

Complies: The standard PHAZIR Rx system is configured with a 3 mm diffuse reflectance sampling probehead suitable for analysis of solids and diffusely scattering liquids, pastes, and semi-solid samples.




2.1 Solids Analysis in Glass Vials

The system shall support diffuse reflectance measurements solids through the bottom and sides of inexpensive glass vials. An adapter must be available to enable measurements through the side walls of vials and manually rotating vials, while maintaining proper orientation of alignment of the vial. The adapter must be easily user installable and demounted without the need for tools or alignment.

Complies: An optional vial adapter is available which permits diffuse reflectance measurements through the side of 19 mm diameter glass vials. The adapter attached to the PHAZIR Rx sampling head with a pin located magnetic mount which requires no tools. Note: the reference mount must be removed to accommodate sampling adapters.

2.2 Analysis of solids in plastics liners

The system must provide the ability to measure powdered raw materials, typical of pharmaceutical raw materials, directly through polyethylene bag liners with typical 2 – 6 mil thicknesses. This enables rapid non-invasive measurements without the need to open liners and exposing the material to potential contamination and exposing the operators to the material.

Complies: The PHAZIR Rx is able to perform direct measurements through typical bag liners. Reference spectra of typical pharmaceutical materials have been taken through bag liners and methods with up to 250 materials have been validated thus ensuring the viability of this convenient sampling method.

2.3 Liquids Analysis The system must permit the ability to measure liquids in transmission using inexpensive, disposable, sampling vials and/or rectangular quartz cuvettes. Disposable vials should have an inner diameter ID path length of approximately 5 – 6 mm. Short path length cuvettes should be available with path lengths of 1 – 2 mm.

Complies: The PHAZIR Rx supports a disposable liquid vial transmission adapter which accommodates 5 mm disposable (5 ml) glass vials which are measured in a single pass transmission measurement configuration. The PHAZIR Rx also support a short path length quartz cuvette adapter.




2.4 Qualitative Analysis

The system shall incorporate on-board qualitative analysis using Principal Component Analysis (PCA) or Spectral Matching with correlation methods. The system must provide the ability to display the predicted qualitative quantitative results and the spectrum. It must be possible to acquire NIR spectral data, predict qualitative analysis results, and to store the results in an on board database without the need for the system to be connected to a PC.

Complies: The PHAZIR Rx supports PCA and Spectral Matching qualitative methods. The operator is able to toggle from predicted results, to the spectrum, and to analysis statistics. The PHAZIR Rx system incorporates on-board Chemometrics and data pre-treatment. Once an application is developed and uploaded to the PHAZIR Rx a PC is no longer required.

2.5 Quantitative Analysis

The system shall provide the ability to perform quantitative Analysis using partial least squares (PLS) The system shall have the ability to perform PLS quantitative predictions without the need for an external PC. The system must provide the ability to display the predicted quantitative results and the spectrum. It must be possible to acquire NIR spectral data, predict quantitative analysis results, and to store the results in an on board database without the need for the system to be connected to a PC.

Complies: The PHAZIR Rx supports PLS quantitative methods. The operator is able to toggle from predicted results, to the spectrum, and to analysis statistics. The PHAZIR Rx system incorporates on-board Chemometrics and data pre-treatment. Once an application is developed and uploaded to the PHAZIR Rx a PC is no longer required.




2.6 Data Pretreatment In order to perform near-infrared analysis with the on-board computer, common data pretreatment methods must be available on the system. Data pretreatment reduces or eliminates unwanted spectral variations. Available pre-treatment methods must include S. Golay Smoothing, derivative calculation, vector normalization, MSC and SNV.

Complies: The PHAZIR Rx and Polychromix Method Development Software support a comprehensive range of data pre-treatment methods including all of these required functions.

2.7 Power - Indicator The Operator most have a visual indication of the battery power level and a function of battery capacity.

Complies: The PHAZIR Rx’s LCD display normally presents a power indicator in order to estimate available battery charge.

2.8

Power – Power Savings

The system must have operating mode to save power during periods of inactivity.

Complies: The main power consumer is the light source. The PHAZIR Rx has a standby mode whereby the source can be turned off if the unit has not been operated within a specified period of time. The parameter unit is minutes. The default setting is 10 minutes.

2.9 Power – Low Power Warning and Automatic Shutdown

The system must indicate to the operator when the battery power levels are approaching the lower operating limit. The unit must automatically shut down safely when the battery power is too low.

Complies: The PHAZIR Rx prompts the user when 10% of the capacity is approached. At 5% the unit powers down automatically.




2.10 Power – Hard Off The system must be able to operate successfully after a hard off condition, such as when the battery is removed during operation.

Complies: The PHAZIR Rx has been tested for hard off condition. While a controlled shutdown is always preferred, the embedded LINUX computer architecture is engineered to recover from hard off conditions.

2.11 Power – Main Power Voltage

The system must be able to operate from main power (110/220 V)

Complies: The PHAZIR Rx has a charging port on the battery which can be used to both charge the battery and to operate the system from main power.

2.12 Environmental Light / Stray Light

Since the system must be used in a portable manner it must not be negatively affected by environmental light conditions (i.e. dark conditions, bright conditions, exposure to room lighting etc.) Since room light conditions can vary dramatically in typical work environments it must not be necessary for the users to make a determination when/if stray light or dark current measurement are to be made.

Complies: The PHAZIR Rx system automatically measures and adjusts stray light and dark current automatically and continually.

2.13 On-board Database

The system shall store all parameters associated with a measurements and result in an on board database. These parameters must include the following:

- User - Time/Date - Predicted results - Spectrum - Group ID information - Sample ID Information - OQ/PQ Test Results

Complies: The PHAZIR Rx contains an on-board database. All available parameters are stored in this database which can subsequently be transferred to the Data Management Software database which resides on a Microsoft Windows PC.




2.14 On-board Memory and Method and Data Capacity

a. The system shall provide adequate on-board memory to store at least 99 methods and a complete set of 5,000 measurement results. b. The system must provide a function to be able to synchronize the data in the PHAZIR Rx with a PC based software with database functions for long term data archiving.

Complies: a. The available memory in the PHAZIR Rx system capacity for at least 99 methods and 10,000 measurement results. b. The PHAZIR Data Management software provides capability to synchronize PHAZIR Rx data with a PC database system for long term data archiving.

3. System Performance Requirements 3.1 Detector The system must use a single,

high sensitivity, high linearity detector suitable for quantitative and qualitative analysis.

Complies: The PHAZIR Rx incorporates high performance InGaAs photodiode detectors. The extended range configuration (1600 – 2400 nm) incorporates a thermoelectrically, peltier cooled InGaAs NIR photodiode detector.

3.3 Spectral range The systems should have the ability to analyze any spectral region in the near infrared region and must be available to measure in the 2000 – 2400 near infrared combination band region.

Complies: The PHAZIR Rx system is available in a standard configuration (1600 – 2400 nm). The PHAZIR Rx is able to perform analytical measurements in the desirable so-called combination region between 2000 – 2400 where spectral differences between materials is greatest. Note: Custom configuration may not be compatible with the wavelength range of NIST-traceable standards or Polychromix pre-built applications.




3.4 Spectroscopic Performance

The system shall have performance characteristics for photometric linearity, noise low flux, noise high flux, that meet the acceptance criteria for USP 1119 NIR Qualification Protocol.

Complies. The PHAZIR Rx system meets and exceeds all performance acceptance criteria for USP 1119. All PHAZIR Rx systems are factory tested according to USP 1119 protocols and acceptance criteria and a certificate of conformity is provided with each system.

3.5 USP 1119 NIR Qualification

The system must comply with the requirements of USP 1119 NIR (see instrument performance)

Complies: Each unit is factory tested to the USP 1119 standards

3.6 USP 1119 Photometric Linearity

The system shall have a photometric linearity as demonstrated with a diffuse reflectance standard set (99%, 40%, 10% and 2%) with a USP acceptance criteria: Slope 1.0 +/- 0.05 Intercept 0.0 +/- 0.05 The photometric linearity shall be performed at one wavelength, generally 2000 nm.


3.7 USP 1119 Photometric Noise – High Flux

The system shall achieve noise levels of diffuse reflectance measurement of a 99% photometric reference standard with a 0.3 x 10-3 average RMS values, no RMS noise values greater than 0.8 x 10-3 at three discrete wavelength ranges.

Complies: Each unit is factory tested to the USP 1119 standards.




3.8 USP 1119 Photometric Noise -Low Flux

The system shall achieve noise levels of diffuse reflectance measurement of a 10% photometric reference standard with a 1.0 x 10-3 average RMS values, no RMS noise values greater than 2 x 10-3 at three discrete wavelength ranges.


3.9 USP 1119 Wavelength Accuracy

The system shall achieve wavelength accuracy better than the USP 1119 acceptance criteria of : +/- 1.5 nm

Complies: The System is factory tested to the USP 1119 standards

4.0

Regulatory Requirements

4.0 21 CFR Part 11 Compliance

The system must comply with the 21 CFR Part 11 electronic records and electronic document control standards.

Complies: See the Polychromix 21 CFR Part 11 Compliance Statement for a complete description.

4.1 IQ/OQ/PQ manual The system must incorporate a comprehensive IQ/OQ/PQ documentation set. The documentation should be well organized and explained with concise instructions so either the customer and/or Polychromix trained personnel can execute the test plan. The IQ/OQ/PQ test plan should include report logs to document the results of each test. The IQ/OQ test plan should also contain Design Qualification specifications.

Complies: A comprehensive IQ/OQ/PQ qualification manual is available for the PHAZIR Rx system.




4.2 IQ/OQ/PQ validation services

Program to provide training and certification to Polychromix employees and representatives to assist GMP manufacturers in the execution of IQ/OQ/PQ test plans.

Complies: Polychromix offers optional support validation services with factory training and certified representatives.

4.3 OQ/PQ Administration

The system shall provide a software tool to assist the system administrator in the configuration of the OQ/PQ functions. These tools should allow the administrator to specify the OQ/PQ expiration period and a warning period indicating that a OQ/PQ expiration period is close to expiration.

Complies: The PHAZIR Setup Utility provides these functions.




4.4 OQ/PQ Indicator The system must provide a graphical, color-coded, indicator to show whether the PHAZIR has passed all OQ/PQ tests within the expiration period specified by the system administrator. The indicator shall provide an icon with the following color code meanings: Green=All PHAZIR OQ/PQ tests have passed within the expiration interval and the system is ready for use. Yellow= All PHAZIR OQ/PQ tests have passed within the expiration interval but the expiration period is close to expiration (an administrator variable). The system is ready for use. Red= PHAZIR OQ/PQ tests have expired. OQ or PQ test procedures must be successfully completed prior to use. White w/ red “X”= PHAZIR OQ/PQ tests have failed. OQ or PQ test procedures must be successfully completed prior to use.

Complies: The System has a color coded graphical indicator to show the status of the OQ/PQ tests.

4.5 OQ/PQ Wizard The system shall include an on-board utility to guide the user through qualification operation for OQ & PQ including prompting the user to introduce specific reference standard, acquire spectral data, evaluate this measurement data vs. USP and Polychromix acceptance criteria and generate tabulated results.

Complies: The system contains a USP 1119 wizard which step the operator through USP 1119 based OQ instrument verification procedures and the Polychromix PQ test.




4.6 Dockable PQ verification standards

The system validation utilities will support the traceable reference materials specified in USP 1119. In addition the system must provide a dockable set of reference materials suitable for day-to-day PQ testing. These standards shall permit verification of wavelength accuracy and photometric linearity.

Complies: The PHAZIR Rx’s reference mount content all the reference materials necessary for PQ testing. The reference magnetically docks underneath the PHAZIR Rx sample head.

4.7 Certificate of Conformity

The system must be certified by the manufacture insuring that each unit is individually tested and meets minimum acceptance criteria.

Complies: Each PHAZIR Rx is factory tested according USP 1119 protocols. Each instrument has a certificate of conformity.

4.8 Traceable Reference Standards

The system shall support traceable reference standards when appropriate and available.

Complies: The system utilizes traceable reference standards required by USP 1119 including a traceable NIR reflectance wavelength standard (SRM 1920a or equivalent) and traceable NIR reflectance photometric standards.

4.9 PQ Standards and process

The system shall include the necessary non-traceable standard to verify the system performance on a day-to-day basis. The system shall provide the means to test the system signal-to-noise, photometric linearity, and wavelength.

Complies, The system includes non-traceable standards and function to provide this day-to-day testing in the system PQ function.

5.0

Environmental, Safety & Statutory Requirements

5.1 CE Rating The system shall be CE rated

and marked.

Complies: The System is CE rated




5.2 Source - Eye Safety / Laser Safety

The light source must be of low power to prevent potential eye injury due to exposure.

Complies: The PHAZIR Rx light source is a low power tungsten bulb which has a power output below any safety concerns.

5.3 Explosion Proof Rating

The system shall be rated for general use.

The PHAZIR Rx is rated for general purpose use. Note: PHAZIR Rx should not be used in work areas that require special explosion proof ratings.

6.0

Informational Management Requirements

6.1 Communications The system must provide a

standard interface to a PC in order to permit the transfer of spectral data from the system to a PC and for generated methods to be transferred from the PC to the system.

Complies: The PHAZIR Rx incorporates a standard USB connection to PCs.




6.2 PHAZIR Setup Utility

The system shall provide a software utility to configure user accounts. The function should include defining the following: a. user logins b. user passwords c. user access permission level to PHAZIR Setup Utility and PHAZIR Data management System d. 4 levels of electronic signature e. Group IDs and sample IDs f. OQ/PQ expiration periods g. Manage Traceable standard certified values h. Managing System Applications i. Enable user scan marks j. Optional between GMT and local time k. Option to force the use of encrypted PHAZIR Data Files to secure transfer of data between PHAZIR analyzer and PC software l. Setting to require login to access PHAZIR analyzer and PC software packages. m. Setting to automatically logout the user from the System if the System has been left idle for more than a number of minutes specified in the standby setting of System Applications. n. Setting to require character by character login entry rather than selecting from a menu list o. Setting to automatically log users off of PHAZIR Setup Utility and PHAZIR Data Management software when PC is left idle for more than a specified number of minutes.

Complies: The PHAZIR Rx Setup Utility software package provides all required functions. When the PHAZIR Rx is configured, or synchronized, with the PHAZIR Rx Setup utilities, all related settings and parameters are transferred to the PHAZIR Rx analyzer.




6.2 Cont.

p. Option to enable/disable user from accessing the System q. Permission setting to disable System USB port r. Permission setting to disable the user’s ability to change System Applications s. Permission setting to disable the user’s ability to access the PQ function t. Permission setting to disable the user’s ability to access the OQ function u. Function to edit Group IDs and Sample IDs on the System

6.2.1 Minimum of 99 users

The System shall be designed for multi-user facility and shall accommodate at least 99 users.

The System is designed and tested to accommodate at least 99 users.

6.3 Data Management The System will provide a data management software utility with the following functions: a. Import and export System database tables b. Display System database information c. Display spectral graph to visualize data d. Permit user selection of database information e. Manage synchronization of System databases with PC based database f. Manage electronic signatures g. Generation of printed reports

Complies: The PHAZIR Software contains all of the functions in the PHAZIR Data Management Software.




6.4 Method Development

The system must support a software development tool to enable the development of NIR qualitative and quantitative methods.

Complies: The Polychromix Method Generation Software provides a convenient tool to import spectral data from the System, develop methods, and store the methods on the System.

6.4.1 Method Development – Data Import

The method development software must be able to import calibration spectra to generate System Applications.

Complies: The Polychromix Method Generator can import non-encrypted System data files or encrypted System data files using the import/export function in PHAZIR Data Management System software.

6.4.2 Method Development – Model Visualization

The method development software must be able to generate models.

Complies: Polychromix Method Generator can produce model visualization of spectral matching with cross correlation plots and multi-dimension principal component models with acceptance thresholds.

6.4.3 Method Development – Non-Editable Methods

The system must be able to generate methods which cannot be changed or modified by unauthorized users.

Complies: PHAZIR Method Generator has functions to generate encrypted, uneditable methods.

6.5 Identification mode

The system shall provide the ability to generate qualitative libraries which can be searched in identification mode. The unknown spectrum is compared against a library and the best match above a threshold value is considered the resulting match. The result is considered “Not Identified” in the case that the top match’s value does not exceed the minimum threshold value.

Complies: PHAZIR Rx can be used in qualitative identification mode.




6.6 Conformity mode (pass/fail)

The system shall provide the ability to generate a qualitative library which can be searched in conformity mode which means the materials GroupID (or class) is pre-selected, the unknown spectrum is searched against only the library members of selected GROUPID (or class). The results is PASS if the top match’s value exceeds the minimum threshold value, or FAIL if the top match does not exceed the minimum threshold value.

Complies: PHAZIR Rx can be used in qualitative conformity mode.

• See Traceability Matrix is Section 7 for an itemized listing of 21 CFR Part 11

specifications.

2.3.2 Product Functional Requirements Specifications for microPHAZIR RxTM Near-Infrared Spectrometer.

The system Functional Requirements Specifications (FRS) is organized according to the various categories, the justifications, and implementation.

microPHAZIR RxTM Functional Requirement SpecificationsNo. Requirement Justification Implementation 1.0 Operational Performance - Basic Design 1.1 Size The design and form factor of the

microPHAZIR RxTM system should allow operators to comfortably use the system with one hand.

Complies: The microPHAZIR RxTM was engineered with ergonomics and operator comfort in mind. The system’s size, weight, and balance permit comfortable operation with one hand.




1.2 Weight Since this is intended to be used by operators who will hold the unit with one hand, the system must fit comfortably in the hand and must not exceed 3.0 lbs

Complies: The microPHAZIR RxTM weighs less than 2.75 lbs in a typical configuration.

1.3.1 Robustness The system will be used for portable applications. It must be robust, reliable, and capable of being relocated and operated without the need for any optical and mechanical alignment or adjustment.

Complies: The microPHAZIR RxTM can be operated in a completely portable manner without optical realignment.

1.3.2 Robustness-Orientation

The system must be able to operate in any orientation. This is important as the system may be operated in a horizontal or vertical orientation.

Complies: The microPHAZIR RxTM can be operated in any orientation without affecting the system performance.

1.3.3 Robustness-environment

The system must be able to tolerate vibration, temperature, and shock conditions that could be expected in routine portable operation.

Complies: The system is rated from operation from 5 to 125 degrees F which is adequate for typical pharmaceutical manufacturing work environments.

1.4 Permanently aligned optical system

The system light modulator must be permanently aligned and robust so that no optical adjustments (either manual or automatic) are required.

Complies: The microPHAZIR RxTM incorporates a factory permanently aligned optical module which requires no user adjustment.

1.5 Wear-free scanner The systems light modulator must free of any wearing properties that might determinate the optical performance over time or under extreme operation.

Complies: The microPHAZIR RxTM MEMS chip is a frictionless modulator with no wearing characteristics or performance degeneration with use.




1.6 Source – Life The system light source must be long lasting and operate for a least one year of typically operation.

Complies: The microPHAZIR RxTM light source and operating conditions permit the standard light source to operate for over 2 years of operation. To prevent unscheduled source replacement Polychromix recommends exchanging the light source annually.

1.7 Source Exchange NIR sources must be user changeable without special user supplied tools.

Complies: The microPHAZIR RxTM source access panel only requires a standard Phillips screwdriver. The Allen wrench used for removing and reinstalling the source module is build into and is stored in the source housing assembly.

1.8 Source – Cost of Ownership

The system must have a low long term cost of ownership.

Complies: The only standard consumable is the NIR light source. The source costs less than $30 and is user replaceable.

1.9 Power – Battery Capacity

The unit must be able to be operated from a battery for a period of time not less than 4 hours (i.e. 50% of a typical work shift).

Complies: The microPHAZIR battery operating life is not less than 5 hours of continuous use.

1.10 Battery Exchange

The battery must be easily replaced by the user within 30 seconds.

Complies: The microPHAZIR battery has a quick change mount which can be user interchanged in seconds.

1.11 Battery-Charging ports

Batteries should have independently charged so that one or more batteries can be charged when they are disconnected from the System.

Complies: Batteries have a separate charging port which allows them to be charged separately while the microPHAZIR RxTM is being operated. Optional batteries and chargers are available.




1.12 Main Power The system battery charger shall be powered from standard main power voltage and current.

Complies: The microPHAZIR RxTM system can operate from main power.

1.13 Reference & wavelength standard mount

The system must incorporate a suitable reference material for diffuse reflectance background measurements and wavelength verification. The device should attach to the System so that is may be accessed without the need for tools to install, use, or remove.

Complies: The microPHAZIR RxTM incorporates a Reference Cap which contains a background reference material and a polystyrene wavelength verification standard. These internal standards are completely automated so the user doesn’t need to manually introduce them.

1.14 Lanyard The system must incorporate a safety lanyard to prevent accidental dropping the system.

Complies: A safety wrist lanyard is attached to the rear mount of the microPHAZIR RxTM.

1.15 Measurement trigger

The system must incorporate a trigger to start a measurement/evaluation sequence.

Complies: A start measurement trigger is located conveniently under the microPHAZIR RxTM which permits comfortable one hand operation.

1.16 LED measurement indicators

The system shall incorporate an indicator when a measurement scan is in progress and when the system is ready to use.

Complies: The microPHAZIR RxTM has a rear LCD display.

1.17 Color LCD Display The system shall incorporate a color LCD to present the user operating instructions and to present measurements results which could include spectral plots or text results.

Complies: All results and operating instruction required for using the microPHAZIR RxTM system are presented on the color LCD screen.

1.18 USB Port The system shall provide a standard USB connection in order to upload methods, apply administrative settings, and to retrieve data from the on-board database.

Complies: A standard mini-USB port is available to provide secure communications with a PC.




2.0 Functional Requirements 2.0 Solids Analysis The system must be capable of

performing diffuse reflectance analysis of solids with an adequate analysis area.

Complies: The standard which system is configured with a 3 mm diffuse reflectance sampling probehead suitable for analysis of solids and diffusely scattering liquids, pastes, and semi-solid samples.

2.1 Solids Analysis in Glass Vials

The system shall support diffuse reflectance measurements solids through the bottom and sides of inexpensive glass vials.

Complies: The microPHAZIR RxTM has a durable isolation window located on the sampling head. Vials can be placed directly on the sampling head to be measured either through the bottom or side of sample vials.

2.2 Analysis of solids in plastics liners

The system must provide the ability to measure powdered raw materials, typical of pharmaceutical raw materials, directly through polyethylene bag liners with typical 2 – 6 mil thicknesses. This enables rapid non-invasive measurements without the need to open liners and exposing the material to potential contamination and exposing the operators to the material.

Complies: The microPHAZIR RxTM is able to perform direct measurements through typical bag liners. Reference spectra of typical pharmaceutical materials have been taken through bag liners and methods with up to 250 materials have been validated thus ensuring the viability of this convenient sampling method.

2.3 Liquids Analysis The system must permit the ability to measure liquids in transmission using inexpensive sampling cells Short path length cuvettes should be available with path lengths of 1 – 2 mm.

Complies: The microPHAZIR RxTM offers an adapter for inexpensive cuvettes with are available in 1,2, and 5 mm path lengths.




2.4 Qualitative Analysis

The system shall incorporate on-board qualitative analysis using Principal Component Analysis (PCA) or Spectral Matching with correlation methods. The system must provide the ability to display the predicted qualitative quantitative results and the spectrum. It must be possible to acquire NIR spectral data, predict qualitative analysis results, and to store the results in an on board database without the need for the system to be connected to a PC.

Complies: The microPHAZIR RxTM supports PCA and Spectral Matching qualitative methods. The operator is able to toggle from predicted results, to the spectrum, and to analysis statistics. The microPHAZIR RxTM system incorporates on-board Chemometrics and data pre-treatment. Once an application is developed and uploaded to the microPHAZIR RxTM, a PC is no longer required.

2.5 Quantitative Analysis

The system shall provide the ability to perform quantitative Analysis using partial least squares (PLS) The system shall have the ability to perform PLS quantitative predictions without the need for an external PC. The system must provide the ability to display the predicted quantitative results and the spectrum. It must be possible to acquire NIR spectral data, predict quantitative analysis results, and to store the results in an on board database without the need for the system to be connected to a PC.

Complies: The microPHAZIR RxTM supports PLS quantitative methods. The operator is able to toggle from predicted results, to the spectrum, and to analysis statistics. The microPHAZIR RxTM system incorporates on-board Chemometrics and data pre-treatment. Once an application is developed and uploaded to the microPHAZIR RxTM, a PC is no longer required.




2.6 Data Pretreatment In order to perform near-infrared analysis with the on-board computer, common data pretreatment methods must be available on the system. Data pretreatment reduces or eliminates unwanted spectral variations. Available pre-treatment method must include S. Golay Smoothing, derivative calculation, vector normalization, MSC and SNV.

Complies: The microPHAZIR RxTM and Polychromix Method Development (*1) Software support a comprehensive range of data pre-treatment methods including all of these required functions. *1 formerly called PHAZIR Method Generator software

2.7 Power - Indicator The Operator most have a visual indication of the battery power level and a function of battery capacity.

Complies: The microPHAZIR RxTM LCD display normally presents a power indicator in order to estimate available battery charge.

2.8

Power – Power Savings

The system must have operating mode to save power during periods of inactivity.

Complies: The main power consumer is the light source. The microPHAZIR has a standby mode whereby the source can be turned off if the unit has not been operated within a specified period of time. The parameter unit is minutes. The default setting is 10 minutes.


The system must indicate to the operator when the battery power levels are approaching the lower operating limit. The unit must automatically shut down safely when the battery power is too low.

Complies: The microPHAZIR RxTM prompts the user when 10% of the capacity is approached. At 5% the unit powers down automatically.




2.10 Power – Hard Off The system must be able to operate successfully after a hard off condition, such as when the battery is removed during operation.

Complies: The microPHAZIR RxTM has been tested for hard off condition. While a controlled shutdown is always preferred, the embedded LINUX computer architecture is engineered to recover from hard off conditions.

2.11 Power – Main Power Voltage

The system must be able to operate from main power (110/220 V)

Complies: The microPHAZIR RxTM has a charging port on the battery which can be used to both charge the battery and to operate the system from main power.

2.12 Environmental Light / Stray Light

Since the system must be used in a portable manner it must not be negatively affected by environmental light conditions (i.e. dark conditions, bright conditions, exposure to room lighting etc.) Since room light conditions can vary dramatically in typical work environments it must not be necessary for the users to make a determination when/if stray light or dark current measurement are to be made.

Complies: The microPHAZIR RxTM system automatically measures and adjusts stray light and dark current automatically and continually.

2.13 On-board Database

The system shall store all parameters associated with a measurements and result in an on board database. These parameters must include the following:

- User - Time/Date - Predicted results - Spectrum - Group ID information - Sample ID Information - OQ/PQ Test Results

Complies: The microPHAZIR RxTM contains and on-board database all available parameters are stored in this database which can subsequently be transferred to the Data Management Software database which resided on a Microsoft Windows PC.




2.14 On-board Memory and Method and Data Capacity

a. The system shall provide adequate on-board memory to store at least 99 methods and a complete set of 5,000 measurement results. b. The system must provide a function to be able to synchronize the data in the System with a PC based software with database functions for long term data archiving.

Complies: a. The available memory in the microPHAZIR RxTM system capacity for at least 99 methods and 10,000 measurement results. b. The PHAZIR Data Management software provides capability to synchronize microPHAZIR RxTM data with a PC database system for long term data archiving.

3. System Performance Requirements 3.1 Detector The system must use a single,

high sensitivity, high linearity detector suitable for quantitative and qualitative analysis.

Complies: The microPHAZIR RxTM incorporates high performance InGaAs photodiode detectors. The extended range configuration (1600 – 2400 nm) incorporates a thermoelectrically, peltier cooled InGaAs NIR photodiode detector.

3.3 Spectral range The systems should have the ability to analyze any spectral region in the near infrared region and must be available to measure in the 2000 – 2400 near infrared combination band region.

Complies: The microPHAZIR RxTM system is available in a standard configuration (1600 – 2400 nm). The microPHAZIR RxTM is able to perform analytical measurements in the desirable so-called combination region between 2000 – 2400 where spectral differences between materials is greatest. Note: Custom configuration may not be compatible with the wavelength range of NIST-traceable standards or Polychromix pre-built applications.




3.4 Spectroscopic Performance

The system shall have performance characteristics for photometric linearity, noise low flux, noise high flux, that meet the acceptance criteria for USP 1119 NIR Qualification Protocol.

Complies. The microPHAZIR RxTM system meets and exceeds all performance acceptance criteria for USP 1119. All microPHAZIR RxTM systems are factory tested according to USP 1119 protocols and acceptance criteria and a certificate of conformity is provided with each system.

3.5 USP 1119 NIR Qualification

The system must comply with the requirements of USP 1119 NIR (see instrument performance)


3.6 USP 1119 Photometric Linearity

The system shall have a photometric linearity as demonstrated with a diffuse reflectance standard set (99%, 40%, 10% and 2%) with a USP acceptance criteria: Slope 1.0 +/- 0.05 Intercept 0.0 +/- 0.05 The photometric linearity shall be performed at one wavelength, generally 2000 nm.


3.7 USP 1119 Photometric Noise – High Flux

The system shall achieve noise levels of diffuse reflectance measurement of a 99% photometric reference standard with a 0.3 x 10-3 average RMS values, no RMS noise values greater than 0.8 x 10-3 at three discrete wavelength ranges.

Complies: Each unit is factory tested according to the USP 1119 standards.




3.8 USP 1119 Photometric Noise -Low Flux

The system shall achieve noise levels of diffuse reflectance measurement of a 10% photometric reference standard with a 1.0 x 10-3 average RMS values, no RMS noise values greater than 2 x 10-3 at three discrete wavelength ranges.


3.9 USP 1119 Wavelength Accuracy

The system shall achieve wavelength accuracy better than the USP 1119 acceptance criteria of : +/- 1.5 nm


4.0


4.0 21 CFR Part 11 Compliance

The system must comply with the 21 CFR Part 11 electronic records and electronic document control standards.

Complies: See the Polychromix 21 CFR Part 11 Compliance Statement for a complete description.

4.1 IQ/OQ/PQ manual The system must incorporate a comprehensive IQ/OQ/PQ documentation set. The documentation should be well organized and explained with concise instructions so either the customer and/or Polychromix trained personnel can execute the test plan. The IQ/OQ/PQ test plan should include report logs to document the results of each test. The IQ/OQ test plan should also contain Design Qualification specifications.

Complies: A comprehensive IQ/OQ/PQ qualification manual is available for the microPHAZIR RxTM




4.2 IQ/OQ/PQ validation services

Program to provide training and certification to Polychromix employees and representatives to assist GMP manufacturers in the execution of IQ/OQ/PQ test plans.

Complies: Polychromix offers optional support validation services with factory training and certified representatives.

4.3 OQ/PQ Administration

The system shall provide a software tool to assist the system administrator in the configuration of the OQ/PQ functions. These tools should allow the administrator to specify the OQ/PQ expiration period and a warning period indicating that a OQ/PQ expiration period is close to expiration.

Complies: The PHAZIR Setup Utility provides these functions.




4.4 OQ/PQ Indicator The system must provide a graphical, color-coded, indicator to show whether the PHAZIR has passed all OQ/PQ tests within the expiration period specified by the system administrator. The indicator shall provide an icon with the following color code meanings: Green=All PHAZIR OQ/PQ tests have passed within the expiration interval and the system is ready for use. Yellow= All PHAZIR OQ/PQ tests have passed within the expiration interval but the expiration period is close to expiration (an administrator variable). The system is ready for use. Red= PHAZIR OQ/PQ tests have expired. OQ or PQ test procedures must be successfully completed prior to use. White w/ red “X”= PHAZIR OQ/PQ tests have failed. OQ or PQ test procedures must be successfully completed prior to use.

Complies: The microPHAZIR RxTM system has a color coded graphical indicator to show the status of the OQ/PQ tests.

4.5 OQ/PQ Wizard The system shall include an on-board utility to guide the user through qualification operation for OQ & PQ including prompting the user to introduce specific reference standard, acquire spectral data, evaluate this measurement data vs. USP and Polychromix acceptance criteria and generate tabulated results.

Complies: The system contains a USP 1119 wizard which step the operator through USP 1119 based OQ instrument verification procedures and the Polychromix PQ test.




4.6 Dockable PQ verification standards

The system validation utilities will support the traceable reference materials specified in USP 1119. In addition the system must provide a dockable set of reference materials suitable for day-do-day PQ testing. These standards shall permit verification of wavelength accuracy and photometric linearity.

Complies: The microPHAZIR RxTM reference mount content all the reference materials necessary for PQ testing. The reference magnetically docks underneath the microPHAZIR RxTM sample head.

4.7 Certificate of Conformity

The system must be certified by the manufacturer insuring that each unit is individually tested and meets minimum acceptance criteria.

Complies: Each microPHAZIR RxTM is factory tested according USP 1119 protocols. Each instrument has a certificate of conformity.

4.8 Traceable Reference Standards

The system shall support traceable reference standards when appropriate and available.

Complies: The system utilizes traceable reference standards required by USP 1119 including a traceable NIR reflectance wavelength standard (SRM 1920a or equivalent) and traceable NIR reflectance photometric standards.

4.9 PQ Standards and process

The system shall include the necessary non-traceable standard to verify the system performance on a day-to-day basis. The system shall provide the means to test the system signal-to-noise, photometric linearity, and wavelength.

Complies, The system includes non-traceable standards and function to provide this day-to-day testing in the system PQ function.

5.0

Environmental, Safety & Statutory Requirements

5.1 CE Rating The system shall be CE rated

and marked.

Complies: microPHAZIR RxTM is CE rated




5.2 Source - Eye Safety / Laser Safety

The light source must be of low power to prevent potential eye injury due to exposure.

Complies: The microPHAZIR RxTM light source is a low power tungsten bulb which has a power output below any safety concerns.

5.3 Explosion Proof Rating

The system shall be rated for general use.

The microPHAZIR is rated for general purpose use. Note: microPHAZIR RxTM should not be used in work areas that require special explosion proof ratings.

6.0

Informational Management Requirements

6.1 Communications The system must provide a

standard interface to a PC in order to permit the transfer of spectral data from the system to a PC and for generated methods to be transferred from the PC to the system.

Complies: The microPHAZIR incorporates a standard USB connection to PCs.




6.2 PHAZIR Setup Utility

The system shall provide a software utility to configure user accounts. The function should include defining the following: a. user logins b. user passwords c. user access permission level to PHAZIR Setup Utility and PHAZIR Data management System d. 4 levels of electronic signature e. Group IDs and sample IDs f. OQ/PQ expiration periods g. Manage Traceable standard certified values h. Managing PHAZIR Applications i. Enable user scan marks j. Optional between GMT and local time k. Option to force the use of encrypted System Data Files to secure transfer of data between the System and PC software l. Setting to require login to access System and PC software packages. m. Setting to automatically logout the user from the System if the System has been left idle for more than a number of minutes specified in the standby setting of System Applications. n. Setting to require character by character login entry rather than selecting from a menu list o. Setting to automatically log users off of PHAZIR Setup Utility and PHAZIR Data Management software when PC is left idle for more than a specified number of minutes.

Complies: The microPHAZIR Setup Utility software package provides all required functions. When the microPHAZIR RxTM is configured, or synchronized, with the PHAZIR Setup utilities, all related settings and parameters are transferred to the microPHAZIR RxTM analyzer.




6.2 Cont.

p. Option to enable/disable user from accessing the PHAZIR analyzer q. Permission setting to disable System USB port r. Permission setting to disable the user’s ability to change System Applications s. Permission setting to disable the user’s ability to access the PQ function t. Permission setting to disable the user’s ability to access the OQ function u. Function to edit Group IDs and Sample IDs on the System

6.2.1 Minimum of 99 users

The system shall be designed for multi-user facility and shall accommodate at least 99 users.

The System is designed and tested to accommodate at least 99 users.

6.3 Data Management The system will provide a data management software utility with the following functions: a. Import and export PHAZIR database tables b. Display PHAZIR database information c. Display spectral graph to visualize data d. Permit user selection of database information e. Manage synchronization of PHAZIR databases with PC based database f. Manage electronic signatures g. Generation of printed reports

Complies: The PHAZIR Tools software contains all of the required functions in the PHAZIR Data Management Software.




6.4 Method Development

The system must support a software development tool to enable the development of NIR qualitative and quantitative methods.

Complies: The Polychromix Method Generation Software provides a convenient tool to import spectral data from microPHAZIR RxTM, develop methods, and store the methods on the microPHAZIR RxTM.

6.4.1 Method Development – Data Import

The method development software must be able to import calibration spectra to generate PHAZIR Applications.

Complies: The Polychromix Method Generator can import non-encrypted microPHAZIR RxTM data files or encrypted PHAZIR data files using the import/export function in PHAZIR Data Management System software.

6.4.2 Method Development – Model Visualization

The method development software must be able to generate model.

Complies: Polychromix Method Generator can produce model visualization of spectral matching with cross correlation plots and multi-dimension principal component models with acceptance thresholds.

6.4.3 Method Development – Non-Editable Methods

The system must be able to generate methods which cannot be changed or modified by unauthorized users.

Complies: Polychromix Method Generator has functions to generate encrypted, uneditable methods.

6.5 Identification mode

The system shall provide the ability to generate qualitative libraries which can be searched in identification mode. The unknown spectrum is compared against a library and the best match above a threshold value is considered the resulting match. The result is considered “Not Identified” in the case that the top match’s value does not exceed the minimum threshold value.

Complies: microPHAZIR RxTM can be used in qualitative identification mode.

Polychromix




6.6 Conformity mode (pass/fail)

The system shall provide the ability to generate a qualitative library which can be searched in conformity mode which means the materials GroupID (or class) is pre-selected, the unknown spectrum is search against only the library members of selected GROUPID (or class) and the results is PASS if the top match’s value exceeds the minimum threshold value, or FAIL if the top match does not exceed the minimum threshold value.

Complies: microPHAZIR RxTM can be used in qualitative conformity mode.

• See Traceability Matrix is Section 7 for an itemized listing of 21 CFR Part 11 specifications.




Chapter 3 Installation Qualification

3.0 Purpose

Installation Qualification involves the checking of the instrumentation, computer system and software against the supplier standards of operating environment, physical connection, safety requirements, and functional parameters prior to the initialization of the system. IQ confirms that the system was installed correctly.

3.1 Overview The System Installation Qualification procedure consists of a series of individual tests. The procedure provides step-by-step guidance through each test. Each test has an acceptance criterion which is to be met in order for a test to be considered “passed”. All tests must be successfully passed in order for the system to be qualified and to be considered ready for use. Tests that fail are reported in the non-conforming product section and must be retested. The “tester” and the “witness” sign and date each report summary log. The review and approval is signed by an authority who verifies that all testing has been performed and is approved. If your industry or company does not require such a signature, complete the field with “N/A”. A chapter is successfully completed only when all tests for the chapter have passed and signed in the IQ Test Log. The following tests will verify that:

• That the system has been delivered undamaged and as ordered • That the software has been delivered as ordered and is of correct issue • That all required documentation has been supplied and is of correct issue • That the selected environment is suitable for the system • That safety and environmental information relating to the operation of the

instrument has been provided • That the initial response of the instrument is as expected





3.2 Installation Qualification Test Procedures PCX-IQ-TEST1 General Inspection

Procedure Inspect the shipping box for any sign of obvious damage. Inspect all items

for any sign of damage due to shipping. Note: Contact Polychromix if there are any signs of damage in shipment or if any items appear to be damaged.

Acceptance Criteria

If there are no signs of obvious damage, then this test is considered PASSED.

PCX-IQ-TEST2 Inventory of shipment

Procedure Open the packing box(s). Unpack each item and compare to the packing

list and/or customer order. Locate the system user manual (this may be located in the IQ/OQ/PQ manual)

Acceptance Criteria

If all the items are present, this test has PASSED




PCX-IQ-TEST3 Review of Safety Guidelines

Procedure Review Chapter Two - Safety of the System user manual. Be familiar with

safe operating conditions and safety specifications.

Acceptance Criteria

When the safety instructions have been read and understood then this test is PASSED.

PCX-IQ-TEST4 Document Model and Serial Number

Procedure Locate the Serial Number

Note {PHAZIR): The serial number is printed on a label located on the base of the system. Remove the battery and look for the label. The Serial number is also available from the firmware which can be accessed from the System menus when the system is powered up. The four digits after the “PZ” are the system model numbers. The last four digits are the system serial number. PZ#### - #### {microPHAZIR} The serial number is printed on a label located inside the battery compartment on the handle of the microPHAZIR.

Acceptance Criteria

When the system serial number had been located and recorded in the Test Record Log, this test is PASSED.

PCX-IQ-TEST5 Electrical Power

Procedure The PHAZIR contains a battery that need to be charged periodically. The system comes with a power adapter which can accommodate main power voltages from 100 – 240 VAC. If required verify the main power voltage is between 100 – 240 VAC. This can be performed with a volt meter or by connecting the System charger




into the outlet and observing the LED indicators. Charger Method -locate the System charger -Plug the charger into main power outlet Voltmeter method -set the volt meter to the appropriate scale VAC (consult the manual for the voltmeter) -measure the voltage on the main power receptacle

Acceptance Criteria

Battery charger method:If the battery charger’s LED turn either green or red, with the battery connected to the charger, then this test is PASSED. Voltmeter Method: If the voltage is between 100 – 240 VAC then this test has PASSED. Record the measured voltage. If this test is not required indicate “N/A”

PCX-IQ-TEST6 Battery - Installing the Battery

Procedure In order to complete the remaining test the System battery will need to be at least partially charged. Charge the battery now. Make sure the System is powered off. Consult the user manual. Install the battery into the handle of the System.

Acceptance Criteria

When the battery is at least partially charged and installed in the System, this test is PASSED.




PCX-IQ-TEST7 Powering Up the SystemProcedure (1) Power up the System.

-{PHAZIR Only} The LED on the rear of the system should turn yellow -Observe the message “loading software” on the LCD display -Observe the message “loading configuration … (2) Log into System {PHAZIR } (3) Observe the message “A new background scan is required. Please setup the reference material and press Continue” {microPHAZIR} Background scans are completed automatically

Acceptance Criteria

When these messages have appeared, then this test is PASSED

PCX-IQ-TEST8 Installation of PHAZIR SETUP UTILITY and PHAZIR DATA MANAGEMENT System

Background The PHAZIR SETUP Utility provides operators with software tools to create and manage user accounts and other System settings. The PHAZIR Data Management system provides the operator with software tools to manage electronics signatures, archive results, and generate reports.

Procedure (1) Locate the PHAZIR Tools software CD (2) Run Start. (see PHAZIR Tools installation window below).

Reference the PHAZIR Data Management System and PHAZIR Setup Utility user manuals which are included in on the installations CD.

(3) Start the PHAZIR Setup Utility (4) Login as ADMIN with no password (this is the initial default login

with administrative password). (5) Select the About button (6) Verify the software release version (7) Exit the PHAZIR Setup Utility and start the PHAZIR Data

Management System software. (8) Login as ADMIN with no password (this is the initial default login

with administrative password).




(10) Select Help|About(11) Verify the software release version (12) Locate the IQ-Appendix A. Compare the release versions for PHAZIR Setup Utility and PHAZIR Data Management System with the release versions in IQ-Appendix A.

Acceptance Criteria

If the installed versions of the PHAZIR Setup Utility and PHAZIR Data Management System match the release versions defined in IQ-Appendix A then this test is PASSED. Record the version number is the IQ Report Log.

PHAZIR Tools installation window

PCX-IQ-TEST9 Installation of System Software (firmware) Procedure (1) Verify the System firmware version by selecting the Config soft

button (2) Select the Version menu item (3) If the System Software version matches the System Software

version listed in IQ-Appendix A, then this test is PASSED. Proceed to the Acceptance Criteria

(4) If the System Software version does not match the System Software version listed in IQ-Appendix A then you will need to install it now.

(5) Locate the PHAZIR Tools software CD (6) Find the /PHAZIR Tools/PHAZIR System Software directory (7) Make sure PHAZIR is powered up ready to connect to the PC.

Verify the PHAZIR display indicates “USB cable attached” (8) Open HHappupg.exe. Follow the instructions (9) Wait for the System to reboot. (10) To confirm that the proper version is installed, Select the Config





soft button and select the Version menu item.

Acceptance Criteria

If the installed System Software matches the version defined in IQ-Appendix-A then this test is PASSED. Record the System firmware version in the IQ Report Log.

PCX-IQ-TEST10 Installation of Polychromix Method Generator Software Background Polychromix Method Generator is an optional software tool to develop

qualitative and quantitative application. While validation of the Polychromix Method Generator software is outside the scope of this qualification process, the installation of the software is supported. Polychromix Method Generation software is an optional package which may or not be purchased and present. If Polychromix Method Generator software was not purchased then mark this test N/A

Procedure (1) If Polychromix Method Generator was not purchased proceed to the Acceptance criteria.

(2) If the Polychromix Method Generator was installed open Polychromix Method Generator and select About Polychromix MG in the Help menu. If the Polychromix Method Generator version matches the Polychromix Method Generator version listed in IQ-Appendix-A, proceed to the Acceptance criteria.

(3) If Polychromix Method Generator needs to be installed or updated locate the Polychromix Method Generator installation disk.

(4) Open Polychromix -MG-Setup and follow the instructions. (5) When Polychromix Method Generator is installed, select About

Polychromix MG in the Help menu

Acceptance Criteria

If the Polychromix Method Generator Software was not purchased record N/A in the IQ Report Log. If the installed Polychromix Method Generator version matches IQ-Appendix-A then this test is PASSED. Record the version number is the IQ Report Log.




PCX-IQ-TEST11 Registration of Polychromix Method Generator Background The Polychromix Method Generator software requires a registration code. Procedure (1) Open the Help menu

(2) Select the Register menu item (3) Email the registration code to Polychromix at

[email protected] or to the direct email address of Polychromix technical support staff.

(4) The authorization code will be emailed back to the operator. (5) The operator should input the authorization code in the subsequent

registration menu field. Note: If the Polychromix Method Generator is not properly registered the operator will be able to use all the software functions except saving methods.

Acceptance Criteria

When the Polychromix Method Generator is successfully registered then this test is PASSED.

PCX-IQ-TEST12 Setting Time & DateProcedure The System time/date stamp is determined by the PC time/date stamp.

Each time the PHAZIR Setup Utility configures the System, the time/date stamp is applied. Therefore is it important that the PC time/date is correct. Verify that the PC time and date is set correctly using the Windows Control Panel Time and Date program.

Acceptance Criteria

This test is PASSED when the PC time and date is set properly.

mailto:[email protected]




PCX-IQ-TEST13 Setting PHAZIR Setup Utilities for OQ & PQ Monitor Procedure (1) Login to PHAZIR Setup Utility with an account with administrator

rights (example ADMIN) (2) Click the Basic Config menu button (3) Set the General and Security options as required according to your

user specifications. The general recommendations are provided in Figure 1 below

(4) Click Save (5) Click on the OQ/PQ Setup menu button (6) Set the OQ/PQ options as required according to your user

specifications. The general recommendations are provided in figure 2 below.

(7) Click Save (8) Plug PHAZIR into USB port and wait for the message “USB Cable

Attached” (9) Click the Config button in the PHAZIR Setup Utility software.

Follow the instruction within the PHAZIR Setup Utility (10)Press Config button again to start configuration process. When completed, observe the following message

“Your device(s) has been configured successfully, please unplug them from the USB and wait for them to restart”.

(11)Unplug the USB cable. Observe PHAZIR display which will indicate “updating”. {PHAZIR Instructions} Then observe the PHAZIR display which will indicate “A new background scan is required….”. This indicates that the configuration process is complete.

Acceptance Criteria

If process is successfully completed, no error messages are reported, and the OQ/PQ Monitor icon (in the upper right corner for the display) is present (the color status isn’t important at this point), then this test is PASSED.

Polychromix




Figure 1 Figure 2

The Polychromix System Installation Qualification is complete. Proceed to the next chapter.




Chapter 4 Performance Qualification

4.0 Purpose

In performance qualification, the system is tested on an ongoing basis with a frequent test interval. Previous operational qualification has shown that the equipment is acceptable for its intended purpose; therefore, a single performance qualification standard can be used to re-verify performance on a continuing basis. The user may have a method-specific reference sample to perform this kind of control, provided that the sample is stable over time and in typical conditions.

4.1 Overview The System Performance Qualification procedure consists of a series of individual tests. The procedure provides step-by-step guidance through each test. The results of the test are documented in Report Test Logs. Tests that fail are reported in the non-conforming product section of the Report Test Log, a corrective action is taken, and the test is repeated. The “tester” and the “witness” sign and date each Report Test Log. When applicable, an “approver” countersigns. If not applicable the field is completed with “N/A” or similar wording. A chapter is successfully completed only when all tests for the chapter have passed. Performance Qualification normally takes place initially after the completion of the Installation Qualification, and Operational Qualification and at regularly defined intervals. Performance Qualifications intervals of daily or each use are recommended for portable instruments.





4.2 Test Procedures

PCX-PQ-TEST1 Execute Performance Qualification Procedure (1) Press the Config soft button

(2) Select the PQ (Qual and Cal) menu item (3) Press Select Item key

{PHAZIR INSTRUCTIONS}

(4) Position the PHAZIR Reference Cap on the PHAZIR sampling head with in the background position as shown in the picture on the PHAZIR display (i.e. narrow end of the reference piece cone pointing to the top of the System with the background material in the measurement area.

(5) Pull trigger (6) Observe the display indicates “scanning (1 of 6 … 2 of 6)” (7) Rotate the reference piece as shown in the picture on the System display

(i.e. wide end of the reference piece pointing to the top of the System with the polystyrene wavelength material in the measurement area.

(8) Pull the trigger (9) Observe the display indicated “scanning 3 of 6” (10) Place the System White Reference on the nose as shown in the

picture on the PHAZIR display (i.e. narrow end of the reference piece cone pointing to the top of the System with the background material in the measurement area.

(11) Pull trigger (12) Observe the display indicates scanning (4 of 6 … 5 of 6) (13) Rotate the reference piece as shown in the picture on the System

display (i.e. wide end of the reference piece pointing to the top of the PHAZIR with the polystyrene wavelength material in the measurement area.

(14) Pull the trigger (15) Observe the display indicates “scanning 6 of 6” (16) Observe the display indicates “calculating”. (17) Observe the display shows the tabulated results. (18) Return the PHAZIR reference cap to the original storage position.

{microPHAZIR INSTRUCTIONS} This The PQ testing process is completely automated on the microPHAZIR.

Acceptance Criteria

The PQ test has PASSED when all tabulated test results are marked “Passed”

Polychromix




PCX-PQ-TEST2 Generation of PQ Test Report

Background This test involves generation of a PQ report using the PHAZIR DATA MANAGEMENT software. When the PQ test are performed on the System the results are stored in the file PQ-TestData-#### (#### = the serial number of the System.

Procedure (1) Open the PHAZIR Data Management software (2) Connect the System to the USB connector (3) Select File/Import data.

{PHAZIR INSTRUCTIONS}

(4) Select /PHAZIR/PQ-TestData* {microPHAZIR INSTRUCTIONS}

(5) Select /microPHAZIR/PQ-TestData*}

(6) Highlight the most recent PQ test result in the data table (7) Select Report Settings from the Edit menu (8) Select the PQ-Report and click OK (9) Select View/Run Report

(10) Select Print and select an available printer. You may also save the report file if desired.

Acceptance Criteria

This test has PASSED when a report is generated

PCX-PQ-TEST3 Verification of OQ/PQ Monitor Background The PHAZIR Setup Utility has a feature to monitor to expiration period and status

of OQ/PQ tests. When properly configured the OQ/PQ Monitor displays a colored icon.

Procedure (1) Observe a green icon in the upper right corner of the PHAZIR display. This indicates that PHAIZR Setup Utility OQ/PQ settings are properly configured and that the OQ & PQ tests have passed within the expiration period.

Acceptance Criteria

The PQ test has PASSED when all of the USP 1119 tabulated test results are marked passed.

The Polychromix System Performance Qualification is complete.




Chapter 5 Operational Qualifications

5.0 Purpose

In Operational Qualification, the instruments performance is verified using a series of external certified standards. The measurements of these standards are used to verify that the system operates within target specifications. The purpose of Operational Qualification is to ensure that an instrument is suitable for its intended purpose. Similar to any spectrophotometric device, NIR instruments need to be qualified for both wavelength and photometric response.

5.1 Overview The System Operational Qualification procedure consists of a series of individual tests. The procedure provides step-by-step guidance through each test. Each test has acceptance criteria which are to be met in order for a test to be considered “passed”. All tests must be successfully passed in order for the system to be qualified and considered ready for use. The results of the test are documented in the OQ Report Test Logs. Tests that fail are reported in the non-conforming product section of the Report Test Log and must be retested. The “tester” and the “witness” sign and date each Report Test Log. The review and approval is signed by an authority who verifies that all testing has been performed and is approved. If your industry or company does not require such a signature, complete the field with “N/A”. A chapter is successfully completed only when all tests for the chapter have passed and signed in the OQ Test Log.

• Operational Qualification normally takes place initially after the completion of the Installation Qualification, at regularly defined intervals, or after service and preventative maintenance that should require the re-execution of the Operational Qualification procedures.

• Operational qualification can be performed by the user or supplier. • Operational qualification should be performed after the installation of a new version

of the system software.





5.2 USP 1119 Test Protocol and Using Traceable Standards

This chapter verifies the performance of the system according to the USP 1119 protocol (USP 1119, chapter 28, Near-Infrared Spectrophotometry). The USP 1119 protocol outlines test procedures and acceptance criteria for qualification of near-infrared spectroscopy systems. The USP 1119 protocol tests the following instrument performance parameters

- Wavelength Accuracy - Photometric Linearity - Noise

The USP 1119 protocol requires the use of specific traceable standards to verify the NIR system’s wavelength and photometric responses. The following standards are required:

- SRM 1920a (or equivalent) NIR wavelength reflectance traceable standard - NIR photometric linearity traceable reflectance standard set with nominal 99%,

40%, 10%, and 2% standards These standards can be supplied by the customer, purchased from Polychromix, or may be made available through a Polychromix traceable standards rental programs. It is essential that these standards be available at the time of the execution of this chapter that the standards be in good condition that the standards certification be within the expiration period.

5.3 Working with and Handling Traceable Standards When working with traceable standards it is important that you handle them with care and avoid contaminating the surface of the standard. Some standard such as the SRM 1920, and some sets of photometric standard, may have glass windows. Glass windowed standard can be cleaned if necessary. Some photometric standards do not have glass isolation windows. It is important that this surface be kept free from contamination. Do not attempt to clean these surfaces. When working with traceable standard it will be necessary to be able to identify the various standards. Standards are available from different vendors and therefore will have different part numbering systems. Generally traceable standards will have a label on the back of the standards will can be used to identify the standard. The expiration date for the




standards may be printed on the label or may be present in other documents which are provided with the standard. For example Avian Technologies’ 10% photometric standard has a part number FGS-10-01.c. The “10” indicates that this is a nominal 10% standard. The Kemeny Associates traceable wavelength standard may have a part number KA-1920x. Each standard will have a response table which will list the nominal and certified value for the standards at various wavelengths. You will need to be able to locate the necessary values from the tables and enter these values in the PHAZIR Setup Utilities OQ/PQ configuration. If you have any questions regarding how to identify standards or the certified values please contact the Polychromix service department for advice. All Polychromix provided standards are incorporated in the calibration system and their calibration periods are controlled. Only standards within their calibration period are supplied. Should their calibration period be exceeded while in use, return them to Polychromix for recertification and do not use them for the OQ test protocols. Polychromix traceable standards are labeled with “T&Mxxxx” numbers. These numbers are reverse traceable to their manufacturer’s identification. Polychromix maintains the originally supplied certifications and measurement values. Copies of these certificates are provided when customers purchase or rent these. The Standard(s) serial or certification numbers and expiration date will be recorded as part of the OQ test protocol. Copies of the Standard(s) certification will be attached to the test report upon completion.




5.4 Test Procedures

PCX-OQ-TEST1 Locating and Preparing Traceable Reference Standards Background The first OQ test involves verification of the performance of the System

against the USP 1119 NIR Qualification protocol. Requirements: The USP 1119 test will require a traceable near-infrared reflectance wavelength standard (SRM 1920a or equivalent) and a set of four traceable near-infrared reflectance photometric standards.

Procedure

(1) Locate and familiarize yourself with the traceable standard and their corresponding certified values. (2) Locate the calibration period end date and verify that the date has not been exceeded.

Acceptance Criteria

This test is passed when the 2 sets of traceable standards and their certified values have been located and the standards have been verified to be within their calibration period.

PCX-OQ-TEST2 Configuration of PHAZIR SETUP UTILILTY OQBackground Each traceable reference standard has unique certified values. The certified

calibration values for the traceable standards you will be using in the Operational Qualification (OQ) must be configured in the PHAZIR Setup Utility Software Program.

Procedure (1) Open the PHAZIR Setup Utility Software (2) Login as ADMIN or as a user with Administrative permissions. (3) Select OQ/PQ Setup (4) Verify that the certified values for the photometric standard (2%, 10%,

40%, and 99%) and wavelength standards are correctly entered. These values are unique to each set of traceable standards.

(5) Enable the OQ/PQ Monitoring (6) Set the OQ & PQ expiration periods to the desired values. Note: Normally these are as follows:

PQ Expiration: 24 hoursPQ Warning: 20 hoursOQ Expiration: 365 days




OQ Warning: 350 days(7) Click SAVE after the values are entered. (8) Connect the PHAZIR to the USB port (9) Click on the Config Phazir button.

Acceptance Criteria

Record the certified values for the 4 traceable photometric standards and the traceable wavelength standard. (Note the number of significant figures to be recorded.) Record the PHAZIR Setup OQ/PQ parameters for PQ and OQ expiration and warning periods. This test is passed when the correct certified values for the reference standards are entered and the System is configured with the OQ/PQ settings.

PCX-OQ-TEST3 Recording Serial Numbers and Expiration Periods for Traceable Standards

Procedure Record the serial numbers and expiration periods for the traceable standards used for OQ.

Acceptance Criteria

This test has PASSED when the serial number and expiration periods for the standards have been recorded.




PCX-OQ-TEST4 Execute Operation Qualification Performance Verification Background Note: In the execution of this test the Operator will be prompted to present

various reference materials to the System. Place the reference materials directly on the front of the System sampling head. Ensure that the reference material is covering the sampling area.

- Pay close attention as to which reference material is being requested. The 10% and 99% standards are request two consecutive times. Try not to move the standard in between these measurements.

- If you make a mistake and present the incorrect standard you may press the Back soft button and move back one operational step.

- Handle the standards with care.

Procedure Select the Config soft button (1) Select Applications Select If the Select Force OQ/PQ on login was not set in the PHAZIR Setup Utility then select Application Select and select OQ from the menu If the Select Force OQ/PQ on Login was setup in the PHAZIR Setup Utility then the System OQ software will start automatically. You will see the following message “OQ Pull Trigger to Initiate OQ”. Pull trigger to start OQ program. Pull the trigger (2) Step 1 of 8: PHAZIR will display the following message “Place the 99%

reference on the nose and pull trigger. Place the 99% standard on the PHAZIR’s nose and pull the trigger. The PHAZIR will scan for about 10 seconds.

(3) Step 2 of 8: System will display the following message “Place the 2% reference on the nose and pull trigger. Place the 2% standard on the System’s nose and pull the trigger. The System will scan for about 10 seconds.

(4) Step 3 of 8: System will display the following message “Place the 10% reference on the nose and pull trigger. Place the 10% standard on the System’s nose and pull the trigger. The Scan will scan for about 10 seconds.

(5) Step 4 of 8: Step 4 involved re-measurement of the 10% standards. This will run automatically after the completion of step 3.






(8) Step 7 of 8: Step 7 involves re-measurement of the 99% standard. This will run automatically after the completion of step 6.

(9) Step 8 of 8: System will display the following message “Place Wavelength reference (SRM 1920) on the nose and pull trigger. Place the Wavelength reference on the System’s nose and pull the trigger. The System will scan for about 10 seconds.

(10) System will now calculate the results and compare the measured results to the USP 1119 acceptance criteria. The PASS / FAIL results are tabulated on the System display.

(11) Review the Pass / Fail results.

Acceptance Criteria

The OQ test has PASSED when all of the USP 1119 tabulated test results are marked passed.

PCX-OQ-TEST5 Generation of OQ Test Report

Background This test involves generation of a OQ report using the PHAZIR DATA MANAGEMENT software. When the OQ tests are performed on the System the results are stored in the file OQ-TestData-#### (#### = the serial number of the System.

Procedure (1) Open the PHAZIR Data Management software and log in as administrator.

(2) Connect the System to the USB connector (3) Select File/Import data. (4) Select /PHAZIR/OQ-TestData* (5) Highlight the most recent OQ test result in the data table (6) Select Report Settings from the Edit menu (7) Select the OQ-Report and click OK (8) Select View/Run Report (9) Select Print and select an available printer. You may also save the report

file if desired.

Acceptance Criteria

This test has PASSED when a report is generated

Polychromix




PCX-OQ-TEST6 File traceable standards information

Procedure Photocopy the all of the available documentation for the traceable standards including certificates and certified values.

Acceptance Criteria

This test has PASSED when the serial number and expiration periods for the standards have been recorded.

The Polychromix System Operational Qualification is complete. Proceed to the next chapter.




Chapter 6 Glossary

6.0 Purpose The following glossary of terms provides definitions and references to terms used within this qualification plan.

6.1 General Terminology and References Accuracy: The accuracy expresses the closeness of agreement between the value, which is accepted either as a conventional true value (in house standard) or an accepted reference value (international standard) and the value found (mean value) obtained by applying the test procedure a number of times. Accuracy provides an indication of the systematic errors. Application Software: Software written to meet specific requirements; applications software can be either customized to the site installation or a commercially available product with site-specific configuration. Acceptance Criteria: defined for validation or qualification protocols as minimum values which must be met in order for the process to be considered validated or the equipment to be qualified. Acceptance Criteria (software): The criteria a software program must meet to successfully complete a test phase or to achieve delivery requirements. Archiving: The act of moving/copying files from the system onto a long term storage medium. Implied by the action is the ability to restore those files to the system in the same state as at the time of moving/copying. ASCII: The American Standard Code for Information Interchange is a computer industry recognized standard method for assigning specific binary codes to represent specific alphanumeric characters. ASTM: American Society for Testing and Materials.





Audit Trail: This shows the history of an electronic record. All functions applied to any kind of data are recorded in the audit trail. Bias: The error between the observed mean of an analytical method and the true value (nominal value). Bias may be positive (yielding high results) or negative (yielding low results). Calibration: The set of operations, which establish, under specific conditions, the relationship between values indicated by a measurement system or process and the corresponding known values. Calibration Set: “Sample set incorporating all chemical and physical variations normally encountered during routine manufacture, used to generate and optimize a regression model. The samples must cover the range required in the method.” (PASG) Calibration Test Set: A sub-division of the calibration set used to internally assess and verify the calibration model. cGMP: Current Good Manufacturing Practice Change Control: A formal process in which changes to equipment, systems, procedures, or processes are proposed by individuals or units planning to implement them. The changes are reviewed by qualified representatives of Quality Assurance and/or other appropriate disciplines to determine whether they will affect the status of the validation or qualification. The reviewers shall determine whether it is required to revalidate the system or take other actions necessary to maintain the validated state to the system. A qualification/validation study is designed for defined parameters and measures specified outcomes. Any modification made to equipment, systems, processes or procedures may change the parameter or affect the expected outcomes. Therefore any change that is made after initial validation is complete must be controlled. “Change control” must be a formal process following a pre-determined procedure set out in a Quality Assurance document (e.g. a QA SOP or in the Master Validation Plan). The change control procedure should include the planning and submission of a proposal for the change with a rationale and anticipated impact of the function, operation or performance. Closed system: An environment in which system access is controlled by persons who are responsible for the content of electronic records that are on the system CITAC: Co-operation on International Traceability in Analytical Chemistry. A forum for worldwide cooperation collaboration on the mechanisms needed to ensure the validity and comparability of analytical data on a global basis.




Code of Federal Regulations: Collection of all regulations issued by the U.S. Government agencies. Computer System: A system composed of computer(s), peripheral equipment such as disks, printers, and terminals, and the software necessary to make them operate together (ANSI/IEEE Standard) Critical Equipment: Equipment, which can directly affect the manufactured product quality attributes, the determination of those attributes, the judgment of those attributes, product identification, or product distribution Critical Process: Defined under GMP as a process that may cause variation in the quality of the pharmaceutical Digital Signatures: are defined as “electronic signature based upon cryptographic method of originator authentication, computed by using a set of rules and a set of parameters such that the identity of the signer and the integrity of the data can be verified.” Design Qualification: Defines the function and operation specifications of the instrument and may describe the conscious decisions in the selection of the supplier. Design Specifications: See Design Qualification Electronic Signatures: are defined as “a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.” Electronic Records: are defined in 21 CFR Part 11 as “any combination of text, graphics, data, audio, pictorial, or other information representation in digital form that is created, modified, maintained, archived, retrieved, or distributed by a computer system. Examples include methods for instrument control and data evaluation, original data as captured by the computer, metadata methods such as quantitative analysis calibrations, integration, and libraries, manipulated data, analysis reports, logbooks and audit trails. Equipment Qualification: EQ is a formal process that provides documented evidence that the system (equipment or instrument) is fit for its intended purpose, that it performs according to specifications agreed to by the user and supplier, and that it is kept in a state of maintenance and calibration consistent with its use. EQ is often, divided into four stages: Design Qualifications (DQ), Installation Qualification (IQ), Operational Qualification (OQ) and Performance Qualification (PQ). End User: A person who has direct use of a system to perform their work function.




EP: European Pharmacopoeia, Official compendium of the member states of the Council of Europe, which includes all EC and EFTA countries. Evidence of Validation: The collection of documentation, test results, observation, expert opinion or other supporting material demonstrating that an independent review has determined conformity to regulatory guidelines and/or a convincing demonstration of a system’s current accuracy and reliability, expected continued accuracy and reliability, audibility, managerial control, and maintenance of data integrity. FDA: US Food and Drug Agency, a part of the Department of Health and Human Services, responsible for regulating clinical research and approval of marketing permits for food, drugs, medical devices and cosmetics in the United States. FDA-483: An indication of an adverse finding by the FDA. A 483 is often used in conjunction with a regulatory letter, which contains a detailed description of the findings and the action proposed. Final Report/Final Validation Report: At the conclusion of the Equipment Qualification (IQ/OQ/PQ) activities a final report should be prepared. This report should summarize and reference all protocols and results. It should derive a conclusion(s) regarding the validation status of the system. The final report should be reviewed and approved by the validation team and/or appropriate management. Functional Requirement Specification: This document describes the detailed functionality of the system (equipment or instrument). It is usually developed by the supplier. This document may be linked to the Operational Qualification (OQ) documents, which test for required functions. Function Specification: The functional specification defines the overall requirement of the instrument (system) including the operational qualification and other critical factors relating to its use. GALP: Good Automated Laboratory Practice GAMP: Good Automated Manufacturing Practice GLP: Good Laboratory Practice. Regulations of the FDA which, define the requirements for nonclinical studies that will be submitted to a regulatory agency. US GLPs are found in 21 CFR Part 58. GMP: Good Manufacturing Practice. Also known as current Good Manufacturing Practices. Regulations of the FDA, which define the requirements for manufacture, processing or holding of a drug to assure that it meets the requirements of the Federal Food, Drug and Cosmetics Act for safety and has the identity and strength to meet the




quality and purity characteristics that it claims. US regulations for GMP are found in 21 CFR Part 11. ICH: International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use. ILAC: International Laboratory Accreditation Cooperation. Working for international acceptance of data generated b accredited organizations. Developed under the ISO Guide 25. ISO: International Organization for Standardization. Agency responsible for developing international standards. Installation Qualification: Procedures to verify that the system (equipment or instrument) was received as purchased and that it is properly installed in the selected environment and that the environment is suitable for the operation and use of the system. Installation Qualification (IQ): (USP 1119 Definition): The IQ requirement help ensure that the hardware and software are installed to accommodate safe and effective use of the instrument at the desired location. IQ: See Installation Qualifications JP: Japanese Pharmacopoeia, Official pharmacopoeia of Japan Life Cycle: The phases a product goes through between when it is conceived and when it is no longer available for use. Life Cycle Document: A document describing each step of the lifecycle of a product. Limit of detection: The lowest amount of analyte in a sample, which can be detected but not quantitated as an exact value. Limits of quantitation: The lowest amount of an analyte that can be measured quantitatively in a sample with acceptable accuracy and precision. LOD: See limit of detection LOQ: See limits of quantitation Master Validation Plan (MVP): This document is a high level document that describes validation for an entire plant or production area. This document communicates the overall company philosophy and approach to validation.




Meta Data: are the processing parameters needed to derive the Result Data from the Raw Data. NIST: National Institute for Standards in the United States. Provides traceable standard reference materials for mid-infrared and near-infrared spectroscopy systems. Open System: Means an environment in which system access is not controlled by persons responsible for the content of electronic records on the system. Operational Qualification (OQ): is the process of demonstrating with evidence that the system (equipment or instrument) will function according to its operational specifications in the selected environment. OQ may involve establishing with evidence that the system (or instrument) meets published performance specification and/or as defined in the design qualification (DQ) phase. Operational Qualification (OQ): (USP 1119 Definition): “In operational qualification, an instrument performance is characterized using standard to verify that the system operates within target specifications. The purpose of the operational qualification is to demonstrate that instrument performance is suitable for the intended application. Because there are so many different approaches for measuring NIR spectra, operational qualification using standards with known spectral properties is recommended. Using external traceable reference standards does not justify omitting the instrument’s internal quality control procedures. As is the case with any spectrophotometric device wavelength uncertainty, photometric linearity, and noise characteristics of NIR instruments should be qualified against target specifications for the intended application.” OQ: See Operational Qualification PASG: Pharmaceutical Analysis Science Group (UK) PAT: Process Analytical Technology, an initiative of the FDA with the aim to understand and control the manufacturing process of drugs and drug related material. “PAT is a system for designing, analyzing, and controlling manufacturing through timely measurements (i.e., during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality“. PHAZIR Setup Utility: Is a part of the PHAZIR Rx Software Suite. The Utility provides a method to setup user accounts, configure OQ/PQ tests, manage PHAZIR applications, and control the uploading of configuration to the PHAZIR. PHAZIR Data Management Software: Is a part of the PHAZIR Rx Software Suite. The PHAZIR Data Management software provide functions to archive data collected on the PHAZIR onto a PC, manage electronic signatures and records, and generate reports.




PHAZIR Reference Cap: The PHAZIR reference cap holds a background material used for acquiring a background (also referred to as background scan) and a Polychromix polystyrene wavelength standard that is used as the primary standard in calibration of the PHAZIR wavelength (x-axis) The PHAZIR reference cap is located on the bottom of the front tip of the PHAZIR. PHAZIR OQ/PQ Monitor: PHAZIR function which manages the OQ/PQ expiration periods. The PHAZIR Monitor displays a color coded icon which allows users to instantly know if the OQ/PQ test has been successfully executed within the defined expiration period. The PHAZIR Monitor is “green” when both tests of been passed within the expiration period, “red” if the tests have failed and/or the expiration period is elapsed, and “yellow” if the tests are close to the defined expiration period. The configuration and setup of the PHAZIR Monitor is controlled by the PHAZIR Setup Utility. PMA: Pharmaceutical Manufacturers Association in the United States. A trade association that represents over 100 firms. Performance Qualification: Confirms that the system (equipment or instrument) consistently continues to perform as required according to specifications appropriate for its routine use. Performance Qualification (PQ): (USP 1119 Definition): Performance Qualification demonstrates that the NIR measurement consistently operates within target specifications defined by the user for a specific application; it is often referred to as the system suitability. Performance qualification for NIR measurements can include comparing a sample or standard spectrum to previously recorded spectra. Comparison of spectra taken over time from identical samples or reference standard materials can form the basis for evaluating the long-term stability of an NIR measurement system. The objective is to demonstrate that no wavelength shift or change in detector sensitivity has occurred during the ongoing analysis. PQ: See Performance Qualification Performance Validation: Synonymous with Performance Qualification Performance Verification: Synonymous with Performance Qualification Precision: The closeness of agreement between values obtained in an assay. It is expressed as the coefficient of variation (%CV). Raw Data: This is the measured data generated by the instrument which is stored e.g. on the hard disk of a PC.




“Raw data” means any laboratory worksheets, records, memoranda, notes, or exact copies thereof, that are the result of original observation and activities of a nonclinical laboratory study and are necessary for the reconstruction and evaluation of the report of that study. In the event that the exact transcripts of raw data have been prepared (e.g., tapes which have been transcribed verbatim, dated, and verified accurate by signature), the exact copy or exact transcript may be substituted for the original source as raw data. “Raw data” may include photographs, microfilm or microfiche copies, computer printouts, magnetic media, including dictated observations, and recorded data from automated instruments. Result Data: are results derived from the raw data by manipulation or evaluation functions. Reference Material: A material or substance one or more properties of which are sufficiently well established to be used for calibrating an apparatus, assessing measurement methods or for assigning values to materials. Ruggedness: An indication of how resistant the process is to typical variations in operations, such as those to be expected when using different analysts, different instruments and different lots. Selectivity: is the ability of an analytical assay to measure the analyte in a sample in the presence of the other components expected to be present in the product. This parameter is measured for identity test, for content or potency test and for purity tests to ensure that the assay provides an accurate statement of the identity, potency or purity of a product. Selectivity is normally expressed as the bias of the % error between the measured and known value. SOP: Standard Operating Procedure. Source code: An original computer program in a legible form (programming language), translated into machine-readable form for execution by the computer. Specificity: See Selectivity Supplier: The system (instrument or equipment) manufacturer, or approved representative agent. SRM: Standard References Material used as calibration standards occasionally used to validate equipment. SRM standards are often supplied by organizations such as the National Institute of Standards (NIST). SRM 1920a: Traceable near-infrared wavelength reflectance standard. This or an equivalent standard is required for USP 1119 test protocol.




Standard Operating Procedure (SOP): Documented instructions that should be followed when operating a process for the process to be considered valid. Required under GLP regulations. Written documents that describe the detailed steps to be followed in order to accomplish a particular task. System: The collection of all instrument hardware, software, firmware, and sampling accessories that provides a specific function or set of functions required for analysis. System Maintenance Log: This is a log designed to keep track of maintenance both to repair the instrument and regularly schedule preventative maintenance. System Reference Specifications (SRS): Equivalent to User Requirement Specifications. System Validation: System validation is the comprehensive process of determining the reliability, accuracy and completeness of a system including hardware and software; and the ability of that system to track, recall, preserve, and manipulate data free of system-induced variance. The validation process includes the examination of standard operating procedures (SOP’s), system testing procedures; vendor-related verification studies, system technical and user documentation; security protocols and the planning and procedures for recovery in the event of a disaster. Traceability: The property of a result of a measurement whereby it can be related to appropriate standards, generally national or international standards or fundamental constants of nature, through an unbroken chain of comparisons. User: The organization purchasing the system (equipment or instrument) including its management and staff. User Requirement Specification: The user requirement specification defines the overall requirements for the instrument, the key performance characteristics of the instrument and ranges over which the instrument is required to operate and consistently perform, and other critical factors relating to its use. URS are normally prepared by the user but may incorporate information provided by the supplier including functional requirement specification (FRS). USP: United States Pharmacopoeia USP 1119: Test protocols published by USP to verify performance of near-infrared spectrometer systems. The protocol verifies the wavelength accuracy, noise, and photometric linearity using traceable standards.




Validation: is the process of evaluating the performance of a specific measuring procedure and checking that the performance meets certain pre-set criteria. Validation establishes and provides documented evidence that the measuring procedure is fit for a particular purpose. “Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce product meeting it’s predetermined specifications and quality attributes”, FDA 1987 Validation Plan: This term is commonly used in GMP/cGMP laboratories defines the document that supports the Validation Master Plan (VMP) for specific pieces of equipment.




6.2 Polychromix Specific Terminology OQ/PQ Monitor: This is a function in the PHAZIR Tools Software which monitors the status of OQ & PQ testing intervals. The function keeps track of the defined expiration period and reports to the user if the PHAZIR has been OQ & PQ qualified within the specified period of time. The function provides a color coded icon on the PHAZIR LCD display which indicates the OQ & PQ status. OQ & PQ Wizard: This is a PHAZIR System Software function which guides the user through OQ & PQ qualification procedures. Operators are prompted to place specified external reference standards in the measurement position, measurements are obtained, and performance characteristics are compared against USP 1119 (in the case of OQ) and Polychromix defined criteria (in the case of PQ). PHAZIR Application: The method file that is created by Polychromix Method Generator (or other program) which provides the measurement parameters, calibration equations or libraries, for quantitative and qualitative analysis. PHAZIR Data Files: This is a file were results from PHAZIR Applications are stored. Records can include spectral information, predicted results, time/date stamp, user ID information, and all other information available. The PHAZIR Data Files may be available in a text editable formation or encrypted binary formats which cannot be user edited. PHAZIR Data Management Software: Member of the Polychromix PHAZIR Tools Software which provides long term data archiving, management of electronic signatures and records, and report generation. Also called PDMS. Polychromix Method Generator Software: This is a Polychromix PC software package which can be used to generate qualitative and quantitative PHAZIR applications. (Formerly called PHAZIR Method Generator Software.) PHAZIR Tools Software: This suite of software was designed to meet current GMP and industry best practice regulatory compliance. The suite consists of the PHAZIR Setup Utility and PHAZIR Data Management Software which operate on a MS Windows PC, and a PHAZIR System Software which operates on the PHAZIR analyzer. (Formerly called PHAZIR Rx Software Suite) PHAZIR Reference Cap: A component which mounts under the PHAZIR measurement head which contains both a spectralon reference standard which is used to obtain background measurements and a polystyrene standard which is used for wavelength verification and calibration.

Polychromix




PHAZIR Setup Utility: Member of the Polychromix PHAZIR Rx software suite which provides User Account management, OQ & PQ parameters, definition of Scan Marks, GroupIDs and Sample Information Fields, and configuration and synchronization of the PHAZIR Setup Utility and PHAZIR analyzer.




Chapter 7 USP 1119

7.0 Purpose

This chapter explains the implementation of the USP 1119 Near Infrared chapter.

7.1 Overview of USP 1119 USP 1119 provides guidance regarding best practices for NIR instrument qualification and calibration procedures. The protocol published in chapter 28 details procedures to verify

wavelength calibration photometric noise, photometric linearity

of Near-infrared systems. The protocol defined the test procedures, reference standard that are to be used, and the recommended acceptance criteria. A summary of the tests and acceptance criteria is listed below.

7.2 USP Specification and Acceptance Criteria

USP 1119 Recommended Near-IR Instrument Specifications Wavelength Uncertainty SRM 1920a reference material referencing bands

located at 1261, 1681, or 1935 nm

Acceptance criteria tolerance +/- 1 nm at 1200 nm (+/- 8 cm-1 at 8300 cm-1)+/- 1 nm at 1600 nm (+/- 8 cm-1 at 6250 cm-1)

+/- 1.5 nm at 2000 nm (+/- 8 cm-1 at 5000 cm-1)Reference Standard SRM 1920a or equivalent

Photometric Linearity AOBS VS AREF at 1200, 1600, 2000 nm

Acceptance criteria tolerance Slope = 1.0 +/- 0.05; Intercept = 0.0 +/- 0.05Reference Standard





Photometric Noise Measured for 100 nm (300 cm-1) segments between

1200 and 2200 nm (8300 and 4500 cm-1

Average RMS for measurements at high light flux

Reference Standard 99% SRM Photometric standard Acceptance criteria tolerance Less than 1 x 10-3; no RMS noise greater than 0.8 x

10-3Average RMS for measurements at low light flux

Reference Standard 10% SRM Photometric standard Acceptance criteria tolerance Less than 1 x 10-3; no RMS noise greater than 2.0 x

10-3




7.3 USP 1119 Wavelength Accuracy Wavelength Accuracy is determined by measuring a certified traceable near-infrared wavelength standard such as SRM 1920a or equivalent and comparing the measured wavelength location of a defined band verse the actual location. A background scan is acquired using either the SRM 99% standard or the PHAZIR background reference. A sample measurement is obtained by positioning the SRM 1920a standard over the PHAZIR measurement head. Experimental Parameters Number of Sample Scans : 20 scans Number of Background Scans : 20 scans Background Reference Material : 99% SRM or PHAZIR background reference Sample Reference Material(s) : 1920a SRM or equivalent Wavelength 1321 nm for PHAZIR models 0917 and 1018 1847.5 nm for PHAZIR models 1624 and PHAZIR Rx The location of the band at either 1321 or 1847.5 is compared to the certified band locations and tolerances within the USP 1119 acceptance criteria.

Plot illustrating the spectrum of the SRM 1920a





7.4 USP 1119 Photometric Linearity Photometric linearity is determined by measuring a set of certified traceable near-infrared reflectance standards. A background (or reference scan is obtained using the 99% reference standards. Sample measurements are obtained in reflectance of the 40%, 10%, and 2% reference standards. The certified values for the traceable reference standards with responses at the various wavelengths can be found in the calibration certificate tables which are provide with the standards. A linear regression is calculated from the measured vs. true values which produces a slope and offset value. The slope and offset values must fall within the USP acceptance criteria in order for the test to be considered passed. To perform this test a background or reference scan is obtained using the 99% SRM standards. Sample measurements are obtained using the 40%, 10%, and 2% standards. Experimental Parameters Number of Sample Scans : 20 scans Number of Background Scans : 20 scans Background Reference Material : 99% SRM standard Sample Reference Material(s) : 40%, 10%, 2% reference standards Wavelength 2000 nm for PHAZIR Rx model 1624 *Note 80%, 20%, and 5% standards are also available.


Plot of 40%, 10%, and 2% photometric linearity standards from 900 - 1700

Plot of 40%, 10%, and 2% photometric linearity standards from 1600 – 2400 nm




7.5 USP 1119 Photometric Noise Photometric noise is determined by measuring the spectroscopic noise, over pre-defined spectral regions, under high flux (99% SRM) and low flux (10% SRM) conditions.

7.6 USP 1119 Photometric Noise High Flux Experimental Parameters Number of Sample Scans : 20 scans Number of Background Scans : 20 scans Background Reference Material : 99% SRM standard Sample Reference Material(s) : 99% SRM Ranges: : PHAZIR Rx model 1624 : 1800 – 1900 nm, 1900 – 2000 nm, 2000 – 2100 nm The RMS noise is determined for each region. The average value of all three regions and the maximum noise in any one region is compared against the USP 1119 acceptance criteria.

Plot illustrating the noise from 1600 – 2400 nm





7.8 USP 1119 Photometric Noise Low Flux Experimental Parameters Number of Sample Scans : 20 scans Number of Background Scans : 20 scans Background Reference Material : 10% SRM standard Sample Reference Material(s) : 10% SRM Ranges: : PHAZIR Rx model : 1800 – 1900 nm, 1900 – 2000 nm, 2000 – 2100 nm PHAZIR 1624 model : 1800 – 1900 nm, 1900 – 2000 nm, 2000 – 2100 nm PHAZIR 0917 model ranges : 1000 – 1100 nm, 1100 – 1200 nm, 1200 – 1300 nm PHAZIR 1018 model ranges : 1200 – 1300 nm, 1300 – 1400 nm, 1400 – 1500 nm The RMS noise is determined for each region. The average value of all three regions and the maximum noise in any one region is compared against the USP 1119 acceptance criteria.

7.9 Working with Traceable Standards When not in use, return standard to its storage container. Improper handling can affect the performance of the standards. Avoid getting fingerprints on the measurement surfaces of standard and keep them in a dry and clean condition. Refer to the manufacturer’s recommendation before attempting to clean the measurement surface of reference standards. Reference standards may have expiration dates. Make sure that the standards you use to qualify your system are within the expiration period. The following tables are actual certificates of analysis for traceable wavelength and photometric standards. NOTE: These certificates of analysis for the traceable photometric and wavelength standards are only examples. Always use the values from certificate of analysis that corresponds to your specific traceable standard(s).




7.10 Examples of Traceable Standards

Typical Calibration Certificate





Typical Photometric traceable standard set table of certified response values





Typical Calibration Certificate





Typical Wavelength traceable standard set table of certified response values


Polychromix




7.10 Suppliers of Near-infrared Traceable Standards Avian Technologies PO Box 822 Wilmington, OH 45177 937-655-8767 [email protected] Kemeny Associates LLC 6748 Phil Lewis Way Middleton WI 53562 608-577-3637




IQ-Appendix-A

1.0 Purpose

The purpose of this addendum is to define the precise versions of software packages which are required for this release and this qualification test plan.

2.0 Overview The PHAZIR Rx system requires three interconnected software packages including:

• PHAZIR Setup Utility • PHAZIR Data Management Software • PHAZIR System Software

And one optional software package • Polychromix Method Generator Software

3.0 Required Software Packages PHAZIR Setup Utility Software Version 3.10.01PHAZIR Data Management Software Version 3.10.01PHAZIR System Software Version 3.101

3.1 Optional Software Packages Polychromix Method Generator Version 3.101

Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx V3.1 IQ/OQ/PQ Manual IQ – Appendix - A of 143




Section 2 – Test Logs

Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx V3.1 IQ/OQ/PQ Manual Test Logs of 143



Polychromix, 30 Upton Drive, Wilmington, MA 01887 - - - PROPIETARY INFORMATION - - - FSCM: None Doc. #: PCX13Rx91-0002 Rev D Title: PHAZIR Rx V3.1 IQ/OQ/PQ Manual Test Logs of 143

Installation Qualification – IQ Test Log IQ - Step TEST PASSED FAILED N/A PCX-IQ-1 General Inspection PCX-IQ-2 Inventory of Shipment PCX-IQ-3 Review of Safety Guidelines PCX-IQ-4 Document Model and Serial Number Model Serial Number System (PHAZIRTM or microPHAZIRTM)

TEST PASSED FAILED N/A PCX-IQ-5 General electrical power Voltage * Mark N/A if not required. IQ - Step TEST PASSED FAILED N/A PCX-IQ-6 Battery Installation IQ - Step TEST PASSED FAILED N/A PCX-IQ-7 Powering up the System




IQ - Step TEST PASSED FAILED N/A PCX-IQ-8 Installation PHAZIR Setup Utility and PHAZIR Data

Management Systems

Software Package Version Software Version for PHAZIR Setup Utility Software Version for PHAZIR Data Management System IQ - Step TEST PASSED FAILED N/A PCX-IQ-9 Installation of System Software System Software Version (firmware) Version Software Version IQ - Step TEST PASSED FAILED N/A PCX-IQ-10 Installation of Polychromix Method Generator

Software

PCX-IQ-11 Registration of Polychromix Method Generator Software Package Registration Code Software Registration Code IQ - Step TEST PASSED FAILED N/A PCX-IQ-12 Setting Time & Date IQ - Step TEST PASSED FAILED N/A PCX-IQ-13 Setting PHAZIR Setup Utility for OQ & PQ Monitor




Comments and Non-conforming Products The above series of tests have been properly completed according to the procedures outlined in the IQ protocol. Tester: _______________________ ______________________ Date:____________ Name Signature Witness: _______________________ ______________________ Date:____________ Name Signature Review: _______________________* ______________________ Date:____________ Approval Name Signature * Note: Fill in with “N/A if your company or industry does not require an approval.




Operational Qualification – OQ Test Log TEST PASSED FAILEDPCX-OQ-1 Locating & Preparing Traceable Standards PCX-OQ-2 Configuration of PHAZIR Setup Utilities OQ PCX-OQ-2 Photometric Standards Significant Figures Certified Value to be recorded 99% Standard 3 decimal places

Reflectance Factor 40% Standard 3 decimal places



Reflectance Factor Wavelength Standard Certified

Value Significant Figures to be recorded

Wavelength Standard 1 decimal place

Software Parameter PQ Expiration PQ Warning OQ Expiration OQ Warning PCX-OQ-3 Std. Type Serial / Certification Number Expiration Date 99% Standard 40% Standard 10% Standard 2% Standard Wavelength Standard




TEST PASSED FAILEDPCX-OQ-4 OQ Test TEST PASSED FAILEDPCX-OQ-5 Generation OQ Test Report

*Attach OQ Test Report*

TEST PASSED FAILEDPCX-OQ-6 Attach Test Sample – Traceable Standards

Certification Copies to Test Report.

Comments and Non-conforming Products The above series of tests have been properly completed according to the procedures outlined in the OQ protocol. Tester: _______________________ ______________________ Date:____________ Name Signature Witness: _______________________ ______________________ Date:____________ Name Signature Review: _______________________* ______________________ Date:____________ Approval Name Signature * Note: Fill in with “N/A if your company or industry does not require an approval.

Polychromix




Performance Qualification – PQ Test Log TEST PASSED FAILED N/A PCX-PQ-1 Execute Performance Qualification PCX-PQ-2 Generation of PQ Test Report

*Attach PQ Test Report*

PCX-PQ-3 Verification of OQ/PQ Monitor Comments and Non-conforming Products The above series of tests have been properly completed according to the procedures outlined in the PQ protocol. Tester: _______________________ ______________________ Date:____________ Name Signature Witness: _______________________ ______________________ Date:____________ Name Signature Review: _______________________* ______________________ Date:____________ Approval Name Signature * Note: Fill in with “N/A if your company or industry does not require an approval.




Section 3 – Product Certifications

1.0 Purpose This section contains copies of product and system certifications This section includes the following certificate copies for product version 3.1:

• PHAZIR RxTM and microPHAZIR RX TM Validation and Conformity Statement • Software Validation Certificate – PHAZIRTM Tools • Software Validation Certificate – PHAZIRTM Method Generator • 21 CFR Part 11 Compliance – PPAZIR RxTM and microPHAZIR RxTM

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Section 4 - Information

This section contains the following as applicable: Copies of the Polychromix ISO9001:2000 and the ISO9001:2008 certificates Note: The following are supplied with each shipped product in either paper or electronic format as applicable:

Appendix documents Customer order information (quotation, order, and packing lists) Reference documentation for traceable standards if supplied by Polychromix Product Certification PHAZIR Rx and microPHAZIR Rx Regulatory and 21 CFR Part 11 Compliance Statement Product Brochures (optional)

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Polychromix ISO9001:2000 Registration Certificate – Valid until January 16, 2010





Polychromix ISO9001:2008 Registration Certificate – Valid beginning January 17, 2010





Section 5 - Personnel Training

1.0 Purpose This section provides information on the training of Polychromix personnel on the PHAZIR Rx IQ/OQ/PQ testing that are described in chapters 3, 4 and 5 of this manual, Software Validation per the PCX13STP0001 Software Test Plan, and PHAZIR Rx system requalification processes.

2.0 Background Personnel Qualifications As described in PCXQ0005, 0006, and 0007, the Polychromix Training Related documents, personnel is chosen based on their background, experience, and education applicable to their required functions within Polychromix. Additional training is performed as needed to reinforce the required technical expertise and awareness of the Quality Management System. Personnel is periodically evaluated relative to their performance within their assigned responsibilities. Personnel with the demonstrated experience of the PHAZIR Rx system, hardware, software, and firmware operational principles, are chosen to perform IQ/OQ/PQ, Software testing, and System Requalification at customer’s sites when needed. Trainer Qualifications The trainer is a Senior Polychromix employee with all the above stated attributes, and who also has proven superior technical understanding of the PHAZIR Rx analyzer, the various related software packages, its Firmware, and intended usage, a proven understanding of the pharmaceutical and related market requirements, and the ability to interrelate well with both Polychromix personnel and its customers. Training Records Training Attendance Sheet – This form is available at the end of this chapter. It includes the topic(s) that have been covered in the training process, the names, signatures, and titles of the personnel that attended the training session, the training date, and the trainer’s name responsible for the provided training.

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Training Certificate – A certificate is available at the end of this chapter. It is intended to be printed on a color printer to provide the completed certificate with original signatures and dates. The provided certificate is specific for a provided training and may be altered by the trainer or designee to suit the performed training. The completed certificate is provided to those training attendees that the trainer agrees have met the minimum requirements of the training material presentation and process(es) involved. Record Retention – The original training attendance sheet and certificate is used to provide an electronic copy which is placed on the ISO_QMS Server in the training section. The trainer determines the section that this training folder resides in and generates applicable folders for the provided training. The determined training folder contains:

• A copy or reference to the training material, presentations, etc that were used, • A copy of the completed Training Attendance Sheet, and • A copy of each provided certificate.

If desired the training folder may also contain electronic copies of training notes that the trainer may have generated. Training records are maintained on-line indefinitely. The trainees are provided the original training Certificates, and if required by HR, copies are maintained in their personnel files.

3.0 Training Process A prerequisite for training is a working knowledge of the PHAZIR Rx analyzer, the various related software packages, its Firmware, and intended usage. To help facilitate training, the trainer may require the personnel to be trained to have read the applicable documents that will be used during the training. These documents, the IQ/OQ/PQ Manual, and / or the PCX13STP0001 Software Test Plan, or other related documents are then used to provide hands on training with a, or several, operational PHAZIR Rx analyzer, and the required test standards. All training attendees sign in using the attendance sheet, and fill in their name, signature, title and training date. The trainer completes the trainer section of the sheet and saves it for later use. The trainer explains the processes and their industry required needs, and trains the attending personnel using the described processes and the records to be generated as a result of the testing.

Polychromix




The trainer verifies that the testing progresses as required in the documents, along with the required signatures and other validations, and resolves any questions that may arise. The trainer verifies that the required tests and validations have been performed and meet the requirements outlined in the governing documents. The trainer provides insight and training for personnel who will perform such testing at customer’s sites to assure that the Polychromix image is properly represented. When satisfied with the progress and results of the training, the trainer completes the training certificate and provides them to the personnel that have proven to be capable to perform the work correctly. The trainer makes electronic copies of the provided certificates and the attendance sheet, and places them in a prepared folder in the training section of the ISO_QMS Server. The trainer confers with HR to determine if additional copies are needed for personnel folders and provides these as needed. In order to maintain the acquired knowledge and required practices, the trainer schedules retraining of the attending personnel in the year following the training anniversary. At the trainer’s discretion, retraining is scheduled with applicable software updates.




Training Attendance Form Training Function: Date:

Attendees - Please Print Signature Department

Trainer: Title:

Polychromix

PHAZIR RxTM and microPHAZIRTM Validation Training

13Rx91-0002 Rev D PHAZIR Rx V3.1 IQ/OQ/PQ Manual - Training of 143

On ____ / ____ / ________, Day Month Year

Has successfully met all training requirements for the PHAZIR Rx Validation Process, and may herewith perform such PHAZIR Rx validations for Polychromix’ customers

as part of their efforts to integrate the PHAZIR Rx into their operations.

Witness T ainerr


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Section 6 - System Recertification

1.0 Purpose This section provides the information needed to perform PHAZIR Rx system requalification at the customer’s site. It is assumed that the customer’s device is in full operational condition. This service does not include repair.

2.0 Background The PHAZIR Rx requires requalification when system changes are made, or periodically. Periodic requalification is typically annual. This system requalification is frequently provided as a service to Polychromix customers at the Polychromix facility when customers return the instrument for servicing. This service is performed utilizing the existing practices outlined in the IQ OQ PQ manual, and the information provided in this section is not required. On occasion, customers request the periodic requalification to be performed at their site. For that purpose, this section applies.

3.0 Preparatory Actions The assigned service person who will provide the requalification service at the customer’s site is responsible to have all required materials available, verified, and ready for travel to the customer’s site. This includes:

• A soft and hard copy (as needed) of the IQ OQ PQ Manual, (Located in Product Folder 13-91.)

• A soft and hard copy (as needed) of the PCX13STP0001 Software Test Plan,

(Located in Product Folder 13-94.) (Note: Do not use prior copies of these documents unless their revision is verified to be current. The Product Folder contains the current version of these documents.)

• The latest approved versions of software and firmware, • Required hardware items, a new spare light source as a minimum, • Applicable Wavelength Standards, (see System Requalification form, section 4) • Applicable Linearity Standards, (see System Requalification form, section 4)

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(Note: Verify that all Wavelength and Linearity Standards are within their prescribed calibration period. DO NOT USE Measurement Standards that are out of their calibration period. Obtain new ones if needed and provide them to the Polychromix calibration department for inclusion into the calibration system or have them recalibrated.)

• A #2 Phillips Screwdriver • A 0.050 Allen Wrench • Paper copies of the “Polychromix Annual PHAZIR Rx System

Requalification” form located at the end of this section • A soft or hard copy of the most recent training certificate to this process.

4.0 Requalification Process The training undergone by the Polychromix representative who performs this service has provided the required details of the process. This section does not provide requalification details. The “Polychromix Annual PHAZIR Rx System Requalification” form is intended to provide a record of the service performed, and captures the signatures of the Polychromix representative, the customer’s witness, and the customer’s approval of the provided service, and the performance date. The form serves the combined purpose of a checklist and a record. Additionally, records are required to be legible. To that end, write all information with a pen, blue is preferred, and assure that it is legible by both the customer and Polychromix. Individual customers may have additional requirements. A customer witness must be present throughout the requalification service. That witness will sign the applicable IQ / OQ / PQ forms as well as the completed requalification form. A- Complete the top section by capturing the Model and Serial Number of the

unit being requalified, and the customer’s company name and their location, city and state / country is sufficient.

B- In all cases, where “Original Condition” is called for, write in the as found condition before performing any service.

C- All blank spaces must be filled in with the service that has been performed, or if not performed write N/A and justify.

D- When performing IQ / OQ / PQ or other such lengthy tests that have their own records, complete these and attach them to the form.

E- When the requalification work is complete, perform the needed customer training if required. Ask the customer who, beside the witness and owner

Polychromix

Document TitlePHAZIR Rx & microPHAZIR Rx Version 3.1 IQ/OQ/PQ Manual

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should receive the training and have these attendees complete the personnel section of the training attendance fields. Complete the training topic and the trainer’s fields and provide the training.

F- Capture any additional information regarding the unit being serviced into the “Additional Comments” section.

G- Sign the “Polychromix Representative” field and for clarity write the name underneath, and date it with the service date.

H- Obtain the customer signature of the person authorizing the service, and request that the customer provide any additional comments they would like as part of this record.

I- Request that the customer copy all pages of the completed form and any additional collected test results, certification, etc.

5.0 Record Keeping Provide the copy to the customer for their record keeping requirements. Provide the original to the Polychromix Sales Department, who will forward it to be scanned and placed into the applicable electronic customer service file. Record retention times are as written in the IQ / OQ / PQ section of this document.

PCX13Rx91-0002 Rev D of 143

Polychromix Annual PHAZIR Rx System RecertificationPolychromix Annual PHAZIR Rx System Recertification

microPHAZIR Rx & PHAZIR Rx Recertification of Model Number: , Serial Number: Customer Name: , Location:

The following actions were performed to re-qualify the above named unit: 1- Preventive Maintenance – Actions Performed. Original Condition:

2- Inspection – Describe Results Original Condition:

3- Backup Items Backed Up:

Backed up to:

Form Page 1


4- PQ - Recalibration – Describe Actions Original Condition:

Traceable Standards Used for Recalibration and Requalification / OQ below: Note: All Standards have a 1 Year Calibration Period.

Name: Fluorilon - Wavelength Std. , S/N: , T&M #: , Cal Date: Name: Polystyrene - Wavelength Std. , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 1 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 2 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 3 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 4 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 5 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 6 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 7 , S/N: , T&M #: , Cal Date: Name: % Linearity Std. 8 , S/N: , T&M #: , Cal Date: 5- Source Changes – Software / Firmware Upgrades – Describe Actions

Name Current Version

New Version

Light Source was changed . 6- Upgrade (if required). List upgrades below or write N/A if not required

7- OQ - System Requalification Original Condition: a. Traceable Standards Same as in PQ – Recalibration Above: b. IQOQPQ performed: attach copies of completed reports Form Page 2


c. 8- Training (if required). List personnel trained below or write N/A if not required Training Topic: Personnel Name Signature Title: Date:

Additional Comments:

This system re-qualification was performed by: Polychromix Representative: , Date: Witnessed By: , Title: , Date: Accepted By: , Title: , Date: Customer Comments:

Form Page 3

Polychromix


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Section 7 – Traceability Matrix for Functional Requirement Specifications

1.0 Purpose This section contains a traceability matrix which illustrates the validation of each of the PHAZIR RxTM and microPHAZIR RxTM Functional Requirement Specification with the corresponding Polychromix qualification and validation plan. This matrix is prepared to assist in the facilitation of the PHAZIR RxTM and microPHAZIR RxTM into a Master Validation Plan.

2.0 Background The table below lists all of the PHAZIR RxTM and microPHAZIR RxTM system Functional Requirements Specifications by item number (column 1), and description (column 2). Column 3 indicates those FRS items which are verified during the product design review process. Column 4 denotes those specifications which are verified during the system test plans which are executed prior to each version release. Column 5 denotes those items which are qualified during the execution of the standard IQ/OQ/PQ qualification process. Column 6 denotes compliance items that are the users’ responsibility.

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Polychromix




Traceability Matrix for Functional Requirement Specifications

PHAZIRTM and microPHAZIRTM Design Qualification - Functional Requirement Specification Traceability Matrix

Design

Validation System Test Plan Process

IQ/OQ/OQ Process

User Responsibility

1.0 Operational Performance - Basic Design 1.1 Size X 1.2 Weight X 1.3.1 Robustness X 1.3.2 Robustness-Orientation X 1.3.3 Robustness-environment X 1.4 Permanently aligned optical system X 1.5 Wear-free scanner X 1.6 Source – Life X 1.7 Source Exchange X 1.8 Source – Cost of Ownership X 1.9 Power – Battery Capacity X 1.10 Battery Exchange X

1.11 Battery-Charging ports X 1.12 Main Power X 1.13 Reference & wavelength standard mount X 1.14 Lanyard X 1.15 Measurement trigger X 1.16 LED measurement indicators X 1.17 Color LCD Display X 1.18 USB Port X 2.0 Functional Requirements 2.0 Solids Analysis X 2.1 Solids Analysis in Glass Vials X 2.2 Analysis of solids in plastics liners X 2.3 Liquids Analysis X 2.4 Qualitative Analysis X 2.5 Quantitative Analysis X 2.6 Data Pretreatment X 2.7 Power – Indicator X 12.8

Power – Power Savings X


X

2.10 Power – Hard Off X

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2.11 Power – Main Power Voltage X 2.12 Environmental Light / Stray Light X 2.13 On-board Database X 2.14 On-board Memory and Method and Data

Capacity: X

2.14a The system shall provide adequate on-board memory to store at least 99 methods and a complete set of 5,000 measurement results.

X

2.14b The system must provide a function to be able to synchronize the data in the PHAZIR with a PC based software with database functions for long term data archiving.

X

3. System Performance Requirements 3.1 Detector X 3.3 Spectral range

1600 – 2400 nm X

3.4 Spectroscopic Performance: The system shall have performance characteristics for photometric linearity, noise low flux, noise high flux, that meet the acceptance criteria for USP 1119 NIR Qualification Protocol.

X STP-002 OQ

3.5 USP 1119 NIR Qualification X STP-002 OQ 3.6 USP 1119 Photometric Linearity : The

system shall have a photometric linearity as demonstrated with a diffuse reflectance standard set (99%, 40%, 10% and 2%) with a USP acceptance criteria: Slope 1.0 +/- 0.05 Intercept 0.0 +/- 0.05 The photometric linearity shall be performed at one wavelength, generally 2000 nm.

X STP-002 OQ

3.7 USP 1119 Photometric Noise – High Flux: The system shall achieve noise levels of diffuse reflectance measurement of a 99% photometric reference standard with a 0.3 x 10-3 average RMS values, no RMS noise values greater than 0.8 x 10-3 at three discrete wavelength ranges.

X STP-002 OQ

3.8 USP 1119 Photometric Noise -Low Flux The system shall achieve noise levels of diffuse reflectance measurement of a 10% photometric reference standard with a 1.0 x 10-3 average RMS values, no RMS noise values greater than 2 x 10-3 at three discrete wavelength ranges.

X STP-002 OQ

Polychromix




3.9 USP 1119 Wavelength Accuracy The system shall achieve wavelength accuracy better than the USP 1119 acceptance criteria of : +/- 1.5 nm

X STP-002 OQ

4.0


4.0 21 CFR Part 11 Compliance (see system compliance statement, attached copy)

X STP-014

11.10 X 11.10(a) X X 11.10(b) X 11.10(c) X 11.10(d) X 11.10(e) X 11.10(f) X 11.10(g) X 11.10(h) X 11.10(i) X X 11.10(j) X 11.10(k) X 11.10(k)(1) X 11.10(k)(2) X 11.30 X X 11.50 X 11.50(a)(1) X 11.50(a)(2) X 11.50(a)(3) X 11.50(b) X 11.70 X 11.100(a) X 11.100(b) X X 11.100(c) X X 11.100(c)(1) X X 11.100(c)(2) X X 11.200 X 11.200(a) X X 11.200(a)(1) X 11.200(a)(1)(i) X 11.200(a)(1)(ii) X 11.200(a)(2) X X 11.200(a)(3) X X 11.200(b) X 11.300 X 11.300(a) X 11.300(b) X X 11.300(c) X 11.300(d) X X

Polychromix




11.300(e) X 4.1 IQ/OQ/PQ manual X STP-002 4.2 IQ/OQ/PQ validation services X STP-014 4.3 OQ/PQ Administration X STP-002 4.4 OQ/PQ Monitor X STP-002 4.5 OQ/PQ Wizard X STP-002 4.6 Dockable PQ verification

Standards X STP-002

4.7 Certificate of Conformity X STP-014 4.8 Traceable Reference Standards X STP-002 4.9 PQ Standards and process X STP-002 PQ 5.0 Environmental, Safety & Statutory

Requirements

5.1 CE Rating X 5.2 Source - Eye Safety / Laser Safety X 5.3 Explosion Proof Rating: General Purpose X 6.0 Informational Management Requirements 6.1 Communications: The system must provide a

standard interface to a PC in order to permit the transfer of spectral data from the system to a PC and for generated method to be transferred from a PC to the system.

X STP-003

6.2.a user logins X STP-001 6.2.b user passwords X STP-001 6.2.c user access permission level to PHAZIR

Setup Utility and PHAZIR Data management System

X STP-001

6.2.d 4 levels of electronic signature X STP-006 6.2.e Group IDs and sample IDs X STP-003 6.2.f OQ/PQ expiration periods X STP-002 6.2.g Manage Traceable standard certified values X STP-002 6.2.h Managing PHAZIR Applications X STP-010 6.2.i Enable user scan marks X STP-010 6.2.j Optional between GMT and local time X STP-004 6.2.k Option to force the use of encrypted PHAZIR

Data Files to secure transfer of data between PHAZIR analyzer and PC software

X STP-004

6.2.l Setting to require login to access PHAZIR analyzer and PC software packages.

X STP-001

6.2.m Setting to automatically logout the user from the PHAZIR if the PHAZIR has been left idle for more than a number of minutes specified in the standby setting of PHAZIR Applications.

X STP-005

6.2.n Setting to require character by character login entry rather than selecting from a menu list

X STP-001

6.2.o Setting to automatically log users off of PHAZIR Setup Utility and PHAZIR Data Management software when PC is left idle for more than a specified number of minutes

X STP-005

Polychromix




6.2.p Option to enable/disable user from accessing the PHAZIR analyzer

X STP-007

6.2.q Permission setting to disable PHAZIR Analyzer USB port

X STP-007

6.2.r Permission setting to disable the user’s ability to change PHAZIR Applications

X STP-007

6.2.s Permission setting to disable the user’s ability to access the PHAZIR PQ function

X STP-002

6.2.t Permission setting to disable the user’s ability to access the PHAZIR QQ function

X STP-002

6.2.u Function to edit Group IDs and Sample IDs on the PHAZIR analyzer

X STP-003

6.2.1 Minimum of 99 users X STP-013 6.3.a Import and export PHAZIR database table X STP-009 6.3.b Display PHAZIR database information X STP-011 6.3.c Display spectral graph to visualize data X STP-009 6.3.d Permit user selection of database information X STP-011 6.3.e Manage synchronization of PHAZIR

databases with PC based database X STP-009

STP-011

6.3.f Manage electronic signatures X STP-006 6.3.g Generation of printed reports X STP-009 6.4 Method Development: The system must

support a software development tool to enable the development of NIR methods

X STP-003

6.4.1 Method Development – Data Import: The method development software must be able

to import calibration spectra to generate PHAZIR Applications

X STP-010

6.4.2 Method Development – Model Visualization: The method development software must be

able to generate model.

X STP-010

6.4.3 Method Development – Non-Editable Methods: The system must be able to

generate methods which cannot be changed or modified by unauthorized users.

X STP-003

6.5 The system shall provide the ability to generate qualitative libraries which can be

searched in identification mode. The unknown spectrum is compared against a

library and the best match above a threshold value is considered the resulting match. The

result is considered “Not Identified” in the case that the top match’s value does not

exceed the minimum threshold value.

X STP-003

Polychromix




6.6 Conformity mode (pass/fail): The system shall provide the ability to generate a

qualitative library which can be searched in conformity mode which means the materials

GroupID (or class) is pre-selected, the unknown spectrum is search against only the

library members of selected GROUPID (or class) and the results is PASS if the top

match’s value exceeds the minimum threshold value, or FAIL it the top match does

not exceed the minimum threshold value.

X STP-003

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