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Qualification of UHPLC SystemsAgilent 1220, 1260, and 1290 Infinity UHPLC Series and Selected Non-Agilent UHPLC Models, with operating pressure range above 400 bar

REVIEW DOCUMENT NAME:Agilent_Recommended_EQP_UHPLC

EQUIPMENT QUALIFICATION PLAN (EQP)

Agilent Enterprise Edition Compliance Services

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Agilent_Recommended_EQP_UHPLC

© Agilent Technologies, Inc. 2013

Enterprise Edition Compliance Services

No reproduction, translation, or use without permission

Document Released: September 2013

How to Use This DocumentThis document is an Equipment Qualification Plan (EQP). It covers Design Qualification (DQ), Installation Qualification (IQ), Operational Qualification (OQ), scheduled repeat OQ, and Re-Qualification after Repair (RQ). It contains information on how Enterprise Edition Compliance Services work, and also provides a full list of the tests and checks performed as part of Agilent’s standard Enterprise Edition IQ and OQ services.

The hardware IQ and OQ procedures listed in this document include fixed tests and checks at Agilent recommended criteria and limits, both for Agilent and non-Agilent systems (see attachment).

All tests in this document exist in all Agilent delivery tools. However, customer-selectable variance to the standard hardware OQ setpoints is possible to enable testing of chromatography system(s) over their intended range of use. All setpoint menu selections in the Variance Section are with the validated range of Enterprise Edition. The inventory of systems covered by the EQP will be maintained as a separate record.

To facilitate the EQP review and approval process, this document is best viewed on-screen using Adobe ®. Also, there are several pdf file attachments included with this document: (i) Non-Agilent test specifications; (ii) Question and Answer document; (iii) 21 CFR Part11 Conformance Checklist for the Agilent Compliance Engine (ACE) – the Enterprise Edition delivery tool; (iv) EE 1.76 EQR comparison with previous revisions.

To approve this EQP simply print to paper and sign. To add variances see instructions below. Keep copies for your own records. Verbal confirmation of approval is sufficient for Agilent service to proceed with scheduling and delivery.

To make variances to the standard hardware OQ setpoints:[1] Use the pull-down button to select the alternative approval statement “shall follow...the standard specifications with VARIANCES to OQ setpoints...”; [2] Complete the “EQP Record of Variances to Setpoints from Standard OQ Specifications” later in this document; [3] Print EQP to paper and [4] ENSURE THE VARIANCE REQUEST IS COMMUNICATED to Agilent service engineer BEFORE first OQ delivery starts. Do not e-mail/FAX/post copies of your approved EQP to Agilent. BUT CUSTOMER MUST PROVIDE A COPY OF ANY EQP WITH VARIANCES TO AGILENT OPERATOR ON-SITE TO ENSURE THE VARIANCES ARE ENTERED INTO DELIVERY TOOL. NO EXTRA FEE TO DELIVER SETPOINT VARIANCES.

For a full process description, click here to go to the EQP Record of Variances section.

Approval of EQPThe undersigned person(s) approve the following:

[1] the use of Enterprise Edition Compliance Services and delivery of the IQ and/or OQ and/or RQ checks and tests appropriate to the actual configuration, make, and model of those systems covered by the service;[2] the specifications described in this Standard EQP Review Document where the tests, setpoints, and limits shall follow...

the STANDARD FIXED Agilent recommended specifications.

Name and Role Signature and Date

[You cannot save form entries with Adobe Reader. Typed entries and menu selections are printed on your official paper copy when you print.]

DO NOT SEND AGILENT A COPY OF YOUR APPROVED EQP. THIS DOCUMENT IS YOUR OWN RECORD OF APPROVAL.

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ContentsTo go to a section, click on one of the section titles below.

Sections Page

How Enterprise Edition Compliance Services Work ................................................................................................. 4

Design Qualification (DQ) .............................................................................................................................................. 5

Installation Qualification (IQ) Hardware ..................................................................................................................... 6

Operational Qualification (OQ) Hardware ................................................................................................................... 7

Standard OQ Test Specifications for Analytical-Scale UHPLC Systems (*) ............................................................. 7

OQ Test Design and Rationale for UHPLC Systems .................................................................................................. 9

EQP Record of Variances to Setpoints from Standard OQ Specifications .............................................................. 13

Re-Qualification after Repair (RQ) Hardware ........................................................................................................... 14

Legal, Endorsement, and Revision History ............................................................................................................... 15

Why Has Agilent Introduced the New Compliance Service, Called Enterprise Edition?IntroductionAgilent (then we were HP Analytical) introduced OQPV for our own LC and GC instruments in the early 1990’s and since then we have delivered well over 100,000 OQPV reports to customers around the world. Despite the undoubted success and acceptance of our old OQPV (now called Classic Edition to distinguish from the new Enterprise Edition service) times have changed. Expectations and requirements of an OQ have slightly shifted. The number and type of instruments and software used by our customers has increased. And of course we are truly in the new world of computers and electronic media.

So Agilent set out with a team of international experts 3 years ago to create an upgraded compliance service that would meet the new demands but crucially maintain the fundamental requirements:

• Always pass FDA and national agency audits without over-testing or under-testing;

• Challenge the LC or GC system with a scientifi cally sound methodology that provides valuable performance data.

• Meet the quality needs of customers and the spirit & intention of the GLP & GMP laws.

• Offer this service at a cost-effective price that makes it more than just worthwhile – we hope it is the simplest & best qualifi cation choice that a customer can make.

What Are The High Level Changes In Enterprise Edition And What Were The Drivers For These Changes?The fi rst big driver was the software environment. A greatly increased number of chromatography data system (CDS) products are available to control LC and GC systems. Agilent has ChemStation, Cerity, EZChrom, OpenLab and some specialist LCMS/GCMS software. Our customers also use Empower, Chromeleon, Atlas, Turbochrom and many others. Classic OQPV was built into ChemStation software. The Classic OQPV is a miracle of validated and almost fully automated OQ testing. But these benefi ts are therefore limited to Agilent instruments running on ChemStation. To provide all our customers, and customers of non-Agilent instruments, a single OQ solution as good as (or better than) OQPV – it was clear we had to develop an automation tool independent of ChemStation and any other CDS.

The Agilent Compliance Engine (ACE) is our new software tool that manages the workfl ow and protocols, calculates results and produces the reports. Naturally it is fully validated and tested. Our service engineers carry “ACE laptops” in the same way as they carry “ChemStation laptops”. Alternatively our contract customers can have the ACE software on their own laptops or installed with Agilent OpenLab networked CDS.

Table of contents: [click on title for fast navigation]

What Are The High Level Changes In Enterprise Edition And What Were The Drivers For These Changes?

Any Other Practical Or Process Changes In Enterprise Edition?

Let’s Dive Into The Details – How Do The Protocols And Tests In Enterprise Edition Compare To Classic Edition?

List Of Enterprise Edition OQ Tests Versus Classic OQPV Tests For LC:

What About The Reports, How Are These Different To OQPV Reports?

What Would I Have To Do If I Wanted To Move My Annual OQ Service From Classic To Enterprise Edition?

What Are The Main Risks To Migrating To Enterprise Edition And How To Avoid Them?

Finally, Can You Summarize The High Level Comparison Of Enterprise Edition Versus Classic Edition Compliance Services?

EE 1.76 Comparison Document

Q & A: Why Change? Part 11 Checklist (ACE)Tests definitions for Non-Agilent Systems

PDF file attachments to this electronic EQP (open the attachments folder for this document in Adobe):

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How Enterprise Edition Compliance Services WorkEnterprise Edition is designed to fit the traditional quality systems used by firms and recognized by regulatory agencies worldwide.

How Enterprise Edition aligns with a traditional, paper-based methodology is described below:

[i] Policy documents dictate the need for validation & qualification of GMP/GLP systems and usually mention the DQ/IQ/OQ/PQ model. The precise procedures for IQ & OQ for each type of equipment are prescribed in an approved SOP, perhaps called SOP #123: Qualification of UHPLC Systems. In Enterprise Edition, the EQP has the same role as the traditional Qualification SOP.

[ii] The traditional SOP provides lists of tests & limits for the range of system configurations found in the lab or department. The EQP follows this concept. The inventory of systems covered by an SOP or EQP changes over time – so this is kept as a separate record.

[iii] The traditional Qualification SOP typically has blank results forms as attachments to be photocopied for each IQ or OQ event – the results recorded in ink with manual calculations. In Enterprise Edition this execution process is streamlined and automated by use of Adobe forms and the Agilent Compliance Engine (ACE) delivery tool. It provides reports with no hand-writing errors; validated calculations; automated pass/fail report; traceability to raw data and a count of number of times a test was run. This automation provides efficiency and enforces compliance to procedure.

[iv] The traditional Qualification SOP is approved and released only once – replacing need to author individual protocols for each chromatography system. This is the same concept for the EQP. The appropriate tests for each individual configuration are automatically selected by ACE from the list in the approved EQP – at time of delivery. The final reports are unique for each system and each qualification event – but the single approved EQP can cover a lab, department or as wide a scope as desired.

(v) In the traditional qualification methodology there is no convenient provision to record the actual workflow of the tests execution and results. In the event that a test is repeated during the Enterprise Edition delivery, ACE maintains a counter per test which is automatically incremented for GxP compliant work, and the engineer should generate a deviation note within the ACE report.

Figure 1:This EQP Review Document is the record of IQ checks and OQ / RQ tests, setpoints, and limits for UHPLC systems. The tests already exist in the automation tool called ACE and are ready to run after the EQP is approved. ACE holds the test forms applicable to the full range of UHPLC configurations plus a validated calculation and report generator engine. At time of delivery, a record of individual system configuration is made by the operator and entered into ACE. The correct test forms are automatically selected by ACE from its internal catalog of test designs. Each test in the catalog has a blank results template form. The appropriate setpoints and limits for the individual UHPLC system are added by ACE to the forms according to the approved EQP. When each test is run, the results are calculated and forms completed and then collated to make a single final report called an Equipment Qualification Report (EQR), which is provided in secure PDF format or optional CD disk – printable to paper and stored in a binder and/or customers’ network storage system.

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Design Qualification (DQ)Design Qualification (DQ) for commercial lab instruments is recommended by some, but not all, guidances and procedures. Defintions of DQ found in guidances and firm-specific validation procedures vary widely around the world. Some firms require nothing more than a record (such as certificate) from the instrument manufacturer demonstrating that the lab system has been designed for purpose and manufactured to a quality standard. Others treat DQ as the development of a user requirement specification document (URS) which can be matched to the IQ and OQ specifications for a manufacturer. Other firms consider DQ as including the vendor selection activities.

USP Chapter <1058> pre-published in USP 31/Supplement defines DQ:

Design qualification (DQ) is the documented collection of activities that define the functional and operational specifications of the instrument and criteria for selection of the vendor, based on the intended purpose of the instrument. Design qualification (DQ) may be performed not only by the instrument developer or manufacturer but also may be performed by the user. The manufacturer is generally responsible for robust design and maintaining information describing how the analytical instrument is manufactured (design specifications, functional requirements, etc.) and tested before shipment to users. Nonetheless, the user should ensure that commercial off-the-shelf (COTS) instruments are suitable for their intended application and that the manufacturer has adopted a quality system that provides for reliable equipment. Users should also determine capability of the manufacturer for support installation, services, and training.

For your reference, Agilent provides the following statements for DQ purposes:

1. All Agilent LC, LCMS, UHPLC, UHPLC_MS, GC, and GCMS hardware and software laboratory products including the ACE software used to deliver qualification services, are designed, manufactured, and tested according to Agilent internal Quality Life-Cycle Development Procedures.

2. Certificates of Agilent testing, validation, and conformance to standards are provided with new Agilent instruments and similar certification is provided for ACE software. These documents are checked and recorded in Enterprise Edition Compliance Services IQ.

3. Agilent maintains information describing how products are manufactured and maintains a problem and bug reporting program as required by international software quality guidelines.

4. The OQ specifications in this EQP can be used, as appropriate, by the user to prepare URS. The OQ specifications in this EQP represent the levels of performance acceptable to regulatory agencies for the technique; conform to typical specifications found in Validation literature; are equally suitable for OQ at installation and on-going OQ throughout operational lifetime; are equivalent to the OQ specifications published in the legacy Agilent Classic OQPV protocols; and are suitable for most user requirements.

5. Agilent Technologies is capable of installation, support, preventive maintenance, on-going qualification and re-qualification after repair and user training worldwide.

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Installation Qualification (IQ) HardwareHardware IQ checks and tests for Agilent software products include the following:

1. Purchase Order Documents: Allows the customer to verify that the instrument being qualified matches their design requirements (if available) and purchase order.

2. Preparation and Installation Documents: Gathers and records information about preparation and installation documents.

3. System and Installation Documentation: Gathers and records information about reference and user manuals for initial installations.

4. Product Quality Assurance Documents: Collects and records certificates and other forms that verify that the vendor has developed and built the product according to internal standards.

5. Start Up Test: Verifies that all modules start up properly.

6. Instrument Check: Demonstrates that all modules of the instrument are correctly installed and connected. It does not test instrument performance as fully as OQ. This test is not necessary and therefore skipped if an OQ is to be performed by Agilent operator at installation after IQ.

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Operational Qualification (OQ) HardwareStandard OQ Test Specifications for Analytical-Scale UHPLC Systems

Test Name Setpoints and Parameters Limits

Pump Flow Accuracy and Precision

Flow Rate 1 = 0.500 ml/minuteFlow Rate 2 = 5.000 ml/minute*

Accuracy ≤ 3.00 % from setpointPrecision ≤ 0.50 % RSD

Column Temperature Accuracy and Stability

Temperature 1 = 80.0 °CTemperature 2 = 40.0 °C**Stability measured at Temperature 2

Diff. from setpoint ≤ 3.0 °C (≥ 60 °C)Diff. from setpoint ≤ 2.0 °C (< 60 °C)Stability ≤ 1.0 °C

Wavelength Accuracy (UV-Vis) Wavelength 1 = 205 nm [Maximum]Wavelength 2 = 245 nm [Minimum]Wavelength 3 = 273 nm [Maximum]

Accuracy ≤ 2 nm

Wavelength Accuracy (FLD) Wavelength 1 = 350 nm [Maximum]Wavelength 2 = 397 nm [Maximum]

Accuracy ≤ 3 nm

Signal Noise and Drift (VWD) ASTM baseline noiseSlope of regression fit for drift

Noise: ≤ 0.040 mAUDrift ≤ 0.500 mAU/hr

Signal Noise and Drift (DAD) ASTM baseline noiseSlope of regression fit for drift

G4212A/B Noise: ≤ 0.030 mAUG4212A/B Drift: ≤ 3.000 mAU/hrOther DADs Noise: ≤ 0.050 mAUOther DADs Drift: ≤ 5.000 mAU/hr

Signal Noise and Drift (MWD) ASTM baseline noiseSlope of regression fit for drift

Noise: ≤ 0.050 mAUDrift: ≤ 5.000 mAU/hr

Signal Noise and Drift (RID) ASTM baseline noiseSlope of regression fit for drift

Noise: ≤ 10.000 nRIUDrift: ≤ 400.000 nRIU/hr

Signal Noise and Drift (ELSD) ASTM baseline noiseSlope of regression fit for drift

Noise: ≤ 2.000 mVDrift : ≤ 5.000 mV/hr

Signal Noise and Drift (CD) ASTM baseline noiseSlope of regression fit for drift

Noise: ≤ 0.100 uSDrift ≤ 10.000 uS/hour

Signal to Noise (UV-Vis) Signal height is divided by ASTM baseline noise for known concentration and known conditions.

DAD Signal to noise ≥ 10,000Other UV-Vis Signal to noise ≥ 3,000

Signal to Noise (RID) Signal height is divided by ASTM baseline noise for known concentration and known conditions.

Signal to noise ≥ 2,000

Signal to Noise (FLD) Signal height of Raman peak is divided by noise at different wavelength in flat region of emmision spectrum.

Signal to noise ≥ 400

* 2.000 ml/min for G4220B 1290 pump ** T2 = 60.0 °C for 1120 and 1220 systems

Key:

Fixed HPLC setpoints/limits Variance allowed for setpoint(s)

Fixed UHPLC setpoints/limits

See attachements for recommended test definitions for Non-Agilent Systems

For multiple-detector systems, only one execution of the Injection Precision & Carry-Over tests will be performed in the standard test program – by default using the UV detector if present. Repeat execution of the test can be added as optional tests for a nominal fee.

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Operational Qualification (OQ) Hardware (continued)Standard OQ Test Specifications for Analytical-Scale UHPLC Systems (continued)


Injection Precision (UV-Vis) Injection volume on column = 10 ul Height RSD ≤ 2.00 %Area RSD ≤ 1.00 %

Injection Precision (RID) Injection volume on column = 20 ul Height RSD ≤ 2.00 %Area RSD ≤ 1.00 %

Injection Precision (ELSD) Injection volume on column = 20 ul Height RSD ≤ 3.00 %Area RSD ≤ 3.00 %

Injection Precision (FLD) Injection volume on column = 5 ul (2 ul for 1290 w/ CTC samplers)

Height RSD ≤ 2.00 %Area RSD ≤ 2.00 % *

Injection Precision (CD) Injection volume on column = 25 ul Height RSD ≤ 2.00 %Area RSD ≤ 1.00 %

Injection Carry Over (UV-Vis) Injection volume on column = 10 ul Height carry over ≤ 0.20 %Area carry over ≤ 0.10 %

Injection Carry Over (RID) Injection volume on column = 20 ul Height carry over ≤ 0.40 %Area carry over ≤ 0.20 %

Injection Carry Over (FLD) Injection volume on column = 5 ul (2 ul for 1290 w/ CTC samplers)

Height carry over ≤ 0.40 %Area carry over ≤ 0.20 %

Injection Carry Over (CD) Injection volume on column = 25 ul Height carry over ≤ 1.00 %Area carry over ≤ 1.00 %

Response Linearity (UV-Vis) 5 concentrations of certified reference standard Coefficient of determination (r2) ≥ 0.99900R/F precision ≤ 5.00 % RSD

Response Linearity (RID, CD) 5 concentrations of certified reference standard Coefficient of determination (r2) ≥ 0.99500R/F precision ≤ 10.00 % RSD

Gradient Composition Accuracy (UV-Vis, CD)

20.00 %, 40.00 %, 60.00 %, 80.00 % steps Accuracy ≤ 2.00 %

Gradient Composition Noise and Drift (UV-Vis)

20.00 %, 40.00 %, 60.00 %, 80.00 % steps Composition noise ≤ 2.00 %Composition drift ≤ 2.00 %

Gradient Composition Noise and Drift (CD)

20.00 %, 40.00 %, 60.00 %, 80.00 % steps Composition noise ≤ 3.50 %Composition drift ≤ 3.50 %

Gradient Composition Linearity (UV-Vis, CD)

Linear gradient from 100 % to 0 % Coefficient of determination (r2) ≥ 0.99900**(at start, 50:50 zone, end)***

Sample Temperature Accuracy Temperature = 4.0 °CSamples four vials of water in different tray positions

Diff. from setpoint ≥ –2.0 °C, ≤ 5.0 °C

* Area RSD ≤ 1.00 % with CTC samplers** r2 ≥ 0.997 for 1260 600 bar pump with AIV*** r2 ≥ 0.99000 for CD

Key:



End of Section – Standard OQ Test Specifications for Agilent Analytical-Scale UHPLC Systems

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Operational Qualification (OQ) Hardware (continued)OQ Test Design and Rationale for UHPLC Systems

Many GMP/GLP enforcement agency inspectors now ask firms to provide a risk assessment of their equipment and computer systems plus a science-based rationale for subsequent validation and qualification testing.

GENERAL RISK STATEMENT: Any HPLC, LCMS, UHPLC, UHPLC_MS, GC, or GCMS system used for raw material testing or final drug product / medical device testing in GMP or used in formal GLP studies will likely fall into a HIGH RISK category. This risk assessment will imply the need for IQ & OQ & on-going qualification. ANY USER SPECIFIC RISK ANALYSIS SUPERCEDES THIS GENERAL RISK STATEMENT.

The rest of this section outlines the science-based rationale for each test in the Agilent hardware OQ plus a brief test design and procedure description.

The recommended set of hardware OQ tests described in this EQP derives from Agilent’s intepretation of FDA, USP, and GAMP4 guidelines and other authoritative expert literature.

OQ test design incorporates both modular and holistic testing, which is a proven and regulatory acceptable approach. Direct metrology is used to test pump flow rates and thermal-controlled column compartment and autosampler modules. Holistic chemical testing is used for the evaluation of the following critical instrument characteristics: linearity, precision, signal to noise, and carry over.

Certified reference standards and calibrated traceable thermometers and digital flowmeters are used.

Considering the number of setpoints, parameters, and conditions of each recommended OQ test, the proven concepts of worst case, range, and representative have been applied. If a property or characteristic is known to have its worst performance at one end of a range of use, this is the setpoint that should be tested and other setpoints are not required. If a property or characteristic has no known worst case, testing at the high and low points of the range of use is required. If there are too many possible use cases and conditions to realistically test (and none is a worst case), a representative sample for test is the best approach.

The test design for HPLC systems covers UV absorbance, fluorescence, evaporative light scattering, refractive index, and conductivity detectors; isocratic, binary, tertiary, and quaternary pumps; most autosampler models; and fraction collectors.

Tests for HPLC Systems (Non-MSD)

1. Pump Flow Accuracy and Precision

Rationale: Accuracy of flow is important for comparability between systems and transferring methods. Flow precision is critical for repeatability of peak height and area.

Procedure: A calibrated digital flowmeter is attached to the waste line of the system flowing pure water at representative back pressure provided by a small guard column. Six readings are taken at each setpoint to determine the flow accuracy and precision. Flow accuracy is calculated as the absolute % difference of the mean of the six flow readings against the setpoint. The precision is calculated as the %RSD of the six flow readings. The two default setpoints (0.5ml/min and 5.0 ml/min) are evaluated in the core test. Extra setpoints and flexible test range are only available in customer-configured EQPs for flow, temperature, and some other tests. The repeat measurements of flow in the flow precision test eliminate the need for measurement of retention time precision (which is an indirect approach to determining flow precision).

2. Column Temperature Accuracy and Stability

Rationale: The thermostat accuracy is important for comparability between systems and transferring methods. Column temperature stability is critical for repeatability of peak height and area.

Procedure: A calibrated digital temperature meter and a proprietary probe are used to measure the temperature of the flowing eluent. With the use of a T-piece, the temperature probe is positioned to be in contact with the heated eluent. A typical column compartment temperature range of use is tested. At the high end of the range, after stabilization, the temperature accuracy is calculated as the absolute difference between what was measured and the setpoint. (continues on next page)

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Operational Qualification (OQ) Hardware (continued)OQ Test Design and Rationale for Analytical Scale UHPLC Systems (continued)

After completing this measurement at the low end of the range, six readings are taken every four minutes and temperature stability is calculated as the absolute difference between the highest and lowest measured temperatures. The temperature accuracy is calculated as the average of the six readings compared to the setpoint. All readings are reported in Celsius. Both sides of the Agilent column compartment are tested at the same time.

3. Wavelength Accuracy

Rationale: Wavelength accuracy is critical for accuracy of quantitative and qualitative analysis. Wavelength accuracy is also important for comparability between systems and transferring methods.

Procedure for UV absorbance detector (UV, VWD, DAD, PDA, etc.): A traceable caffeine standard is used to determine the wavelength accuracy. In one procedure, for certain models, the caffeine is trapped in the flow cell and a programmable timetable is used to determine the wavelength maxima (205 and 273 nm) and minimum (245 nm). For other models (for example, DAD and PDA), a caffeine injection is made and a spectrum is acquired. The spectral maxima and minimum are determined directly from the scan or the table of scan results. The wavelength accuracy is determined as the absolute difference between the measured and certified wavelength values.

Procedure for fluorescence detector: The detector cell is filled with pure water. Using a programmable timetable, the excitation (350 nm) and Raman band emission (397 nm) wavelengths are determined. The wavelength accuracy is determined as the absolute difference between the measured and theoretical peaks of Raman scattering (in nm).

4. Signal Noise and Drift

Rationale: This test gives an indication of detector sensitivity and stability.

Procedure for UV absorbance detectors: Pumping water at 1 ml/min, the signal is monitored at a specified wavelength over a twenty minute period. The signal noise is calculated based on ASTM E685-93 as the average peak-to-peak noise in a number of signal segments. The drift is calculated as the slope of the linear regression for the signal.

Procedure for evaporative light scattering detectors: With no flow and the inlet to the detector capped, the signal is monitored over a twenty minute period. The signal noise is calculated based on ASTM E685-93 as the average peak-to-peak noise in a number of signal segments. The drift is calculated as the slope of the linear regression for the signal.

Procedure for refractive index detectors: Pumping water at 1 ml/min, the signal is monitored over a twenty minute period. The signal noise is calculated based on ASTM E685-93 as the average peak-to-peak noise in a number of signal segments. The drift is calculated as the slope of the linear regression for the signal.

5. Injection Precision

Rationale: System precision is critical for accuracy of quantitation. Autosampler performance contributes to system precision.

Procedure: A short column is used to separate the evaluation standard from the void volume. Using a traceable standard, six injections from the same standard are made and the height, area, average height, average area, %RSD of height and %RSD of area are determined and calculated.

6. Injection Carry Over

Rationale: Low carry over from a previous injection is critical for accuracy of quantitative and reliability of qualitative analysis. This test challenges the injector system in the HPLC system.

Procedure: Following the six-injection precision test, a blank injection is made. The carry over result is calculated as a ratio of the area of any residual peak found in the blank injection to the area of the previous injection (expressed as a percentage).

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7. Signal to Noise

Rationale: Sensitivity is a critical performance feature in quantitative and qualitative analysis. A signal-to-noise value of a representative compound at known concentration provides sensitivity statistics. This measurement is especially critical to establish level of detection.

Procedure for UV absorbance detector and refractive index detector: An evaluation standard is injected and the calculated height, divided by the ASTM noise monitored over a specified range, provides the signal-to-noise result. Procedure for fluorescence detector: Using pure water in the flow cell, the signal is monitored at the emission maximum wavelength of the Raman band of water and then, using a timetable, switched to a no emission wavelength where the noise is monitored. Signal to noise is calculated as the height of the Raman band peak divided by the monitored noise in a spectral region where no scattering is expected.

8. Response Linearity

Rationale: The linearity of a detector is a critical parameter to establish for reliable and accurate quantitative results and is important for comparability between systems and transferring methods.

Procedure: A series of five traceable standards which represent typical concentrations range are injected and evaluated. The response linearity is calculated by determining the coefficient of determination (r2) of the peak areas versus concentration. It is now recognized that regression statistics alone are insufficient and non-sensitive indicators of linearity. Therefore, the % RSD of the response factors for all five peaks is also calculated. In addtion, as an optional extra linearity statistic, ratios of peak areas in the set of five injections can be reported. For example, up to two ratios such as Peak 2 to Peak 1 and Peak 5 to Peak 2 can be selected in the EQP Record of Variances section.

9. Gradient Composition

Rationale: Accuracy and stability of solvent mixing online is critical for consistent and accurate quantitative analysis. Gradient composition is also important for comparability between systems and transferring methods.

Procedure: [Pre-requisite: UV detector is installed.] An acetone tracer is used to determine the solvent gradient composition accuracy, stability, and linearity. The test challenges the system by making compositional changes from 0% to 100% in 20% increments. In addition, a linear ramp down from 100% to 0% is performed where the composition linearity is determined between ranges 95, 75, and 25%. All composition accuracies are calculated as the absolute difference between the mean composition at each setpoint and the theoretical composition. Stability is determined by the noise and drift at each composition step. Linearity is calculated from 95% to 5% in the linear portion of the gradient.

10. Sample Temperature Accuracy

Rationale: The thermostat accuracy is important for comparing systems and transfer methods.

Procedure: Four vials are filled with water and allowed to equilibrate to the temperature setpoint. Similar to the column compartment, the temperature of the water is measured using a traceable digital temperature meter and proprietary probe. Accuracy is determined as the difference between the measured temperature and the setpoint.

11. Fraction Collection (only applicable if collector is installed)

Rationale: It is important to demonstrate that a fraction collector can collect fractions based on peak detection or time.

Procedure: Two injections of a traceable standard are made and fractions are collected in peak-based or time-based mode.

This is a qualitative test in which collected fractions are re-injected to prove that they are fractions of the traceable standard.

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The following tests are NOT INCLUDED in the standard OQ for UHPLC but can be ordered as EXTRA COST TESTS.

Test Name Setpoints and Parameters Limits IncludeInjection Linearity (UV-Vis) Any choice of 5 injection volumes.

Constant concentration standard is 5 ug/ml caffeine.

Coefficient of determination (r2) ≥ 0.99900R/F precision ≤ 5.00 % RSD

Injection Response (UV-Vis) Same setpoint as Injection Precision test. Average area ≥ 1,200,000 and ≤ 1,800,000 counts (For standard cell with 20 ul injection. Result is corrected for path length and attenuation.)

Wavelength Accuracy (Extended Test, UV-Vis)

Wavelength 1, 2, 3, 4 = 361, 416, 451, 537 nm [Maximum]

Accuracy ≤ 2 nm

Key:



Additional Test 1. Injection Linearity (optional extra test available in custom-configured EQP)

Rationale: Injection linearity of variable volume UHPLC injector systems is normally not critical to quantitative or qualitative analysis. Most UHPLC analytical methods use fixed and only nominal injection volumes and do not use variable volume injections within a single analysis. However, some users may wish to use variable volume injection if the linearity is demonstrated.Procedure: Five injections of increasing volumes of the same traceable caffeine standard are made. Injection linearity is calculated from the coefficient of determination (r2) of the peak areas versus injection volume. Also, %RSD of the response factor for all five peaks is calculated.

Additional Test 2. Injection Response (optional extra test available in custom-configured EQP)

Rationale: The accuracy of the injected volume is normally not critical to quantitative or qualitative analysis. Most UHPLC analytical methods use fixed and only nominal injection volumes and results are not affected by even moderate inaccuracy in actual injected volume. However, it may be important for comparability between systems and transferring methods, and it is useful as a diagnostic for establishing that the correct injection syringe/loop/device is installed. Procedure: A known traceable caffeine standard is injected six times (in the precision tests) and the average response is calculated. The injection response is the mean of the average areas corrected for sample concentration, cell path length, and attenuation, and the response within an acceptance window indicates correct volume injected.

Additional Test 3. Wavelength Accuracy, Extended Test: (optional extra test available in custom-configured EQP)

Rationale: Wavelength accuracy is critical for accuracy of quantitative and qualitative analysis. Wavelength accuracy is also important for comparability between systems and transferring methods.Procedure for UV absorbance detector (UV, VWD, DAD, PDA, etc.): A traceable holmium oxide standard is used to determine the wavelength accuracy. In one procedure, for certain models, the holmium oxide is trapped in the flow cell and a programmable timetable is used to determine the wavelength maxima (241, 278, 287, 361, 416, 451, 537 and/or 641 nm).For other models (for example, DAD and PDA), a holmium oxide injection is made and a spectrum is acquired. The spectral maxima are determined directly from the scan or the table of scan results. The wavelength accuracy is determined as the absolute difference between the measured and certified wavelength values.

of 16






Operational Qualification (OQ) Hardware (continued)EQP Record of Variances to Setpoints from Standard OQ Specifications

IGNORE THIS SECTION IF YOU ACCEPT AND APPROVE THE FIXED STANDARD QUALIFICATION TESTS AND SETPOINTS RECORDED IN THE PRECEDING PAGES OF THIS STANDARD EQP.

EQP with Variance Approval Process: Customer Actions:1. View in Adobe®; select required setpoint variances below; select the alternative approval statement on page 2.2. Print to paper to save the selections; sign page 2 of this EQP.3. Ensure the approved EQP with Variances is provided to Agilent operator on the day of the first delivery before start of OQ.

Counter-sign and date the Agilent operator signature on this page. [End of EQP with Variance approval process. Next step: wait for your qualification reports.]

Agilent Operator Actions:1. Enter and save the customer change requests on this page into the ACE tool.2. Sign and date this page on the customer copy to verify that you made the changes in ACE; return signed copy to customer

for counter-signature.3. Deliver the qualification by following this EQP and any setpoint variances. (Note: Once the EQP Variances are entered into

ACE these are saved for all future OQ/RQ events where applicable.)

Test Name Setpoint Standard Variance UnitsPump Flow Accuracy and Precision Flow Rate 1 0.500 ml/minute

Flow Rate 2 5.000 ml/minuteColumn Temperature Accuracy and Stability Temperature 1 80.0 °C

Temperature 2 40.0 °CInjection Precision, Carry Over (UV-Vis / RID) Injection Vol. on Column 20 / 10 ulInjection Precision, Carry Over (CD) Injection Vol. on Column 25 ulInjection Precision (ELSD) Injection Vol. on Column 20 ulSample Temperature Accuracy Temperature 4.0 °CResponse Linearity (UV-Vis, RID optional extra statistic)

1st Peak Area Ratio Not applicable2nd Peak Area Ratio Not applicable

Wavelength Accuracy (Extended Test, UV-Vis) Wavelength 1 361 nmWavelength 2 416 nmWavelength 3 451 nmWavelength 4 537 nm

Injection Linearity Injection Volume 1 Not applicable ulInjection Volume 2 Not applicable ulInjection Volume 3 Not applicable ulInjection Volume 4 Not applicable ulInjection Volume 5 Not applicable ul

Injection Response Injection Volume Not applicable ul

For a fully tailored operational qualification program using all the flexibility of Enterprise Edition, contact your local Agilent representative and/or e-mail [email protected] with your OQ test specification requirements. Fees may apply.

Agilent Operator (verifies variances are entered into ACE):

Name:

Signature, Date:

Customer:

Name:

Signature, Date:

of 16






Re-Qualification after Repair (RQ) HardwareIn the event of a hardware breakdown followed by an engineering repair of a qualified instrument, it is necessary to re-qualify the system to an appropriate level before release back into operational use.

Agilent offers a service contract to repair and re-qualify an instrument during the period between scheduled annual OQs.

The level of re-testing is prescribed in the RQ section of ACE: a form is displayed for the operator showing all types of repair possible and the re-testing required. Part of an example form is shown below.

Re-Qualification After Repair

Pump Strategies

Repair/Replace Strategy Modules OQ/PV Testing

Internal pump head parts, active inlet valve (or AIV cartridge), (parts of) check valves, reference valves, inlet manifold or pump drive, or taking pump head apart to clean (versus repair)

Any pump Flow Accuracy & Precision

Pulse damper, pressure transducer Any pump Flow Accuracy & Precision

Multi-channel gradient valve Quaternary Flow Accuracy & Precision Gradient Composition

The full list of repair and re-test guidance is available for review by customers of the RQ service.

The RQ form in ACE prescribes which tests the operator must perform for each repair circumstance. The test procedure, setpoints, and limits will be an exact repeat of the previous OQ test (a so called regression testing strategy).

Dual-Acceptance LimitsWithin the Equipment Qualification Plan (EQP) of the Agilent Enterprise Edition, each of the tests final result can be compared against two different limits if required. This allows customer-configured OQ to report against a User Limit (limit1) and the Agilent Recommended Limit (limit2) simultaneously.

The Standard_EQP documents have both Limit1 & Limit2 values set the same – effectively de-activating this feature. Custom_EQP’s can also be prepared on request, making effective use of the Two-Limit feature of the Agilent Compliance Engine (ACE). In those cases, “Limit2” will always be the Agilent Recommended limit, and “Limit1” will be the limit requested by the user. Agilent will not be under any obligation regarding the OQ testing results against User-requested limits that are more stringent than the Agilent Recommended ones.

of 16






Legal, Endorsement, and Revision HistoryEnterprise Edition and its primary components (ACE software tool, procedures, test design, metrology tools, chemical reference standards, operator training materials) has been designed, developed, tested, validated, and released for commercial use following Agilent’s Life-Cycle Development Quality Assurance methodology.

Date: September 2013

Services R&D Manager: Michael F. Pope. Santa Clara, California USAServices Quality Manager: Julio Hector. Santa Clara, California USA

Enterprise Edition is endorsed by Dr. Ludwig Huber on behalf of labcompliance.com.

ACE software is patented. Copyright is claimed by this statement for all original work comprising Enterprise Edition. Any unauthorized use, reproduction, or translation will be prosecuted to the maximum extent possible by law. All customer copies of EQP approval, final qualification reports, and raw data provided to customer at delivery of the service become the property of the customer.

Revision History of UHPLC Enterprise Edition Protocols.

A.01.83 September 2013 No UHPLC specific changes.A.01.82 April 2013 (1) Added support for (1) G4260A/B and G4621 A/B ELSD Detectors (former Varian 380, 385); (2) High-

Dynamic Range LC Configurations and G4234 column switching valve..– Updated Gradient Composition linear limits for 1260 600 bar pump with AIV to 0.997 from 0.999 running a single gradient test; added option to run two gradient tests (A/C channel and B/D channel) for AIV configuration with 0.999 limit. No regulatory impact for previously approved EQP’s.

A.01.81 January 2013 Added support for (1) Agilent 1220 DAD, (2) additional Waters, Dionex and GE ATKA modules and systems (see Compatibility Matrix for details). Updated step 1–4 accuracy label text in Gradient Composition test (analytical and capillary scales). Calculations remain unchanged. Updated accuracy check calculation in Pump Flow Precision for Preparative Scale sytems. No regulatory impact. Corrected typo on FLD carry-over test limits.

A.01.80. July 2012 Added support for G42204A 1290 Quaternary pump. Re-instated Injection Precision test for FLD systems. Updated acquisition method to measure noise on the Raman current in the Signal-to-Noise test for FLD systems. Improved calculation to separate the artifact from the standard and carry over peaks. Updated ASTM algorithm for Signal-to-Noise and Noise & Drift tests. Updated test limits for 1220 system and Flow Accuracy & Precision test.

A.01.79. April 2012 Updated linear limits for 1260 600 bar pump with AIV.– Added support for diverse Thermo and Waters additional equipment.

A.01.78. February 2012 Added support for Waters H-Class pump, injector, column compartment, valve, and detector; Acquity ELSD. No regulatory impact for previously approved Standard_EQPs.

A.01.77. December 2011 No changes to LC impacting regulatory approvalA.01.76. August 2011 No changes to LC. Protocol revision made independent from ACE revisions. No regulatory impact for

previously-approved Standard_EQP documents.A.01.75. March 2011 (1) Added support for Agilent 1260 Bio LC. No regulatory impact for previously-approved Standard_EQP

documents.A.01.74. September 2010 (1) Added support for Agilent 1220 and 1260 Infinity Systems. (2) Added Tests definitions for non-Agilent

Systems. No regulatory impact for previously-approved Standard_EQP documents.A.01.73. June 2010 (1) Added Additional Tests Selection Boxes. (2) Added Additional Tests Variances tables.

No regulatory impact.A.01.72. January 2010 No UHPLC-specific changes.A.01.71. October 2009 (1) Added initial UHPLC Agilent 1290 Inifinity LC systems support; (2) added E-signature fields; (2) changed

nomenclature used to list limits (NO REGULATORY IMPACT).Earlier revisions No UHPLC support

End of EQP Review Document


Information, descriptions and specifications in thispublication are subject to change without notice.

© Agilent Technologies, Inc. 2013Published in USA, October 22, 2013

www.agilent.com/chem/enterprise

of 16

Standard OQ Test Specifications for Analytical Scale HPLC Non-Agilent SystemsAgilent Enterprise Edition compliance services offer a harmonized testing program across different manufacturers. The same approach and methodology is applied, using tests specially designed to be compatible with all major chromatography data systems and applicable to the different hardware systems.

The following table summarizes Agilent’s recommendation for the qualification of non-Agilent systems. Individual test specifications are defined for general-purpose conditions, with broader operating conditions not optimized for any specific manufacturer. Tests definitions, rationale and procedures are common to the Agilent systems, and therefore described in the main HPLC Qualification documents.

Note the different conditions for some tests depending on the intended operating pressure range.


Pump Flow Accuracy and Precision (below 400 bar)

Flow Rate 1 = 0.500 ml/min (*) Flow Rate 2 = 3.000 ml/min

Accuracy ≤ 5.00% from setpoint (**) Precision ≤ 0.50% RSD

Pump Flow Accuracy and Precision (over 400 bar)

Flow Rate 1 = 0.500 ml/min (*) Flow Rate 2 = 3.000 ml/min

Accuracy ≤ 3.00% from setpoint Precision ≤ 0.50% RSD


Temp 1 = 60.0 °C Temp 2 = 40.0 °C Stability measured @ temp2

Diff. from setpoint ≤ 3.0 °C Diff. from setpoint ≤ 3.0 °C Stability ≤ 1.0 °C

Wavelength Accuracy (UV) 205 nm, 273 nm Accuracy ≤ 3 nm

Wavelength Accuracy (FLD) 350 nm, 397 nm Accuracy ≤ 3 nm

Signal Noise & Drift UV ASTM baseline noise. Slope or regression fit for drift

Noise ≤ 0.100 mAU Drift ≤ 10.000 mAU/hr

Signal Noise & Drift (RID) ASTM baseline noise. Slope or regression fit for drift

Noise ≤ 10.000 nRIU Drift ≤ 400.000 nRIU/hr

Signal Noise & Drift (ELSD) ASTM baseline noise. Slope or regression fit for drift

Noise ≤ 2.000 mV Drift ≤ 5.000 mV/hr

Signal Noise & Drift (CD) ASTM baseline noise. Slope or regression fit for drift

Noise ≤ 0.100 uS Drift ≤ 10.000 uS/hr

Signal to Noise (UV) 250 ng of caffeine ≥ 3000 (6*)

Signal to Noise (RID) 50 ug of glycerin ≥ 2000

Signal to Noise (FLD) N/A ≥ 400

NON-AgiLeNT HPLC HArdwAre OPerATiONAL QuALifiCATiON

Agilent enterprise edition Compliance Services

Page 1 of 4

of 4

Agilent_Recommended_EQP


Document Released: June 2013 Enterprise Edition Compliance Services



Injection Precision (UV, RID) (below 400 bar)

Injection volume on column = 20 ul (***) Height RSD ≤ 2.00% (4*) Area RSD ≤ 2.00%

Injection Precision (UV) (above 400 bar)

Injection volume on column = 10 ul Height RSD ≤ 2.00% Area RSD ≤ 1.00%

Injection Precision (FLD) Injection volume on column = 5 ul Height RSD ≤ 2.00% Area RSD ≤ 2.00%

Injection Precision (ELSD) Injection volume on column = 20 ul Height RSD ≤ 3.00% Area RSD ≤ 3.00%

Injection Precision (CD) Injection volume on column = 25 ul Height RSD ≤ 2.00% (4*) Area RSD ≤ 1.00%

Injection Carry Over (UV, RID) (below 400 bar)

Injection volume on column = 20 ul (***) Height RSD ≤ 1.00% (5*) Area RSD ≤ 1.00%

Injection Carry Over (UV) (above 400 bar)

Injection volume on column = 10 ul Height RSD ≤ 0.20% Area RSD ≤ 0.10%

Injection Carry Over (FLD) Injection volume on column = 5 ul Height RSD ≤ 0.40% Area RSD ≤ 0.20%

Injection Carry Over (CD) Injection volume on column = 25 ul Height RSD ≤ 1.00% Area RSD ≤ 1.00%

Response Linearity (UV) 5 concentrations of certified reference standard Coef. of determination (r2) ≥ 0.99900 R/F Precision ≤ 5.00% RSD

Response Linearity (RID, CD) 5 concentrations of certified reference standard Coef. of determination (r2) ≥ 0.99500 R/F Precision ≤ 10.00% RSD

Gradient Composition (UV) 20, 40, 60, 80% gradient steps Linear Gradient from 100% to 0%

Step Accuracy ≤ 2.00% (7*) Step Noise ≤ 2.00% Step Drift ≤ 2.00% Coef. Of Determination (r2) ≥ 0.99900

Gradient Composition (CD) 20, 40, 60, 80% gradient steps Linear Gradient from 100% to 0%

Step Accuracy ≤ 2.00% Step Noise ≤ 3.50% Step Drift ≤ 3.50% Coef. Of Determination (r2) ≥ 0.99000

Sample Temperature Accuracy Temperature = 5.0 Samples four vials of water in different tray positions

Diff. from setpoint ≥ -2.0 ; ≤ 5.0

Key:Fixed HPLC setpoints/limits Fixed UHPLC setpoints/limits Variance allowed for setpoint(s)

(*) Flow rate 1 = 1.00 ml/min for GE AKTA Flow rate 2 = 2.00 m/min for Waters Acquity

(**) Accuracy ≤ 10.00% for GE AKTA(***) Injection volume = 10 ul for Acquity H-Class

(4*) Height and area RSD ≤ 5.00% for GE AKTA (5*) Height and area RSD ≤ 2.00% for GE AKTA(6*) Signal to noise ≥ 15000 for GE AKTA(7*) Gradient step accuracy, noise, and drift ≤ 5.00% for GE AKTA

For multiple-detector systems, only one execution of the Injection Precision & Carry-Over tests will be performed in the standard test program. Repeat execution of the test can be added as optional tests for a nominal fee.

Standard OQ Test Specifications for Analytical-Scale HPLC non-Agilent Systems (continued)

of 4

Agilent_Recommended_EQP


Document Released: June 2013 Enterprise Edition Compliance Services


extra tests available for HPLC non-Agilent Systems QualificationThe following tests are NOT INCLUDED in the standard OQ for HPLC but can be ordered as EXTRA COST TESTS. You can select the check boxes on the right and attach this document to your OQ EQP documentation for a record of the qualification conditions.

Test Name Setpoints and Parameters Limits IncludeInjection Linearity (UV-Vis) Any choice of 5 injection volumes.

Constant concentration of caffeine standard

Coefficient of determination (r2) ≥ 0.99900R/F precision ≤ 5.00% RSD

Injection Response (UV-Vis) Same setpoint as Injection Precision test.

Average area ≥ 1,200,000 and ≤ 1,800,000 counts (For standard cell with 20 ul injection. Result is corrected for path length and attenuation.)

Wavelength Accuracy Extended tests

wavelength 1 = 361 nm wavelength 2 = 416 nm wavelength 3 = 451 nm wavelength 4 = 537 nm

Accuracy ≤ 3 nm

Fixed setpoints/limits Variance allowed for setpoint(s)

Agilent recommended Volumes for LC injection Linearity Test

Detector Types: UV-VIS, UV,CD

Max Volume Injec Vol 1 Injec Vol 2 Injec Vol 3 Injec Vol 4 Injec Vol 5

5 µl 1 2 3 4 5

10 µl 2 4 6 8 10

20 µl 1 5 10 15 20

25 µl 1 5 10 15 25

40 µl 5 10 20 30 40

50 µl 5 10 25 40 50

100 µl 5 10 20 50 100

250 µl 10 50 150 200 250

500 µl 50 100 250 400 500

900 µl 50 100 200 500 900

1000 µl 50 100 200 500 1000

2000 µl 100 500 1000 1500 2000

Detector type: UV-VIS Surveyor

Max Volume Injec Vol 1 Injec Vol 2 Injec Vol 3 Injec Vol 4 Injec Vol 5

100 µl 20 40 50 60 70

Protocol Revision: LC.A.01.82

Document Released: June 2013


© Agilent Technologies, Inc. 2013Published in USA, June 14, 2013


Page 4 of 4

Agilent Enterprise Edition — Review DocumentRisk Assessment and Conformance to FDA 21 CFR Part 11 ChecklistAgilent Compliance Engine – Main Rev. A.01.20, 01.30, 01.40, 01.50, 01.60, 01.70, 02.00, A.02.10

Conformance Checklist

Software ProductAgilentAutomatedComplianceEngineRevisions A.01.20 1.30 1.40 1.50 1.601.70, A.02.00, and A.02.10.The software enabling tool of the Enterprise Edition compliance service for for LC, GC, MS, SW, UV, and Disso.

DescriptionProprietary commercial software developed by Agilent Technologies Inc. The software is used to manage the procedures, collect data, calculate derived data and results and generate final reports of equipment qualification testing. The reports are electronic records.

Intended Use and Regulatory Environment

Agilent Compliance Engine is intended as a tool for delivering Equipment Qualification services on laboratory instruments such as chromatography systems. The predicate rules affecting this software and intended use are: all the FDA and equivalent international predicate laws (including national GMP’s and GLP’s) that relate to equipment qualification, calibration and system validation.

Risk Assessment: MEDIUM

Risk assessment of a computer system, according to latest FDA guidance and GAMP guidance, depends on the definition and intended use of the electronic records handled by the system. The Agilent Compliance Engine software handles equipment qualification records / calibration records. These records are secondary data - not directly related to either drug product quality or patient safety or confidentiality.

Record Retention Period

GMP: Typically less than 10 yearsGLP: Typically more than 10 years

The retention periods for the equipment qualification records / calibration records produced by Agilent Compliance Engine should be defined by customer policies & procedures. These corporate rules

are in turn interpretations of GMP or GLP regulations. For GMP regulated labs, the retention period must ensure availability of calibration records for relevant lab test equipment up to the date of disposal of the last drug batch record that referenced the lab test equipment.

The retention period for a given record maybe as little as 1 year or as much as 10 years. GMP rules on retention periods of qualification / calibration records vary between country and region.

The retention period guidelines for qualification / calibration records of test equipment used in GLP studies can vary widely from country and region.

Some corporate interpretations of FDA and OECD GLP rules infer an indefinite retention period for all GLP study data including related secondary data such as lab equipment qualification / calibration records.

Raw Data / Original Record Definition

The raw data (GMP terminology) or original records (GLP terminology) for Agilent Compliance Engine are here defined as the electronic records generated as Acrobat pdf documents.

Paper prints of the Acrobat documents are copies. The paper prints represent true and accurate copies of the electronic documents.

of 5 © Agilent Technologies, Inc. 2012

Agilent Enterprise Edition — ReviewDocumentRisk Assessment and Conformance to FDA 21 CFR Part 11 ChecklistAgilent Compliance Engine - Main Rev. A.01.20, 01.30, 01.40, 01.50, 01.60, 01.70, 02.00, A.02.10

Issued: Aug 11 — Revision 0.8 (added ACE version 2.10)


FDA 21 CFR Part 11 Assessment

Reference: 21 CFR Part 11 Part B Electronic Records 11.10 Controls for Closed Systems

a. Validation of systems to ensure accuracy, reliability, consistent intended performance, and the ability to discern invalid or altered records.

Intermediate detector signal electronic data are in human readable form when viewed using Agilent Compliance Engine, EZChrom, Cerity ECM software products or a number of other commercially available viewers in Electronic Document Managements Systems. Paper print copies can be made of the raw data if necessary.

Access to Agilent Compliance Engine machines is limited by operating system security managed by Agilent IT policies.

Agilent Compliance Engine software is validated by the developer (Agilent Technologies Inc.) as part of the Enterprise Edition compliance service R1668A. See “Declaration of Compliance Product Validation Revision Date 15-November- 2005”.

Each individual instance of Agilent Compliance Engine software is qualified by automated IQ at installation. In addition all installations on the Agilent engineer’s production laptops are qualified by automated software IQ and semi-automated OQ plus a manufacturer’s A/D connection calibration check.

b. The ability to generate accurate and complete copies of records in both human readable and electronic form suitable for inspection, review, and copying by the agency.

All the report records and associated information (such as supporting certificates, training data) handled by Agilent Compliance Engine are in Adobe Acrobat pdf.

Copies are complete, accurate and in human readable form in both paper-printed and electronic formats.

c. Protection of records to enable their accurate and ready retrieval throughout the records retention period.

Agilent Compliance Engine protects work-in-progress records by use of software access control and access control to the Agilent Compliance Engine machines. Final records are secured by Adobe Acrobat 7 digital signature and secure burning on to ISO 9660 format CD-ROM. The lifetime of the CD media is 100 years.

These electronic records may in turn then be copied onto secure centralized electronic document management systems (EDMS).

Accuracy and completeness of each report record is ensured by the secure file format.

d. Limiting system access to authorized individuals.

Agilent Compliance Engine software access is limited by a log-in with password rights assigned only to trained and certified operators.

e. Use of secure, computergenerated, time-stamped audit trails to independently record the date and time of operator entries and actions that create, modify, or delete electronic records. Record changes shall not obscure previously recorded information. Such audit trail documentation shall be retained for a period at least as long as that required for the subject electronic records and shall be available for agency review and copying.

The report records generated by Agilent Compliance Engine have system generated time stamps automatically inserted into the footer of each page of the reports.

Qualification Report records, once completed and saved, cannot be altered, therefore no audit trail of changes is necessary or appropriate.

f. Use of operational system checks to enforce permitted sequencing of steps and events, as appropriate.

Agilent Compliance Engine software enforces all the sequences and steps that are critical to quality and data integrity during execution of an equipment qualification protocol.





h. Use of device (e.g., terminal) checks to determine the validity of the source of data input or operational instruction, as appropriate.

11.30 Controls for open systems. Procedures and controls to ensure authenticity, integrity, and as appropriate, confidentiality. Include additional measures beyond 11.10 requirements such as document encryption and use of digital signature standards.

have the education, training, and experience to perform their assigned tasks. Only trained and certified engineer/operators have access to Agilent Compliance Engine machines and software for the purposes of executing instrument qualification.

g. Use of authority checks to ensure that only authorized individuals can use the system, electronically sign a record, access the operation or computer system input or output device, alter a record, or perform the operation at hand.

Agilent Compliance Engine software access is limited by a log-in with password rights assigned only to trained and certified operators.

Access to Agilent Compliance Engine machines is limited by operating system security to authorized individuals.

Individually assigned Agilent Digital certificates are used in any Acrobat digital signatures.

Device checking between Agilent Compliance Engine machines and the Analog Digital Converter is assured by the software driver design and the calibration & OQ check of Agilent Compliance Engine machines. This is the only appropriate device check requirement.

i. Determination that persons who develop, maintain, or use electronic record/electronic signature systems have the education, training, and experience to perform their assigned tasks.

All members of the R&D and product support teams involved in the development of the software

j. The establishment of, and adherence to, written policies that hold individuals accountable and responsible for actions initiated under their electronic signatures, in order to deter record and signature falsification.

The official training modules in Training@Agilent for GXP compliance and operator training courses for Agilent Compliance Engine software covers the above requirements.

k. Use of appropriate controls over systems documentation including: (1) Adequate controls over the distribution of, access to, and use of documentation for system operation and maintenance. (2) Revision and change control procedures to maintain an audit trail that documents time-sequenced development and modification of systems documentation.

Agilent’s product life-cycle documentation system meets these requirements.

Agilent Compliance Engine is a closed system.

However, electronic distribution and sharing of the records produced by the system is envisaged. Acrobat 7 Digital certification may be applied to ensure authenticity and integrity of the records when outside of Agilent Compliance Engine or outside a validated EDMS. This digital signature technology meets the legal requirements for digital signatures in all USA State laws and relevant European Directives.

Part C Electronic Signatures 11.100 General requirements.

Approval of the records by compliant electronic signature can be performed during ‘checkin’ to customers’ own validated EDMS.

SAFE technology electronic signature approval is offered with Enterprise Edition qualification services when Agilent Compliance Engine is combined with Cerity ECM system. The SAFE technology e-signature is technically fully compliant to the electronic signature requirements of 21 CFR Part 11 and ensures a very high degree of security.

Alternatively use of a compliant ‘hybrid’ hand-written ink signature procedure is made possible by the secure e-records with unique identification on every page and document pagination.





11.300 Controls for identification codes/passwords.

a. Maintaining the uniqueness of each combined identification code and password, such that no two individuals have the same combination of identification code and password.

Conclusionc. Following loss management procedures to electronically deauthorize lost, stolen, missing, or otherwise potentially compromised tokens, cards, and other devices that bear or generate identification code or password information, and to issue temporary or permanent replacements using suitable, rigorous controls.Uniqueness of password/

username combination is ensured by use of Windows NT log-on for the Agilent Compliance Engine machine and enforcement of full email address as username for the Agilent Compliance Engine software login. In both cases the username is unique and therefore the combination is unique.

b. Ensuring that identification code and password issuances are periodically checked, recalled, or revised (e.g., to cover such events as password aging).

Passwords/usernames for Agilent Compliance Engine software access are managed by the Agilent Product Support Engineer and will be recalled or revised periodically and for cause. Passwords for Agilent Compliance Engine machines (using Windows log-on) have enforced annual changes.

No tokens, cards or devices are currently used in the Agilent Compliance Engine system.

d. Use of transaction safeguards to prevent unauthorized use of passwords and/or identification codes, and to detect and report in an immediate and urgent manner any attempts at their unauthorized use to the system security unit, and, as appropriate, to organizational management.

Password issuance is at time of operator training and certification. Sharing of passwords is prohibited. Unauthorized use of Agilent Compliance Engine is detectable at delivery of reports generated by Agilent Compliance Engine.

e. Initial and periodic testing of devices, such as tokens or cards, that bear or generate identification code or password information to ensure that they function properly and have not been altered in an unauthorized manner.

No tokens, cards or devices are currently used in the Agilent Compliance Engine system.

Agilent Compliance Engine is a medium risk, commercial-off-the-shelf (COTS) software with adequate controls and electronic records/electronic signatures compliance for its intended use.

AgilentEnterprise Edition Compliance

Technical Overview

Differences between revision A.01.76 Enterprise Edition (EE) qualification products and previous revisions

Enterprise Edition revision A.01.76 is a result of seven years of evolution of a

fl exible service delivery system based on the Agilent Automated Compliance

Engine (ACE). During that time the qualifi cation protocol underwent its own

evolution, resulting in the highly successful A.01.7x series of products. A.01.76

is the result of the migration of the A.01.75 product to the enhanced delivery

platform. In that process the thoroughly tested suite of tests were ported intact.

This means that moving from A.01.7x to this new revision will result in the same

approved test coverage, set points, and limits.

A comparison of revision A.01.76 of the Agilent Enterprise Edition Equipment Qualification Report (EQR) with previous versions of this protocol

2

Enhancements to the A.01.76 Equipment Qualification Report (EQR)

Agilent improved the effectiveness of

the Equipment Qualifi cation Plan (EQP)

process and improved the structure

and clarity of the EQR. The effect is a

substantial gain in overall quality and

effectiveness.

1. The electronic version of the EQP

establishes set point and limit

conditions. The report includes the

name and signature information

attributed to the EQR.

2. Enhanced support for complex

system confi gurations allows a

single comprehensive confi guration

description without need for

attachments or appendix.

3. Chromatographic plots can be

displayed along with meta-data

within each test. Where appropriate,

meta-data are also displayed in

graphical form.

4. All set points for a given test are

contained within the test, for a result

that is easier to review. A single fi nal

Pass/Fail assessment can be made

for all set points within a test.

5. Individual report sections now can

be ordered and confi gured to your

specifi c needs.

6. The summary “Certifi cate of System

Qualifi cation” can be issued as a

standalone document.

7. Independent data analysis removes

any perception of self-justifi ed

acceptance, and eliminates reliance

on other product validations.

8. Handling of attachments is

enhanced to manage all supporting

documentation despite disparate

sources and document types.

Equipment calibration and personnel

qualifi cation records, certifi cates

of analysis for samples used, and

time-stamped comments and

deviation records are managed in

separate sections of the Attachment

appendix. Users are prompted to

validate attachments to ensure

consistency of the fi nal report.

9. Supporting information for the EQR

is optimized for electronic review

and storage. Sections required to

make an acceptable printed version

are added to the document only

when a printed report is requested.

These graphics, taken from example

reports, illustrate improvements made

to the A.01.76 EQR.

Response Linearity : Detector Module 1,

G1314C, UV or UV-Vis: Response Linearity 112000

9000

6000

3000

0

0 70 140 210 280

Are

a

Peak area values

response_linearity002




response_linearity006Regression values

Injection Precision MS : Dectector Module 2,

G6130A - AP-ESI Source: Source Mode 1480000

450000

420000

390000

3600001 2 3 4 5 6

Are

a

Area

Average Area: 414467.7

Low Limit: 373020.9High Limit: 455914.4

Figure 1. Concentration results from Response Linearity test.

Figure 2. Reproducibility of the Injection Precision test.

Figure 3. Session vital constants documented on the front cover and footer of each page of the report,

including system ID and service and creation date/time stamps.

Service Date:System ID:

Friday, July 08, 2011 Creation Date: July 08, 2011 2:16:37 PM6130_RRLC_RA

Page 53 / 85

3

Figures 4 and 5. Graphical representation of the channel composition steps fi rst and second derivative,

for enhanced event-detection reliability in identifi cation and reporting.

Figure 6. Audit log test details, showing data path and host name for traceability.

Impact of differences between EQR revisions

1. No changes to test defi nitions or

testing methodology. The Enterprise

Edition procedural approach is

based on a balanced combination of

metrology and chromatography data,

not based on inference, and without

second-level data. This yields a

system characterization that is free

from risk.

2. Changes to the integration

algorithm: EQR’s generated in

revision A.01.76 use a self-contained

data reduction engine to ensure

independence from the measured

system, and guarantee compatibility

with the native data system.

Suitability of the new calculation

engine is described in the certifi cate

of validation of the delivery tool ACE

2.0. This software application is

designed as a Commercial-Off-the-

Shelf (COTS) product following a

strict life-cycle quality system.

3. Information that does not add value

to the report is eliminated. One-time

information is removed from

pre-approval archival documentation

to eliminate redundancy in service-

specifi c reports.

4. Some logging information moved

to test-specifi c section. Examples

include the “Data Audit Log”,

now integrated into each test,

where it is relevant to the results

and now easier to review. This

follows enhancements made in

automation and traceability, and

more fl exible support for use-cases.

This eliminates the need to copy

data from the system controller

(chromatography data system, or

CDS) to the qualifi cation engine

(ACE 2.0) – now integrated into the

same logical unit.

5. Some sections have a slightly

modifi ed structure to support the

primary use of the A.01.76 EQP as an

electronic document – yet it remains

completely compatible with paper-

based record retention policies. For

instance, the EQR paper signature is

moved to the attachments section.

ACE A.01.7x Name ACE 1.76 EQR Status Regulatory Impact

1 Report Cover Has new graphics Default None

2 Printed Signature Moved to Attachments section Optional None

3 Disclaimer & Warranty Now included on the signature page Default None

4 Table of Contents No changes Default None

5 Test Summary No changes Default None

6 Report Details Superseded now that sections and their sequence order are confi gurable Removed None

7 Concise Revision History Name Changed to “Protocol Details”. Lists revisions per individual test Default None

8 Detailed Revision History Available as external document Removed None

9 Scope & Purpose Not part of the qualifi cation report Removed None

10 Glossary No major Changes. Eliminates non-service related terms. Optional None

11 Qualifi cation Details. Renamed “Service Details”. No other changes. Default None

12 Instrument Details No Changes Default None

13 Protocol, Materials & Calibrated Tools Moved to independent sections Default None

14 General Procedure & Data Export Not part of the qualifi cation results. Removed None

15 Calculation Formulas No changes. Optional None

16 Declaration of Change Control No formal changes Default None

17 Tests Reports No formal changes. New calculation engine. Default Under COTS

18 Digital Data transfer log Removed as independent section. Data is interleaved into each specifi c test. Removed None

19 EQR Electronic Attachments Superseded by the new Attachments section Default None

20 EQR Reference Documentation Superseded by the new Attachments section Default None

21 Electronic Signature No major changes Default None

22 Certifi cate of System Qualifi cation No changes. Optional placement in front or end of report. Can also be issued as stand-alone document

Default None

Information, descriptions and specifi cations in thispublication are subject to change without notice.

© Agilent Technologies, Inc. 2011Published in USA, December 8, 2011

5990-9518EN


Page-by-page comparison of A.01.75 and A.01.76 reports, with assessment of individual impacts

ACE A.01.76 has the same level of

report detail as A.01.75. The report

format aggregates test and related

sections, is easier to review, while

enhancing overall data quality and

information richness of the service.

The report is supported by extensive

graphical elements and corroborated by

auxiliary documents to assure a self-

contained, audit-ready fi nal document.

The following table itemizes the

individual sections within the EQR,

denoting their differences from

previous revisions and assessment of

its regulatory impact to the service.

Note that without exception there

are no modifi cations made beyond

a layout and document structure

re-arrangement, all immaterial to

the signifi cance of the regulatory

information provided by the service.

Why Has Agilent Introduced The New Compliance Service, Called Enterprise Edition? Table of contents: [click on title for fast navigation]

What Are The High Level Changes In Enterprise Edition And What Were The Drivers For These Changes?

Any Other Practical Or Process Changes In Enterprise Edition?

Let’s Dive Into The Details – How Do The Protocols And Tests In Enterprise Edition Compare To Classic Edition?

List Of Enterprise Edition OQ Tests Versus Classic OQPV Tests For LC:

What About The Reports, How Are These Different To OQPV Reports?

What Would I Have To Do If I Wanted To Move My Annual OQ Service From Classic To Enterprise Edition?

What Are The Main Risks To Migrating To Enterprise Edition And How To Avoid Them?


Introduction Agilent (then we were HP Analytical) introduced OQPV for our own LC and GC instruments in the early 1990’s and since then we have delivered well over 100,000 OQPV reports to customers around the world. Despite the undoubted success and acceptance of our old OQPV (now called Classic Edition to distinguish from the new Enterprise Edition service) times have changed. Expectations and requirements of an OQ have slightly shifted. The number and type of instruments and software used by our customers has increased. And of course we are truly in the new world of computers and electronic media. So Agilent set out with a team of international experts 3 years ago to create an upgraded compliance service that would meet the new demands but crucially maintain the fundamental requirements:

• Always pass FDA and national agency audits without over-testing or under-testing;

• Challenge the LC or GC system with a scientifically sound methodology that provides valuable performance data.

• Meet the quality needs of customers and the spirit & intention of the GLP & GMP laws.

• Offer this service at a cost-effective price that makes it more than just worthwhile – we hope it is the simplest & best qualification choice that a customer can make.

What Are The High Level Changes In Enterprise Edition And What Were The Drivers For These Changes? The first big driver was the software environment. A greatly increased number of chromatography data system (CDS) products are available to control LC and GC systems. Agilent has ChemStation, Cerity, EZChrom, OpenLab and some specialist LCMS/GCMS software. Our customers also use Empower, Chromeleon, Atlas, Turbochrom and many others. Classic OQPV was built into ChemStation software. The Classic OQPV is a miracle of validated and almost fully automated OQ testing. But these benefits are therefore limited to Agilent instruments running on ChemStation. To provide all our customers, and customers of non-Agilent instruments, a single OQ solution as good as (or better than) OQPV - it was clear we had to develop an automation tool independent of ChemStation and any other CDS. The Agilent Compliance Engine (ACE) is our new software tool that manages the workflow and protocols, calculates results and produces the reports. Naturally it is fully validated and tested. Our service engineers carry “ACE laptops” in the same way as they carry “ChemStation laptops”. Alternatively our contract customers can have the ACE software on their own laptops or installed with Agilent OpenLab networked CDS.

© Agilent Technologies, Inc. 2008 Page 1 of 8 Document Release Date: May 2008

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What Are The High Level Changes In Enterprise Edition And What Were The Drivers For These Changes? (continued) Another driver, somewhat related to the first, was the demand that Agilent performs the LC and GC qualification using the customers’ own CDS as controller. Theory and good practice in validation implies testing in the everyday operating conditions and using the full computer + hardware system in a ‘holistic’ manner. Classic OQPV did not allow this. Enterprise Edition does. Additionally, our customers demanded the exact same OQ on their non-Agilent instruments. Sometimes called ‘multi-vendor compliance’ this capability is fully realized in Enterprise Edition by virtue of:

• The independence of ACE software • Extensive R&D to make a protocol of tests that

works on Agilent and non-Agilent LC and GC with the same robustness and reliability as old OQPV

• Training for our service engineers on both the hardware & software of the main non-Agilent systems

The third driver comes from shifts in typical LC usage and the greater regulatory enforcement we see. Qualification is a fairly mature subject nowadays. No longer are customers simply asked ‘do you perform qualification and calibration?’ FDA and EMEA inspectors increasingly look deeper and check that annual OQ adequately (within reason and practicality) tests the range of operational use of an LC or GC. The GMP and GLP guidelines have always stated this, there’s no change in the regulations. It is the range of use that has shifted and in parallel the regulatory enforcement.

Classic OQPV tests HPLC pump flow rate performance at 1ml/min and 2 ml/min set points. (1.5ml/min flow rate is found in hundreds of analytical methods around the world). Nowadays we see customers running much lower flow rates and much higher flow rates. Also many customers use some LC methods with elevated column temperature. OQPV only tested at 40C. Most of the metrology tests in Enterprise Edition now allow a wider range of testing. Our HPLC pump flow test in Enterprise Edition now defaults at the recommended points 0.500 ml/min and 5.000 ml/min. The Column Compartment is tested at 40C and 80C as the standard OQ set points in Enterprise Edition. The fourth driver follows from the third. One size OQ may not fit all needs. We therefore made the service to allow customers to have an OQ protocol made especially for their set points and even added some extra tests not in OQPV that have long been requested by customers. Agilent provides a standard protocol – the Global Equipment Qualification Plan (EQP) – which we believe is the simplest choice and should meet most requirements. But now it is possible for customers to select some set point changes in a ‘Variance to Global EQP’ section. This is a simple selection page in the Global EQP Review Document. For deeper changes than set points (such as extra tests, limit changes, custom-forms etc.) - a customer-configured EQP can be made on demand. Customers can simply make their change requests via their Agilent representative or communicate directly to Agilent corporate via a special email address: [email protected]

Any Other Practical or Process Changes in Enterprise Edition? Yes. Approval of the protocol (called EQP) before execution of the OQ is massively simplified, especially for GC systems. For GC, a customer needs only to sign the recommended EQP and this covers all configurations (inlets, detectors etc.) of Agilent GC in his lab. No more need for individual GC protocols to be made each time before a scheduled OQ, sent by mail as paper document and approved by customer for each OQ event. It’s the same simple process for LC, LCMS & GCMS. Approval of the Global EQP also covers the hardware IQ protocol and any software IQ & OQ ordered at time of new instrument purchase. All the tests & checks in our standard hardware IQ and software IQ & OQ are listed in the Global EQP for each of the four techniques – LC, LCMS, GC and GCMS. Approval of the reports, called Equipment Qualification Reports (EQR), is the biggest change. The standard deliverable is a CD disk with links to the IQ and/or OQ report(s) plus raw data and other supporting information. The EQR is a secure pdf with a single page for customer approval signature – compare this to over 80 pages in OQPV that need both service engineer and customer to sign & date at the bottom of each of the paper sheets. This is all made possible by the technology of secure pdf and active pdf forms – fully proven electronic media, 100% acceptable to FDA and national agencies, 21 CFR Part 11 compliant records – and you can always print to paper anyway. This design meets Agilent’s intentions to follow FDA’s GMP for 21st Century initiative, world-wide environmental concerns over excessive paper usage and many customers’ strategies towards paperless (or ‘less paper’) laboratories.


mailto:[email protected]

Let’s Dive Into The Details – How Do The Protocols And Tests in Enterprise Edition Compare to Classic Edition? The answer is multi-dimensional; we’ve already mentioned single protocols, pdf reports, customer selectable set points, works on non-Agilent instruments & software and other enhancements. But it’s also worth noting that Agilent made a complete re-analysis of our OQ test design for LC and GC and MS systems. The goal was an ideal OQ – avoid over-testing or under-testing; align with current literature and international norms but do not significantly deviate from the Classic OQPV given its ‘international bench-mark’ status. Agilent hired more internationally recognized experts into the development team and used the input of independent critics (including customers and agency representatives) to assess what changes and additions should be made to Classic OQPV. Concepts that have not changed at all include:

• Always perform direct metrology for temperature and flow using the best calibrated test equipment – indirect measurements for flow and temperature, as used in some competitor protocols, were considered susceptible to error caused by variation in columns/ambient conditions etc. and therefore regardless of their design elegance, the inferred final results can never be as absolute or comparable as direct metrology.

• In LC tests avoid the variable contribution to the system performance of the analytical column, by not inserting a test column – OQ aims to test only the hardware, not hardware plus an arbitrary choice of analytical column.

• We continue to use caffeine as the chemical reference standard for LC precision, carry-over, linearity and UV detector wavelength accuracy tests. It is a ‘representative sample’, has continuity with OQPV and matches international standards and …

…published literature, it has proven acceptability to auditors, safety & stability, ease of use, cost, accuracy of pre-made solutions. And the fact that it has a nice spectral maximum at 205nm makes it the best choice for low UV verification. The names of the tests are similar or identical to OQPV. • All the calculation formulae remain the same where

the test design is unchanged. • The standard OQ suite of tests for GC is kept the

same in terms of operator procedure and limits. • All service engineers must be trained and certified

before they can deliver the service. • The software tool and the test designs are fully

validated and maintained for quality/bug fixes etc. by a large support team following Agilent’s ISO approved life-cycle methodology.

IQ checks are the same in Enterprise Edition as in Classic Edition IQ. Changes:

• Now called OQ not OQPV to align with literature and current guidance nomenclature for GMP/GLP.

• Wander is a unique Agilent proprietary algorithm. This is removed to align with literature and other comparable protocols.

• The holmium oxide internal check is not reported in Enterprise Edition OQ because this was considered a pre-OQ diagnostic or calibration check. It is anyway performed in Agilent PM service before the OQ.

• All precision tests (flow precision, injection precision and temperature stability over time) use 6 readings to align with latest literature & guidance and allow statistically comparable RSD results.

None of the changes affect the regulatory compliance status.

Enhancements and Additions: • The Gradient Performance test has been re-designed

and enhanced. A different gradient slope is used that tests & challenges more aspects of gradient performance and provides some extra very useful information.

• The column compartment temperature test now uses a special T-piece that allows measurement of the temperature of the water flowing out of the thermal exchange blocks.

• Signal to Noise test has been added to; ensure cell cleanliness (in LC), replace absolute area check (in GC), harmonize with MS qualifications that require signal to noise checks, provide a comparable sensitivity results and thereby provide more system performance data.

• To align with current literature and provide more sensitive measure of linearity - the response linearity test now adds Response Factor (R/F) Precision.

• For labs running non-Agilent CDS (e.g. Empower): we can control the instrument during OQ with Empower, collect the digital signal data from Empower, calculate the results in ACE – this provides a full ‘holistic’ OQ that simultaneously qualifies the instrument hardware and the Empower control & data acquisition.

• Two Limit Feature: Each test final result can be calculated against two limits if required. This allows customer-configured OQ to report against a User Limit (limit1) and the Agilent Recommended Limit (limit2) simultaneously. Or, as is common in process instrument calibration, the idea of a Warning Limit and Action Limit can be applied. Lab workers are used to Upper Limit and Lower Limit in their control chart procedures but Two Limit Reporting is new to LC and GC qualification. The standard Global EQPs have both limit1 & limit2 values set the same – effectively de-activating this feature.


List of Enterprise Edition OQ tests for 1200/1100 LC versus Classic OQPV tests for 1100 LC:

Test Name in Enterprise Edition Set Point / Parameter in Enterprise Edition for 1200/1100 series LC

Limits in Enterprise Edition A.01.60 Difference to Classic OQPV

Pump Flow Accuracy and Precision Flow rate 1 = 0.500 ml/minute

Flow rate 2 = 5.000 ml/minute

Accuracy <=5.00%

Precision <= 0.50%

Same limits.

Set points widened from previous 1ml/min and 2ml/min


Temperature 1 = 80.0 C* Temperature 2 = 40.0 C For any temperature

Accuracy <=3.0C Accuracy <=2.0C Stability <=1.0C

Same limit for the 40C set point as OQPV. Stability was only measured at 40C with 0.5C limit in OQPV. Test design is enhanced to measure flow temperature in Enterprise Edition whereas OQPV tested the thermal block temperature.

Wavelength Accuracy (UV-VIS) Wavelength 1 =205nm [Maximum] Wavelength 2 =245nm [Minimum] Wavelength 3 =273nm [Maximum]

<=2 nm Same limit & set point

Wavelength Accuracy (FLD) Wavelength 1=350nm [Maximum] Wavelength 2=397nm [Maximum]

<=3 nm Same limit & set point

Signal Noise and Drift (UV-VIS) Noise Drift

Noise VWD (0.04), DAD/MWD (0.05). Drift VWD (0.5), DAD/MWD (5.0)

Same limits (mAU and mAU/hr) The proprietary & unique Wander calculation in OQPV is removed.

Signal Noise and Drift (RID) Noise Drift

<= 10.000 nRIU <=400.000 nRIU/hour

Same limit & set point Same limit & set point

Signal to Noise (UV-VIS) Signal to Noise >= 3000 New test

Signal to Noise (RID) Signal to Noise >=2000 New test

Signal to Noise (FLD) Signal to Noise >=400 New test

Injection Precision (UV and RID) Height RSD Area RSD

<=2.00% <=1.00%


Injection Carry Over (UV-VIS and RID)

Height Carry Over Area Carry Over

<=0.40% <=0.20%



Test Name in Enterprise Edition Set Point / Parameter in Enterprise Edition for 1200/1100 series LC

Limits in Enterprise Edition A.01.60 Difference to Classic OQPV

Response Linearity (UV-VIS)

Coefficient of Determination (r2) R/F Precision

>=0.99900 <=5.00%

Same limit & set point New parameter & limit

Response Linearity (RID)

Coefficient of Determination (r2) R/F Precision

>=0.99500 <=10.00%

OQPV limit is 0.9990. Injection volume was 2uL in OQPV this is now 5uL New parameter & limit

Gradient Composition Composition Accuracy, Composition Noise, Composition Drift <=2.00% New test design, new parameters.

High Coefficient of Determination (r2) Mid Coefficient of Determination (r2) Low Coefficient of Determination (r2)

>=0.99900 >=0.99900 >=0.99900

New parameter & limit. This tests linearity at start of gradient. New parameter & limit. This tests linearity at the 50:50 zone. New parameter & limit. This tests linearity at end of gradient.

Sample Temperature Accuracy

Set point 4C Additional Set point is Selectable

>= -2.0C to <=5.0C +/-3.0C setpoints >10C C

Same limit & set point hoice not available in OQPV

Injection Linearity (UV-VIS only) Coefficient of Determination (r2) R/F Precision

>=0.999000 <= 5.00%

New optional extra test - choice not available in OQPV

Injection Response (UV-VIS) For a known injection vol. / conc. / path length the peak area is predictable (within a range).

>= 1,200,000 to <= 1,800,000 counts

(std cell path length)

This is a new semi-quantitative test of Injection Accuracy - choice not available in OQPV

*For routine qualification of installed base 1050, 1090 LC systems the column temperature set point recommendation is 60C limit +/- 3C The new instruments – LCMS, ELSD, CTC etc. never were covered by Classic OQPV so are not listed here. Injection Linearity and Injection Response are only available in Custom EQP For GC there are no significant changes to set points and limits in the core OQ tests. The main changes are:

• The signal to noise test replaces the old absolute area test and oven temperature is now measured directly with calibrated probe & meter. • The harmonized look and feel of the reports (EQR) is an improvement and “tidy-up” of the Classic reports which were different for different GC models. • The thermal qualification and response linearity tests that were separate services are now simply optional extra tests in Enterprise Edition – so this further harmonizes

the look & feel of GC reports.


What About The Equipment Qualification Reports (EQR), How Are These Different To OQPV Reports?

The easiest way to check is simply to look at the extract of an example hardware OQ report provided in EQP attachment. The main differences are: • A report (plus all raw data) is delivered to a customer as a single secure pdf on a dedicated CD disk. View it on your computer using freely available Acrobat Reader ™. • It’s got a color front page and one click to the back pages shows a summary of results that can be used as your Qualification Certificate. Print just these 4 or 5 pages for

your paper copy and this will save paper, provide all the summary information required and you can keep the pdf records on the disk and/or your own network storage system for full auditable electronic records.

First Two Pages of EQR Last two or three (depends on size of system & OQ) Pages of EQR - the Certificate • In between the two front cover pages and certificate back pages of a hardware EQR are:

o All the details and descriptions of the tests & the system being tested o A detailed test summary section that shows pass/fail per test, the number of times each test was run and overall OQ status o The raw values and calculated results for each test run plus pass/fail status and Chromatograms o Data integrity and audit log pages to ensure trustworthiness and allow easy traceability to raw data o Copies of certificates for the equipment, chemical standards and service engineer training o Sections with General information, glossary, list of Formulas etc. Request these to be not included in future EQR to make shorter reports if you have multiple OQs delivered.


What Would I Have To Do If I Wanted To Move My Annual OQ Service From Classic To Enterprise Edition? The simplest answer is - just download and approve one or all of the Agilent published EQPs for LC, LCMS, GC or GCMS (as required) and order the service contract as usual. But most customers have situations that require slightly more complex actions. If a lab has an SOP on calibration/qualification that references the Agilent OQPV by name or even copies out the OQPV tests and limits - we need to ensure Agilent’s new service does not clash with a customer’s SOP. Check carefully the words in the SOP for any exception phrases such “…or approved alternative” or “… or following Agilent’s current recommended procedures”. Many customers have simply made their old SOP obsolete– the EQP approval substitutes for an SOP. Some firms have an efficient SOP deviation process where QA Manager/Director can issue a simple form stating the Agilent Enterprise Edition service and the signed EQP(s) is an approved alternative to the current local Qualification SOP. This allows instant use of Enterprise Edition and gains you time to consider how/whether to make a new SOP. For thorough QA review and approval we provide a description of the service in the Global EQP Review Documents, more information on the Agilent web site Compliance Services section, a Part 11 Conformance document and example EQP as attachments to each Global EQP and this document. If the above is not enough, and a “vendor audit” is deemed appropriate by your QA Department we provide a CD with Agilent’s Life-Cycle documentation proving the full testing & validation of Enterprise Edition and ACE. This CD is available to QA auditors under signed confidential disclosure agreement – having the documents on CD has saved firms the expense of on-site audit visits to our offices in Delaware, USA or Waldbronn, Germany.

What Are The Main Risks To Migrating To Enterprise Edition and How to Avoid Them? We don’t believe there are any regulatory compliance risks using Enterprise Edition – in fact we are confident it is the safest, most sustainable and convenient option for firms large and small. But the previous chapter mentioned the need to ensure your own SOPs align with (or at least do not clash with) the protocols of Enterprise Edition. Keeping a copy of your signed approval of your EQP(s) is an expectation. Keeping copies of the reports and your approvals is essential. The CD and report format make that easier and more convenient than paper reports to search for past records and performance data. Ink signatures on the page two print-out of the secure pdf report and/or on the EQR CD disk; are both 21 CFR Part 11 compliant ‘hybrid ink on paper signatures linked to an electronic record’. At first some customers found the Agilent service engineer took longer to deliver the LC OQ report because there are some ‘first-time’ preparation things to do. After that Enterprise Edition OQ takes about the same time as Classic OQPV on average. Some early engagements had lost time at the first OQ events because the customer had not approved the EQP or wanted to make last minute adjustments. Pre-approval of EQP is therefore checked now by our schedulers when they call customer to arrange the dates of the PM & OQ event. A Qualification Binder is shipped with new instruments ordered with Enterprise Edition IQ & OQ and is provided for all systems under a PM & OQ contract. To ensure any scheduled Agilent service engineer that arrives on-site will execute the right customer-configured EQP you approved – keep a CD copy handy in the lab, just in case your regular engineer (who knows your requirements and has your EQP in his ACE laptop) is not available. Agilent engineers save a copy of the approved EQP on every report CD – so once the first one is completed there is always a copy for any other Agilent service engineer to follow. Once the first couple of OQ deliveries are completed in a lab contract and you gain familiarity with the new report style etc. then the benefits and efficiency gains start to be fully enjoyed. We can reduce the size of reports by turning-off the repetitive text sections. The first time you need to electronically forward a copy of an OQ report for remote reviewing (because the usual approver is out of office) or have to search & compare instrument performance data across multiple makes of LC in your lab or have an external audit of your lab’s qualification system – you’ll appreciate why your firm invested in Enterprise Edition compliance services.



Yes, in the following table.

Table: List of Characteristics of an Analytical Instrument Qualification (AIQ) Program and check against Enterprise and Classic Edition OQ programs

Characteristic Enterprise Edition OQ Classic Edition OQPV

Meets the letter, spirit & intentions of cGMP and GLP regarding Equipment Qualification Yes Yes

Acceptable to (and used by the Labs of) International Agency auditors Yes Yes

QA approved system in major Pharmaceutical firms Yes Yes

Compatible with Agilent LC, LCMS and GC, GCMS instruments Yes Yes

Compatible with leading non-Agilent LC and GC instruments so can be used as an Enterprise-wide program Yes No

Compatible with ChemStation CDS Yes Yes

Compatible with all Agilent CDS and most non-Agilent CDS (e.g. OpenLab, EZChrom, MassHunter, Empower) Yes No

Adequate for compliance without delivering “over-testing” Yes Yes

Provides a protocol with fixed recommended tests & limits Yes Yes

Provides customer selectable setpoints then a fixed protocol for future use, containing these tests & limits Yes No

Comprehensive final report with automated results calculation and pass/fail status reporting Yes Yes

Flexible size final report in secure pdf that can be printed to paper in full, or in part (to save paper) Yes No

Final report in secure pdf with single signature Yes No

Reports with searchable electronic data & results Yes No
