Abstract
This paper outlines how pharmaceutical companies best use external resources to support compound management activities while their internal resources focus on core responsibilities. It also elaborates on compound management workflows in support of High Throughput Screening, Lead Identification and Lead Optimization at Roche’s Nutley research site.
Introduction
A decision about outsourcing compound management activities may be made easily for large Pharma to supplement available internal resources especially if the work does not involve core activities. Internal resources and limited budget are other reasons for outsourcing. Small biotech acquisitions, laboratory consolidation, site closure, and laboratory clean up have in the past necessitated a collaboration with an external partner as well.
Core Activities at Roche Nutley Compound Management
Core activities within the local inventory are storage, data handling and distribution of single use plates for HTS assays and providing follow-up assay plates for hit confirmation and IC50 determination. Cherry picking for follow-up assays are centralized at the headquarters, however reformatting and serial dilution is performed locally.
Project support includes reagent handling for the chemistry laboratories. End-user ordering in-house developed software application allows structure searching and ordering commercially available reagents from external vendors. Reagent bottles are received centrally, barcoded and tracked in the database before distribution to the chemistry laboratories. The software application also allows tracking of reagent availability in the local central warehouse and the laboratory next door for easy access.
Compound registration support to the global registration system is provided as well. Compound handling workflows for lead identification and lead optimization are centralized in local inventories. All compounds synthesized in the chemistry laboratories are submitted to the compound management group. Requests are placed via a web application for all assays which are run within each project. Powder or solution requests are fulfilled on workstations including custom plates. All steps in the life of a sample are tracked at the database level and can be retrieved at any time.
Compounds are collected from different projects and combined into plates for ADME and DMPK groups to streamline their workflows. Distribution history and assay results are retrieved on demand.
Project driven drug like molecules received from chemistry laboratories are plated as part of the general screening library for global distribution. They are assembled in library subsets based on physicochemical properties, target orientation and diversity. The entire library is shared across all research sites as the high throughput screening library for HTS assays.
In addition to the core activities described above, there are other projects that the compound management group is involved with e.g. laboratory clean-up which may require processing source vials, rebottling into standard vials, QC over legacy samples, replating the corporate collection, purchase of external collections, integration of collections from acquired small biotechnology companies.
Opportunities for Outsourcing
There have been a number of outsourcing opportunities in the past few years especially in the areas mentioned in the above paragraph. The first small outsourced project was to integrate about 10,000 single compounds from Medicinal Chemistry laboratories due to the acquisition of a small biotechnology company. These samples needed to be quality controlled, rebottled into standard vials, sample weight determined and plated for inclusion into the general screening library.
The next few projects were related to a research site closure. Approximately, 30,000 bottles with unknown tare weights and non-readable barcodes needed rebottling. Another 25,000 samples from Medicinal Chemistry laboratories required rebottling, structure and associated data registration plus quality control. In addition, 6,000 synthetic intermediates required rebottling plus structure and associated data registration.
There also was a need to assess and evaluate the competency of several external partners who were being considered for these outsourcing activities. We reviewed recommendations from other Pharma colleagues plus our own at other sites. We checked for customer references, established contacts and chose the perfect fit. The final step was to set up the contract with the internal law department and sign it.
The first initiative to integrate the 10,000 single compounds due to a biotech acquisition, involved the following process: Roche’s responsibilities were to register the compounds into the internal structure registration system and provide structural and associated data, prepare and ship pre-tared source vials, with associated file, provide barcoded plates to the contractor and prepare all customs paperwork, import and export.
The contractors’ responsibilities were to transfer all samples into the pre-tared vials, perform LC-MS over each sample, and run an NMR over samples with unclear LC-MS results. Returned data included analysis results for selection for inclusion into the screening library. Selection for inclusion to the screening library was made by Roche. Roche provided the contractor with the list of compounds to be plated in the required format. The contractor prepared the plates and shipped the source vials along with the plates back to Roche.
Project implementation of the work due to site closure was somewhat more complex since it consisted of three different parts. First one was to transfer samples into standard 8-ml pre-tared vials. Roche shipped 30,000 source vials with the equivalent number of 8-ml pre-tared vials. Contractor rebottled the samples and transferred them to Roche with the associated data which included source barcode, new barcode, tare and the net weight.
The second part of this project consisted of rebottling, structure registration and quality control. Approximately, 25,000 vials, in various size containers, were sent to the contractor along with 8, 30, 120 and 250 ml pre-tared and barcode labeled vials. All samples were transferred into one 8-ml vial and if necessary into one additional larger vial. All remaining samples in the original source containers were returned to Roche. LC-MS analysis was performed over each sample and an NMR was run over samples with unclear LC-MS results. The returned data included sample data, QC and registration data. They were in rd file formats and ISIS databases. Roche reviewed QC data and decided upon appropriate sample disposition.
The last part of this project was to rebottle synthetic intermediates. Some 6,000 samples in various size containers were sent to contractor along with 8, 30, 120 and 250 ml pre-tared and barcode labeled vials. All samples were transferred into one 8-ml vials and if necessary into one additional larger vials. The remaining samples were returned to Roche. No quality control was performed over these intermediates. The data was returned to Roche containing the original barcode, new barcode, tare and net weights of the sample. Roche then registered them into the internal structure database and made them available as synthetic intermediates to the global research community.
Conclusion
Overall, we had positive experiences in both projects. The lesson learned was that working with smaller sets of compounds worked very well for us compared to a large sets of compounds. Clear two way communication with the external partner is paramount in this type of collaboration. A secondary point to consider is reviewing internal SOPs with safety department for any packaging issues.
We strongly believe that the in-house compound management group is the hub for all samples flowing from the chemistry into the biology laboratories. Therefore, core activities need to be performed by a strong compound management group within the Roche organization. Outsourcing may be an option for special projects such as described in this paper and requires establishment of a business relationship with a preferred external partner.
Janet Diratsaoglu completed her B.S. degree and M.S. degree in chemistry at the University of Karlsruhe in Germany. She joined Roche Nutley in 1989 as an assistant information scientist and became the head of chemical information services in 1994.
In 1997, she was appointed to head the chemical information and the compound inventory management groups in Nutley in support of chemistry, oncology, metabolic diseases and HTS groups in research.