hss method migration from g1888a to 7697a for usp increasing the headspace flow (if using gc+hs...

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  • HSS Method Migration From G1888A to 7697A For USP

    Brian Jia

    Headspace Product Support Engineer

    Cassie Eisele

    Headspace Product Manager


    Agilent Restricted


  • Agenda

    • Intro to USP

    • Background on method conversion issues

    • Existing tools to help you and customers

    • New Technical Overview

    • Migrating a method


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  • Intro to USP What are residual solvents?

    • Organic Volatile Impurities (OVI’s) are organic chemicals used in the manufacturing of active pharmaceutical ingredients (APIs) or final product

    • Commonly known as residual solvents and refers to the amount not removed during purification of the final drug product

    • Levels are monitored for safety and/or environmental reasons and for their effect on product form that may effect solubility, stability or bioavailability.

    • QA labs routinely use United States Pharmacopeia (USP) Method to monitor residual solvents. This basic method is used worldwide for quality control.


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  • Three Classes of Solvents

    •Class 1

    oUnacceptable toxicities

    oShould be avoided, unless their use can be strongly justified and a risk

    assessment study is performed

    •Class 2

    oLess severe toxicities

    oShould be limited

    •Class 3

    oLess toxic

    oShould be used where practical

    Other solvents may be used but only after approval from regulatory agency


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  • Two Procedures

    • Procedure A

    - First procedure to run to see if a residual solvent is identified above the

    permitted daily exposure (PDE) limit

    - Uses a 624 phase column, such as 123-0334UI

    • Procedure B

    - If a residual solvent is identified above the permitted daily exposure

    (PDE) limit, procedure B is performed to confirm analyte identity

    - Uses a wax phase column with a different selectivity, such as 19091N-


    • Typical dual column setup is HS-GC-FID


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  • System Suitability Requirements

    • Procedure A

    - s/n of 1,1,1-trichloroethane > 5

    - s/n of all Class 1 solvents > 3

    - Resolution of acetonitrile and methylene chloride > 1

    • Procedure B

    - s/n of benzene > 5

    - s/n of all Class 1 solvents > 3

    - Resolution of acetonitrile and cis-dichloroethene > 1


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  • Background

    • Some customers are having difficulty migrating methods from the G1888A to


    • We are especially seeing this with Pharma customers running the residual solvents application

    • Leads to more time spent on escalations

    • Why are they having so much trouble?

    • 7697A has onboard pneumatics control to achieve active backpressure control. This changes loop fill

    behavior and causes there to be new method parameters.


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  • Existing Tools - Method Conversion Wizard

    Standalone or as part of headspace driver


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  • Enter in existing G1888 method parameters


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  • Get recommended starting conditions for 7697A method that can then be optimized for best

    performance. Depending on customer’s needs the Default settings may not be best.

    Missing Pressure

    Equilibration Time


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  • White Paper

    • Thermal Zone Considerations for the

    Agilent 7697A Headspace Sampler,

    February 2012, 5990-9892EN

    • Explains why you no longer need to

    operate the headspace with oven

    and loop zones at different



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  • Application Notes

    • Optimizing Vial Pressurization Parameters for the Analysis of USP

    Residual Solvents using the 7697A Headspace Sampler, September 2011,


    • Analysis of USP Residual Solvents with Improved Repeatability

    Using the Agilent 7697A Headspace Sampler, August 2012, 5990-7625EN

    • Analysis of USP Residual Solvents using the Agilent 7697A

    Headspace Sampler with the Agilent 7890B Gas Chromatograph, January

    2013, 5991-1834EN

    • Applying the Agilent 5977A MSD to the Analysis of USP Residual

    Solvents with the 7697A Headspace Sampler and 7890B GC, March 2013,



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  • Technical Overview

    • System Parameter and Performance

    Comparison Between Agilent 7697A

    and Agilent G1888A Headspace

    Samplers for USP , September

    2014, 5991-5182EN

    • Discusses:

    - Differences between the instruments

    - Explains method parameters

    - Recommended starting point for

    method settings

    - Comparative Studies

    • Available on Support Portal



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  • Why is this useful?

    • Many customers will have to do a method transfer in order to use the

    7697A in place of their G1888 or 7694 for their validated method

    - Since it is not a new technology they should not have to do a complete


    - It is up to the customer to determine what is most appropriate for their


    • They need to document why there are differences in the method and

    ideally why these new method parameters are an improvement over the

    previous method

    • They also need to do some sort of comparative testing between the


    • This technical overview can be used as a resource for method transfer and

    SOP documentation


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  • Considerations for Migrating a Method

    Two ways to migrate the method depending on

    chromatography requirements:

    • Higher sensitivity from the 7697A

    - With the addition of the onboard electronic pneumatics the 7697A injects

    more sample on column

    - This leads to higher sensitivity but as a trade-off the peaks will be a little

    more broad

    • Means less resolution between peaks

    • More similar resolution to G1888

    - If the customer wants their resolution to be more like the G1888 they can

    drop the final loop pressure to a lower value

    - This lowers the amount of sample that makes it on column allowing for

    the peaks to be more narrow and improves resolution


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  • Method Migration

    • Not all parameters will change when migrating the method!

    • Temperature settings (oven, loop, and transfer line temperatures) can stay

    the same

    - HOWEVER, if a customer wants to take advantage of the advanced

    thermal control of the 7697A they no longer need a temperature

    differential between the oven and loop temperatures!!!

    • See White Paper 5990-9892EN for details

    • Timing settings can stay the same:

    - Vial Equilibration Time

    - Injection Duration

    - GC Cycle Time


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  • Method Migration Below is a summary of method parameters that will change with migration.

    The 7697A parameters depend on if the customer wants higher sensitivity out of

    the 7697A or more similar resolution to the G1888A.

    The method can be optimized by adjusting the final loop pressure, shaking, and

    vial fill mode. Increasing GC split flow can improve resolution as well.


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  • Tips for Improving Peak Shape

    • May notice low boiling point solvents (e.g. Methanol) have a wider peak shape on the 7697A

    • Tips to improve resolution and peak shape of low boiling solvents:

    - Lower the final loop pressure

    - Use a smaller sample loop size

    - Increase GC inlet septum purge flow

    - Increase GC inlet split flow

    - Use split liner (glass wool removed)

    - Increase HS flow (if using GC + HS control mode)

    • Not all of these changes will be needed for every customer and not every customer will be able to make some of these changes (depends on method validation)


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  • Tips for Improving Peak Shape Lower the final loop pressure

    Acetonitrile (1) and methylene chloride (2) resolution comparison between 7697A and G1888A headspace samplers on an

    Agilent J&W DB-624UI column, part number 123-0334UI. Top chromatogram shows 7697A at max sensitivity settings.

    Middle chro


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