Incorporating Sample Collections From Acquired Companies into GSK – Simple? Darren Rimmer...
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Transcript of Incorporating Sample Collections From Acquired Companies into GSK – Simple? Darren Rimmer...
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)
Harlow3 M solutions (cap.4M)1.6 M solids (cap.2M)
Philadelphia2.5M solutions (cap.2.8M)
Philadelphia2.5M solutions (cap.2.8M)
Madrid2.5 M solutions (cap.2.6M)
Madrid2.5 M solutions (cap.2.6M)
North Carolina0.7 M solutions (cap.2M)
North Carolina0.7 M solutions (cap.2M)
Sample Processing - Solutions
Description Cellzome CP Cellzome HDB GSK
Tube 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
as
s
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
Co
nce
ntr
atio
n m
M
0 100 200 300 400 500 600 70005
1015202530354045
Concentration of Heidelberg Samples
Sample number
Co
nce
ntr
atio
n
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
Property of GlaxoSmithKline