neil garton purification strategy group neurology & gi ...julie quayle (tom smith) purification...

Neil Garton

Purification Strategy Group

Neurology & GI CEDD

Harlow

• Background

• The Challenge

• Recommendations

• Implementation & Statistics

• Summary & Learning Points

• Post-merger (GW & SB) Purification Group established in Jan 2002 with x-site, x-CEDD/DR representation

Remit defined:

“To provide an ongoing vision of a significantly more efficient purification process and present the broader chemistry community with a heightened awareness of, and training in, the appropriate best techniques and equipment through shared best practice.”

Could we improve purification efficiency tenfold?• 1/10th of the time, not 10 at once!• Time: Hands-on or compound cycle time?

Process

– Comments, issues and ideas collected from Harlow and Stevenage chemists

Brainstorm the ideas generated - Reduced to 5 areasProcess and Bottlenecks

Revolutionary Ideas

New Kit and Technology

Alternative Infrastructure

People, Attitudes and Training

• Apply automated chromatography routinely (80% of samples; MDAP, Horizon, SQ16X/FM-2)

• Training provided for chemists via local reps

• Apply purification policy & standardise kit

Standardisation

Right Technique, First Time

Purification Multi-tasking

Purification Experts

Centralised Purification Lab

Lab Technicians

All

Che

mis

try

on R

esin

sFluorous Chemistry

Smarter Chemistry

Autom

ation on PDP

Purification Service

Employ More Chemists

More Automation Capacity

Outsource PurificationsOvern

ight Purifi

cations

Disposab

le Glas

sware

Improved InstrumentationMass

-Dire

cted, N

ormal

Phase

Improved Evaporation

• Only 6% purifications >10 g

• 48% purifications <200 mg

• Focus on fully automating 80% <10 g purifications

• Subdivide into smaller (<200 mg) and larger scale solutions

<50 mg

9%

50-100mg

15%

100-200mg

24%200mg-1g

27%

1g-10g

19%

10-20g

3%

>20g

3%

Manual

– Conventional glass

– Biotage Flash 40

– Argonaut FlashMasterPersonal

Semi-Automated

– Biotage Quad 3

– Argonaut GradMaster

– Argonaut FM Lite/Parallel

Fully Automated

– Argonaut FlashMaster II

– Isco SQ16x

– Biotage Horizon

– Waters Fractionlynx Mass Directed Autoprep

– Biotage FLEX

• To handle 80% of <200 mg samples (multiple injections)

• 1 MDAP already installed, recommended 2 additional instruments (as dictated by demand)

• 1 FLEX to be used for poorly ionising samples

• Vision of future MDAP developments may include larger injections (~100 mg), 24/7 run times, SFC

• Increased productivity during standard day

• Extends working hours over lunch, meetings & night

• Chemists to have access to systems with detection & fraction collecting capability (>200 mg 10 g+)

- 2 per lab recommended, demand driven introduction

• Recommendation of zero purchase of non-detecting, non-collecting systems - accepted, but not banned

• Multi-column system with UV detection, fractioncollection & multiple solvent lines - 1 per lab, demand driven introduction

• To purify arrays & additional samples – Open Access(>200 mg 10 g+) - Evaluations to be undertaken

• Introduction in parallel with single column systems to automate 80% of >200 mg purifications

• PG* to provide training for ‘chromatography champions’ - 1 per lab for wider dissemination- ensures unbiased outlook

• PG to arrange demonstrations & training for new kit with ‘champions’ and manufacturers

• Demand for instruments likely to depend on enthusiasm and drive of these lab reps

* PG = Purification Group

• PG to formulate Harlow purification policy - Purchases to be recommended on continual basis

• ‘Best practice’ shared across GSK

• Allows leverage of the purchasing power of GSK

• Can influence new technologies to fulfil our needs, not be driven by suppliers’ estimation of our needs

• PG empowered to standardise on best kit

• Single unbiased evaluation across CEDDs

• Comparisons with similar (competitor) products- provide feedback to manufacturers

• Less training required - greater efficiency

• Data collected over 1 month period (Oct ’02, Jun ’03, Mar ’04)

• Chemists asked to record scale of purifications... (<50 mg, 50-100 mg, 100-200 mg, 200 mg -1 g, 1-10 g, 10-20 g, >20 g)

...correlated against purification technique used

Oct ‘02 (200 mg-10 g):

• ~55% Purifications using pre-packed silica cartridges(Incl. Quad 3, Flash 40, Jones Personal, FlashMaster Lite/Parallel, Silica SPE)

• ~15% Free flow silica chromatography

• Approx. 12 chemists per lab, 4 labs/floor, 3 floors

• 2 Biotage Horizon systems per lab

• >1 Argonaut FlashMaster II instrument per floor

• 1 Waters FractionLynx MDAP per floor

• 1 Biotage FLEX

• Numerous manual instruments

• Additional purchases made since March

• No significant change in scale of chemistry undertaken in Med Chem

March ‘04

50-100mg21%

100-200mg25%

200mg-1g23%

1g-10g18%

10-20g3%

>20g3%

<50 mg7%

<50 mg9%

50-100mg15%

100-200mg24%200mg-1g

27%

1g-10g19%

10-20g3%

>20g3%

October ‘02

• Dramatic profile change over 18 mths in target area (80% <10 g)

• 73% fully automated

• 9% partially automated0%

20%

40%

60%

80%

100%

<50mg 50-100 100-200

200-1g 1g-10g 10-20g >20g Total

October ‘02

0%

20%

40%

60%

80%

100%

<50mg 50-100 100-200 200-1g 1g-10g 10-20g >20g Total

March ‘04

Full Automation

Partial Automation

No Automation

Chromatography March 04(all scales)

Full Automation71%

Partial Automation

8%

No Automation21%

• Horizon, MDAP and FM II (3Q’03) successfully adopted

• Most pre-packed cartridges transferred to automated kit

• Remaining 25% due to solubility, queues, distance, scale, solvents

23%FM2

All Chromatography March ‘04

Horizon26%

MDAP21%

Quad7%

Personal4%

Lite/Parallel1%

ManualBiotage

6%

Free Flow Silica5%

Silica SPE7%

Frythe Jan- March 2004 - Back row

Full Automation

Partial Automation

No Automation

Harlow March 2004 - Front row

0%

20%

40%

60%

80%

<50mg 50-100 100-200 200-1g 1g-10g 10-20g >20g Total

100%

• Differences between two GSK sites, despite purchase of identical technologies

• Good locations, ‘champions’ and spare capacity needed to ensure automation target reached

• Strategy of automation & standardisation implemented Oct ‘02 – driven from ‘ground up’

• Strategy supported by training plan – ‘chromatography champions’

• Standardisation necessary to harness GSK purchasing power and obtain key kit modifications

• GSK Verona (Psy) & Tres Cantos (MMPD) represented

• Statistics required in order to monitor success

• Automation increase from ~0-71% over 2 years

• 60% increase in purifications undertaken!

• Management buy-in from outset essential

• Demand driven purchases needed for success – space & technician support (if appropriate)

• Choice of local ‘champions’ & location of kit critical for adoption of new technologies

• Realistic time-lines for delivery of new technologies & adoption of techniques – intuitive/open access

• Limit to automation (80%?) – solubility, scale, solvents

Purification Group

Harlow

Robert Sheppard

David Cooper

Kam Jandu

Andrew Doran

Gregory Jonas

Julie Quayle

(Tom Smith)

Purification Group

Stevenage

Simon Macdonald

Tim Underwood

Gail Mills

Heather Hobbs

Helen Weston

Tim Longstaff

Martyn Deal

(Graham Inglis)

(Mike Woodrow)

Line Management

Harlow

Frank King

Colin Frydrych

Andy Takle

Dave Smith

Rob Ward

• 48% purifications <200 mg

• Only 6% purifications >10 g• No real change in scale

October ‘02

<50 mg9%

50-100mg15%

100-200mg24%200mg-1g

27%

1g-10g19%

10-20g3%

>20g3%

<50 mg

50-100mg

100-200mg

200mg-1g

1g-10g

10-20g

>20g

March ‘04

50-100mg21%

100-200mg25%

200mg-1g23%

1g-10g18%

10-20g3%

>20g3%

<50 mg7%

• MDAP figure encouraging in only 3 months since inception

• Should grow with more instruments / familiarity

• MDAP limited by capacity?

• Aim is for MDAP use for ~80% of samples in this range

% Different techniques used ( <50mg scale)

MDAP54%

Single SystemBiotage

1%

Quad2%

Horizon6%

PersonalF-master

6%

Free Flow Silica

10%

Silica SPE11%

SCX/ SAX3%

Single InjectionHPLC

2%Flex5%

Single InjectionHPLC

Flex

MDAP

Single SystemBiotage

Quad

Horizon

PersonalF-master

Lite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

% Different techniques used (50-100mg scale)

Single InjectionHPLC

1% Flex16%

MDAP12%

Single SystemBiotage

4%Quad17%

Silica SPE17%

SCX/ SAX14%

Lite/ Parallel1%

Horizon9%

PersonalF-master

5%

Free Flow Silica4%

Single InjectionHPLC

Flex

MDAP

Single SystemBiotage

Quad

Horizon

PersonalF-master

Lite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

• Challenge to use MDAP for 200 mg samples in timely manner

• Currently not time/instrument efficient - larger column?

• Too large scale for MDAP - need other automation

• Biotage Horizon (13%) encouraging - 4 months / limited no.

% Different techniques (200 mg - 1 g)

Quad3%

Horizon13%

PersonalF-master

16%

Silica SPE11%

SCX/ SAX17%

Single SystemBiotage

22%

Lite/ Parallel6%

Free Flow Silica

11%

MDAP1%

Single InjectionHPLC

Flex

MDAP

Single SystemBiotage

Quad

Horizon

PersonalF-master

Lite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

% Different techniques used (100 - 200 mg)

Horizon6%

Lite/ Parallel25%

Free Flow Silica4%

Silica SPE15%

SCX/ SAX18%

MDAP1%

Single SystemBiotage

8%Quad12%

PersonalF-master

9%

Flex2%

Single InjectionHPLC

Flex

MDAP

Single SystemBiotage

Quad

Horizon

PersonalF-master

Lite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

• Need to address concerns of free flow silica users

• Single/Multiple automated column systems could make big impact (50%+)

• Encourage use of Flash 75 & Horizon cf free flow silica

• Small % of overall separations - not major concern

% Different techniques used (1 g - 10 g)

Single InjectionHPLC

1%

Lite/ Parallel2%

Free Flow Silica 16%

SCX/ SAX14%

Silica SPE6%

PersonalF-master

12%

Horizon12%

Single SystemBiotage

37%

Single InjectionHPLC

Flex

MDAP

Single SystemBiotage

Quad

Horizon

PersonalF-master

Lite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

% Different techniques used (10 - 20 g)

PersonalF-master

5%

Lite/ Parallel3%

Quad11%

Single SystemBiotage

18%

Free Flow Silica47%

SCX/ SAX

16%

Single InjectionHPLCFlex

MDAP

Single SystemBiotageQuad

Horizon

PersonalF-masterLite/ Parallel

Free Flow Silica

Silica SPE

SCX/ SAX

• ‘Single system’ includes Flash 75 use

All Chromatography

Single System6%

MDAP21%

Flex0%

Quad7%

Horizon26%

Life/Parallel1%

Personal4%

FM223%

Free Flow Silica5%

Silica SPE7%