Equipment Qualification Plan (EQP) · (C) Agilent Technologies Inc. 2005-2009 Page 4 of 22 No...

Standard_EQP_UHPLCMS Document Released: October 2009 Enterprise Edition Compliance Services

Qualification of UHP_LCMS Systems

REVIEW DOCUMENT NAME:Standard_EQP_UHPLCMS

Equipment Qualification Plan (EQP)Agilent Enterprise Edition Compliance Services

1290 Infinity UHPLC Series with 6000, 6100, 6200, 6300, 6400,and 6500 Series LCMS Systems

Standard_EQP_LCMS Document Released: October 2009 Enterprise Edition Compliance Services

(C) Agilent Technologies Inc. 2005-2009 of 22 No reproduction, translation or use without permission

ACE Software

(a) (b) (c)

(d) (e) (f) (g)



pcoombes

Stamp



pcoombes

Placed Image

pcoombes

Placed Image

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?

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

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

http://www.chem.agilent.com/cag/wad/forms/showform.asp?fpv_id=601

pcoombes

Placed Image

http://www.chem.agilent.com/Scripts/Generic.ASP?lPage=59954&indcol=N&prodcol=N

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

Column Temperature Accuracy and Stability

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.


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


Agilent Enterprise Edition

Risk Assessment and Conformance to FDA 21 CFR Part 11 Checklist Agilent Compliance Engine Rev. A.01.20, 01.30, 01.40, 01.50, 01.60, 01.70 Conformance Checklist

Software Product Agilent Compliance Engine Revisions A.01.20/30/40/50/60. The software enabling tool of the Enterprise Edition compliance service for LC, GC and MS.

Description Proprietary 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 years GLP: Typically more than 10 years

Issued: May 09 – Revision 0.6 (added ACE version A.1.70) Page 1 of 4 © Agilent Technologies Inc. 2005-2009

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.



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.

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.

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.

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.

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

e. Use of secure, computer-generated, 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.



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.

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

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 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.

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.

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.

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 ‘check-in’ 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.

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 log-in. 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 NT log-on) have enforced annual changes.

c. 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.

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.

Conclusion

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.

1 of 2

© 2005-2009 by Agilent Technologies

Equipment

Qualification Report

Document Revision A.01.70

Enterprise EditionCreation Date: 15-Jun-2009 11:26

Technique Type:LCMS - Operational Qualification

System ID: Agilent 6130 single quad LCMS

EQP Name: Standard_EQP_LCMS

Service Date: 15-Jun-2009

Organization Name: Agilent Technologies Inc

Organization Location: Englewood, CO

Section PagePage

1 / 21/73

2 of 2

© 2005-2009 by Agilent Technologies Enterprise Edition Compliance Services

Equipment Qualification Report

This is the report of the qualification testing performed on the system identified on the front cover and the footer. Refer to test details(for the IQ) and the test summary section (for OQ and RQ) that follows on page 3 for final qualification status. The original copy of thisEquipment Qualification Report (EQR) is a secure electronic document in Acrobat 7 format.

Signatures indicating EQR review and approval may be maintained (1) as paper records following local procedures or (2) throughelectronic approval using electronic document management systems. Any additional system release processes shall follow localprocedures and are beyond the scope of this document.

The following table (which is always blank in the original electronic record) is provided for hybrid paper/electronic record signatures. Asrequired, print and sign this page or add your electronic signature.

Name/Role (Printed) Signature Date

________________________________________________________________________________________________________________________

________________________________________________________________________________________________________________________

________________________________________________________________________________________________________________________

________________________________________________________________________________________________________________________

________________________________________________________________________________________________________________________

________________________________________________________________________________________________________________________

REGULATORY DISCLAIMERThis document provides a protocol to verify and record instrument configuration and evidence of proper operation. It has been prepared fromour interpretation of applicable regulations as well as industry best practices. The document is designed to provide an important component of acomplete compliance package. Validation depends upon many factors and use of this protocol alone does not assure compliance. AgilentTechnologies makes no promises or representations as to its sufficiency for any specific regulatory program.

WARRANTYAgilent Technologies makes no warranty of any kind to this material, including but not limited to, the implied warranties or merchantability andfitness for a particular purpose. Agilent Technologies shall not be liable for errors contained herein or for incidental or consequential damages inconnection with the furnishing, performance, or use of this material.

All rights reserved. Reproduction, adaptation, or translation without prior written permission is prohibited, except as allowed under the copyrightlaws. November 2005.

________________________________________________________________________________________________________________________Service Date: 15-Jun-2009 Creation Date: 15-Jun-2009 11:26System ID: Agilent 6130 single quad LCMS

Cover Section PagePage

2 / 22/73

Enterprise Edition Compliance Services© 2005-2009 by Agilent Technologies

LCMS - Operational Qualification

Table of Contents

Section Page________________________________________________________________________________________________________________________

Service Date:________________________________________________________________________________________________________________________

15-Jun-2009 Creation Date: 15-Jun-2009 11:26System ID: Agilent 6130 single quad LCMS

Table of Contents Section Page 1 / 2

Test Summary 5________________________________________________________________________________________________________________________

Report Details 7________________________________________________________________________________________________________________________

Concise Revision History 8________________________________________________________________________________________________________________________

Scope and Purpose 9________________________________________________________________________________________________________________________

Glossary 10________________________________________________________________________________________________________________________

Qualification Details 12________________________________________________________________________________________________________________________

Instrument Details 13________________________________________________________________________________________________________________________

Protocol, Materials, and Calibrated Tools Details 17________________________________________________________________________________________________________________________

General Procedure 22________________________________________________________________________________________________________________________

Calculation Formulas 26________________________________________________________________________________________________________________________

Declaration of Change Control 31________________________________________________________________________________________________________________________

Tests 32________________________________________________________________________________________________________________________

Pump 1 Flow Accuracy and Precision 32________________________________________________________________________________________________________________________

Pump 2 Flow Accuracy and Precision 34________________________________________________________________________________________________________________________

Column Temperature Accuracy and Stability 36________________________________________________________________________________________________________________________

Vacuum Verification 38________________________________________________________________________________________________________________________

Scan Verification (AP-ESI) 39________________________________________________________________________________________________________________________

Response Linearity (MSD/AP-ESI) 42________________________________________________________________________________________________________________________

Injection Precision (MSD/AP-ESI) 49________________________________________________________________________________________________________________________

Injection Carry Over (MSD) 57________________________________________________________________________________________________________________________

Signal to Noise (MSD/AP-ESI) 61________________________________________________________________________________________________________________________

Digital Data Transfer Audit Log 64

Page

________________________________________________________________________________________________________________________

3/73



Test SummaryDocument Revision A.01.70

Purpose

This section includes a status for each scheduled test and the overall qualification. For each test that is run, (1) the status isautomatically determined based on pre-defined limits, and (2) the total number of times the test was run is displayed.

To view detailed results and specifications for a test, refer to the test result sections in the body of this EQR. In Adobe, use the searchtool to navigate directly to a particular test.

Test Status


Test Summary Section Page 1 / 2

Pump 1 Flow Accuracy and Precision

Status: PASS Runs: 1

Pump 2 Flow Accuracy and Precision




Vacuum Verification


Scan Verification (AP-ESI)


Response Linearity (MSD/AP-ESI)


Injection Precision (MSD/AP-ESI)


Injection Carry Over (MSD)

Status: PASS Runs:

Page

1

5/731 of 1



Report DetailsDocument Revision A.01.70

Purpose

The content of the report will be as follows.

Section________________________________________________________________________________________________________________________

Cover Included in this report

Test Summary Included in this report

Report Details Included in this report

Concise Revision History Included in this report

Detailed Revision History Not included in this report

Scope and Purpose Included in this report

Glossary Included in this report

Service Details Included in this report

Instrument Details Included in this report

Protocol, Materials, and Calibrated Tool Details Included in this report

General Procedure and Data Export Procedures Included in this report

Calculation Formulas Included in this report

Declaration of Change Control Included in this report

Tests Included in this report

Digital Data Transfer Audit Log Included in this report

Chromatograms/Traces Included in this report

Attachments Included in this report

Certificate of Qualification Included in this report

Service Date:________________________________________________________________________________________________________________________


Report Details Section PagePage

1 / 17/73

1 of 1



Scope and PurposeDocument Revision A.01.70

This Equipment Qualification Report (EQR) documents the characteristics of the system listed in the footer. The tests and acceptancelimits represent the qualification user requirements for the system, and they are defined in the Equipment Qualification Plan (EQP)listed in the footer.

This EQR and the raw data generated during the qualification are provided on the Equipment Qualification Report CD. The originalcopy of this EQR is a secure electronic document in Abobe's portable document format (PDF).

________________________________________________________________________________________________________________________

The Enterprise Edition Compliance Services program uses a single protocol set to deliverqualification across systems regardless of the model or manufacturer.

Tests and calculations are automated.

The entire process can be paperless.

Agilent Compliance Engine is the validated software tool used to generateQualification Reports. This Qualification Report is provided as an electronic recordstored on CD.

The test procedures, limits, and report format follow the instructions in the relevantEquipment Qualification Plan. The CD contains all the results, raw data, and meta-data associated with this system qualification event.


Scope and Purpose Section PagePage

1 / 19/73



Instrument DetailsDocument Revision A.01.70


Instrument Details Section Page 1 / 4

Purpose

This section contains details of the system being qualified.

To properly configure a service protocol, (1) complete all mandatory fields that are marked with an asterisk; (2) select items fromthe drop-down lists for required Manufacturer, Name, and Model Number fields.

Instrument Identification

System ID: Agilent 6130 single quad LCMS

Service Configuration: Mass Spec Only

Scale: * Analytical

Comment: LCMS Example OQ

Instrument Details

*

Category: Software Installed

Manufacturer: Agilent Technologies

Type: ChemStation

Version: B.04.01 SR1

Product Number(s): G2710BA

Comment:

Page

None

13/73



Calculation FormulasDocument Revision A.01.70

Purpose

This section includes calculation formulas for all available tests. Depending upon which tests are scheduled, all or some apply to yourqualification.

Formulas

Service Date:________________________________________________________________________________________________________________________


Calculation Formulas Section PagePage

1 / 526/73



Calculation Formulas Section Page 2 / 5Page 27/73



Pump 1 Flow Accuracy and PrecisionDocument Revision A.01.70

Purpose

This test uses a calibrated digital flowmeter to determine the accuracy and precision of solvent flow rate.

Customer Reference

Not specified

Configuration Details

Model: G1312B

Procedure

In this test, the flow accuracy is calculated as the absolute % difference between the mean of the six flow readings and the setpoint,and flow precision is calculated as the %RSD of the six flow readings.

1. Use the digital flowmeter to measure and record six consecutive flow rates for each of the settings in the Conditions section.2. Run the Agilent Compliance Engine evaluation.3. Continue with the next test or, if applicable, repeat this one.

Conditions

Flow Rate 1: 0.500 ml/minute


Channel: B For binary and ternary pumps only


Pump 1 Flow Accuracy and Precision Section PagePage

1 / 232/73


Measurements and Results________________________________________________________________________________________________________________________


Measurements Results

Reading 1: 0.497 ml/minute Accuracy (as % error): 0.53 %

Reading 2: 0.498 ml/minute User Limit <= 5.00

Reading 3: 0.497 ml/minute Recommended Limit <= 5.00

Reading 4: 0.497 ml/minute Status: PASS

Reading 5: 0.497 ml/minute

Reading 6: 0.498 ml/minute Precision: 0.10 %RSD

Results User Limit <= 0.50

Average: 0.497 Recommended Limit <= 0.50

STD Deviation: 0.001 Status: PASS

________________________________________________________________________________________________________________________



Reading 1: 5.001 ml/minute Accuracy (as % error):0.03 %

Reading 2: 5.002 ml/minute User Limit<= 5.00

Reading 3: 5.001 ml/minute Recommended Limit<= 5.00

Reading 4: 5.002 ml/minute Status: PASS

Reading 5: 5.001 ml/minute

Reading 6: 5.001 ml/minute Precision: 0.01 %RSD


Average: 5.001 Recommended Limit <= 0.50

STD Deviation: 0.001 Status: PASS

Overall Test Status

PASS Runs: 1


Pump 1 Flow Accuracy and Precision Section PagePage

2 / 233/73



Column Temperature Accuracy and StabilityDocument Revision A.01.70

Purpose

This test uses a calibrated digital thermometer to determine the accuracy and stability of column temperature.

Customer Reference

Not specified


Model: G1316C

Procedure

In this test, the column temperature accuracy is calculated as the absolute difference between the measured temperature andsetpoint. The temperature stability is calculated as the absolute difference between the highest and lowest measured temperatures.

1. As described in the Conditions section, set up the flow rate and set the column temperature to Temperature 1.2. Allow the column temperature to stabilize.3. Use the digital thermometer to measure and record the column temperature.4. As described in the Conditions section, change the column temperature to Temperature 2 and allow it to stabilize.5. Use the digital thermometer to immediately measure and record the temperature reading, and then measure and record fivesubsequent temperature readings at intervals of at least four minutes.6. Run the Agilent Compliance Engine evaluation.7. Continue with the next test or, if applicable, repeat this one.

Conditions

Flow Rate: 1.00 ml/minute Temperature 1: 80.0 °C Temperature 2: 40.0 °C


Temperature 1: 80.0 °C


Time Temperature Difference from Setpoint: 0.7 °C

1. 79.3 °C User Limit <= 3.0

Recommended Limit <= 3.0

Status: PASS


Column Temperature Accuracy and Stability Section PagePage

1 / 236/73


Measurements and Results (continued)________________________________________________________________________________________________________________________

Temperature 2: 40.0 °C


Time Temperature

1. 39.8 °C Difference from Setpoint: 0.2 °C

2. 39.8 °C User Limit <= 2.0

3. 39.7 °C Recommended Limit <= 2.0

4. 39.8 °C Status:PASS

5. 39.8 °C

6. 39.7 °C Stability: 0.1 °C


Average: 39.8 °C Recommended Limit <= 1.0

High: 39.8 °C Status:PASS

Low: 39.7 °C

Overall Test Status

Data Integrity Check: Not performed Direct measurement. No data files used.

PASS Runs: 1


Column Temperature Accuracy and Stability Section PagePage

2 / 237/73



Vacuum VerificationDocument Revision A.01.70

Purpose

This test uses the available vacuum readings from the instrument or customer data station to verify that the vacuum is operatingproperly.

Customer Reference

Not specified


Model: G6130A

Procedure

In this test, a pressure reading is obtained and compared to an allowable range.

1. On a system at vacuum, read the high vacuum and enter it in the Measurements and Results section.2. Run the Agilent Compliance Engine evaluation.3. Continue with the next test or, if applicable, repeat this one.

Measurements and Results

High Vacuum: 5.1E-6 torr

Minimum: 0.000003 torr

Maximum: 0.00002 torr

Status: PASS

Overall Test Status

PASS Runs: 1


Vacuum Verification Section PagePage

1 / 138/73



Scan VerificationDocument Revision A.01.70

Purpose

This test introduces a standard with known masses into the mass spectrometer and then compares the observed masses to the knownones.

Customer Reference

Not specified


Model: G6130A

Source: AP-ESI

Mode: Positive

Procedure

In this test, accuracy is calculated as the absolute difference between the known and observed mass.

1. Make sure that the correct calibrant is used.2. Perform a mass assignment analysis.3. Review the report, find the values closest to the Known values in the Measurements section, and enter them in the Observedcolumn.4. Run the Agilent Compliance Engine evaluation.5. Continue with the next test or, if applicable, repeat this one.



Mass Known Accuracy: 0.020000 m/z

1. 118.09 m/z User Limit + - 0.20

Observed Recommended Limit + - 0.20

118.11 m/z Status:

PASS


Scan Verification Section PagePage

1 / 339/73





2. 622.03 m/z User Limit + - 0.20


621.98 m/z Status:

PASS________________________________________________________________________________________________________________________


3. 922.01 m/z User Limit + - 0.20


921.97 m/z Status:

PASS________________________________________________________________________________________________________________________


4. 1521.97 m/z User Limit + - 0.20


1522.01 m/z Status:

PASS________________________________________________________________________________________________________________________


5. 2121.93 m/z User Limit + - 0.20


2122.01 m/z Status:

PASS________________________________________________________________________________________________________________________

Mass Known Accuracy: Not applicable m/z

6. Not applicable m/z User Limit + - 0.20


Not applicable m/z Status:

Not applicable



2 / 340/73

Enterprise Edition Compliance ServicesEnterprise Edition Compliance Services© 2005-2009 by Agilent Technologies







Not applicable________________________________________________________________________________________________________________________





Not applicable________________________________________________________________________________________________________________________





Not applicable________________________________________________________________________________________________________________________





Not applicable

Overall Test Status

Data Integrity Check: Not performed Direct measurement. No data files used.

PASS Runs: 1



3 / 341/73



Response LinearityPurpose

Document Revision A.01.70

This test uses a traceable standard to determine response linearity.

Customer Reference

Not specified


Model: G6130A

Source: AP-ESI

Software Type: ChemStation

Procedure

In this test, response linearity is calculated by determining the coefficient of determination (r2) of the peak areas versus concentration.

1. Complete the Configuration and Conditions sections.2. Set up the instrument and create a sequence as described in the Conditions section.3. Run the sequence.4. Review the chromatograms and, as applicable, adjust the integration parameters.5. Run the Agilent Compliance Engine evaluation.6. Continue with the next test or, if applicable, repeat this one.

Conditions

Flow Rate: 0.8 ml/minute

Injection Volume On Column: 5 ul

Run Time: 2.0 minutes (or as determined by scouting run)

Sequence:

Line 1: Mobile phase blank, 1 injectionLine 2: Standard 1, 1 injectionLine 3: Standard 2, 1 injection

Line 4: Standard 3, 1 injectionLine 5: Standard 4, 1 injectionLine 6: Standard 5, 1 injection

Configuration

Detector: Mass spec

Y-Axis Unit: Abundance

Evaluated Mass for MSD: 311 +/- Not applicable m/z


Response Linearity Section PagePage

1 / 242/73


Configuration (continued)

Value Units

Standard 1 Concentration (lowest): 0.010 ug/ml From Certificate of Analysis

Standard 2 Concentration: 0.025 ug/ml



Standard 5 Concentration (highest): 1.000 ug/ml



Peak 1 Area: 26,497.000 Coefficient of Determination (r2): 0.99696

Peak 2 Area: 52,458.000 User Limit >= 0.98000

Peak 3 Area: 188,227.000 Recommended Limit >= 0.98000

Peak 4 Area: 938,275.000 Status: PASS

Peak 5 Area: 1,680,882.000

Peak area units: Abundance*s

Overall Test Status

Data Integrity Check: Pass Data files were transferred without any errors.

PASS Runs: 1


Response Linearity Section PagePage

2 / 243/73


Chromatography Report Document Revision A.01.70 Enterprise Edition Compliance Services

Data file analyzed for this test:

C:\ACE_A.01.70\Results\TestData\lc_rlin_ms1\Data\response_linearity002.cdf

Acquisition operator:

M hoppe

Acquisition method:

Unavailable metadata in this file. NO IMPACT on data integrity/traceability.

Source data file name:

x:\_ace_data\lcms\sq\analytical\190509_1\rlessq02.aia\mssig01.cdf

Instrument serial number:


Exported date and time: 05/20/2009 07:25:29

Data integrity check: Pass

Analysis method:

C:\ACE_A.01.70\MethodTemplates\LC\Analytical\lcms.oq.response_linearity.met

Chromatographic output generated: 15-Jun-2009 10:26

Service Date: 15-Jun-2009System ID: Agilent 6130 single quad LCMS

Chromatography Report Section Page 1 / 5Page 44/73


Chromatography Report Enterprise Edition Compliance Services


C:\ACE_A.01.70\Results\TestData\lc_rlin_ms1\Data\response_linearity003.cdf


M hoppe

Acquisition method:



x:\_ace_data\lcms\sq\analytical\190509_1\rlessq03.aia\mssig01.cdf



Analysis method:

C:\ACE_A.01.70\MethodTemplates\LC\Analytical\lcms.oq.response_linearity.met






Injection PrecisionDocument Revision A.01.70

Purpose

This test uses a traceable standard to determine injection precision.

Customer Reference

Not specified


Model: G1367C

Model: G6130A

Source: AP-ESI


Procedure

In this test, the mean, standard deviation, and % RSD of six standard injections are calculated.


Conditions


Injection Comment:

Run Time: minutes (or as determined by scouting run)

Flow Rate: ml/minute

Detection Mode: Mass spec




Injection Precision Section PagePage

1 / 249/73


Conditions (continued)

Sequence:Line 4: Evaluation standard, 1 injectionLine 5: Evaluation standard, 1 injectionLine 6: Evaluation standard, 1 injectionLine 7: Evaluation standard, 1 injection

Line 1: Mobile phase blank, 1 injectionLine 2: Evaluation standard, 1 injectionLine 3: Evaluation standard, 1 injection

Configuration Value Units

Evaluation Standard Concentration: 0.100 ug/ml (from Certificate of Analysis)


Measurements Area Height

Measured Value 1 193,623.000 Abundance*s 41059 Abundance






Results

Average Height: 40417.17 Abundance

STD Deviation Height: 472.17 Abundance

Average Area: 191,564.83 Abundance*s

STD Deviation Area: 4,890.625 Abundance*s

Height RSD: 1.17 %

User Limit <= 10.00


Status: PASS

Area RSD: 2.55 %

User Limit <= 10.00


Status: PASS

Overall Test Status


PASS Runs: 1


Injection Precision Section PagePage

2 / 250/73




C:\ACE_A.01.70\Results\TestData\lc_ip_ms1\Data\injection_precision002.cdf


M hoppe

Acquisition method:



x:\_ace_data\lcms\sq\analytical\190509_1\ipessq02.aia\mssig01.cdf





Analysis method:

C:\ACE_A.01.70\MethodTemplates\LC\Analytical\lcms.oq.injection_precision.met









M hoppe

Acquisition method:






Analysis method:










M hoppe

Acquisition method:






Analysis method:







Injection Carry OverPurpose Document Revision A.01.70

This test uses a traceable standard to determine injection carry over.

Customer Reference

Not specified


Model: G1367C

Model: G6130A

Source: AP-ESI


Procedure

If carry over is performed immediately after precision, it is calculated as the response of the blank injection as a percentage of theresponse of the previous injection. If carry over is performed standalone, it is calculated using a standard injection.

1. Complete the Configuration and Conditions sections.2. If the Injection Precision test was just performed, go to step 3; otherwise, create and run the sequence as described in theConditions section.3. Review the chromatograms and, as applicable, adjust the integration parameters.4. Run the Agilent Compliance Engine evaluation.5. Continue with the next test or, if applicable, repeat this one.

Conditions


Injection Comment: None

Run Time: 2.0 minutes (or as determined by scouting run)

Flow Rate: 0..8 ml/minute

Detection Mode: Mass spec



Sequence:

Line 1: Evaluation standard, 1 injectionLine 2: Mobile phase blank, 1 injection


Injection Carry Over Section PagePage

1 / 257/73


Configuration Value Units(from Certificate of Analysis)Evaluation Standard Concentration: 1.000 ug/ml


Measurements Area Height

Standard Peak 1,629,269.00 Abundance*s 334,379.00 Abundance

Carry Over Peak 5,815.000 Abundance*s 1,292.000 Abundance

Results

Carry Over: 0.36 % 0.39 %

User Limit <= 1.00 <= 1.00

Recommended Limit <= 1.00 <= 1.00

Status: PASS PASS

Overall Test Status


PASS Runs: 1


Injection Carry Over Section PagePage

2 / 258/73




C:\ACE_A.01.70\Results\TestData\lc_co_ms1\Data\injection_carryover001.cdf


M hoppe

Acquisition method:



x:\_ace_data\lcms\sq\analytical\190509_1\coessq01.aia\mssig01.cdf





Analysis method:







Signal to NoiseDocument Revision A.01.70

Purpose

This test uses a traceable standard or water to determine signal to noise.

Customer Reference

Not specified


Model: G6130A

Source: AP-ESI


Procedure

In this test, the height of the signal is divided by the calculated noise of a single injection.


Conditions


Injection Comment: None

Run Time: 2.5 minutes

Flow Rate: 0.8 ml/minute

Noise Evaluation

Start Time: 0.90 minutes

Duration: 1.10 minutes

Sequence:

Line 1: Evaluation standard, 1 injection


Signal to Noise Section PagePage

1 / 261/73


Configuration

Detector: Mass spec



Value Units

Evaluation Standard Concentration: 0.010 ug/ml (from Certificate of Analysis)


Measurements

Noise (ASTM): 23.130764 Abundance (uncorrected)

23.130764 Abundance (corrected to use same units as signal)

Height: 5,273.000 Abundance (corrected for differences between nominal andreported concentration; analog data is corrected forthe applied signal reduction [range/attenuation])Results

Signal to Noise: 228

User Limit >= 20

Recommended Limit >= 20

Status: PASS

Overall Test Status


PASS Runs: 1


Signal to Noise Section PagePage

2 / 262/73




C:\ACE_A.01.70\Results\TestData\lc_sn_ms1\Data\signal_to_noise001.cdf


M hoppe

Acquisition method:



x:\_ace_data\lcms\sq\analytical\190509_1\snessq01.aia\mssig01.cdf





Analysis method:

C:\ACE_A.01.70\MethodTemplates\LC\Analytical\lcms.oq.signal_to_noise.met


Noise Start (minutes): 0.9 Noise Duration (minutes): 1.1





Digital Data Transfer Audit LogDocument Revision A.01.70

Purpose

This document provides a complete list of the digital chromatography data files transferred into ACE during a discrete equipmentqualification event such as OQ or RQ.

This audit log is generated automatically by the Data Copier utility of ACE. The data integrity of each file listed has been checked usingmulti-component checksum verification. No corrupted or tampered files will appear in this log. The completeness of the set of files foreach OQ or RQ test is verified by ACE during the data transfer process. ACE does not allow an incomplete set of data files to be usedin test result calculation.

Visual scanning of the list below allows an easy check of the original source path of the files. If necessary, a reviewer can check thislist against the folders and files of the source chromatography data system.

Data PathFile Name Acquisition D/T Transferred D/T________________________________________________________________________________________________________________________

Service Date:________________________________________________________________________________________________________________________


Digital Data Transfer Audit Log Section Page 1 / 2


Common data path (if applicable)No data file used Not foundNo data file used Not found

Scan Verification (AP-ESI)

Common data path (if applicable)No data file used Not found

Response Linearity (MSD/AP-ESI)

X:\_ACE_DATA\LCMS\SQ\Analytical\190509_1rlessq02.aia Not found 20-May-2009 07:29:48rlessq03.aia Not found 20-May-2009 07:29:48rlessq04.aia Not found 20-May-2009 07:29:48rlessq05.aia Not found 20-May-2009 08:07:06rlessq06.aia Not found 20-May-2009 07:29:48

Injection Precision (MSD/AP-ESI)

X:\_ACE_DATA\LCMS\SQ\Analytical\190509_1ipessq02.aia Not found 20-May-2009 07:29:48ipessq03.aia Not found 20-May-2009 07:29:48ipessq04.aia Not found 20-May-2009 07:29:48ipessq05.aia Not found 20-May-2009 07:29:48ipessq06.aia Not found 20-May-2009 07:29:48ipessq07.aia Not found

Page

20-May-2009 07:29:48

64/73



Electronic SignatureDocument Revision A.01.70

Full Name of Signer: Mark Hoppe

Logged On User Name: [email protected]

Signature Creation Date: 15-Jun-2009 11:26

Meaning of Signature: Executed protocol and published this original version of document

This signature page cannot be created and ACE cannot publish this report to PDF unless the ACE sign-off action has been executed. The ACE sign-off is an electronic signature as defined by US FDA 21 CFR Part 11, and it requires two distinct identification components: unique username and personal password.

A trained operator who understands the meaning and legal status of an electronic signature has executed the ACE sign-off.

21 CFR Part 11 [Docket No. 92N-0251] RIN 0910-AA29 Electronic Records; Electronic Signatures

Section 11.50 requires signature manifestations to contain information associated with the signing of electronic records. This information must include the printed name of the signer, the date and time when the signature was executed, and the meaning (such review, approval, responsibility, and authorship) associated with the signature.

In addition, this information is subject to the same controls as for electronic records and must be included in any human readable forms of the electronic record (such as electronic display or printout).

Under Sec. 11.70, electronic signatures and handwritten signatures executed to electronic records must be linked to their respective records so that signatures cannot be excised, copied,or otherwise transferred to falsify an electronic record by ordinary means. Under the general requirements for electronic signatures, at Sec. 11.100, each electronic signature must be unique to one individual and must not be reused by, or reassigned to, anyone else. Before anorganization establishes, assigns, certifies, or otherwise sanctions an individual's electronic signature, the organization shall verify the identity of the individual.

✔ ✔

Section 11.200 provides that electronic signatures not based on biometrics must employ at least two distinct identification components such as an identification code and password. In addition, when an individual executes a series of signings during a single period of controlled system access, the first signing must be executed using all electronic signature components and the subsequent signings must be executed using at least one component designed to be used only by that individual. When an individual executes one or more signings not performed during a single period of controlled system access, each signing must be executed using all of the electronic signature components.

Electronic signatures not based on biometrics are also required to be used only by their genuine owners and administered and executed to ensure that attempted use of an individual's electronic signature by anyone else requires the collaboration of two or more individuals.

Under Sec. 11.300, electronic signatures based upon use of identification codes in combination with passwords must employ controls to ensure security and integrity. The controls must include the following provisions: (1) The uniqueness of each combined identification code and password must be maintained insuch a way that no two individuals have the same combination of identification code and password;(2) persons using identification codes and/or passwords must ensure that they are periodicallyrecalled or revised; (3) loss management procedures must be followed to deauthorize lost, stolen, missing, or otherwise potentially compromised tokens, cards, and other devices that bear or generate identification codes or password information; (4) transaction safeguards must be used to prevent unauthorized use of passwords and/or identification codes, and to detect and report any attempt to misuse such codes.

✔ ✔

Adobe Acrobat digital signature (in addition to e-signature, if required)

Ink signature (in addition to e-sig, if required)


Electronic Signature Section Page 1 / 1Page 70/73

Certificate of System Qualification Agilent Technologies

LCMS - Operational QualificationDocument Revision A.01.70 © 2005-2009 by Agilent Technologies______________________________________________________________________________________________________________________________________________________________________________________________________________________________________________System ID: Agilent 6130 single quad LCMSOrganization Name: Agilent Technologies IncOrganization Location: Englewood, COService Date: 15-Jun-2009EQP Name: Standard_EQP_LCMS_______________________________________________________________________________________________________________________L1 (Limit 1): User Limit SP: Setpoint from Test SpecificationL2 (Limit 2): Recommended Limit A: Actual/average measured value_______________________________________________________________________________________________________________________

Service Date:________________________________________________________________________________________________________________________


Certificate of System Qualification Section Page

SP:

1 / 3

SP:

L1:L1:

L1:L1:

A:

A:

L2:L2:

L2:L2:

______________________________________________________________________________________________________________________

Pump 1 Flow Accuracy and Precision PASS

Flow Rate 1: Accuracy (as % error): 0.53 % Precision: 0.10 %RSD0.500

ml/minuteml/minute <= 5.00 <= 0.50

0.497 <= 5.00 <= 0.50



5.001 <= 5.00 <= 0.50

SP:

SP:

L1:L1:

L1:L1:

A:

A:

L2:L2:

L2:L2:

______________________________________________________________________________________________________________________

Pump 2 Flow Accuracy and Precision PASS



0.501 <= 5.00 <= 0.50



4.998 <= 5.00 <= 0.50

SP:

SP:

L1:L1:

L1:

A:

A:

L2:L2:

L2:

______________________________________________________________________________________________________________________

Column Temperature Accuracy and Stability PASS

Temperature 1:

Difference from setpoint:

Difference from setpoint: 0.7 °C80.0

°C°C <= 3.0

79.3 <= 3.0

Temperature 2: 0.2 °C Stability: 0.1 °C40.0

°C°C <= 2.0 <= 1.0

39.8 <= 2.0 <= 1.0

______________________________________________________________________________________________________________________

Vacuum Verification PASS

High Vacuum: 5.1E-6 torrMinimum: 0.000003Maximum:

Page

0.00002

71/73

Agilent Technologies

Service Date:________________________________________________________________________________________________________________________


Certificate of System Qualification Section Page 2 / 3

L1:L1:

L1:L1:

L1:L1:

L1:L1:

L1:L1:

L2:L2:

L2:L2:

L2:L2:

L2:L2:

L2:L2:

______________________________________________________________________________________________________________________

Scan Verification (AP-ESI) PASS

Known Mass 1: 118.09 m/z Known Mass 6: Not applicable m/z

Accuracy:Accuracy:

Accuracy:Accuracy:

Accuracy:Accuracy:

Accuracy:Accuracy:

Accuracy:Accuracy: 0.020000

m/zm/z

m/zm/z

m/zm/z

m/zm/z

m/zm/z Not applicable+ - 0.20 + - 0.20+ - 0.20 + - 0.20

Known Mass 2: 622.03 m/z Known Mass 7: Not applicable m/z0.050000 Not applicable

+ - 0.20 + - 0.20+ - 0.20 + - 0.20


+ - 0.20 + - 0.20+ - 0.20 + - 0.20


+ - 0.20 + - 0.20+ - 0.20 + - 0.20


+ - 0.20 + - 0.20+ - 0.20 + - 0.20

L1:L2:

______________________________________________________________________________________________________________________

Response Linearity (MSD/AP-ESI) PASS

Detector: Mass spec

Coefficient of Determination (r2): 0.99696>= 0.98000>= 0.98000

______________________________________________________________________________________________________________________

Injection Precision (MSD/AP-ESI) PASS


Height RSD: 1.17 % Area RSD: 2.55 %L1:L1: <= 10.00 <= 10.00L2:L2: <= 10.00 <= 10.00

______________________________________________________________________________________________________________________

L1:L1:L2:L2:

Injection Carry Over (MSD) PASS


Area Carry Over 0.36 % Height Carry Over 0.39 %<= 1.00 <= 1.00<= 1.00 <=

Page

1.00

72/73

Equipment Qualification Plan (EQP) · (C) Agilent Technologies Inc. 2005-2009 Page 4 of 22 No...

Documents

Transcript of Equipment Qualification Plan (EQP) · (C) Agilent Technologies Inc. 2005-2009 Page 4 of 22 No...