Incorporating Sample Collections From Acquired Companies into GSK – Simple?

Darren RimmerPrincipal ScientistGSK Stevenage4th September 2013

Property of GlaxoSmithKline

Abstract

Within large Pharma, the acquisition of smaller companies is becoming more common. One of the consequences (and challenges) of company acquisition, is how Compound Management groups incorporate the acquired sample collections into current corporate sample collections. This talk shares a description of how GSK performed this with the recent acquisition of Cellzome and the importance of quality checks both from an IT and an Analytical perspective.

Property of GlaxoSmithKline

Challenges of Incorporating Compound Collections

Formatting of inventory data – GSK vs NewCo formats?

Compound registration practices?

Automated storage vs manual storage?

Differing labware types?

Background

GSK examples of smaller company acquisitions

– Sirtris (2008)– Human Genome Sciences (2012)

Cellzome

– Drug discovery company identifying new generation of kinase-targeted drugs to treat inflammatory diseases

– Based across 2 sites

1. Chesterford Park (CP), Cambridge UK– Solid collection ~6000– Solution collection ~7000

2. Heidelberg (HDB), Germany– Solution collection ~70,000

Compound Management GSK

Harlow3 M solutions (cap.4M)1.6 M solids (cap.2M)

Philadelphia2.5M solutions (cap.2.8M)

Madrid2.5 M solutions (cap.2.6M)

North Carolina0.7 M solutions (cap.2M)

Sample Processing - Solutions

Description Cellzome CP Cellzome HDB GSKTube manufacturer

Matrix Matrix ABGene

Tube cap type Non-split bung Non-split bung Split septum bung

Tube identifier Non-barcoded, printed label

2D barcode 2D barcode

Storage method Manual -20oC freezer

Manual -20oC freezer

Fully automated store -20oC

Solvent DMSO DMSO DMSO

Concentration ~30mM ~10mM ~10mM

Volume tracked No (manual spreadsheets)

Yes Yes

Data Checks Comparison of Cellzome and GSK Registration databases

Registrars checking structure representation – SMILES string

Registration then undertaken on ~80,000 structures – without this step, no downstream processes can occur!

Computational chemists also performed comparisons of Cellzome’s collections vs the GSK collections - helped to determine the value of compound addition to GSK’s collections

Compound Processing - Solutions

CP Solutions had no accurate volume recorded

Use of Brooks Tube AuditorTM (TA*) to obtain accurate volume of individual

Tubes *(GSK own a prototype version)

– Allowed measurement of solution +/- 10ul within each matrix tube

– Processes a rack of 96 Tubes at a time

– A row of 8 tubes at a time are picked up and an image is created:

Compound Processing - Solutions

The TA then detects the bottom of the tube and the meniscus of the solution within each tube to create a measurement, which is then used to calculate the individual volumes

Once the tube volumes have been measured, an output file is created

Compound Processing - Solutions

Before running each tube rack from CP, we had to remove the labels on each tube. Leaving these labels on meant inaccurate readings from the TA as it confused the meniscus with the top/bottom of the label itself

1. 2. 3. 4.

1. Non-barcoded Matrix tube

2. Matrix type 1

3. Matrix type 2

4. ABGene tube

The positions of the tubes within each rack were also checked against the Inventory details, for confirmation that tubes were physically in the correct positions

Data Capture and IT Requirements At this stage we now have a file created from the Tube Auditor, plus the

original manual inventory from CP Cellzome

IT ‘application’ required plus design of workflow for the transfer of Cellzome Matrix tubes into GSK ABGene tubes:

TA creates CSV file

ABGene tube scanner creates

CSV file

Load file into Cellzome

applicationRun Evo

Load compounds into

GSK solution store

Quality control LCMS

Compound Processing - Solutions

Tecan EvoTM used for the solution Tube to Tube transfer

The ‘Cellzome application’ creates a file to run on the EvoTM using EVOwareTM

– EVOwareTM file contains details of Matrix rack name, volumes in each tube and their position within the Matrix tube rack

– The output of the EVOwareTM is a file that contains the new ABGene tube rack barcode, volumes in each tube and their position within the ABGene tube rack

Quality Control of Cellzome Solutions

The GSK QA project established a baseline for the quality of compounds in the GSK screening collection

GSK now has an industry-leading high quality collection due to ongoing QA

Cellzome collection required QA prior to inclusion in the compound collection

– Chesterfield Park Solutions - LC-UV-MS of all solutions (~7k)

– Heidelberg Solutions - 10% selected for LC-UV-MS as ~70k in total

Purity and identity fails were removed following analysis

10% of all the compounds submitted for QC ~1.4K were analysed using Chemiluminescence Nitrogen Detection (CLND) to get an idea of the concentration

QC Results LC-MS Analysis 6580 Chesterfield Park solutions were analysed by LCMS with 94% pass rate.

6000 Heidelberg solutions were analysed by LC-MS with 97% pass rate.

– Heidelberg solutions were externally acquired from many different suppliers.

– Cellzome had carried out their own internal QC on these samples.

– Majority of suppliers had a >90% pass rate and identification of poor quality suppliers were consistent with GSK’s experience.

A B C D E F G H I J K L M N O P Q R S T U V50

55

60

65

70

75

80

85

90

95

100 Comparison of Suppliers

Supplier

% p

ass

QC Results CLND Analysis

CLND was completed for approx 10% of compounds.

Expected concentrations were 30mM for Chesterfield Park and 10mM for Heidelberg.

There was a spread of concentration values obtained, with the Heidelberg solutions being closer to their target value of 10mM.

0 100 200 300 400 500 600 7000

10

20

30

40

50

60

Concentration of Chesterfield Park Solutions

Sample Number

Conc

entra

tion

mM

0 100 200 300 400 500 600 70005

1015202530354045

Concentration of Heidelberg Samples

Sample number

Conc

entra

tion

mM

Expected concentration 10mMMedian concentration = 8.8mMRange of Conc = 0.8 to 32.3mM

Expected concentration 30mMMedian Concentration = 21.1mMRange of concentration from 1.4mM to 52.7mM

Conclusions Main conclusion – resource intensive and longer than expected to complete

Data integrity

– Demonstrated the need for careful data management in the use of automated stores

HDB data

– Volume tracked by Inventory management application

Use of the Brooks TA was crucial for determining volumes of the CP solutions

– CP solutions removal of labels for identification (7000 in total!)

– Detection of precipitates

Good data increases confidence of having the right sample, with the right data each time

Conclusions – QC LCMS

Use of high throughput LCMS allowed a high number of compounds to be analysed in a short period of time

Provided confirmation of high quality collections from CP and HDB. Was also crucial in highlighting any compound processing errors during the tube to tube transfers

The 10% HDB solution samples QC’d was a large enough set to give confidence for the total set of samples received for transfer.

The LCMS checks have proved vital for determining the required purity and correct identity of samples entering the GSK solution collections

Maintains the high integrity of any solution collection and provides confidence in the quality of compound handling processes

Acknowledgements

Emily Munsey, Industrial placement student (University of Bath), SMTech GSK

David Leigh, SMTech GSK

Warren Miller, Cellzome IT

Friedrich Reinhard and Christina Rau, Cellzome

Nigel Ramsden, Cellzome

Julie Quayle & Zoe Blaxill, Analytical Chemistry GSK

Ken Miles, SMTech IT GSK

Rob Hughes & Neil Hardy, SMTech Automation GSK

Ian Mawer, Registrar GSK

....and many others from Cellzome and GSK

Tecan

RTS

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