HSS Method Migration From G1888A to 7697A For USP <467>

Brian Jia

Headspace Product Support Engineer

Cassie Eisele

Headspace Product Manager

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Agenda

• Intro to USP <467>

• 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 <467> 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 <467> 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-

113

• 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

7697A

• 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

temperatures

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Application Notes

• Optimizing Vial Pressurization Parameters for the Analysis of USP <467>

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

5990-9106EN

• Analysis of USP <467> Residual Solvents with Improved Repeatability

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

• Analysis of USP <467> 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 <467> Residual

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

5991-2079EN

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Technical Overview

• System Parameter and Performance

Comparison Between Agilent 7697A

and Agilent G1888A Headspace

Samplers for USP <467>, September

2014, 5991-5182EN

• Discusses:

- Differences between the instruments

- Explains method parameters

- Recommended starting point for

method settings

- Comparative Studies

• Available on Support Portal

NEW!!

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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

revalidation

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

laboratory

• 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

instruments

• 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 chromatogram shows 7697A with similar resolution to G1888A, shown in bottom chromatogram.

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Tips for Improving Peak Shape Lower the final loop pressure

Acetonitrile (1) and cis-dichloroethene (3) resolution comparison between 7697A and G1888A headspace samplers on an

Agilent J&W HP-INNOWax column, part number 19091N-113. Top chromatogram shows 7697A at max sensitivity settings.

Middle chromatogram shows 7697A with similar resolution to G1888A, shown in bottom chromatogram.

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Acetonitrile (1) and methylene chloride (2) resolution comparison between different sample loops (0.1, 1,

and 3 mL) on an Agilent J&W DB-624UI column, part number 123-0334UI. The overlay chromatograms

show 7697A with less sensitivity but better resolution on the smaller sample loop as compared to the

bigger sample loop.

7697A, 624 Column, Class 2A

Blue: Loop 0.1 mL, R 4.3

Red: Loop 1 mL, R 2.6

Green: Loop 3 mL R 0.7

1

2

Tips for Improving Peak Shape Smaller Sample Loop Size

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Increasing the GC inlet septum purge flow reduces sensitivity and improves resolution.

When increasing septum purge flow from 3 mL/min, to 10 or 15 mL/min, the resolution of

acetonitrile (1) and methylene chloride (2) increases from 2.6 to 3.2 or 3.5, respectively.

Tips for Improving Peak Shape Increase GC Inlet Septum Purge Flow

624 column, Class 2A

Blue: 7697A default vial parameters, GC inlet

septum purge flow at 3 mL/min, R 2.6

Red: 7697A default vial parameters, GC inlet

septum purge flow at 10 mL/min, R3.2

Green: 7697A default vial parameters, GC

inlet septum purge flow at 15 mL/min, R 3.5

1

2

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624 column, Class 2A

Blue: 7697A default vial parameters, GC inlet

split ratio 5:1, R 2.6

Red: 7697A default vial parameters, GC inlet

split ratio 10:1, R 3.4

Green: 7697A default vial parameters, GC

inlet split ratio 20:1, R 4.0

Increasing the GC inlet split flow improves resolution but reduces sensitivity.

When increasing split ratio from 5 (split flow 12.5 mL/min) to 10 (split flow 25 mL/min) or 20 (split flow 50

mL/min), the resolution of acetonitrile (1) and methylene chloride (2) increases from 2.6 to 3.4 or 4.0,

respectively.

Tips for Improving Peak Shape Increase GC Inlet Split Flow

1

2

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Using split liner (w/o glass wool) improves the peak shape of low boiling point solvent (e.g. Methanol)

but doesn’t improve resolution, using 5:1 split.

Tips for Improving Peak Shape Use Split Liner

Blue: 7697A default vial parameters, splitless liner 5181-8818. R

2.6.

Red: 7697A default vial parameters, split liner 5183-4647 w/o

glass wool. R 2.4

acetonitrile

Methylene chloride

methanol

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Tips for Improving Peak Shape Increase Headspace Flow (GC+HS Control)

Increasing the Headspace flow (if using GC+HS Control) improves resolution but reduces sensitivity.

When increasing Headspace from 10 mL/min to 15 mL/min or 20 mL/min, the resolution of acetonitrile (1)

and methylene chloride (2) increases from 1.7 to 2.4 or 2.9, respectively.

624 column, Class 2A

Blue: 7697A default vial parameters,

Headspace flow 10 mL/min, R 1.7

Red: 7697A default vial parameters,

Headspace flow 15 mL/min, R 2.4

Green: 7697A default vial parameters,

Headspace flow 20 mL/min, R 2.9 1

2

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Summary

• The new method parameters for the 7697A introduced with the onboard electronic pneumatics is causing some migration issues for customers

• A new Technical Overview was just published to help those customers make the migration

• If you run into issues with peak shape with the 7697A you can try:

- Lowering the final loop pressure

- Using a smaller sample loop size

- Increasing GC inlet septum purge flow

- Increasing GC inlet split flow

- Using split liner (glass wool removed)

- Increasing HS flow (if using GC + HS control)

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Questions?

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